tbuckley/cabot-search huggingface dataset:
Neoadjuvant bevacizumab (B) and trastuzumab (T) in combination with weekly paclitaxel (P) as neoadjuvant treatment in HER2-positive breast cancer: Results from a phase II trial (AVANTHER).
Authors: Maria Fernandez Abad, Isabel Calvo, Noelia Martinez, Mercedes Herrero, Yolanda Quijano, Hipolito Duran, Mariola Garcia Aranda, Ana Suárez, Fernando López-Ríos, Diego Perez, Sofia Perea, Manuel Hidalgo, Laura García-Estevez
Journal: Journal of Clinical Oncology (2012)

602 Background: B in combination with T has showed meaningful activity in patients (pts) with metastatic HER2-positive breast cancer. AVANTHER is a Phase II trial of preoperative systemic therapy combining B with T and P in a weekly regimen in HER2 positive breast cancer to assess safety and efficacy of the combination. Methods: Pts with centrally-confirmed HER2-positive (IHC 3+ or FISH positive) breast cancer (stage II or III including locally advanced) received neoadjuvant chemotherapy (NC) with weekly P (80mg/m 2 /week) for 12 weeks in combination with weekly T (4mg/kg loading dose and 2 mg/kg maintenance) and B (15mg/kg every 3 weeks) for 4 cycles. After surgery all pts received T (1 year) and liposomal doxorubicin plus cyclophosphamide every 3 weeks (4 cycles); primary endpoint was rate of pathological complete response (pCR) in breast and axilla. For all patients, a tissue sample at baseline as well as at surgery was collected for biomarker analyses. Results: A total of 44 pts have been enrolled. Median tumor size: 3.9 cm. Seven (19.4%) pts had stage IIA; 17 (47.2%) stage IIB; 8 (22.2%) stage IIIA and 4 (11.1%) stage IIIB. Twenty-one (58.3%) pts had both positive-hormonal receptors and 10 (27.8%) were hormone receptor negative. Eight (22.2%) pts had sentinel biopsy before NC, being negative in 6 (16.7%) cases. Data from surgery (only from 36 pts): pCR was achieved in 16 (44.4%) pts. Safety and tolerability were good, with rare adverse events of grade ≥3 [1 (2.8%) episode of severe hypertension]. Conclusions: These data show that the combination of P with T and B without an anthracycline for 12 weeks is very effective as NC in HER2 positive breast cancer pts with a high rate of pCR and minimal side effects.
Dermatological manifestations in Noonan syndrome
Authors: D. Bessis, J. Miquel, E. Bourrat, C. Chiaverini, F. Morice‐Picard, C. Abadie, F. Manna, C. Baumann, M. Best, P. Blanchet, A.‐C. Bursztejn, Y. Capri, C. Coubes, F. Giuliano, S. Guillaumont, S. Hadj‐Rabia, M.‐L. Jacquemont, C. Jeandel, D. Lacombe, S. Mallet, J. Mazereeuw‐Hautier, N. Molinari, V. Pallure, C. Pernet, N. Philip, L. Pinson, P. Sarda, S. Sigaudy, Y. Vial, M. Willems, D. Genevievé, A. Verloes, H. Cavé
Journal: British Journal of Dermatology (2019)

Noonan syndrome (NS) is a genetic disorder affecting up to 1 in 1000 people. It is recognised by an unusual facial appearance, heart defects and small stature. Some people with features of NS also have lots of small dark brown flecks on their skin (lentigines), a condition formerly known as LEOPARD syndrome but now called NS with multiple lentigines (NSML). There are also some atypical (unusual) “Noonan‐like” syndromes: this overlapping group of “Rasopathies” also includes Costello syndrome and cardio‐facio‐cutaneous syndrome. About 10 genes responsible for these conditions are now known, but the dermatological (skin) features of the different genetic types have never been clearly defined. Therefore, these French doctors, based at 10 different hospitals, systematically recorded the skin abnormalities seen in patients with any kind of NS attending their clinics over a 4‐year period, and correlated them with NS subtype and gene. Of 129 patients, aged from 9 months to 77 years, three quarters had mutations (changes) in the PTPN11 gene and of these 65 were diagnosed as NS and 34 as NSML. Dermatological features in the NS patients were mild and non‐specific such as easy bruising, raised hair follicles (keratosis pilaris), lax skin or wavy hair. NSML patients additionally had dozens of lentigines, larger brown patches and usually had particular PTPN11 mutations. NS patients with mutations in a different gene were more likely to have striking skin features including unusually curly hair, sparse eyebrows, marked keratosis pilaris or multiple moles. This research highlights the value of careful dermatological documentation in patients with genetic syndromes.
Physician burnout: moral injury is a questionable term
Authors: Michael J Asken
Journal: BMJ (2019)

