tbuckley/cabot-search huggingface dataset:
Therapeutic Modulation of the Immune Response in Arrhythmogenic Cardiomyopathy
Authors: Stephen P. Chelko, Angeliki Asimaki, Justin Lowenthal, Carlos Bueno-Beti, Djahida Bedja, Arianna Scalco, Nuria Amat-Alarcon, Peter Andersen, Daniel P. Judge, Leslie Tung, Jeffrey E. Saffitz
Journal: Circulation (2019)

Background: Inflammation is a prominent feature of arrhythmogenic cardiomyopathy (ACM), but whether it contributes to the disease phenotype is not known. Methods: To define the role of inflammation in the pathogenesis of ACM, we characterized nuclear factor-κB signaling in ACM models in vitro and in vivo and in cardiac myocytes from patient induced pluripotent stem cells. Results: Activation of nuclear factor-κB signaling, indicated by increased expression and nuclear accumulation of phospho-RelA/p65, occurred in both an in vitro model of ACM (expression of JUP 2157del2 in neonatal rat ventricular myocytes) and a robust murine model of ACM (homozygous knock-in of mutant desmoglein-2 [ Dsg2 mut/mu t ]) that recapitulates the cardiac manifestations seen in patients with ACM. Bay 11-7082, a small-molecule inhibitor of nuclear factor-κB signaling, prevented the development of ACM disease features in vitro (abnormal redistribution of intercalated disk proteins, myocyte apoptosis, release of inflammatory cytokines) and in vivo (myocardial necrosis and fibrosis, left ventricular contractile dysfunction, electrocardiographic abnormalities). Hearts of Dsg2 mut/mut mice expressed markedly increased levels of inflammatory cytokines and chemotactic molecules that were attenuated by Bay 11-7082. Salutary effects of Bay 11-7082 correlated with the extent to which production of selected cytokines had been blocked. Nuclear factor-κB signaling was also activated in cardiac myocytes derived from a patient with ACM. These cells produced and secreted abundant inflammatory cytokines under basal conditions, and this was also greatly reduced by Bay 11-7082. Conclusions: Inflammatory signaling is activated in ACM and drives key features of the disease. Targeting inflammatory pathways may be an effective new mechanism-based therapy for ACM.
Quality of reporting in systematic reviews published in dermatology journals
Authors: D.O. Croitoru, Y. Huang, A. Kurdina, A.‐W. Chan, A‐M. Drucker
Journal: British Journal of Dermatology (2019)

Reporting of systematic reviews (SRs) using PRISMA increases transparency and reproducibility; adherence in the dermatology literature has not been assessed.To assess selected, primarily methodological items from the PRISMA reporting guideline among SRs published in dermatology journals.We reviewed SRs published from 2013 to 2017 in the five highest-impact dermatology journals according to the Science Citation Index. We descriptively assessed reporting of selected PRISMA items, the proportion of PRISMA items fully and partially reported, and whether SRs described using a preregistered protocol. We used univariate and multivariate linear regression to evaluate associations between exposures (year, protocol registration, funding source, type of included study, disease and journal), and outcomes (proportion of PRISMA items fully reported, and fully and partially reported, for each SR).We identified 136 SRs. All had more than one inadequately reported PRISMA item. Protocol registration (73%) and risk of bias (38%) were most often unreported. Reporting improved over time in our primary multivariate analysis [fully reported vs. partially and not reported, β = 2·48; 95% confidence interval (CI) 0·73-4·27] and secondary analysis (fully and partially reported vs. not reported, β = 1·28, 95% CI 0·06-2·50). Only 15% (20 of 136) of SRs stated that their protocols were registered; this was associated with PRISMA adherence to the evaluated PRISMA items in our primary multivariate analysis (β = 10·05, 95% CI 2·89-17·2) and secondary analysis (β = 8·87, 95% CI 3·84-13·9).SR reporting in dermatology journals is often inadequate but improving over time; protocol registration is associated with better reporting. What's already known about this topic? No studies to date have examined the adherence of dermatology systematic reviews (SRs) to reporting guidelines, such as PRISMA. In other medical fields, reporting is variable with some improvement in adherence to reporting standards over time. What does this study add? Among SRs published in five dermatology journals from 2013 to 2017, all (n = 136) had at least one inadequately reported PRISMA item, while 93% (127 of 136) had at least one fully nonreported item. Reporting improved over time and SRs that stated use of a preregistered protocol were associated with better reporting. Several items remain commonly underreported in dermatology SRs. Authors, reviewers, journal editors and editorial committees should encourage preregistration of SR protocols and improved SR reporting.
Chromosomal Instability and mTORC1 Activation through PTEN Loss Contribute to Proteotoxic Stress in Ovarian Carcinoma
Authors: M. Herman Chui, Sasha A. Doodnauth, Natalie Erdmann, Rodger E. Tiedemann, Fabrice Sircoulomb, Ronny Drapkin, Patricia Shaw, Robert Rottapel
Journal: Cancer Research (2019)

