tbuckley/cabot-search huggingface dataset:
First-in-human study of HM95573, a novel oral RAF inhibitor, in patients with solid tumors.
Authors: Yong Sang Hong, Jeeyun Lee, Hye Sook Han, Soo Jung Lee, Jin-Soo Kim, Baek-Yeol Ryoo, Hyeong-Seok Lim, Dae Ho Lee, Kyu-Pyo Kim, Jeong Eun Kim, Se Hoon Park, Seung Tae Kim, Ki Hyeong Lee, Moon Ki Choi, Hyesun Han, Young su Noh, Yo Han Kim, Jahoon Kang, Jeewoong Son, Tae Won Kim
Journal: Journal of Clinical Oncology (2016)

2570 Background: HM95573 is a novel and selective RAF kinase inhibitor which showed potent anti-tumor activities in BRAF, KRAS and NRAS mutant model in vitro and in vivo. This phase 1 trial evaluated the safety, tolerability, pharmacokinetics (PK), and anti-tumor activity of HM95573 in patients with solid tumors. Interim results from the phase 1 study are presented here. Methods: Patients who had solid tumor with BRAF, KRAS or NRAS mutation were enrolled. HM95573 was administered everyday with 21-day cycle and treatment cycle has been repeated until disease progression or dose-limiting toxicity (DLT). Dose escalation was performed with PK-guided dose escalation method until target AUC achieved or the first DLT observed. Safety assessments include adverse events (AE), laboratory test, ophthalmologic and dermatological assessments, physical examination, vital signs, and ECG. Serial blood samples were collected on Cycle1Day1, Cycle2Day1, and Cycle3Day1 for PK analysis. Tumor responses were assessed every 6 weeks. Results: Total 31 patients were enrolled in 5 cohorts and doses of each cohort were 50mg QD, 100mg QD, 200mg QD, 200mg BID and 300mg BID. Mean terminal half-life of HM95573 was within the range of 50 to 80 hours after single dosing. However, dose regimen was changed from QD to BID to maximize drug exposure with current formulation. Tumor types from 31 patients were colorectal cancer (68%), melanoma (23%), lung cancer (3%), GIST (3%) and bladder cancer (3%); the BRAF (45%), KRAS (45%) or NRAS (10%) mutation. One patient at 200mg BID experienced grade 3 skin rash as a DLT and up to 300 BID, the maximum tolerated dose was not reached. HM95573 was well tolerated up to 300mg BID; Most of AEs were generally Grade 1 or 2 and most frequent drug-related AE was rash (17%). One patient with NRAS mutant melanoma (200mg QD) experienced an unconfirmed partial response at 12 weeks, and 9 patients had stable disease. Conclusions: Overall, HM95573 was well tolerated up to 300 BID as exposure increased. Preliminary evidence of anti-tumor activity has been observed from 200mg QD, however, current phase 1 study will explore higher doses to evaluate the therapeutic potential of HM95573 further. Clinical trial information: NCT02405065.
Dapagliflozin Binds Specifically to Sodium-Glucose Cotransporter 2 in the Proximal Renal Tubule
Authors: Chiara Ghezzi, Amy S. Yu, Bruce A. Hirayama, Vladimir Kepe, Jie Liu, Claudio Scafoglio, David R. Powell, Sung-Cheng Huang, Nagichettiar Satyamurthy, Jorge R. Barrio, Ernest M. Wright
Journal: Journal of the American Society of Nephrology (2016)

