tbuckley/cabot-search huggingface dataset:
A 15-Gene Immune, Stromal, and Proliferation Gene Signature that Significantly Associates with Poor Survival in Patients with Pancreatic Ductal Adenocarcinoma
Authors: Raju Kandimalla, Hideo Tomihara, Jasjit K. Banwait, Kensuke Yamamura, Gagandeep Singh, Hideo Baba, Ajay Goel
Journal: Clinical Cancer Research (2020)

Pancreatic ductal adenocarcinoma (PDAC) is a lethal disease with dismal survival rates. Tumor microenvironment (TME), comprising of immune cells and cancer-associated fibroblasts, plays a key role in driving poor prognosis and resistance to chemotherapy. Herein, we aimed to identify a TME-associated, risk-stratification gene biomarker signature in PDAC.The initial biomarker discovery was performed in The Cancer Genome Atlas (TCGA, n = 163) transcriptomic data. This was followed by independent validation of the gene signature in the International Cancer Genome Consortium (ICGC, n = 95), E-MTAB-6134 (n = 288), and GSE71729 (n = 123) datasets for predicting overall survival (OS), and for its ability to detect poor molecular subtypes. Clinical validation and nomogram establishment was undertaken by performing multivariate Cox regression analysis.Our biomarker discovery effort identified a 15-gene immune, stromal, and proliferation (ISP) gene signature that significantly associated with poor OS [HR, 3.90; 95% confidence interval (CI), 2.36-6.41; P < 0.0001]. This signature also robustly predicted survival in three independent validation cohorts ICGC [HR, 2.63 (1.56-4.41); P < 0.0001], E-MTAB-6134 [HR, 1.53 (1.14-2.04); P = 0.004], and GSE71729 [HR, 2.33 (1.49-3.63); P < 0.0001]. Interestingly, the ISP signature also permitted identification of poor molecular PDAC subtypes with excellent accuracy in all four cohorts; TCGA (AUC = 0.94), ICGC (AUC = 0.91), E-MTAB-6134 (AUC = 0.80), and GSE71729 (AUC = 0.83). The ISP-derived high-risk patients exhibited significantly poor OS in a clinical validation cohort [n = 119; HR, 2.62 (1.50-4.56); P = 0.0004]. A nomogram was established which included the ISP, CA19-9, and T- and N-stage for eventual clinical translation.We report a novel gene signature for risk-stratification and robust identification of patients with PDAC with poor molecular subtypes.
A mountable toilet system for personalized health monitoring via the analysis of excreta
Authors: Seung-min Park, Daeyoun D. Won, Brian J. Lee, Diego Escobedo, Andre Esteva, Amin Aalipour, T. Jessie Ge, Jung Ha Kim, Susie Suh, Elliot H. Choi, Alexander X. Lozano, Chengyang Yao, Sunil Bodapati, Friso B. Achterberg, Jeesu Kim, Hwan Park, Youngjae Choi, Woo Jin Kim, Jung Ho Yu, Alexander M. Bhatt, Jong Kyun Lee, Ryan Spitler, Shan X. Wang, Sanjiv S. Gambhir
Journal: Nature Biomedical Engineering (2020)
Response to: ‘Glucocorticoid withdrawal in lupus: to do or not to do?’ by Acharya
Authors: Alexis Mathian, Micheline Pha, Zahir Amoura
Journal: Annals of the Rheumatic Diseases (2020)

