tbuckley/cabot-search huggingface dataset:
Calmodulin/CaMKII inhibition improves intercellular communication and impulse propagation in the heart and is antiarrhythmic under conditions when fibrosis is absent
Authors: Hiroki Takanari, Vincent J.A. Bourgonje, Magda S.C. Fontes, Antonia J.A. Raaijmakers, Helen Driessen, John A. Jansen, Roel van der Nagel, Bart Kok, Leonie van Stuijvenberg, Mohamed Boulaksil, Yoshio Takemoto, Masatoshi Yamazaki, Yukiomi Tsuji, Haruo Honjo, Kaichiro Kamiya, Itsuo Kodama, Mark E. Anderson, Marcel A.G. van der Heyden, Harold V.M. van Rijen, Toon A.B. van Veen, Marc A. Vos
Journal: Cardiovascular Research (2016)

Aim In healthy hearts, ventricular gap junctions are mainly composed by connexin43 (Cx43) and localize in the intercalated disc, enabling appropriate electrical coupling. In diseased hearts, Cx43 is heterogeneously down-regulated, whereas activity of calmodulin/calcium-calmodulin protein kinase II (CaM/CaMKII) signalling increases. It is unclear if CaM/CaMKII affects Cx43 expression/localization or impulse propagation. We analysed different models to assess this. Methods and results AC3-I mice with CaMKII genetically inhibited were subjected to pressure overload (16 weeks, TAC vs. sham). Optical and epicardial mapping was performed on Langendorff-perfused rabbit and AC3-I hearts, respectively. Cx43 subcellular distribution from rabbit/mouse ventricles was evaluated by immunoblot after Triton X-100-based fractionation. In mice with constitutively reduced CaMKII activity (AC3-I), conduction velocity (CV) was augmented (n = 11, P < 0.01 vs. WT); in AC3-I, CV was preserved after TAC, in contrast to a reduction seen in TAC-WT mice (−20%). Cx43 expression was preserved after TAC in AC3-I mice, though arrhythmias and fibrosis were still present. In rabbits, W7 (CaM inhibitor, 10 µM) increased CV (6–13%, n= 6, P< 0.05), while susceptibility to arrhythmias decreased. Immunoconfocal microscopy revealed enlarged Cx43 cluster sizes at intercalated discs of those hearts. Total Cx43 did not change by W7 (n= 4), whereas Triton X-100 insoluble Cx43 increased (+21%, n= 4, P< 0.01). Similar findings were obtained in AC3-I mouse hearts when compared with control, and in cultured dog cardiomyocytes. Functional implication was shown through increased intercellular coupling in cultured neonatal rat cardiomyocytes. Conclusion Both acute and chronic CaM/CaMKII inhibition improves conduction characteristics and enhances localization of Cx43 in the intercalated disc. In the absence of fibrosis, this reduced the susceptibility for arrhythmias.
P51 Inadequate compensation by glutamine synthetase and increased glutaminase activity contributes to hyperammonaemia in cirrhosis
Authors: M Jover, L Noiret, A Habtesion, V Balasubramaniyan, Y Sharifi, M Romero-Gomez, N Davies, R Jalan
Journal: Gut (2010)

