tbuckley/cabot-search huggingface dataset:
The mucin MUC1 modulates the tumor immunological microenvironment through engagement of the lectin Siglec-9
Authors: Richard Beatson, Virginia Tajadura-Ortega, Daniela Achkova, Gianfranco Picco, Theodora-Dorita Tsourouktsoglou, Sandra Klausing, Matthew Hillier, John Maher, Thomas Noll, Paul R Crocker, Joyce Taylor-Papadimitriou, Joy M Burchell
Journal: Nature Immunology (2016)
Calcite Single Crystals as Hosts for Atomic‐Scale Entrapment and Slow Release of Drugs
Authors: Giulia Magnabosco, Matteo Di Giosia, Iryna Polishchuk, Eva Weber, Simona Fermani, Andrea Bottoni, Francesco Zerbetto, Pier Giuseppe Pelicci, Boaz Pokroy, Stefania Rapino, Giuseppe Falini, Matteo Calvaresi
Journal: Advanced Healthcare Materials (2015)

Adv. Healthcare Mater. 2015, 4, 1510–1516 There was an error in the concentrations of doxorubicin reported in the originally published article; in the original version they were expressed in M instead of mM. The correct concentrations of doxorubicin should be expressed in mM and are: 5 × 10−4 mM; 5 × 10−3 mM; 5 × 10−2 mM, 5 × 10−1 mM and 5 mM throughout the article, with the exception of page 1511, right column, lines 6 and 14, where the concentration 5 × 10−3 M is correct. The arguments and conclusions of the original article are not affected. The authors apologize for any inconvenience caused.
Evaluation of Kras mutations and angiogenic biomarkers in patients with advanced non-small cell lung cancer (NSCLC) receiving single-agent sorafenib (S).
Authors: R. J. Kelly, J. Force, A. Rajan, C. Keen, B. Turkbey, L. Cao, M. Raffeld, S. M. Steinberg, J. J. Wright, G. Giaccone
Journal: Journal of Clinical Oncology (2010)

7626 Background: S is an oral multikinase inhibitor that targets the Ras/Raf/MEK/ERK pathway at the level of Raf kinase. At present there are no predictive biomarkers to improve patient selection and predict response to angiogenic inhibitors in NSCLC. Kras mutation status, angiogenesis markers (VEGF, bFGF, FLT-1, PLGF-1) and correlative imaging with DCE-MRI to determine early changes in tumor vascular characteristics were evaluated. Methods: Patients received S (400 mg po bid daily, in continuous 4 week cycles) in an effort to determine activity and tolerability and to measure its biological effects. Responses were evaluated every 8 weeks by RECIST. Kras mutations at codons 12, 13 and 61 were analyzed (n = 24). Two vascular permeability parameters Ktrans and Kep were measured by DCE-MRI at baseline and day 15 of cycle 1 (n = 27). Cytokine analysis was performed with serial plasma samples obtained on days 0, 14, 28 and 54 (n = 18). Results: 37 pts with previously treated stage IV NSCLC were enrolled in this single center phase II trial. Two pts (5%) had PRs and 19 had SD (51%) of 3-17 months. Drug related toxicity was consistent with the known side effects of S. Kras mutational status (17 wildtype, 7 mutations) and DCE-MRI were not associated with clinical outcome. In exploratory analyses with up to 18 pts, 3 plasma based parameters with levels below their respective median values in pg/mL demonstrated potential trends towards an association with improved OS by having univariate two-tailed p-values < 0.10: VEGF at day 0 < 150 had survival better than VEGF > 151+ (p = 0.014), bFGF at day 14 < 11.1 had survival better than bFGF > 11.2+ (p = 0.025) and FLT-1 at day 0 < 180 had survival better than FLT-1 > 181+ (p = 0.078). Conclusions: In this pt population with advanced NSCLC, Kras mutational status and DCE-MRI showed no correlation with response to S. Plasma based VEGF/FLT-1 and bFGF levels may act as biomarkers indicative of early angiogenesis inhibition. Confirmation of these findings would be worthwhile in a larger independent patient population. No significant financial relationships to disclose.
Two year progression free survival in stage IV NSCLC patients treated with pemetrexed continuation maintenance.
Authors: Jason Nathaniel Macklis, Fatima Saleem, Fatema Mohammed Esmail, Sanjib Basu, Mary J. Fidler, Philip Bonomi, Marta Batus
Journal: Journal of Clinical Oncology (2016)

