tbuckley/cabot-search huggingface dataset:
Efficacy, Safety, and Regulatory Approval of Food and Drug Administration–Designated Breakthrough and Nonbreakthrough Cancer Medicines
Authors: Thomas J. Hwang, Jessica M. Franklin, Christopher T. Chen, Julie C. Lauffenburger, Bishal Gyawali, Aaron S. Kesselheim, Jonathan J. Darrow
Journal: Journal of Clinical Oncology (2018)

Purpose The breakthrough therapy program was established in 2012 to expedite the development and review of new medicines. We evaluated the times to approval, efficacy, and safety of breakthrough-designated versus non-breakthrough-designated cancer drugs approved by the US Food and Drug Administration (FDA). Methods We studied all new cancer drugs approved by the FDA between January 2012 and December 2017. Regulatory and therapeutic characteristics (time to FDA approval, pivotal trial efficacy end point, novelty of mechanism of action) were compared between breakthrough-designated and non-breakthrough-designated cancer drugs. Random-effects meta-regression was used to assess the association between breakthrough therapy designation and hazard ratios for progression-free survival (PFS), response rates (RRs) for solid tumors, serious adverse events, and deaths not attributed to disease progression. Results Between 2012 and 2017, the FDA approved 58 new cancer drugs, 25 (43%) of which received breakthrough therapy designation. The median time to first FDA approval was 5.2 years for breakthrough-designated drugs versus 7.1 years for non-breakthrough-designated drugs (difference, 1.9 years; P = .01). There were no statistically significant differences between breakthrough-designated and non-breakthrough-designated drugs in median PFS gains (8.6 v 4.0 months; P = .11), hazard ratios for PFS (0.43 v 0.51; P = .28), or RRs for solid tumors (37% v 39%; P = .74). Breakthrough therapy-designated drugs were not more likely to act via a novel mechanism of action (36% v 39%; P = 1.00). Rates of deaths (6% v 4%; P = .99) and serious adverse events (38% v 36%; P = 0.93) were also similar in breakthrough-designated and non-breakthrough-designated drugs. Conclusion Breakthrough-designated cancer drugs were associated with faster times to approval, but there was no evidence that these drugs provide improvements in safety or novelty; nor was there a statistically significant efficacy advantage when compared with non-breakthrough-designated drugs.
Histidine-rich glycoprotein-induced vascular normalization improves EPR-mediated drug targeting to and into tumors
Authors: Benjamin Theek, Maike Baues, Felix Gremse, Robert Pola, Michal Pechar, Inka Negwer, Kaloian Koynov, Benjamin Weber, Matthias Barz, Willi Jahnen-Dechent, Gert Storm, Fabian Kiessling, Twan Lammers
Journal: Journal of Controlled Release (2018)
Case-control study on risk factors for acute hepatitis E in Germany, 2012 to 2014
Authors: Mirko Faber, Mona Askar, Klaus Stark
Journal: Eurosurveillance (2018)

Background Notified cases of hepatitis E have increased 40-fold in the past 10 years in Germany. Food safety is a major concern as hepatitis E virus (HEV) RNA has been detected in ready-to-eat retail-level food products. The objective of this case–control study was to assess risk factors for autochthonous symptomatic hepatitis E and explore reasons for delays in diagnosis. Methods: Demographic, clinical and exposure data from notified hepatitis E cases and individually matched population controls were collected in semi-standardised telephone interviews. Conditional logistic regression analysis was used to calculate matched odds ratios (mOR) and population attributable fractions (PAF). Results: In total, 270 cases and 1,159 controls were included (mean age 53 years, 61% men in both groups). Associated with disease were: consumption of undercooked pork liver, pork, wild boar meat, frankfurters, liver sausage and raw vegetables; contact with waste water (occupational) and various host factors (mORs between 1.9 and 34.1, p value &lt; 0.03). PAF for frankfurters and liver sausage were 17.6%, and 23.6%, respectively. There were statistically significant differences in the clinical presentation and hospitalisation proportion of acute hepatitis E in men and women. Diagnosis was preceded by more invasive procedures in 29.2% of patients, suggesting that hepatitis E was not immediately considered as a common differential diagnosis. Conclusions: Our study suggests that there are indeed sex-specific differences in disease development and lends important epidemiological evidence to specific ready-to-eat pork products as a major source for autochthonous hepatitis E. A review of existing consumer recommendations and production methods may be indicated.
AODTU-001 Radiofrequency ablation in patients with symptomatic anaemia secondary to gastric antral vascular ectasia
Authors: C Magee, G Lipman, R Sweis, M Banks, L Lovat, C Murray, R Haidry
Journal: Gut (2017)