Response to: 'Glucocorticoid withdrawal in lupus: to do or not to do?' by AcharyaWe thank Acharya for her interest in our study showing that in patients with systemic lupus erythematosus (SLE) with a quiescent disease and a stable treatment regimen, for at least 1 year, withdrawal of 5 mg of prednisone was associated with a fourfold increase (ie, 27%), in the risk of flare onset, as defined by the SELENA-SLEDAI flare index and the British Isles Lupus Assessment Group index during a 1-year follow-up. 1 2Acharya states that these findings contrast with those from two previous published studies on the same subject. 3 4The latter studies are, however, not comparable to ours.As pointed out by Acharya, the Steroids In the Maintenance of remission of Proliferative Lupus nephritis (SIMPL) trial was a small pilot study, including only 15 patients, that was however not designed to assess the efficacy or safety of maintaining low-dose prednisone administration. 3With respect to the report of Moroni et al, in their study treatment withdrawal in patients with SLE with nephritis included not only glucocorticoids but also immunosuppressants. 4We would like to argue that the results of the CORTICOLUP trial are consistent with those of recently published observational studies, indicating that treatment with low-dose glucocorticoids prevents relapse in about one-fifth to one-third of patients with SLE with no or very low disease activity. 5 6 As suggested by Acharya, the results might have been different had the majority of patients been on immunosuppressant therapy.We, of course, do acknowledge that the results of the CORTI-COLUP study cannot be extrapolated to all patients in remission.The percentage of patients treated with an immunosuppressant in the CORTICOLUP study, amounting to 27%, reflects the clinical practice of our team.Moreover, our practice is comparable to that of other teams. 5 7Yet, the indication of an immunosuppressive treatment is not evidence based, especially in patients in remission, and depends to date on the decision of the physician and therefore varies according to his/her convictions.Finally, in the interaction analysis shown in figure 3 in our study, 2 there was no significant interaction between the effect of prednisone maintenance and immunosuppressants or hydroxychloroquine.To conclude, like Acharya, we believe that prescribing an immunosuppressant or a biologic might reduce the use of prolonged glucocorticoid therapy to prevent relapse of the disease.However, this belief has to be proved and balanced with the infectious and oncological risk possibly brought about by long-term exposure to this type of medication.
Economic Evaluation of Chimeric Antigen Receptor T-Cell Therapy by Site of Care Among Patients With Relapsed or Refractory Large B-Cell Lymphoma
Authors: Gary H. Lyman, Andy Nguyen, Sophie Snyder, Matthew Gitlin, Karen C. Chung
Journal: JAMA Network Open (2020)

Chimeric antigen receptor (CAR) T-cell therapies are currently administered at a limited number of cancer centers and are primarily delivered in an inpatient setting. However, variations in total costs associated with these therapies remain unknown.
Current understanding of metal ions in the pathogenesis of Alzheimer’s disease
Authors: Lu Wang, Ya-Ling Yin, Xin-Zi Liu, Peng Shen, Yan-Ge Zheng, Xin-Rui Lan, Cheng-Biao Lu, Jian-Zhi Wang
Journal: Translational Neurodegeneration (2020)

The homeostasis of metal ions, such as iron, copper, zinc and calcium, in the brain is crucial for maintaining normal physiological functions. Studies have shown that imbalance of these metal ions in the brain is closely related to the onset and progression of Alzheimer's disease (AD), the most common neurodegenerative disorder in the elderly.Erroneous deposition/distribution of the metal ions in different brain regions induces oxidative stress. The metal ions imbalance and oxidative stress together or independently promote amyloid-β (Aβ) overproduction by activating β- or γ-secretases and inhibiting α-secretase, it also causes tau hyperphosphorylation by activating protein kinases, such as glycogen synthase kinase-3β (GSK-3β), cyclin-dependent protein kinase-5 (CDK5), mitogen-activated protein kinases (MAPKs), etc., and inhibiting protein phosphatase 2A (PP2A). The metal ions imbalances can also directly or indirectly disrupt organelles, causing endoplasmic reticulum (ER) stress; mitochondrial and autophagic dysfunctions, which can cause or aggravate Aβ and tau aggregation/accumulation, and impair synaptic functions. Even worse, the metal ions imbalance-induced alterations can reversely exacerbate metal ions misdistribution and deposition. The vicious cycles between metal ions imbalances and Aβ/tau abnormalities will eventually lead to a chronic neurodegeneration and cognitive deficits, such as seen in AD patients.The metal ions imbalance induces Aβ and tau pathologies by directly or indirectly affecting multiple cellular/subcellular pathways, and the disrupted homeostasis can reversely aggravate the abnormalities of metal ions transportation/deposition. Therefore, adjusting metal balance by supplementing or chelating the metal ions may be potential in ameliorating AD pathologies, which provides new research directions for AD treatment.
Will Simplifying the Finnegan Neonatal Abstinence Scoring Tool Improve Outcomes for Infants With Opioid Exposure?
Authors: Ju Lee Oei, Trecia Wouldes
Journal: JAMA Network Open (2020)

Lori A. Devlin, DO; Janis L. Breeze, MPH; Norma Terrin, PhD; Enrique Gomez Pomar, MD; Henrietta Bada, MD; Loretta P. Finnegan, MD; Kevin E. O’Grady, PhD; Hendrée E. Jones, PhD; Barry Lester, PhD; Jonathan M. Davis, MD
Conditional immune toxicity rate in patients with metastatic renal and urothelial cancer treated with immune checkpoint inhibitors
Authors: Pier Vitale Nuzzo, Gregory R Pond, Sarah Abou Alaiwi, Amin H Nassar, Ronan Flippot, Catherine Curran, Kerry L Kilbridge, Xiao X Wei, Bradley A McGregor, Toni Choueiri, Lauren C Harshman, Guru Sonpavde
Journal: Journal for ImmunoTherapy of Cancer (2020)

