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Hemophagocytic lymphohistiocytosis (HLH) is a systemic inflammatory syndrome of inappropriate immune cell activation which can be rapidly fatal if not recognized and treated. Here we discuss a case of a 26-year-old male with HIV on antiretroviral therapy who presented with sepsis secondary to soft tissue infection and ultimately progressed to multi-organ dysfunction despite broad-spectrum antibiotics and an improvement in soft tissue infection. Continued fever and pancytopenia without an explanation found during additional infectious and rheumatologic testing eventually led to bone marrow biopsy and laboratory criteria consistent with HLH. Although pancytopenia is a common finding in patients with HIV, here it marked a more rapidly progressing and fatal disease, HLH. Here we highlight the difficulty in identifying and diagnosing this rare condition, including a discussion of the characteristics, outcomes, underlying etiologies, and treatment of HLH in patients with HIV.

On the basis of technology acceptance model (TAM) and decomposed theory of planned behaviour (DTPB), the present study is aimed at studying customer satisfaction in online banking in India. Data collected from 750 respondents from both public and private sector banks were used to test the mediated model using the hierarchical regression. The results supported that perceived usefulness acted as a partial mediator in the relationship between various independent variables, such as awareness of online banking services, security, knowledge of Internet, self-efficacy, intention to adopt, trust, easy to use, and dependent variable, that is, customer satisfaction. Implications for research and practising managers are discussed.

Identifying the mechanisms mediating cisplatin response is essential for improving patient response. Previous research has identified base excision repair (BER) and mismatch repair (MMR) activity in sensitizing cells to cisplatin. Cisplatin forms DNA adducts including interstrand cross-links (ICLs) that distort the DNA helix, forcing adjacent cytosines to become extrahelical. These extrahelical cytosines provide a substrate for cytosine deaminases. Herein, we show that APOBEC3 (A3) enzymes are capable of deaminating the extrahelical cytosines to uracils and sensitizing breast cancer cells to cisplatin. Knockdown of A3s results in resistance to cisplatin and induction of A3 expression in cells with low A3 expression increases sensitivity to cisplatin. We show that the actions of A3s are epistatic with BER and MMR. We propose that A3-induced cytosine deamination to uracil at cisplatin ICLs results in repair of uracils by BER, which blocks ICL DNA repair and enhances cisplatin efficacy and improves breast cancer outcomes.

Introduction Changes in medical education and health care delivery have limited the ability of fourth-year medical students to perform the role of an intern prior to graduating from medical school. To address this issue, many schools have instituted residency preparation courses (sometimes referred to as boot camps) particularly for students entering surgical fields. Courses for students entering nonprocedural fields are less common and most assess increases in self-reported confidence without providing objective evidence of a gain in knowledge or skills improvement. Materials and Methods We used a Plan, Do, Study, Act (PDSA) model to develop and pilot cycle 1 of a nonprocedural internship preparation elective in 2019. Feedback was used to refine the course and map sessions to core competencies outlined by the Accreditation Council of Graduate Medical Education (ACGME) for PDSA cycle 2. The curriculum was adapted for remote synchronous delivery due to the coronavirus pandemic in spring 2020 using a combination of didactic lectures containing embedded polls and case-based role play responses using a chat box. Students completed anonymous surveys assessing self-perceived levels of confidence, as well as an objective comprehensive assessment after course completion. Results A total of 89 students participated in the course. Pre-session confidence was lowest for transfusion medicine, handling pages from nursing while on call, and knowledge of the role of a chief resident. A statistically significant increase in median scores for self-reported knowledge or confidence was seen in all sessions. The percentage of students reporting that they were either confident or extremely confident also increased significantly after each session (p