Kidneys contribute to glucose homeostasis by reabsorbing filtered glucose in the proximal tubules via sodium-glucose cotransporters (SGLTs). Reabsorption is primarily handled by SGLT2, and SGLT2-specific inhibitors, including dapagliflozin, canagliflozin, and empagliflozin, increase glucose excretion and lower blood glucose levels. To resolve unanswered questions about these inhibitors, we developed a novel approach to map the distribution of functional SGLT2 proteins in rodents using positron emission tomography with 4-[ 18 F]fluoro-dapagliflozin (F-Dapa). We detected prominent binding of intravenously injected F-Dapa in the kidney cortexes of rats and wild-type and Sglt1-knockout mice but not Sglt2-knockout mice, and injection of SGLT2 inhibitors prevented this binding. Furthermore, imaging revealed only low levels of F-Dapa in the urinary bladder, even after displacement of kidney binding with dapagliflozin. Microscopic ex vitro autoradiography of kidney showed F-Dapa binding to the apical surface of early proximal tubules. Notably, in vivo imaging did not show measureable specific binding of F-Dapa in heart, muscle, salivary glands, liver, or brain. We propose that F-Dapa is freely filtered by the kidney, binds to SGLT2 in the apical membranes of the early proximal tubule, and is subsequently reabsorbed into blood. The high density of functional SGLT2 transporters detected in the apical membrane of the proximal tubule but not detected in other organs likely accounts for the high kidney specificity of SGLT2 inhibitors. Overall, these data are consistent with data from clinical studies on SGLT2 inhibitors and provide a rationale for the mode of action of these drugs.
The Use of Recombinant FXIII in a Major Acute Bleeding Episode of a Patient with Congenital FXIII Deficiency – the First Experience
Authors: Zoltan Boda, Anita Arokszallasi, Adrienne Kerenyi, Zsuzsanna Bereczky, Laszlo Muszbek, Gyorgy Pfliegler, Agota Schlammadinger
Journal: Blood (2014)
Matrix Metalloproteinase 13 (MMP13) Upregulation Is Essential for Multiple Myeloma Related Bone Lytic Lesion
Authors: Jing Fu, Shirong Li, Rentian Feng, Huihui Ma, Farideh Sabeh, G David Roodman, Markus Mapara, Stephen J Weiss, Suzanne Lentzsch
Journal: Blood (2012)
Familial Gigantiform Cementoma on 99mTc MDP Bone Scintigraphy
Authors: Xiaona Jin, Hongli Jing, Yu Liu, Fang Li
Journal: Clinical Nuclear Medicine (2016)

A 14-year-old girl underwent a Tc MDP bone scan to evaluate multiple fractures. The images showed not only expected increased activity at the fracture sites of lower extremities but also intense activity in both sides of the maxilla and mandible. Microscopic examination of the mandible was consistent with a diagnosis of gigantiform cementoma.
P2-265: Docetaxel–induced interstitial pneumonitis (DIIP) in non–small cell lung cancer patients
Authors: Chi Hong Kim, Sung Kyoung Kim, Byoung Yong Shim, Myeong Im Ahn, Sung Hwan Kim, Deog Kon Cho, Kyu Do Cho, Jinyoung Yoo, Hoon-Kyo Kim
Journal: Journal of Thoracic Oncology (2007)
Early predictors of prolonged overall survival (OS) in patients (pts) on first-line chemotherapy (CT) for metastatic colorectal cancer (mCRC): An ARCAD study with individual patient data (IPD) on 10,962 pts.
Authors: Dirkje Willemien Sommeijer, Qian Shi, Everardo D. Saad, Elisabeth Coart, Marc E. Buyse, Tomasz Burzykowski, Jeffrey P. Meyers, Tim Maughan, Richard A. Adams, Matthew T. Seymour, Leonard Saltz, Richard M. Goldberg, Jean-Yves Douillard, Hans-Joachim Schmoll, Cornelis J. A. Punt, Christophe Tournigand, Benoist Chibaudel, Aimery De Gramont, Daniel J. Sargent, John Raymond Zalcberg
Journal: Journal of Clinical Oncology (2014)

