tbuckley/cabot-search huggingface dataset:
Cardiotoxicity of weekly trastuzumab (T) plus epirubicin (E) and paclitaxel (P) for HER2-positive locally advanced (LA) and/or metastatic (M) breast cancer (BC): A feasibility phase II study
Authors: C. Nisticò, E. Bria, F. Cuppone, A. Carpino, V. Vaccaro, S. Barberi, I. Sperduti, D. Giannarelli, F. Cognetti, E. Terzoli
Journal: Journal of Clinical Oncology (2007)

11509 Background: The introduction of T for patients (pts) overexpressing HER-2 changed the natural history of BC. The adjunction of T to anthracyclines and taxanes for both LABC and MBC provided a significant incidence of unexpected cardiotoxicity. Given the low cardiac toxicity in our previous experience with weekly ET in unselected MBC pts, a feasibility phase II study aimed to cardiotoxicity was planned. Methods: Pts affected by untreated LABC/MBC overexpressing HER-2 by FISH/CISH amplification or 3-positive Dako- Test, underwent weekly T (4–2 mg/kg/week), day 1, and E (25 mg/m 2 /week) plus P (80 mg/m 2 /week), day 2, plus G-CSF support, for 16/24 consecutive weeks in absence of progression or toxicity, in LA/M pts, respectively. Pts with significant cardiac disease/L-FEV&lt;50% were excluded. Primary endpoint was the rate of pts with L-FEV reduction &gt;10% after 12 weeks. An optimal 2-stage Simon design was applied. With a power of 90% at a 5% significance level, assuming a toxicity rate of 30% as unacceptable, and less than 10% as acceptable, an initial group of 15 pts was required; with 11 pts with no toxicity, a second step with further 21 pts (total 36) was planned. Non-cardiac toxicity and activity were evaluated as secondary end-points. Results: From May 2004 to November 2006, 15 pts entered the study. Patient characteristics: median age=47 (range 37–69); LABC/MBC=4/11; positive hormonal receptor 8/7; menopausal pre/post=7/8; PS 0/1=14/1; number of met sites 1/2/3=7/6/2. Median baseline- and post-week-12-L-FEV was 69% (range 64–77) and 65% (range 61–76), respectively. With a median number of courses of 13 (range 8–24), 3 pts had a &gt;10% L-FEV reduction (20%), with an overall median L-FEV reduction of 5.2%. No EKG alteration or specific symptoms were registered. With a 17-months median follow-up, 13 pts were evaluable for response. Eight response (61.5%, 95% CI 9- 87) were documented, with a median response duration of 9 months. No grade 3–4 toxicity were registered, with the exception of severe alopecia. Conclusions: The weekly administration of T plus E and P is extremely tolerable, also with regard to L-FEV reduction. The low L- FEV reduction rate allowed entering the second step of the study. No significant financial relationships to disclose.
Abstract P170: Visit-to-visit Blood Pressure Variability Is Associated With Functional Decline In Older Adults: The S.ages Cohort
Authors: Laure Rouch, Jean-Sébastien Vidal, Olivier Hanon
Journal: Circulation (2020)

Objective: To investigate the impact of visit-to-visit systolic, diastolic, mean arterial pressure and pulse pressure variability on functional decline in non-institutionalized patients aged ≥ 65 years. Methods: 3042 subjects from the S.AGES (elderly subjects) cohort underwent clinical examinations every 6 months during 3 years. Systolic, diastolic, mean arterial pressure and pulse pressure variability were evaluated using standard deviation, coefficient of variation, average real variability, successive variation, variation independent of mean and residual standard deviation. Functional decline was assessed using the Activities of Daily Living (ADL) and Instrumental Activities of Daily Living (IADL) scales and defined over time as any help required to perform at least one task. Cox proportional hazards models were used for the analyses. Results: Among the 3042 subjects, 527 (17.3%) had functional decline (ADL) over time. After adjustment for demographics, systolic blood pressure, antihypertensive drugs, coronary artery disease, diabetes mellitus, chronic heart failure, atrial fibrillation, transient ischemic attack or stroke, smoking, dyslipidemia and Mini Mental State Examination at baseline, higher systolic blood pressure variability was associated with greater risk of functional decline (ADL) (adjusted HR per 1-SD increase of coefficient of variation = 1.12, 95% CI [1.03-1.22], p&lt;0.01). Similar results were observed for diastolic blood pressure variability (adjusted HR = 1.11, 95% CI [1.01-1.22], p=0.03) and mean arterial pressure variability (adjusted HR = 1.15, 95% CI 1.05-1.25, p&lt;0.01). Higher pulse pressure variability was no longer significantly associated with functional decline after adjustment for age (p=0.6). Similar patterns were found with all indicators of variability and loss of autonomy defined using IADL. Conclusion: Higher blood pressure variability could be a novel risk factor for functional decline and controlling blood pressure instability a promising interventional target in preserving autonomy in older adults.
Pulmonary toxicity of cytotoxic agents: A meta-analysis
Authors: Y. Takiguchi, Y. Tada, K. Kurosu, S. Sakao, K. Tatsumi, K. Nagao, T. Kuriyama
Journal: Journal of Clinical Oncology (2007)

