tbuckley/cabot-search huggingface dataset:
Hyperglycaemia in CF adversely affects BK channel function critical for mucus clearance
Authors: Charles D. Bengtson, Michael D. Kim, Abeer Anabtawi, Jianghua He, John S. Dennis, Sara Miller, Makoto Yoshida, Nathalie Baumlin, Matthias Salathe
Journal: European Respiratory Journal (2020)

Large-conductance, Ca 2+ -activated, voltage-dependent K + (BK) channel function is critical for adequate airway hydration and mucociliary function. In airway epithelia, BK function is regulated by its γ-subunit, leucine-rich repeat-containing protein 26 (LRRC26). Since patients with cystic fibrosis (CF)-related diabetes mellitus (CFRD) have worse lung function outcomes, this study determined the effects of hyperglycaemia on BK function in CF bronchial epithelial (CFBE) cells in vitro and evaluated the correlation between glycaemic excursions and mRNA expression of LRRC26 in the upper airways of CF and CFRD patients. CFBE cells were redifferentiated at the air–liquid interface (ALI) in media containing either 5.5 mM or 12.5 mM glucose. BK activity was measured in an Ussing chamber. Airway surface liquid (ASL) volume was estimated by meniscus scanning and inflammatory marker expression was measured by quantitative real-time PCR and enzyme-linked immunosorbent assay (ELISA). CF patients were assessed by 7 days of continuous glucose monitoring (CGM). LRRC26 mRNA expression was measured by quantitative real-time PCR from nasal cells obtained at the end of glucose monitoring. BK currents were significantly decreased in CFBE cells cultured under high glucose. These cells revealed significantly lower ASL volumes and increased inflammation, including the receptor for advanced glycation endproducts (RAGE), compared to cells cultured in normal glucose. In vivo , nasal cell expression of LRRC26 mRNA was inversely correlated with hyperglycaemic excursions, consistent with the in vitro results. Our findings demonstrate that hyperglycaemia induces inflammation and impairs BK channel function in CFBE cells in vitro . These data suggest that declining lung function in CFRD patients may be related to BK channel dysfunction.
Highly Sensitive Flexible Iontronic Pressure Sensor for Fingertip Pulse Monitoring
Authors: Qiupeng Lin, Jun Huang, Junlong Yang, Yi Huang, Yifan Zhang, Yueji Wang, Jianming Zhang, Yan Wang, Linlin Yuan, Minkun Cai, Xingyu Hou, Weixing Zhang, Yunlong Zhou, Shi Guo Chen, Chuan Fei Guo
Journal: Advanced Healthcare Materials (2020)

Abstract The pulse is a key biomedical signal containing various human physiological and pathological information highly related to cardiovascular diseases. Pulse signals are often collected from the radial artery based on Traditional Chinese Medicine, or by using flexible pressure sensors. However, the wrist wrapped with a flexible pressure sensor exhibits unstable signals under hand motion because of the concave surface of the wrist. By contrast, fingertips have a convex surface and therefore show great promises in stable and long‐term pulse monitoring. Despite the promising potential, the fingertip pulse signal is weak, calling for highly sensitive detecting devices. Here, a highly sensitive and flexible iontronic pressure sensor with a linear sensitivity of 13.5 kPa −1 , a swift response, and remarkable stability over 5000 loading/unloading cycles is developed. This sensor enables stable and high‐resolution detection of pulse waveform under both static condition and finger motion. Fingertip pulse waveforms from subjects of different genders, age, and health conditions are collected and analyzed, suggesting that fingertip pulse information is highly similar to that of the radial artery. This work justifies that fingertip is an ideal platform for pulse signals monitoring, which would be a competitive alternative to existing complex health monitoring systems.
Abstract #5316: Curcumin inhibits ectopic human coagulation factor VII synthesis in breast cancer cells by targeting p300/CBP activity
Authors: Shiro Koizume, Naho Yokota, Etsuko Miyagi, Fumiki Hirahara, Yoshiyasu Nakamura, Akira Yoshida, Eiju Tsuchiya, Wolfram Ruf, Yohei Miyagi
Journal: Cancer Research (2009)