High-grade serous ovarian carcinoma commonly arises from fallopian tube secretory epithelium and is characterized by a high level of chromosomal instability. To model the acquisition of aneuploidy during early carcinogenesis, chromosome missegregation was induced in immortalized tubal epithelial cells, which proved acutely detrimental to cellular fitness. The phenotype was characterized by accumulation of misfolded proteins, activation of the unfolded protein response (UPR), decreased protein synthesis, and enhanced vulnerability to proteasome inhibition. However, chromosome missegregation also resulted in heightened transformation potential, assessed by colony formation in soft agar. Ovarian cancer cells retained intrinsic sensitivity to proteasome inhibitors under adherent culture conditions, but acquired resistance as spheroids (recapitulating their native configuration in ascites) by downregulating protein synthesis via mTORC1 suppression. Loss of PTEN drove constitutive mTORC1 activity, enhanced proteotoxic stress, as evidenced by UPR induction, and resensitized tumor spheroids to proteasome inhibition both in vitro and in vivo. In cohorts of primary ovarian carcinomas, mTORC1 and UPR signaling pathways were closely associated. These results implicate attenuation of protein synthesis as a protective mechanism in tumor spheroids, which may explain the overall poor response to bortezomib in clinical trials of patients with advanced ovarian cancer. However, patients with PTEN-deficient tumors may represent a subpopulation potentially amenable to treatment with proteasome inhibitors or other therapeutic agents that disrupt protein homeostasis. SIGNIFICANCE: Chromosome instability and protein synthesis are important factors that determine the efficacy of proteotoxic stress-inducing agents, such as proteasome inhibitors, in the treatment of ovarian cancer.Graphical Abstract: http://cancerres.aacrjournals.org/content/canres/79/21/5536/F1.large.jpg.
Soundings: Reader's consent
Authors: James Owen Drife
Journal: BMJ (2003)

To help you decide whether or not to read this article, there are certain things we need to tell you. You should think about them and share them with your family, close friends, or chatroom. This will empower you to give—or withhold—your consent to reading this column.

In the past, like other journals, we relied on “implied consent.” By opening the BMJ, turning it the right way up and finding the back pages you were deemed to agree to read Soundings. This is no longer adequate.

Thanks to consumer organisations like ARMA (Action for Readers of Medical Articles), we now know what trauma may affect unprepared readers. At special risk are recently retired doctors who, never having unwrapped the BMJ for 30 years, go to the back pages expecting advertisements for holiday cottages. Several have recovered substantial damages for stress caused by magical realism or in your face opinions.

Please be advised, therefore, that reading Soundings may cause these unintended side effects:

Laughter Claims that “laughter is the best medicine” are not evidence based. On the contrary, it may seriously damage your health. Do not read Soundings while eating pretzels or drinking soup from those deceptively cool polystyrene cups. From January 2005 the European Reading Time Directive (ERTD) will prohibit solitary reading or reading with a full bladder.

Tears Sad stories can distress those of a sensitive disposition. We have set up a 24 hour helpline to provide counselling for people upset by these articles. This in no way affects your legal rights.

Anger Under the ERTD, before reading this column you must have undergone a course of anger management. Such courses are provided online at bmj.com/areyoulookingatme?

Drowsiness In certain circumstances Soundings may cause you to fall asleep. Therefore you must not read it while driving, operating machinery, giving (or receiving) psychotherapy, or assisting at laparoscopic surgery.

