tbuckley/cabot-search huggingface dataset:
The NOTCH–FOXM1 Axis Plays a Key Role in Mitochondrial Biogenesis in the Induction of Human Stem Cell Memory–like CAR-T Cells
Authors: Taisuke Kondo, Makoto Ando, Nao Nagai, Wataru Tomisato, Tanakorn Srirat, Binbin Liu, Setsuko Mise-Omata, Mari Ikeda, Shunsuke Chikuma, Hiroshi Nishimasu, Osamu Nureki, Mitsuyo Ohmura, Noriyo Hayakawa, Takako Hishiki, Ryosuke Uchibori, Keiya Ozawa, Akihiko Yoshimura
Journal: Cancer Research (2019)

Recent studies have shown that stem cell memory T (TSCM) cell-like properties are important for successful adoptive immunotherapy by the chimeric antigen receptor-engineered-T (CAR-T) cells. We previously reported that both human and murine-activated T cells are converted into stem cell memory-like T (iTSCM) cells by coculture with stromal OP9 cells expressing the NOTCH ligand. However, the mechanism of NOTCH-mediated iTSCM reprogramming remains to be elucidated. Here, we report that the NOTCH/OP9 system efficiently converted conventional human CAR-T cells into TSCM-like CAR-T, "CAR-iTSCM" cells, and that mitochondrial metabolic reprogramming played a key role in this conversion. NOTCH signaling promoted mitochondrial biogenesis and fatty acid synthesis during iTSCM formation, which are essential for the properties of iTSCM cells. Forkhead box M1 (FOXM1) was identified as a downstream target of NOTCH, which was responsible for these metabolic changes and the subsequent iTSCM differentiation. Like NOTCH-induced CAR-iTSCM cells, FOXM1-induced CAR-iTSCM cells possessed superior antitumor potential compared with conventional CAR-T cells. We propose that NOTCH- or FOXM1-driven CAR-iTSCM formation is an effective strategy for improving cancer immunotherapy. SIGNIFICANCE: Manipulation of signaling and metabolic pathways important for directing production of stem cell memory-like T cells may enable development of improved CAR-T cells.
Principles Governing Establishment versus Collapse of HIV-1 Cellular Spread
Authors: Jason M. Hataye, Joseph P. Casazza, Katharine Best, C. Jason Liang, Taina T. Immonen, David R. Ambrozak, Samuel Darko, Amy R. Henry, Farida Laboune, Frank Maldarelli, Daniel C. Douek, Nicolas W. Hengartner, Takuya Yamamoto, Brandon F. Keele, Alan S. Perelson, Richard A. Koup
Journal: Cell Host & Microbe (2019)
Baseline Immune Dysregulation in Autologous Stem Cell Transplant Recipients Is Associated with a 'Graft Versus Host'-like Syndrome and Results in Poor Outcomes
Authors: Theodora Anagnostou, Mrinal M. Patnaik, Cynthia L Forsman, Reona Sakemura, Mark R. Litzow, Dennis A. Gastineau, Francis K Buadi, Luis Porrata, Julia S Lehman, William J. Hogan, Shahrukh K. Hashmi, Saad Sirop Kenderian
Journal: Blood (2017)
EU drug approval should include price evaluation, says expert panel
Authors: Elisabeth Mahase
Journal: BMJ (2019)

New drugs should not be approved for sale in the European Union (EU) unless pharmaceutical companies agree to a fair price, an expert panel has urged.

Speaking at the European Public Health Alliance’s Universal Access and Affordable Medicines forum in Brussels on 14 November, experts from across the EU spoke about the need for greater transparency from the pharmaceutical industry to make drug pricing fairer.