Blood coagulation factor VII (fVII) is a key component of the extrinsic coagulation cascade that is produced predominantly by hepatocytes. Tissue factor/fVIIa complex formation on the cell surface triggers key pathogenic mechanisms in cancer, including cell motility, invasion, cell survival, and angiogenesis. We have shown that various cancer cells ectopically synthesize fVII, resulting in activation of cell motility and invasion[1]. Notably, the ectopic expression was prominent in breast cancer cell lines [1]. Here, we show by real-time RT-PCR and immunohistochemical analysis that fVII expression is a frequent finding in primary breast cancer. Expression levels in breast cancer tissues were mostly comparable to or higher than those of normal liver tissues. We further characterized mechanisms of hepatic and ectopic fVII gene (FVII) expression to identify molecular targets enabling selective inhibition of the ectopic expression. Unlike hepatic expression, we previously found that HNF-4 binding to the promoter is not required for ectopic FVII expression, although Sp1 binding is essential [2]. Furthermore, we reported novel nuclear targets of basal hepatocytic and ectopic FVII expression, including transcription factors Egr-1 [2], USF-1 [2]. In the present study we additionally show that CREB also plays a role in basal hepatocytic and ectopic FVII expression. Chromatin immunoprecipitation analysis revealed that histone H4 at active FVII promoter region was highly acetylated both in hepatic and breast cancer cells. Methylation of arginine residues of histones was also similar between hepatic and ectopic FVII expression. However, histone acetyltransferases (HATs) p300 and CBP are recruited to the promoter region of the FVII gene specifically in breast cancer cells although additional HATs, PCAF and SRC-1 can be recruited in hepatocytes. We further show that HAT recruitment can be targeted for selective inhibition of ectopic fVII synthesis. Curcumin, a component of the spice turmeric, can selectively inhibit ectopic fVII expression by displacing p300/CBP activity from the FVII promoter. These results suggest a strategy to inhibit ectopic fVII synthesis in cancer cells without impairment of the physiological hemostatic process. References: 1. Koizume S, et al. Cancer Res. 66:9453-9460, 2006. 2. Koizume S, et al. the 99th AACR annual meeting, San Diego, CA, 2008.  Citation Information: In: Proc Am Assoc Cancer Res; 2009 Apr 18-22; Denver, CO. Philadelphia (PA): AACR; 2009. Abstract nr 5316.
Helen Salisbury: How will we run flu clinics in a pandemic?
Authors: Helen Salisbury
Journal: BMJ (2020)

In previous years, the queue for our flu vaccine clinic has been in place well before we open the doors. Patients pile into the waiting room, register with the reception staff, and roll up their sleeves in anticipation. There’s jolly banter between neighbours and occasional harrumphing if people think they’ve been kept waiting too long. Doctors and nurses try not to be drawn into too much conversation before giving the injection, preceded by the traditional warning, “Sharp scratch” (although, as it really isn’t a scratch, I’ve resorted to saying, “Sharp, now”).

We’ve been thinking about how to run our clinics this year, considering the need …
Phase II Study of Pembrolizumab As First-Line, Single-Drug Therapy for Patients With Unresectable Cutaneous Squamous Cell Carcinomas
Authors: Eve Maubec, Marouane Boubaya, Peter Petrow, Marie Beylot-Barry, Nicole Basset-Seguin, Lydia Deschamps, Jean-Jacques Grob, Brigitte Dréno, Isabelle Scheer-Senyarich, Coralie Bloch-Queyrat, Marie-Thérèse Leccia, Andreea Stefan, Philippe Saiag, Florent Grange, Nicolas Meyer, Julie de Quatrebarbes, Monica Dinulescu, Delphine Legoupil, Laurent Machet, Olivier Dereure, Ouidad Zehou, Henri Montaudié, Ewa Wierzbicka-Hainaut, Yannick Le Corre, Sandrine Mansard, Sarah Guégan, Jean-Philippe Arnault, Sophie Dalac, François Aubin, Céline Alloux, Isabelle Lopez, Soufian Cherbal, Annick Tibi, Vincent Lévy
Journal: Journal of Clinical Oncology (2020)

