tbuckley/cabot-search huggingface dataset:
Safety and antitumor activity of biweekly MDX-1106 (Anti-PD-1, BMS-936558/ONO-4538) in patients with advanced refractory malignancies.
Authors: M. Sznol, J. D. Powderly, D. C. Smith, J. R. Brahmer, C. G. Drake, D. F. McDermott, D. P. Lawrence, J. D. Wolchok, S. L. Topalian, I. Lowy
Journal: Journal of Clinical Oncology (2010)

2506 Background: Programmed death-1 (PD-1), a T-cell inhibitory receptor, may suppress antitumor immunity. MDX-1106, a fully human IgG4 PD-1 blocking antibody, has shown antitumor activity and limited toxicity after intermittent dosing (Brahmer et al., ASCO 2009). This multicenter trial evaluates safety, antitumor activity, pharmacokinetics (PK), and immunological correlates of extended biweekly dosing. Methods: Patients (pts) had treatment refractory metastatic non-small cell lung cancer (NSCLC), renal cell carcinoma (RCC), melanoma (MEL), or prostate cancer (CRPC), and no history of autoimmune disease. Escalation of biweekly MDX-1106 dosing at 1, 3, or 10 mg/kg IV was studied. Enrollment at the MTD was expanded to 16 pts in each indication, plus colon cancer. Tumor assessments after every 4 doses (one cycle) used RECIST. Pts received up to 12 treatment cycles, until progression (PD) or complete response (CR). Clinically stable pts with early PD could continue until further PD or deterioration. Results: Four, 4, and 8 pts accrued at 1, 3, and 10 mg/kg, respectively. MTD was not reached. Grade 1/2 drug-related adverse events in > 2 pts included fatigue (9 pts/56.3%), nausea (4 pts/25.0%), and diarrhea, xerostomia, and pruritus (3 pts/18.8% each). One possibly drug-related SAE, myelodysplastic syndrome, rapidly emerged in a MEL pt previously treated with cytotoxic chemotherapy. As of Dec 2009, 6/16 (37.5%) evaluable pts had objective tumor responses, including 3 at 1 mg/kg (RCC/CR, RCC/PR, MEL/PR), 2 at 3 mg/kg (NSCLC/PR, MEL/PR) and one at 10 mg/kg (MEL/PR). All responses are ongoing (3-13+ mo). Preliminary PK estimates of trough/peak antibody levels after 2 cycles are ∼ 25/40, 50/110, 150/300 ug/ml for 1, 3, and 10 mg/kg, respectively. Expansion cohort enrollment at 10 mg/kg is nearly complete, and the 1 and 3 mg/kg cohorts have been expanded with 16 MEL pts each. Grade 3/4 adverse events remain uncommon. Conclusions: MDX-1106 administered biweekly is well tolerated and has antitumor activity at 1-10 mg/kg. Correlative tumor and immunologic studies are underway. Objective responses with limited toxicity in multiple malignancies warrant further investigation of PD-1 blockade. Author Disclosure Employment or Leadership Position Consultant or Advisory Role Stock Ownership Honoraria Research Funding Expert Testimony Other Remuneration Medarex Amplimmune, Bristol-Myers Squibb, Dendreon, Medarex, ProTox Amplimmune, Bristol-Myers Squibb Institute for Medical Education Research, Medarex Medarex
Adherence to Oral Glucose-Lowering Therapies and Associations With 1-Year HbA1c: A Retrospective Cohort Analysis in a Large Primary Care Database
Authors: Andrew J. Farmer, Lauren R. Rodgers, Mike Lonergan, Beverley Shields, Michael N. Weedon, Louise Donnelly, Rury R. Holman, Ewan R. Pearson, Andrew T. Hattersley
Journal: Diabetes Care (2015)