Introduction  Gastric astral vascular ectasia (GAVE) is a rare cause of gastrointestinal bleeding (GIB). Patients often require regular blood transfusions and many require oral or intravenous iron to manage symptomatic anaemia. Endoscopic therapy includes argon plasma coagulation (APC), YAG laser therapy and band ligation. In some patients, these measures are unsuccessful and they remain transfusion dependent with significant effects on health and quality of life. Radio-frequency ablation (RFA) may provide a solution.  Method  Patients who had remained anaemic and/or transfusion or iron dependent were eligible. Other causes of GIB were excluded. Treatment with RFA was carried out with focal RFA at 12 J/cm2 with 3 applications to all visible areas of GAVE by a single endoscopist. Patients had up to 2 RFA treatments 6 weeks apart before entering the follow up phase. Data were collected before and after treatment.  The primary outcome was change in haemoglobin (Hb) 3 months after treatment. Secondary outcomes were a reduction in frequency of blood transfusions and/or iron (PO or IV) in the 3 months before and after RFA treatment. Endoscopic surface area (SA) regression of areas of GAVE were analysed by asking 3 expert endoscopists to estimate the overall% change in SA following treatment by examining endoscopic images of the stomach before and after treatment.  Results  16 patients have undergone RFA for refractory GAVE. The median age was 70 years (IQR 56–84). 13/16 (82%) were female. 12 were previously treated with APC, 3 with LASER and 2 of those treated with APC had also had band ligation. In the 3 months prior to treatment, 11/16 were on oral iron, 2/16 were on IV iron. 11/16 required blood transfusions. 8/16 required both iron and blood transfusions. The median number of RFA treatments was 1 (IQR 1–2). No patients had recorded complications of RFA.  The mean pre-treatment Hb was 99.5 g/L (95% CI 90.3–108.6 g/L). The mean post treatment Hb at 3 months after treatment was 121 g/L (95% CI 112–129 g/L). The mean change in Hb was +20.5 g/L (95% CI 8.8–30.0 g/L) (p=0.0026).  Post treatment, only 2/11 (18%) of the patients who required transfusion prior to the procedure had ongoing transfusions. Only 2/13 (15%) patients who were previously on iron had ongoing iron requirements.  The mean surface area regression when scored by 3 upper GI endoscopists was 51.6%. [95% CI 38.7–64.4]  Conclusion  RFA for patients with symptomatic anaemia due to GAVE is a novel treatment therapy for a difficult cause of GI bleeding. This single centre experience suggests it can reduce transfusion dependence and iron supplementation in some patients with an improved Hb after treatment. The required number of treatments is small and it appears safe.  Disclosure of Interest  None Declared
HepFree: Screening migrant patients for viral hepatitis in primary care. A 90,000 patient randomised controlled trial indicates benefits are most obvious in older patients
Authors: S. Flanagan, V.J. Appleby, J. Gaviria, J. Kunkel, V. Madurasinghe, S. Eldridge, S. Moreea, K. Agarwal, E. Barnes, C. Griffiths, M. Pitt, A. Salmon, G. Foster
Journal: Journal of Hepatology (2018)
Treatment of patients with decompensated cirrhosis with DAAs improves clinical symptoms without affecting their MELD score
Authors: J. Romano, O. Sims, J. Richman, M. Tansia, M. Shoreibah, P. Fitzmorris, Y. Guo, V. Kommineni, K. Lakshmi, O. Massoud
Journal: Journal of Hepatology (2018)
Cumulative Risk Distribution for Interval Invasive Second Breast Cancers After Negative Surveillance Mammography
Authors: Janie M. Lee, Linn Abraham, Diana L. Lam, Diana S.M. Buist, Karla Kerlikowske, Diana L. Miglioretti, Nehmat Houssami, Constance D. Lehman, Louise M. Henderson, Rebecca A. Hubbard
Journal: Journal of Clinical Oncology (2018)