Carin Uyl-de Groot, director of the Institute for Medical Technology Assessment at Erasmus University, Rotterdam, said, “We need a change in law. After European Medicines Agency (EMA) registration, we need to identify …
Effectiveness of first-generation 5HT3 receptor antagonist plus dexamethasone plus aprepitant in controlling delayed chemotherapy-induced nausea and vomiting in patients with colorectal cancer: A propensity score-matched analysis
Authors: T. Hayashi, M. Shimokawa, K. Matsuo, H. Iihara, J. Nishimura, T. Nakano, T. Egawa
Journal: Annals of Oncology (2019)
Phase 2 Results of the iR2 Regimen (Ibrutinib, Lenalidomide, and Rituximab) in Patients with Relapsed/Refractory (R/R) Non-Germinal Center B Cell-like (Non-GCB) Diffuse Large B-Cell Lymphoma (DLBCL)
Authors: Radhakrishnan Ramchandren, Peter Johnson, Nilanjan Ghosh, Jia Ruan, Kirit M. Ardeshna, Roderick Johnson, Gregor Verhoef, David Cunningham, Sven de Vos, Shireen Kassam, Luis Fayad, John Radford, Sarah Bailly, Fritz Offner, David Morgan, Javier Munoz, Jerry Ping, Kevin Kwei, Karl Eckert, Jutta K. Neuenburg, Andre Goy
Journal: Blood (2019)
Nilotinib concentration in Cell Lines and CML CD34+ Cells Is Not Mediated by Active Uptake or Efflux by Major Drug Transporters
Authors: Joanne Mountford, Andrea Davies, Niove E Jordanides, Athina Giannoudis, Claire M Lucas, Sophia Hatziieremia, Robert J Harris, Heather G Jorgensen, Munir Pirmohamed, Tessa L Holyoake, Richard E Clark
Journal: Blood (2008)
Chief cell in stomach have stem cell activity and potential to develop gastric cancer
Authors: A. Yamamura, J. Matsuo, M. Lim Yi Hui, D. Liana Heng, K. Kofu, Z.H. Md, D. Douchi, K.G. Yeoh, T. Kamei, T. Naitoh, M. Osato, M. Unno, Y. Ito
Journal: Annals of Oncology (2019)
Life History Theory and economic modernity
Authors: Martin Hewson
Journal: Behavioral and Brain Sciences (2019)

Baumard's new explanation of the Industrial Revolution shows that Life History Theory holds great potential. Here, I suggest two related hypotheses for examination. One is that there are long-term roots of slow life traits and preferences. The other is that Life History Theory can explain other aspects of economic modernity such as the Scientific Revolution and bureaucratic states. If so, then Life History Theory offers a way to reconcile several bodies of evidence and lines of explanation into a coherent general account of economic modernity.
A phase I study of modified irinotecan (CPT-11) plus cisplatin (CDDP) [m-IP] against paclitaxel/carboplatin [TC] -resistant and recurrent ovarian cancer
Authors: T. Suzuki, M. Morishita, M. Matsuura, T. Fujimoto, R. Tanaka, E. Ito, Y. Ebina, T. Saito
Journal: Journal of Clinical Oncology (2007)

