tbuckley/cabot-search huggingface dataset:
Phase I expansion trial of an oral TORC1/TORC2 inhibitor (CC-223) in nonpancreatic neuroendocrine tumors (NET).
Authors: Monica M. Mita, Edward M. Wolin, Tim Meyer, John J. Nemunaitis, Emily K. Bergsland, Amit Mahipal, Lilly Wong, Xiaoling Wu, James Carmichael, Rajesh Chopra, Kristen Hege, Johanna C. Bendell
Journal: Journal of Clinical Oncology (2013)

e15004 Background: Clinical activity of everolimus, an allosteric TORC1-selective inhibitor, has been established in pancreatic NET. CC-223 is an ATP-competitive inhibitor of the mTOR kinase, inhibiting both TORC1 and TORC2 complexes. Methods: Following establishment of the MTD (reported at ASCO 2012), subjects with non-pancreatic NET and selected other tumors were enrolled in expansion cohorts of up to 20 evaluable subjects. CC-223 was dosed at 45 mg once daily in 28 day cycles until disease progression. Results: As of 09 January, 2013, 101 solid tumor subjects have been treated. Preliminary results from the NET cohort (n=23) are reported here. Subjects with non-pancreatic tumors of gut origin with progression within 12 months and receiving ongoing treatment with somatostatin analogs (SSA) were eligible. The majority of tumors were of midgut origin with liver metastases; 9 subjects had refractory carcinoid syndrome despite SSA use. The most common (&gt; 20%) related adverse events (all grades) were stomatitis, diarrhea, fatigue, anorexia, nausea and rash. In addition, related serious adverse events included one case of transient dehydration/renal insufficiency (1). CC-223 dose reduction to 30 or 15 mg was required in 57% of subjects, usually during cycle 1 or 2, but thereafter treatment was well tolerated. Inhibition of TORC1 (p4EBP1) and TORC2 (pAKT) biomarkers was confirmed in blood cells. Reduction in glucose uptake (&gt; 25% change in SUV) on PET imaging at day 15 was observed in 54% (7/13) subjects. All evaluable subjects (n=10) reported stable disease (SD) with treatment ongoing at up to 9 cycles (median 6; range 4 – 9). Although not prospectively collected, 6 subjects with refractory carcinoid syndrome reported complete resolution of flushing (5) or improvement in diarrhea (1). Symptom improvement generally occurred within the first week of dosing and persisted despite dose reduction in 5 subjects. Conclusions: Encouraging signals of biomarker and clinical activity were observed in NET including prolonged SD and symptomatic improvement in subjects with refractory carcinoid syndrome. Due to the frequency of early dose reductions, the NET cohort will be explored further at a starting dose of 30 mg QD. Clinical trial information: NCT01177397.
Inducible laryngeal obstruction: an official joint European Respiratory Society and European Laryngological Society statement
Authors: Thomas Halvorsen, Emil Schwarz Walsted, Caterina Bucca, Andrew Bush, Giovanna Cantarella, Gerhard Friedrich, Felix J.F. Herth, James H. Hull, Harald Jung, Robert Maat, Leif Nordang, Marc Remacle, Niels Rasmussen, Janet A. Wilson, John-Helge Heimdal
Journal: European Respiratory Journal (2017)

Inducible laryngeal obstruction (ILO) describes an inappropriate, transient, reversible narrowing of the larynx in response to external triggers. ILO is an important cause of a variety of respiratory symptoms and can mimic asthma. Current understanding of ILO has been hampered by imprecise nomenclature and variable approaches to assessment and management. A task force of the European Respiratory Society (ERS) and European Laryngological Society (ELS) was thus set up to address this, and to identify research priorities. A literature search identified relevant articles published until June 2016, using all identifiable terms for ILO, although including only articles using laryngoscopy. In total, 172 out of 252 articles met the inclusion criteria, summarised in sections on diagnostic approach, aetiology, comorbidities, epidemiology and treatment. The consensus taxonomy published by ERS, ELS and the American College of Chest Physicians (ACCP) in 2015 is used throughout this statement. We highlight the high prevalence of ILO and the clinical impact for those affected. Despite recent advances, most aspects of this condition unfortunately remain incompletely understood, precluding firm guidance. Specifically, validated diagnostic and treatment algorithms are yet to be established, and no randomised control studies were identified in this search; hence we also make recommendations for future research.
Systematically optimized topical delivery system for Loperamide hydrochloride: Formulation design, in vitro and in vivo biopharmaceutical evaluation
Authors: Jianhui Shu, Jingjing Zhao, Fang Guo
Journal: Asian Journal of Pharmaceutical Sciences (2017)

