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Inheritance of red kernel and hull colour were studied in eight crosses between white kernel/red kernel rice varieties viz., Karjat 4/Patni 6, Panvel 2/MO 17, Palghar 1/MO 8, Ratnagiri 5/TKM 9, Karjat 184/Munga, Karjat 6/Bela, Ratnagiri 24/Valai and Karjat 8/MO 8 during rabi 2013-14 using their parents, F1's, F2's and BC1, BC2 populations. Segregation pattern reveled that red kernel in rice is governed by one dominant gene in six crosses fitting the F2 chi square ratio 3:1 while as it was governed by two dominant gene in two crosses exhibiting F2 chi square ratio 9:7 which indicated complementary type of gene action and were confirmed in BC1F1 fitting chi square ratio 1:1 red kernel to white kernel ratio. The inheritance pattern of hull colour in six crosses; brown hull colour was dominant over straw hull colour; governed by two independent genes, one dominant and one recessive gene fitting F2 chi square ratio 13:3. Similarly, in two other crosses, brown hull colour was dominant over golden yellow and yellow hull colour fitting F2 chi square ratio 9:7 and governed by two dominant gene with complementary type gene action. The inheritance studies of red kernel rice are very important to bred biofortified rice varieties. [ABSTRACT FROM AUTHOR]

Abstract Background Aromatase inhibitors (AI) that inhibit breast cancer cell growth by blocking estrogen synthesis have become the treatment of choice for post-menopausal women with estrogen receptor positive (ER+) breast cancer. However, some patients display de novo or acquired resistance to AI. Interactions between estrogen and growth factor signaling pathways have been identified in estrogen-responsive cells as one possible reason for acquisition of resistance. Our laboratory has characterized an autocrine growth factor overexpressed in invasive ductal carcinoma named PC-Cell Derived Growth Factor (GP88), also known as progranulin. In the present study, we investigated the role GP88 on the acquisition of resistance to letrozole in ER+ breast cancer cells Methods We used two aromatase overexpressing human breast cancer cell lines MCF-7-CA cells and AC1 cells and their letrozole resistant counterparts as study models. Effect of stimulating or inhibiting GP88 expression on proliferation, anchorage-independent growth, survival and letrozole responsiveness was examined. Results GP88 induced cell proliferation and conferred letrozole resistance in a time- and dose-dependent fashion. Conversely, naturally letrozole resistant breast cancer cells displayed a 10-fold increase in GP88 expression when compared to letrozole sensitive cells. GP88 overexpression, or exogenous addition blocked the inhibitory effect of letrozole on proliferation, and stimulated survival and soft agar colony formation. In letrozole resistant cells, silencing GP88 by siRNA inhibited cell proliferation and restored their sensitivity to letrozole. Conclusion Our findings provide information on the role of an alternate growth and survival factor on the acquisition of aromatase inhibitor resistance in ER+ breast cancer.

Despite being a rare phenomenon, pericardial hydatid cysts present unique diagnostic challenges and require a multimodality imaging as well as a multidisciplinary approach for a curative management. The authors here present a case of a middle aged man who was referred to them for management of new onset atrial flutter with mitral regurgitation., (© 2024 Wiley Periodicals LLC.)

Introduction: Podcasts are a popular way to learn and engage at the convenience of the listener. Education is incorporating podcasts to supplement and reinforce students learning inside and outside the classroom., Methods: The authors created a podcast covering the Top 200 commonly prescribed medications. This was to help students recall and reinforce medication knowledge they typically must learn on their own., Results: Student performance on post-tests improved (p = 0.0011) compared to pre-tests with an effect size r of 0.39 (0.37, 0.32, and 0.42 for P1, P2 and P3 respectively). Students reported the content was easy to follow, and they enjoyed learning from other students. The total number of plays for the podcast as of 19 July 2023 were 882. Each episode had a range of one to 89 number of plays., Discussion: The podcast was well received by students, and drug knowledge increased. While the podcasts were shorter in time, they still provided the foundational information for a first-year pharmacy student to know. Overall, podcasts provide another way to help students retain and reinforce material learned inside and outside the classroom., Competing Interests: Declaration of competing Interest None., (Copyright © 2024 Elsevier Inc. All rights reserved.)

