tbuckley/cabot-search huggingface dataset:
Cumulative incidence rates for CNS and non-CNS progression by baseline CNS metastases status using data from two alectinib phase II studies.
Authors: Shirish M. Gadgeel, Alice Tsang Shaw, Fabrice Barlesi, Lucio Crino, James Chih-Hsin Yang, Anne-Marie C. Dingemans, Dong-Wan Kim, Filippo De Marinis, Mathias Schulz, Shiyao Liu, Susan Meredith Fish, Ahmed Kotb, Sai-Hong Ignatius Ou
Journal: Journal of Clinical Oncology (2016)

9063 Background: Alectinib showed robust efficacy and safety in two phase II studies (NP28673 [NCT01801111] and NP28761 [NCT01871805]) of patients (pts) with previously treated ALK+ NSCLC. A pooled analysis of these studies also showed highly consistent efficacy of alectinib in the central nervous system (CNS) (Gadgeel et al, WCLC 2015). This exploratory analysis used these pooled data to evaluate the cumulative incidence rate (CIR) of CNS and non-CNS progression for pts with and without CNS metastases (mets) at baseline (BL). Methods: All pts (n = 225) were ≥ 18 years with confirmed ALK+ NSCLC, which had progressed after prior crizotinib. They received 600 mg oral alectinib twice daily. All patients had BL imaging to detect CNS mets, with further prospective imaging as per the protocols. In this analysis, response was determined by RECIST v1.1, and progression (PD) categorized as CNS or non-CNS. CIR was calculated using competing risks methodology. Results: BL characteristics were similar in pts with (n = 136) or without (n = 89) BL CNS mets. Median follow-up was 12.8 months. CIRs at 6, 12 and 18 months are shown in the Table. In the BL CNS mets group, pts with prior radiation (RT; n = 95) had a slightly more rapid rate of CNS PD (39.7% [29.6–49.8] at 12 months) than those with no prior RT (n = 41; 20.1% [7.6–32.6] at 12 months) (p < 0.05), perhaps due to, for e.g., greater disease burden. Conclusions: These pooled phase II study data suggest that alectinib is effective in pts with BL CNS mets, regardless of prior RT. Based on the low incidence of CNS PD in pts without CNS mets at BL, alectinib may also have a potential preventative effect in these pts. The ongoing phase III ALEX study will assess rate of CNS relapse in pts receiving first-line alectinib vs crizotinib. Clinical trial information: NCT01801111 and NCT01871805.Months CIR (%) CNS PD No BL CNS mets vs BL CNS mets CIR (%) Non-CNS PD No BL CNS mets vs BL CNS mets CIR (%) Death No BL CNS mets vs BL CNS mets 6 5.8 (0.9–10.8) vs 24.0 (16.8–31.3) 28.9 (19.4–38.5) vs 18.8 (12.1–25.4) 5.7 (0.8–10.5) vs 5.2 (1.5–9.0) 12 7.0 (1.6–12.4) vs 33.7 (25.6–41.9) 36.2 (26.0–46.4) vs 26.9 (19.3–34.6) 9.3 (3.2–15.4) vs 6.0 (2.0–10.1) 18 9.0 (2.5–15.5) vs 42.3 (32.3–52.4) 61.2 (45.0–77.5) vs 35.2 (20.1–50.3) 9.3 (3.2–15.4) vs 6.0 (2.0–10.1)
A guiding map for inflammation