Markers of inflammation, including crown-like structures of the breast (CLS-B) and infiltrating lymphocytes (IL), have been identified in breast tissue and associated with increased risk of breast cancer (BrCa), however most of this work has been performed in primarily non-Hispanic white women. Here, we examined whether CLS-B and IL are associated with invasive BrCa in African American (AA) women. We assessed breast biopsies from three 5-year age-matched groups: BrCa-free AA women (50 Volunteer) from the Komen Normal Tissue Bank (KTB) and AA women with a clinically-indicated biopsy diagnosed with benign breast disease (BBD) from our Detroit cohort who developed BrCa (55 BBD-cancer) or did not develop BrCa (47 BBD only, year of biopsy matched to BBD-cancer). Mean adipocyte diameter and total adipose area were estimated from digital images using the Adiposoft plugin from ImageJ. Associations between CLS-B, IL, and BrCa among KTB and Detroit biopsies were assessed using multivariable multinomial and conditional logistic regression models. Among all biopsies, Volunteer and BBD only biopsies did not harbor CLS-B or IL at significantly different rates after adjusting for logarithm of adipocyte area, adipocyte diameter, and BMI. Among clinically-indicated BBD biopsies, BBD-cancer biopsies were more likely to exhibit CLS-B (odds ratio (OR) = 3.36, 95% Confidence Interval (CI): 1.33–8.48) or IL (OR = 4.95, 95% CI 1.76–13.9) than BBD only biopsies after adjusting for total adipocyte area, adipocyte diameter, proliferative disease, and BMI. CLS-B and IL may serve as histological markers of BrCa risk in benign breast biopsies from AA women.

Background Remote monitoring is associated with improved patient outcomes; however, adoption and adherence to remote monitoring via home-based consoles remains suboptimal. BlueSync technology in new generation pacemaker and CRT-P models enables the implanted device to communicate directly with patient-owned, Bluetooth-equipped smartphones/tablets and an app (MyCareLink Heart). The app can automatically retrieve information from the cardiac device and transmit the data to the remote network, eliminating the need for traditional remote monitoring consoles. Objectives To characterize the communication process between implanted pacemakers and smart device remote monitoring apps by assessing the success of prescheduled remote transmissions in the first month of follow-up. Additionally, to assess the feedback of both patients and clinicians about the process of device pairing. Methods Enrollment in the BlueSync Field Evaluation began in April 2018 and was completed November 2018. Follow-up is ongoing. Prior to enrollment in the evaluation, patients completed the device pairing process with the app using their own compatible smartphone or tablet. Patient and clinician questionnaires were completed at the time of the device pairing process. After enrollment, successful completion of scheduled transmissions occurring in the first month were analyzed. Results Preliminary data includes 241 enrolled patients with mean age of 64.7±15.5 yrs (min 20, max 90 yrs), who completed device pairing between their implanted device and their smart device app. Of enrolled patients, 79% felt that the device paring was easy to do, 85% were satisfied with the amount of time it took to complete it, and 93% felt that they would be comfortable using the app. Clinicians reported that 67% of the device pairings took less than 20 minutes and 78% felt patients would be able to use the app independently. At the time of analysis 174 patients had at least one scheduled transmission within the first month, and collectively had a total of 322 scheduled transmissions. Out of these, 309 (96%, 95% CI: 93%-98%) were successfully completed. MyCareLink Heart App Conclusions Initial experience with the world's first app based remote monitoring system for Bluetooth enabled pacemakers demonstrated success to scheduled transmissions in the first month across a wide range of patient ages. Patients and clinicians reported high satisfaction with this novel technology. Acknowledgement/Funding Medtronic PLC

Chronic graft-versus-host disease (cGVHD) remains the leading cause of non-relapse mortality after allogeneic stem cell transplantation (SCT) for haematological malignancies. Manifestations of GVHD in the central nervous system (CNS) present as neurocognitive dysfunction in a significant proportion of patients. Neuroinflammation in the cortex of mice and humans in acute GVHD is dependent on host resident microglia-derived TNF. However, the mechanisms driving cGVHD in the CNS are yet to be elucidated. Here, our studies of murine cGVHD revealed a hippocampal-dependent spatial learning and memory deficit associated with inflammation and persistent IFN-γ upregulation. Hippocampal RNA sequencing identified perturbations to structural and functional synapse-related gene expression, in the context of upregulated genes associated with antigen presentation and IFN-γ responses. Brain T cell infiltration was initially dominated by CD8 T cells with an eventual expansion in CD4 T cells, in parallel with a marked infiltration of MHC Class II-expressing bone marrow-derived macrophages (BMDM). After day 70, BMDM constituted 50% of the brain macrophage pool and exhibited a transcriptional signature distinct from host resident microglia. Transfer of MHC class II–deficient BM grafts resulted in attenuated neuroinflammation, implicating donor BMDM as critical mediators of CNS cGVHD. Our identification of the hippocampus as a cGVHD target, and disease mediators distinct from those in the acute phase, highlights the necessity to pursue alternative therapeutic targets for late-stage neurological manifestations post-SCT.