13015 Background: CPT-11/CDDP is effective regimen for ovarian cancer. Particularly against ovarian cancer resistant to prior chemotherapy, a 40% response rate was reported (Sugiyama T Cancer Letters, 1998). However, every 4 weeks treatment with CPT-11 day 1, 8, and 15, administration on day 15 was skipped in about 60% due to toxicity, and the relative dose intensity of IP was 66.7% in non-small cell lung cancer (Saito H Am J Clin Oncol 2006). We planed Phase I study, in consideration of the effect of prior chemotherapy in TC-resistant ovarian cancer, a modified CPT-11 (day 1, 8) and CDDP (day 1) for every 4 weeks treatment (m-IP). The aim of this study conducted to examine the dose limiting toxicity (DLT), to evaluate the maximum tolerated dose (MTD), and define the recommended dose (RD) for a phase II study. Methods: Patients with TC-resistant ovarian cancer having a PS 0–1, age 30–75 years, normal organ functions, and written informed consent. CPT-11 was administered intravenously over 90 minutes on day 1 and day 8, plus CDDP was day 1, repeated every 4 weeks. The dose escalation schedule was defined: Doses of CPT-11/CDDP (mg/m 2 ) were 60/60 at level 1, 70/60 at level 2 and 70/70 at level 3. DLT were determined as Grade 4 hematological toxicity and = Grade 3 non-hematological toxicity occurred, and when dosing on day 8 was delayed for more than 8 days due to toxicity. Results: Nine patients were enrolled (level 1/2/3: 3/3/3). DLTs, at level 1 and 2, no patients developed. At level 3, grade 3 nausea and vomiting and delayed treatment on day 8 due to anorexia, were observed in all of 3 patients. Therefore, MTD was determined to be level 3 and RD was determined to be level 2 (CPT-11: 70mg/m 2 , CDDP: 60mg/m 2 ). Major =Grade 3 toxicities observed were leukopenia, neutropenia, nausea, and vomiting. No Grade 4 hematological toxicities were observed. Diarrhea was mild. Antitumor effect at RD was observed in 1 patient with CR, 1 patient with PR and 1 patient with PD. Conclusions: The MTD of m-IP was CPT-11 70mg/m 2 and CDDP 70mg/m 2 (level 3), the RD was CPT-11 70mg/m 2 and CDDP 60mg/m 2 (level 2). Preliminary response are promissing associated with tolerable toxicity for TC-resistant and recurrent ovarian cancer. A Phase II study is currently conducted. No significant financial relationships to disclose.
Correspondence to ‘Slope sign’: a feature of large vessel vasculitis?
Authors: Marcin Milchert, Marek Brzosko, Anne Bull Haaversen, Andreas P Diamantopoulos
Journal: Annals of the Rheumatic Diseases (2019)

We have read with great interest the observation of Dasgupta et al. 1 We would like to propose an extended definition of slope sign in giant cell arteritis (GCA) formerly named slide sign,2,3 and present our method of assessing it by using the anteromedial ultrasound examination method of the large supraaortic vessels.4

Slope sign is a pathologically increased intima-media thickness (IMT)5 that spreads over a long arterial segment and slides down to a normal brachial artery where a normal intima-media structure (double line) is observed. This definition contains a description of pathological findings in the axillary artery—a typical location for vasculitis in GCA, contrasting with normal findings in brachial artery—which is usually not involved by vasculitis.6 Slope sign may not be limited to the place of arterial bifurcation of the subscapular artery, which is a typical location of atherosclerotic plaque. A transition zone …
Economic Evaluation of Brief Cognitive Behavioral Therapy vs Treatment as Usual for Suicidal US Army Soldiers
Authors: Samantha L. Bernecker, Kelly L. Zuromski, Justin C. Curry, Jane J. Kim, Peter M. Gutierrez, Thomas E. Joiner, Ronald C. Kessler, Matthew K. Nock, M. David Rudd, Craig J. Bryan
Journal: JAMA Psychiatry (2019)

<h3>Importance</h3> Brief cognitive behavioral therapy (BCBT) is a clinically effective intervention for reducing risk of suicide attempts among suicidal US Army soldiers. However, because specialized treatments can be resource intensive, more information is needed on costs and benefits of BCBT compared with existing treatments. <h3>Objective</h3> To evaluate the cost-effectiveness of BCBT compared with treatment as usual for suicidal soldiers in the US Army. <h3>Design, Setting, and Participants</h3> A decision analytic model compared effects and costs of BCBT vs treatment as usual from a US Department of Defense (DoD) perspective. Model input data were drawn from epidemiologic data sets and a clinical trial among suicidal soldiers conducted from January 31, 2011, to April 3, 2014. Data were analyzed from July 3, 2018, to March 25, 2019. <h3>Interventions</h3> The strategies compared were treatment as usual alone vs treatment as usual plus 12 individual BCBT sessions. Treatment as usual could include a range of pharmacologic and psychological treatment options. <h3>Main Outcomes and Measures</h3> Costs in 2017 US dollars, suicide attempts averted (self-directed behavior with intent to die, but with nonfatal outcome), suicide deaths averted, and incremental cost-effectiveness ratios, assuming a 2-year time horizon for treatment differences but including lifetime costs. <h3>Results</h3> In the base-case analysis, BCBT was expected to avert approximately 23 to 25 more suicide attempts and 1 to 3 more suicide deaths per 100 patients treated than treatment as usual. Sensitivity analyses assuming a range of treatment effects showed BCBT to be cost saving in most scenarios. Using the federal discount rate, the DoD was estimated to save from $15 000 to $16 630 per patient with BCBT vs treatment as usual. In a worst-case scenario (ie, assuming the weakest plausible BCBT effect sizes), BCBT cost an additional $1910 to $2250 per patient compared with treatment as usual. <h3>Conclusions and Relevance</h3> Results suggest BCBT may be a cost-saving intervention for suicidal active-duty soldiers. The costs of ensuring treatment fidelity would also need to be considered when assessing the implications of disseminating BCBT across the entire DoD.
Editor's Note: PrLZ Protects Prostate Cancer Cells from Apoptosis Induced by Androgen Deprivation via the Activation of Stat3/Bcl-2 Pathway
Authors: Dong Zhang, Dalin He, Yan Xue, Ruoxiang Wang, Kaijie Wu, Hongjun Xie, Jin Zeng, Xinyang Wang, Haiyen E. Zhau, Leland W.K. Chung, Luke S. Chang, Lei Li
Journal: Cancer Research (2019)