3538 Background: To expedite drug development and improve treatment (trt) decisions, early indicators of trt efficacy are needed. We evaluated the pt-level association between early tumor shrinkage (ETS; ≥ 20% decrease from baseline), early objective tumor response (EOTR; CR/PR by RECIST), and early nonprogression status (EnPD;CR/PR/SD by RECIST) at 6, 8/9, or 12 weeks (wks) with OS, and compared these with standard endpoints (best overall response [BOR] and confirmed response [ConfR]) in pts treated with 1st-line CT. Methods: 16 phase III trials, including 10,962 pts on 5FU-LV/capecitabine alone or with oxaliplatin/irinotecan, from the ARCAD database were analyzed. Associations between early endpoints and OS were tested by stratified Cox models with a landmark approach. Prediction performance was compared by the C-index (c), a measure of relative accuracy to distinguish those at high versus low risk of death (higher value indicates better risk discrimination). Results: ETS and EOTR were significant predictors of OS with similar hazard ratios (HRs) to BOR and ConfR (p <0.0001; see Table). Pts without early progression (non-PD) showed the largest risk reduction (HRs ~ 0.3). Adjusting for age, performance status, number of metastases, and prior trt, significance remained. C-indices were similar across early endpoints, and similar to those for BOR and ConfR. Conclusions: Early responses are significantly associated with prolonged OS in mCRC pts on 1st-line chemotherapy. Early PD strongly correlates with an increased hazard of death. The pt-level prediction accuracy is as strong as for standard endpoints with the advantage of earlier tumor evaluation. Similar performance of ConfR implies the lack of utility for response confirmation. Formal surrogacy testing at trial level is ongoing. Weeks EOTR ETS EnPD BOR ConfR HR (95% CI) [c] HR (95% CI) [c] HR (95% CI) [c] HR (95% CI) [c] HR (95% CI) [c] 6 .61 (.54-.69) [.55] .61 (.55-.67) [.57] .31 (.27-.36) [.56] .59 (.56-.63) [.58] .65 (.59-.70) [.55] 8/9 .60 (.62-.69) [.58] .64 (.57-.71) [.57] .24 (.19-.30) [.56] 12 .61 (.56-.65) [.58] .63 (.58-.67) [.57] .35 (.32-.39) [.57]
A phase I clinical trial on the combined intravenous (IV) and intradermal (ID) administration of autologous TriMix-DC cellular therapy in patients with pretreated melanoma (TriMixIDIV).
Authors: B. Neyns, S. Wilgenhof, A. M. T. Van Nuffel, D. Benteyn, C. Heirman, I. Van Riet, A. Bonehill, J. Corthals, K. Thielemans
Journal: Journal of Clinical Oncology (2011)

2519 Background: Autologous monocyte derived dendritic cells (DC) electroporated with synthetic messenger RNA (smRNA) encoding CD40 ligand, a constitutively active TLR4, and CD70 (TriMixDC), together with smRNA encoding fusion-proteins of a HLA-class II targeting signal and a melanoma associated antigen are immunogenic when administered ID (Wilgenhof et al. ASCO AM 2009). The TriMixIDIV clinical trial investigates the safety, immunogenicity, and activity of combined ID and IV administration in patients with pretreated melanoma. Methods: Following leukapheresis, immature DC (derived from adherent PBMC cultured for 6 days in IL-4/GM-CSF supplemented medium) are electroporated with smRNA encoding MAGE-A3, MAGE-C2, Tyrosinase and gp100 linked to DC-LAMP, and TriMix smRNA. TriMix-DC are cryopreserved and 24.106 viable DC are administered by 4 ID/IV-injections q2w, and a 5th-injection on w16. The number of IV administered DC was escalated from 4.106, over 12.106, to 20.106 in cohort 1, 2 and 3 respectively. Tumor response assessments are performed by 18F-PET/CT at baseline and in w8, 16 and 24. Immunomonitoring is performed by analysis of DTH infiltrating lymphocytes (DIL) at an ID injection site. Results: 11 pts (9M/2F; med age 54, range 40–77) with stage IV pretreated melanoma, have initiated study treatment. TriMix-DC related AE's: gr2 local skin injection site reactions (all pts); fever & lethargy (gr1, 1 pt in cohort 1); chills (gr2, 2 pts in cohort 3). Vaccine-specific DIL were documented in 6/7 pts (5/7 pts had a CD137+CD8+ and 4/7 pts a CD4+ T-cell response). As of Jan 2011, 8 pts were evaluated for response (RECISTv1.1): 1 CR, 1 PR, 3 SD, and 3 PD; regression of metastases occurred in lung- (2 pts) and lymph node metastases (3 pts); 4/8 pts remain progression-free after respectively 3.1, 3.6, 7.7 and 8.2 mths of follow-up. Conclusions: TriMix-DC therapy by combined IV/ID administration is feasible, safe, and immunogenic. Durable anti-melanoma activity is observed across the investigated IV-dose levels and compares favorably with our prior observations with TriMix-DC administered ID-only.
Pretreatment HIV-drug resistance in Mexico and its impact on the effectiveness of first-line antiretroviral therapy: a nationally representative 2015 WHO survey
Authors: Santiago Ávila-Ríos, Claudia García-Morales, Margarita Matías-Florentino, Karla A Romero-Mora, Daniela Tapia-Trejo, Verónica S Quiroz-Morales, Helena Reyes-Gopar, Hezhao Ji, Paul Sandstrom, Jesús Casillas-Rodríguez, Juan Sierra-Madero, Eddie A León-Juárez, Marisol Valenzuela-Lara, Carlos Magis-Rodríguez, Patricia Uribe-Zuñiga, Gustavo Reyes-Terán
Journal: The Lancet HIV (2016)
The influence of season and distance to a cancer centre on lung cancer treatment rates.
Authors: Joanna Gotfrit, Caleb Jonker, Glenwood D. Goss, Scott Andrew Laurie, Garth Andrew Nicholas, Tinghua Zhang, Paul Wheatley-Price
Journal: Journal of Clinical Oncology (2016)