Background Immune checkpoint inhibitors (ICIs) are associated with immune-related adverse events (irAEs). Although the incidence and prevalence of irAEs have been well characterized in the literature, less is known about the cumulative incidence rate of irAEs. We studied the cumulative incidence of irAEs, defined as the probability of irAE occurrence over time and the risk factors for irAE development in metastatic urothelial carcinoma (mUC) and renal cell carcinoma (mRCC) patients treated with ICIs. Methods We identified a cohort of patients who received ICIs for mUC and mRCC. irAEs were classified using Common Terminology Criteria for Adverse Event (CTCAE) V.5.0 guidelines. The monthly incidence of irAEs over time was reported after landmark duration of therapy. Cumulative incidence of irAEs was calculated to evaluate the time to the first occurrence of an irAE accounting for the competing risk of death. Prognostic factors for irAE were assessed using the Fine and Gray method. Results A total of 470 patients were treated with ICIs between July 2013 and October 2018 (mUC: 199 (42.3%); mRCC: 271 (57.7%)). 341 (72.6%) patients received monotherapy, 86 (18.3%) received ICIs in combination with targeted therapies, and 43 (9.2%) received dual ICI therapy. Overall, 186 patients (39.5%) experienced an irAE at any time point. Common irAEs included hypothyroidism (n=42, 22.6%), rush and pruritus (n=36, 19.4%), diarrhea/colitis (n=35, 18.8%), transaminitis (n=32, 17.2%), and pneumonitis (n=14, 7.5%). Monthly incidence rates decreased over time; however, 17 of 109 (15.6%, 95% CI: 9.4% to 23.8%) experienced their first irAE at least 1 year after treatment initiation. No differences in cumulative incidence were observed based on cancer type, agent, or irAE grade. On multivariable analysis, combined ICI therapy with another ICI or with targeted therapy (p&lt;0.001), first-line ICI therapy (p=0.011), and PD-1 inhibitor therapy (p=0.007) were all significantly associated with irAE development. Conclusions This study quantitates the incidence of developing irAEs due to ICI conditioned on time elapsed without irAE development. Although the monthly incidence of irAEs decreased over time on therapy, patients can still develop delayed irAEs beyond ICI discontinuation, and thus, continuous vigilant monitoring is warranted.
Women whose cervical cancer was missed can have surrogacy abroad paid for by the NHS
Authors: Clare Dyer
Journal: BMJ (2020)

The NHS can be ordered to pay for surrogacy treatment abroad if a hospital’s negligence leaves a woman infertile, the UK Supreme Court has ruled in a landmark judgment.

By a 3-2 majority, the court decided that it would not be against public policy to allow a woman who developed cervical cancer after several smear tests and biopsies were wrongly interpreted to be awarded damages covering surrogacy treatment abroad.1

Lady Hale, who gave the leading judgment, said that the woman, referred to as XX, was aged 29 when her cancer was discovered in 2013. “She had a cervical smear test in 2008, which was wrongly …
Tumor Mutation Burden and Depression in Lung Cancer: Association With Inflammation
Authors: Daniel C. McFarland, Devika R. Jutagir, Andrew H. Miller, William Breitbart, Christian Nelson, Barry Rosenfeld
Journal: Journal of the National Comprehensive Cancer Network (2020)

Patients with lung cancer with greater systemic inflammation have higher rates of depression. Tumor mutation burden (TMB) predicts immunotherapy response in patients with lung cancer and is associated with intratumoral inflammation, which may contribute to systemic inflammation and depression. This study evaluated whether higher TMB was associated with increased depression and systemic inflammation in patients with lung cancer.Patients with metastatic lung cancers were evaluated for depression severity using the Hospital Anxiety and Depression Scale. TMB was measured using the Memorial Sloan Kettering-Integrated Mutation Profiling of Actionable Cancer Targets. Inflammation was evaluated using C-reactive protein (CRP) level and neutrophil-to-lymphocyte ratio (NLR).A total of 96 patients with adequate TMB testing were evaluated. The average number of mutations (TMB) was 10.8 (SD, 10.9). A total of 19% of patients endorsed clinically significant depression symptoms. TMB was significantly correlated with depression severity (r = 0.34; P=.001) and NLR (r = 0.37; P=.002) but not CRP level (r = 0.19; P=.07). TMB was also higher in patients receiving chemotherapy (mean, 12.0) and immunotherapy (mean, 14.4) versus targeted therapy (mean, 4.8). A multivariate model found that TMB (β = 0.30; P=.01) and CRP level (β = 0.31; P=.01) were independently associated with depression; there was no significant interaction effect of TMB × CRP and depression. A similar multivariate model showed no independent effect for NLR and depression (β = 0.16; P=.17) after accounting for TMB.These data provide evidence for biologic depression risk in patients with lung cancer who have high levels of TMB. The underlying mechanism of the association is not clearly related to inflammation but warrants further analysis to broadly elucidate the mechanism of biologically derived depression in cancer.
PBX1 expression in uterine natural killer cells drives fetal growth
Authors: Yonggang Zhou, Binqing Fu, Xiuxiu Xu, Jinghe Zhang, Xianhong Tong, Yanshi Wang, Zhongjun Dong, Xiaoren Zhang, Nan Shen, Yiwen Zhai, Xiangdong Kong, Rui Sun, Zhigang Tian, Haiming Wei
Journal: Science Translational Medicine (2020)