Confusion People with anhumoria (congenital inability to see the joke) may become seriously disoriented. If you have been told that you have this condition, stop reading immediately and turn to any article with “guidelines” in the title.

If you are comfortable with this information and wish to proceed, please sign below in the presence of a witness. Happy (and safe) reading!
Pharyngeal stricture treated by endoscopic adhesiolysis
Authors: Xia Xie, Jian-Ying Bai, En Liu, Xue Peng, Feng-Yu Xiao, Shi-Ming Yang, Chao-Qiang Fan
Journal: Endoscopy (2019)

Most pharyngeal strictures are treated with dilation, laser ablation or surgery. However, these methods may sometimes be ineffective, expensive or are associated with many complications. Therefore, we need to find a minimally invasive treatment alternative. To our knowledge, the efficacy of steroid injection combined with endoscopic balloon dilation has been verified in various studies [1]. And endoscopic radial incision and cutting has been used to treat patients with esophageal anastomotic strictures [2] [3]. It is unclear whether endoscopic treatment is effective and safe for pharyngeal stricture.
Prospective Evaluation of Thrombo-Hemorrhagic Events and Hypercoagulation Markers in Patients with Acute Promyelocytic Leukemia (APL) Receiving All-Trans Retinoic Acid (ATRA) Plus Chemotherapy
Authors: Anna Falanga, Laura Russo, Marina Marchetti, Carmen J Tartari, Laura Castellani, Eros Di Bona, Barry Woodhams, Alessandro Rambaldi, Francesco Lo Coco
Journal: Blood (2017)
Sodium–Glucose Cotransporter-2 Inhibitors: Lack of a Complete History Delays Diagnosis
Authors: Bruce R. Leslie, Leslie E. Gerwin, Simeon I. Taylor
Journal: Annals of Internal Medicine (2019)

On 15 May 2015, the U.S. Food and Drug Administration (FDA) warned that administration of sodium-glucose cotransporter-2 (SGLT2) inhibitors could lead to ketoacidosis in patients with diabetes mellitus. This announcement came more than 2 years after the FDA's first approval of an SGLT2 inhibitor, although the phenomenon had been known for more than 125 years. Luminaries of diabetes research (including Josef von Mering, Frederick Allen, I. Arthur Mirsky, and George Cahill) had described ketosis and ketoacidosis induced by administration of the phytochemical phlorizin, the prototypical SGLT inhibitor, as well as in patients with familial renal glucosuria, a condition that is considered a natural model of SGLT2 inhibition. Neither government regulators nor manufacturers of SGLT2 inhibitors evinced an awareness of this extensive historical record. The absence of historical inquiry delayed notice of ketoacidosis as an adverse reaction, which could have reduced the burden of illness from these drugs.
First Evidence That Bone Marrow Cells Contribute to the Construction of Tissue-Engineered Vascular Autografts In Vivo
Authors: GokiMatsumura, SachikoMiyagawa-Tomita, ToshiharuShin’oka, YoshitoIkada, HiromiKurosawa
Journal: Circulation (2003)

Background— Materials commonly used to repair complex cardiac defects lack growth potential and have other unwanted side effects. We designed and tested a bone marrow cell (BMC)–seeded biodegradable scaffold that avoids these problems. Methods and Results— To demonstrate the contribution of the BMCs to histogenesis, we labeled them with green fluorescence, seeded them onto scaffolds, and implanted them in the inferior vena cava of dogs. The implanted grafts were analyzed immunohistochemically at 3 hours and subsequently at 2, 4, and 8 weeks after implantation using antibodies against endothelial cell lineage markers, endothelium, and smooth muscle cells. There was no stenosis or obstruction caused by the tissue-engineered vascular autografts (TEVAs) implanted into the dogs. Immunohistochemically, the seeded BMCs expressing endothelial cell lineage markers, such as CD34, CD31, Flk-1, and Tie-2, adhered to the scaffold. This was followed by proliferation and differentiation, resulting in expression of endot...
Which factors are influencing good digital education? Analysis on ecancer programs from major international congresses.
Authors: Danny Burke, Eva Thalmann, Gordon McVie
Journal: Journal of Clinical Oncology (2019)