19573 Background: Pulmonary toxicity is one of the most serious adverse effects of cytotoxic agents, and affected patients require discontinuation of the anti-cancer therapy, and it even proves fatal in many cases. Its incidence, however, may be considerably biased, as it may be influenced by many factors such as intercurrent medications or co-morbidities. The purpose of our study was to evaluate the incidences of pulmonary toxicity by cytotoxic agents in published data relating to prospective randomized comparative studies. Methods: A Medline literature search was conducted to extract prospective randomized comparative studies (either phase II or III) that included docetaxel, paclitaxel, irinotecan, vinorelbine and gemcitabine. Comparisons had to be performed between regimens with and without one of these agents, in addition to best supportive care with or without other common agent(s), so as to be able to clearly attribute the toxicity to the agent. Reports lacking detailed toxicity data were excluded. Results: The table below summarizes the results of the finally evaluated 47 studies (5 to 12 per agent) fulfilling the criteria. As many studies showed no pulmonary toxicity, standard statistical methods for meta-analysis were not applicable. Conclusions: The present study analyzing data in prospective randomized comparative studies might minimize bias of the relative incidence of pulmonary toxicity. Pulmonary toxicity was rarely encountered in randomized comparative studies. No increase in frequency was shown by the inclusion of any of the five cytotoxic agents. [Table: see text] No significant financial relationships to disclose.
SARS-CoV-2 is an appropriate name for the new coronavirus
Authors: Yuntao Wu, Wenzhe Ho, Yaowei Huang, Dong-Yan Jin, Shiyue Li, Shan-Lu Liu, Xuefeng Liu, Jianming Qiu, Yongming Sang, Qiuhong Wang, Kwok-Yung Yuen, Zhi-Ming Zheng
Journal: The Lancet (2020)
Discovery of the first potent proteolysis targeting chimera (PROTAC) degrader of indoleamine 2,3-dioxygenase 1
Authors: Mingxing Hu, Weilin Zhou, Yijie Wang, Dongping Yao, Tinghong Ye, Yuqin Yao, Bin Chen, Gongping Liu, Xifei Yang, Wei Wang, Yongmei Xie
Journal: Acta Pharmaceutica Sinica B (2020)

Cancer immunotherapy is revolutionizing oncology and has emerged as a promising strategy for the treatment of multiple cancers. Indoleamine 2,3-dioxygenase 1 (IDO1), an immune checkpoint, plays an important role in tumor immune escape through the regulation of multiple immune cells and has been regarded as an attractive target for cancer immunotherapy. Proteolysis Targeting Chimeras (PROTAC) technology has emerged as a new model for drug research and development for its advantageous mechanism. Herein, we reported the application of PROTAC technology in targeted degradation of IDO1, leading to the discovery of the first IDO1 PROTAC degrader 2c, which induced significant and persistent degradation of IDO1 with maximum degradation (dmax) of 93% in HeLa cells. Western-blot based mechanistic studies indicated that IDO1 was degraded by 2c through the ubiquitin proteasome system (UPS). Label-free real-time cell analysis (RTCA) indicated that 2c moderately improved tumor-killing activity of chimeric antigen receptor-modified T (CAR-T) cells. Collectively, these data provide a new insight for the application of PROTAC technology in tumor immune-related proteins and a promising tool to study the function of IDO1.
DNA hypermethylation during tuberculosis dampens host immune responsiveness
Authors: Andrew R. DiNardo, Kimal Rajapakshe, Tomoki Nishiguchi, Sandra L. Grimm, Godwin Mtetwa, Qiniso Dlamini, Jaqueline Kahari, Sanjana Mahapatra, Alexander Kay, Gugu Maphalala, Emily M. Mace, George Makedonas, Jeffrey D. Cirillo, Mihai G. Netea, Reinout van Crevel, Cristian Coarfa, Anna M. Mandalakas
Journal: Journal of Clinical Investigation (2020)