e20654 Background: Continuation pemetrexed maintenance is associated with longer survival in stage IV non-squamous NSCLC pts. We observed that some of our non-squamous NSCLC pts treated with pemetrexed continuation maintenance had relatively long disease control. The objective of our single institution retrospective study was to determine the number of these pts whose progression free survival was ≥ 24 months. Another objective was to evaluate baseline clinical characteristics including neutrophil/lymphocyte ratios in patients with PFS > 24 months vs < 24 months. Methods: Pts with stage IV NSCLC who received at least once cycle of pemetrexed/platinum with planned pemetrexed maintenance (N = 216) between May 2010 and December 2013 were included in this retrospective analysis. Patient demographics, NLR at baseline, first and last dates of pemetrexed therapy, and date of progression were recorded. Pts were grouped according to duration of response ≥ 24 months vs < 24 months. Potential associations between patient demographics and NLR for the two groups were assessed using a Mann-Whitney-Wilcoxon test. Results: Median age 66, male/female 40.3%/59.7%, 22% never smoker. The median progression free survival was 180.5 days. 30 pts (13.8%) had no progression of disease at ≥ 24 months since starting treatment with pemetrexed/platinum followed by pemetrexed maintenance. A PFS ≥ 24 months was associated with a lower baseline NLR (median 3.3 vs 4.57; 25-75 percentile 2.318-3.983 vs 2.755-7.885; p = 0.0046 ). Longer PFS was not significantly related to gender, age, performance status, sites of metastases, or number of disease sites. Conclusions: Median PFS fails to capture what happens to pts at the end of the PFS curve and thus does not inform pts or practitioners about maximum derived benefit from treatment. We found a relatively large percentage of pts (13.8%) treated with pemetrexed/platinum followed by pemetrexed were free from disease progression at ≥ 24 months. Longer PFS was associated with lower baseline NLR - a marker of inflammation correlated with tumor cachexia and progression. Studies evaluating other clinical and molecular parameters associated with longer disease control are planned.
Impact of Azacitidine (AZA) Prior to Allogeneic Stem Cell Transplantation (allo-SCT) for Myelodysplastic Syndromes (MDS): A Large-Scale Study on Behalf of the SFGM-TC and GFM Groups
Authors: Gandhi Damaj, Julia Salleron, Marie Robin, Mauricette Michallet, Mohamad Mohty, Vigouroux Stephane, Yves Beguin, Alice Garnier, Bruno Lioure, Jean El Cheikh, Nathalie Fegueux, Jérôme Cornillon, Lionel Ades, Sylvie Francois, Marie T Rubio, Sophie Park, Federico Garnier, Pierre Fenaux, Ibrahim Yakoub-Agha
Journal: Blood (2011)
General practice should be recognised as specialty in UK, leaders argue
Authors: Gareth Iacobucci
Journal: BMJ (2016)

General practice leaders have called on the government and the General Medical Council to correct the “anachronistic anomaly” whereby GP postgraduate training remains unrecognised as a medical specialty in the United Kingdom.

In a joint statement,1 GP leaders from the BMA and the Royal College of General Practitioners (RCGP) from across the four UK nations said that this recognition was “long overdue” given the rigorous training and examination that GPs undergo.

The move—which would require the government to make changes to primary UK legislation—has been prompted …
Resolvin D2 Enhances Postischemic Revascularization While Resolving Inflammation
Authors: Michael J. Zhang, Brian E. Sansbury, Jason Hellmann, James F. Baker, Luping Guo, Caitlin M. Parmer, Joshua C. Prenner, Daniel J. Conklin, Aruni Bhatnagar, Mark A. Creager, Matthew Spite
Journal: Circulation (2016)

Background: Resolvins are lipid mediators generated by leukocytes during the resolution phase of inflammation. They have been shown to regulate the transition from inflammation to tissue repair; however, it is unknown whether resolvins play a role in tissue revascularization following ischemia. Methods: We used a murine model of hind limb ischemia (HLI), coupled with laser Doppler perfusion imaging, microcomputed tomography, and targeted mass spectrometry, to assess the role of resolvins in revascularization and inflammation resolution. Results: In mice undergoing HLI, we identified resolvin D2 (RvD2) in bone marrow and skeletal muscle by mass spectrometry (n=4–7 per group). We also identified RvD2 in skeletal muscle biopsies from humans with peripheral artery disease. Monocytes were recruited to skeletal muscle during HLI and isolated monocytes produced RvD2 in a lipoxygenase-dependent manner. Exogenous RvD2 enhanced perfusion recovery in HLI and microcomputed tomography of limb vasculature revealed greater volume, with evidence of tortuous arterioles indicative of arteriogenesis (n=6–8 per group). Unlike other treatment strategies for therapeutic revascularization that exacerbate inflammation, RvD2 did not increase vascular permeability, but reduced neutrophil accumulation and the plasma levels of tumor necrosis factor-α and granulocyte macrophage colony-stimulating factor. In mice treated with RvD2, histopathologic analysis of skeletal muscle of ischemic limbs showed more regenerating myocytes with centrally located nuclei. RvD2 enhanced endothelial cell migration in a Rac-dependent manner, via its receptor, GPR18, and Gpr18 -deficient mice had an endogenous defect in perfusion recovery following HLI. Importantly, RvD2 rescued defective revascularization in diabetic mice. ConclusionS: RvD2 stimulates arteriogenic revascularization during HLI, suggesting that resolvins may be a novel class of mediators that both resolve inflammation and promote arteriogenesis.
Case 27-1968
Authors: Robert W. Carey, Benjamin Castleman
Journal: New England Journal of Medicine (1968)

