tbuckley/cabot-search huggingface dataset:
Comparison of survival predictors in colorectal cancer (CRC) patients of different races.
Authors: Neal Patel, Nneoma Olivia Okoronkwo, Ying Margie Tang, Victor Tsu-Shih Chang, Basil Kasimis, Trent P Wang, Tanganyika Barnes, Janet Cogswell, Melanie L. Gonzalez, Jan Einhorn, Maryann Sullivan, Fengming Zhong
Journal: Journal of Clinical Oncology (2013)

e14661 Background: We studied comorbidity and other survival predictors for patients (pts) with CRC and compared the pts of different races. Methods: In an IRB-approved protocol, we reviewed the records of pts diagnosed with CRC at a VA medical center from 01/01/2003 to 12/31/2011 for demographics, stage, grade, ECOG performance status (PS), CEA, hemoglobin (HGB), and albumin (ALB) at diagnosis (dx). Comorbidity was assessed with the Charlson Comorbidity Index (CCI), the Cumulative Illness Rating Scales (CIRS), and the Kaplan-Feinstein Index (KFI). Statistical analyses were performed with SAS 9.2/Stata 11.0. We compared the pts by race groups Caucasian (C) vs African American (A). Results: There were 279 men. 156 pts (55.9%) were race C, 106 pts (38%) race A, 15 pts (5.4%) Hispanics, and 2 pts (0.7%) Asians. The median (M) age at dx was 70 (45-90) years. 132 pts (47.3%) were deceased. Age, grade, stage, ECOG PS, HGB, ALB, and CEA were similar between group A and C. In group A, M CCI is 4.2 (0.8-14), M CIRS 15 3.0 (0-5), M CIRS16 5 (0-13), M CIRS17 2 (0-6), M CIRS18 0 (0-1), M CIRS 19 0 (0-1), M KFI 2 (0-3). In group C, Median (M) CCI is 4.2 (0.4-19.6), M CIRS15 3.0 (0-6), M CIRS16 6 (0-13), M CIRS17 2 (0-13), M CIRS18 0 (0-1), M CIRS 19 0 (0-1) and M KFI 2 (0-3). By univariate analysis, for group A, grade, stage, ECOG PS, HGB, CCI, CIRS16, CIRS 19 and KFI are significant predictors. For group C, age, grade, stage, ECOG PS, HGB, ALB, and CIRS16 are significant predictors for survival. Summary for significant multivariate predictors are shown in the Table. Conclusions: This study from a larger population confirms our earlier findings (ASCO 2012 e14125). Grade, stage, ECOG PS, and CIRS 19 are independent survival predictors for veterans with CRC. Age, stage, ECOG PS, ALB and CIRS19 are independent predictors of survival for group C pts with CRC. Grade, stage, ECOG PS, and CIRS19 are predictors for group A pts with CRC. This variation may suggest biological difference between races. More studies are needed to confirm this. Supported by NJCCR. [Table: see text]
Diving beneath the surface: addressing gender inequities among clinical investigators
Authors: Whitney H. Beeler, Lilia M. Cortina, Reshma Jagsi
Journal: Journal of Clinical Investigation (2019)

Earlier this year, Dr. Anna Wåhlin made headlines for sending a $3.6 million submarine beneath the ice shelf of Thwaites glacier to study -for the first time everhow warming Antarctic waters are contributing to glacial melting, rising sea levels, and climate change (1).Following this historic achievement came a series of articles and podcasts detailing not only the importance of her team's findings, but also the significance that she (a woman!) led this scientific mission.Indeed, Dr.
Banning tobacco sales to under 21s reduces smoking, study finds
Authors: Stijntje Dijk, Pat Lok
Journal: BMJ (2019)

Local US laws banning the sale of tobacco to people aged under 21 have reduced smoking among 18-20 year olds, a study has found.1

Researchers from Yale University examined the impact of “tobacco 21” policies and found that they decreased the likelihood of an 18-20 year old becoming an established smoker by an estimated 1.2 percentage points, as compared with young people who were not exposed to the policies.