Mycobacterium tuberculosis (M. tuberculosis) has coevolved with humans for millennia and developed multiple mechanisms to evade host immunity. Restoring host immunity in order to improve outcomes and potentially shorten existing therapy will require identification of the full complement by which host immunity is inhibited. Perturbation of host DNA methylation is a mechanism induced by chronic infections such as HIV, HPV, lymphocytic choriomeningitis virus (LCMV), and schistosomiasis to evade host immunity. Here, we evaluated the DNA methylation status of patients with tuberculosis (TB) and their asymptomatic household contacts and found that the patients with TB have DNA hypermethylation of the IL-2/STAT5, TNF/NF-κB, and IFN-γ signaling pathways. We performed methylation-sensitive restriction enzyme-quantitative PCR (MSRE-qPCR) and observed that multiple genes of the IL-12/IFN-γ signaling pathway (IL12B, IL12RB2, TYK2, IFNGR1, JAK1, and JAK2) were hypermethylated in patients with TB. The DNA hypermethylation of these pathways was associated with decreased immune responsiveness with decreased mitogen-induced upregulation of IFN-γ, TNF, IL-6, CXCL9, CXCL10, and IL-1β production. The DNA hypermethylation of the IL-12/IFN-γ pathway was associated with decreased IFN-γ-induced gene expression and decreased IL-12-inducible upregulation of IFN-γ. This study demonstrates that immune cells from patients with TB are characterized by DNA hypermethylation of genes critical to mycobacterial immunity resulting in decreased mycobacteria-specific and nonspecific immune responsiveness.
Abstract 57: Vulnerable Populations, Disparities, and the U.S. Tobacco Endgame
Authors: Douglas Levy
Journal: Circulation (2020)

Background: Since 1964 when the first Surgeon General’s report on smoking was published, the decline in smoking has been steepest among those with the most education. As smoking has become denormalized, it is increasingly concentrated in vulnerable populations that are marginalized by socioeconomic status, mental health, race/ethnicity, or sexual orientation. This analysis uses the National Health Interview Survey (NHIS) to assess current trends in cigarette smoking among vulnerable vs. non-vulnerable populations. Methods: Current cigarette smoking among adult NHIS respondents was tracked from 1999-2018. Vulnerable populations were defined by low socioeconomic status (&lt;100% federal poverty level, &lt;high school education, Medicaid recipient), low mental health (Kessler 6 score≥5), or race/ethnicity with elevated smoking (American Indian, multiracial). Sensitivity analyses added food insecurity and minority sexual orientation (non-straight), available starting 2013, to the definition of vulnerability. Regression analysis projected future smoking trends. Results: Smoking rates in all sub-groups declined from 1999 to 2018. Among the non-vulnerable, smoking declined from 19.2% to 9.7%; among the vulnerable, smoking rates were 10 percentage points higher, declining from 30.5% to 19.5%. Smoking rates among vulnerable populations are now double the rates in non-vulnerable populations. The proportion of smokers classified as vulnerable increased from 47.7% to 58.6%; the proportion of cigarettes consumed by vulnerable smokers increased from 50.1% to 60.4%. Expanding the definition of vulnerability to include those food insecure and in sexual minorities, the proportion of smokers classified as vulnerable (2018) was 61.63%. The most common vulnerabilities in the population (2018) were low socioeconomic status (25.5%) and poor mental health (22.0%); (7.8% were both). In 2018, as the number of vulnerabilities increased (0, 1, 2, ≥3), so did the smoking rate (9.4%, 14.6%, 21.7%, 31.7%, respectively, p&lt;0.001). Using linear regression to extrapolate current trends, non-vulnerable populations will eliminate cigarette smoking in 2037, vulnerable populations in 2060. Conclusion: Existing public health policy and social trends are reducing smoking rates among all smokers, but absent concentrated effort to reduce smoking in vulnerable populations, health disparities from disproportionate tobacco use will increase and reverberate for decades.
TCT-745 Feasibility and outcomes of transcatheter aortic valve implantation in high-risk patients with stenotic bicuspid aortic valves
Authors: Radoslaw Parma, Piotr Pysz, Zofia Parma, Wojciech Wojakowski, Grzegorz A. Smolka, Andrzej J. Ochala
Journal: Journal of the American College of Cardiology (2014)
Role of non-coding RNAs and RNA modifiers in cancer therapy resistance
Authors: Xinyi Zhang, Kai Xie, Honghua Zhou, Yuwei Wu, Chan Li, Yating Liu, Zhaoya Liu, Qian Xu, Shuang Liu, Desheng Xiao, Yongguang Tao
Journal: Molecular Cancer (2020)