OBJECTIVE The impact of taking oral glucose-lowering medicines intermittently, rather than as recommended, is unclear. We conducted a retrospective cohort study using community-acquired U.K. clinical data (Clinical Practice Research Database [CPRD] and GoDARTS database) to examine the prevalence of nonadherence to treatment for type 2 diabetes and investigate its potential impact on HbA1c reduction stratified by type of glucose-lowering medication. RESEARCH DESIGN AND METHODS Data were extracted for patients treated between 2004 and 2014 who were newly prescribed metformin, sulfonylurea, thiazolidinedione, or dipeptidyl peptidase 4 inhibitors and who continued to obtain prescriptions over 1 year. Cohorts were defined by prescribed medication type, and good adherence was defined as a medication possession ratio ≥0.8. Linear regression was used to determine potential associations between adherence and 1-year baseline-adjusted HbA1c reduction. RESULTS In CPRD and GoDARTS, 13% and 15% of patients, respectively, were nonadherent. Proportions of nonadherent patients varied by the oral glucose-lowering treatment prescribed (range 8.6% [thiazolidinedione] to 18.8% [metformin]). Nonadherent, compared with adherent, patients had a smaller HbA1c reduction (0.4% [4.4 mmol/mol] and 0.46% [5.0 mmol/mol] for CPRD and GoDARTs, respectively). Difference in HbA1c response for adherent compared with nonadherent patients varied by drug (range 0.38% [4.1 mmol/mol] to 0.75% [8.2 mmol/mol] lower in adherent group). Decreasing levels of adherence were consistently associated with a smaller reduction in HbA1c. CONCLUSIONS Reduced medication adherence for commonly used glucose-lowering therapies among patients persisting with treatment is associated with smaller HbA1c reductions compared with those taking treatment as recommended. Differences observed in HbA1c responses to glucose-lowering treatments may be explained in part by their intermittent use.
CCR4 promotes medullary entry and thymocyte–dendritic cell interactions required for central tolerance
Authors: Zicheng Hu, Jessica N. Lancaster, Chayanit Sasiponganan, Lauren I.R. Ehrlich
Journal: The Journal of Experimental Medicine (2015)

Autoimmunity results from a breakdown in central or peripheral tolerance. To establish central tolerance, developing T cells must enter the thymic medulla, where they scan antigen-presenting cells (APCs) displaying a diverse array of autoantigens. If a thymocyte is activated by a self-antigen, the cell undergoes either deletion or diversion into the regulatory T cell (T reg) lineage, thus maintaining self-tolerance. Mechanisms promoting thymocyte medullary entry and interactions with APCs are incompletely understood. CCR4 is poised to contribute to central tolerance due to its expression by post-positive selection thymocytes, and expression of its ligands by medullary thymic dendritic cells (DCs). Here, we use two-photon time-lapse microscopy to demonstrate that CCR4 promotes medullary entry of the earliest post-positive selection thymocytes, as well as efficient interactions between medullary thymocytes and DCs. In keeping with the contribution of thymic DCs to central tolerance, CCR4 is involved in regulating negative selection of polyclonal and T cell receptor (TCR) transgenic thymocytes. In the absence of CCR4, autoreactive T cells accumulate in secondary lymphoid organs and autoimmunity ensues. These studies reveal a previously unappreciated role for CCR4 in the establishment of central tolerance.
METABOLISM OF EPINEPHRINE AND NOREPINEPHRINE
Authors: H. BLASCHKO
Journal: Pharmacological Reviews (1954)

Although many details of the chemical reactions in which catechol amines are formed or destroyed remain to be elucidated, new lines of enquiry have come to the fore: these deal with the interrelations between chemical changes and spatial distribution of active substances. The adrenal medullary cell has been an object of histochemical study since the days of Vulpian and Henle; it may be hoped that the new findings will lead to an increased understanding of the mechanism by which the release of mediator is translated into secretory activity. Similarly, increased knowledge of the sites of enzymic inactivation of adrenaline and noradrenaline may pave the way for a more precise location of the sites of their biological action in the effector cell.
Use of predictive gene expression signature from advanced-stage serous papillary ovarian cancer to identify biologically relevant molecular targets for chemoresponse
Authors: L. Ozbun, T. Bonome, M. Radonovich, C. Pise-Masison, J. Brady, N. Caplen, M. Johnson, S. C. Mok, M. J. Birrer
Journal: Journal of Clinical Oncology (2007)