The editors are publishing this note to alert readers to a concern about this article (1). The sense and antisense siRNA sequences reported to target STAT3 are in fact both predicted to target the CEP104 gene. The STAT3 knockdown results were not confirmed by an additional siRNA as this was the only STAT3 siRNA used in the study.
Branched Photoswitchable Tethered Ligands Enable Ultra-efficient Optical Control and Detection of G Protein-Coupled Receptors In Vivo
Authors: Amanda Acosta-Ruiz, Vanessa A. Gutzeit, Mary Jane Skelly, Samantha Meadows, Joon Lee, Puja Parekh, Anna G. Orr, Conor Liston, Kristen E. Pleil, Johannes Broichhagen, Joshua Levitz
Journal: Neuron (2019)
KEYNOTE-826: A phase III randomized study of chemotherapy with or without pembrolizumab for first-line treatment of persistent, recurrent, or metastatic cervical cancer
Authors: K. Fujiwara, R. Shapira-Frommer, J. Alexandre, B. Monk, T. Fehm, N. Colombo, M.V. Caceres, K. Hasegawa, C. Dubot, J.J. Li, K. Stein, S.M. Keefe, K. Tewari
Journal: Annals of Oncology (2019)
Diabetes in Normal-Weight Individuals: High Susceptibility in Nonwhite Populations
Authors: Unjali P. Gujral, K.M. Venkat Narayan
Journal: Diabetes Care (2019)

Type 2 diabetes is one of the most prevalent diseases of our time. There are an estimated 425 million people with diabetes worldwide, and 625 million people are projected to have the disease by 2045 (1). Over the next three decades, the largest increases in diabetes prevalence and overall numbers of people with the disease are expected to occur in low- and middle-income countries and among nonwhite ethnic minorities living in high-income nations (1). Overweight and obesity are well-established risk factors for diabetes; however, evidence suggests that the relationship between body weight and diabetes risk may differ by race/ethnicity (2–4), which has implications for the prevention, screening, and treatment of individuals who develop diabetes with a BMI below the overweight or obesity range.

In their article in this issue of Diabetes Care , Zhu et al. (5) examined racial/ethnic disparities in the prevalence of diabetes by BMI category in a large, racially/ethnically and geographically diverse cohort of 4.9 million adults. Individuals enrolled in the cohort were members of three integrated health care systems in the U.S. in the years 2012–2013 and were from six racial/ethnic groups including white, black, Hispanic, Asian, Hawaiian/Pacific Islander, and American Indian/Alaskan Native. They found that the age-standardized prevalence of diabetes increased across BMI categories among all racial/ethnic groups. However, compared with whites, all other racial/ethnic groups had a higher prevalence of diabetes at any given BMI, and these differences were more pronounced in lower BMI categories. Strikingly, in those with a normal weight, the prevalence of diabetes was 5.0% in whites, 10.1% in Asians and American Indians/Alaskan Natives, 13.0% in …
State-Specific Prevalence of Obesity Among Children Aged 2–4 Years Enrolled in the Special Supplemental Nutrition Program for Women, Infants, and Children — United States, 2010–2016
Authors: Liping Pan, Heidi M. Blanck, Sohyun Park, Deborah A. Galuska, David S. Freedman, Anna Potter, Ruth Petersen
Journal: MMWR Morbidity and Mortality Weekly Report (2019)