Abstract: Acute rheumatic fever and Takayasu arteritis are examples of autoimmune diseases that commonly affect the cardiovascular system. We report an infrequent co-occurrence of both these diseases in an adolescent male. It may appear that in some individuals, the rheumatic fever may act as a trigger for the development of large vessel vasculitis. This possibility should be considered in patients on follow-up if they develop fresh features of cardiovascular compromise despite appropriate medical, interventional, or surgical therapy for rheumatic heart disease., (Copyright © 2024 Copyright: © 2024 Journal of Postgraduate Medicine.)

Seizures are caused by abnormally synchronous brain activity that can result in changes in muscle tone, such as twitching, stiffness, limpness, or rhythmic jerking. These behavioral manifestations are clear on visual inspection and the most widely used seizure scoring systems in preclinical models, such as the Racine scale in rodents, use these behavioral patterns in semiquantitative seizure intensity scores. However, visual inspection is time-consuming, low-throughput, and partially subjective, and there is a need for rigorously quantitative approaches that are scalable. In this study, we used supervised machine learning approaches to develop automated classifiers to predict seizure severity directly from noninvasive video data. Using the PTZ-induced seizure model in mice, we trained video-only classifiers to predict ictal events, combined these events to predict an univariate seizure intensity for a recording session, as well as time-varying seizure intensity scores. Our results show, for the first time, that seizure events and overall intensity can be rigorously quantified directly from overhead video of mice in a standard open field using supervised approaches. These results enable high-throughput, noninvasive, and standardized seizure scoring for downstream applications such as neurogenetics and therapeutic discovery., Competing Interests: 7Competing Interests The Jackson Laboratory has filed a provisional patent on the methods described here.

Introduction: In fall 2017, West Coast University School of Pharmacy implemented ExamSoft for testing. Three courses in each didactic year employed ExamSoft. Prior to this, courses had Scantron-based exams. We surveyed the students to assess their perception of ExamSoft. We hypothesized that students' inherent bias towards technology affected their perception of ExamSoft., Methods: To assess this hypothesis, we conducted a survey of all students. The survey contained questions about comfort with technology and nine questions on students' perceptions of ExamSoft and its usefulness., Results: The survey responses were stratified according to the preference of respondents towards technology and its use in exams. Respondents were stratified into three groups: tech-embracers, tech-skeptics, and neutral. Our results showed that respondents classified as tech-skeptics tended to have a more negative view of ExamSoft and its perceived impact on their grades than students stratified as tech-embracers or neutral., Conclusions: Our study suggests that students' inherent bias towards technology plays an important role in their perception of computer-based testing. Assessing incoming students' comfort with technology and student orientation activities to help acquaint students with new technology could help improve their acceptance of educational technology used for testing., Competing Interests: Declaration of Competing Interest None., (Copyright © 2021 Elsevier Inc. All rights reserved.)

Automated detection of complex animal behaviors remains a challenging problem in neuroscience, particularly for behaviors that consist of disparate sequential motions. Grooming is a prototypical stereotyped behavior that is often used as an endophenotype in psychiatric genetics. Here, we used mouse grooming behavior as an example and developed a general purpose neural network architecture capable of dynamic action detection at human observer-level performance and operating across dozens of mouse strains with high visual diversity. We provide insights into the amount of human annotated training data that are needed to achieve such performance. We surveyed grooming behavior in the open field in 2457 mice across 62 strains, determined its heritable components, conducted GWAS to outline its genetic architecture, and performed PheWAS to link human psychiatric traits through shared underlying genetics. Our general machine learning solution that automatically classifies complex behaviors in large datasets will facilitate systematic studies of behavioral mechanisms., Competing Interests: BG, AP, HH, GS, VP, VK No competing interests declared, (© 2021, Geuther et al.)

