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Inflammatory breast cancer (IBC) is a rare and aggressive form of breast cancer, which accounts for approximately 3% of cases of breast malignancies. Diagnosis relies largely on its clinical presentation, and despite a characteristic phenotype, underlying molecular mechanisms are poorly understood. Unique clinical presentation indicates that IBC is a distinct clinical and biological entity when compared to non-IBC. Biological understanding of non-IBC has been extrapolated into IBC and targeted therapies for HER2 positive (HER2+) and hormonal receptor positive non-IBC led to improved patient outcomes in the recent years. This manuscript reviews recent discoveries related to the underlying biology of IBC, clinical progress to date and suggests rational approaches for investigational therapies.
Inflammatory breast cancer (IBC) is a rare and aggressive phenotype of breast cancer encompassing approximately 3% of newly diagnosed breast tumors . IBC tends to affect younger women when compared to locally advanced non-IBC with a median age at diagnosis of 57 years . Among African Americans the annual incidence is estimated at 3 (2.8-3.2) per 100,000 compared to 2.1(2.1-2.2) per 100,000 among white women . IBC has no histological diagnostic criteria and its diagnosis is based primarily on its clinical presentation. In 1956, Haagensen et al. described diagnostic criteria for IBC including a rapidly enlarging breast, erythema involving at least one-third of the breast, generalized induration, and biopsy proven carcinoma . These remain the cornerstone diagnostic criteria for IBC . IBC is also characterized by distinct skin changes including diffuse erythema and edema (peau-d’orange) often without a clinically evident underlying mass, which is presumed to be secondary to lymphangiogenesis and tumor emboli in the lymphatics [6–8]. It usually has an abrupt onset and rapid progression, with a high risk of axillary lymph node involvement and distant metastases at the time of initial diagnosis . Despite multimodality therapy, survival rates are lower than those for non-IBC. Patients with IBC have poorer prognosis when compared to locally advanced non-IBC (5-year overall survival rates of 62% versus 81%) [10–12]. Its distinct clinical presentation and aggressive course indicate that IBC is in fact a distinct biological entity. Furthermore, the majority of newly diagnosed cases are at least stage III with approximately 30% of de novo stage IV . Moreover, IBC has been associated with high incidence of micrometastatic disease, defined by detection of either bone marrow metastasis or circulating tumor cells (CTCs) suggesting difficulty in clinical outcome comparison with non-IBC and potential need for extended treatment beyond standard multimodality treatment [13, 14].
The standard management of IBC involves a multimodality approach, including primary systemic chemotherapy followed by mastectomy, axillary lymph node dissection, and radiation therapy, which has led to improved survival outcomes [15, 16]. The National Comprehensive Cancer Center (NCCN) guidelines list the standard approach to IBC as neoadjuvant chemotherapy with an anthracycline based regimen and a taxane .
HER2 is a transmembrane receptor which when overexpressed stimulates a multitude of growth factor signaling pathways in breast cancer cells . IBC is associated with higher prevalence of over-expression of HER2 when compared to non-IBC with estimates ranging from 40-58% [11, 19–23]. If HER2 is overexpressed, chemotherapy with trastuzumab in combination with pertuzumab is indicated as part of the systemic preoperative regimen. Mastectomy with axillary lymph node dissection is standard in IBC patients who respond to pre-operative chemotherapy. Following surgery, postmastectomy radiation including the chest wall and supraclavicular nodes plus or minus the internal mammary nodes is recommended, as well as adjuvant endocrine therapy if indicated.
Further understanding of the molecular biology of non-IBC has led to significant advances in the treatment of breast cancer, which in conjunction with improved screening strategies, Have increased survival rates [24–26]. For instance, the comprehensive genomic analysis of breast cancer through The Cancer Genome Atlas (TCGA) program supports not only that breast cancer is a heterogeneous disease but drug development strategies should take in to account molecular aberrations specific of each subtype . An increased understanding of IBC biology has been relatively hampered by its rarity and maybe more importantly by its underdiagnosis or misdiagnosis as a consequence of subjective diagnostic criteria . Researchers are attempting to better characterize the molecular biology of IBC, in hopes that this will ultimately guide developmental therapeutics efforts for this rare form of breast caner. This information combined with the current understanding about the aggressive clinical presentation, high frequency of micrometastatic disease and early recurrence rates can provide leads to improved therapies. In addition, clinical trial design should also take into account the positive correlation between pathologic complete response rate (pCR) with disease-free survival benefit for a subset of patients with IBC (i.e.: HER2+ IBC) as trials assessing the efficacy of neoadjuvant treatments are inherently shorter . This manuscript aims to review the discoveries in the biology of IBC while highlighting the rationale for developmental therapeutics approaches.
Besides differences observed from oncoprotein and gene copy number analyzes (e.g. HER2 expression/amplification) RNA next generation sequencing (NGS) technologies have allowed for better understanding of the mutational landscape of IBC . A seminal work was conducted under the auspices of the IBC World Consortium by Van Laere et al. who reported results of Affymetrix gene expression profiling and molecular classification using the PAM50-algorithm derived from 137 patients with IBC and 252 patients in non-IBC . Four robust IBC-sample clusters were identified, associated with the different molecular subtypes (p < 0.001), all of which were identified in IBC with a similar prevalence as in non-IBC, except for the luminal A subtype (19% in IBC vs. 42% in non-IBC; p < 0.001) and the HER2-enriched subtype (22% in IBC vs. 9% in non-IBC; p < 0.001). Overall, 75% of the IBC samples were classified under the classically more aggressive subtypes, basal-like, HER2-enriched, claudin-low, or luminal B subtypes, whereas these subtypes account for 54% of the non-IBC samples. The number of genes with a uniquely IBC-specific gene expression profile represented only 3% of the global expression differences. Similar results were observed when triple negative breast cancer (TNBC) IBC samples (n=39) were compared with TNBC, non-IBC (n=49) . No unique IBC-specific subtypes were identified by mRNA gene-expression profiling of those tumors. Nonetheless the limited number of genes assessed by the PAM50 platform could account for failure to observe specific genomic signature in IBC samples.
Alternative techniques to gene expression assays were also implemented in order to classify IBC. Among them are epigenetic analyses such as evaluation DNA methylation pattern and also gene copy number imbalances, both of which may capture genomic signatures which account for differential tumor behavior [33, 34]. For instance, Van der Auwera et al. reported results of methylation profiling on a cohort of IBC (n = 19) and non-IBC (n = 43) samples using the Illumina Infinium platform . Methylation assay comparison of IBC with non-IBC led to the identification of only four differentially methylated genes (TJP3, MOGAT2, NTSR2 and AGT). Mutational landscape imbalances of 49 IBCs and 124 non-IBCs were determined using high-resolution array-comparative genomic hybridization . Genomic landscapes were overall similar when comparing the two groups. Differences were however appreciated, such as the more frequent gain of 1q, 8q and 17q regions in IBCs, or the more frequent loss of 4p, 8p, 11q, and 16q regions in non-IBCs. The median percentage of probe sets displaying a copy number aberrations for a sample was numerically higher in IBCs (3.7%, range 0.01–14%) than in non-IBCs (1.9%, range 0.01–26%; p = 6.1), even if a great variability between samples existed for both types, suggesting that the genome of IBC is more unstable.
Most recently, Hamm et al. used a custom hybridization capture-based probe library using Agilent SureDesign portal (Agilent Technologies) to analyze 20 primary IBC specimens . This panel captured full coding regions of 208 cancer relevant genes and introns of 13 genes to detect the substitution, deletions, copy number changes in the 208 targeted genes and structural rearrangements in 17 genes. Analysis of the types of genetic variants revealed that missense mutations were the most common variant (73%), followed by frameshifts (8%), splice site alterations (6%), nonsense mutations (5.5%), amplifications (5.5%), and in-frame insertions-deletions (3%). In total, NGS identified 391 genetic variants in 19 IBC tissues. The 5 most commonly altered genes were: TP53 (58%), HER2 (53%, all amplifications), ATM (53%), APC (37%), and HER3 (26%).
In comparison with the mutational profile of a large non-IBC cohort (825 samples) in the TCGA, mutations in the p53 and PIK3CA genes are equally common when compared to the IBC mutational landscape . FGFR and HER2 aberrations seem to occur at similar frequency in non-IBC when compared to IBC, whereas PIK3CA mutations are more common in non-IBC (38%), probably because frequently associated with luminal disease. Moreover, PTEN abnormalities are less common in non-IBC (3%) [27, 38].
Qualitative mutational landscapes have also been performed in larger series in recent years. Ross et al. reported a comprehensive genomic profiling on 53 IBC, formalin-fixed, paraffin-embedded specimens using the hybrid capture-based, FoundationOne™ assay . The 53 sequenced IBC cases harbored a total of 266 genomic alterations (GA) with an average of 5.0 GA/tumor (range 1–15). The most frequently altered genes were TP53 (62%), MYC (32%), PIK3CA (28%), HER2 (26%), FGFR1 (17%), BRCA2 (15%), and PTEN (15%). In the TNBC subset of IBC, 8/19 (42%) showed MYC amplification (median copy number 8X, range 7–20) as compared to 9/32 (28%) in non-TNBC IBC (median copy number 7X, range 6–21). Although at 32%, the MYC amplification in IBC appeared to represent enrichment in this tumor type, comparison with the 24% MYC amplification rate in the non-IBC breast cancers did not reach statistical significance (p = 0.26) . While these small studies offer some insights in novel molecular differences, larger studies are needed to confirm and validate differences. Furthermore, non-genomic molecular characterization may be able to explain the phenotypic discordance between IBC and non-IBCs, such exploring the epigenome, metabolome, microenvironment, and immunogenic characterization.
The HER2 gene encodes a transmembrane tyrosine kinase receptor that belongs to the epithelial growth factor receptor (EGFR) family. This family of receptors includes four members (EGFR/HER1, HER2, HER3 and HER4) that function by stimulating growth factor signaling pathways such as the PI3K/AKT/mTOR pathway . Activation of receptor kinase function occurs predominantly via ligand-mediated hetero- or homo-dimerization. In the case of HER2, activation is also thought to occur in a ligand-independent manner, particularly when the receptor is found to be mutated or overexpressed . Targeted strategies against the HER family have been developed in the realm of breast cancer. For instance the humanized monoclonal antibodies (e.g.: trastuzumab) prevent the dimerization of HER2 with other HER receptors. Pertuzumab in particular inhibits the pairing of the most potent signaling heterodimer, HER2/HER3, thereby providing a potent strategy for dual HER2 inhibition . Furthermore small molecule tyrosine kinase inhibitors such as lapatinib have the ability to inhibit the kinase activity of these HER receptors opposing further cancer cell proliferation and survival .
A subgroup analysis of 62 patients with HER2+ IBC enrolled in a large phase 3 trial (NOAH trial) reported a 54.8% in breast pCR to neoadjuvant trastuzumab in combination with chemotherapy, versus 19.3% for patients receiving only chemotherapy (p = 0.004) . In this study 235 patients with HER2+ locally advanced non-IBC or IBC were randomized to treatment with or without neoadjuvant and adjuvant trastuzumab . Neoadjuvant chemotherapy consisted of doxorubicin 60 mg/m2 plus paclitaxel 150 mg/m2, every 3 weeks for three cycles, followed by paclitaxel 175 mg/m2 administered every 3 weeks for four cycles. Cyclophosphamide (600 mg/m2), methotrexate (40 mg/m2), and fluorouracil (600 mg/m2) were then given on days 1 and 8 every 4 weeks for three cycles. In the overall study population chemotherapy combined with trastuzumab significantly improved in breast pCR rate to 43% and event-free survival (EFS) in patients with HER2+ breast cancer hazard ratio of 0.59, 95%CI 0.38-0.90; p = 0.013. After a median follow-up of 5.4 years the EFS benefit derived from trastuzumab treatment is maintained with a 5-year EFS rate of 58% (95% CI 48-66) in this patient population .