Purpose The aim of the current study was to characterize the risk of interval invasive second breast cancers within 5 years of primary breast cancer treatment. Methods We examined 65,084 surveillance mammograms from 18,366 women with a primary breast cancer diagnosis of unilateral ductal carcinoma in situ or stage I to III invasive breast carcinoma performed from 1996 to 2012 in the Breast Cancer Surveillance Consortium. Interval invasive breast cancer was defined as ipsilateral or contralateral cancer diagnosed within 1 year after a negative surveillance mammogram. Discrete-time survival models—adjusted for all covariates—were used to estimate the probability of interval invasive cancer, given the risk factors for each surveillance round, and aggregated across rounds to estimate the 5-year cumulative probability of interval invasive cancer. Results We observed 474 surveillance-detected cancers—334 invasive and 140 ductal carcinoma in situ—and 186 interval invasive cancers which yielded a cancer detection rate of 7.3 per 1,000 examinations (95% CI, 6.6 to 8.0) and an interval invasive cancer rate of 2.9 per 1,000 examinations (95% CI, 2.5 to 3.3). Median cumulative 5-year interval cancer risk was 1.4% (interquartile range, 0.8% to 2.3%; 10 th to 90th percentile range, 0.5% to 3.7%), and 15% of women had ≥ 3% 5-year interval invasive cancer risk. Cumulative 5-year interval cancer risk was highest for women with estrogen receptor– and progesterone receptor–negative primary breast cancer (2.6%; 95% CI, 1.7% to 3.5%), interval cancer presentation at primary diagnosis (2.2%; 95% CI, 1.5% to 2.9%), and breast conservation without radiation (1.8%; 95% CI, 1.1% to 2.4%). Conclusion Risk of interval invasive second breast cancer varies across women and is influenced by characteristics that can be measured at initial diagnosis, treatment, and imaging. Risk prediction models that evaluate the risk of cancers not detected by surveillance mammography should be developed to inform discussions of tailored surveillance.
DNA methylation profiling of hepatitis C virus patients treated with direct acting antivirals identifies consistent methylation changes in livers and blood
Authors: A. Vasanthakumar, D. Quarless, E. Dilmukhametova, M. Abunimeh, C. Konefal, S. Abel, K. Idler, G. Lauer, A. Kim, R. Chung, D. Cohen, J.W. Davis, E. Dumas, J.F. Waring
Journal: Journal of Hepatology (2018)
CTCF boundary remodels chromatin domain and drives aberrant HOX gene transcription in acute myeloid leukemia
Authors: Huacheng Luo, Fei Wang, Jie Zha, Haoli Li, Bowen Yan, Qinghua Du, Fengchun Yang, Amin Sobh, Christopher Vulpe, Leylah Drusbosky, Christopher Cogle, Iouri Chepelev, Bing Xu, Stephen D. Nimer, Jonathan Licht, Yi Qiu, Baoan Chen, Mingjiang Xu, Suming Huang
Journal: Blood (2018)
Recombination activity of human recombination-activating gene 2 (RAG2) mutations and correlation with clinical phenotype
Authors: Irit Tirosh, Yasuhiro Yamazaki, Francesco Frugoni, Francesca A. Ververs, Eric J. Allenspach, Yu Zhang, Siobhan Burns, Waleed Al-Herz, Lenora Noroski, Jolan E. Walter, Andrew R. Gennery, Mirjam van der Burg, Luigi D. Notarangelo, Yu Nee Lee
Journal: Journal of Allergy and Clinical Immunology (2018)
P284HDL preserves mitochondrial complex I activity during myocardial reperfusion injury
Authors: J Barreto, I Bonilha, V Virginio, M Santana, A C Sposito
Journal: Cardiovascular Research (2018)