Meanwhile, the team found no significant change in the likelihood of smoking among 23-25 year olds in policy exposed areas, …
Oxaliplatin, 5-fluorouracil, and folinic acid as first-line chemotherapy for elderly patients with advanced gastric cancer
Authors: I. Choi, K. Lee, D. Oh, J. Kim, S. Lee, D. Kim, S. Im, T. Kim, D. Heo, Y. Bang
Journal: Journal of Clinical Oncology (2006)

14155 Background: We investigated the efficacy and safety of an oxaliplatin, 5-fluorouracil (5-FU), and folinic acid (FA) as first-line chemotherapy for elderly patients with advanced gastric cancer. Methods: Chemotherapy-naïve patients (≥65 yr of age) with histologically confirmed, locally advanced or recurrent/metastatic gastric cancer were studied. Chemotherapy consisted of oxaliplatin 100 mg/m 2 and FA 100 mg/m 2 (2-hour intravenous infusion), then 5-FU 2400 mg/m 2 (46-hour continuous infusion) every 14 days. Results: A total of 24 patients were enrolled between September 2003 and July 2005. Of 22 evaluable patients, none achieved complete response (CR) and 11 achieved partial response (PR), resulting in an overall response rate of 50%. Median progression-free survival (PFS) was 5.4 months (95% CI: 5.1–5.8 months) and median overall survival (OS) was 7.4 months (95% CI: 4.4–10.4 months). The main toxicities were anemia and leucopenia, which were observed in 39.8% and 19.0%, respectively, of the total cycles administered. There were 2 cycles of grade 4 leucopenia and febrile neutropenia was not observed. Conclusions: This oxaliplatin/5-FU/FA regimen shows good efficacy and an acceptable toxicity profile in elderly patients with advanced gastric cancer. No significant financial relationships to disclose.
Predictors of febrile neutropenia among Medicare patients with breast, lung and colorectal cancer
Authors: W. D. Hosmer, M. D. Wong, J. L. Malin
Journal: Journal of Clinical Oncology (2007)

9120 Background: Neutropenia and associated impaired immunity is the major dose limiting toxicity for systemic chemotherapy administration. Current guidelines recommend the prophylactic use of G-CSF when the risk of febrile neutropenia (FN) is approximately 20% because it decreases the duration and risk of FN. Advanced age has been identified as a risk factor for FN; however, little is known about the impact of other factors on the incidence of FN in the elderly. Methods: We analyzed SEER-Medicare data on patients diagnosed between 1995 and 2000 with breast, colorectal, and lung cancer, who received chemotherapy within 11 months of diagnosis. We examined a number of factors that might potentially be associated with FN in the first cycle of chemotherapy, including patient demographics, cancer stage at diagnosis, number of myelosupressive chemotherapeutics, frequency of chemotherapy administration, and comorbid conditions, including previous history of anemia and other blood disorders. Outcome was defined as admission to hospital within 30 days of initial chemotherapy administration with neutropenia (ICD9 288.0) coded as an admission diagnosis. Results: Of 18,637 patients who met inclusion criteria 751 (4.0%) had an episode of FN within 30 days of initial chemotherapy administration. In multivariate logistic regression analysis, independent predictors of FN included cancer type (lung cancer, OR 3.77, CI: 1.02–13.9, as compared to breast cancer) and history of blood disorder (OR 1.49, CI: 1.10–2.0), with a trend towards history of COPD (OR 1.19, CI: 0.98–1.44) and three or more myelosupressive agents (OR 4.01, CI: 0.76–21.2, as compared to non-myelosupressive chemotherapy). Initiating chemotherapy less than 1 month after cancer diagnosis was also associated with a higher odds of developing FN (OR 1.88, CI:1.42–2.49 compared to 3 months or more after diagnosis). Discussion: By utilizing the SEER-Medicare dataset we were able to examine predictors of febrile neutropenia in a large population of elderly patients with common malignancies. Knowledge of predisposing factors for neutropenia will allow more tailored prophylactic use of G-CSF in this at-risk population. No significant financial relationships to disclose.
Modulating chromatin accessibility by transactivation and targeting proximal dsgRNAs enhances Cas9 editing efficiency in vivo
Authors: Guanwen Liu, Kangquan Yin, Qianwei Zhang, Caixia Gao, Jin-Long Qiu
Journal: Genome biology (2019)

The CRISPR/Cas9 system is unable to edit all targetable genomic sites with full efficiency in vivo. We show that Cas9-mediated editing is more efficient in open chromatin regions than in closed chromatin regions in rice. A construct (Cas9-TV) formed by fusing a synthetic transcription activation domain to Cas9 edits target sites more efficiently, even in closed chromatin regions. Moreover, combining Cas9-TV with a proximally binding dead sgRNA (dsgRNA) further improves editing efficiency up to several folds. The use of Cas9-TV/dsgRNA thus provides a novel strategy for obtaining efficient genome editing in vivo, especially at nuclease-refractory target sites.
Paclitaxel (P) and cisplatin (C) concurrent with radiotherapy (RT) for larynx preservation (LP) in advanced resectable laryngeal (L) and hypopharyngeal (HP) squamous cell carcinoma (SCC): Final results of a prospective phase II trial.
Authors: Ulisses Ribaldo Nicolau, Thiago Bueno Oliveira, Andre Lopes Carvalho, Rosane O Santana, Adriana D Valadares, Joao Victor Salvajoli, Ludmilla T.D. Chinen, Bertha Catherine B. Araujo, Sandro José Martins, Dalvaro Oliveira Castro Junior, Luiz Paulo Kowalski, Olavo Feher
Journal: Journal of Clinical Oncology (2012)