PURPOSE To evaluate first-line pembrolizumab monotherapy efficacy and safety in patients with unresectable cutaneous squamous cell carcinomas (CSCCs). PATIENTS AND METHODS Patients, predominantly men, with their CSSCs’ immunohistochemically determined programmed cell death-ligand 1 (PD-L1) status determined (tumor proportion score threshold, 1%), received pembrolizumab (200 mg every 3 weeks). The primary endpoint was the 39-patient primary cohort’s objective response rate at week 15 (ORR W15 ). Secondary objectives were best ORR, overall survival (OS), progression-free survival (PFS), duration of response (DOR), safety, ORR according to PD-L1 status and health-related quality of life using Functional Assessment of Cancer Therapy–General (FACT-G) score. An 18-patient expansion cohort, recruited to power the study to evaluate the ORR W15 difference between PD-L1+ and PD-L1– patients, was assessed for ORR, disease control rate, and safety, but not survival. RESULTS Median age of all patients was 79 years. The primary cohort’s ORR W15 was 41% (95% CI, 26% to 58%), including 13 partial and 3 complete responses. Best responses were 8 partial and 8 complete responses. At a median follow-up of 22.4 months, respective median PFS, DOR, and OS were 6.7 months, not reached, and 25.3 months, respectively. Pembrolizumab-related adverse events affected 71% of the patients, and 4 (7%) were grade ≥ 3. One death was related to rapid CSCC progression; another resulted from a fatal second aggressive head and neck squamous cell carcinoma diagnosed 15 weeks postinclusion. ORR W15 for the entire population was 42%; it was significantly higher for PD-L1+ patients (55%) versus PD-L1– patients (17%; P = .02). Responders’ W15 total FACT-G score had improved ( P = .025) compared with nonresponders. CONCLUSION First-line pembrolizumab monotherapy exhibited promising anti-CSCC activity, with durable responses and manageable safety. PD-L1 positivity appears to be predictive of pembrolizumab efficacy.
Abstract IA16: ER stress responses shape the ovarian cancer immune-microenvironment
Authors: Juan R. Cubillos-Ruiz
Journal: Clinical Cancer Research (2020)

Abstract Harnessing the intrinsic ability of our immune system to eliminate malignant cells represents the most promising new anticancer strategy since the development of chemotherapy. While cancer immunotherapy has been designated a scientific breakthrough, tumor-induced immunosuppression represents a major impediment to the success of this new approach in ovarian cancer. We uncovered that ovarian cancer inhibits the development of protective antitumor immunity by inducing a state of persistent “endoplasmic reticulum (ER) stress” in intratumoral dendritic cells (DCs) and T cells. First, we identified that sustained activation of the IRE1-XBP1 arm of the ER stress response in DCs was necessary for the aggressive and accelerated progression of primary and metastatic ovarian cancers in various preclinical models of disease. Mechanistically, intratumoral DCs exhibited constitutive IRE1-XBP1 activation, which was fueled by lipid peroxidation byproducts that caused ER stress by modifying ER-resident chaperones. Persistent XBP1 activation induced a comprehensive triglyceride biosynthetic program promoting accumulation of lipid droplets that subsequently impaired DC antigen presentation to T cells. Conditional deletion or therapeutic silencing of IRE1 or XBP1 in DCs restored their immunogenic function in the tumor and delayed ovarian cancer progression by eliciting protective antitumor T-cell responses. In addition, we recently demonstrated that ovarian cancer also triggers abnormal IRE1-XBP1 activation in T cells to control their mitochondrial function and antitumor activity. XBP1 upregulation in T cells isolated from human ovarian cancer specimens was associated with decreased intratumoral T-cell infiltration and reduced IFNG expression. Ascites fluid from ovarian cancer patients inhibited glucose uptake and caused N-linked protein glycosylation defects in T cells, leading to XBP1-driven mitochondrial dysfunction. Mechanistically, maladaptive XBP1 signaling limited the influx of glutamine necessary to sustain mitochondrial respiration under glucose-deprived conditions. Hence, ovarian cancer hosts lacking XBP1 selectively in T cells demonstrated superior antitumor immunity, delayed malignant progression, and increased overall survival. Taken together, our studies revealed that ovarian cancer provokes persistent IRE1-XBP1 signaling in immune cells to shape the tumor microenvironment and evade immune control. These findings provide a new mechanistic understanding of immunosuppression in ovarian cancer and offer novel avenues for immunotherapeutic intervention. Citation Format: Juan R. Cubillos-Ruiz. ER stress responses shape the ovarian cancer immune-microenvironment [abstract]. In: Proceedings of the AACR Special Conference on Advances in Ovarian Cancer Research; 2019 Sep 13-16, 2019; Atlanta, GA. Philadelphia (PA): AACR; Clin Cancer Res 2020;26(13_Suppl):Abstract nr IA16.
Covid-19: US needs a national plan to fight rising infections, experts say
Authors: Janice Hopkins Tanne
Journal: BMJ (2020)