This study aimed to develop a suitable topical delivery system containing diethylene glycol monoethyl ether (DGME) for Loperamide hydrochloride (Lop). Two factors, three levels Central-Composite design were applied by generating a quadratic polynomial equation to form contour plots and response surface for prediction of responses as two selected independent variables with EtOH-DGME ratio and EtOH concentration. The response variables flux and skin retention were determined in in vitro hairless mouse skin model. The selected optimum formulation was evaluated for the skin transport characteristics by developing dermatokinetic analysis model and the results demonstrated DGME improved the delivery of Lop into skin deep layers, which was further confirmed by confocal laser scanning microscopy (CLSM) study. In vitro skin permeation was found to have triphasic correlation with plasma AUC in the in vivo pharmacokinetic study. The in vitro-in vivo correlation enabled the prediction of pharmacokinetic profile of Lop from in vitro permeation results. Therefore, the optimum formulation capable of enhancing Lop intracutaneous depot could be a candidate for topical delivery of Lop as analgesics.
An Alternative Donor Is a Valid Option Compared to a Matched-Unrelated in Allogeneic Stem Cell Transplantation for Acute Lymphoblastic Leukemia in CR2: A Report of 841 Patients from the EBMT Acute Leukemia Working Party
Authors: Eolia Brissot, Myriam Labopin, Domenico Russo, Sonja Martin, Christoph Schmid, Bertram Glass, Ron Ram, Zubeyde Nur Ozkurt, Jakob Passweg, Joan Hendrik Veelken, Donald Bunjes, Jane F. Apperley, Mohamad Mohty, Sebastian Giebel, Arnon Nagler
Journal: Blood (2016)
New Recurrently Mutated Genes in Classical Hodgkin Lymphoma Revealed By Whole-Exome Sequencing of Microdissected Tumor Cells
Authors: Enrico Tiacci#, Alexander Penson#, Gianluca Schiavoni#, Erik Ladewig#, Elisabetta Fortini#, Yuchun Wang, Ariele Spanhol-Rosseto, Alessandra Venanzi, Alessandro M. Gianni, Simonetta Viviani, Antonello Cabras, Barbara Crescenzi, Cristina Mecucci, Laura Pasqualucci°, Raul Rabadan°, Brunangelo Falini°
Journal: Blood (2016)
Natural immunoglobulin M initiates an inflammatory response important for both hepatic ischemia reperfusion injury and regeneration in mice
Authors: Keely Marshall, Junfei Jin, Carl Atkinson, Ali Alawieh, Fei Qiao, Biao Lei, Kenneth D. Chavin, Songqing He, Stephen Tomlinson
Journal: Hepatology (2017)

Complement plays a role in both hepatic ischemia reperfusion (IR) injury (IRI) and liver regeneration, but it is not clear how complement is activated in either process. We investigated the role of self-reactive immunoglobulin M (IgM) antibodies in activating complement after hepatic IR and liver resection. Natural IgM antibodies that recognize danger-associated molecular patterns (neoepitopes) activate complement following both hepatic IR and liver resection. Antibody-deficient Rag1-/- mice were protected from hepatic IRI, but had increased hepatic injury and an impaired regenerative response after 70% partial hepatectomy (PHx). We identified two IgM monoclonal antibodies (mAbs) that specifically reversed the effect of Rag1 deficiency in both models; B4 (recognizes Annexin IV) and C2 (recognizes subset of phospholipids). Focusing on the B4-specific response, we demonstrated sinusoidal colocalization of IgM and C3d in Rag1-/- mice that were reconstituted with B4 mAb, and furthermore that the Annexin IV neoepitope is specifically and similarly expressed after both hepatic IR and PHx in wild-type (WT) mice. A single-chain antibody construct (scFv) derived from B4 mAb blocked IgM binding and reduced injury post-IR in WT mice, although, interestingly, B4scFv did not alter regeneration post-PHx, indicating that anti-Annexin IV antibodies are sufficient, but not necessary, for the regenerative response in the context of an entire natural antibody repertoire. We also demonstrated expression of the B4 neoepitope in postischemic human liver samples obtained posttransplantation and a corollary depletion in IgM recognizing the B4 and C2 neoepitopes in patient sera following liver transplantation. Conclusion: These data indicate an important role for IgM in hepatic IRI and regeneration, with a similar cross-species injury-specific recognition system that has implications for the design of neoepitope targeted therapeutics. (Hepatology 2018;67:721-735).
David Oliver: “Progressive dwindling,” frailty, and realistic expectations
Authors: David Oliver
Journal: BMJ (2017)