Human papillomavirus (HPV) is associated with the development of head and neck squamous cell carcinomas (HNSC). Cisplatin is used to treat HNSC and induces DNA adducts including interstrand crosslinks (ICLs). Previous reports have shown that HPV positive HNSC patients respond better to cisplatin therapy. Our previous reports highlight that loss of base excision repair (BER) and mismatch repair (MMR) results in cisplatin resistance. Of importance, uracil DNA glycosylase (UNG) is required to initiate the BER response to cisplatin treatment and maintain drug sensitivity. These previous results highlight that specific cytidine deaminases could play an important role in the cisplatin response by activating the BER pathway to mediate drug sensitivity. The APOBEC3 (A3) family of cytidine deaminases are enzymes that restrict HPV as part of the immune defense to viral infection. In this study, the Cancer Genome Atlas (TCGA) HNSC data were used to assess the association between the expression of the seven proteins in the A3 cytidine deaminase family, HPV-status and survival outcomes. Higher A3 G expression in HPV-positive tumors corresponds with better overall survival (OS) (HR 0.33, 95 % CI 0.11-0.93, p = 0.04). FaDu and Scc-25 HNSC cell lines were used to assess alterations in A3, BER and MMR expression in response to cisplatin. We demonstrate that A3, Polβ, and MSH6 knockdown in HNSC cells results in resistance to cisplatin and carboplatin as well as an increase in the rate of ICL removal in FaDu and Scc-25 HNSC cells. Our results suggest that A3s activate BER in HNSC, mediate repair of cisplatin ICLs and thereby, sensitize cells to cisplatin which likely contributes to the improved patient responses observed in HPV infected patients.

Background: Diabetes is one of the largest global health emergencies of the 21st century. As per International Federation of Diabetes some 425 million people worldwide are estimated to have diabetes. The prevalence is higher in urban versus rural (10.2% vs 6.9%). India had 72.9 million people living with diabetes of which, 57.9% remained undiagnosed as per the 2017 data. The objectives of the present study were to identify subjects who at risk of developing Diabetes by using Indian diabetes risk score (IDRS) in the Urban field practice area of Rajarajeswari Medical College and Hospital (RRMCH).Methods: A cross sectional study was conducted using a Standard questionnaire of IDRS on 150 individuals aged ≥20 years residing in the Urban field practice area of RRMCH. The subjects with score or =60 were categorized as having low risk, moderate risk and high risk for developing diabetes type-2 respectively.Results: Out of total 150 participants, 36 (24%) were in high-risk category (IDRS≥60), the majority of participants 61 (41%) were in the moderate-risk category (IDRS 30–50) and 53 (35%) participants were found to be at low-risk (

Background Fibroadenomas are common benign breast lesions, and studies of European American women indicate a persistent, increased risk of breast cancer after diagnosing a fibroadenoma on biopsy. This association has not been independently assessed in African American women, despite reports that these women are more likely to present with fibroadenomas. Methods The study cohort included 3853 African American women with a breast biopsy completed between 1997 and 2010 in metropolitan Detroit. Biopsies were microscopically reviewed for benign breast lesions, including fibroadenoma, proliferative disease, and atypia. Risk of breast cancer within the cohort was estimated using relative risk ratios and 95% CIs calculated using multivariable log-binomial regression. Relative risk of breast cancer in this cohort compared with African American women in the broader metropolitan Detroit population was estimated using standardized incidence ratios (SIRs). Results Fibroadenomas occurred more frequently in biopsies of younger women, and other types of benign breast lesions were less likely to occur when a fibroadenoma was present (p = 0.008 for lobular hyperplasia; all other p values