Authors: Mihai G Netea, Frances Balkwill, Michel Chonchol, Fabio Cominelli, Marc Y Donath, Evangelos J Giamarellos-Bourboulis, Douglas Golenbock, Mark S Gresnigt, Michael T Heneka, Hal M Hoffman, Richard Hotchkiss, Leo A B Joosten, Daniel L Kastner, Martin Korte, Eicke Latz, Peter Libby, Thomas Mandrup-Poulsen, Alberto Mantovani, Kingston H G Mills, Kristen L Nowak, Luke A O'Neill, Peter Pickkers, Tom van der Poll, Paul M Ridker, Joost Schalkwijk, David A Schwartz, Britta Siegmund, Clifford J Steer, Herbert Tilg, Jos W M van der Meer, Frank L van de Veerdonk, Charles A Dinarello
Journal: Nature Immunology (2017)
Olaparib tablets as maintenance therapy in patients with platinum-sensitive, relapsed ovarian cancer and a BRCA1/2 mutation (SOLO2/ENGOT-Ov21): a double-blind, randomised, placebo-controlled, phase 3 trial
Authors: Eric Pujade-Lauraine, Jonathan A Ledermann, Frédéric Selle, Val Gebski, Richard T Penson, Amit M Oza, Jacob Korach, Tomasz Huzarski, Andrés Poveda, Sandro Pignata, Michael Friedlander, Nicoletta Colombo, Philipp Harter, Keiichi Fujiwara, Isabelle Ray-Coquard, Susana Banerjee, Joyce Liu, Elizabeth S Lowe, Ralph Bloomfield, Patricia Pautier, Jacob Korach, Tomasz Huzarski, Tomasz Byrski, Patricia Pautier, Michael Friedlander, Philipp Harter, Nicoletta Colombo, Sandro Pignata, Giovanni Scambia, Maria Nicoletto, Fiona Nussey, Andrew Clamp, Richard Penson, Amit Oza, Andrés Poveda Velasco, Manuel Rodrigues, Jean-Pierre Lotz, Frédéric Selle, Isabelle Ray-Coquard, Diane Provencher, Aleix Prat Aparicio, Laura Vidal Boixader, Clare Scott, Kenji Tamura, Mayu Yunokawa, Alla Lisyanskaya, Jacques Medioni, Nicolas Pécuchet, Coraline Dubot, Thibault de la Motte Rouge, Marie-Christine Kaminsky, Béatrice Weber, Alain Lortholary, Christine Parkinson, Jonathan Ledermann, Sarah Williams, Susana Banerjee, Jonathan Cosin, James Hoffman, Richard Penson, Marie Plante, Allan Covens, Gabe Sonke, Florence Joly, Anne Floquet, Susana Banerjee, Holger Hirte, Amnon Amit, Tjoung-Won Park-Simon, Koji Matsumoto, Sergei Tjulandin, Jae Hoon Kim, Laurence Gladieff, Roberto Sabbatini, David O'Malley, Patrick Timmins, Daniel Kredentser, Nuria Laínez Milagro, Maria Pilar Barretina Ginesta, Ariadna Tibau Martorell, Alfonso Gómez de Liaño Lista, Belén Ojeda González, Linda Mileshkin, Masaki Mandai, Ingrid Boere, Petronella Ottevanger, Joo-Hyun Nam, Elias Filho, Salima Hamizi, Francesco Cognetti, David Warshal, Elizabeth Dickson-Michelson, Scott Kamelle, Nathalie McKenzie, Gustavo Rodriguez, Deborah Armstrong, Eva Chalas, Paul Celano, Kian Behbakht, Susan Davidson, Stephen Welch, Limor Helpman, Ami Fishman, Ilan Bruchim, Magdalena Sikorska, Anna Słowińska, Wojciech Rogowski, Mariusz Bidziński, Beata Śpiewankiewicz, Antonio Casado Herraez, César Mendiola Fernández, Martina Gropp-Meier, Toshiaki Saito, Kazuhiro Takehara, Takayuki Enomoto, Hidemichi Watari, Chel Hun Choi, Byoung-Gie Kim, Jae Weon Kim, Roberto Hegg, Ignace Vergote
Journal: The Lancet Oncology (2017)
Racial and Ethnic Differences in Homicides of Adult Women and the Role of Intimate Partner Violence — United States, 2003–2014
Authors: Emiko Petrosky, Janet M. Blair, Carter J. Betz, Katherine A. Fowler, Shane P.D. Jack, Bridget H. Lyons
Journal: MMWR Morbidity and Mortality Weekly Report (2017)