5500 Background: The aim of our study was to develop and validate a gene expression signature predictive for chemoresponse in advanced stage serous papillary ovarian cancer. Methods: Gene expression profiling was performed on 52 chemonaive, microdissected advanced stage, high-grade papillary serous ovarian cancers using Affymetrix whole-genome microarrays. Patient samples were grouped based on chemoresponse. 19 nonresponders were refractory to chemotherapy, 14 responders relapsing 6 months were considered chemosensitive. Each group was divided into training/validation sets. To generate a predictive gene signature, class prediction algorithms were applied to genes differentially expressed between chemosensitive/resistant or chemosensitive/refractory tumors (p&lt;0.001) using leave-one-out cross-validation. Array validation was performed by qRT-PCR. Select genes underwent biological validation in a series of ovarian cancer cell lines. Results: 31 genes predictive for resistance and 105 genes predictive for refractory to chemotherapy were identified. Percentages of arrays accurately predicted in independent validation sets were 90% (9/10) for resistant and 92% (12/13) for refractory gene signatures. Correlations between microarray/qRT-PCR data were robust for both resistant (17/23 genes) and refractory gene signatures (25/34 genes). Data mining of the predictive signatures using PathwayStudio software identified several biological processes (collagen regulation, apoptosis, cell survival, and DNA repair) implicated in conferring resistance to chemotherapy. We transiently transfected RNAi molecules to silence several signature genes and determine their contribution to taxol/cisplatin sensitivity in a series ofl ovarian cancer cell lines. Preliminary data showed DUSP1 gene expression knockdown potentiated cisplatin sensitivity in SKOV3/OVCA429 cell lines, while POLH knockdown potentiated cisplatin sensitivity in OVCA429/OVCA420 cell lines. Conclusions: A gene expression signature predicts for chemoresponse in ovarian cancers, and has identified novel targets of biological/therapeutic interest. No significant financial relationships to disclose.
Aetiology of diarrhoeal disease and evaluation of viral–bacterial coinfection in children under 5 years old in China: a matched case–control study
Authors: L.L. Li, N. Liu, E.M. Humphries, J.M. Yu, S. Li, B.R. Lindsay, O.C. Stine, Z.J. Duan
Journal: Clinical Microbiology and Infection (2015)

Globally, diarrhoeal diseases are the second leading cause of death among children under 5 years old. Few case-control studies on the aetiology of diarrhoea have been conducted in China. A case-control study on 922 children under 5 years old who presented with diarrhoea and individually matched controls was conducted in China between May 2011 and January 2013. Quantitative PCR was used to analyze stool samples for 10 diarrhoeal pathogens. Potential enteric pathogens were detected in 377 (81.8%) of 461 children with diarrhoea and 215 controls (46.6%, p <0.001). Rotavirus, norovirus GII, Shigella and adenovirus were qualitatively associated with diarrhoea. Using receiver operating characteristic curves, the optimal cutoff threshold for defining a symptomatic individual was 72, 5840, and 10(4) copies per reaction for rotavirus (odds ratio 259), norovirus GII (odds ratio 10.6) and Shigella (odds ratio 5.1). The attributable fractions were 0.18 for rotavirus, 0.08 for norovirus GII, 0.01 for Shigella and 0.04 for adenovirus. Coinfections between pathogens were common. Two pairs, rotavirus and adenovirus, and norovirus GII and Salmonella were positively associated. The co-occurrence of rotavirus and sapovirus, astrovirus, enterotoxigenic Escherichia coli or Campylobacter jejuni only occurred in children with disease. Coinfection was not correlated with clinical symptoms. Quantitative data are critical. Our results indicate that increased pathogen loads increase the OR between diarrhoea and rotavirus, norovirus GII and Shigella. Coinfections with rotavirus and norovirus GII are common and occur in a nonrandom distribution. Despite testing for ten diarrhoeal pathogens, over two-thirds of cases do not have a recognized attributable cause.
The American Community in Bangkok, Thailand: A Model of Social Disintegration
Authors: GEORGE KOJAK
Journal: American Journal of Psychiatry (1974)

The author suggests that the high prevalence of psychopathology (as measured by the number of marital problems and emotional problems of adolescents requiring professional care) noted in the American community in Bangkok, Thailand, during 1971-1972 was related to social disintegration. Comparison with a relatively integrated American community in Japan reveals a strikingly lower prevalence of psychopathology. The author notes that this observation substantiates the theory of Leighton and associates that the state of social integration of an environment affects the mental health of the population.
Genetic diagnosis for chemosensitivity with drug-resistance genes in epithelial ovarian cancer
Authors: Jun Naniwa, Wakae Kawaguchi, Ruri Kaneko, Kazunori Uegaki, Muneaki Shimada, Masakuni Takahashi, Hiroaki Itamochi, Yasunobu Kanamori, Junzo Kigawa, Naoki Terakawa
Journal: Cancer Research (2005)