BerkshireRelatives of sick older patients have an understandable need to know why their loved ones are deteriorating or failing to recover, or exactly why they died.This can lead to misunderstandings, formal complaints, fraught meetings, or upsetting inquests.Over the years I've seen my share of this in my own practice.I've also worked on numerous cases as an independent investigator or expert witness.In some cases aspects of care were poor, sometimes indefensibly so.And even in someone with serious health problems, failings in care can worsen decline or cause avoidable harm and distress.Often, however, the medical care was good or exemplary, communication was open and frequent, but still the complaints and misunderstandings came.During my career society has become ever more high tech and "can do"-and perhaps less comfortable with death and dying.I'd say that people have become less willing to accept the very real limits of medicine.Often, no one is to blame when older, frailer people with long term conditions and acute illness deteriorate.That's just (late) life.People have become less willing to accept the very real limits of medicine
Dental procedures, antibiotic prophylaxis, and endocarditis among people with prosthetic heart valves: nationwide population based cohort and a case crossover study
Authors: Sarah Tubiana, Pierre-Olivier Blotière, Bruno Hoen, Philippe Lesclous, Sarah Millot, Jérémie Rudant, Alain Weill, Joel Coste, François Alla, Xavier Duval
Journal: BMJ (2017)

Objective To assess the relation between invasive dental procedures and infective endocarditis associated with oral streptococci among people with prosthetic heart valves.Design Nationwide population based cohort and a case crossover study.Setting French national health insurance administrative data linked with the national hospital discharge database.Participants All adults aged more than 18 years, living in France, with medical procedure codes for positioning or replacement of prosthetic heart valves between July 2008 and July 2014.Main outcome measures Oral streptococcal infective endocarditis was identified using primary discharge diagnosis codes. In the cohort study, Poisson regression models were performed to estimate the rate of oral streptococcal infective endocarditis during the three month period after invasive dental procedures compared with non-exposure periods. In the case crossover study, conditional logistic regression models calculated the odds ratio and 95% confidence intervals comparing exposure to invasive dental procedures during the three month period preceding oral streptococcal infective endocarditis (case period) with three earlier control periods.Results The cohort included 138 876 adults with prosthetic heart valves (285 034 person years); 69 303 (49.9%) underwent at least one dental procedure. Among the 396 615 dental procedures performed, 103 463 (26.0%) were invasive and therefore presented an indication for antibiotic prophylaxis, which was performed in 52 280 (50.1%). With a median follow-up of 1.7 years, 267 people developed infective endocarditis associated with oral streptococci (incidence rate 93.7 per 100 000 person years, 95% confidence interval 82.4 to 104.9). Compared with non-exposure periods, no statistically significant increased rate of oral streptococcal infective endocarditis was observed during the three months after an invasive dental procedure (relative rate 1.25, 95% confidence interval 0.82 to 1.82; P=0.26) and after an invasive dental procedure without antibiotic prophylaxis (1.57, 0.90 to 2.53; P=0.08). In the case crossover analysis, exposure to invasive dental procedures was more frequent during case periods than during matched control periods (5.1% v 3.2%; odds ratio 1.66, 95% confidence interval 1.05 to 2.63; P=0.03).Conclusion Invasive dental procedures may contribute to the development of infective endocarditis in adults with prosthetic heart valves.
<i>Haemophilus influenzae</i> biofilms in primary ciliary dyskinesia: a moving story
Authors: Amelia Shoemark
Journal: European Respiratory Journal (2017)

Mucociliary clearance is a first line of defence against airway infection. Motile cilia function is important for the transport of inhaled bacteria and other unwanted particulate matter away from the lungs. Primary ciliary dyskinesia (PCD) is an inherited condition in which motile cilia function is disrupted. Patients with PCD suffer from poor mucociliary clearance of the upper and lower airways leading to chronic wet cough, rhinusinusitis, otitis media and reoccurring infections [1]. The most commonly isolated organism from PCD sputum or nasal lavage is Haemophilus influenzae [1]. Non-typeable Haemophilus influenzae (NTHi) have been shown to form biofilms in the adenoids and middle ear of children with otitis media [2, 3]. The study by Walker et al. [4] in this issue of the European Respiratory Journal poses the question: is the respiratory epithelium in PCD susceptible to NTHi biofilms due to motile ciliary dysfunction? Impaired motile cilia function in the PCD cells results in susceptibility to NTHi biofilm development <http://ow.ly/9D2u30eamR6>
Sodium Thiosulfate in the Treatment of Lung and Breast Calciphylaxis
Authors: Guohua Shen, Rui Huang, Bin Liu, Anren Kuang
Journal: Clinical Nuclear Medicine (2017)