e20536 Background: Our tertiary Canadian academic cancer centre serves a population as far as 200km away. Additionally, winter brings challenges of extreme cold and snowstorms. We assessed whether driving time or winter season affected access to treatment for non-small cell lung cancer (NSCLC) patients at our institution. Methods: With ethics approval, we performed a retrospective analysis of stage IIIB and IV NSCLC outpatients seen from 2009 to 2012. Patients were stratified by driving time from our cancer centre. Driving time was calculated using online mapping websites. Demographics, treatment and survival data were collected. Results: Overall, 514 patients were included, 420 living < 60 minutes and 94 ≥ 60 minutes from the cancer centre. There were no differences in baseline demographics (Table). Overall, 55% of patients received systemic therapy. For patients living closer vs further, driving time had no impact on receiving systemic therapy (55% vs 53% p = 0.72) or median OS (7.4 vs 8.0 months, p = 0.55). However, median time from diagnosis to first treatment was shorter in patients living closer (51 vs 67 days, p = 0.012). 133 patients were seen during winter months, 106 vs 27 residing < 60 vs ≥ 60 minutes away. Patients seen during winter months were as likely to receive systemic therapy as those seen during the rest of the year (56% vs 54%, p = 0.80) and had similar survival (8.4 vs 7.0 months, p = 0.69). During winter months, no difference was observed in treatment rates between patients living closer vs further away (58% vs 48%, p = 0.38). Conclusions: A long travel time to the cancer centre, even in winter months, did not adversely impact treatment rates for advanced NSCLC. These results are reassuring and suggest that centralization of medical oncology services does not limit uptake of available care options. Demographics Patients living < 60 mins from cancer centre (n = 420) Patients living ≥ 60 mins from cancer centre (n = 94) P- value Age < 70 (%) 59 51 0.14 Male (%) 57 52 0.42 PS 0-2 (%) 70 76 0.47 Weight loss ≥ 5% (%) 50 44 0.50 Constitutional symptoms (%) 63 60 0.21 Anemia (%) 6 3 0.72 Leukocytosis (%) 35 34 0.97 Thrombocytosis (%) 26 18 0.24 Renal dysfunc tion (%) 90 89 0.83
PI-PLCbeta1 Expression in Patients with High-Risk Myelodysplastic Syndromes Is Affected by Azacitidine Treatment.
Authors: Carlo Finelli, Matilde Y. Follo, Costanza Bosi, Sara Mongiorgi, Cristina Clissa, Giovanni Martinelli, Michele Baccarani, Alberto M. Martelli, Lucio Cocco
Journal: Blood (2007)
Conflicting Interpretation of Genetic Variants and Cancer Risk by Commercial Laboratories as Assessed by the Prospective Registry of Multiplex Testing
Authors: Judith Balmaña, Laura Digiovanni, Pragna Gaddam, Michael F. Walsh, Vijai Joseph, Zsofia K. Stadler, Katherine L. Nathanson, Judy E. Garber, Fergus J. Couch, Kenneth Offit, Mark E. Robson, Susan M. Domchek
Journal: Journal of Clinical Oncology (2016)