auricles.EMT was defined using aSMA immunostaining.The top 22 ranked compounds were validated in multiple epicardial cell lines using aSMA immunostaining and qRT-PCR for EMT related genes.With the two highest responders, concentration-response experiments are currently being conducted to determine the optimal dosage.Conclusion: It is feasible and effective to perform high-throughput experiments using human primary epicardial derived cells to identify EMT activators.Furthermore, two compounds were found that can induce EMT in epicardial derived cells and may therefore serve as a potential therapeutic to improve the epicardial regenerative response.In the future, my research will focus on optimizing strategies to deliver these EMT-inducing compounds to the epicardium of the infarcted heart.
The expanding constellation of immune checkpoints: a DNAMic control by CD155
Authors: Vincenzo Bronte
Journal: Journal of Clinical Investigation (2018)

The clinical benefits that have been achieved for a group of cancer patients with metastatic disease on checkpoint inhibitor therapy have kindled intense interest in understanding tumor-induced escape from T lymphocyte control. Other lymphoid cells also participate in tumor control; in particular, NK cells can limit hematogenous cancer metastasis spread and are also subject to negative regulation by developing cancers. In this issue of the JCI, Li and colleagues define an unanticipated role for the stress-induced protein CD155 in cancer metastasis. The presence of CD155 on the surface of cancer cells was shown to promote tumor invasiveness, while its upregulation in tumor environment-infiltrating myeloid cells restrained antitumor immunity by impairing antitumor T lymphocytes and NK cell function. Together, these results support further exploration of strategies for targeting CD155.
68Ga-Labeled PSMA Uptake in Nonprostatic Malignancies
Authors: Dharmender Malik, Rajender Kumar, Bhagwant Rai Mittal, Harmandeep Singh, Anish Bhattacharya, Shrawan Kumar Singh
Journal: Clinical Nuclear Medicine (2018)

Abstract PET/CT with 68 Ga-labeled prostate-specific membrane antigen (PSMA) is increasingly recognized as the best imaging modality for disease staging and detection of recurrent prostate cancer. Despite its name, PSMA expression has been reported in a number of nonprostatic benign and malignant pathologies. Apparently, angioneogenesis is the mechanism attributed to increased 68 Ga-PSMA uptake at these sites. Here we illustrate the utility of 68 Ga-PSMA in 5 nonprostatic malignancies that could open up new possibilities for diagnostics and theranostic concepts with PSMA labeled radioligands in nonprostate tumor entities.
Court rejects parents’ appeal over life support for son
Authors: Clare Dyer
Journal: BMJ (2018)

The case of Alfie Evans, a profoundly brain damaged toddler, is back with the UK Supreme Court after three appeal court judges ruled that his parents’ latest appeal was “wholly misconceived.”

Thomas Evans and Kate James are awaiting a decision from a panel of three Supreme Court justices on whether they will hear a further appeal.