A 19-year-old woman, with normal kidney function, was diagnosed as having visceral calciphylaxis, especially diffuse breast and lung calcification. The calcification findings were clearly shown on CT, and bone scintigraphy revealed diffuse uptake in the thoracic area. Although there was no standard therapeutic approach for this clinical setting, the patient received empiric therapy with sodium thiosulfate. After 5 months of consecutive therapy, the calcification condition had a striking regression.
Abbott Laboratories offers fix for 745 000 pacemakers vulnerable to hacking
Authors: Owen Dyer
Journal: BMJ (2017)

Three quarters of a million patients around the world use pacemakers with cybersecurity vulnerabilities that could potentially be sabotaged remotely by hackers with radiofrequency equipment, the US Food and Drug Administration has warned.

A non-invasive firmware patch should resolve the problem, said Abbott Laboratories, which took on responsibility for these devices when it bought their manufacturer, St Jude Medical, earlier this year.

But Abbott has not disclosed how many of the implantable cardiac devices were sold in Britain, saying only that “we are in discussions with regulatory bodies in the UK on next steps.”

The FDA said that 465 000 of the pacemakers are implanted in US patients, and Abbott acknowledged that a further …
Hyaluronan-CD44 interaction with leukemia-associated RhoGEF (LARG) and EGF receptor promotes Rho/Ras co-activation and PLCε-Ca2+ signaling leading to cytoskeleton modification and head and neck squamous cell carcinoma progression
Authors: Lilly Y. W. Bourguignon, Eli Gilad, Amy Brightman, Falko Diedrich, Patrick Singleton
Journal: Cancer Research (2006)

172   In this study we have examined the interaction of CD44 [a major hyaluronan (HA) receptor] with a RhoA-specific guanine nucleotide exchange factor (LARG, Leukemia-Associated RhoGEF) in human Head and Neck Squamous Cell Carcinoma cells (HNSCC-HSC-3 cell line). Immunoprecipitation and immunoblot analyses indicate that CD44 and the LARG protein are expressed in HSC-3 cells; and that these two proteins are physically associated as a complex  in vivo . HA-CD44 binding induces LARG-specific RhoA signaling and PLCe activity. In particular, the activation of RhoA-PLCe by HA stimulates IP 3  production, intracellular Ca 2+  mobilization and the upregulation of Ca 2+ /calmodulin-dependent kinaseII (CaMKII) leading to phosphorylation of the cytoskeletal protein, filamin. Phosphorylated filamin then modifies its interaction with filamentous actin resulting in tumor cell migration. The CD44-LARG complex also interacts with the EGF receptor (EGFR). Most importantly, the binding of HA to the CD44-LARG-EGFR complex activates the EGFR receptor kinase which, in turn, promotes Ras-mediated stimulation of a downstream kinase cascade including the Raf-1 and ERK pathways leading to HNSCC cell growth. Using a recombinant fragment of LARG (the LARG-PDZ domain) and  in  vitro  binding assays, we have determined that the LARG-PDZ domain serves as a direct linker between CD44 and EGFR. Transfection of the HSC-3 cells with LARG-PDZcDNA significantly reduces LARG association with CD44 and EGFR. Overexpression of the LARG-PDZ domain also functions as a dominant-negative mutant (similar to the PLC/CaMKII and EGFR/MAPK inhibitor effects) to block HA/CD44-mediated signaling events (e.g. EGFR kinase activation, Ras/RhoA co-activation, Raf-ERK signaling, PLCe-mediated IP 3  production, intracellular Ca 2+  mobilization, CaMKII activity, filamin phosphorylation and filamin-actin binding) and to abrogate tumor cell growth/migration. Taken together, we believe that CD44 interaction with LARG and EGFR plays a pivotal role in Rho/Ras co-activation, PLCe-Ca 2+  signaling and Raf/ERK upregulation required for CaMKinaseII-mediated cytoskeleton function, and in head and neck squamous cell carcinoma progression.
The international men's health movement
Authors: P. Baker
Journal: BMJ (2001)

Men's health is emerging as an important issue in an increasing number of countries around the world, notably the United Kingdom, Austria, Switzerland, Australia, and the United States. There is also increasing interest in working with men on sexual and reproductive health issues in parts of Central and South America, Africa, and Asia. However, progress towards international contact and collaboration between men's health advocates with an interest that extends beyond traditional clinical concerns such as erectile dysfunction or prostate cancer has so far been extremely slow.