Purpose Massively parallel sequencing allows simultaneous testing of multiple genes associated with cancer susceptibility. Guidelines are available for variant classification; however, interpretation of these guidelines by laboratories and providers may differ and lead to conflicting reporting and, potentially, to inappropriate medical management. We describe conflicting variant interpretations between Clinical Laboratory Improvement Amendments–approved commercial clinical laboratories, as reported to the Prospective Registry of Multiplex Testing (PROMPT), an online genetic registry. Methods Clinical data and genetic testing results were gathered from 1,191 individuals tested for inherited cancer susceptibility and self-enrolled in PROMPT between September 2014 and October 2015. Overall, 518 participants (603 genetic variants) had a result interpreted by more than one laboratory, including at least one submitted to ClinVar, and these were used as the final cohort for the current analysis. Results Of the 603 variants, 221 (37%) were classified as a variant of uncertain significance (VUS), 191 (32%) as pathogenic, and 34 (6%) as benign. The interpretation differed among reporting laboratories for 155 (26%). Conflicting interpretations were most frequently reported for CHEK2 and ATM, followed by RAD51C, PALB2, BARD1, NBN, and BRIP1. Among all participants, 56 of 518 (11%) had a variant with conflicting interpretations ranging from pathogenic/likely pathogenic to VUS, a discrepancy that may alter medical management. Conclusions Conflicting interpretation of genetic findings from multiplex panel testing used in clinical practice is frequent and may have implications for medical management decisions.
Primary Clinical and Angiographic Outcomes of the EVOLVE Trial: A Randomized Evaluation of a Novel Bioabsorbable Polymer-Coated, Everolimus-Eluting Coronary Stent
Authors: Ian T Meredith, Stefan Verheye, Christophe Dubois, Joseph Dens, Jean Fajadet, Didier Carrie, Simon Walsh, Keith G Oldroyd, Olivier Varenne, Seif El-Jack, Raul Moreno, Anita A Joshi, Dominic J Allocco, Keith D Dawkins
Journal: Journal of the American College of Cardiology (2011)
Collapsing glomerulopathy is common in the setting of thrombotic microangiopathy of the native kidney
Authors: David Buob, Mélanie Decambron, Viviane Gnemmi, Marie Frimat, Maxime Hoffmann, Raymond Azar, Jean-Dominique Gheerbrant, Thomas Guincestre, Christian Noël, Marie-Christine Copin, François Glowacki
Journal: Kidney International (2016)
JAK2, As Well As PDL1 and PDL2, are Recurrently Targeted by 9p24 Structural and Numerical Aberrations in Lymphoid Neoplasms of Both B- and T-Cell Origin
Authors: Katrien Van Roosbroeck, Thomas Tousseyn, Julio Finalet Ferreiro, Idoya Lahortiga, Lucienne Michaux, Barbara Cauwelier, Barbara Pienkowska-Grela, Gregor Verhoef, Chantal Doyen, Ivan Theate, Christiane De Wolf-Peeters, Peter Vandenberghe, Iwona Wlodarska
Journal: Blood (2011)
DNA vaccination targeting mesothelin combined with anti-GITR antibody induces rejection of pancreatic adenocarcinoma
Authors: Mary C. Gaffney, Peter Goedegebuure, Hiroyuki Kashiwagi, John R. Hornick, Reuben I. Thaker, Timothy Eberlein, William G. Hawkins
Journal: Cancer Research (2006)

1395  Introduction: Mesothelin is a membrane bound glycoprotein that is over-expressed in 100% of pancreatic adenocarcinomas. Regulatory T-cells inhibit the immune response to cancer and vaccines. Here, we target mesothelin using a xenogeneic DNA vaccine in combination with anti-GITR antibody in an attempt to overcome T-reg suppression and reject pancreatic cancer. Materials and Methods: Mice were vaccinated with a gene gun and 4μg of full length human mesothelin cDNA once a week, for three weeks. Experimental groups consisted of 10-15 mice per group. Anti-GITR antibody (TolerRx/ Clone 2F8) (1mg/mouse) injections were given IP one day prior to the 2nd and 3rd vaccinations. Intradermal injections of 50,000 cells/mouse of a syngeneic murine mesothelin expressing pancreatic cell line were given 4 days after the final vaccination. Tumor free survival was measured and plotted using a Kaplan-Meier curve, and experimental groups were compared using a log-rank test. Results were considered significant when there was a p value of less than 0.05. Results: Fifty percent of mice vaccinated with mesothelin alone versus 0% of non-treated mice were tumor free 25 days after tumor injections (p
Fludarabine Metabolite Level On Day Zero Does Not Affect Outcomes Of Hematopoietic Cell Transplantation In Patients With Normal Renal Function
Authors: Cameron D. Griffiths, Ella S.M Ng, Bill Kangarloo, Tyler S Williamson, Reanne Booker, Ping Yue, Peter Duggan, Mary Lynn Savoie, Christopher Brown, Andrew Daly, James A Russell, Jan Storek
Journal: Blood (2013)
Sex Differences in Binge Eating: Gonadal Hormone Effects Across Development
Authors: Kelly L. Klump, Kristen M. Culbert, Cheryl L. Sisk
Journal: Annual Review of Clinical Psychology (2017)