Introduction  In cirrhosis, the function of the urea cycle is compromised which leads to accumulation of ammonia. In this situation, ammonia metabolism is regulated by glutamine synthetase (GS) and glutaminase (GA) making them important therapeutic targets. The relative contributions of these enzymes in the different organs in regulating ammonia metabolism in cirrhosis are unclear.  Aim  To study the protein expression and activity of glutamine synthetase (GS) and glutaminase (GA) enzymes in the different organs in a model of chronic liver disease (bile duct ligation: BDL).  Method  Ten male Sprague–Dawley rats were studied (260.7±10.57)g: 4 sham operated, and 6 following bile duct ligation (BDL). We measured plasma levels for: ammonia and standard biochemical markers. Expression of GS and GA were determined by Western-blotting (described as % of sham expression) and activity by end point methods in liver, kidney, gut, muscle, lung and frontal cortex (brain).  Results  Plasma ammonia was increased in BDL rats vs. Sham (45.97±14.72 vs 106.2±59.10) μmol/l). The most important organs for GS activity were the liver > lung = frontal cortex > muscle > kidney = gut. In cirrhosis, liver GS activity is reduced by 7 fold (62.61±8.29 SHAM vs 8.98±2.67* BDL). The most important organs for GA function in disease were: lung (0.70±1.4 SHAM vs 4.19±2.24* BDL) > kidney (1.24±0.09 SHAM vs 1.68±0.58* BDL) > gut (0.43±0.14 SHAM vs 1.14±0.51* BDL) (activities expressed as mIU/mg protein; *P  Gut Liver Kidney Muscle Lung Frontal cortex Brain SHAM GS (0.78+0.67) (62.61+8.29) (0.87+1.24) (1.75+0.48) (2.98+4.26) (2.74+1.14) GA (0.43+0.14) (1.84+0.58) (1.24+0.09) (0.37+0.14) (0.70+1.4) (0.61+0.30) BDL GS (0.84+0.84) (8.98+2.67)* (0.86+0.78) (1.92+0.63) (2.15+3.14) (3.22+0.35) GA (1.14+0.51)* (0.52+0.16)* (1.68+0.58)* (0.38+0.11) (4.19+2.24)* (0.63+0.20).  Conclusion  Inadequate compensation by GS and increased GA activity account for hyperammonemia observed in cirrhosis. For the first time, these data indicate the importance of the lung in regulating ammonia metabolism through GS and also GA, activities of both of which are increased in cirrhosis. In order to reduce ammonia levels in cirrhosis, it would be advantageous for novel drugs to target GS stimulation and Glutaminase inhibition simultaneously.
Origin and Role of a Subset of Tumor-Associated Neutrophils with Antigen-Presenting Cell Features in Early-Stage Human Lung Cancer
Authors: Sunil Singhal, Pratik S. Bhojnagarwala, Shaun O'Brien, Edmund K. Moon, Alfred L. Garfall, Abhishek S. Rao, Jon G. Quatromoni, Tom Li Stephen, Leslie Litzky, Charuhas Deshpande, Michael D. Feldman, Wayne W. Hancock, Jose R. Conejo-Garcia, Steven M. Albelda, Evgeniy B. Eruslanov
Journal: Cancer Cell (2016)
Determination of evidence-based diagnostic thresholds for upper limb lymphedema secondary to treatment for cancer.
Authors: Elizabeth S Dylke, Geoff P Schembri, Deborah Black, Leigh C. Ward, Dale L Bailey, Elizabeth A Bailey, Jane McNeil Beith, Kathryn M. Refshauge, Sharon Kilbreath
Journal: Journal of Clinical Oncology (2013)

9616 Background: Diagnosis of upper limb lymphedema (LE) secondary to treatment for cancer has been complicated by the range of diagnostic thresholds used. Traditional thresholds were arbitrarily chosen but recently normative-based cut-offs have been established. However, the diagnostic power of these thresholds has not been compared to changes identified with lymphoscintigraphy, the gold standard for diagnosis of LE. The aim of this study was to determine thresholds for commonly used clinical diagnostic tools based on lymphatic imaging outcomes. Methods: Women previously diagnosed with LE secondary to treatment for cancer (n=67), and women without LE (n=20) participated. Lymphoscintigraphy was completed and the presence and severity of dermal back flow qualitatively scored as none to mild or moderate to severe by an experienced nuclear medicine physician. On the same day, circumference measurements and segmental bioimpedance spectroscopy (BIS) for 10 cm intervals from the ulnar styloid to 40 cm proximal were recorded. The BIS inter-limb ratio for each segment and the inter-limb circumference differences were compared to diagnostic thresholds based on 2 and 3 standard deviations (SD) above the mean from normative data. Results: The number of BIS segments and circumferences measurements above a 3SD threshold correlated significantly with the dermal backflow score (R s = 0.710 and 0.824 respectively).The number of abnormal BIS segments detected did not differ significantly between a 2SD and 3SD threshold (χ 2 =0.23 p=0.63). Of the 20 new abnormal segments detected, 7 were from participants with no or mild evidence of dermal backflow on lymphoscintigraphy including 3 from control participants. In contrast, 46 new abnormal inter-limb circumference differences, all from those with a LE diagnosis, were detected using a 2SD threshold (χ 2 = 31.785, p&lt;0.001) Conclusions: The need for a standardized, evidenced-based approach for identification of LE is essential. We recommend diagnostic thresholds for segmental BIS be set at 3SD above the mean to minimize false positive diagnoses whereas a lower threshold of 2SD is necessary for the less sensitive inter-limb circumference difference measurements.
Adjuvant enzalutamide (Enza) for men with high-risk prostate cancer (HRPCa) after radical prostatectomy (RP).
Authors: Moshe Chaim Ornstein, Andrew J. Stephenson, Paul Elson, Allison Janine Tyler, Pam Profusek, Petros Grivas, Brian I. Rini, Eric A. Klein, Jorge A. Garcia
Journal: Journal of Clinical Oncology (2016)