I think that use of the term “moral injury” in medicine1 is highly inappropriate, as explained in an upcoming publication and briefly summarised below.2

The concept of moral injury, poignant as a psychoemotional impact of war, is misplaced when applied to the practice of medicine. Suggesting equivalence between the experience of warriors and the (very real) …
Abnormal Regulation of Intracellular Calcium in Human Megakaryocytes Contributes to the Pathophysiology of Calr-Mutant Myeloproliferative Neoplasms
Authors: Christian Andrea Di Buduo, Vittorio Abbonante, Elisa Rumi, Daniela Pietra, Francesco Moccia, Giovanni Barosi, Vittorio Rosti, Mario Cazzola, Alessandra Balduini
Journal: Blood (2018)
Reply to Michael Froehner and Christian Thomas's Letter to the Editor re: Sebastian Berg, Alexander P. Cole, Marieke J. Krimphove, et al. Comparative Effectiveness of Radical Prostatectomy Versus External Beam Radiation Therapy Plus Brachytherapy in Patients with High-risk Localized Prostate Cancer. Eur Urol 2019;75:552–5
Authors: Sebastian Berg, Alexander Cole, Quoc-Dien Trinh
Journal: European Urology (2019)
Polyomaviruses of the skin
Authors: J.C. Sheu, J. Tran, P.L. Rady, H. Dao, S.K. Tyring, H.P. Nguyen
Journal: British Journal of Dermatology (2019)

Human polyomaviruses (HPyV) are small viruses that are known to infect humans. Altogether, 14 different types of polyomaviruses have been discovered in humans, and since the 2008 discovery of the first cutaneous (skin) polyomavirus, Merkel cell polyomavirus (MCPyV), six more species have been found in the skin: Trichodysplasia spinulosa polyomavirus (TSPyV), HPyV6, HPyV7, HPyV9, HPyV10, and HPyV13. Of these cutaneous species, only MCPyV, TSPyV, HPyV6, and HPyV7 have been shown to have a definite link with diseases of the skin. MCPyV is a main cause of Merkel cell carcinomas. TSPyV is one of the factors that causes trichodysplasia spinulosa. HPyV6 and HPyV7 have been recently linked to itchy skin rashes. The roles of HPyV9, HPyV10, and HPyV13 in causing skin disease, if any, are still unknown, but their molecular features have provided some insight into the way they function. In this review, the authors, based in the U.S.A., summarize the known molecular mechanisms, clinical presentation (e.g. symptoms), and targeted therapies (treatments) of each of the seven cutaneous human polyomaviruses. The authors hope that increased awareness and recognition by medics of human polyomaviruses will lead to increased reports of human polyomavirus‐associated diseases and a better understanding of how to diagnose and treat these conditions.
Abstract 18400: Opposite Roles of the Soluble Epoxide Hydrolase Domains in the Development of Vascular Calcification
Authors: Olivier Varennes, Romuald Mentaverri, Thomas Duflot, Thibaut Objois, Gaëlle Lenglet, Carine Avondo, Christophe Morisseau, Gilles Kauffenstein, Mouad Hamzaoui, Matthieu Leuillier, Michel Brazier, Saïd Kamel, Isabelle Six, Jérémy Bellien
Journal: Circulation (2017)

Background: Soluble epoxide hydrolase (sEH) metabolizes endothelium-derived epoxyeicosatrienoic acids (EETs) through its hydrolase domain and also possesses a phosphatase domain, whose biological r...
Correspondence on the debate regarding the haemodynamic definition of pulmonary hypertension
Authors: Bradley A. Maron, Gaurav Choudhary, Ryan J. Tedford, Evan Brittain
Journal: European Respiratory Journal (2019)