Homicide is one of the leading causes of death for women aged ≤44 years.* In 2015, homicide caused the death of 3,519 girls and women in the United States. Rates of female homicide vary by race/ethnicity (1), and nearly half of victims are killed by a current or former male intimate partner (2). To inform homicide and intimate partner violence (IPV) prevention efforts, CDC analyzed homicide data from the National Violent Death Reporting System (NVDRS) among 10,018 women aged ≥18 years in 18 states during 2003-2014. The frequency of homicide by race/ethnicity and precipitating circumstances of homicides associated with and without IPV were examined. Non-Hispanic black and American Indian/Alaska Native women experienced the highest rates of homicide (4.4 and 4.3 per 100,000 population, respectively). Over half of all homicides (55.3%) were IPV-related; 11.2% of victims of IPV-related homicide experienced some form of violence in the month preceding their deaths, and argument and jealousy were common precipitating circumstances. Targeted IPV prevention programs for populations at disproportionate risk and enhanced access to intervention services for persons experiencing IPV are needed to reduce homicides among women.
A Crohn's syndrome-associated insertion polymorphism (3020incC) in the NOD2 gene is not associated with psoriasis vulgaris, palmo-plantar pustulosis (PPP) or guttate psoriasis.
Authors: C Young, M H Allen, A Cuthbert, M Ameen, C Veal, J Leman, A D Burden, B Kirby, C E M Griffiths, C G Mathew, R C Trembath, J N W Barker
Journal: British Journal of Dermatology (2002)
Environmental and genetic risk factors for t(14;18) subtypes of diffuse large B-cell lymphoma in a population-based, case-control study
Authors: Lindsay Morton, James Cerhan, Patricia Hartge, Bhavana Dave, Mohammad Vasef, Dennis Weisenburger, Smrati Jain, Louis Staudt, Wendy Cozen, Scott Davis, Richard Severson, Nathaniel Rothman, Stephen Chanock, Sophia Wang
Journal: Cancer Research (2007)

1713   BACKGROUND: The t(14;18)(q32;q21) chromosomal translocation is observed in 30-50% of diffuse large B-cell lymphomas (DLBCL) and 70-90% of follicular lymphomas, making it one of the most common cytogenetic abnormalities in non-Hodgkin lymphoma (NHL). This translocation results in the deregulation of the anti-apoptotic gene  BCL2  on chromosome 18 by joining it with the immunoglobulin heavy chain (IgH) gene on chromosome 14. Although the t(14;18) alone is insufficient to cause NHL, it may represent a common etiologic pathway for some NHLs in combination with other risk factors. To date, only two studies have evaluated environmental risk factors for NHL by t(14;18) status, and no research on genetic risk factors for NHL by t(14;18) status has been published. Therefore, we evaluated the differential environmental and genetic risk factors for the t(14;18) subtypes of DLBCL in a population-based, case-control study.  METHODS: A total of 280 DLBCL cases with paraffin-embedded tissue and 1057 population-based controls were identified during 1998-2000 in four geographic areas of the United States. We determined the t(14;18) status using an interphase fluorescence  in situ  hybridization (FISH) assay with a dual-fusion probe in 277 of 280 DLBCL cases. Data on demographic characteristics and risk factors for lymphoma were obtained by interview. We also conducted genotype analysis of single nucleotide polymorphisms (SNPs) in immune response and DNA repair pathways. In preliminary analyses, we used logistic regression models to estimate case-case odds ratios (ORs) and 95% confidence intervals (CIs) for those environmental risk factors (asthma, autoimmune conditions, body mass index, family history of NHL, and sun exposure) and SNPs ( TNF  G308A,  IL10  T3575A,  FCGR2A  H165R,  RAG1  K820R, and  LIG4  Thr9Ile) previously found to be associated with NHL in our main study.  RESULTS: The t(14;18) was detected in 127 of 277 (46%) DLBCL cases. Compared with cases without the t(14;18), cases with the t(14;18) tended to be older ( LIG4  (DNA ligase IV) 9 Ile allele (rs1805388; Thr/Thr is referent; Thr/Ile OR=0.4; Ile/Ile OR=0.2; p-trend=0.005). Additional analyses of the t(14;18) subtypes of DLBCL in relation to environmental risk factors, including organochlorines, and gene-based pathway analyses will be presented.  CONCLUSIONS: Preliminary analyses suggest that there may be specific environmental and genetic risk factors for DLBCL subtypes defined by t(14;18), suggesting etiologically distinct mechanistic pathways.
Association Between Patient Age and Lymph Node Positivity in Thin Melanoma
Authors: Andrew J. Sinnamon, Madalyn G. Neuwirth, Pratyusha Yalamanchi, Phyllis Gimotty, David E. Elder, Xiaowei Xu, Rachel R. Kelz, Robert E. Roses, Emily Y. Chu, Michael E. Ming, Douglas L. Fraker, Giorgos C. Karakousis
Journal: JAMA Dermatology (2017)