Exposure to lead (Pb) during childhood can result in learning disabilities and behavioral problems. Although described in animal models, whether Pb exposure also alters neuronal differentiation in the developing brains of exposed children is unknown. Here, we investigated the effects of physiologically relevant concentrations of Pb (from 0.4 to 1.9μM) on the capacity of human embryonic stem cells (hESCs) to progress to a neuronal fate. We found that neither acute nor chronic exposure to Pb prevented hESCs from generating neural progenitor cells (NPCs). NPCs derived from hESCs chronically exposed to 1.9μM Pb throughout the neural differentiation process generated 2.5 times more TUJ1-positive neurons than those derived from control hESCs. Pb exposure of hESCs during the stage of neural rosette formation resulted in a significant decrease in the expression levels of the neural marker genes PAX6 and MSI1. Furthermore, the resulting NPCs differentiated into neurons with shorter neurites and less branching than control neurons, as assessed by Sholl analysis. DNA methylation studies of control, acutely treated hESCs and NPCs derived from chronically exposed hESCs using the Illumina HumanMethylation450 BeadChip demonstrated that Pb exposure induced changes in the methylation status of genes involved in neurogenetic signaling pathways. In summary, our study shows that exposure to Pb subtly alters the neuronal differentiation of exposed hESCs and that these changes could be partly mediated by modifications in the DNA methylation status of genes crucial to brain development.

Background: This phase I, open-label, first-in-human study determined dose-limiting toxicities (DLTs) and maximum tolerated dose (MTD) of PD 0332991, an oral cyclin-dependent kinase 4/6 inhibitor with potent anti-proliferative activity in vitro/vivo. Methods: A total of 33 patients with retinoblastoma protein-positive advanced solid tumours or non-Hodgkin's lymphoma refractory to standard therapy or for which no therapy was available received PD 0332991 once daily (QD) for 14 days followed by 7 days off treatment (21-day cycles; Schedule 2/1). Results: Six patients had DLTs (18% four receiving 200 mg QD; two receiving 225 mg QD); the MTD was 200 mg QD. Treatment-related, non-haematological adverse events occurred in 29 patients (88%) during cycle 1 and 27 patients (82%) thereafter. Adverse events were generally mild–moderate. Of 31 evaluable patients, one with testicular cancer achieved a partial response; nine had stable disease (⩾10 cycles in three cases). PD 0332991 was slowly absorbed (mean Tmax 4.2 h) and eliminated (mean half-life 26.7 h). Volume of distribution was large (mean 3241 l) with dose-proportional exposure. Using a maximum effective concentration model, neutropenia was proportional to exposure. Conclusion: PD 0332991 was generally well tolerated, with DLTs related mainly to myelosuppression. The MTD, 200 mg QD, is recommended for phase II study.

Introduction: Obesity is a risk factor for breast cancer, including the more aggressive triple-negative (TN) subtype, but the relevance of obesity to prognosis remains unclear. Unlike other subtypes, triple-negative breast cancer (TNBC) is not hormonally responsive and is characterized by a lack of estrogen receptor, progesterone receptor, and human epidermal growth factor receptor-2 expression. Thus, obesity-related development of TN tumors is unlikely to rely on the peripheral aromatization of androgens to estrogens in fat. Chronic, low-grade inflammation elicited by obesity could increase risk of TNBC. Here we sought to assess which mechanisms mediate obesity’s effect on normal tissue and TN tumors using a gene expression approach. Because African American women are more likely to be obese and twice as likely to develop TNBC compared to white women, understanding the mechanisms of obesity-related risk of TNBC is critical for this high-risk group. Methods: We performed whole-genome expression profiling on formalin-fixed, paraffin-embedded samples from 104 African American women with TNBC (59 tumor, 45 adjacent normal). Body mass index was obtained by medical record abstraction, and women with BMI at least 30 kg/m2 were classified as obese. Gene Ontology (GO) was used to identify biologic processes enriched in differentially expressed genes by obesity status in tumors and adjacent normal tissue (p-value Results: 28 (47%) TNBC tumor and 29 (64%) adjacent normal samples were from obese women. Among genes more highly expressed in tumors from obese compared to nonobese women, GO analysis revealed enrichment for proinflammatory processes involving regulation of immune system, activation of immune responses, leukocyte activation, and neutrophil activation (FDR-corrected p-value Conclusions: Obesity modifies the immune cell environment present not only in TN tumors but also in the surrounding normal tissue. Obesity promotes a more proinflammatory setting within TN tumors, and in contrast, an anti-inflammatory setting in normal tissue adjacent. These findings may have important implications for understanding how obesity influences TNBC risk and prognosis, particularly among African American women who are at high risk for both. Citation Format: Asra N. Shaik, Julie L. Boerner, Michele L. Cote, Gregory Dyson, Rouba Ali-Fehmi, Sudeshna Bandyopadhyay, Kristen S. Purrington. Immune cell infiltrates differ by obesity in tumor and adjacent normal breast tissue in African American women with triple-negative breast cancer [abstract]. In: Proceedings of the AACR Special Conference: Advances in Breast Cancer Research; 2017 Oct 7-10; Hollywood, CA. Philadelphia (PA): AACR; Mol Cancer Res 2018;16(8_Suppl):Abstract nr B01.