Presentation of Case First admission. A thirty-eight-year-old woman entered the hospital because of a pustular skin eruption.She had been well until seven months previously, when there was the onset of intermittent fever, anorexia and a cough productive of rust-colored sputum. Axillary and cervical masses appeared four months thereafter and subsequently enlarged. Six weeks before admission a pruritic skin eruption developed; the skin became excoriated and covered with pustules. She had lost 64 pounds in weight.On examination a pustular and papular eruption was present over the skin. The optic fundi were normal. Numerous large, discrete, firm, nontender cervical, . . .
A TFPI Inhibitory Half Life Extended Fusion Peptide Proves Efficacy in FVIII Knock out Mice and Marmoset Monkeys
Authors: Michael Dockal, Rudolf Hartmann, Thomas Polakowski, Erwin Panholzer, Willibald Kammlander, Frank Osterkamp, Ulrich Reineke, Alexandra Schiviz, Werner Hoellriegl, Friedrich Scheiflinger
Journal: Blood (2014)
The ICD in Heart Failure — Time for a Rethink?
Authors: John J.V. McMurray
Journal: New England Journal of Medicine (2016)

In a number of primary-prevention trials, implantable cardioverter–defibrillators (ICDs) have been shown to reduce the risk of premature death among patients with left ventricular systolic dysfunction after myocardial infarction and among patients with heart failure and reduced ejection fraction.1 The evidence of a benefit is less robust for patients with heart failure who do not have coronary artery disease; the single largest trial, involving 458 such patients, did not show a significant reduction in mortality in association with ICD therapy.2 As a result, the current guideline recommendations are based on a meta-analysis of small trials involving patients with nonischemic cardiomyopathy, . . .
Incidence of Neonatal Abstinence Syndrome — 28 States, 1999–2013
Authors: Jean Y. Ko, Stephen W. Patrick, Van T. Tong, Roshni Patel, Jennifer N. Lind, Wanda D. Barfield
Journal: MMWR Morbidity and Mortality Weekly Report (2016)

Neonatal abstinence syndrome (NAS) is a postnatal drug withdrawal syndrome that occurs primarily among opioid-exposed infants shortly after birth, often manifested by central nervous system irritability, autonomic overreactivity, and gastrointestinal tract dysfunction (1). During 2000-2012, the incidence of NAS in the United States significantly increased (2,3). Several recent publications have provided national estimates of NAS (2,3); however, data describing incidence at the state level are limited. CDC examined state trends in NAS incidence using all-payer, hospital inpatient delivery discharges compiled in the State Inpatient Databases of the Healthcare Cost and Utilization Project (HCUP) during 1999-2013. Among 28 states with publicly available data in HCUP during 1999-2013, the overall NAS incidence increased 300%, from 1.5 per 1,000 hospital births in 1999, to 6.0 per 1,000 hospital births in 2013. During the study period, significant increases in NAS incidence occurred in 25 of 27 states with at least 3 years of data, with annual incidence rate changes ranging from 0.05 (Hawaii) to 3.6 (Vermont) per 1,000 births. In 2013, NAS incidence ranged from 0.7 cases per 1,000 hospital births (Hawaii) to 33.4 cases per 1,000 hospital births (West Virginia). The findings underscore the importance of state-based public health programs to prevent unnecessary opioid use and to treat substance use disorders during pregnancy, as well as decrease the incidence of NAS.
Suspected sepsis: summary of NICE guidance
Authors: Andreas Freitag, Margaret Constanti, Norma O’Flynn, Saul N Faust
Journal: BMJ (2016)

#### What you need to know

The UK Parliamentary and Health Service Ombudsman inquiry “Time to Act” found failures in the recognition, diagnosis, and early management of those who died from sepsis,1 which triggered this guidance. In sepsis the body’s immune and coagulation systems are switched on by an infection and cause one or more body organs to malfunction with variable severity. The condition is life threatening. Although most people with infection do not have and will not develop sepsis, non-specific signs and symptoms can lead to late recognition of people who might have sepsis. We would like clinicians to “think sepsis” and recognise symptoms and signs of potential organ failure when they assess someone with infection, in a similar way to thinking “Could this chest pain be cardiac in origin?”