In the NeoSphere trial patients with HER2+ IBC were enrolled into the study but represented less than 10% of the overall study population . Patients treated pertuzumab and trastuzumab plus docetaxel had a significantly improved pCR rate 45.8% [95% CI 36.1–55.7] compared with those given trastuzumab plus docetaxel; 29.0% [20.6–38.5]; p = 0.0141). Likewise in the Tryphaena phase 2 trial, among the 225 patients with HER2+ breast cancer treated with the combination of pertuzumab, trastuzumab and chemotherapy in the neoadjuvant setting only 13 had HER2+ IBC . pCR rates defined as the absence of invasive carcinoma in the breast ranged from 61-66% among patients treated with dual HER2 targeted and chemotherapy.
Kaufman et al. reported results of 126 patients with relapsed or refractory HER2+ IBC who were treated with lapatinib 1500 mg once daily in a non-randomized, open-label, phase 2 study . Seventy five percent of the patients had been treated with at least one line trastuzumab-based regimen. No patients achieved a complete response. The objective response rate by clinically evaluable skin-disease criteria was 40% but the objective response by rate by RECIST was only 15% (95% CI 9-24), which included only patients with metastatic or locally advanced, measurable disease. Median PFS was 14.6 weeks (95% CI 12.1–16.0), with median duration of response of 20.9 weeks (12.7–32.1). Likelihood of response to lapatinib was not affected by previous treatment with trastuzumab. A total of 45 (32%) study participants had serious adverse events, the most common ones were dyspnea (eight patients) and pleural effusion (six). Five patients had fatal adverse events that were possibly treatment related.
EGFR is over-expressed in approximately 30% of patients with IBC and correlates with poor outcome [21, 22]. Of note EGFR has been implicated in IBC cell survival and metastasis in vitro and in vivo [49–51]. SUM149 pre-clinical cell models showed significant sensitivity to sensitivity to inhibition of EGFR and other members of the HER family [49, 52, 53]. Lapatinib is not only a potent inhibitor of the HER2 but also inhibits EGFR tyrosine kinase domains and has shown significant clinical efficacy in non-IBC HER2+ breast cancer [54, 55].
In a phase 2 single arm trial 49 patients with IBC were stratified according HER2 and EGFR expression in two different groups: cohort A (HER2+ plus or minus EGFR+ IBC) or cohort B (HER2- and EGFR+) . Patients received lapatinib at 1,500 mg/d for 14 days, then lapatinib at 1,500 mg/d plus weekly paclitaxel (80 mg/m2) for 12 weeks, followed by surgical resection or additional chemotherapy. pCR occurred in 18.2% (95% CI, 5.2% to 40.3%) of cohort A patients. Combined clinical response rate was 78.6% (95% CI, 63.2% to 89.7%) in cohort A patients. Cohort B was terminated because of slow accrual and lack of efficacy observed in IBC patients with HER2-/EGFR+ tumors enrolled onto a parallel study, EGF103009 . These results indicate modest activity of lapatinib in patients with HER2+ IBC. Matsuda et al. recently reported preliminary results of phase 2 trial of neoadjuvant treatment with 4 cycles of the combination of anti-EGFR monoclonal antibody panitumumab (2.5 mg/kg) combined with nab-paclitaxel (100 mg/m2), and carboplatin (AUC 2) weekly followed by 4 cycles of FEC (5-fluorouracil, 500 mg/m2; epirubicin, 100 mg/m2; cyclophosphamide, 500 mg/m2) . A total of 35 patients with HER2- IBC were treated and 7 of the 16 patients with triple negative IBC achieved a pCR (44%; 95% CI: 0.20-0.70). Retrospective data support that pCR rates of < 25% are generally obtained among patients with IBC treated with and anthracycline combined a taxane in the neoadjuvant setting .
These results indicate that EGFR could be a valuable target for treatment development in IBC. Targeting of multiple molecular aberrations may be one the promising strategies. For instance, preliminary evidence also supports that c-MET is overexpressed in IBC . Further studies are needed to evaluate the potential role of c-MET inhibition in IBC.
Aberrations in the PIK3/AKT/mTOR pathway are among the most common genomic abnormalities in breast cancer and are observed across in all subtypes of the disease . In the metastatic setting mTOR inhibitor everolimus has shown significant clinical efficacy in combination with aromatase inhibitor and is now commonly used treatment option for patients with hormonal receptor, HER2- metastatic breast cancer progressing on anti-estrogen therapy . AKT gene is not frequently mutated in breast cancer [62, 63]. However its activation by upstream molecules such as PIK3CA is a common phenomenon in breast tumors across different subtypes, which leads to activation of multiple AKT substrates controlling tumor growth and apoptosis [64, 65].
Immunohistochemical analysis of 45 cases of IBC showed over-expression of phosphorylated mTOR in approximately 90% of the cases . Of note all tumor tissues were obtained from mastectomy specimens after treatment with anthracycline and or taxanes. In addition, patients with invasive, previously treated non-IBC also showed equally elevated rates of mTOR activation. Ross et al. recently reported the results of a cross-sectional study involving patients with metastatic IBC that had a diagnostic biopsy of primary tumor or metastatic lesion and subsequent NGS by Foundation One™ panel . The analysis of 53 IBC tumor samples revealed a total of 266 genomic alterations were observed. Of note, abnormalities in the PI3K/AKT/mTOR pathway were seen in up 65% of the samples analyzed and 41 patients (77%) had HER2- disease. Furthermore, Hamm et al. evaluated 19 patients with primary and metastatic IBC using a targeted NGS panel that covered whole coding regions of 208 of the most common cancer related genes (copy numbers and somatic mutations) and rearrangements in 17 well characterized cancer genes . Activity of the PI3K/AKT/mTOR pathway was further confirmed by immunohistochemistry for phosphorylated S6 in 95% (n = 18) of cases, a target of mTOR kinase activity.
A recent small cross-sectional study of 12 patients with diagnosis of HER2+ IBC who had tumor tissue biopsy upon progression on HER2 targeted therapy evaluated HER1-3 through reverse-phase protein microarrays (RPMA) assay analysis . Phosphorylation of HER1-3 downstream signaling pathways such as JAK2, AKT/mTOR and MEK1/2 were analyzed. Interestingly, 83% had mTOR activation, and most of these patients also had accumulation of its downstream proteins, S6 ribosomal protein and 4E-BP-1. In addition, 78% of patients with HER2 activation also had mTOR activation indicating that the AKT/PIK3/mTOR pathway could be a mechanism of resistance to HER2 targeted therapies in IBC.
The mTORC1 inhibitor rapamycin and everolimus showed only modest inhibitory activity of IBC HER2+ and HER2- pre-clinical cell models (SUM190 and SUM149 respectively) when compared with targeted agents such as lapatinib, sorafenib, and sunitinib indicating that further understanding of the PIK3/AKT/mTOR is needed in IBC [68, 69]. In parallel, in non-IBC HER2+ tumor mTOR inhibition with everolimus combined with trastuzumab only lead to modest improvement in PFS when compared to placebo . In summary, future studies are needed to investigate the potential clinical impact of the PIK3/AKT/mTOR inhibition in IBC.
The vascular endothelial growth factor (VEGF) is an important angiogenic mediator in breast cancer . VEGF-A is a multifunctional cytokine widely expressed by tumor cells that acts through receptors (VEGFR-1, VEGFR-2, and neuropilin) expressed on vascular endothelium and on some other cells. It increases microvascular permeability, induces endothelial cell migration and division, reprograms gene expression, promotes endothelial cell survival, prevents senescence, and induces angiogenesis . VEGF targeted therapy with the monoclonal antibody against VEGF-A, bevacizumab; seem to have modest clinical efficacy in patients with metastatic breast cancer [73, 74]. IBC is known to have high rates of endothelial cell proliferation and vascular density when compared to non-IBC, which could suggest potentially greater sensitivity to antiangiogenic therapies . Wedam et al. reported results of a small cohort of 21 patients with both IBC (n=20) and (n=1) non-IBC treated with bevacizumab for cycle 1 (15 mg/kg on day 1) followed by six cycles of bevacizumab with doxorubicin (50 mg/m2) and docetaxel (75 mg/m2) every 3 weeks in the neoadjuvant setting . Tumor biopsies were collected on cycles 1, 4, and 7; a median decrease of 66.7% in phosphorylated VEGFR2 in tumor cells and median increase of 128.9% in tumor apoptosis were seen after bevacizumab alone. These changes persisted with the addition of chemotherapy. One patient had a complete pathological had a complete pCR and 14 have partial clinical response overall response rate (ORR) of 67% (95% CI, 43% to 85.4%). The ORR results are comparable with historical controls treated with anthracycline/taxane combination without bevacizumab in the neoadjuvant setting (ORR 81%) .
The BEVERLY-1 (UCBG-0802) trial was a phase 2, single-arm trial, in which women with non-metastatic HER2- IBC were treated with neoadjuvant intravenous fluorouracil (500 mg/m2), epirubicin (100 mg/m2), cyclophosphamide (500 mg/m2), and bevacizumab (15 mg/kg) during cycles 1–4 (21 days-cycle), then docetaxel (100 mg/m2) and bevacizumab during cycles 5–8 . After surgery, patients received adjuvant intravenous bevacizumab. After neoadjuvant therapy, only 19 of the 100 patients evaluable for efficacy analysis achieved a pCR. The most frequent grade 3–4 events during the neoadjuvant phase were neutropenia (89%), febrile neutropenia (37%), and mucositis 23%) and during the adjuvant phase the most frequent grade 3–4 adverse event was proteinuria (7%). One (1%) patient died of thrombotic microangiopathy after cycle 1, which was thought to be related to bevacizumab. Two patients (3%) developed transitory heart failure.
In the BEVERLY-2 study 52 patients with HER2+ IBC were treated with fluorouracil, epirubicin, cyclophosphamide, and bevacizumab (cycles 1–4) and docetaxel, trastuzumab, and bevacizumab (cycles 5–8) before surgery, followed by trastuzumab and bevacizumab for 30 weeks after surgery . After neoadjuvant therapy, 33 of 52 patients had a pCR according to central review (63.5%, 95% CI 49.4–77.5). The most common adverse events were asthenia and nausea (both occurred in 36 [69%] of 52 patients). Only one grade 3 or worse adverse event regarded as related to bevacizumab was reported (hypertension, one patient). It is important to note that the pCR rates of this HER2+ IBC cohort was comparable to previously published studies, which did not add bevacizumab to the neoadjuvant treatment regimen of patient IBC . Taken together these results indicate that the addition of bevacizumab to chemotherapy does not significantly improve pathological complete response rate in IBC.
One could hypothesize that higher expression of several non-VEGF angiogenic, lymphangiogenic, and vasculogenic factors could make blockade of VEGF by bevacizumab insufficient . Indeed, pre-clinical data support that multityrosine kinase inhibitors such as sorafenib and sunitinib exert inhibitory activity against SUM149 IBC cell models . For instance, pazopanib is an oral angiogenesis inhibitor targeting VEGF receptors 1-3, platelet-derived growth factor receptors-α/−β [82, 83]. Cristofanilli et al. reported results of a multi-center phase 2 study evaluating lapatinib, pazopanib, or the combination in patients with relapsed HER2+ inflammatory breast cancer . In Cohort 1, 76 patients were randomized 1:1 to receive lapatinib 1,500 mg plus placebo or lapatinib 1,500 mg plus pazopanib 800 mg (double-blind) once daily until disease progression, unacceptable toxicity, or death. Due to high-grade diarrhea observed with this dose combination in another study (VEG20007), Cohort 1 was closed. The protocol was amended such that an additional 88 patients (Cohort 2) were randomized in a 5:5:2 ratio to receive daily monotherapy lapatinib 1,500 mg, lapatinib 1,000 mg plus pazopanib 400 mg, or pazopanib 800 mg monotherapy, respectively. The primary endpoint was ORR and secondary endpoints included duration of response, progression-free survival (PFS), overall survival, and safety. In Cohort 1, ORR for the lapatinib (n = 38) and combination (n = 38) arms was 29% and 45%, respectively; median PFS was 16.1 and 14.3 weeks, respectively. Grade 3 adverse events were more frequent in the combination arm (71%) than in the lapatinib arm (24%). Dose reductions and interruptions due to AEs were also more frequent in the combination arm (45 and 53%, respectively) than in the lapatinib monotherapy arm (0 and 11%, respectively). In Cohort 2, ORR for patients treated with lapatinib (n = 36), lapatinib plus pazopanib (n = 38), and pazopanib (n = 13) was 47, 58, and 31%, respectively; median PFS was 16.0, 16.0, and 11.4 weeks, respectively. In the lapatinib, combination, and pazopanib therapy arms, grade ≥3 AEs were reported for 17, 50, and 46% of patients, respectively. The lapatinib-pazopanib combination was associated with a numerically higher ORR but no increase in PFS compared to lapatinib alone, which was a secondary endpoint of the study. The combination also had increased toxicity resulting in more dose reductions, modifications, and treatment delays. As novel agents are developed that are better tolerated, the improve response rates in this study may suggest a role for multi-target angiogenesis agents in IBC.