Introduction: Obesity is associated with an increased breast cancer (BrCa) incidence. Adipose inflammation, marked by crown-like lesions in the breast (CLS-B) or dying adipocytes surrounded by macrophages, has been previously associated with BMI, aromatase expression, and systemic inflammation - all BrCa risk correlates. However, CLS-B has not been well described in normal or pre-malignant tissue, nor ever described in African American women (AAW). Here we examined whether CLS-B is associated with risk of benign breast disease (BBD) and BrCa in AAW, who suffer a higher incidence of breast cancer, poorer breast cancer outcomes, and a higher prevalence of obesity than women of other ethnicities. Methods: We assessed breast biopsies from three age-matched groups including 50 AAW with no history of BBD or BrCa from the Komen Normal Tissue Bank (KTB) and AAW with BBD from our Detroit cohort who developed cancer (55 BBD cases) or did not develop breast cancer (47 BBD controls). Slides were assessed by pathologists (KK, RAF) for CLS-B presence. Associations between tissue type and CLS-B presence among KTB and BBD samples were assessed using chi-square tests. Association between tissue types and CLS-B adjusting for BMI was assessed using the Mantel-Haenszel test. Results: The KTB, BBD controls and BBD cases groups were matched for age, consisted of approximately 15% CLS-B presence by study group and BMIKTBBBD controlsBBD casesN (%) with CLS-B presenceN=44N=44N=42BMI Conclusions: These findings suggest that CLS-B may serve as an important histological marker of BrCa risk in benign breast biopsies. Our study population exhibited higher rates of obesity than other BBD and CLS-B studies of European American women highlighting the need to include diverse populations in future studies examining BrCa risk. These findings have potential implications for modeling BrCa risk, particularly among AAW, for whom obesity is prevalent. Citation Format: Asra N. Shaik, Katrin Kiavash, Karri Stark, Julie L. Boerner, Julie J. Ruterbusch, Rouba Ali-Fehmi, Michele L. Cote. Adipose inflammation and the risk of benign and malignant breast disease in African American women [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr LB-337.

Cisplatin is a DNA damaging chemotherapeutic which forms interstrand crosslinks (ICL) and intrastrand adducts that induce replication fork collapse and lead to apoptosis. These adduct sites can be repaired through several repair pathways, the most important being nucleotide excision repair (NER). Cisplatin and carboplatin ICLs form a unique structure that forces cytosines flanking the adduct site to become extrahelical. Our lab has previously shown that base excision repair (BER) and mismatch repair (MMR) mediate sensitivity to cisplatin and carboplatin as a consequence of nonproductive processing of DNA flanking the ICL structure. The APOBEC3 (A3) protein family of cytidine deaminases have recently been implicated in cancer development and have potential to deaminate the extrahelical cytosines formed by cisplatin ICLs. Polβ knockdown MDA-MB-231 cells are resistant to cisplatin in vivo compared to wild-type cells (p Citation Format: Kayla L. Conner, Asra N. Shaik, Jordan White, Wen Lei, Michele L. Cote, Steve M. Patrick. APOBEC3 family of cytidine deaminases in sensitizing triple-negative breast cancer cells to cisplatin and carboplatin [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 3366.