Background: Quantification of mitral regurgitation (MR) has always required an "integrated approach" as there is no single gold-standard method. We investigated a new Doppler-derived parameter "left ventricular early inflow-outflow index (LVEIO)" for the quantification of MR and its likelihood to predict severe MR in correlation with already established parameters in an Indian population including a large subset of patients with rheumatic etiology., Methods: A prospective study was performed at a major tertiary care center in western India over a 5-month period. Five hundred patients diagnosed with isolated MR including 260 (52%) patients with rheumatic etiology were included in the study after applying exclusion criteria. We analyzed MR using color flow jet, effective regurgitant orifice area (EROA), and vena contracta (VC) width. LVEIO is a simplification of the regurgitant volume (RV) method, which was calculated as "E velocity divided by LV outflow velocity integrated over the systolic ejection period left ventricular outflow tract velocity time integral" and compared with the established parameters., Results: LVEIO was 4.65 ± 1.45, 6.56 ± 1.52, and 9.91 ± 3.70 among patients diagnosed with mild, moderate, and severe MR, respectively (p < 0.001). Those with LVEIO ≥8 were the most likely to have severe MR (positive likelihood ratio: 10.42). LVEIO had specificity of 93.25% for diagnosis of severe MR with positive predictive value of 86.36%. There was positive correlation observed between LVEIO and VC width (r = 0.591), RV (r = 0.410), and EROA (r = 0.778) (all p < 0.001) in the Pearson correlation test. The specificity of LVEIO remained consistent in diagnosing severe MR in patients with rheumatic etiology., Conclusion: LVEIO is a simple yet specific Doppler echocardiographic parameter for estimation of severity of MR including that of rheumatic etiology., (Copyright © 2018 Cardiological Society of India. Published by Elsevier B.V. All rights reserved.)

Background: There is a dearth of data regarding the appropriateness of elective percutaneous coronary intervention (PCI) in a limited-resource country such as India. In an attempt to rationalise the use of PCI, Appropriate Use Criteria (AUC) were developed for cardiovascular care in the USA. In the Indian context, considering the high prevalence of coronary artery disease, the dramatic rise in the number of revascularization procedures and an increasing role of government/private reimbursements, application of AUC could potentially guide policy to optimize the utilization of resources and the benefit-risk ratio for individual patients., Objectives: The study sought to determine the overall and year-wise trends in the appropriateness of elective PCI using the AUC and also understand the impact of the government health insurance scheme (GHIS)., Material and Methods: The inpatient records of all patients undergoing elective PCI, at a single large tertiary care centre in Western India, from January 2009 to December 2014 were retrospectively analysed (n=972, 759 males, 213 females) by a neutral observer. The AUC scores and subsequent ranking were calculated using the dedicated web-based software and each PCIwas ranked as either 'appropriate', 'uncertain' or 'inappropriate'. Elective PCI performed within a month after the index acute coronary syndrome (ACS) was considered as 'ACS' while applying the AUC. All other indications were considered as 'non-ACS'. Nearly 95% of elective PCI performed after July 2012 were covered under theGHIS and therefore the period January 2009-June 2012 was compared with the July 2012- December 2014 to assess the impact of this scheme., Results: A total of 894 elective PCI (379 and 515 PCI in the ACS setting and non-ACS setting respectively) performed on 857 patients were analysed. The elective PCI performed in the pre-GHIS and GHIS period were 458 and 436 respectively. As per AUC, 352 (39.6 ± 4.4 %) of the overall elective PCI were ranked as 'appropriate', while 487 (55.3 ± 4.1 %) cases as 'uncertain' and 55 (5.1 ± 0.6 %) cases as 'inappropriate'. An overall year-wise temporal trend in the proportion of cases in any of the AUC rankings did not show any significant trends(p > 0.05). However, 80.4 ± 7.3 % of elective PCI in the ACS setting were categorised as 'appropriate' and 82.6 ± 6.9 % of elective PCI in non-ACS setting were ranked as 'uncertain'. With state-wide implementation of the GHIS, the total number of elective PCI increased by 50% (436 in the 3½ year pre-GHIS study period as against 458 in the 2½ year GHIS study period). The introduction of GHIS led to a marginal increase (p > 0.05) in the average annual number of elective PCI in non-ACS setting as opposed to a 120% rise in the number of elective PCI done in the ACS setting (p < 0.001) and the delay in performing PCI after coronary angiogram reduced from 55.8 ± 43.6 days to 33 ± 22.9 days (p < 0.01). Also, the ratio of men: women undergoing elective PCI rationalised from 5.4:1 to 2.7:1 (p < 0.001). With the introduction of the GHIS, the share of 'inappropriate' elective PCI in the ACS setting increased from 1.34 % to 4.81 % (p =0.065). However, there was also a fall in 'appropriate' elective PCI in the non-ACS setting from 15.0 ± 3.2% to 7 ± 1.6% (p < 0.001)., Conclusion: On applying the 2012 updated AUC, about 5 % of overall elective PCI were deemed as 'inappropriate'. About four in every five elective PCI in the non-ACS setting were of 'uncertain' appropriateness. The implementation of the GHIS not only significantly reduced the gender bias and delay in seeking interventional coronary care but also led to a significant rise in the proportion of PCI performed in the ACS setting. However, there was also a rise in 'inappropriate' PCI in the ACS setting and a significant fall in 'appropriate' PCI in the non-ACS setting after introduction of the GHIS.., (Copyright © 2016. Published by Elsevier B.V.)