JAK kinases are activated through tyrosine phosphorylation of the cytoplasmic domains of cytokine receptors upon cytokine binding. JAK2 activation promotes recruitment to the receptor complex of the transcription factors STAT3 and STAT5 . JAK2-mediated STAT phosphorylation leads to the formation of stable homodimers and heterodimers, which leads to their nuclear translocation. Once in the nucleus, STAT molecules bind specific promoter DNA sequences that result in the transcription of genes that regulate cell proliferation, differentiation, and apoptosis (e.g., Bcl-xL, cyclin D1, and PIM1) [85, 86]. STAT3 has been implicated in many aspects of tumorigenesis, including differentiation, proliferation, apoptosis, increased sensitivity to cytotoxic agents, angiogenesis, recruitment of immune cells, and metastasis . Evidence supports that, in breast cancer, JAK2 activates STAT3 and is found to be significantly activated when compared to non-neoplastic breast tissue [88, 89]. In one series of 45 samples of previously treated IBC samples immunohistochemical analysis showed activated JAK2 (pJAK2) levels were similar between IBC (95.2%, 1+ or 2+) and treated IDC (91.7%, 1+ or 2+; 4.2%, 3+), untreated IDC had lower levels (80.0%, 0; 20.0%, 1+) (p < 0.0001). For pSTAT3, 55.0% of IBC tumors had 1+ or 2+ levels with 45% of tumors having level 0. In treated IDC, 62.5% had 1+ or 2+ expression with 37.5% of tumors having level 0. This is in contrast to untreated IDC where 92.3% of tumors had 0 level (p = 0.0001) . These results indicate that JAK/STAT pathway activation could lead to treatment resistance in IBC. A phase 1/2 study of combination ruxolitinib (kinase inhibitor of JAK/STAT) with neoadjuvant chemotherapy for triple negative IBC is ongoing (NCT02041429).
MYC oncoprotein interacts closely with the cell cycle machinery in depriving the cell of the normal control of progression through the G1 phase of the cell cycle into the S phase. MYC protein acting with its Max partner is able to induce expression of the growth-promoting cyclin D2 and CDK4 (Figure (Figure1)1) [90, 91]. At the same time MYC can promote degradation of p27Kip1 CDK inhibitor as well as E2F1 favoring advancement into the S phase [92, 93].
Ross et al. reported the results of genomic sequencing of 53 IBC samples from the primary or a metastatic site . Alterations in cell cycle regulatory genes were identified as follows: MYC (31%), CCND1 (9%), RB1 alterations (9%), and CDKN2A (8%). All MYC aberrations consisted of amplifications. Of the 19 TNBC IBC cases 8 (42%) had MYC amplification, whereas only 9 among 36 non-TNBC IBC cases harbored MYC amplification in 9 (25%). Indeed, the luminal, estrogen receptor- positive, IBC cell line (SUM190) exhibited significant sensitivity to CDK4/6 inhibitor (palbociclib) when compared to other solid tumors . While a standard of care in conjunction with anti-hormone therapy in ER+ MBC, the clinical efficacy of palbociclib has not been reported in IBC.
In a previous series of studies, RhoC GTPase overexpression has been identified in >90% of IBCs and defined RhoC as a mammary oncogene involved in conferring the metastatic phenotype in IBC and estrogen receptor negative non-IBC [96–98]. Protein farnesyl transferase inhibitors revert the RhoC GTPase-induced inflammatory breast cancer phenotype . Tipifarnib is an oral protein farnesyl transferase inhibitor. Despite the pre-clinical rationale, in a phase 2 trial of 22 patients with HER2- IBC, only one patient achieved a pCR after treatment with tipifarnib and conventional anthracycline/taxane-based neoadjuvant chemotherapy indicating lack of single activity of tipifarnib . One potential strategy for future drug development could be to combine farnesyltranferase enzyme inhibitors with STAT3 targeted therapies in IBC and there also seems to be interaction between these two pathways in non-IBC . Furthermore, IBC pre-clinical models support that RhoC GTPase is a substrate for Akt1 and its phosphorylation is absolutely essential for IBC cell invasion . Future drug development should take into account potential interactions between RhoC GTPase and the PIK3/AKT/mTOR pathway.
EML4/ALK fusion is present in about 5% of patients with non-small cell lung cancer (NSCLC) . The presence of EML4/ALK translocation is predictive of clinically meaningful benefit from treatment with the oral tyrosine kinase inhibitor crizotinib and alectinib in patients with NSCLC [104, 105]; ALK aberrations are also thought be rare in non-IBC (<1%) . Analysis of 25 samples of IBC for ALK genetic abnormalities was performed. These studies revealed that 20/25 (80%) had some form of ALK aberration (i.e.: increased copy number, low level ALK gene amplification, or ALK gene expression), with an increased prevalence of ALK alterations in basal-like IBC. One of 25 patients was identified as having an EML4-ALK translocation . A recent preliminary report indicated that ALK protein over-expression is not thought to be a feature of IBC . The predictive value of ALK genomic aberrations is being assessed in an ongoing phase 1 trial in which patients with solid tumors including IBC, will be treated with LDK378 (selective inhibitor of ALK) (NCT01283516).
Polycomb group (PcG) protein enhancer of Zeste homolog 2 (EZH2) is among the DNA methylation modulation mechanisms, which interacts-within the context of the PcG repressive complexes 2 and 3 (PRC2/3)-with DNA methyltransferases (DNMTs) and associates with DNMT activity in vivo. Binding of DNMTs to several EZH2-repressed genes depends on the presence of EZH2 . EZH2 is frequently expressed (~75%) in human IBC and its expression correlates with worse clinical outcome . EZH2 is expressed at higher levels in human IBC cell lines compared with normal human mammary epithelial cells, and the knockdown of EZH2 expression significantly suppressed cell growth and tumor spheroid formation of human IBC cells in vitro. In addition, EZH2 knockdown inhibited the migration and invasion of IBC cells. Significantly, EZH2 knockdown suppressed the angiogenesis and tumor growth of IBC cells in vivo . Furthermore pre-clinical evidence supports that epigenic modulation through histone deacetylase inhibitors (HDAC) may be promising in IBC models. Robertson et al. reported results of in vivo and in vitro IBC models supporting antitumor activity of the HDAC inhibitor romidepsin . Not only did HDAC inhibition cause lower levels of VEGF-A and hypoxia-induced factor 1α in a xenograft model but it also blocked self-renewal/clonogenicity of tumor spheroids. In addition, romidepsin alone effectively inhibited SUM149 primary tumor growth and was synergistic with paclitaxel in blocking development of SUM149 metastatic lesions at multiple sites. Preliminary results from a phase 1 trial which tested the combination of romidepsin with nab-paclitaxel among 9 patients with metastatic, refractory HER2- IBC showed one complete response and two disease stabilizations . Toxicities related to romidepsin included neutropenia, anemia and fatigue. Ongoing studies are evaluating HDAC inhibitors alone or in combination with targeted therapies [114, 115].
Immunotherapy with checkpoint inhibitors has made a significant impact in the treatment of melanoma, renal cell carcinoma and NSCLC in recent years [116–119]. New agents such as nivolumab and pembrolizumab [a fully human IgG4 programmed death 1 (PD-1) immune-checkpoint inhibitor antibody] selectively blocks the interaction of the PD-1 receptor with its two known programmed death ligands, PD-L1 and PD-L2, disrupting the negative signal that regulates T-cell activation and proliferation . There is preliminary evidence of positive correlation between high mutational burden of tumors and clinical benefit from immunotherapy strategies (i.e. checkpoint inhibitors anti-CTLA-4 and anti-PD-1 antibodies), with remarkable effects seen with tumors displaying the highest rates of mutations such as melanoma [121, 122]. This is also illustrated by the anti-tumoral immunologic response to anti-PD-1 antibody in patients with colorectal cancer and increased mutational burden secondary to mismatch repair deficiency . Nonetheless lack of definition and standardization of measures of tumor mutational load, and prospective validation of its predictive value indicate that better understanding of biomarkers predictive of benefit from immune checkpoint inhibition remains an unmet need.
The potential importance of immune checkpoint-guided therapy in breast cancer is underscored by recent report of PD-1 inhibitor activity in triple negative non-IBC. Pembrolizumab, which is a monoclonal anti-PD-1 antibody was tested in a phase 1b trial on 32 female patients with PD-L1 immunohistochemistry (IHC) + and heavily pretreated metastatic recurrent triple negative non-IBC. The disease control rate (i.e., percentage of patients with best response of complete response, partial response, or stable disease for ≥ 24 weeks) was 25.9% (95% CI, 11.1% to 46.3%) . Avelumab, an anti-PD-L1 IgG1 antibody, showed modest anti-tumor activity among 57 patients with triple negative non-IBC with only 5 partial responses observed (8.8%; 95% CI: 2.9, 19.3) . In patients with triple negative non-IBC who had PD-L1+ immune cells within the tumor, 44.4% (4 of 9) had partial responses, compared with 2.6% (1 of 39) for triple negative non-IBC and PD-L1– immune cells.
The role of immune infiltrate and immune checkpoints was also investigated in relation with genomic abnormalities in IBC samples . The pathological examination of 20 IBC tissue samples identified a subset of IBC tumors associated with infiltration of immune cells. IHC staining identified the majority of infiltrating cell populations as CD8+ cytotoxic T cells and high levels of CD8+ infiltration were observed in 5/12 tumors. In order to explore the possible role of PD-L1 in IBC, the investigators performed IHC staining of IBC tissues. Evaluation of PD-L1 staining demonstrated low-intensity tumor cell staining in 3/12 tumors studied and high-intensity tumor cell staining in 1/12 tumors. PD-L1 mRNA expression has been reported to by as high as 38% among patients with IBC, which is higher that non-IBC (28%) and correlates positively with pCR .
Notably, somatic mutation rates were significantly higher in high infiltration vs. low infiltration tumors (p<0.05) . The authors speculated that this correlation between somatic mutation rate and immune cell infiltration might be related to the exposure of tumor neo-antigens to the immune system. A phase 2 clinical trial for patients with metastatic IBC assessing the efficacy of anti-PD-1 inhibitor monoclonal antibody (pembrolizumab) is under development (NCT02411656) (Table (Table11).
IBC is rare but aggressive disease, in which improvements in therapeutic strategies are urgently needed. Its presentation, aggressive clinical course, and frequent distant recurrence indicate that IBC is in fact a distinct clinical biological entity rather than a subtype on the spectrum of locally advanced breast cancer. Key molecular differences include significant alterations in the PI3K and JAK/STAT pathways, elevated aberrations in DNA-repair genes and cell-cycle regulations suggesting of significant genomic instability contributing to treatment resistance. Furthermore higher rates of HER2 overexpression/amplification are seen in IBC and neoadjuvant treatment with trastuzumab resulted in improved outcomes for patients with HER2+ IBC . There is no prospective trial appropriately powered to assess the efficacy of neoadjuvant treatment with chemotherapy combined with pertuzumab and trastuzumab in HER2+ IBC. Nonetheless based on improved pCR rates seen in non-IBC these agents are recommended by current guidelines for the neoadjuvant treatment of HER2+ IBC.
As with other rare or under diagnosed diseases the evidence for the treatment of IBC stems from small prospective trials and subgroup analysis of larger non-IBC prospective studies. As IBC has no histological diagnostic criteria, every effort must be made to accomplish international standardization of diagnosis and treatment and facilitate future research [5, 127]. Research groups have also initiated prospective biorepository studies in order to facilitate future tumor tissue and blood-based biomarker studies in IBC (NCT00477100, NCT00646555, NCT00340158). Efforts are increasing to improve the biological understanding of IBC and to conduct clinical trials, which are specific for patients with IBC (Table (Table1).1). Nonetheless in the ever-expanding field of biomarker-based research reliable correlations between pCR and tumor genomic aberrations remain to be determined in IBC, except for HER2 amplification .
Further understanding of molecular biology of IBC focusing on the tumor microenvironment and immunity may help explain the different clinical behaviors of IBC and non-IBC e.g. the role of mesenchymal transitional cells in promoting E-cadherin (pivotal to IBC metastasis) expression in IBC cell models and metastases in xenografts [50, 75].
CONFLICTS OF INTEREST
The authors declare no potential conflicts of interest