5071 Background: Management of HRPCa remains a clinical challenge. Novel AR inhibitors are now standard of care in castration-resistant prostate cancer (CRPC) and could potentially impact outcome in HRPCa men following RP. We conducted a phase II study evaluating the efficacy/safety of Enza in men with HRPCa who have undergone RP. Methods: HRPCa pts (≥pT3a, GS≥8, iPSA≥20 ng/mL, positive lymph nodes (LN), or ≥35% chance of biochemical recurrence (BCR) at 5 yrs based on MSKCC’s nomogram) with undetectable PSA within 3 months from RP were eligible. All men received Enza 160mg PO daily in 28-day cycle until disease progression, drug intolerability, consent withdrawal, or completion of study at 24 months. Trial accrual goal was set at N=40 to provide 80% power to detect a 75% decrease in the risk of BCR from the 55% rate seen historically (2-sided test with 5% type 1 error). Results: 42 men were enrolled. Median age 60 (range 43-70), based on biopsy 19 were GS7; 16 GS8, 7 GS9. 35 men had cT1, 7 cT2, median iPSA was 8.2 (range 0.77-38). On prostatectomy pathology: 21 men had pT3b; 22 +ve margins; 21 SVI; 10 had +ve LN. Median number of cycles is 12 (range 2-24). With median follow-up of 11.1 months (range 2.7-22.3), all men remain free of BCR. 6 men discontinued treatment; 2 completed 24 months of therapy, 3 for toxicity (2 had G3 fatigue, 1 had G3 fatigue and arthralgias/myalgias); 1 withdrew consent. Dose reduction was required in 1 man (G3 fatigue). Adverse events (AE) occurring in >10% of men are listed in Table 1. Conclusions: Adjuvant Enza in men with HRPCa following RP is safe and relatively well-tolerated. At present analysis, no BCR has occurred. Additional efficacy and safety analysis is ongoing. Clinical trial information: NCT01927627.Adverse events (AE). AE Grade 1 Grade 2 Grade 3 Total Gynecomastia or breast/nipple soreness/pain 30 (71%) 10 (24%) 0 40 (95%) Fatigue 29 (69%) 1 (2%) 3 (7%) 33 (79%) Neurologic 19 (45%) 2 (5%) 0 21 (50%) Arthralgia/myalgia 12 (29%) 0 1 (2%) 13 (31%) Hyperglycemia 13 (31%) 0 0 13 (31%) Hot flashes/flushing 11 (26%) 0 0 10 (26%) Alopecia 11 (26%) 0 0 11 (26%) Weight gain 7 (17%) 2 (5%) 0 9 (21%) Nausea/Vomiting 6 (14%) 0 0 6 (42%) Low lymphocyte 4 (10%) 1 (2%) 0 5 (12%) Dry skin 5 (12%) 0 0 5 (12%) Most severe AE per man 24 (57%) 15 (36%) 3 (7%)
A phase I window, dose escalating and safety trial of metformin in combination with induction chemotherapy in relapsed refractory acute lymphoblastic leukemia: Metformin with induction chemotherapy of vincristine, dexamethasone, doxorubicin, and PEG-asparaginase (VPLD).
Authors: Julio C. Barredo, John M. Goldberg, Gregory Hale, Jonathan Benjamin Gill, Bhuvana Setty, Tiffany Smith, Jae K Lee, Damon R. Reed
Journal: Journal of Clinical Oncology (2016)