A subset of uterine natural killer cells promotes fetal growth through regulation of growth-promoting factors by PBX1.
Supporting colleagues during covid-19: the intensive care consultant
Authors: Adrian O’Dowd
Journal: BMJ (2020)

<h3>Objectives</h3> Physical exercise has beneficial effects on cardiovascular risk factors. Knowledge about the effect of exercise intensity, specifically walking speed, on cardiovascular risk factors is limited. We report the relationship between walking speed and changes in cardiovascular risk factors in participants of a 12-day walking tour to Santiago de Compostela. <h3>Design</h3> Prospective cohort study. <h3>Setting</h3> Single-centre study with healthy middle-aged volunteers. <h3>Participants</h3> Healthy middle-aged men (n=15) and women (n=14). Subjects using lipid-lowering medication were excluded. <h3>Intervention</h3> Participants walked 281±10 km of the classical route to Santiago de Compostela in 12 days in 2009. <h3>Primary and secondary outcome measures</h3> Walking speed was recorded and blood pressure, weight, waist circumference, lipids and glucose were measured every other day. Changes in risk factors were compared between gender-pooled groups with faster and slower walking speed. Second, the relationship between walking speed and changes in risk factors was quantified using a linear mixed effects model. <h3>Results</h3> In the faster walking speed (4.6±0.2 km/h) group, high-density lipoprotein cholesterol (HDL-c) increased more than in the slower walking speed (4.1±0.2 km/h) group (difference in change between groups: 0.20; 95% CI −0.02 to 0.42 mmol/l), while low-density lipoprotein cholesterol (LDL-c) and total cholesterol decreased more in the slower walking speed group (differences in changes between groups: LDL-c: −0.50; 95% CI −0.88 to −0.12 mmol/l and total cholesterol: −0.75; 95% CI −1.19 to −0.31 mmol/l). A 1 km/h higher walking speed was related to an increase in HDL-c (0.24; 95% CI 0.12 to 0.30 mmol/l), LDL-c (0.18; 95% CI −0.16 to 0.42 mmol/l) and total cholesterol (0.36; 95% CI 0.12 to 0.60 mmol/l), adjusted for age, gender, smoking, body mass index and heart rate, during the whole walking tour. <h3>Conclusions</h3> Walking the same distance faster improves HDL-c more, while LDL-c and total cholesterol decrease more with lower walking speed independent of changes in body weight in healthy middle-aged subjects.
A novel protein encoded by circFNDC3B inhibits tumor progression and EMT through regulating Snail in colon cancer
Authors: Zihao Pan, Jianye Cai, Jiatong Lin, Huinian Zhou, Jingwen Peng, Jinliang Liang, Long Xia, Qi Yin, Baojia Zou, Jun Zheng, Liang Qiao, Lei Zhang
Journal: Molecular Cancer (2020)