More than half of all new melanoma diagnoses present as clinically localized T1 melanoma, yet sentinel lymph node biopsy (SLNB) is controversial in this population given the overall low yield. Guidelines for SLNB have focused on pathologic factors, but patient factors, such as age, are not routinely considered.To identify indicators of lymph node (LN) metastasis in thin melanoma in a large, generalizable data set and to evaluate the association between patient age and LN positivity.A retrospective cohort study using the National Cancer Database, an oncology database representing patients from more than 1500 hospitals throughout the United States, was performed (2010-2013). Data analysis was conducted from October 1, 2016, to January 15, 2017. A total of 8772 patients with clinical stage I 0.50 to 1.0 mm thin melanoma undergoing wide excision and surgical evaluation of regional LNs were included for study.The primary outcome of interest was presence of melanoma in a biopsied regional LN. Clinicopathologic factors associated with LN positivity were characterized, using logistic regression. Age was categorized as younger than 40 years, 40 to 64 years, and 65 years or older for multivariable analysis. Classification tree analysis was performed to identify high-risk groups for LN positivity.Among the study cohort (n = 8772), 333 patients had nodal metastases, for an overall positivity rate of 3.8% (95% CI, 3.4%-4.2%). A total of 4087 (54.0%) patients were women. Median age was 56 years (interquartile range [IQR], 46-67) in patients with negative LNs and 52 years (IQR, 41-61) in those with positive LNs (P < .001). In multivariable analysis, younger age, female sex, thickness of 0.76 mm or larger, increasing Clark level, mitoses, ulceration, and lymphovascular invasion were independently associated with LN positivity. In decision tree analysis, patient age was identified as an important risk stratifier for LN metastases, after mitoses and thickness. Patients younger than 40 years with category T1b tumors 0.50 to 0.75 mm, who would generally not be recommended for SLNB, had an LN positivity rate of 5.6% (95% CI, 3.3%-8.6%); conversely, patients 65 years or older with T1b tumors 0.76 mm or larger, who would generally be recommended for SLNB, had an LN positivity rate of only 3.9% (95% CI, 2.7%-5.3%).Patient age is an important factor in estimating lymph node positivity in thin melanoma independent of traditional pathologic factors. Age therefore should be taken into consideration when selecting patients for nodal biopsy.
Abstract 048: Identifying Genetic Modifiers for Cardiomyopathy via Mutagenesis Screening
Authors: Yonghe Ding, Xiaolei Xu
Journal: Circulation Research (2013)