Introduction: Atypical hyperplasia (also known as proliferative disease with atypia), while categorized as a benign finding, has been consistently associated with an increased risk of subsequent breast cancer that persists for decades after initial diagnosis. There are various other lesions that are classified as benign breast disease (BBD) that are routinely identified by pathologists that may also increase risk and be of use to inform breast cancer risk models. We sought to identify which BBD lesions were associated with increased risk of breast cancer in an African American (AA) cohort. Methods: Benign breast biopsies from 3,895 AA women diagnosed with BBD between 1997 and 2010 in metropolitan Detroit were reviewed for 12 benign features including columnar alterations, ductal ectasia, ductal hyperplasia, fibrosis, apocrine metaplasia, lobular hyperplasia, calcifications, cysts, intraductal papilloma, radial scar, sclerosing adenosis, and fibroadenomas. Women were followed for subsequent breast cancer using the Metropolitan Detroit Cancer Surveillance System, part of the Surveillance, Epidemiology, and End Results (SEER) cancer registry. Associations between BBD features and subsequent breast cancer were examined using chi-square tests. Features that had a significant chi-square test result were also combined into scores describing the overall number of BBD features identified, termed busy breast score. Multivariable log-binomial regression with backward selection based on BIC criteria was performed to assess risk ratio and 95% confidence intervals of breast cancer on 12 candidate features. Multivariable log-binomial regression was performed for busy breast score as well. All regression models were adjusted for age at biopsy and overall impression for presence of proliferative disease with or without atypia using non-proliferative disease as the reference. Models were checked for multicollinearity using a variable inflation factor (VIF). Results: Of the 3,895 AA women in the BBD cohort, 210 developed a subsequent breast cancer. The median age at biopsy among those without a subsequent cancer (controls) was 47 years of age, while cases were 53 years of age (p-value Conclusions: Columnar alterations confer increased risk of breast cancer beyond the risks associated with atypical hyperplasia, as does the presence of multiple types of BBD lesions in a single biopsy. These estimates may help improve the current risk assessment models for African American women and highlight the need for additional research regarding the utility of closer surveillance and potentially chemoprevention for reduction of breast cancer in these women. Citation Format: Michele L. Cote, Wei Chen, Julie J. Ruterbusch, Eman Abdulfatah, Visakha Pardeshi, Asra N. Shaik, Marcel T. Ghanim, MHD Fayez Daaboul, Daniel W. Visscher, Sudeshna Bandyopadhyay, Rouba Ali-Fehmi. Benign breast disease and subsequent breast cancer risk: The Detroit cohort. [abstract]. In: Proceedings of the AACR Special Conference: Improving Cancer Risk Prediction for Prevention and Early Detection; Nov 16-19, 2016; Orlando, FL. Philadelphia (PA): AACR; Cancer Epidemiol Biomarkers Prev 2017;26(5 Suppl):Abstract nr A25.