This paper describes the development, implementation, and students' perceptions of a new trilayer approach of teaching (TLAT). The TLAT model involved blending lecture, in-class group activities, and out-of-class assignments on selected content areas and was implemented initially in a first-year integrated pharmacy course. Course contents were either delivered by traditional lectures or by the TLAT. A survey instrument was distributed by SurveyMonkey to determine students' perceptions of the TLAT model. Descriptive statistics were used for data analysis. Students' performance in a total of 225 examination and quiz questions was analyzed to evaluate whether the TLAT model improved students' learning. Students' ( n = 98) performance scores for TLAT-based and lecture-based questions were 83.3 ± 10.2 and 79.5 ± 14.0, respectively ( P < 0.05). Ninety-three percent of students believed that in-class group activities enhanced conceptual understanding of course materials, helped them take responsibility of their own learning, and enhanced their overall learning experiences. More than 80% of respondents felt that solving cases and developing concept maps helped them sharpen creative and critical thinking skills. In addition, 90% of the respondents indicated that the homework throughout the semester helped them stay up to date and focused with the progress of the course. The use of the TLAT model led to an improvement in student learning of complex concepts. Moreover, the results suggest that this model improves students' self-reliance and attitudes toward learning. Our findings should serve as an impetus for inclusion of diverse active learning strategies in pharmacy education., (Copyright © 2017 the American Physiological Society.)

Background: Percutaneous balloon pulmonary valvuloplasty is the procedure of choice for uncomplicated severe or symptomatic pulmonary stenosis. The present study describes our experience in balloon pulmonary valvuloplasty using the Inoue balloon catheter in adolescent and adult patients., Aims: To assess the immediate and mid-term outcomes of percutaneous balloon valvuloplasty with Inoue balloon catheter in adolescent and adult patients., Methods and Results: Between June 2010 and July 2015, we performed percutaneous balloon pulmonary valvuloplasty with Inoue balloon catheter in 32 patients (59.37% females) aged 8 to 54 years (mean 23.6±11.5). Following the procedure, the mean right ventricular systolic pressure and the pulmonary valvular peak-to-peak systolic gradient decreased from (121.6±42.4 to 61.19±24.5mmHg, p=0.001) and (100.9±43.3 to 36.4±22.5mmHg, p=0.001), respectively. Twenty patients (Group A) showed immediate optimal results with post-procedure peak systolic gradient <36mmHg while 12 patients (Group B) had suboptimal results. An increase in pulmonary regurgitation by one grade was detected in 17 patients (53.2%). Twenty-three patients available for follow-up (mean duration, 2.75 years [range 0.25-5 years]) had a mean residual peak gradient of 23.6±2.51mmHg on Doppler echocardiography with attenuation of reactive RVOT stenosis in all Group B patients. There was no further increase in grade of pulmonary regurgitation or restenosis on mid-term follow-up., Conclusion: Percutaneous Inoue balloon technique is an attractive alternative with excellent mid-term results for adolescents and adults with isolated pulmonary stenosis., (Copyright © 2016. Published by Elsevier B.V.)