We read with interest the balanced and well-constructed debate on the new haemodynamic definition of pulmonary hypertension (PH) published recently in the European Respiratory Journal [1, 2]. The current era of cardiopulmonary medicine is (or at least should be) at its best when defined by evidence-based decision-making. Thus, we agree with Hoeper and Humbert [1], who elegantly chronicle the trajectory of data through time that ultimately caused reconsideration to the mean pulmonary artery pressure (mPAP) threshold associated with clinical risk, now inclusive of >28 000 patients [3–6]. Since the basis of the original PH definition was largely arbitrary, the arc of debate toward a revised understanding on PAP was inevitable. In this regard, it seemed rational to modernise and align the definition of PH with the empirical evidence showing risk at lower mPAP values. Additional data are needed to clarify the haemodynamic spectrum of clinical risk in pulmonary hypertension <http://bit.ly/2ZXgld8>
Systemic silencing of Phd2 causes reversible immune regulatory dysfunction
Authors: Atsushi Yamamoto, Joanna Hester, Philip S. Macklin, Kento Kawai, Masateru Uchiyama, Daniel Biggs, Tammie Bishop, Katherine Bull, Xiaotong Cheng, Eleanor Cawthorne, Mathew L. Coleman, Tanya L. Crockford, Ben Davies, Lukas E. Dow, Rob Goldin, Kamil Kranc, Hiromi Kudo, Hannah Lawson, James McAuliffe, Kate Milward, Cheryl L. Scudamore, Elizabeth Soilleux, Fadi Issa, Peter J. Ratcliffe, Chris W. Pugh
Journal: Journal of Clinical Investigation (2019)

Physiological effects of cellular hypoxia are sensed by prolyl hydroxylase (PHD) enzymes which regulate HIFs. Genetic interventions on HIF/PHD pathways reveal multiple phenotypes that extend the known biology of hypoxia. Recent studies unexpectedly implicate HIF in aspects of multiple immune and inflammatory pathways. However such studies are often limited by systemic lethal effects and/or use tissue-specific recombination systems, which are inherently irreversible, un-physiologically restricted and difficult to time. To study these processes better we developed recombinant mice which express tetracycline-regulated shRNAs broadly targeting the main components of the HIF/PHD pathway, permitting timed bi-directional intervention. We have shown that stabilization of HIF levels in adult mice through PHD2 enzyme silencing by RNA interference, or inducible recombination of floxed alleles, results in multi-lineage leukocytosis and features of autoimmunity. This phenotype was rapidly normalized on re-establishment of the hypoxia-sensing machinery when shRNA expression was discontinued. In both situations these effects were mediated principally through the Hif2a isoform. Assessment of cells bearing regulatory T cell markers from these mice revealed defective function and pro-inflammatory effects in vivo. We believe our findings have shown a new role for the PHD2/Hif2a couple in the reversible regulation of T cell and immune activity.
Physician Impairment and Rehabilitation: Reintegration Into Medical Practice While Ensuring Patient Safety: A Position Paper From the American College of Physicians
Authors: Philip J. Candilis, Daniel T. Kim, Lois Snyder Sulmasy
Journal: Annals of Internal Medicine (2019)

Physician impairment, the inability to carry out patient care responsibilities safely and effectively, is a problem of functioning. However, the presence or treatment of a potentially impairing illness or other condition does not necessarily imply impairment. This American College of Physicians position paper examines the professional duties and principles that should guide the response of colleagues and the profession to physician impairment. The physician should be rehabilitated and reintegrated into medical practice whenever possible without compromising patient safety. At the same time, physicians have a duty to seek help when they are unable to provide safe care. When identifying and assisting colleagues who might be impaired, physicians should act on collegial concern as well as ethical and legal guidelines that require reporting of behavior that puts patients at risk. Health care institutions and the profession should support practice environments in which patient safety is prioritized and physician wellness and well-being are addressed. Physician health programs should be committed to best practices that safeguard patient safety and the rights of physician-patients.
John Adam Dormandy: championed new approaches to tackling peripheral arterial disease
Authors: Matt Limb
Journal: BMJ (2019)

John Dormandy was a consultant vascular surgeon, researcher, and medical educator best known for innovative work on the diagnosis and management of peripheral arterial disease. He had a leading role in developing, and garnering international support for, uniform guidelines that had a major impact on vascular care among specialists.

The Trans-Atlantic Inter-Society Consensus on Management of Peripheral Arterial Disease (TASC) was published in 2000.1 Dormandy, a former president of clinical medicine at the Royal Society of Medicine, was the genial force behind it, steering cooperation between medical and surgical society experts in Europe and North America.

“TASC became the standard for describing the severity of the problem that patients had and then defining what options there were to try and treat them,” says Alison Halliday, professor of vascular surgery at Oxford University who worked with Dormandy at St George’s Hospital, London. “It was the first time anybody had tried to get this general view on the complex picture of lower limb artery disease,” she says.

Dormandy, who became a consultant vascular surgeon at St George’s Hospital in 1973, would later set up a clinical trials unit there for new treatments and comparisons of drug therapy. He initiated and led numerous multicentre studies on the treatment of critical limb ischaemia, including prostacyclin trials, and on secondary prevention of vascular events in diabetic patients.