Three scientific organisations have proposed plans for the US to gain control of the pandemic as a leading Democrat declared that it was a "public health catastrophe" with more infections and deaths than any other country, South Carolina Democrat James Clyburn, chairman of the House of Representatives Select Subcommittee on the Coronavirus Crisis, said at a committee hearing on 31 July that President Donald Trump had downplayed the urgency of the pandemic and deferred responsibility to individual states.Clyburn said that the US urgently needed a national plan to contain the virus.An article in Vanity Fair reported that the president's son-in-law, Jared Kushner, had a secret project to set up a national system of oversight and coordination to provide supplies, test kits, and establish a surveillance programme.It claimed that the plan was dropped because the virus hit Democrat states hardest, rather than Trump's Republican base. 1 1
Seizure control as a new metric in assessing efficacy of tumor treatment in low-grade glioma trials (vol 19, pg 12, 2016)
Authors: E.K. Avila, M. Chamberlain, D. Schiff, J.C. Reijneveld, T.S. Armstrong, R. Ruda, P.Y. Wen, M. Weller, J.A.F. Koekkoek, S. Mittal, Y. Arakawa, A. Choucair, J. Gonzalez-Martinez, D.R. MacDonald, R. Nishikawa, A. Shah, C.J. Vecht, P. Warren, M.J. van den Bent, L.M. DeAngelis
Journal: Neuro-Oncology (2017)
Clinical Portrait of the SARS-CoV-2 Epidemic in European Patients with Cancer
Authors: David J. Pinato, Alberto Zambelli, Juan Aguilar-Company, Mark Bower, Christopher C.T. Sng, Ramon Salazar, Alexia Bertuzzi, Joan Brunet, Ricard Mesia, Elia Seguí, Federica Biello, Daniele Generali, Salvatore Grisanti, Gianpiero Rizzo, Michela Libertini, Antonio Maconi, Nadia Harbeck, Bruno Vincenzi, Rossella Bertulli, Diego Ottaviani, Anna Carbó, Riccardo Bruna, Sarah Benafif, Andrea Marrari, Rachel Wuerstlein, M. Carmen Carmona-Garcia, Neha Chopra, Carlo Tondini, Oriol Mirallas, Valeria Tovazzi, Marta Betti, Salvatore Provenzano, Vittoria Fotia, Claudia Andrea Cruz, Alessia Dalla Pria, Francesca D'Avanzo, Joanne S. Evans, Nadia Saoudi-Gonzalez, Eudald Felip, Myria Galazi, Isabel Garcia-Fructuoso, Alvin J.X. Lee, Thomas Newsom-Davis, Andrea Patriarca, David García-Illescas, Roxana Reyes, Palma Dileo, Rachel Sharkey, Yien Ning Sophia Wong, Daniela Ferrante, Javier Marco-Hernández, Anna Sureda, Clara Maluquer, Isabel Ruiz-Camps, Gianluca Gaidano, Lorenza Rimassa, Lorenzo Chiudinelli, Macarena Izuzquiza, Alba Cabirta, Michela Franchi, Armando Santoro, Aleix Prat, Josep Tabernero, Alessandra Gennari, Gian Carlo Avanzi, Mattia Bellan, Luigi Mario Castello, Maria Martinez, Meritxell Mollà, Mario Pirisi, Lorenza Scotti, Judith Swallow
Journal: Cancer Discovery (2020)

Abstract The SARS-CoV-2 pandemic significantly affected oncology practice across the globe. There is uncertainty as to the contribution of patients' demographics and oncologic features to severity and mortality from COVID-19 and little guidance as to the role of anticancer and anti–COVID-19 therapy in this population. In a multicenter study of 890 patients with cancer with confirmed COVID-19, we demonstrated a worsening gradient of mortality from breast cancer to hematologic malignancies and showed that male gender, older age, and number of comorbidities identify a subset of patients with significantly worse mortality rates from COVID-19. Provision of chemotherapy, targeted therapy, or immunotherapy did not worsen mortality. Exposure to antimalarials was associated with improved mortality rates independent of baseline prognostic factors. This study highlights the clinical utility of demographic factors for individualized risk stratification of patients and supports further research into emerging anti–COVID-19 therapeutics in SARS-CoV-2–infected patients with cancer. Significance: In this observational study of 890 patients with cancer diagnosed with SARS-CoV-2, mortality was 33.6% and predicted by male gender, age ≥65, and comorbidity burden. Delivery of cancer therapy was not detrimental to severity or mortality from COVID-19. These patients should be the focus of shielding efforts during the SARS-CoV-2 pandemic. This article is highlighted in the In This Issue feature, p. 1426
Patterns of Firearm Ownership and Opinions on Firearm Policies Among Adults in California
Authors: Julia P. Schleimer, Rocco Pallin, Garen J. Wintemute, Amanda Charbonneau, Nicole Kravitz-Wirtz
Journal: JAMA Network Open (2020)