e16046 Background: Since the results of the RTOG 9111 trial, cisplatin based chemoradiation (CRT) has been the standard of care for LP in advanced laryngeal SCC. Recently, the role of taxanes in managing head and neck SCC has been studied. In 2002 we reported the interim results of a phase II clinical study designed to test the efficacy of P and C concurrent with RT for organ preservation in advanced L and HP SCC. Here we report the long term survival and LP rates. Methods: Eligible patients had untreated advanced L and HP SCC, stage T3N0 or higher and suitable for radical total laryngectomy. Treatment consisted of weekly P (30 mg/m 2 ) and C (20 mg/m 2 ) concurrent to RT up to 7040 cGy in 180 cGy/day fractions. Response evaluation was performed at 5040 cGy and at 4 weeks after completing RT. Salvage surgery was planned for patients not responding at 5040 cGy, residual tumor at the end of RT or at the time of local recurrence. Neck dissection was planned for clinically positive neck (cN1-3). Results: Between 06/1999 and 10/2001, 48 patients were enrolled in a single institution (35 L; 13 HP), 40 male and 8 female with a 58-year median age (39-74). The majority had T3 (64%) N1-3 (52%) disease and 38% needed tracheostomy prior to treatment. Grade (G) 3 and 4 mucositis was noted in 27% of patients, G 3-4 odynophagia in 50%, G 3-4 radiodermatitis in 35% and G 3-4 leucopenia in 13%, with no treatment related death. Two patients needed salvage surgery, one after 5040 cGy and one after 7040 cGy. The complete response rate to treatment was 95%. At a median follow up of 66 months the LP rate at 2 and 5 years were 88% and 54%, respectively. Recurrence free survival (RFS) was 51% at 2 and 47% at 5 years and overall survival (OS) was 81% and 52% at 2 and 5 years, respectively. Conclusions: The finding of similar LP rate and survival compared to the recent reports of high dose cisplatin CRT and neoadjuvant 3 drug CT followed by CRT in an advanced disease population suggests a role for platinum plus taxane as a radiosensitizer regimen in this scenario with acceptable toxicity, but further evaluation in a direct comparative trial with the standard regimen is needed.
Correction to: Molecular and pharmacological modulators of the tumor immune contexture revealed by deconvolution of RNA-seq data
Authors: Francesca Finotello, Clemens Mayer, Christina Plattner, Gerhard Laschober, Dietmar Rieder, Hubert Hackl, Anne Krogsdam, Zuzana Loncova, Wilfried Posch, Doris Wilflingseder, Sieghart Sopper, Marieke Ijsselsteijn, Thomas P. Brouwer, Douglas Johnson, Yaomin Xu, Yu Wang, Melinda E. Sanders, Monica V. Estrada, Paula Ericsson-Gonzalez, Pornpimol Charoentong, Justin Balko, Noel Filipe da Cunha Carvalho de Miranda, Zlatko Trajanoski
Journal: Genome Medicine (2019)

It was highlighted that the original article [1] contained a typesetting mistake in the name of Noel Filipe da Cunha Carvalho de Miranda. This was incorrectly captured as Noel Filipe da Cunha Carvahlo de Miranda. It was also highlighted that in Fig. 3C the left panels Y-axis were cropped and in Fig. 5C, CD8 bar was cropped. This Correction article shows the correct Figs. 3 and 5. The original article has been updated.
The neuropathological diagnosis of Alzheimer’s disease
Authors: Michael A. DeTure, Dennis W. Dickson
Journal: Molecular Neurodegeneration (2019)