Obesity negatively affects children's health because of its associations with cardiovascular disease risk factors, type 2 diabetes, asthma, fatty liver disease, victimization stemming from social stigma and bullying, and poor mental health (e.g., anxiety and depression) (1). Children who have overweight or obesity in early childhood are approximately four times as likely to have overweight or obesity in young adulthood as their normal weight peers (2). Obesity prevalence is especially high among children from low-income families (3). In 2010, the overall upward trend in obesity prevalence turned downward among children aged 2-4 years enrolled in the Special Supplemental Nutrition Program for Women, Infants, and Children (WIC), a program of the U.S. Department of Agriculture (USDA); prevalence decreased significantly in all racial/ethnic groups and in 34 of the 56 WIC state or territory agencies during 2010-2014 (4). A more recent study among young children enrolled in WIC reported that the overall obesity prevalence decreased from 15.9% in 2010 to 13.9% in 2016 and statistically significant decreases were observed in all age, sex, and racial/ethnic subgroups (3). However, this study did not provide obesity trends at the state level. In collaboration with USDA, CDC used data from the WIC Participant and Program Characteristics (WIC PC) to update state-specific trends through 2016. During 2010-2016, modest but statistically significant decreases in obesity prevalence among children aged 2-4 years enrolled in WIC occurred in 41 (73%) of 56 WIC state or territory agencies. Comprehensive approaches that create positive changes to promote healthy eating and physical activity for young children from all income levels,* strengthen nutrition education and breastfeeding support among young children enrolled in WIC, and encourage redemptions of healthy foods in WIC food packages could help maintain or accelerate these declining trends.
Breast cancer patients in a female sexual medicine and women’s health program: A cross-sectional retrospective study.
Authors: Jeanne Carter, Sally Saban, Ashley Arkema, Deborah J. Goldfrank, Shari Beth Goldfarb
Journal: Journal of Clinical Oncology (2019)

8 Background: Cancer treatment impacts sexual health and QOL with symptoms of vulvovaginal dryness, dyspareunia, and sexual dysfunction. There are limited data on specific sexual changes in patients with varying treatments. We examined patient-reported and exam outcomes of breast cancer patients’ initial consults at Female Sexual Medicine &amp; Women’s Health Program (FSMWHP) at Memorial Sloan Kettering Cancer Center. Methods: We obtained a limited waiver to evaluate medical records and Female Sexual Medicine Clinic Assessment Forms (FSMCAFs) of initial consults at FSMWHP from 6/29/12–12/23/16. The FSMCAF is composed of a pelvic exam checklist, sexual function measures (Female Sexual Function Index-FSFI; Sexual Activity Questionnaire-SAQ), vulvovaginal health measures (Vaginal Assessment Scale—VAS; Vulvar Assessment Scale—VuAS), and questions about concerns. Descriptive statistics were calculated using SPSS. Results: 446 women were categorized by menopausal status and endocrine therapy. Subcohorts were: postmenopausal with aromatase inhibitors (AIs) alone (30%), tamoxifen followed by AI (22%), tamoxifen alone (16%) or no therapy (16%), and pre/peri-menopausal with tamoxifen alone (9%) or no therapy (5%). In postmenopausal women, initial consults avg. 3.3 yrs post-treatment (pre/peri avg. 1.8 yrs). Endocrine use avg. 3 yrs. across groups. 99% of postmenopausal women scored &lt; 26.6 on FSFI, indicating sexual dysfunction (tamoxifen alone avg: 13.7; tamoxifen followed by AI avg: 10.4). Vulvovaginal dryness and severe dyspareunia were highest in postmenopausal women with endocrine exposure (AI alone: 83% and 36%; tamoxifen alone: 66% and 32%). Related exam outcomes (pH &gt; 6.5, petechiae, vulvovaginal atrophy, minimal/no moisture) were also highest in postmenopausal women (AI alone: 30%, 13%, 78%, 89%; tamoxifen alone: 19%, 5%, 65%, 70% respectively). Conclusions: Sexual health concerns are common in breast cancer patients. Endocrine exposure and menopause can negatively impact tissue quality. Women exposed to AIs appear to have the poorest self-reported and clinical outcomes. Proactive sexual health interventions, including early counseling, are warranted in these patients.
The contribution of sleep to social inequalities in cardiovascular disorders: a multi-cohort study
Authors: Dusan Petrovic, José Haba-Rubio, Carlos de Mestral Vargas, Michelle Kelly-Irving, Paolo Vineis, Mika Kivimäki, Solja Nyberg, Martina Gandini, Murielle Bochud, Peter Vollenweider, Angelo d’Errico, Henrique Barros, Silvia Fraga, Marcel Goldberg, Marie Zins, Andrew Steptoe, Cyrille Delpierre, Raphael Heinzer, Cristian Carmeli, Marc Chadeau-Hyam, Silvia Stringhini
Journal: Cardiovascular Research (2019)