domain: medical


text:
||Recombinant Human CYP20A1 protein, fused to His-tag, was expressed in E.coli and purified by Ni-sepharose.
||This gene encodes a member of the cytochrome P450 superfamily of enzymes. The cytochrome P450 proteins are monooxygenases that catalyze many reactions involved in drug metabolism and synthesis of cholesterol, steroids and other lipids. This protein lacks one amino acid of the conserved heme binding site. It also lacks the conserved I-helix motif AGX(D,E)T, suggesting that its substrate may carry its own oxygen.
||The protein is stored in PBS buffer at -20℃. Avoid repeated freezing and thawing cycles.
||1M PBS (58mM Na2HPO4,17mM NaH2PO4, 68mM NaCl, pH8. ) added with 300mM Imidazole and 0.7% Sarcosyl, 15%glycerol.

domain: chemistry


text:
With all the noise about Donald Trump, how about the other guy- the one a heartbeat away from the Oval Office? Richard Lutz checks the facts
Mike Pence will be Vice President come the new White House regime.
He is a former Democrat who voted for Jimmy Carter in 1976 and listed JFK and Martin Luther Jnr as among his heroes. Then he veered right – very conservative – becoming a Congressman and then governor of Indiana. His role model now is former VP Dick Cheney.
So, where does the new Vice President stand on things? Here’s a quick rundown:
ABORTION: An unwavering opponent. While governor, Indiana saw a bill become law banning women from having an abortion on the basis of gender or serious disability. In 2007 he wanted to strip Planned Parenthood of funding. He says it’s “morally wrong” to back stem cell research. A federal judge later blocked the law. “I’m pro-life,” he said during the campaign.
GUNS: Two years ago as Indiana governor, he signed a bill allowing guns to be kept in vehicles on school property (opposed by state school bodies) and allowed the powerful National Rifle Association to train the National Guard in carrying concealed weapons. He opposes any restriction on assault rifles.
IMMIGRATION: While in the governor’s chair, he unsuccessfully tried to block Syrian refugees from settling in Indiana. And earlier this year, before being picked as a VP choice, a federal judge said a move by him to stop federal funding for refugee re-settlement was unconstitutional. But he did distance himself from Trump’s “total ban” on Muslim entrance into the States. He backed the Mexican Wall promise.
GAY RIGHTS: He originally backed the Religious Freedom Restoration Act which critics say simply discriminated against LGBT people by allowing businesses to refuse service on religion grounds. Under pressure, he later added an amendment to ensure this law did not discriminate against gay men and women. In 2000 he said that Congress should oppose expansion of gay anti-discrimination laws. He backed calls for ‘conversion therapy’ to change sexual orientation. Pence opposes same sex marriages. As a Congressman, he opposed federal funding to support HIV and AIDS care.
CLIMATE: He refutes the scientific facts on climate change. “Global warning is a myth” he wrote in 2001. In 2009 he led an effort to stop stricter anti-emission laws in the States. Two month ago, he seemingly flip-flopped, saying there was no question that human activity affects the climate and environment.
More on Pence? Click here