This guidance provides a pragmatic approach for patients with infection who are assessed in the community, emergency departments, and hospitals by a wide range of general and specialist healthcare professionals. It includes guidance on assessment of risk factors followed by a detailed structured assessment of potential clinical signs and symptoms of concern.

Definitions of sepsis have been developed,2 but these offer limited explanation on how to confirm or rule out the diagnosis in general clinical settings or in the community.3 Current mechanisms to diagnose sepsis and …
Outcome and follow-up of glioblastoma patients treated with bevacizumab based therapy in 2nd lign treatment.
Authors: Benjamin Auberger, Marie Robert, Friederike Schlurmann, Laura Deiana, Isabelle Quintin-Roue, Helene Simon, Petra Miglierini, Mario Campone, Phong Dam-Hieu, Jean-Sebastien Frenel, Elsa Magro, Carole Gourmelon, Jerome Martin-Babau
Journal: Journal of Clinical Oncology (2016)

e13502 Background: Glioblastoma is the most frequent primary malignancie of the brain associated with a bad prognosis. 1st lign standard treatment is based on radiation with temozolomide. At recurrence most patients receive a bevacizumab based treatment alone or with chemotherapy. This treatment improves the progression free survival (PFS) and quality of life (QoL) of patients but failed to demonstrated an improvement in overall survival (OS). It is however widely used because of the few treatments alternatives. The aim of this study was to describe bevacizumab treatment regarding outcomes of patients and their outcomes after progression following this treatment. Methods: A retrospective study was conducted in 2 cancer centers of France between 2007 and 2015. All patients treated for glioblastoma receiving bevacizumab based treatment were analysed. Data cut-off was the 01.11.2015 Results: 130 patients received bevacizumab (85 men and 45 women). Median age was 59.52 years old. The mean time between diagnosis of glioblastoma and 2nd lign treatment was of 11.58 months. Patients received a mean number of 8.4 cycles of bevacizumab IC95% (7.32 ; 9.47). Median PFS following bevacizumab treatment initiation was 4.85 months and median OS was 6.6 months. 31 patients (23.8%) died during the 2nd lign treatment due to disease progression. 16 patients were lost to follow-up. At progression 55 patients (42.3%) were still well enough to receive a 3rd lign treatment. They received fotemustine (43.6%), lomustine (20%), metronomic temozolomide (14.5%), continued bevacizumab with another cytotoxic (12.7%) or another treatment (9%). 28 patients received best supportive care. Median OS following 3rd lign treatment initiation was 4.16 months whereas best supportive care gave a median OS of 1.31 months. Conclusions: In this real world study bevacizumab in 2nd lign treatment for glioblastomas is associated with a median PFS of 4.85 months and median OS of 6.6 months. 3rd line treatment seems to make sense for patients remaining in good performance status. The efficiency is modest with an median OS of just over 4 months. It is necessary to identify the profiles of patients and to determine the best therapeutic combination.
Methotrexate (M) area under the curve (AUC) and creatinine clearance (CrCl) as prognostic factors in primary central nervous system lymphoma (PCNSL).
Authors: P. G. Morris, L. E. Abrey, A. S. Reiner, K. Panageas, B. Seko, L. M. DeAngelis, A. M. Omuro
Journal: Journal of Clinical Oncology (2010)