Sleep disturbances exhibit a strong social patterning, and inadequate sleep has been associated with adverse health outcomes, including cardiovascular disorders (CVD). However, the contribution of sleep to socioeconomic inequalities in CVD is unclear. This study pools data from eight European cohorts to investigate the role of sleep duration in the association between life-course socioeconomic status (SES) and CVD.
Smooth muscle cell–specific fibronectin-EDA mediates phenotypic switching and neointimal hyperplasia
Authors: Manish Jain, Nirav Dhanesha, Prakash Doddapattar, Mehul R. Chorawala, Manasa K. Nayak, Anne Cornelissen, Liang Guo, Aloke V. Finn, Steven R. Lentz, Anil K. Chauhan
Journal: Journal of Clinical Investigation (2019)

Fibronectin–splice variant containing extra domain A (Fn-EDA) is associated with smooth muscle cells (SMCs) following vascular injury. The role of SMC-derived Fn-EDA in SMC phenotypic switching or its implication in neointimal hyperplasia remains unclear. Herein, using human coronary artery sections with a bare metal stent, we demonstrate the expression of Fn-EDA in the vicinity of SMC-rich neointima and peri-strut areas. In mice, Fn-EDA colocalizes with SMCs in the neointima of injured carotid arteries and promotes neointima formation in the comorbid condition of hyperlipidemia by potentiating SMC proliferation and migration. No sex-based differences were observed. Mechanistic studies suggested that Fn-EDA mediates integrin- and TLR4-dependent proliferation and migration through activation of FAK/Src and Akt1/mTOR signaling, respectively. Specific deletion of Fn-EDA in SMCs, but not in endothelial cells, reduced intimal hyperplasia and suppressed the SMC synthetic phenotype concomitant with decreased Akt1/mTOR signaling. Targeting Fn-EDA in human aortic SMCs suppressed the synthetic phenotype and downregulated Akt1/mTOR signaling. These results reveal that SMC-derived Fn-EDA potentiates phenotypic switching in human and mouse aortic SMCs and neointimal hyperplasia in the mouse. We suggest that targeting Fn-EDA could be explored as a potential therapeutic strategy to reduce neointimal hyperplasia.
Detecting Breast Cancer in Women with Dense Breasts
Authors: Dan L. Longo
Journal: New England Journal of Medicine (2019)

Screening asymptomatic patients for cancer is based on a simple premise: cancers that are detected early before they produce symptoms should be easier to cure than those that progress to become clinically detectable. In practice, tools have been developed to realize the detection of clinically undetectable cancers, but the effect of their application on overall survival has been enormously challenging to demonstrate. Several factors contribute to the difficulty in proving the value of cancer screening. First, any test will have false negatives, in which case a patient’s cancer goes undetected. Second, tests for cancer are quite often falsely positive because . . .