Eating disorders are highly sexually differentiated disorders that exhibit a female predominance in risk. Most theories focus on psychosocial explanations to the exclusion of biological/genetic influences. The purpose of this descriptive review is to evaluate evidence from animal and human studies in support of gonadal hormone effects on sex differences in binge eating. Although research is in its nascent stages, findings suggest that increased prenatal testosterone exposure in males appears to protect against binge eating. Although pubertal testosterone may exert additional protective effects, the prenatal period is likely critical for the decreased risk observed in males. By contrast, studies indicate that, in females, it is the lack of prenatal testosterone coupled with the organizational effects of pubertal ovarian hormones that may lead to increased binge eating. Finally, twin data suggest that changes in genetic risk may underlie these hormone influences on sex differences across development.
GPs earned £90 600 on average in 2014-15
Authors: Tom Moberly
Journal: BMJ (2016)

General practitioners in the United Kingdom earned an average of £90 600 (€107 000; $120 000) in 2014-15, official figures show.

NHS Digital, which published the data, said that this figure is not statistically significantly different from GPs’ earnings in the previous year.

The earnings data cover both NHS and private income and were derived from anonymised tax data from …
The lectin-like domain of thrombomodulin suppresses leucocyte lung infiltration in a murine ischemia reperfusion model
Authors: Nele Geudens, Marlies Van de Wouwer, Bart Vanaudenaerde, Arne Neyrinck, Filip Rega, Caroline Van De Wauwer, Antoon Lerut, Eric Verbeken, Geert Verleden, Edward Conway, Dirk Van Raemdonck
Journal: European Respiratory Journal (2006)
FOXP3+ Tregs require WASP to restrain Th2-mediated food allergy
Authors: Willem S. Lexmond, Jeremy A. Goettel, Jonathan J. Lyons, Justin Jacobse, Marion M. Deken, Monica G. Lawrence, Thomas H. DiMaggio, Daniel Kotlarz, Elizabeth Garabedian, Paul Sackstein, Celeste C. Nelson, Nina Jones, Kelly D. Stone, Fabio Candotti, Edmond H.H.M. Rings, Adrian J. Thrasher, Joshua D. Milner, Scott B. Snapper, Edda Fiebiger
Journal: Journal of Clinical Investigation (2016)

In addition to the infectious consequences of immunodeficiency, patients with Wiskott-Aldrich syndrome (WAS) often suffer from poorly understood exaggerated immune responses that result in autoimmunity and elevated levels of serum IgE. Here, we have shown that WAS patients and mice deficient in WAS protein (WASP) frequently develop IgE-mediated reactions to common food allergens. WASP-deficient animals displayed an adjuvant-free IgE-sensitization to chow antigens that was most pronounced for wheat and soy and occurred under specific pathogen-free as well as germ-free housing conditions. Conditional deletion of Was in FOXP3+ Tregs resulted in more severe Th2-type intestinal inflammation than that observed in mice with global WASP deficiency, indicating that allergic responses to food allergens are dependent upon loss of WASP expression in this immune compartment. While WASP-deficient Tregs efficiently contained Th1- and Th17-type effector differentiation in vivo, they failed to restrain Th2 effector responses that drive allergic intestinal inflammation. Loss of WASP was phenotypically associated with increased GATA3 expression in effector memory FOXP3+ Tregs, but not in naive-like FOXP3+ Tregs, an effect that occurred independently of increased IL-4 signaling. Our results reveal a Treg-specific role for WASP that is required for prevention of Th2 effector cell differentiation and allergic sensitization to dietary antigens.