Alfie, who will be 2 years old in May, has an undiagnosed condition, thought to be mitochondrial, …
Expression profiling of 728 miRNAs in a NASH model identifies excellent correlations of hepatic and circulation miR-34a levels with histological lesions in rats and men
Authors: G. Cordonnier, F. Texier, N. Benoit, D. Nathalie, F.B. Sudrick, J. Brozek, R. Hanf, A. Sanyal
Journal: Journal of Hepatology (2018)
P72New variant in CMYA5 gene is associated with early-onset restrictive cardiomyopathy and autism-spectrum disorder
Authors: A Kiselev, T Kornishina, A Sergushichev, N Smolina, A Klyushina, T Pervunina, M L Bang, G Sjoberg, T Sejersen, A Kostareva
Journal: Cardiovascular Research (2018)
Marked reduction in the prevalence of hepatitis C viremia among people who inject drugs during 2nd year of the Treatment as Prevention (TraP HepC) program in Iceland
Authors: T. Tyrfingsson, V. Runarsdottir, I. Hansdottir, O.M. Bergmann, E.S. Björnsson, B. Johannsson, B. Sigurdardottir, R.H. Fridriksdottir, A. Löve, T.J. Löve, G. Sigmundsdottir, U.B. Hernandez, M. Heimisdottir, M. Gottfredsson, S. Olafsson
Journal: Journal of Hepatology (2018)
New leadership for the WHO Regional Office for the Eastern Mediterranean: exceptional election in an exceptional time
Authors: Samer Jabbour, Sameen Siddiqi, Rita Giacaman, Hani Serag, Jawad Al-Lawati, Amirhossein Takian, Habiba Ben Romdhane, Elsheikh Badr, Laith J Abu-Raddad, Aida Seif El-Dawla, Salwa Najjab, Driss Moussaoui, Mustafa Khogali, Yousef Khader, Bothaina Attal, Iman Nuwayhid
Journal: The Lancet (2018)
Inducible ablation of TGFß receptor type 2 limited to hepatic stellate cells potently inhibits liver fibrosis and attenuates inflamation
Authors: O. Molokanova, K. Schönig, S.-Y. Weng, X. Wang, S. Ohngemach, A. Nikolaev, D. Strand, L. Eshkind, D. Schuppan, S. Lorenz
Journal: Journal of Hepatology (2018)
P2Y1 receptor blockade normalizes network dysfunction and cognition in an Alzheimer’s disease model
Authors: Nicole Reichenbach, Andrea Delekate, Björn Breithausen, Kevin Keppler, Stefanie Poll, Theresa Schulte, Jan Peter, Monika Plescher, Jan N. Hansen, Nelli Blank, Armin Keller, Martin Fuhrmann, Christian Henneberger, Annett Halle, Gabor C. Petzold
Journal: The Journal of Experimental Medicine (2018)

Astrocytic hyperactivity is an important contributor to neuronal-glial network dysfunction in Alzheimer’s disease (AD). We have previously shown that astrocyte hyperactivity is mediated by signaling through the P2Y1 purinoreceptor (P2Y1R) pathway. Using the APPPS1 mouse model of AD, we here find that chronic intracerebroventricular infusion of P2Y1R inhibitors normalizes astroglial and neuronal network dysfunction, as measured by in vivo two-photon microscopy, augments structural synaptic integrity, and preserves hippocampal long-term potentiation. These effects occur independently from β-amyloid metabolism or plaque burden but are associated with a higher morphological complexity of periplaque reactive astrocytes, as well as reduced dystrophic neurite burden and greater plaque compaction. Importantly, APPPS1 mice chronically treated with P2Y1R antagonists, as well as APPPS1 mice carrying an astrocyte-specific genetic deletion (Ip3r2−/−) of signaling pathways downstream of P2Y1R activation, are protected from the decline of spatial learning and memory. In summary, our study establishes the restoration of network homoeostasis by P2Y1R inhibition as a novel treatment target in AD.
Junior doctor whistleblowers need protection they can trust, says Robert Francis
Authors: Abi Rimmer
Journal: BMJ (2018)

Junior doctors feel vulnerable as whistleblowers and need the same level of protection as trainee nurses, Robert Francis QC has said.

Francis, who led the 2013 inquiry into the scandal at Mid Staffordshire NHS Foundation Trust, also chaired the 2014 Freedom to Speak Up review, commissioned by the government to recommend ways to improve the culture around whistleblowing in the NHS.1

Speaking at a Westminster Health Forum event on patient safety on 26 April, Francis said that doctors in training thought that they did not have enough protection when speaking out about concerns. …
Identification of the fast progression and spontaneous regression liver fibrosis phenotypes by a serological collagen turnover profile
Authors: S.T. Hjuler, D.G.K. Rasmussen, M.J. Nielsen, D. Leeming, S. Gardner, Z. Goodman, K. Patel, D. Schuppan, M. Karsdal
Journal: Journal of Hepatology (2018)
Disparities in Mortality of Hispanic Patients with Cystic Fibrosis in the United States. A National and Regional Cohort Study
Authors: Jason Rho, Chul Ahn, Ang Gao, Gregory S. Sawicki, Ashley Keller, Raksha Jain
Journal: American Journal of Respiratory and Critical Care Medicine (2018)