Introduction: The majority of the 1.6 million breast biopsies performed annually in the United States are benign; however, several breast cancer risk models consider a benign biopsy a factor that increases risk of subsequent breast cancer. Fibroadenomas (FA), benign tumors of epithelial and stromal tissue, occur frequently in premenopausal women and more frequently in African American (AA) women than European American (EA) women. A small increased risk of subsequent breast cancer due to FA has been reported in some studies of EA women. We sought to investigate whether the risk of this lesion differs for AA women. Methods: Benign breast biopsies from 3895 AA women diagnosed between 1997 and 2010 in metropolitan Detroit were reviewed for 12 benign features including FA, ductal ectasia, fibrosis, apocrine metaplasia, ductal hyperplasia, lobular hyperplasia, calcifications, cysts, intraductal papilloma, radial scar, sclerosing adenosis, and columnar alterations. These features were also used to categorize FA into simple and complex FA, where complex FA occurs when FA is accompanied by at least one of the following features: cysts, calcifications, apocrine metaplasia or intraductal papilloma. Women were followed for subsequent breast cancer using the Detroit Surveillance, Epidemiology, and End Results (SEER) cancer registry. Associations between FA and other benign lesions were examined using chi-square tests. Risk of breast cancer was estimated by relative risk ratios and 95% confidence intervals calculated using logistic regression. All models were adjusted for age at biopsy and additionally adjusted for presence of proliferative disease with or without atypia. Results: Of the 3895 AA women, 46.5% presented with FA on biopsy. FA occurred more frequently in biopsies of younger women (p-value < 0.001) and were less likely to include the other benign lesions assessed (all p-value < 0.001). Of the 210 identified breast cancers that developed in this cohort, 72 cancers developed in women with FA on biopsy. FA were associated with a reduction in risk of breast cancer after adjusting for age at biopsy (RR=0.64, 95% CI: 0.48, 0.86) compared to women without FA on biopsy. Reduction in risk was somewhat attenuated when analysis was adjusted for proliferative disease with or without atypia (RR = 0.67, 95%CI: 0.48, 0.936). Similar associations were seen with simple FA (RR =0.61, 95% CI: 0.35, 1.01) and complex FA (RR =0.70, 95% 0.35, 1.01) after adjustment for age at biopsy and proliferative disease with or without atypia. Conclusions: FA are negatively associated with other benign breast disease features. Risk of breast cancer may be reduced in women with FA compared to women with other types of benign lesions. These findings have important implications for modeling breast cancer risk particularly among AA women for whom FAs are common. Citation Format: Asra N. Shaik, Julie J. Ruterbusch, Eman Abdulfatah, Marcel T. Ghanim, MHD Fayez Daaboul, Visakha Pardeshi, Rouba Ali-Fehmi, Daniel W. Visscher, Sudeshna Bandyopadhyay, Michele L. Cote. Fibroadenomas on benign breast biopsy and subsequent breast cancer risk in an African American cohort. [abstract]. In: Proceedings of the AACR Special Conference: Improving Cancer Risk Prediction for Prevention and Early Detection; Nov 16-19, 2016; Orlando, FL. Philadelphia (PA): AACR; Cancer Epidemiol Biomarkers Prev 2017;26(5 Suppl):Abstract nr A16.

Alterations in pancreatic milieu to adapt to physiological shifts occurring in conditions of obesity and metabolic syndrome (MS) have been documented, though mechanisms leading to such a state have remained elusive so far. The data presented here tries to look at the gravity of metabolic insult during the early and prolonged phases of obesity/insulin resistance (IR) depicted in WNIN/Ob strain of rats—an obese euglycemic mutant rat model developed indigenously at our institute which is highly vulnerable for a variety of degenerative diseases. The present results in situ show the participation of several confounding factors in the pancreatic milieu that collectively coprecipitates for a state of profound inflammation in the pancreas (among Mutant compared to Lean/Control) which gets worsened with age. These include hypertrophy, macrophage infiltration (CD11b/TNF /IL6), apoptosis, -cell vacuolation, hyperinsulinemia (HI), and stress markers (RL-77/HSP104/TBARS) all of which correlated well with indices for obesity (2-3 fold), IR (1.5-3 fold), and HI (2-3 fold). Further, supportive data was also obtained from in vitro studies using islet cell cultures amongst phenotypes. Taken together, these results advocate that inflammation was the major precipitating factor to cause islet cell dysfunctions ( in situ and in vitro) in these Mutant rats compared to their Lean littermates and parental Control.

Nowadays, concerns about global climate change and rising prices of crude oil and natural gas make the need for clean energy from coal more important than ever. Gasification of coal is a major clean coal technology that will play a significant role in the coming decades, both for power generation and for the production of chemicals and synthetic fuels. Gasification is a technology in which coal is reacted with air, oxygen, steam, carbon dioxide, or a mixture of these gases to yield a gaseous product (called syngas) consisting of carbon monoxide, hydrogen, and some methane and carbon dioxide. After cleaning, syngas can be used either as raw material for the synthesis of liquid fuels and chemicals coal-to-liquids technologies, as a reductant in pyrometallurgical processes (e.g. direct reduction of iron), or as a source of energy for the generation of electric power (in integrated gasification combined cycle systems) or a combination of these products. This chapter provides an overview on the pyrolysis and gasification chemistry and the current status of coal gasification technologies. Keywords: clean coal technology; coal; gasification; pyrolysis; syngas