Abstract As the standard treatments for cancer, chemotherapy and radiotherapy have been widely applied to clinical practice worldwide. However, the resistance to cancer therapies is a major challenge in clinics and scientific research, resulting in tumor recurrence and metastasis. The mechanisms of therapy resistance are complicated and result from multiple factors. Among them, non-coding RNAs (ncRNAs), along with their modifiers, have been investigated to play key roles in regulating tumor development and mediating therapy resistance within various cancers, such as hepatocellular carcinoma, breast cancer, lung cancer, gastric cancer, etc. In this review, we attempt to elucidate the mechanisms underlying ncRNA/modifier-modulated resistance to chemotherapy and radiotherapy, providing some therapeutic potential points for future cancer treatment.
Abstract P401: Associations Between High-density Lipoprotein Subclasses and Coronary Artery Calcification Vary by Menopausal Stage. The Study of Women's Health Across the Nation Hdl Ancillary Study
Authors: Samar R El Khoudary, Alexis Nasr, Xirun Chen, Karen A Matthews, Trevor Orchard, Maria M Brooks, Jeff Billheimer, Dan McConnell, Imke Janssen, Susan A Everson-rose, Deborah Martin, Dan Rader
Journal: Circulation (2020)

Objective: Higher levels of high-density lipoproteins cholesterol (HDL-C) may not always be cardio-protective in midlife women. Nuclear magnetic resonance (NMR) spectroscopy HDL subclasses have shown strong associations with CVD risk beyond HDL-C. Preliminary work suggests significant declines in large HDL particles (HDL-P) and overall HDL size, but increases in small HDL-P during the perimenopause stage. Our objective was to assess whether associations between NMR HDL subclasses and risk of coronary artery calcification (CAC) vary by menopausal stage. Design: We assessed 283 women (at baseline : age 51.4 ± 3.0 years; 56.6% Pre-/Early peri-, 8.8% late peri-, 34.6% post-menopausal) who had NMR HDL subclasses and CAC Agatston score measured once (N=48 [17%]) or twice (N=235 [83%]) around menopause. CAC presence was defined as CAC&gt;0. Effect modifications of menopausal stage on associations between HDL subclasses and CAC presence overtime were tested using generalized estimating equation for binary outcome. Final models were adjusted for study site, race and time varying: age, body mass index, physical activity, alcohol consumption, insulin resistance, triglycerides and low-density lipoprotein cholesterol. Results: In final models, menopausal stage modified the associations of small HDL-P (p=.009), large HDL-P (p=.05) and overall HDL size (p=.007) with CAC presence ( Table ). Higher concentration of small HDL-P, lower concentration of large HDL-P, and smaller overall HDL size significantly associated with greater risk of CAC presence during the late-peri stage compared to pre-/early peri-menopausal stage ( Table) . Conclusions: Changes in HDL subclasses during the menopause transition may increase the likelihood of measurable CAC developing in women, particularly during the later peri-menopausal stage. Characterizing associations of HDL composition and function metrics with CVD risk over the menopause transition is critical to better understand the relationship of HDL to coronary disease in midlife women.
Abstract P120: Women With Menopause After Age 45 and Take Hormone Therapy After Age 60 Increase the Risk of Cardiovascular Disease
Authors: Dongshan Zhu, Hsin-Fang Chung, Annette Dobson, Nirmala Pandeya, Gita Mishra
Journal: Circulation (2020)