Estrogen deprivation has a profound effect on the female brain. One of the most obvious examples of this condition is hot flushes. Although estrogens relieve these typical climacteric symptoms, many women do not want to take them owing to unwanted side-effects impacting, for example, the uterus, breast and blood. Therefore, there is a need for developing safer estrogen therapies. We show here that treatment with 10β,17β-dihydroxyestra-1,4-dien-3-one (DHED), a novel brain-targeting bioprecursor prodrug of the main human estrogen, 17β-estradiol, alleviates hot flushes in rat models of thermoregulatory dysfunction of the brain. Oral administration of DHED elicits a significant reduction of tail skin temperature (TST) rise representing hot flushes in the morphine-dependent ovariectomized rat model and results in the restoration of estrogen deprivation-induced loss of diurnal rhythm in TST. These beneficial effects occur without detrimental peripheral hormonal exposure; thus, the treatment avoids potentially harmful stimulation of estrogen-sensitive peripheral organs, including the uterus and the anterior pituitary, or the proliferation of MCF-7a breast cancer cell xenografts. Our promising preclinical assessments warrant further considerations of DHED for the development of a brain-selective 17β-estradiol therapy to relieve hot flushes without undesirable peripheral side-effects.

Obesity is a risk factor for breast cancer progression. Breast cancer patients who are overweight or obese or have excess abdominal fat have an increased risk of local or distant recurrence and cancer-related death. Hormone depletion therapies can also cause weight gain, exacerbating the risk for these patients. To understand the effect of obesity on hormone-dependent human breast cancer tumors, we fed ovariectomized athymic nude mice a diet containing 45% kcal fat and 17% kcal sucrose (high fat sucrose diet (HFSD)), 10% kcal fat (low fat diet (LFD)), or a standard chow diet (chow). The mice fed the HFSD developed metabolic abnormalities consistent with the development of obesity such as weight gain, high fasting blood glucose, and impaired glucose tolerance. These mice also developed hyperinsulinemia and insulin resistance. The obese mice also had a higher tumor growth rate compared to the lean mice. Furthermore, the obese mice showed a significantly reduced responsiveness to letrozole. To understand the role of obesity in this reduced responsiveness, we examined the effect of insulin on the growth of MCF-7Ca cells in response to estrogen or letrozole. The presence of insulin rendered MCF-7Ca cells less responsive to estrogen and letrozole. Exogenous insulin treatment of MCF-7Ca cells also resulted in increased p-Akt as well as ligand-independent phosphorylation of ERα. These findings suggest that diet-induced obesity may result in reduced responsiveness of tumors to letrozole due to the development of hyperinsulinemia. We conclude that obesity influences the response and resistance of breast cancer tumors to aromatase inhibitor treatment., (© 2015 Society for Endocrinology.)

Mortality following breast cancer diagnosis is mainly due to the development of distant metastasis. To escape from the primary site, tumor cells undergo the epithelial-to-mesenchymal transition (EMT), which helps them acquire a more motile and invasive phenotype. In our previous study, we showed that class I selective HDAC inhibitor entinostat reverses the EMT phenotype through reversal of epigenetic repression of E-cadherin. Recent evidence suggests that a subset of cells within a breast tumor may drive the metastatic outgrowth following escape from the primary site. These cells, termed tumor-initiating cells (TIC), represent a great threat to overall prognosis. They are critical in terms of drug resistance and tumor initiation at metastatic sites. Acquisition of EMT traits has also been shown to impart TIC phenotype to the cells, making EMT a "dual-threat" for prognosis. In the current study, we show that entinostat treatment can reduce the percentage of TIC cells from triple-negative breast cancer (TNBC) cells. Entinostat treatment was able to reduce the CD44(high)/CD24(low) cell population, ALDH-1 activity, as well as protein and mRNA expression of known TIC markers such as Bmi-1, Nanog, and Oct-4. Next, we inoculated MDA-MB-231 cells transfected with firefly luciferase (231/Luc) in mammary fat pad of NSG mice. The mice were then treated with entinostat (2.5 mg/kg/d), and tumor development and formation of metastasis were assessed by bioluminescence imaging. Treatment with entinostat significantly reduced tumor formation at the primary site as well as lung metastasis. As such, entinostat may help prevent development of distant metastasis., (©2015 American Association for Cancer Research.)