10530 Background: Acute Lymphoblastic Leukemia (ALL) remains a major cause of cancer-related deaths in children. We identified the AMP activated protein kinase (AMPK) as a potential target for ALL therapy due to its regulatory effects on the unfolded protein response (UPR), leading to increased vulnerability of ALL cells to endoplasmic reticulum (ER) stress inducers. In vitro, metformin leads to ALL cell death via AMPK-mediated inhibition of the UPR. Methods: Metformin was administered twice daily continuously on a 28 day cycle in addition to the Vincristine, Dexamethasone, PEG-Asparaginase and Doxorubicin (VPLD) systemic regimen and CNS-directed therapy. Metformin doses were increased in a standard 3+3 phase I design with three dose levels evaluated, 666, 1,000 and 1,333 mg/m2/day. Pharmacokinetic (PK) and pharmacodynamic evaluation of the AMPK and ER stress/UPR pathways were ascertained on days 1 and 7, and treatment response was assessed on day 29. Results: Twelve patients have been enrolled. DL3 was the maximum administered dose with 2 related DLT’s of diarrhea and acidosis. A single DLT of hypoglycemia and acidosis during an episode of sepsis was observed in DL2. Infectious SAE’s occurred in 7 patients and 2 patients had posterior reversible encephalopathy syndrome. Both died of disease progression within 30 days of coming off study. A single patient had stable disease, 2 had a partial response, and 3 achieved a complete response. PK studies demonstrated levels within the therapeutic range for patients with diabetes, and pharmacodynamics showed induction ER stress induction and inhibition of the UPR. Conclusions: This trial is ongoing.We found induction of ER stress with inhibition of UPR similar to that observed to mediate metformin-induced apopotosis in vitro. The chemotherapeutic backbone was tolerable and yielded responses in a heavily pretreated population. Toxicities attributable to metformin occurred in all dose levels, but DLT’s were only observed in dose levels above the standard dosing for diabetes. Clinical trial information: NCT01324180.
Independence days
Authors: J. Oldham, I. Rutter
Journal: BMJ (1999)

Education and debate p 797 

The creation of primary care trusts has raised the prospect, as perhaps never before, of a substantial shift from the independent contractor status of general practitioners to that of salaried employees. This is not a policy objective, but the forces for change cannot be underestimated and are causing serious concern among most general practitioners.1 The proposed structure, governing arrangements, and powers of primary care trusts will allow the transition to employed status with greater ease and perhaps persuasion. Equally, there are some general practitioners who see employed status as an answer to the responsibilities of on call work and equity purchase and in any event not core to a general practitioner's primary purpose.1 The debate is often ideological and political; we want to examine the concept from evidence based principles of organisational design and behaviour.

Theory about the genesis of organisational structure has long focused on environmental uncertainty and complexity as key concepts that mould structure.2–4 Briefly, the more stable an environment, the more rigid the structure, with a list of rigid policies relatively unchanging. …
HLA-G 3'UTR +2960 14-bp INDEL (Ins/Del) polymorphism is associated to improved DFS of stage II-III CRC patients
Authors: M. Garziera, E. Bidoli, E. Cecchin, E. Mini, S. Nobili, S. Lonardi, A. Buonadonna, D. Errante, N. Pella, M. D'Andrea, F. De Marchi, A. De Paoli, E. De Mattia, C. Zanusso, G. Toffoli
Journal: Annals of Oncology (2015)
Relationship between late potentials and left ventricular function in patients with coronary artery disease.
Authors: Tsuyoshi Konta, Kozue Ikeda, Isao Kubota, Kai Tsuiki, Shoji Yasui
Journal: Circulation (1988)