2040 Background: High doses of M are used in chemotherapy for PCNSL to penetrate the blood-brain barrier. However, M clearance may vary significantly among individuals, and a retrospective study suggested that lower M AUC and higher CrCl are associated with worse prognosis. This suggested that fast eliminators may require higher M doses or risk being under-treated. In this study, we seek to characterize inter-individual variability in M AUC and its prognostic implications in a prospective data set, in order to determine whether M AUC should be used to individually tailor M doses. Methods: In a phase II trial, patients with newly diagnosed PCNSL received 5-7 cycles of R-MPV-A: d1 rituximab 500 mg/m2; d2 M 3.5 mg/m2, vincristine 1.4 mg/m2; d1-7 procarbazine 100 mg/m2/d on odd-cycles. This was followed by whole-brain radiotherapy (23.4 Gy to patients in CR; 45 Gy otherwise) and consolidation Ara-C. M AUC and CrCl were calculated from cycle 1 and correlated with progression-free survival (PFS). A subset of this trial has been reported (Shah, JCO 2007). Univariate Cox modeling was used to examine predictors of PFS. Results: Thirty-nine patients were included in this analysis (24 men; 15 women); median age 60, range 30-76; median KPS 70, range 50-100. Objective response rate after R-MPV was 92%; 1 patient died from toxicity. After median followup of 3 years, the 2-year PFS was 81% (95% CI 68-95). There was substantial variation in M AUC during cycle 1; median 157 micromol h/l (range 62-2,580). Unlike in the previous report, the PFS was longer in patients with lower M AUC (HR 0.75, 95% CI 0.19-3.0, p = 0.68) and higher CrCl (HR 0.9, 95% CI 0.94-1; p = 0.06), although results did not reach statistical significance. Conclusions: This regimen achieved excellent PFS, but longer followup is needed to evaluate survival. We were unable to confirm the previously described association between higher M AUC and lower CrCl with better prognosis, although our results are limited by sample size and relatively short follow-up. Author Disclosure Employment or Leadership Position Consultant or Advisory Role Stock Ownership Honoraria Research Funding Expert Testimony Other Remuneration Genentech Bristol-Myers Squibb, Genentech Genentech, Novartis, Pfizer, Schering-Plough
ARAMIS trial: Efficacy and safety phase 3 trial of ODM-201 in men with high-risk non-metastatic castration-resistant prostate cancer (nmCRPC).
Authors: Karim Fizazi, Neal D. Shore, Teuvo L. J. Tammela, Toni Sarapohja, Annamari Vuorela, Iris Kuss, Amir Snapir, Matthew Raymond Smith
Journal: Journal of Clinical Oncology (2015)

TPS5080 Background: There is no standard treatment for nmCRPC besides continuing androgen deprivation therapy (ADT). Preventing metastatic disease in nmCRPC is a major unmet need. Patients with nmCRPC who have shorter PSA doubling time (PSADT) are at high risk for metastatic disease or death (Smith et al. J Clin Oncol. 2013;31:3800-6). ODM-201, a novel second-generation oral androgen receptor inhibitor, has shown an excellent safety profile and promising anticancer activity in progressive CRPC (Fizazi et al. Lancet Oncol. 2014;15:975-85). The ARAMIS trial aims to evaluate the efficacy and safety of ODM-201 in high-risk nmCRPC. Methods: This international, randomized, double-blind, placebo-controlled phase 3 trial (NCT02200614) involves over 300 sites in more than 30 countries. 1500 patients on ADT will be randomized 2:1 to ODM-201 600 mg or placebo twice daily. Patients will be stratified by PSADT and baseline use of bone-targeting agent. Eligibility criteria include nmCRPC, PSADT ≤ 10 months, and screening PSA ≥ 2 ng/mL. The primary endpoint is metastasis-free survival based on central independent review of bone scan and CT/MRI every 16 weeks; progression of regional disease is not considered metastasis. Secondary endpoints are OS, time to first symptomatic skeletal event (SSE), initiation of first cytotoxic chemotherapy for prostate cancer, pain progression, and first opioid use. Additional endpoints are PFS, time to first prostate cancer–related invasive procedure, initiation of subsequent antineoplastic therapy, PSA progression, change in ECOG status, and changes in health-related QoL. Endpoints will be analyzed using a stratified log-rank test, accounting for stratification. The trial has 90% power to detect a target hazard ratio of 0.75 based on a 2-sided log-rank test at an overall significance level of 0.05. Kaplan-Meier estimates will be produced for both treatment groups. The ARAMIS trial is open and recruiting, with the first patient randomized in October 2014. Clinical trial information: NCT02200614.
Draft bill for new regulatory structure for medicine in India prompts criticism
Authors: Ganapati Mudur
Journal: BMJ (2016)

An Indian government committee’s proposal for a new regulatory structure to replace the Medical Council of India (MCI) has been met with cautious optimism as well as anger at what some say is a government attempt to end the self regulation of the medical profession.

The four member committee operating under the National Institution for Transforming India, the government’s policy-making think tank, sought public comments on its draft bill that proposed creating a 20 member National Medical Commission (NMC), a new apex body for medical education.

Under the bill’s provisions, members of the NMC will be appointed by the government and will include a mix of senior doctors; officials from the ministries of health, rural development, human resource development, and the department of pharmaceuticals; and individuals from backgrounds such as economics, law, and consumer or patients’ …