Rationale: Patients of Hispanic origin with cystic fibrosis (CF) are the largest growing minority, representing 8.5% of patients with CF in the United States. No national survival analysis of this group has ever been undertaken.Objectives: We aimed to determine whether Hispanic ethnicity within the CF population is associated with worse outcomes and whether any geographic differences exist.Methods: Using U.S. Cystic Fibrosis Foundation Patient Registry data from 2010 to 2014, we performed a retrospective cohort analysis comparing survival rates between Hispanics and non-Hispanics using Kaplan-Meier and Cox regression analysis. A subject's residence was categorized into geographic regions based on U.S. Census Bureau data: Northeast, Midwest, West, and South.Measurements and Main Results: A total of 29,637 patients were included in the study; 2,493 identified themselves as Hispanic. Hispanics had a lower survival probability overall, with a mean age of death of 22.4 ± 9.9 years compared with non-Hispanics of 28.1 ± 10.0 years (P < 0.0001). Multivariate Cox proportional hazards modeling revealed that Hispanic patients with CF had a 1.27 times higher rate of death compared with non-Hispanics (95% confidence interval, 1.05–1.53) after adjusting for covariates including age, sex, genetic mutations, bacterial cultures, lung function, body mass index, use of CF respiratory therapies, low socioeconomic status, pancreatic enzyme use, and CF-related diabetes. When analyzed by region, Hispanics in the Midwest, Northeast, and West had shorter median survivals compared with non-Hispanics, which was not demonstrated in the South.Conclusions: Patients with CF of Hispanic origin have a higher mortality rate than non-Hispanic patients with CF. This pattern was seen in the Midwest, Northeast, and West but not in the South.
Infant Viral Respiratory Infection Nasal Immune-Response Patterns and Their Association with Subsequent Childhood Recurrent Wheeze
Authors: Kedir N. Turi, Jyoti Shankar, Larry J. Anderson, Devi Rajan, Kelsey Gaston, Tebeb Gebretsadik, Suman R. Das, Cosby Stone, Emma K. Larkin, Christian Rosas-Salazar, Steven M. Brunwasser, Martin L. Moore, R. Stokes Peebles, Tina V. Hartert
Journal: American Journal of Respiratory and Critical Care Medicine (2018)

Rationale: Recurrent wheeze and asthma are thought to result from alterations in early life immune development following respiratory syncytial virus (RSV) infection. However, prior studies of the nasal immune response to infection have assessed only individual cytokines, which does not capture the whole spectrum of response to infection.Objectives: To identify nasal immune phenotypes in response to RSV infection and their association with recurrent wheeze.Methods: A birth cohort of term healthy infants born June to December were recruited and followed to capture the first infant RSV infection. Nasal wash samples were collected during acute respiratory infection, viruses were identified by RT-PCR, and immune-response analytes were assayed using a multianalyte bead-based panel. Immune-response clusters were identified using machine learning, and association with recurrent wheeze at age 1 and 2 years was assessed using logistic regression.Measurements and Main Results: We identified two novel and distinct immune-response clusters to RSV and human rhinovirus. In RSV-infected infants, a nasal immune-response cluster characterized by lower non-IFN antiviral immune-response mediators, and higher type-2 and type-17 cytokines was significantly associated with first and second year recurrent wheeze. In comparison, we did not observe this in infants with human rhinovirus acute respiratory infection. Based on network analysis, type-2 and type-17 cytokines were central to the immune response to RSV, whereas growth factors and chemokines were central to the immune response to human rhinovirus.Conclusions: Distinct immune-response clusters during infant RSV infection and their association with risk of recurrent wheeze provide insights into the risk factors for and mechanisms of asthma development.