Rationale: The generation of animal models for human cardiomyopathy creates opportunities to uncover mechanisms of diseases’ pathogenesis and to identify genes that modify the progression of pathogenesis. In contrast to candidate gene-based approaches, the phenotype-based forward genetic screening approach is less effectively employed in a vertebrate, mainly due to the prohibitively enormous colony management efforts. Objective: To identify genetic modifiers of cardiomyopathy through developing an unbiased forward genetic approach in the vertebrate Danio rerio. Methods and Results: Using an expression-based insertional mutagenesis screening strategy, we identified 49 Zebrafish Insertional Cardiac (ZIC) mutants from a collection of ~300 gene break-transposon (GBT) lines. By applying doxorubicin (DOX) stress to these heterozygous ZIC mutants, we initially identified four GBT lines that either enhanced or suppressed DOX-induced cardiomyopathy phenotypes. Here, we focus on the GBT0411 line which significantly enhances DOX-induced cardiomyopathy phenotypes. We cloned the gene and identified a single transposon insertion that disrupts the long nuclei isoform of dnajb6b in this GBT0411 mutant. Consistent with its cardiomyopathy modifier function, we detected a predominant expression of dnajb6b in the heart. While mutations affecting the cytoplasmic functions of DNAJB6 were recently reported to cause limb-girdle muscular dystrophy type 1D, our study suggested that the impaired balance between Dnajb6b long (nuclei) and short (cytoplasmic) isoform accounted for the cardiomyopathy modifier effect. Conclusions: Our results demonstrated the feasibility of identifying genetic modifiers of cardiomyopathy using a forward genetic approach in a vertebrate. Specifically, our data implicate DNAJB6 as a new genetic risk factor for DOX-induced cardiomyopathy. Without any presumption, this forward genetic strategy opens the door to systematically identify genetic factors that modify the progression of cardiomyopathy, which will facilitate the practice of personalized medicine and the development of novel therapies.
Choosing treatments when the effect of alternatives is uncertain
Authors: Iain Chalmers
Journal: BMJ (2017)

In the Head to Head debate on whether doctors have a duty to take part in pragmatic randomised trials, Weijer and colleagues are correct to assert that people should be able to choose how they help others when there is uncertainty about the effects of treatments.1 However, a flawed ethics analysis prompts them to take too narrow a view …
Long-term response after stopping tenofovir disoproxil fumarate in non-cirrhotic HBeAg-negative patients – FINITE study
Authors: Thomas Berg, Karl-Georg Simon, Stefan Mauss, Eckart Schott, Renate Heyne, Dietmar M. Klass, Christoph Eisenbach, Tania Mara Welzel, Reinhart Zachoval, Gisela Felten, Julian Schulze-zur-Wiesch, Markus Cornberg, Marjoleine L. Op den Brouw, Belinda Jump, Hans Reiser, Lothar Gallo, Tobias Warger, Jörg Petersen
Journal: Journal of Hepatology (2017)
Editorial: US Cancer Statistics of Survival: Achievements, Challenges, and Future Directions
Authors: Shahinaz M Gadalla, Brigitte C Widemann
Journal: JNCI Journal of the National Cancer Institute (2017)

Cancer remains the second leading cause of death in the United States, with an estimated 600 920 cancer deaths in 2017 (1).In this issue of the Journal, the American Cancer Society, the Centers for Disease Control and Prevention, the National Cancer Institute (NCI), and the North American Association of Central Cancer Registries deliver their annual update on US cancer incidence and mortality trends (2).The report shows that during 1999 to 2013, cancer rates continued to decrease in men and remained stable in women.In contrast, mortality rates statistically significantly decreased in men and women (1.8% and 1.4% per year, respectively).Cancer site-specific statistics showed few exceptions.While these results are encouraging overall, they raise critical questions: Why do we see rate increases in some cancers?How can we decrease cancer mortality more rapidly?Can we address mortality risk factors within the current standard of care more effectively?Will the surge in new targeted anticancer therapeutics translate to a peak drop in cancer mortality soon?The reported increase in the incidence of certain cancers, such as cancers of the liver, pancreas, thyroid, female breast, and uterus, is alarming, but a fraction of them may be explained by known risk factors such as the expanding obesity epidemic (3).Approximately 38% of US adults and 17% of children and adolescents are obese (4,5).The dramatic decrease in the incidence of cancers linked to tobacco smoking provides proof of concept that changing lifestyle risk factors is important in cancer control.The identified geographic survival differences in this report-with survival for several common cancers being lowest in select Southern and Midwestern states and highest in Northeastern states-cannot be interpreted without considering the possible interaction with the population demographics and/or access to specialty care.Racial differences in cancer incidence and mortality have not changed from previous years.
Non-abstract numerical representations in the IPS: Further support, challenges, and clarifications Authors' Response
Authors: RC Kadosh, Walsh
Journal: Behavioral and Brain Sciences (2009)