domain: news


[More Entertainment] Restaurant review: Danielle’s Cafeteria is a fun neighborhood. the Zoellner lobby before each performance. ‘The Great Russian Nutcracker’ Since 2002, the Moscow Ballet has.
The St. Petersburg Ballet Theatre was founded in 1994 by Russian entrepreneur Konstantin Tachkin, for the purpose of delivering Russian classical ballet to audiences worldwide. They tour extensively, including return visits to Great Britain and South Africa and Grinnell, Iowa.This company is made up mostly of graduates from the famous Vaganova Ballet Academy in St. Petersburg.
Ukrainian dancer Sergei Polunin is a former Principal of The Royal Ballet. He trained at The Royal Ballet School and graduated into the Company in 2007 as an Artist, promoted to Soloist in 2008, First Soloist in 2009 and Principal in 2010. He resigned from the Company in January 2012. Polunin’s.
Dec 6, 2018. Each holiday season, Moscow Ballet's Great Russian Nutcracker take us into a world of yuletide fantasy.
Customer reviews of Moscow Ballet's Great Russian Nutcracker at the Orpheum Theater, Minneapolis, MN. A delightful treat for the whole family!. December 6.
The Moscow Ballet’s Great Russian Nutcracker tells the beloved Christmas story of the. Once or twice a month, we plan to do a review of what was asked and answered.
As an expensive Music Center import, the new Miami City Ballet production of “The Nutcracker” is both unnecessary and. for the great ballet ensembles of Europe — in Moscow, St. Petersburg, Paris —.
Christmas is coming and so is the one and only Moscow Ballet's Great Russian Nutcracker: Dove of Peace Tour! Presenting world-class Russian artists,
Customer reviews of Moscow Ballet's Great Russian Nutcracker at the The Met Philadelphia, Philadelphia, PA. A delightful treat for the whole family!. December.
An Author Wrote A Book That Advocated The Playing Of Classical Music Page 411 XXXII. MUSIC 1360. Music is a Ladder by which Souls May Ascend "We have made it lawful for you to listen to music and singing. Take heed, however, lest listening thereto should cause you to overstep the bounds of propriety and dignity. Dec 19, 2013. So this year the classical music critics of The New York Times had plenty of. of the opera, which features vibrant conducting, atmospheric playing from a. author Bjornstjerne Bjornson about the exploits of
This Christmas give your family the gift of Moscow Ballet's Great Russian Nutcracker! Step into a simpler time filled with sweet dreams and Christmas magic.
Christmas is coming and so is the one and only Moscow Ballet's Great Russian Nutcracker. Presenting world class Russian artists, hand-painted sets, Russian Snow Maidens, and jubilant Nesting Dolls – Great. Comment Review Photo.
The State Kremlin Palace is the main stage of the country – one of the best and most prestigious theatrical and concert venues. Concert programs dedicated to various memorable, historical, anniversary dates, holidays of people and professions that make a significant contribution to the spiritual authority and greatness of our country are the visiting card of the SKP.
Working.com – Canada’s most comprehensive job search engine. Find your dream job today!
Before "The Nutcracker" there was. as guest narrators during Ballet Theater’s tour? Perhaps it is because Prokofiev’s best-known score is a part of everyone in some way. Written in 1936 for the.
Prompted by confusing ads and announcements, many local balletomanes believe the Moscow Grigorovich Ballet is really the Bolshoi in disguise. Not nearly, not yet. The company that danced "The.
“The first act of Nutcracker can drag,” says City Ballet's artistic and executive director. Search “Moscow Ballet's Great Russian Nutcracker review” and see the.
Research Methods In English Literature Brevity Is The Soul Of Wit Oscar Wilde Apr 11, 2018. Oscar Wilde. Life is either a. A happy soul is the best shield for a cruel world. Atticus. There is no. More peace. Brevity is the soul of wit. Nov 10, 2009. its body brevity, and wit its soul. on occasion by Woody Allen, George Bernard Shaw, Oscar Wilde, Dorothy Parker, and I'm told, Yogi Berra. A quotation is a brief expression having wit or wisdom, attributed to some.
Customer reviews of Moscow Ballet's Great Russian Nutcracker at the Florida Theatre, Jacksonville, FL. A delightful treat for the whole family!. December 22.
Dec 13, 2010. Sarah Kaufman chose not to review this production in the Washington Post, writing instead about the ballet horror film Black Swan, and she.
Formed in 1981, The Russian State Ballet & Orchestra of Siberia has now established itself as one of Russia’s leading ballet companies and has built an international reputation for delivering performances of outstanding quality and unusual depth. Both the soloists and the corps de ballet have been.
Hovering above what could have been an artificial theme program was the very spirit of classical ballet as defined by its own idiom. The same classroom vocabulary that every ballet student learns in.
Christmas is coming and so is the one and only Moscow Ballet's Great Russian Nutcracker. Presenting world class Russian artists, hand-painted sets, Russian.
Customer reviews of Moscow Ballet's Great Russian Nutcracker at the Queen Elizabeth Theatre, Vancouver, BC. A delightful treat for the whole family!
Ballet: Ballet, theatrical dance in which a formal academic dance technique—the danse d’ecole—is combined with other artistic elements such as music, costume, and stage scenery. The academic technique itself is also known as ballet. Learn more about the history of ballet in this article.
Vyacheslav Gordeyev was a favorite of American audiences when he danced as a star of the Bolshoi Ballet from 1973 to 1979 in the United States. Now he has come back with his own company from Moscow.
We kicked off our families holiday season this year with a visit to San Francisco. We saw the Moscow's Ballet Great Russian Nutcracker. It truly is one of the ways.
The name Moscow Ballet has commonly been applied to a number of different ballet companies, which include: Moscow Ballet (United States), a Russian ballet company. The Moscow Ballet tours annually in the United States with its Great Russian Nutcracker.
Announcing the one and only Moscow Ballet Great Russian Nutcracker ~ Dove of Peace Tour! The performance will be at the Oncenter Crouse Hinds Theater on Thu, Dec 20, 4:00pm matinee and 8:00pm.
Japanese dancer Fumi Kaneko is a First Soloist of The Royal Ballet. She joined the Company during the 2010/11 Season and was promoted to First Artist in 2012, Soloist in 2013 and First Soloist in 2018. Kaneko trained at the Jinushi Kaoru Ballet School, Osaka. She won gold medal at the Varna.
The BBC artist page for Mikhail Pletnev. Find the best clips, watch programmes, catch up on the news, and read the latest Mikhail Pletnev interviews.
The NYC Ballet Intensive is the east coast flagship program with Josie Walsh and Jo Matos as the Artistic Directors. Josie Walsh: Ages 14 -25
Dec 10, 2014. ARTS REVIEW | Moscow Ballet's Great Russian Nutcracker inspires awe at Orpheum Theatre. By Gino Terrell (TC Daily Planet) | December 10,
Although the original 1892 Marius Petipa production was not a success, Pyotr Ilyich Tchaikovsky’s ballet The Nutcracker began to slowly enjoy worldwide popularity after Balanchine first staged his production of it in 1954. It may now be the most popular ballet in the world. In Russia, choreographer Alexander Gorsky staged a new version of the work in 1919 that addressed many of the criticisms.
Ballet Academy East. BAE’s Pre-Professional Division will delight audiences in their 20th annual spring performance, showcasing the school’s talented dancers in an exciting program of premieres, classics and audience favorites.
Goldstar – the leading membership-based web retailer of half-price live entertainment tickets-announces the nominees for the 6th annuAl Goldstar National Nutcracker Award today. This season- the 120th.
E.T.A. Hoffmann’s 1816 story about a Christmas toy that comes to life has been so eclipsed by the ballet industry that few are familiar with the original text, titled The Nutcracker and. St.
New this year, Moscow Ballet (MB) announces fund-raising partnership with Children’s Miracle Network Hospitals. Nutcracker, originally directed and choreographed by Bolshoi Theatre soloist.
Dec 12, 2018. Such was the case on Monday when I went to see Moscow Ballet's Great Russian Nutcracker at the Avalon Theater in Grand Junction, CO.
Customer reviews of Moscow Ballet's Great Russian Nutcracker at the Louisville Memorial Auditorium, Louisville, KY. A delightful treat for the whole family!
Ballet after 1945 The East-West divide. From the beginning, the dynamic relationship between aesthetics and social demands, between the urge for innovation and the demand for stability, has shaped the art of ballet. Yet the interrelationships between art and history were especially close in.
And Moscow State Ballet is returning to the State Theatre in Easton for the 20th year with its “Great Russian Nutcracker. [More Entertainment] REVIEW: Fusion Jazz Trio shows at Levitt Pavilion.
If there was ever a place childhood dreams came to life, it was the TSB Showplace when the Imperial Russian Ballet performed The Nutcracker to an awed crowd. on stage in front of such a large crowd.
The Bolshoi Ballet presents this evergreen work in a version choreographed by Yuri Grigorovich with music by Tchaikovsky. Principal dancers Anna Nikulina and Denis Rodkin star as Marie and the Prince,
Buy Moscow Ballets Great Russian Nutcracker tickets online at Vivid Seats. You can choose a delivery method, review your order, and submit credit card or.
The Stanislavsky Nemirovich-Danchenko Ballet from Moscow came into its own on Tuesday night with. the company was visibly more at home here than in ”The Nutcracker,” which opened its season last.
Dec 13, 2018. Marking the 25th Anniversary Tour, Moscow Ballet's Great Russian Nutcracker features over-the-top production and world class Russian artists,
Buy Dancing with the Stars tickets at Vivid Seats. Find Dancing with the Stars tour tickets and pick out cheap seats using venue seating charts.
Brevity Is The Soul Of Wit Oscar Wilde Apr 11, 2018. Oscar Wilde. Life is either a. A happy soul is the best shield for a cruel world. Atticus. There is no. More peace. Brevity is the soul of wit. Nov 10, 2009. its body brevity, and wit its soul. on occasion by Woody Allen, George Bernard Shaw, Oscar Wilde, Dorothy Parker, and I'm told, Yogi Berra. A quotation is a brief expression having wit or wisdom, attributed to some. You can see proverbial truth of Shakespeare's saying
Ballet Arts has provided dance education in the Conejo Valley for over 50 years (established – 1962). We have classes in many dance forms but specialize in ballet. Ballet Arts is does not promote sports-like competitions. Our dance education is centered around stage performance.
In the past 10 years, the reviews have spoken for themselves. a pretty important player in the holiday season. Every year, the Moscow Ballet comes to Minneapolis to perform “The Nutcracker.” It’s a.
The Moscow Ballet, despite its official-sounding name, is not on the same level. It is a pickup company of Russian dancers assembled for tours of America. Its “Great Russian Nutcracker,” which played.
The Queen Elizabeth Theatre is a entertainment theatre situated in the heart of Vancouver, Canada. The theatre boasts a absolutely stunning indoor architectural design and a.
Dear audience! Tickets for this event you can buy at the ticket offices of the State Kremlin Palace at ul. Vozdvizhenka, 1. Metro stations: "Biblioteka imeni Lenina", "Arbatskaya", "Borovitskaya".
‘Wunderbar’ is a delicious insight into the surreal and fantastical world of Eddie Izzard. Five years after his last comedy tour Force Majeure made comedy history having played 45 countries including all 50 U.S. States and in four languages, making…
And the choreography (not noted in the program but evidently by Moscow Ballet artistic director Anatoli Emelianov. ventures to the “Land of Peace and Harmony” with the nutcracker-turned-prince to.
The Nutcracker Ballet, based off Hoffmann’s 1800’s fairy tale The Nutcracker and the Mouse King, premiered in St Petersburg in December 1892 to mixed reviews. It took to. Tickets start at $40.


text:
Today I’m introducing you to Borrtex, a composer and piano player from Czeck republic. Borrtex have been playing the piano since the age of 6, but never really appreciated going to music school. Two years ago he did however fall in love with the instrument and eventually started composing.
The song thōughts is taken from the album with the same name, which was released on November 1st of 2019.
Tell us something about the song thōughts!
Funny fact is, that I composed over 30 songs for this particular album, but somehow, the quality of the sound was getting better with each new song, so eventually I started deleting the first ones, and making more of the new ones that sounded just so much better! At the end, I selected only 10 songs that I felt were good enough for the album. The song titled thōughts represents my creative process. For me, thoughts are just melodic ideas that I have in my head while I’m thinking about something. And once it starts making noise in my mind, I need to make it visible. So, sitting behind the piano and just kind of ‘transcribing’ my thoughts into music is the main point for the title of the song. …
Thank you very much for this song! (And the album is also great by the way).