In many ways this is not surprising. The idea that men have specific health needs, experiences, and concerns related to their gender as well as their biological sex is relatively new—certainly much newer than the concept of “women's health.”1 The psychosocial aspects of male health are still not accepted, or even understood, by many health practitioners and policymakers. Moreover, even in those countries where greater attention has been paid to men's health issues, initiatives have generally remained …
Inflammatory monocytes expressing tissue factor drive SIV and HIV coagulopathy
Authors: Melissa E. Schechter, Bruno B. Andrade, Tianyu He, George Haret Richter, Kevin W. Tosh, Benjamin B. Policicchio, Amrit Singh, Kevin D. Raehtz, Virginia Sheikh, Dongying Ma, Egidio Brocca-Cofano, Cristian Apetrei, Russel Tracy, Ruy M. Ribeiro, Alan Sher, Ivo M. B. Francischetti, Ivona Pandrea, Irini Sereti
Journal: Science Translational Medicine (2017)

Activated monocytes in blood promote chronic inflammation and persistent coagulation in HIV-infected patients and SIV-infected macaques.
A phase 3 trial of hyperthermic intraperitoneal chemotherapy (HIPEC) for ovarian cancer.
Authors: Willemien Van Driel, Karolina Sikorska, Jules Schagen van Leeuwen, Henk Schreuder, Ralph Hermans, Ignace de Hingh, Jacobus Van Der Velden, Henriëtte J.G. Arts, Massuger Leon, Arend Aalbers, Verwaal Victor J., Koen van der Vijver, Neil K Aaronson, Gabe S. Sonke
Journal: Journal of Clinical Oncology (2017)

5519 Background: Cytoreductive surgery and systemic therapy are essential for newly diagnosed ovarian cancer. We conducted a multicenter phase 3 trial to study whether the addition of intraperitoneal chemotherapy under hyperthermic conditions (HIPEC) to interval cytoreductive surgery would improve outcome among patients receiving neo-adjuvant chemotherapy for stage III epithelial ovarian cancer. Methods: We randomly assigned patients who showed at least stable disease after three cycles of carboplatin (area under the curve 6) and paclitaxel (175 mg/m 2 ) to receive interval cytoreductive surgery with or without HIPEC using cisplatin (100 mg/m 2 ). Randomization was performed per-operatively and eligible patients had no residual mass greater than 2.5 mm. Three additional cycles of carboplatin and paclitaxel were given post-operatively. The primary endpoint was recurrence-free survival. Overall survival, toxicity, and quality-of-life were key secondary endpoints. Results: A total of 245 patients were randomly assigned to one of the two treatment strategies. In an intention-to-treat analysis, interval cytoreductive surgery with HIPEC was associated with longer recurrence-free survival than interval cytoreductive surgery alone (15 vs. 11 months, respectively; hazard ratio [HR], 0.65; 95% confidence interval [CI], 0.49 to 0.86; P=0.003). At the time of analysis, 49% of patients were alive, with a significant improvement in overall survival favoring HIPEC (48 vs. 34 months; HR, 0.64; 95% CI, 0.45 to 0.91, P=0.01). The number of patients with grade 3-4 adverse events was similar in both treatment arms (28% vs. 24%, p=0.61). Quality-of-life analysis will follow. Conclusions: The addition of HIPEC to interval cytoreductive surgery is well tolerated and improves recurrence free and overall survival in patients with stage III epithelial ovarian cancer. Clinical trial information: NCT00426257.
Safety and persistence of WT1-specific T-cell receptor gene−transduced lymphocytes in patients with AML and MDS
Authors: Isao Tawara, Shinichi Kageyama, Yoshihiro Miyahara, Hiroshi Fujiwara, Tetsuya Nishida, Yoshiki Akatsuka, Hiroaki Ikeda, Kazushi Tanimoto, Seitaro Terakura, Makoto Murata, Yoko Inaguma, Masahiro Masuya, Naoki Inoue, Tomohide Kidokoro, Sachiko Okamoto, Daisuke Tomura, Hideto Chono, Ikuei Nukaya, Junichi Mineno, Tomoki Naoe, Nobuhiko Emi, Masaki Yasukawa, Naoyuki Katayama, Hiroshi Shiku
Journal: Blood (2017)