10501 Background: Factors limit the opportunities for healthcare professionals to attendinternational conferences including lack of financial support or time. Digital education from Independent Medical Education providers is therefore an important source of education for clinicians. One such provider is the ecancer Global Foundation (ecancer), an educational charity who publish ecancer.org. A landmark ecancer activity is sharing developments from conferences with video interviews of experts discussing the key data. Methods: We aim to get a deeper understanding of the factors that influence viewer satisfaction with these resources including whether industry support (through un-restricted educational grants) had a significant impact. Viewer satisfaction is measured using 3 metrics: 1. Viewer feedback; 2. Number of views; 3. Average viewing time. The analysis is based on programs from ASCO GU 2018, ASCO 2018 andESMO 2018 covering prostate and lung cancer education including unsupported as well as industry supported programs by Janssen, and two other pharma companies through unrestricted educational grants. Results: 68 videos were analysed with 95,249 views. This included 4 Expert to Expert Interviews, 4 Expert Panel Discussions and 60 To Camera Interviews. Of the 68 videos, 24 were supported by industry and all were peer-reviewed. Viewer feedback includes Net Promotor Score and a measure of likely impact on clinical practice as a result of watching the video. Conclusions: Expert to Expert and Expert Panel formats achieve higher viewer satisfaction than To Camera Interviews. Viewer satisfaction scores are very similar for industry supported vs non-industry supported content. These findings seem to suggest that the format of the educational video is a more important factor than whether it is supported by industry when impacting viewer satisfaction.[Table: see text]
Materials Stiffness‐Dependent Redox Metabolic Reprogramming of Mesenchymal Stem Cells for Secretome‐Based Therapeutic Angiogenesis
Authors: Haibo Yang, Nicole Mein Ji Cheam, Huan Cao, Melissa Kao Hui Lee, Siu Kwan Sze, Nguan Soon Tan, Chor Yong Tay
Journal: Advanced Healthcare Materials (2019)

Abstract Cellular redox metabolism has emerged as a key tenet in stem cell biology that can profoundly influence the paracrine activity and therapeutic efficacy of mesenchymal stem cells (MSCs). Although the use of materials cues to direct the differentiation of MSCs has been widely investigated, little is known regarding the role of materials in the control of redox paracrine signaling in MSCs. Herein, using a series of mechanically tunable fibronectin‐conjugated polyacrylamide (FN‐PAAm) hydrogel substrates, it is shown that a mechanically compliant microenvironment with native‐tissue mimicking stiffness ( E = 0.15 kPa) can mechano‐regulate the intracellular reactive oxygen species (ROS) level in human adipose‐derived MSCs (ADMSCs). The cells reciprocate to the ROS imbalance by co‐activating the nuclear factor erythroid 2–related factor 2 and hypoxia‐inducible factor 1 alpha stress response signaling pathways to increase the production of vascular endothelial growth factor and basic fibroblast growth factor. Conditioned medium collected from ADMSCs grown on the 0.15 kPa FN‐PAAm is found to significantly promote in vitro and ex ovo vascularization events. Collectively, these findings highlight the importance of delineating critical materials properties that can enable the reprogramming of cellular redox signaling for advanced MSCs‐based secretome regenerative medicine.
Opioid and Benzodiazepine Coprescribing in the United States Before and After US Food and Drug Administration Boxed Warning
Authors: Victoria (Shu) Zhang, Mark Olfson, Marissa King
Journal: JAMA Psychiatry (2019)

This case series study provides a national estimate of opioid and benzodiazepine coprescribing before and after the US Food and Drug Administration (FDA) boxed warning.
Manganese transporter Slc30a10 controls physiological manganese excretion and toxicity
Authors: Courtney J. Mercadante, Milankumar Prajapati, Heather L. Conboy, Miriam E. Dash, Carolina Herrera, Michael A. Pettiglio, Layra Cintron-Rivera, Madeleine A. Salesky, Deepa B. Rao, Thomas B. Bartnikas
Journal: Journal of Clinical Investigation (2019)