Proc Amer Assoc Cancer Res, Volume 46, 2005

5947 

Background/Purpose: Most of patients with advanced ovarian cancer relapse and develop chemoresistance. Although topoisomerase inhibitors, etoposide and CPT-11, have been commonly used as a second-line chemotherapy, no useful predictor of sensitivity to chemotherapy is known. We previously found that MDR-1 gene expression was related to sensitivity of combined chemotherapy with paclitaxel and CBDCA (TJ) and that topoisomerase activity was also associated with sensitivity to topoisomerase inhibitors. Genetic diagnosis is more convenient compared with previous test with using cell culture. We conducted the present study to know whether and how chemosensitivity could be determined by genetic diagnosis with drug-resistance genes including topoisomerase (topo)-I and topo-IIα gene, in epithelial ovarian cancer. Method: To obtain the cut-off values of the gene expression, a total of 62 patients with epithelial ovarian cancer, who had measurable lesions, were examined. Thirty-three patients received TJ therapy as the first line chemotherapy. As the second or third line chemotherapy, 12 patients received EP, consisting of etoposide and CDDP, and 17 received CPT-11 and CDDP. The tumor samples were obtained before chemotherapy. mRNA expressions of multidrug resistance gene-1(MDR-1), multidrug resistance-associated protein-1(MRP-1), topo-I, and topo-IIα were measured by real-time RT-PCR. Responder was defined as a greater than 50% reduction in all measurable lesions without the appearance of new lesions during over 4 weeks. The cut-off value of each gene was determined by ROC curve according to chemoresponse. In order to determine the accuracy of genetic diagnosis, a total of 28 patients (14 TJ, 9 EP, and 5 CPT-11/CDDP ) were newly added. Results: Of 33 patients, 21 patients (63.6%) responded to TJ therapy. MDR-1 expression was significantly higher in non-responders (129.6 ± 61.7 vs 30.6 ± 10.4). Whereas, MRP-1 expression level did not differ between responders and non-responders. EP therapy was effective in 3 of 12 patients. The expression level of topo-IIα was significantly higher in responders (186.1 ± 7.9 vs 61.0 ± 21.9). CPT-11/CDDP therapy was effective in 3 of 17 patients. The expression level of topo-I was higher in responders. MRP-1 mRNA expression did not differ between responders and non-responders in EP and CPT-11/CDDP therapy. The cut-off value was 80 for MDR-1, 90 for topo-IIα, and 200 for topo-I. The accuracy of current genetic diagnosis for chemosensitivity was 85.7 % for TJ, 77.8% for EP and 100.0% for CPT-11/CDDP therapy, respectively. Conclusion: Genetic diagnosis for chemosensitivity may be a useful procedure in epithelial ovarian cancer.
Strategies for clinical implementation of TNM-Immunoscore in resected nonsmall-cell lung cancer