Many neurological and psychiatric maladies originate from the deprivation of the human brain from estrogens. However, current hormone therapies cannot be used safely to treat these conditions commonly associated with menopause because of detrimental side effects in the periphery. The latter also prevents the use of the hormone for neuroprotection. We show that a small-molecule bioprecursor prodrug, 10β,17β-dihydroxyestra-1,4-dien-3-one (DHED), converts to 17β-estradiol in the brain after systemic administration but remains inert in the rest of the body. The localized and rapid formation of estrogen from the prodrug was revealed by a series of in vivo bioanalytical assays and through in vivo imaging in rodents. DHED treatment efficiently alleviated symptoms that originated from brain estrogen deficiency in animal models of surgical menopause and provided neuroprotection in a rat stroke model. Concomitantly, we determined that 17β-estradiol formed in the brain from DHED elicited changes in gene expression and neuronal morphology identical to those obtained after direct 17β-estradiol treatment. Together, complementary functional and mechanistic data show that our approach is highly relevant therapeutically, because administration of the prodrug selectively produces estrogen in the brain independently from the route of administration and treatment regimen. Therefore, peripheral responses associated with the use of systemic estrogens, such as stimulation of the uterus and estrogen-responsive tumor growth, were absent. Collectively, our brain-selective prodrug approach may safely provide estrogen neuroprotection and medicate neurological and psychiatric symptoms developing from estrogen deficiency, particularly those encountered after surgical menopause, without the adverse side effects of current hormone therapies., (Copyright © 2015, American Association for the Advancement of Science.)

Clinically, there are two distinct types of aromatase inhibitor (AI) resistance, namely acquired and innate resistance. Because the underlying mechanisms of these two types of resistance may not be mutually exclusive, strategies to tackle these resistances may not be effective when used interchangeably. Activation of growth factor receptor pathways is the hallmark of acquired AI resistance. These pathways can be targeted either at the cell surface receptor level or their downstream signaling cascades. Currently, everolimus in combination with exemestane represents a new standard of care for patients progressing on non-steroidal AIs. HDAC inhibitors have also shown promising results For innate resistance, the combination of fulvestrant and AI in the front line setting represents a new treatment option, particularly for patients who present with de novo metastatic disease. A Phase III trial is currently ongoing to evaluate the benefit of CDK 4/6 inhibitor, palbociclib, in the first line setting in combination with AI.

Most breast cancer (BC) patients have tumors that express hormone receptors (HRs). Although endocrine therapy, such as aromatase inhibitors, is very effective, most patients with metastatic HR-positive (HR(+)) BC become resistant to endocrine therapy at some point in their treatment and subsequently require chemotherapy. The PI3K/mTOR pathway is often upregulated in endocrine-resistant BC patients and, therefore, has been one of the targets for development of new agents. Recently, a Phase III trial (BOLERO-2) in aromatase inhibitor-resistant BC patients showed a significant improvement in time to progression with the combination of everolimus and exemestane compared with exemestane alone, confirming the importance of the PI3K/mTOR pathway in endocrine-resistant BC. Side effects from mTOR inhibitors are manageable, but early detection and proactive management are required to ensure patients' safety, compliance and continuity of treatment. Thus, mTOR inhibitors offer a new hope and promise for patients with HR(+) BC.

Introduction: Although aromatase inhibitors (AIs; for example, letrozole) are highly effective in treating estrogen receptor positive (ER+) breast cancer, a significant percentage of patients either do not respond to AIs or become resistant to them. Previous studies suggest that acquired resistance to AIs involves a switch from dependence on ER signaling to dependence on growth factor-mediated pathways, such as human epidermal growth factor receptor-2 (HER2). However, the role of HER2, and the identity of other relevant factors that may be used as biomarkers or therapeutic targets remain unknown. This study investigated the potential role of transcription factor hypoxia inducible factor 1 (HIF-1) in acquired AI resistance, and its regulation by HER2., Methods: In vitro studies using AI (letrozole or exemestane)-resistant and AI-sensitive cells were conducted to investigate the regulation and role of HIF-1 in AI resistance. Western blot and RT-PCR analyses were conducted to compare protein and mRNA expression, respectively, of ERα, HER2, and HIF-1α (inducible HIF-1 subunit) in AI-resistant versus AI-sensitive cells. Similar expression analyses were also done, along with chromatin immunoprecipitation (ChIP), to identify previously known HIF-1 target genes, such as breast cancer resistance protein (BCRP), that may also play a role in AI resistance. Letrozole-resistant cells were treated with inhibitors to HER2, kinase pathways, and ERα to elucidate the regulation of HIF-1 and BCRP. Lastly, cells were treated with inhibitors or inducers of HIF-1α to determine its importance., Results: Basal HIF-1α protein and BCRP mRNA and protein are higher in AI-resistant and HER2-transfected cells than in AI-sensitive, HER2- parental cells under nonhypoxic conditions. HIF-1α expression in AI-resistant cells is likely regulated by HER2 activated-phosphatidylinositide-3-kinase/Akt-protein kinase B/mammalian target of rapamycin (PI3K/Akt/mTOR) pathway, as its expression was inhibited by HER2 inhibitors and kinase pathway inhibitors. Inhibition or upregulation of HIF-1α affects breast cancer cell expression of BCRP; AI responsiveness; and expression of cancer stem cell characteristics, partially through BCRP., Conclusions: One of the mechanisms of AI resistance may be through regulation of nonhypoxic HIF-1 target genes, such as BCRP, implicated in chemoresistance. Thus, HIF-1 should be explored further for its potential as a biomarker of and therapeutic target.