domain: entertainment


Deep Cryogenic Treatment – Bucket Teeth
A large mining corporation is striving to substantially reduce the cost of delivered ground engagement equipment by making their bucket teeth last longer through the use of Deep Cryogenic Treatment (DCT). In partnership with our technology partner, Deep Cryogenics International, Induspec created a DCT recipe for these various teeth which ranged in weight from 60 lb to over 250 lb each, manufactured by quality manufacturers such as CAT, MTG, ESCO and others.
Induspec performed a deep cryogenic treatment with multiple tempering heat treatment sequences on the 2,600 lb of bucket teeth over a period of nearly four days. These bucket teeth had been heat treated by the manufacturers to optimize wear resistance and toughness, however due to the fact that only heat treatment and not deep cryogenic treatment, was applied a further improvement in wear resistance could be gained through DCT. Typically the use of DCT on ground engagement tools will yield an extension in useful life of between 20% and 40% .
Induspec is working with our mining customer to quantify the observed benefit of the DCT. The comparison is being evaluated, not in a laboratory setting, but by actually comparing the DCT treated teeth with identical, but untreated teeth in service. Based on the result of these trials, Induspec will work with the customer to develop a financial model which quantifies the savings to be realized overall. When it comes to wear, savings are typically not only realized by having to purchase fewer wear parts, but also in the reduced maintenance labour and the increase operating time of the equipment.
- Date June 22, 2021
- Tags Deep Cryogenic Treatment


text:
1670 James Avenue, Miami Beach, FL, United States
This destination can have additional per person taxes which are excluded in the prices below
Crest Hotel Suites is situated in South Beach, just 40 minutes from Fort Lauderdale-Hollywood International Airport. It is conveniently positioned for those wishing to discover the area's attractions....
Distance to city centre
Distance to airport
Wi-Fi available in all areas
Pets allowed on request. Charges may apply.
Policies vary by room type and provider.
+1 305 531 0321
In Miami Beach, the average nightly rate for 3 stars hotels is 189.498. The expected nightly rate for Crest Hotel Suites is around $181; a price that is 29% cheaper than the city average. HotelsCombined considers Crest Hotel Suites to be a good deal if you’re looking to stay at a 3 stars hotel in Miami Beach.
With a distance of 15.6 km between Crest Hotel Suites and the nearest airport, Miami, the drive typically takes about 19min depending on traffic. Be sure to check traffic trends near the hotel and airport as some areas experience higher traffic than others and can increase your expected travel time.
One of the more popular options today is to take a taxi or ridesharing service directly from Miami to the hotel. This option is often cost-effective, but guests must keep a lookout for peak time rates.
Yes, dogs and most pets, in general, are allowed at Crest Hotel Suites.
Yes, Crest Hotel Suites has a pool for hotel guests. Generally, hotel pools have opening and closing times so be sure to speak to the front desk before using the pool.
You can reach the front desk of Crest Hotel Suites at +1 305 531 0321.
Yes, Crest Hotel Suites has Wi-Fi available to hotel guests.
Crest Hotel Suites check-out time is 11:00, though late check-out may be accommodated if agreed in advance with the hotel reception.
On average, guests have been paying $181 per night to stay at Crest Hotel Suites. Some users have found rooms as low as $36 per night. Enter your dates in the form above to see the price rates available for your stay.
Yes - Crest Hotel Suites does have a restaurant. They also have a bar service for drinks.
If you need to have clothes washed during your stay, you can take advantage of the laundry facilities and service at Crest Hotel Suites. The property also has irons and ironing boards available for guest use.
The popular Ocean Drive is just over 2.6 km from Crest Hotel Suites.

domain: geography


text:
Your Ultimate Guide to Discover Stockholm
Hitting the dance floor in Stockholm
Find the upcoming festivals happening in the city.
- Stockholm Bachata Weekend 2024Stockholm Bachata Weekend 2024 🗓 When: 23rd February – 25th February 2024🌐 Where: Stockholm, Sweden📍 Location: Skeppsbron 2, 111 30 Stockholm, Sweden🎟 Buy your tickets here Don’t get confused.There are many sensual weekends,but none like the 3rd edition of the Stockholm Bachata Weekend 2024,the biggest festival in Scandinavia What can you expect from this festival? and all this … Read more
- Stockholm Sensual Bachata Weekend 2023Stockholm Sensual Bachata Weekend 2023 🗓 When: 3rd November- 5th November 2023🌐 Where: Stockholm, Sweden📍 Location: Quality Hotel Friends. Råsta Strandväg 1, 169 56 Solna, Sweden🎟 Buy your tickets with a discount here How said Swedish people are cold?Only the weather there is cold, discover the high level of the Swedish local community on the first edition of … Read more
Do you want to level up your bachata,
book your bachata private class in the city here
What to do in Stockholm
Stockholm is a beautiful city with many attractions to visit.
If you are attending the Stockholm Bachata Festival, you might want to check out some of the following places:
The Old Town is a must-visit place in Stockholm. It is one of the largest and best-preserved medieval city centers in Europe.
You can wander around the narrow streets and alleys, admire the colorful buildings, and visit some of the many museums and galleries.
This museum is home to the only almost fully intact 17th-century ship that has ever been salvaged, the 64-gun warship Vasa that sank on her maiden voyage in 1628.
The museum displays the ship itself, which has been fitted with masts and sails, as well as thousands of artifacts found with the ship.
Skansen is an open-air museum that showcases Sweden’s cultural heritage. It is one of the oldest open-air museums in the world and features a zoo with Nordic animals such as bears, wolves, lynx, and moose.
This palace is the private residence of the Swedish royal family. It was built in the 17th century and is located on an island in Lake Mälaren. The palace is surrounded by beautiful gardens and parks.
When it comes to restaurants, Stockholm has a lot to offer. Here are some recommendations:
- Oaxen Krog & Slip – This restaurant serves modern Scandinavian cuisine with a focus on local ingredients. It has been awarded two Michelin stars.
- Gastrologik – This restaurant offers a tasting menu that changes daily based on what ingredients are available. It has been awarded two Michelin stars.
- Nook – This restaurant serves Asian-inspired cuisine with a focus on sustainability. It has been awarded one Michelin star.
Where to stay in Stockholm
Are you looking for cheap accommodation in Stockholm for the bachata festival?
Here are some options that might interest you:
- Private room in Hammarby Sjöstad, common space shared! Soderman Stockholm
- Downton Camper by Scandic
- Nobis Hotel Stockholm
Where to eat in Stockholm
Are you looking for some budget-friendly restaurants in Stockholm?
Here are some options for you to try local and international food after an intense night of dancing:
Mom’s Kitchen on Nybrogatan
is a popular affordable cafe that serves European and Swedish cuisine.
another affordable restaurant that serves seafood.
is a budget-friendly restaurant that serves Asian cuisine.
is a budget-friendly restaurant that serves Swedish cuisine.
Fuori Di Pizza is a budget-friendly restaurant that serves Italian cuisine.
Falafelbaren is a budget-friendly restaurant that serves Middle Eastern cuisine.
Gunters Korvar is a budget-friendly restaurant that serves Swedish cuisine.
Other useful information when visiting Stockholm
Stockholm is a city that will make you fall in love with its charm.
The currency used in Stockholm is the Swedish krona (SEK), but you can easily exchange it for EUR.
The population of Stockholm is around 975,000 people.
The plug type used in Stockholm is the European plug type C and F2.
There are two airports in Stockholm:
Arlanda and Bromma.
To commute from Arlanda airport to the city center, you can take the Arlanda Express train which takes only 20 minutes.
If you prefer to take a bus, you can take the Flygbussarna which takes around 45 minutes.
To commute from Bromma airport to the city center, you can take the Flygbussarna which takes around 20 minutes1.
Did you know that Stockholm is built upon numerous islands as well as the mainland of Uppland and Södermanland?
That’s why it’s often called the “Venice of the North”.
Also, did you know that Stockholm has a stunning archipelago consisting of around 30,000 islands, islets, and rocks?


Hot vulcanized ceramic lagging offers improved, lasting pulley protection against abuse of abrasive materials, corroding effects of moisture
For conveying systems operating in harsh environments, wear is inevitable. By investing in the right protection, you can prevent that wear from damaging the system’s major components, which can rack up costs in both replacement and downtime.
Lagging is the coating or cover applied to pulleys, which provides a replaceable wearing surface for the drum pulley, while also improving the friction between the belt and the pulley.
Ceramic Lagging Solves: Premature Wear, Belt Slippage & Tracking Complications
While rubber or urethane lagging is commonly used in material handling applications, ceramic lagging provides an advanced solution for extreme high-wear, high-tension, contaminated and/or wet operating environments, where conventional lagging often wears prematurely and causes slippage.
“The ceramic offers both a higher friction coefficient and a nearly completely wear-proof surface,” says John Calfee, Martin Pulley Engineering & Estimating Manager. “With the higher friction, belts slip less and less tension is required to create the friction needed for driving a belt. This reduces wear due to slippage and can also shrink component sizes, like shafts and bearings, due to the decreased tensions.”
Upgrading to ceramic tile is also a recommended solution if your conventional lagging is prone to material build-up. “The hard surface of the ceramic tiles prevents material build-up, which can help with belt tracking,” says Calfee, “and improve your system’s overall efficiency.”
Hot Vulcanization Has Up To 83% Higher Bonding Strength
While the ceramic tile is designed to withstand abrasion, it’s hot vulcanization adherence to the pulley also leaves no room for error━literally.
Through the hot vulcanization process, the lagging is chemically bound to the pulley. The ceramic tiles are embedded into 60 durometer rubber with high tensile fibers, providing a solid bond with no seams for foreign material to penetrate and cause failures. This is especially ideal for applications exposed to moisture, which can get into a pulley’s steel rims and cause rust.
How does hot vulcanization stack up against other bonding methods?
According to Calfee, Martin has worked closely with independent testing labs to study adhesion strengths of several bonding methods. “Studies found that hot vulcanized lagging yields up to 83% higher bonding strength than conventional cold bonding methods for SBR compounds.”
Learn More About Ceramic Lagging From IBT’s Conveying Systems Group
As specialists in the conveying systems field, IBT Industrial Solutions understands the importance of good systems application in achieving optimum efficiency. With our years of experience in providing conveying systems and components, you can rely on IBT for the best solution to your problems. contact Jim Boatright, the Conveying Systems Business Group Director at IBT Industrial Solutions, or give us a call at 913-677-3151 to learn more.