Authors: T. Donnem, T.K. Kilvaer, S. Andersen, E. Richardsen, E.E. Paulsen, S.M. Hald, S. Al-Saad, O.T. Brustugun, A. Helland, M. Lund-Iversen, S. Solberg, B.H. Gronberg, S.G.F. Wahl, L. Helgeland, O. Fløtten, M. Pohl, K. Al-Shibli, T.M. Sandanger, F. Pezzella, L.T. Busund, R.M. Bremnes
Journal: Annals of Oncology (2015)
Ethnic-Specific Normative Reference Values for Echocardiographic LA and LV Size, LV Mass, and Systolic Function
Authors: K.K. Poppe, R.N. Doughty, J.M. Gardin, F.D.R. Hobbs, J.J.V. McMurray, S.F. Nagueh, R. Senior, L. Thomas, G.A. Whalley, E. Aune, A. Brown, L.P. Badano, V. Cameron, D.S. Chadha, N. Chahal, K.L. Chien, M. Daimon, H. Dalen, R. Detrano, M. Akif Duzenli, J. Ezekowitz, G. de Simone, P. Di Pasquale, S. Fukuda, P.S. Gill, E. Grossman, F.D.R. Hobbs, H.-K. Kim, T. Kuznetsova, N.K.W. Leung, A. Linhart, T.A. McDonagh, M. McGrady, J.J.V. McMurray, J.G. Mill, R. Mogelvang, M.L. Muiesan, A.C.T. Ng, D. Ojji, J.E. Otterstad, D.J. Petrovic, K.K. Poppe, B. Prendergast, E. Rietzschel, H. Schirmer, P. Schvartzman, R. Senior, I. Simova, K. Sliwa, S. Stewart, I.B. Squire, M. Takeuchi, L. Thomas, G.A. Whalley, D.G. Altman, R. Perera, K.K. Poppe, C.M. Triggs, H. Au Yeung, G.A. Beans Picón, K.K. Poppe, G.A. Whalley, T. Anderson, J. Dyck, J.A. Ezekowitz, J.A. Chirinos, M.L. De Buyzere, T.C. Gillebert, E. Rietzschel, P. Segers, C.M. Van daele, R.N. Doughty, K.K. Poppe, H.A. Walsh, G.A. Whalley, R. Izzo, N. De Luca, B. Trimarco, G. de Simone, D.S. Chadha, K. Goel, A. Misra, P.-C. Chen, H.-J. Lin, T.-C. Su, R. Detrano, V. Cameron, A.M. Richards, R. Troughton, R. Mogelvang, J. Skov Jensen, P. Di Pasquale, S. Paterna, M. Akif Duzenli, F.D.R. Hobbs, M.K. Davies, R.C. Davis, A. Roalfe, M. Calvert, M.K. Davies, R.C. Davis, N. Freemantle, P.S. Gill, G.Y.H. Lip, T. Kuznetsova, J.A. Staessen, H.J. Dargie, I. Ford, T.A. McDonagh, J.J.V. McMurray, E. Grossman, G. Galasko, A. Lahiri, R. Senior, A. Brown, M. Carrington, H. Krum, M. McGrady, S. Stewart, C. Zeitz, L. Blauwet, K. Sliwa, S. Stewart, H. Dalen, H.E. Moelmen Hansen, A. Støylen, A. Thorstensen, M. Daimon, H. Watanabe, J. Yoshikawa, S. Fukuda, H.-K. Kim, N.K.W. Leung, A. Linhart, N. Chahal, J.C. Chambers, J. Kooner, R. Senior, J. Davies, I. Loke, L. Ng, I.B. Squire, E. Aune, J.E. Otterstad, D.Y. Leung, A.C.T. Ng, D. Ojji, L. Arnold, S. Coffey, J. d'Arcy, C. Hammond, C. Mabbett, C. Lima, M. Loudon, N. Pinheiro, B. Prendergast, R. Reynolds, L.P. Badano, D. Muraru, D. Peluso, L. Dal Bianco, D.J. Petrovic, J. Petrovic, P. Schvartzman, F.D. Fuchs, T. Katova, I. Simova, K. Kaku, M. Takeuchi, A. Boyd, E.M. Chia, L. Thomas, H. Schirmer, L.C. Angelo, A.C. Pereira, J.E. Krieger, J.G. Mill, S.L. Rodrigues, M.L. Muiesan, A. Paini, E. Agabiti Rosei, M. Salvetti
Journal: JACC. Cardiovascular imaging (2015)
Response to Comment on Erondu et al. Diabetic Ketoacidosis and Related Events in the Canagliflozin Type 2 Diabetes Clinical Program. Diabetes Care 2015;38:1680–1686
Authors: Ngozi Erondu, Mehul Desai, Kirk Ways, Gary Meininger
Journal: Diabetes Care (2015)