We examined the relationship between late potentials and left ventricular function from a hemodynamic point of view in 50 patients with prior myocardial infarction. Late potentials were found in 15 (30%) of 50 patients. A left ventricular aneurysm was found in 28 patients. Late potentials were detected in 14 (50%) of 28 patients with the aneurysm but in 1 (5%) of 22 patients without it (p < 0.01). In the 50 patients, a hemodynamic data from the late potential positive group (n = 15) were compared to those from the late potential negative group (n = 35). The late potential positive group had a significantly lower ejection fraction, cardiac index and stroke volume than the late potential negative group. We further studied the 28 patients with left ventricular aneurysm in a similar way. The cardiac index and stroke volume were also significantly lower in the late potential positive group. The ejection fraction tended to be lower in the late potential positive group. These results suggest that left ventricular function and left ventricular aneurysm are among the factors that influence the development of late potentials.
Contralateral breast cancer: Effect of stage on survival after unilateral breast cancer.
Authors: Lori Uyeno, Carolyn E. Behrendt, Laura Kruper, Steven L. Chen, Courtney Vito
Journal: Journal of Clinical Oncology (2012)

69 Background: Contralateral breast cancer (CBC) is the most common malignancy among breast cancer survivors. We investigated the impact of CBC on overall survival (OS) after unilateral primary breast cancer (UPBC) in women treated with mastectomy. Methods: Using the Surveillance Epidemiology End Results registry, we identified women age 25-80 diagnosed 1998-2006 with UPBC stage 0-III, treated with mastectomy and free of CBC at 1-year landmark. Subjects were split into test and validation samples. Follow-up continued until the earliest occurrence: death, end of 2008, or age 85. Primary risk factor was incident CBC, a time-dependent variable categorized as advanced-stage (IIB-IV), early-stage (0-IIA), or none. Proportional hazards regression adjusted for primary tumor characteristics, treatment including contralateral prophylactic mastectomy (CPM), demographics, and aging. Results: Subjects (n= 109,411, age 53.7[+12.7] years at UPBC diagnosis) were followed median 51 months. Most UPBC were early stage (63%), moderately/poorly differentiated (78%), ER+PR+ (52%). Few (9.8%) women underwent CPM at primary diagnosis. Incident CBC (n=867, 0.79%) was diagnosed median 23.5 (95% CI 1.2-72) months beyond the 1-year landmark. Test and validation samples did not differ. Only CBC of stage IIB-IV increased mortality; early stage CBC had no effect on OS. Among CBC cases, advanced stage was independently associated with aggressive UPBC (more positive nodes; larger tumor; greater extension), African-American race, and shorter time from UPBC. Conclusions: Among women who undergo mastectomy +/-CPM for UPBC, few develop CBC, which impacts survival only when diagnosed at advanced stage. Efforts to improve survival after UPBC should emphasize earlier detection and prevention of advanced-stage CBC, especially in African-American women and women with more aggressive UPBC. [Table: see text]
Drug previously available only through Cancer Drugs Fund is approved for NHS use
Authors: Nigel Hawkes
Journal: BMJ (2016)

A cancer drug originally rejected for use in the NHS and available only through the Cancer Drugs Fund (CDF) has now gained approval because of an undisclosed price cut by the manufacturers. This is the first drug to go through the reappraisal process for drugs paid for by the fund.

The National Institute for Health and Care Excellence (NICE) has recommended bosutinib (Bosulif) for treating myeloid leukaemia despite finding that at list price (£44 799 (€52 000; $58 000) per patient per year) the cost per quality adjusted life year (QALY) would be around £45 000—outside its normal approval range.

A discount agreed by the manufacturer, Pfizer, …
Staffing for infectious diseases, clinical microbiology and infection control in hospitals in 2015: results of an ESCMID member survey
Authors: Y. Dickstein, R. Nir-Paz, C. Pulcini, B. Cookson, B. Beović, E. Tacconelli, D. Nathwani, R. Vatcheva-Dobrevska, J. Rodríguez-Baño, M. Hell, H. Saenz, L. Leibovici, M. Paul
Journal: Clinical Microbiology and Infection (2016)
Letter to the editor: Escherichia coli harbouring mcr-1 gene isolated from poultry not exposed to polymyxins in Brazil
Authors: Silvia AM Lentz, Daiana de Lima-Morales, Victória ML Cuppertino, Luciana de S Nunes, Amanda S da Motta, Alexandre P Zavascki, Afonso L Barth, Andreza F Martins
Journal: Eurosurveillance (2016)