The commentators have raised many pertinent points that allow us to refine and clarify our view. We classify our response comments into seven sections: automaticity; developmental and educational questions; priming; multiple representations or multiple access(?); terminology; methodological advances; and simulated cognition and numerical cognition. We conclude that the default numerical representations are not abstract.
WHO urges countries to fight tobacco industry’s interference
Authors: Anne Gulland
Journal: BMJ (2017)

The tobacco industry continues to “hamper” government efforts to curb smoking by threatening litigation and attempting to undermine scientific evidence when tobacco control policies are introduced, the World Health Organization has warned.1

In its latest report on global tobacco use WHO looks at countries’ adherence to its Framework Convention on Tobacco Control (FCTC), a set of measures that it urges countries to implement to end tobacco use. It advises countries to protect themselves from tobacco industry interference—a key requirement of the FCTC.

The report,1 funded by Bloomberg Philanthropies, a non-governmental organisation founded by the US businessman and former New York City mayor Michael Bloomberg, says that the tobacco industry has “long operated …
PIM1 Inhibition Enhances and Prolongs Plerixafor-Induced Mobilization of HSCs
Authors: Tony Andreas Müller, Anabel Zwick, Sarah Decker, Claudius Klein, Benjamin Rister, Alina Rudorf, Sandra Kissel, Marie Follo, Ralph Wäsch, Anna Lena Illert, Claudia Waskow, Christine Dierks, Justus Duyster
Journal: Blood (2016)
Dual effect of ochratoxin A (OTA) on the expression of organic anion transporters Oat1 and Oat3 in rats
Authors: Vilim Žlender, Marija Ljubojević, Daniela Balen, Davorka Breljak, Hrvoje Brzica, Radovan Fuchs, Naohiko Anzai, Ivan Sabolić
Journal: Journal of the American Society of Nephrology (2007)

OTA is an environmental mycotoxin that can impair human and animal health. In the kidney, OTA primarily targets epithelial cells in the proximal tubule (PT). PT is the major site of organic anion (OA) secretion via basolateral transporters Oat1 (Slc22a6) and Oat3 (Slc22a8). Earlier studies have shown that OTA inhibits the renal secretion of OA p-aminohyppurate (PAH), possibly by targeting the expression of Oat1 and Oat3, but this possibility has not been verified. To see if OTA affects the expression of these two Oats, we treated adult male Wistar rats with various doses of OTA (0, 50, 125, 250 & 500 μ g/kg b.w., p.o.) every 2nd day for 10 days, and determined: a) the expression of Oat1 and Oat3 proteins by Western blotting (WB) of total cell membranes isolated from the kidney and by immunocytochemistry (IC) in tissue cryosections, and b) the tissue expression of Oat1 and Oat2 mRNA by end-point PCR. The WB study of protein expression revealed a dual, dose-dependent effect of OTA ; low doses (50-125 μ g/kg b.w.) increased the expression of Oat1 (~50%) and Oat3 (~300%), whereas high doses (250-500 μ g/kg b.w.) decreased the expression of Oat1 (~70%) but not Oat3 in respect to control. The IC data on staining intensity of both transporters in the PT completely matched the WB data. At the mRNA level the expression of Oat1 was unaffected by low OTA doses and downregulated by high OTA doses, whereas the expression of Oat3 was unaffected by any OTA dose. The mRNA expression of housekeeping gene GAPDH remained unchanged in all OTA-treated animals. We conclude that: a) low doses of OTA upregulate the expression of Oat1 and Oat3 proteins in the rat kidney, while high doses downregulate only the expression of Oat1, b) upregulation of Oat1 and Oat3 proteins is mRNA-unrelated, and seems to be post-transcriptional, c) previously observed inhibition of the renal PAH secretion in rodents may be related to the loss of Oat1 protein ; and d) at lower OAT doses, upregulated Oat1 and Oat3 proteins may enhance OTA uptake and accelerate the development of nephrotoxicity.