We thank Dr. Dhatariya (1) for his interest in our study that assessed the incidence of serious adverse events of diabetic ketoacidosis (DKA) and related events in the canagliflozin type 2 diabetes clinical trial program (2). Our analysis of DKA and related events was based on a standard collection of adverse event reports from investigators and included verbatim terms that map to the specific terms of diabetic ketoacidosis, ketoacidosis, metabolic acidosis, and acidosis from the Medical Dictionary …
A cost analysis of practicing oncology via telemedicine
Authors: G. C. Doolittle, A. O. Spaulding, A. R. Williams
Journal: Journal of Clinical Oncology (2006)

6143 Background: The University of Kansas Medical Center (KUMC) has offered oncology services via interactive tele-video (ITV) to patients in rural Kansas for over a decade. A KUMC oncologist utilizes ITV technology to connect with patients at Hays Medical Center (HMC), which is approximately 265 west of KUMC. The technology enables the oncologist to conduct a complete patient visit without being in physical proximity to the patient. To date, two cost-tracking studies have been conducted to determine expenses associated with the tele-oncology practice. A third study recently analyzed costs incurred during fiscal year 2005 (FY05). Methods: In order to determine the costs of the practice during FY05, HMC and KUMC expenses were monitored for oncology services rendered via telemedicine. An analysis revealed expenses common to a traditional oncology practice and additional expenses unique to a telemedicine practice. Administrative support staff salaries, the oncologist’s contract fees, and nursing staff salaries made up the majority of the traditional practice-related expenses. Costs unique to a tele-oncology practice were those associated with technology including expenses for telemedicine equipment, telecommunication charges, and technician time. Results: Expenses for the tele-oncology practice on the KUMC side totaled $22,848, with $7,331 attributed to technology-related costs and $15,517 attributed to practice-related costs. For HMC, $5,803 in technology-related costs and $30,430 in practice-related costs totaled $36,233. At 235 tele-oncology consults and a combined total expense of $59,081 between KUMC and HMC, the FY05 analysis resulted in an average cost of $251 per consult. When compared to prior studies, this shows a substantial reduction in costs related to the practice of telemedicine. Conclusions: The average cost of a tele-oncology visit in Kansas has consistently decreased significantly since the practice’s 1995 inception. Analyses have revealed that the costs of providing oncology services via telemedicine are closely tied to utilization, as the majority of the expenses are related to personnel rather than technology. Telemedicine has proven itself to be a cost-efficient alternative to offering regular outreach clinics. No significant financial relationships to disclose.
Enhanced Tyrosine Phosphatase Activity Underlies Dysregulated B Cell Receptor Signaling and Promotes Survival of Human Lupus B Cells
Authors: Sarah J. Fleischer, Capucine Daridon, Vanessa Fleischer, Peter E. Lipsky, Thomas Dörner
Journal: Arthritis & Rheumatology (2015)

Systemic lupus erythematosus (SLE) is associated with hyperactivity of B cells and abnormalities of B cell receptor (BCR) signaling. To address the linkage between dysregulated BCR signaling and increased B cell function, we assessed immediate phosphorylation events in lupus B cells.B cells from SLE patients and healthy donors were analyzed by flow cytometry to assess phosphorylated CD22, Syk, and Akt as well as the basal expression of the BCR coreceptors CD22 and CD19. Confocal microscopy studies determined the recruitment of CD22 and the tyrosine phosphatase SH2 domain-containing phosphatase 1 to the activated BCR complex. Additionally, phosphatase activity in SLE versus healthy donor B cells was measured.B cells from SLE patients showed diminished Syk phosphorylation and reduced intracellular calcium release after BCR activation as compared to B cells from healthy donors. This was related to an enhanced activity of tyrosine, but not serine/threonine, phosphatases and was corrected by inhibition of tyrosine phosphatase activity. In contrast to reduced Syk phosphorylation after BCR activation, phosphorylation of Akt was significantly increased in SLE B cells. The disturbed balance between Syk and Akt phosphorylation was significantly correlated with B cell survival following BCR engagement. Furthermore, CD27-, but not CD27+, B cells from SLE patients displayed increased expression and phosphorylation of the inhibitory BCR coreceptor CD22.These results indicate that an imbalance between serine and tyrosine phosphatases in SLE contributes to an intrinsically disturbed balance of BCR-initiated signaling pathways, resulting in enhanced survival of lupus B cells and differentiation into plasma cells.
Bibliographic Metrics at JACC: Cardiovascular Imaging
Authors: Thomas H. Marwick, Y. Chandrashekhar, Stephan Achenbach, Vasken Dilsizian, Zahi A. Fayad, Aloke V. Finn, W. Gregory Hundley, Morton J. Kern, Christopher M. Kramer, Partho P. Sengupta, Leslee J. Shaw, William A. Zoghbi, Jagat Narula
Journal: JACC. Cardiovascular imaging (2011)