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Lithuanian singer & songwriter Annora Ember shares her moody pop single, Demons in my Head, with us. It bears a dark, melodic undertone. There are strong arrangements that make the sound all the more distinctive. The lyrics of this song, which are heartfelt and have great meaning, are made even more impactful by the excellent singing. Compared to the verses, the chorus is a bit brighter.
Annora says the following about the track: ”From all the songs I wrote this my favourite one and the hardest to write too. I remember we even wanted to quit. I’m glad we didn’t. The first time I heard it with production, vocals and everything I was shocked. I was surprised it came out of me and now I can say… I am grateful for my depression and anxiety. I hope you will love my baby as much as I do.”
Check out Demons in my head below!

domain: artistic


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For now, the Xbox store has big and very juicy discounts thanks to Black Friday, that’s why we recommend 5 games.
Xbox already has great discounts thanks to Black Friday 2020 and that is why we show you below five great games that you should get thanks to these discounts.
Watch Dogs: Legion – 33%
The latest installment of Watch Dogs allows us to control more than one agent within a repressed society that needs to be liberated. There are so many things to do in this game that you will hardly get bored with this one. Just a great game.
Tony Hawk’s Pro Skater 1 + 2 – 25%
Two all-time classic games for the price of one, now at a substantial discount. If you could never play these great titles at the time, then don’t waste your time and take advantage of this incredible offer, it is very worth it.
STAR WARS: Squadrons – 40%
This game puts us in the shoes of two different pilots, one that is part of the rebellion and the other that is part of the Empire. The bell it is full of action and memorable scenes and it is highly recommended for all movie fans as it really makes you feel like you are inside this universe.
Crash Bandicoot 4: It’s About Time – 35%
The most recent Crash game that is part of the official timeline, and also one of the best games of the whole year. So If you have the opportunity, do not let it pass through anything in the world, because not only is it full of content everywhere, it also has a great challenge and is very entertaining.
DOOM Eternal – 67%
To put aside all the bad things in life, sometimes you have to play these kinds of games, which make you feel extremely powerful. This is DOOM Eternal, well You will have to fight your way through hordes of enemies from hell with a luxury of violence and excellently animated executions. Don’t hesitate, it’s really amazing.

domain: game


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GAGE, DAVID (1796–1854). David Gage, early settler and legislator, was born in Kentucky in 1796. He moved to Texas from Alabama in 1839 and, on May 21, purchased a fourth of the Leonard Williams league; he settled in the Williams Settlement in southern Rusk County, near Mount Enterprise. A few months later he organized and was made captain of a company of minutemen for protection against the Indians. He served with the company during 1840 and 1841. Gage was elected representative to the Eighth and Ninth congresses of the republic, December 4, 1843, to June 28, 1845, and in 1845 was elected senator for the Fourth District and delegate to the Convention of 1845. After annexation he served three terms in the Texas legislature. He died at his home near Mount Enterprise in 1854.
John S. Ford, Memoirs (MS, John Salmon Ford Papers, Dolph Briscoe Center for American History, University of Texas at Austin). Texas House of Representatives, Biographical Directory of the Texan Conventions and Congresses, 1832–1845 (Austin: Book Exchange, 1941). Texas Legislative Council, Members of the Texas Legislature, 1846–1980 (Austin, 1980?).
The following, adapted from the Chicago Manual of Style, 15th edition, is the preferred citation for this article.Robert Bruce Blake, "GAGE, DAVID," Handbook of Texas Online (http://www.tshaonline.org/handbook/online/articles/fga01), accessed November 28, 2015. Uploaded on June 15, 2010. Published by the Texas State Historical Association.
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Each day's email tells a little bit more of the story of Texas and links to our collection of more than 27,000 articles

domain: history


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Is your hair thinning, or do you just have naturally thin hair? It can be difficult to tell whether you’re truly experiencing hair loss or if your hair is just fine or limp. But there are a few tell-tale signs that will indicate what the true reason is for your thin locks.
Once you’ve identified the cause, you can then pinpoint the best course of action for getting your locks looking full again. We spoke to Bridget Noonan, National Education Manager for L’Oréal Professionnel, to help you determine what your thin locks really need.
Is my hair really thinning, or is it just thin?
According to Bridget, there are a few indicators that will signal whether your hair is thinning, or just thin. “The four major signs of thinning hair are less density, thinner-looking, brittle hair and less volume,” Bridget says.
Now those symptoms could also be true of naturally thin hair. So how can you tell the difference? For one thing, naturally thin hair is usually fine in texture – and fine hair is completely different to thinning hair. “Fine hair’ refers to the thickness or diameter of the individual hair strands,” explains Bridget. “Thin hair refers to the overall density of the hair follicles across the entire scalp.”
If you’re still unsure what your hair type is, Bridget recommends consulting your hair stylist. “Determining hair type involves understanding the different qualities of hair. This includes the hair’s density, texture, and porosity, which is the hair’s ability to hold moisture,” says Bridget. “A hair stylist will use your hair type to recommend a cut and style, colour and styling products that are suitable to your hair type.”
If my hair is thinning, what could be the cause?
“Hair loss and thinning can be caused by a variety of factors such as diet, hereditary factors, stress, hormonal changes, pregnancy, medication and environmental changes, just to name a few,” says Bridget.
Hair thinning can even be the result of seasonal changes, such as shedding during autumn and spring, which is completely normal. But if you’re concerned it’s the result of something more, there are a few areas you can look to see if hair loss is a symptom.
“If someone is suffering a major health issue, they can suffer from stress from this condition as well, which contributes to hair loss and thinning – which can then be compounded with medication to treat the condition,” explains Bridget. “A poor diet or a drastic change in diet can also contribute to hair loss. The body requires vitamins and minerals and other nutrients to assist a healthy scalp and hair growth, so following a strict diet or changing your eating habits may cause some hair loss.”
What can I do about thinning hair?
The first step is to sort out your hair care. If your hair is thinning, it’s time to change up your regular products for more powerful options that will work to visibly increase the density of your hair. “L’Oréal Professionnel SERIOXYL is a hair range powered by Stemoxydine, a molecule that mimics the environment required for stem cell stimulation to awaken dormant follicles for the creation of new hair,” says Bridget.
The potent ingredients in the SERIOXYL range work together to visibly improve hair density. Glucoboost works to target the hair at the roots and provides an immediate energy boost to the root of the hair fibre to facilitate hair growth, while Intra-cylane™ thickens every hair strand instantly by penetrating the hair cortex and expanding within your strands. Meanwhile, other ingredients work to make the hair look stronger and thicker, preventing further weakening of your strands.
The SERIOXYL range is also really easy to incorporate into your routine. The simple three-step system consists of a shampoo, conditioner and Denser Hair Gel which work alongside one another to get your hair looking and feeling fuller.
L’Oréal Professionnel‘s SERIOXYL shampoo and conditioner are available in two different variants – one for thinning hair that’s not coloured, and one for coloured, thinning hair – and can be used whenever you shampoo your hair. L’Oréal Professionnel SERIOXYL Denser Hair Gel is a daily hair treatment for thinning hair that is powered by Stemoxydine 5%, a molecule that mimics the environment required for stem cell stimulation to awaken dormant follicles for the creation of new hair. It acts as an alarm clock to awaken the hair from the dormant phase of the hair growth cycle. When used in conjunction with the Serioxyl shampoo and conditioner over a minimum of three months, your hair will be feeling thick and looking luscious again in no time.
Another step you can take to help reduce hair loss is to make an effort to minimise stress in your life. “Having high stress levels can contribute to hair loss,” says Bridget. “Try to stay relaxed or consider different forms of exercise such as walking, yoga and pilates.”
Have you experienced thinning hair?


I found that I can do scp in mc via
cd /#sh:radek@firebird from the command line.
Is there any way I can
- save this as a favorite?
- Maybe even with the password?
To simplify your setup, you can set up an SSH config file which is located at
The HostName directive is optional if it matches the name given in Host. This is basically an alias to typing
OpenSSH does not support storing passwords since this is normally a bad idea, but it offers a more secure alternative called public key authentication. With public keys, you can log onto multiple servers automatically even if each server has a different password. Public keys use a private key that is normally stored on disk with a password. This password is use to load the private key which is then used to authenticate to the remote server. To avoid typing in the password for the private key all the time, the private key can be loaded into an SSH Public Key Agent such as


IOWA CITY, Iowa — University of Iowa junior Kaleb Young has been awarded an at-large berth to the 2020 NCAA Wrestling Championships in Minneapolis on March 19-21. The NCAA announced the 330-person tournament field Tuesday.
Young is one of five 157-pound wrestlers to earn an at-large berth. His selection means Iowa will send its entire 10-man roster to the national tournament for the first time since 2015.
Young placed fifth at the national tournament a year ago, earning All-America honors at 157 pounds. He is 15-5 this season with six wins over ranked opponents.
Brackets and seeding for the 2020 NCAA Championships will be revealed during a selection show on Wednesday, March 11 at 5 p.m. (CT) on NCAA.com. The @NCAAWrestling Twitter handle will also be releasing the top two seeds for each weight class every 10 minutes from 3 to 5 p.m. leading up to the selection show.
The 2020 NCAA Division I Wrestling Championship are March 19-21-23 at U.S. Bank Stadium in Minneapolis. A complete list of qualifiers is available at NCAA.com.


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PESHAWAR: Khyber Pakhtunkhwa Chief Minister Pervez Khattak has approved an ordinance for maintaining respect and dignity of senior citizens in society and providing them relief.
He also directed early preparation of the draft of Khyber Pakhtunkhwa Senior Citizens Bill for the welfare, facilitation and honour of the people above 60 years.
According to a handout issued here on Tuesday, the Chief Minister signed summary of the ordinance for extending immediate benefits to senior citizens.
For formal approval and enforcement, the ordinance has been sent to the Governor. after signing by the Governor the ordinance will be enforced across the province.
Under the ordinance all citizens including men and women above the age of 60 years will become deserving for provision of several incentives, which include free public transport, free treatment,free entry in parks and libraries while for childless and destitute senior citizens Senior Citizens Old Homes will be built.
Similarly, all registered senior citizens will also get the incentives of the provision of monthly stipends. After the enforcement of the law. Khyber Pakhtunkhwa will take lead in provision of these facilities, ensuring welfare, honour and respect of senior citizens.
The bill will be first legislation for senior citizens in the country.
The Chief Minister has directed the Department of Social Welfare for the preparation of senior citizens Bill.
In last meeting of the provincial cabinet the draft of the bill was approved in principle. However, on the directives of the Chief Minister a cabinet committee was constituted for making the bill comprehensive and realistic.
He also directed the Social Welfare department that instead of wasting time for approval of the bill, it should be enforced through ordinance as soon as possible to provide prompt relief to senior citizens.
For this purpose, he also directed the inclusion of one member each from opposition and treasury benches in its proposed advisory council. Similarly, he also directed the Department of Social Welfare for preparation of comprehensive welfare schemes for senior citizens.
He clarified that dearth of funds will not be excuse in this regard.
The provincial government is presently paying a stipend of Rs 500/ per month to each registered senior citizen in six backward and far-flung districts including Kohistan, Shangla, Battagram, Swabi, Karak and Tank while the Chief Minister has also directed the extension of the scheme to all districts of the province in the next financial year. The Social Welfare department has already completed the registration of senior citizens in the entire province. Furthermore, Pervez Khattak has also directed the preparation of legislation for the welfare of special persons (disabled) across the province. Under these directives all special children and persons in the province will be classified to make basic legislation for provision of free education, treatment and quota in giving scholarships and government employment. Through the implementation of this legislation besides guaranteeing the welfare of special persons, they would be made useful citizens of the society.
ISLAMABAD - Foreign Office spokesperson Nafees Zakaria has said the rocket launch by North Korea on ...