One of the novel treatments was the use of an angiogenesis stimulation to grow new blood vessels. He …
Abstract 15141: The TLR3 Pathway Including Downstream Interferon Regulating Factors, Regulates Vein Graft Remodeling
Authors: Margreet de Vries, Jacco C Karper, Tineke C van der Pouw Kraan, Erna H Peters, Rob C de Jong, Jaap F Hamming, Anton J Horrevoets, Paul H Quax
Journal: Circulation (2013)

INTRODUCTION: Most Toll like receptors (TLRs) augment vein graft thickening and remodeling via MyD88 dependent induction of inflammatory cytokines. TLR3 is unique among the TLRs since signalling oc...
Abstract 17217: ActRIIA-Fc Rebalances Activin/GDF and BMP9 Signaling to Attenuate Experimental Pulmonary Hypertension
Authors: Lai-Ming Yung, Peiran Yang, Geoffrey Bocobo, Teresa Dinter, Megan McNeil, Po-Sheng Chen, Mark Southwood, Nicholas Morrell, Scott Pearsall, Sachindra Joshi, Dianne Sako, Gang Li, Ravindra Kumar, Paul Yu
Journal: Circulation (2018)

Introduction: Therapies targeting the underlying mechanisms of pulmonary arterial hypertension (PAH) might modify the natural history of disease. The genetics of heritable PAH implicate deficient BMP signaling as a pathogenetic driver. Lung tissues from experimental and human PAH exhibit deficient BMP &amp; excessive TGFβ signaling. While previous studies suggest agonism of BMP9 signaling or inhibition of TGFβ signaling may prevent experimental PH, the roles of activin and growth and differentiation factor (GDF) ligand signaling are unclear. ACTRIIA-Fc (sotatercept) is an activin- and GDF8/11-specific ligand trap currently in Phase 2 studies for anemia and multiple myeloma. Hypothesis: ACTRIIA-Fc inhibits activin and GDF8/11 signaling in vascular cells to attenuate experimental PH and pulmonary vascular remodeling. Methods: Impact of ACTRIIA-Fc on BMP &amp; TGFβ signaling was examined in human pulmonary microvascular endothelial (PMVEC) and pulmonary arterial smooth muscle cells (PASMC). ACTRIIA-Fc (15 mg/kg s.c. 2x/week), sildenafil (30 mg/kg p.o. BID) or vehicle were given prophylactically for 4 weeks to rats developing PH following a single injection of MCT (40 mg/kg s.c.), or via single injection of SU5416 (200 mg/kg s.c.) combined with hypoxia (FIO2=0.10, SU-Hx). Alternately, rats were allowed to develop PH following SU-Hx treatment for 3 weeks or MCT treatment for 4 weeks, and then treated with ACTRIIA-Fc (1, 3, or 10 mg/kg s.c. 2x/week) or isotype-matched control antibody (3 weeks under normoxia following SU-Hx, or 2 weeks following MCT). Invasive hemodynamics, RV mass and vascular remodeling were assessed. Results: In PMVEC, ACTRIIA-Fc enhanced BMP9-induced SMAD1/5/8 activation and transcriptional activity, and reversed inhibition of BMP9 signaling by GDF11. ACTRIIA-Fc inhibited GDF8-, GDF11- and activin A-mediated SMAD2 phosphorylation and myogenic differentiation of PASMC. In vivo , a standard dose of ACTRIIA-Fc prevented PH, RV hypertrophy and PV remodeling in MCT- and SU-Hx-rats, with more potency than sildenafil. All doses of ACTRIIA-Fc attenuated PH and RV hypertrophy when given in a delayed fashion after MCT- and SU-Hx-treatment, with graded effects on PV remodeling. Conclusions: ACTRIIA-Fc rebalances GDF11 vs. BMP9 signaling, with distinct effects in vascular endothelium vs. media, and potently inhibits experimental PH in several rodent models. Given its well-defined tolerability, dosing, and efficacy in previous human studies, ACTRIIA-Fc is an attractive candidate for PAH as a novel, mechanism-targeted therapy.
Exercise trials for blood pressure control: keeping it REAL
Authors: Sallie-Anne Pearson, Nicholas Buckley, Emmanuel Stamatakis
Journal: British Journal of Sports Medicine (2019)

A pill that mimicked the effects of physical activity and exercise on the cardiovascular system would be the biggest blockbuster ever. It would be a poly-pill in its range of action with few serious adverse effects. On its patent expiry, the drug would be put in the water supply. Regrettably, there is no such pharmacological miracle in sight. Moreover, the current landscape is such that the dialogue around the expected benefits of exercise is omnipresent but doctors rarely ‘prescribe’ it and relatively few people initiate or adhere to it in the long term.