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Zika Virus Surveillance and Preparedness — New York City, 2015–2016
Authors: Christopher T. Lee, Neil M. Vora, Waheed Bajwa, Lorraine Boyd, Scott Harper, Daniel Kass, Aileen Langston, Emily McGibbon, Mario Merlino, Jennifer L. Rakeman, Marisa Raphael, Sally Slavinski, Anthony Tran, Ricky Wong, Jay K. Varma, Bisrat Abraham, Joel Ackelsberg, Mike Antwi, Sharon Balter, Jennifer Baumgartner, Isaac Benowitz, Marie Antoinette Bernard, Angelica Bocour, Christine Borges, Joseph Burzynski, James E. Cone, Alexander Davidson, Paula Del Rosso, Catherine Dentinger, Bisram Deocharan, Marie Dorsinville, Peter Ephross, Ifeoma Ezeoke, Anne Fine, Ana Maria Fireteanu, Jie Fu, Sharon K. Greene, Scott Hughes, Maryam Iqbal, Jasmine Jacobs-Wingo, Kimberly Johnson, Lucretia Jones, Hannah T. Jordan, Fabienne Laraque, Marcelle Layton, David Lee, Ellen Lee, Kristen Lee, Dakai Liu, David E. Lucero, Michelle Macaraig, Natasha McIntosh, Paul McNamee, Julie Myers, Stephanie Ngai, Pete Papadopolous, Hilary Parton, Eric Peterson, Carolina Pichardo, Robert Pirillo, Celia Quinn, Vasudha Reddy, Alhaji Saffa, Altaf Shaikh, Alaina Stoute, Anna Tate, Brian Toro, Olivia C. Tran, Elaine Vernetti, Don Weiss, Emily Westheimer, Eliza Wilson, Ann Winters, Marie Wong, Winfred Y. Wu, David Yang, Mohammad Younis, Janette Yung
Journal: MMWR Morbidity and Mortality Weekly Report (2016)

Zika virus has rapidly spread through the World Health Organization's Region of the Americas since being identified in Brazil in early 2015. Transmitted primarily through the bite of infected Aedes species mosquitoes, Zika virus infection during pregnancy can cause spontaneous abortion and birth defects, including microcephaly (1,2). New York City (NYC) is home to a large number of persons who travel frequently to areas with active Zika virus transmission, including immigrants from these areas. In November 2015, the NYC Department of Health and Mental Hygiene (DOHMH) began developing and implementing plans for managing Zika virus and on February 1, 2016, activated its Incident Command System. During January 1-June 17, 2016, DOHMH coordinated diagnostic laboratory testing for 3,605 persons with travel-associated exposure, 182 (5.0%) of whom had confirmed Zika virus infection. Twenty (11.0%) confirmed patients were pregnant at the time of diagnosis. In addition, two cases of Zika virus-associated Guillain-Barré syndrome were diagnosed. DOHMH's response has focused on 1) identifying and diagnosing suspected cases; 2) educating the public and medical providers about Zika virus risks, transmission, and prevention strategies, particularly in areas with large populations of immigrants from areas with ongoing Zika virus transmission; 3) monitoring pregnant women with Zika virus infection and their fetuses and infants; 4) detecting local mosquito-borne transmission through both human and mosquito surveillance; and 5) modifying existing Culex mosquito control measures by targeting Aedes species of mosquitoes through the use of larvicides and adulticides.
Delayed gastric emptying and improvement with domperidone in a patient with anorexia nervosa
Authors: D M Russell, M L Freedman, D H Feiglin, K N Jeejeebhoy, R P Swinson, P E Garfinkel
Journal: American Journal of Psychiatry (1983)

A woman with anorexia nervosa who displayed severe bloating after eating was treated with domperidone, a novel compound with prokinetic properties. Both subjective ratings of satiety and assessment of gastric emptying documented improvement.