A probabilistic approach to characterize various fouling processes and their influence on maintenance strategies of heat exchangers is described. Some common fouling models are discussed and, in view of their performance indicators ( U U c ), a strategy for planned maintenance schedules is described. The effect of this strategy on overall costs of these repairable systems is outlined. Trade-offs (continued maintenance vs replacement of the equipment) are examined in terms of cost parameters. The influence of random occurrences of fouling is incorporated in the maintenance strategy.

Sperm whales (Physeter macrocephalus) occur frequently in stranding records worldwide. However, none have been reported along the Pakistani coastline to date. This paper documents the first reported stranding of a sperm whale on the Pakistani coast. Ultimately, this finding is important in the planning of Pakistan's Biodiversity Action Plan and its National Conservation Strategy for marine mammals.

3100 Background: Aberrant Notch signaling is implicated in tumor genesis. Gamma secretase plays a key role in Notch-dependent signaling. The reversible, noncompetitive, selective gamma secretase in...

4553 Background: Docetaxel (Doc) + prednisone is considered the standard of care in first-line treatment of patients (pts) with CRPC. However, response rates are low and response duration is short....

Background: PD 0332991 is a potent, oral, small molecule inhibitor of CDK 4/6 kinase. Preclinical studies identified that human luminal ER+ breast cancer cell lines were uniquely sensitive to G0/G1 arrest and growth inhibition by PD 0332991 and this appears to be related to an intact Rb pathway in this subtype (Finn, SABCS 2008, abstract 5064). These studies also identified the ability of PD 0332991 to act synergistically with anti-hormonal treatment in vitro and to restore sensitivity to hormonal treatment in models of acquired resistance. Based on these observations, a phase I/II randomized study of PD 0332991 in combination with letrozole versus letrozole alone as first-line treatment of metastatic ER+ breast cancer was launched.Methods: Post-menopausal women with ER+, HER2-negative breast cancer were eligible. Other eligibility criteria included Eastern Cooperative Oncology Group performance status of 0 or 1, no brain metastases, and adequate organ function. The phase I part of the study was conducted to assess the safety and tolerability of the combination including dose-limiting toxicities (DLTs). Enrollment in phase I is planned for up to 12 patients. The starting dose was PD 0332991 125 mg daily for 3 weeks followed by 1 week off (Schedule 3/1) and letrozole 2.5 mg daily. Cycle 1 consisted of PD 0332991 administered for 2 weeks alone followed by 1 week off. Subsequent cycles consisted of PD 0332991 on Schedule 3/1 and letrozole administered continuously. Pharmacokinetic samples were collected to assess the potential for a drug–drug interaction (DDI). Archival tumor tissue was required for biomarker evaluation. The tumor assessments were performed every 8 weeks.Results: Nine patients have currently been enrolled and treated; median duration of treatment was 3 months (range Citation Information: Cancer Res 2009;69(24 Suppl):Abstract nr 5069.

Summary: Elemental imaging provides detailed profiling of metal bioaccumulation, offering more precision than bulk analysis by targeting specific tissue areas. However, accurately identifying comparable tissue regions from elemental maps is challenging, requiring the integration of hematoxylin and eosin (H&E) slides for effective comparison. Facilitating the streamlined co-registration of Whole Slide Images (WSI) and elemental maps, TRACE enhances the analysis of tissue regions and elemental abundance in various pathological conditions. Through an interactive containerized web application, TRACE features real-time annotation editing, advanced statistical tools, and data export, supporting comprehensive spatial analysis. Notably, it allows for comparison of elemental abundances across annotated tissue structures and enables integration with other spatial data types through WSI co-registration., Availability and Implementation: Available on the following platforms- GitHub: jlevy44/trace&#95;app , PyPI: trace&#95;app , Docker: joshualevy44/trace&#95;app , Singularity: joshualevy44/trace&#95;app ., Contact: joshua.levy@cshs.org., Supplementary Information: Supplementary data are available.