Introduction: Evidence from clinical trials and observational studies on the relationship between menopausal hormone therapy (MHT) and cardiovascular disease (CVD) risk has been discordant. Hypothesis: We hypothesized that the association between MHT and risk of CVD might be affected by both age at menopause and age when initiated MHT. Methods: We harmonised and pooled individual-level data from 15 studies across five countries/regions (Australia, Scandinavia, USA, Japan, and UK). Postmenopausal women who had reported their MHT status (user or non-user) and CVD status (occurred or not, including coronary heart disease (CHD) and stroke) were included. We used Cox proportional hazards models to estimate hazard ratios (HRs) and 95% confidence intervals (CI) for the association between MHT use and incident CVD. We stratified the analyses by age when initiated MHT and age at natural menopause to examine the interaction between MHT, age initiated MHT, and age at menopause on incident CVD. Results: Overall, 190 625 postmenopausal women were included. We identified 10 601 incident CVD events, including 7615 CHD and 3543 strokes. Around 39% (74 585) women were MHT users. Compared to non-users of MHT, women who were MHT users had 10% higher risk of incident CVD (HR 1.10, 95% CI 1.06-1.14), with HR (95% CI) of (1.15, 1.10-1.20) for CHD and (1.02, 0.96-1.09) for stroke. After stratifying by age at natural menopause, women who experienced menopause after age 45 years and took MHT had around 15% higher risk of CHD, while the significant association with incident stroke was only observed in women who had menopause after 55 years (1.16, 1.01-1.33). After a further stratification by age initiated MHT, we found the significant associations between MHT users and incident CVD were only observed in women who experienced menopause after age 45 years and took MHT at age 60 years or old (Table 1). Conclusions: Postmenopausal women who experienced natural menopause after age 45 years and took MHT after age 60 years had increased risk of incident CVD.
Association of Formulary Exclusions and Restrictions for Opioid Alternatives With Opioid Prescribing Among Medicare Beneficiaries
Authors: Tanvi Rao, Zippora Kiptanui, Paul Dowell, Corey Triebwasser, G. Caleb Alexander, Ilene Harris
Journal: JAMA Network Open (2020)

<h3>Importance</h3> Although there are many pharmacologic alternatives to opioids, it is unclear whether the structure of Medicare Part D formularies discourages use of the alternatives. <h3>Objectives</h3> To quantify the coverage of opioid alternatives and prevalence of prior authorization, step therapy, quantity limits, and tier placement for these drugs, and test whether these formulary exclusions and restrictions are associated with increased opioid prescribing to older adults at the county level. <h3>Design, Setting, and Participants</h3> County fixed-effect models were estimated using a panel of counties across the 50 US states and the District of Columbia over calendar years 2015 and 2016. Data analysis was conducted from July 1 to September 23, 2019. The sample included 2721 counties in 2015 and 2671 counties in 2016 with sufficient data on Medicare Part D formulary design and opioid prescribing. <h3>Main Outcomes and Measures</h3> County-level opioid prescribing rate (number of opioid claims divided by the number of overall claims) and counts of excluded opioid alternatives and opioid alternatives with prior authorization, step therapy, quantity limits, and high-tier placements. <h3>Results</h3> A total of 30 nonopioid analgesics were examined across 28 997 Medicare plans in 2015 and 30 390 plans in 2016. Medicare plans did not cover a mean of 7% of these drugs (interquartile range, 10%; lower to upper limit, 0%-23%). Among covered nonopioids, prior authorization and step therapy were uncommon, with fewer than 5% affected by prior authorization and 0% by step therapy. However, 13% of covered nonopioids had quantity limits (interquartile range, 10%; lower to upper limit, 0%-31%) and 22% were in high-cost tiers (interquartile range, 38%; lower to upper limit, 0%-50%). Increases in the number of nonopioids excluded on Medicare plans in a county were associated with increased opioid prescribing (effect size relative to mean, 2.2%-3.7%;<i>P</i> = .004). Conversely, increases in the number of opioids not covered on Medicare plans in a county was found to be associated with decreased opioid prescribing (effect size relative to mean, 0.8%-1.5%;<i>P</i> = .02). None of the utilization management strategies (prior authorization, step therapy, and quantity limits) examined or high-cost tier placements of nonopioids were associated with increased opioid prescribing. <h3>Conclusions and Relevance</h3> Lack of Medicare coverage for pharmacologic alternatives to opioids may be associated with increased opioid prescribing.