domain: sociology


Karine Jean-Pierre says the White House ‘disagrees’ with World Bank president who dodged question on human causes of climate change but REFUSES to say Biden has confidence in him
- David Malpass dodged a question at NY forum when asked whether ‘manmade burning of fossil fuels is rapidly and dangerously warming the planet’
- He replied: ‘I don’t even know. I’m not a scientist’
- Donald Trump appointed Malpass to his term in 2019
- Climate groups called for him to resign as the remark circulated online
- Then he said humans WERE causing climate change, saying ‘I’m not a denier’
- Biden officials are considering pushing him out, Axios reported
- Potential replacements include John Kerry, Al Gore, former USAID head Raj Shah
- The White House did not knock down the report, and declined to say President Biden had confidence in Malpass
The White House press secretary made the comment at her daily press briefing, following a report that members of the Biden Administration are considering a move to try to force out the Trump-nominated official – a report she declined to explicitly confirm or deny.
She also declined to say President Joe Biden has confidence in Malpass, and even pointed to the challenges of removing him.
‘We disagree with the comments made by President Malpass. We expect the World Bank to be a global leader on climate emission,’ she said.
She said the Treasury Department, which oversees US interactions with global lending institutions, ‘has and will continue to make that expectation clear to the World Bank leadership.’
‘We disagree with the comments made by President Malpass,’ White House Press Secretary Karine Jean-Pierre in reference to comments by the World Bank president who dodged a question on whether human-caused carbon emissions were behind climate change
When a questioner noted she stopped short of saying Biden had confidence in him, Jean-Pierre replied: ‘Removing you requires a majority of shareholders. So that’s something to keep in mind. The US believes the world must be a full partner in delivering on the aggressive global climate agenda, poverty reduction and sustainable development … But again, removal would require majority of stakeholders. It is a partnership.’
She was referring to the Bank’s board of executive directors, which has the power of removal.
Malpass has been under fire since the official, nominated by Trump in 2019, fielded a question this week at a climate forum about whether ‘manmade burning of fossil fuels is rapidly and dangerously warming the planet.’
Administration officials are ‘deeply concerned’ by the comments and are considering moves to oust him, according to Axios.
It comes at a time when the Biden Administration is making climate change a top priority, with the newly enacted Inflation Adjustment Act shoveling $375 billion at climate initiatives.
World Bank President David Malpass wouldn’t directly answer a question about whether ‘manmade burning of fossil fuels is rapidly and dangerously warming the planet.’ Now Biden officials are considering trying to oust him, according to a report
He wouldn’t answer when moderator and Times reporter David Gelles twice asked him: ‘Will you answer the question?’
It was prompted by former Vice President Al Gore calling Malpass a ‘climate denier.’
Later, in an attempted cleanup operation on CNN‘, Malpass denied the charge. He said he was ‘not a denier,’ and told the network: ‘I don’t know the political motivations behind that. It’s clear that greenhouse gas emissions are coming from manmade sources, including fossil fuels, methane, agricultural uses and industrial uses. And so we’re working hard to change that.
He also sought offered a new excuse: ‘I don’t always do the best job in answering the questions or hearing what the questions are.’
Trump nominated Malpass, then a Treasury official, to the post in 2019
Malpass, seen here with Jared Kushner and Ivanka Trump at the Treasury Department, said he is ‘not a denier,’ although a 2010 report indicated he did not believe carbon from human activity was warming the planet
President Joe Biden signed a new law that will steer billions to climate programs including those to boost electric vehicle production
Trump nominated Malpass to lead the World Bank after his longstanding criticisms of the international lending institution.
Back in 2010, Malpass said he did not believe carbon from human activity was warming the planet, the New York Times reported at the time.
He serves a five-year term and was confirmed by a Bank executive board.


text:
- published by Harper Collins Publishers 2015
- ISBN 978-0-00-811660-6
- edited by David Brawn
- 159 pages
- source: my local library
'My name is Hercule Poirot and I am probably the greatest detective in the world.' The dapper, moustache-twirling little Belgian with the egg-shaped head, curious mannerisms and inordinate respect for his own 'little grey cells' solved some of the twentieth century's most puzzling crimes. But what do we really know about the eccentric genius underneath that fussy facade? Sometimes funny, often profound, and always revealing, this book of quotes and comments, from more than 50 Poirot novels and short stories, gives an entertaining glimpse of the man behind the moustache, and the wit and wisdom of the Queen of Crime who created him. Includes an exclusive essay by Agatha Christie from the archives on her love/hate relationship with her most famous creation.
Full of lovely little one-line snippets from some of the Hercule Poirot novels and short stories, this will remind you of why you've enjoyed reading them. I truly wish some one had given it to me in my Christmas stocking!
The Introduction, written by Agatha Christie in 1938, gives us a brief overview how Hercule Poirot came to be and how "there was much more in the little man than I had ever suspected." Her humour comes through when, later, she says, "I am beholden to him financially."
At the back, in References, there is a handy list of the books and short stories in which he actually appeared - there has been a tendency by film and television to locate him in other stories.
I loved it.
My rating: 4.5
Check out the Agatha Christie Reading Challenge Blog Carnival
See also Agatha Christie Novels.

domain: literature


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We are here for your questions anytime 24/7, welcome your consultation.Get Price
Raymond bartlett snow milling technologies specialized for.Various materials such as iron ore coal and additives.Raymond bartlett snow division of arvos group presents technical paper on raymond roller mill specialized for additives grinding in pellet plant and vertical mill technologies vertical roller mill and ball race mill specialized for coal.
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Iron ore processing for the blast furnace.The ore is reduced to 3 4 quot or less it moves out of the mill in a slurry solution the mill discharge is screened at 1 4 quot on trommel screens attached to the mill ore smaller than 1 4 quot is pumped in slurry solution to the wet cobber magnetic separator which begins the process of separating the iron from the non iron material the magnetic iron.Read More
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The grinding of the grading basically is the use of spiral classifier.In order to improve efficiency, to replace the two spiral classifier using hydrocyclone to part of ore dressing plant.Low grade iron ore separation flow chart.Mainly used for separation of low grade iron ore.Iron ore mineral technologies.Iron ore resources.Read More
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Feldspar grinding mill,grinding mill,raymond mill,ball.Sag is an acronym for semi-autogenous grinding.Sag mills are autogenous mills that also use grinding balls like a ball mill.A sag mill is usually a primary or first stage grinder.Sag mills use a ball charge of 8 to 21.The largest sag mill is 42 12.8m in diameter, powered by a.Read More
Ball mill machine iron ore making ball mill.Ball mill is the most widely used kind of grinding equipment zenith ball mills are widely used in various types of ores benefication electricity cement and chemical industries with high comminution ratioit can carry out dry or wet pulverizing and can meet.Chat online.Read More
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Welcome back to another new installment of our weekly ‘DEG Watched at Home Top 20’ list posts where we continue to keep you updated with all of the most popular movies and television shows watched at home each week, compiled and released by the Digital Entertainment Group like always.
This week’s new ‘DEG Watched at Home Top 20 list for June 9, 2022 (compiled of data for the week ended 6.4.22) once again finds ‘Uncharted’ staying steady in the top spot, while ‘Morbius’ slips one spot into third this week as ‘The Lost City’ jumps into second from its place in fifth last week. Meanwhile, ‘Sonic the Hedgehog 2’ holds in fourth for another week followed by ‘Spider-Man: No Way Home’ which improves two spots to return to fifth, rounding out this week’s top five. Continue below to read the full news release with this week’s new ‘DEG Watched at Home Top 20’ list and then let us know what you’ve been watching in the comments!
Jurassic World 5-Movie Collection Roars into the Top 20
On the Watched at Home Top 20 this week, the top titles shuffled a bit, with Spider-Man: No Way Home shoving The Batman out of the Top 5. Further down the chart, the Jurassic World 5-Movie Collection joined Jurassic World: Fallen Kingdom on the chart ahead of Friday’s highly anticipated theatrical release for Jurassic World: Dominion. Other new titles joining the chart include Mark Wahlberg vehicle Father Stu at No. 10 and Michael Bay action thriller Ambulance at No. 20.
DEG compiles the ‘Watched at Home Top 20’ list with the most widely consumed titles on disc and digital during the previous week (outside subscription-based streaming platforms). Assembled with the newest studio and retailer data every seven days, it showcases current consumer enthusiasm for home viewing of the newest film and television releases.
Please see below for the June 9 ‘Watched at Home Top 20’ list:
- Uncharted (Sony)
- The Lost City (Paramount)
- Morbius (Sony)
- Sonic the Hedgehog 2 (Paramount)
- Spider-Man: No Way Home (Sony)
- Dog (MGM)
- The Batman (Warner Bros.)
- Sing 2 (Universal)
- The Contractor (Paramount)
- Father Stu (Sony)
- Top Gun (Paramount)
- Moonfall (Lionsgate)
- Blacklight (Universal)
- X (A24)
- Jurassic World 5-Movie Collection (Universal)
- Jackass Forever (Paramount)
- No Time To Die (MGM)
- Jurassic World: Fallen Kingdom (Universal)
- Better Call Saul S6 (AMC)
- Ambulance (Universal)
Source | DEG: The Digital Entertainment Group
Includes U.S. Digital Sales, Digital Rentals (VOD), DVD & Blu-ray for week ended 6.4.22; excluding Premium
ABOUT THE DIGITAL ENTERTAINMENT GROUP
DEG advocates and promotes entertainment platforms, products, and distribution channels that support the movie, television, audio, consumer electronics, and IT industries. With the objective to support and drive marketing initiatives, DEG’s list has been created to increase awareness and encourage adoption by the public and consuming audience of emerging home entertainment formats and new distribution models. The Watched at Home Top 20 is published each Thursday on DEG’s website, degonline.org, and is distributed in its daily DEN email.


Experimental facilities have been built to visualize transient expanding spherical flames. Facilities include a cylindrical chamber with two end glasses for optical observation. Shadowgraph and Schlieren pictures of flame propagation have been taken using a high speed Charged Coupled Device (CCD) camera. In this paper the optical behavior of spherical flames has been investigated using both Schlieren and Shadowgraph methods. A mathematical model has been developed to predict the intensity of refracted light beams interacting with a transient expanding thin flame. Experimental results are in very good agreement with theoretical model. Schlieren and Shadowgraph techniques have also been used to view smooth, cracked and cellular flames, which are useful in determining the stability of propagating flame.
Schlieren and Shadowgraph Images of Transient Expanding Spherical Thin Flames
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Matlo, M, Parsinejad, F, & Metghalchi, H. "Schlieren and Shadowgraph Images of Transient Expanding Spherical Thin Flames." Proceedings of the ASME 2002 International Mechanical Engineering Congress and Exposition. Energy Conversion. New Orleans, Louisiana, USA. November 17–22, 2002. pp. 71-76. ASME. https://doi.org/10.1115/IMECE2002-39318
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