Colon cancer (CC) is a common malignant cancer. Recently, circFNDC3B was found to exert biological function in multiple cancers. However, it was unclear whether the potential protein encoded by circFNDC3B is involved in carcinogenesis of CC.We used Sanger sequence and RNase R digestion assay to confirm the existence of circFNDC3B, and quantitative real-time PCR was used to evaluate the circRNA's expression. Then fluorescence in situ hybridization (FISH) was performed to study location of circFNDC3B. The identification of protein encoded by circFNDC3B was performed using LC-MS/MS. The function of circFNDC3B-218aa on proliferation, invasion and migration were assessed by CCK8 assays, colony formation assays, transwell assays, wound-healing assays and animal experiments. RNA-sequencing and western blot were used to identify the gene regulated by circFNDC3B-218aa. Finally, glucose metabolism-related assays were performed to further investigate function of circFNDC3B-218aa.CircFNDC3B was localized mostly in the cytoplasm, and was decreased in CC cell lines and tissues. The patients with low circFNDC3B expression had a shorter OS (P = 0.0014) than patients with high expression. Moreover, circFNDC3B inhibited the proliferation, invasion and migration of CC cells. Next, we identified that circFNDC3B could encode a novel protein circFNDC3B-218aa. Furthermore, circFNDC3B-218aa, not circFNDC3B, inhibited the proliferation, invasion and migration of CC. Additionally, the in vivo experiments implied that up-regulated circFNDC3B-218aa exhibited an inhibitory effect on CC progression. By RNA-sequencing, western blot and glucose metabolism-related assays, we found that circFNDC3B-218aa inhibited the expression of Snail, and subsequently promoted the tumor-suppressive effect of FBP1 in CC.The novel circFNDC3B-218aa may serve as a tumor suppressive factor and potential biomarker which may supply the potential therapeutic target for CC.
Emergency Restructuring of a General Surgery Residency Program During the Coronavirus Disease 2019 Pandemic
Authors: Amer H. Nassar, Nicole K. Zern, Lisa K. McIntyre, Dana Lynge, Caitlin A. Smith, Rebecca P. Petersen, Karen D. Horvath, Douglas E. Wood
Journal: JAMA Surgery (2020)

Seattle, Washington, is an epicenter of the coronavirus disease 2019 epidemic in the United States. In response, the Division of General Surgery at the University of Washington Department of Surgery in Seattle has designed and implemented an emergency restructuring of the facility's general surgery resident care teams in an attempt to optimize workforce well-being, comply with physical distancing requirements, and continue excellent patient care. This article introduces a unique approach to general surgery resident allocation by dividing patient care into separate inpatient care, operating care, and clinic care teams. Separate teams made up of all resident levels will work in each setting for a 1-week period. By creating this emergency structure, we have limited the number of surgery residents with direct patient contact and have created teams working in isolation from one another to optimize physical distancing while still performing required work. This also provides a resident reserve without exposure to the virus, theoretically flattening the curve among our general surgery resident cohort. Surgical resident team restructuring is critical during a pandemic to optimize patient care and ensure the well-being and vitality of the resident workforce while ensuring the entire workforce is not compromised.
Protecting Medical Trainees on the COVID-19 Frontlines Saves Us All
Authors: Robert A. Harrington, Mitchell S.V. Elkind, Ivor J. Benjamin
Journal: Circulation (2020)

any fourth-year medical students who have met requirements and normally would be enjoying time off until graduation in May and June are being called to the frontlines to fight the coronavirus disease 2019 (COVID-19) pandemic.Massachusetts became the first state to encourage this practice, enacting plans to issue 90-day provisional licenses to early graduates of all 4 medical schools, transitioning 700 residents and fellows into supervised patient care at least 8 weeks ahead of schedule.Several universities have followed suit in an all-hands-on-deck effort to stop this insidious virus that is cutting a path across the globe, claiming tens of thousands of lives and sickening more than 2 million more.The issue is that dispatching doctors-in-training to perform patient care outside their clinical competencies is a risk.This is further complicated by the contagion of COVID-19, evolving knowledge about the virus and its behavior in the environment, and a critical shortage of personal protective equipment (PPE).If the outbreak in China is any indication, healthcare workers are 3 times more likely than the general population to contract the disease and be vectors of transmission.For example, more than 600 hospital workers in Massachusetts, both clinical and nonclinical, are infected to date.Some were infected through exposure at work and others through community spread.Residents and fellows-whether because of lack of experience, poor preparation, or lack of training-are particularly vulnerable.Although they receive training, it is unclear whether it is evidence based, standardized, or adequate.The position of the American Heart Association is clear: Protect medical trainees on the COVID-19 frontlines, or do not send them in: "All medical professionals want to help, but fellows and residents are being asked to do things they are not fully trained to do and that take them longer to perform than attending physicians," said Mariell Jessup, MD, chief science and medical officer at the American Heart Association."At the very least, we need to ensure they are protected with proper PPE."The Accreditation Council for Graduate Medical Education agrees.As the nation's principal accreditor for residency and fellowship education in medicine, the council has focused on ensuring the safety and supervision of trainees during this crisis."Without adequate PPE and access to sufficient viral testing, our physician faculty and residents and fellows now risk becoming vectors of this deadly virus, endangering their patients, fellow health care workers, and all those they contact," the Accreditation Council for Graduate Medical Education states."The pledge to 'first do no harm' becomes meaningless under these circumstances." 1,2