Loss of ERα in breast cancer correlates with poor prognosis, increased recurrence rates, and higher incidence of metastasis. Epigenetic silencing of E-cadherin (loss of which is associated with more invasive phenotype) is observed in metastatic cell lines and invasive breast cancers. Here, we are showing that entinostat (ENT) can reverse epithelial to mesenchymal transition (EMT), which is considered to be a first step in the process of metastases formation. Triple-negative breast cancer cells such as MDA-MB-231 and Hs578T show a basal phenotype characterized by loss of E-cadherin expression and higher expression of mesenchymal markers such as N-cadherin and vimentin along with transcriptional repressors such as twist and snail. When MDA-MB-231 and Hs578T cells or tumors were treated with ENT, E-cadherin transcription was increased along with reduction in N-cadherin mRNA expression. Chromatin immunoprecipitation assay showed that treatment of MDA-MB-231 and Hs578T cells increased the activation of E-cadherin promoter by reducing the association of twist and snail with the E-cadherin (CDH1) promoter and downregulated both the snail and twist. ENT also inhibited cell migration in vitro. In addition, phosphorylation of vimentin was increased, as well as remodeling of vimentin filaments. ENT treatment also reduced formation of tubulin-based microtentacles, which help floating cells attach to other surfaces. These findings suggest that ENT can reverse EMT and may reduce the formation of metastasis.

Aromatase inhibitors (AIs) are an effective therapy in treating estrogen receptor-positive breast cancer. Nonetheless, a significant percentage of patients either do not respond or become resistant to AIs. Decreased dependence on ER-signaling and increased dependence on growth factor receptor signaling pathways, particularly human epidermal growth factor receptor 2 (EGFR2/HER2), have been implicated in AI resistance. However, the role of growth factor signaling remains unclear. This current study investigates the possibility that signaling either through HER2 alone or through interplay between epidermal growth factor receptor 1 (EGFR/HER1) and HER2 mediates AI resistance by increasing the tumor initiating cell (TIC) subpopulation in AI-resistant cells via regulation of stem cell markers, such as breast cancer resistance protein (BCRP). TICs and BCRP are both known to be involved in drug resistance. Results from in vitro analyses of AI-resistant versus AI-sensitive cells and HER2-versus HER2+ cells, as well as from in vivo xenograft tumors, indicate that (1) AI-resistant cells overexpress both HER2 and BCRP and exhibit increased TIC characteristics compared to AI-sensitive cells; (2) inhibition of HER2 and/or BCRP decrease TIC characteristics in letrozole-resistant cells; and (3) HER2 and its dimerization partner EGFR/HER1 are involved in the regulation of BCRP. Overall, these results suggest that reducing or eliminating the TIC subpopulation with agents that target BCRP, HER2, EGFR/HER1, and/or their downstream kinase pathways could be effective in preventing and/or treating acquired AI resistance.

Trastuzumab (TRZ) is a humanized monoclonal antibody that targets the extracellular domain of the human epidermal growth factor receptor type 2 (Her2). Semitelechelic (ST) poly[N-(2-hydroxypropyl)methacrylamide]-TRZ conjugates are successfully synthesized and evaluated as a potential drug delivery system that actively targets Her2-overexpressing cancer cells. The ST backbone shows favorable characteristics when conjugated to TRZ. The conjugate exhibits comparable and prolonged anticancer activity when compared to free TRZ in Her2 overexpressing breast cancer cell lines., (Copyright © 2012 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.)