This survey study assess whether patterns in firearm ownership are associated with opinions on firearm safety among adults in California.
DAPSA, carotid plaque and cardiovascular events in psoriatic arthritis: a longitudinal study
Authors: Steven Ho Man Lam, Isaac T Cheng, Edmund K Li, Priscilla Wong, Jolie Lee, Ronald Man-Lung Yip, Cheuk-Wan Yim, Shirley K Ying, Martin Li, Tena K Li, Alex Pui-Wai Lee, Lai-Shan Tam
Journal: Annals of the Rheumatic Diseases (2020)

Objective To examine whether Disease Activity in Psoriatic Arthritis (DAPSA) reflecting the inflammatory component of psoriatic arthritis (PsA) can predict cardiovascular (CV) events independent of traditional CV risk factors and subclinical carotid atherosclerosis. Methods A cohort analysis was performed in patients with PsA who had been followed since 2006. The outcome of interest was first CV event. Four different CV disease (CVD) risk scores and DAPSA were computed at baseline. The presence of carotid plaque (CP) and carotid intima-media thickness (CIMT) was also determined in a subgroup of patients using high-resolution ultrasound. The association between DAPSA, CVD risk scores, CP, CIMT and the occurrence of CV events was assessed using Cox proportional hazard models. Results 189 patients with PsA (mean age: 48.9 years; male: 104 (55.0%)) were recruited. After a median follow-up of 9.9 years, 27 (14.3%) patients developed a CV event. Higher DAPSA was significantly associated with an increased risk of developing CV events (HR: 1.04, 95% CI (1.01 to 1.08), p=0.009). The association remained significant after adjusting for all CV risk scores in the multivariable models. In the subgroup analysis, 154 patients underwent carotid ultrasound assessment and 23 (14.9%) of them experienced a CV event. CP was associated with increased risk of developing CV events after adjusting for three CV risk scores and DAPSA, with HR ranging from 2.35 to 3.42. Conclusion Higher DAPSA and the presence of CP could independently predict CVD events in addition to traditional CV risk scores in patients with PsA.
Practice composition and sex differences in physician income: observational study
Authors: Christopher M Whaley, Daniel R Arnold, Nate Gross, Anupam B Jena
Journal: BMJ (2020)

Abstract Objective To assess whether differences in income between male and female physicians vary according to the sex composition of physician practices. Design Retrospective observational study. Setting US national survey of physician salaries, 2014-18. Participants 18 802 physicians from 9848 group practices (categorized according to proportion of male physicians ≤50%, &gt;50-75%, &gt;75-90%, and &gt;90%). Main outcome measures Sex differences in physician income in relation to the sex composition of physician practices after multivariable adjustment for physician specialty, years of experience, hours worked, measures of clinical workload, practice type, and geography. Results Among 11 490 non-surgical specialists, the absolute adjusted sex difference in annual income (men versus women) was $36 604 (£29 663; €32 621) (95% confidence interval $24 903 to $48 306; 11.7% relative difference) for practices with 50% or less of male physicians compared with $91 669 ($56 587 to $126 571; 19.9% relative difference) for practices with at least 90% of male physicians (P=0.03 for difference). Similar findings were observed among surgical specialists (n=3483), with absolute adjusted sex difference in annual income of $46 503 ($42 198 to $135 205; 10.2% relative difference) for practices with 50% or less of male physicians compared with $149 460 ($86 040 to $212 880; 26.9% relative difference) for practices with at least 90% of male physicians (P=0.06 for difference). Among primary care physicians (n=3829), sex differences in income were not related to the proportion of male physicians in a practice. Conclusions Among both non-surgical and surgical specialists, sex differences in income were largest in practices with the highest proportion of male physicians, even after detailed adjustment for factors that might explain sex differences in income.