Naci and colleagues1 recently reported the outcomes of an elegant network meta-analysis, comparing exercise and drug interventions in lowering systolic blood pressure (SBP). They catalogued 391 randomised controlled trials (RCTs) involving nearly 40 000 subjects. After this mammoth effort, they conclude that there are modest but consistent reductions in SBP in exercise interventions across all populations and the SBP-lowering effects of exercise were similar to antihypertensives, particularly in hypertensive people.

In 2018, a BJSM editorial introduced the REAL framework2; incorporating simple principles to increase the usefulness of exercise research. REAL tapped into the global debate about how relevant clinical research really is.3 Here, we appraise the exercise trial literature reviewed by Naci and colleagues by retrofitting the four most relevant aspects of the taxonomy developed by John Ioannidis (Supplemental Table 1); REAL is a …
Best practices for analyzing large-scale health data from wearables and smartphone apps
Authors: Jennifer L. Hicks, Tim Althoff, Rok Sosic, Peter Kuhar, Bojan Bostjancic, Abby C. King, Jure Leskovec, Scott L. Delp
Journal: npj Digital Medicine (2019)

Abstract Smartphone apps and wearable devices for tracking physical activity and other health behaviors have become popular in recent years and provide a largely untapped source of data about health behaviors in the free-living environment. The data are large in scale, collected at low cost in the “wild”, and often recorded in an automatic fashion, providing a powerful complement to traditional surveillance studies and controlled trials. These data are helping to reveal, for example, new insights about environmental and social influences on physical activity. The observational nature of the datasets and collection via commercial devices and apps pose challenges, however, including the potential for measurement, population, and/or selection bias, as well as missing data. In this article, we review insights gleaned from these datasets and propose best practices for addressing the limitations of large-scale data from apps and wearables. Our goal is to enable researchers to effectively harness the data from smartphone apps and wearable devices to better understand what drives physical activity and other health behaviors.
Removal of a migrated biliary stent using new digital cholangioscopy retrieval devices in a transplant patient
Authors: Francesc Bas-Cutrina, Albert Garcia-Sumalla, Julio Velasquez, Claudia F. Consiglieri, Laura Lladó, Joan B. Gornals
Journal: Endoscopy (2019)

A 51-year-old man who had undergone liver transplantation developed a symptomatic anastomotic biliary stricture 23 months after surgery. Endoscopic biliary therapy via endoscopic retrograde cholangiopancreatography (ERCP) was planned. Progressive biliary balloon dilation of the stenosis was performed, with placement of three coaxial plastic stents (8.5-Fr × 12 cm, 8.5-Fr × 9 cm, and 10-Fr × 12 cm; Advanix, Boston Scientific, Natick, Massachusetts, USA).
Distinguishing Tumor from Associated Fibrosis to Increase Diagnostic Biopsy Yield with Polarization-Sensitive Optical Coherence Tomography
Authors: Lida P. Hariri, David C. Adams, Matthew B. Applegate, Alyssa J. Miller, Benjamin W. Roop, Martin Villiger, Brett E. Bouma, Melissa J. Suter
Journal: Clinical Cancer Research (2019)

With recent advancements in personalized medicine, biopsies must contain sufficient tumor for histologic diagnosis and molecular testing. However, inadvertent biopsy of tumor-associated fibrosis compromises tumor yield, resulting in delayed diagnoses and/or repeat procedures when additional tumor is needed. The ability to differentiate tumor from fibrosis intraprocedurally during biopsy could significantly increase tumor yield. Polarization-sensitive optical coherence tomography (PS-OCT) is an imaging modality that is endoscope- and/or needle-compatible, and provides large volumetric views of tissue microstructure with high resolution (∼10 μm) while simultaneously measuring birefringence of organized tissues such as collagen. We aim to determine whether PS-OCT can accurately detect and distinguish tumor-associated fibrosis from tumor.PS-OCT was obtained ex vivo in 64 lung nodule samples. PS-OCT birefringence was measured and correlated to collagen content in precisely matched histology, quantified on picrosirius red (PSR) staining.There was a strong positive correlation between PS-OCT measurement of birefringent fibrosis and total collagen content by PSR (r = 0.793; P < 0.001). In addition, PS-OCT was able to accurately classify tumor regions with >20% fibrosis from those with low fibrosis (≤20%) that would likely yield higher tumor content (P < 0.0001).PS-OCT enables accurate fibrosis detection and can distinguish tumor regions with low fibrosis. PS-OCT has significant potential for clinical impact, as the ability to differentiate tumor from fibrosis could be used to guide intraprocedural tissue sampling in vivo, or for rapid biopsy adequacy assessment ex vivo, to increase diagnostic tumor yield essential for patient care and research.