Manganese (Mn), an essential metal and nutrient, is toxic in excess. Toxicity classically results from inhalational exposures in individuals who work in industrial settings. The first known disease of inherited Mn excess, identified in 2012, is caused by mutations in the metal exporter SLC30A10 and is characterized by Mn excess, dystonia, cirrhosis, and polycythemia. To investigate the role of SLC30A10 in Mn homeostasis, we first generated whole-body Slc30a10–deficient mice, which developed severe Mn excess and impaired systemic and biliary Mn excretion. Slc30a10 localized to canalicular membranes of hepatocytes, but mice with liver Slc30a10 deficiency developed minimal Mn excess despite impaired biliary Mn excretion. Slc30a10 also localized to the apical membrane of enterocytes, but mice with Slc30a10 deficiency in small intestines developed minimal Mn excess despite impaired Mn export into the lumen of the small intestines. Finally, mice with Slc30a10 deficiency in liver and small intestines developed Mn excess that was less severe than that observed in mice with whole-body Slc30a10 deficiency, suggesting that additional sites of Slc30a10 expression contribute to Mn homeostasis. Overall, these results indicated that Slc30a10 is essential for Mn excretion by hepatocytes and enterocytes and could be an effective target for pharmacological intervention to treat Mn toxicity.
Closed Reduction of a Fractured and Dislocated Ankle
Authors: Arvind G. von Keudell, Taufiek K. Rajab, Mark S. Vrahas, Edward K. Rodriguez, Mitchel B. Harris, Michael J. Weaver
Journal: New England Journal of Medicine (2019)

Prompt reduction of a displaced fracture of the ankle decreases the risk of trauma to the skin and soft tissues surrounding the joint. This video focuses on initial management and demonstrates techniques for reducing and splinting a displaced fracture of the ankle as well as the use of a hematoma block for anesthesia.
Quantitative fluorescence endoscopy: an innovative endoscopy approach to evaluate neoadjuvant treatment response in locally advanced rectal cancer
Authors: Jolien J J Tjalma, Marjory Koller, Matthijs D Linssen, Elmire Hartmans, Steven de Jongh, Annelies Jorritsma-Smit, Arend Karrenbeld, Elisabeth G de Vries, Jan H Kleibeuker, Jan Pieter Pennings, Klaas Havenga, Patrick HJH Hemmer, Geke AP Hospers, Boudewijn van Etten, Vasilis Ntziachristos, Gooitzen M van Dam, Dominic J Robinson, Wouter B Nagengast
Journal: Gut (2019)

Quantitative fluorescence endoscopy (QFE) is a new technique that can visualise and quantify fluorescently tagged tumour tissue. In 25 patients with locally advanced rectal cancer (LARC), we evaluated QFE targeting vascular endothelial growth factor A (VEGFA) to detect residual tumour after neoadjuvant chemoradiotherapy (nCRT). QFE detected significantly higher fluorescence in tumour compared with normal rectal tissue and fibrosis, and improved prediction of final pathology results in 16% of patients compared with standard MRI and white-light endoscopy. QFE is a promising technique to aid clinical response assessment in patients with LARC and warrants further validation in larger clinical trials. ClinicalTrials.gov (NCT01972373).

Patients with LARC receive nCRT followed by surgery to achieve local disease control. Interestingly, 15%–27% of patients have a pathological complete response, that is, no residual cancer cells are found in the surgical specimen.1–3 There is an increasing interest in identifying patients with a clinical complete response before surgery, as non-operative management for these patients is associated with high survival rates, reduced morbidity and improved functional outcomes.4–8 However, assessing tumour response after nCRT is challenging. White-light endoscopy provides only morphological information, while MRI cannot always distinguish viable tumour from fibrosis.9–11 QFE is a novel endoscopy technique that visualises and quantitatively measures the presence of targeted fluorescence tracers in tissue. We hypothesised that VEGFA-targeted QFE can be of additional value in restaging patients with LARC. In untreated patients, QFE showed clearly enhanced fluorescence in all rectal tumours compared with normal rectal tissue (figure 1A). The tumour-to-normal ratio of 3.1 (figure 1B) signifies QFE can be used to localise rectal cancer.



Figure 1 
(A) Representative fluorescence images of the quantitative fluorescence endoscopy (QFE) procedure in untreated rectal cancer. From left to right: a high-definition white-light video endoscope image; a white-light image from the QFE fibreoptic, followed by the corresponding near-infrared …