Alzheimer's disease is a progressive neurodegenerative disease most often associated with memory deficits and cognitive decline, although less common clinical presentations are increasingly recognized. The cardinal pathological features of the disease have been known for more than one hundred years, and today the presence of these amyloid plaques and neurofibrillary tangles are still required for a pathological diagnosis. Alzheimer's disease is the most common cause of dementia globally. There remain no effective treatment options for the great majority of patients, and the primary causes of the disease are unknown except in a small number of familial cases driven by genetic mutations. Confounding efforts to develop effective diagnostic tools and disease-modifying therapies is the realization that Alzheimer's disease is a mixed proteinopathy (amyloid and tau) frequently associated with other age-related processes such as cerebrovascular disease and Lewy body disease. Defining the relationships between and interdependence of various co-pathologies remains an active area of investigation. This review outlines etiologically-linked pathologic features of Alzheimer's disease, as well as those that are inevitable findings of uncertain significance, such as granulovacuolar degeneration and Hirano bodies. Other disease processes that are frequent, but not inevitable, are also discussed, including pathologic processes that can clinically mimic Alzheimer's disease. These include cerebrovascular disease, Lewy body disease, TDP-43 proteinopathies and argyrophilic grain disease. The purpose of this review is to provide an overview of Alzheimer's disease pathology, its defining pathologic substrates and the related pathologies that can affect diagnosis and treatment.
Developing genetic markers for melanoma risk assessment
Authors: P. Manga, J. D. Goldberg, I. Belitskaya-Levy, I. Lobach, D. Polsky, A. Pavlick, R. Shapiro, R. Berman, I. Osman, H. Ostrer
Journal: Journal of Clinical Oncology (2009)

9046 Background: Risk assessment for melanoma is currently based on phenotype, family and exposure history. This approach is subject to recall bias and excludes at-risk groups such as those with darker skin pigmentation. Poorly stratified risk pools also result in unnecessary dermatologist visits and biopsies for those at lower risk. Use of genetic markers may improve risk assessment; however few susceptibility markers have been developed to date. There have been a number of reports of association between melanoma and genetic markers though few have been replicated or validated. In addition, these studies frequently utilized specific coding region variants as markers and failed to test the entire gene. We have therefore assembled a case-control cohort in which to search for potential biomarkers for melanoma risk by interrogating genes using recently developed tools for genetic analysis. A pilot study was performed to test the utility of our cohort. Methods: A cohort of 326 individuals diagnosed with melanoma and treated at the New York University Langone Medical Center and 400 controls obtained from the New York Cancer project was assembled. Candidate genes were selected based on involvement in determining melanoma predisposition factors (skin pigmentation and DNA repair capability) and previous studies showing association. Three genes, ERCC1, ERCC4 (DNA repair) and MATP (skin pigmentation) were selected. Tag Single Nucleotide Polymorphisms (tSNPs) were selected using Haploview (Hapmap.org) and DNA genotyped (Sequenom Inc, San Diego, CA). Odds ratios and confidence intervals were computed for each SNP. Results: An association was found between SNP rs11615 at the ERCC1 locus and melanoma (Odds ratio = 1.718, 95% Confidence interval: 1.259 - 2.343 for TT vs TC/CC). Conclusions: A tSNP approach is thus useful in identifying associations in our melanoma case-control cohort. Sequence variation at the ERCC1 locus contributes to melanoma risk and the gene will now be screened for clinically useful susceptibility biomarkers. Additional DNA repair and pigmentation genes will also be interrogated using this approach. Genes found to be associated with melanoma will be screened by high- density SNP analysis to identify the most appropriate biomarker/s for use in risk assessment. No significant financial relationships to disclose.
Serum lipocalin-2 as a potential biomarker of liver irradiation.
Authors: Sadaf Sultan, Giuliano Ramadori, Shakil Ahmad, Margret Rave-Fraenk, Hans Christiansen, Silke Cameron
Journal: Journal of Clinical Oncology (2012)

e13039 Background: Lipocalin-2 is a pleiotropic protein synthesized under acute phase conditions. The source of increased serum levels and the major organ responsible for its production are still unknown. The aim of our study was to prospectively evaluate the Lipocalin-2 (LCN-2) expression in rat liver exposed to single dose x-irradiation. Methods: A single dose of 25 Gy was administered percutaneously to the liver of randomly paired rats after a planning CT scan. Male Wistar rats were sacrificed 1, 3, 6, 12, 24 and 48 hours after irradiation along with sham irradiated control. Blood was taken for ELISA of LCN-2, and organs were removed and deep-frozen for RT-PCR and Western Blot or prepared for immunostaining. Furthermore, hepatocytes, myofibroblasts and Kupffer cells were isolated from the liver of healthy rats and irradiated with 2 Gy ex-vivo. Results: LCN-2 serum levels increased significantly (2.5 mg/ml) within 24 hours after direct liver irradiation. In the liver, LCN-2 specific transcripts increased significantly up to 552 ±109-fold at 24 hours which was further confirmed by Western blot analysis. Immunohistology of liver sections detected positivity in recruited granulocytes within 1 hour after irradiation around the central and portal areas. Ex-vivo irradiated hepatocytes showed a significantly higher LCN-2 expression as compared to myofibroblasts and Kupffer cells. Treatment of isolated, irradiated hepatocytes with acute phase cytokines (IL-6, IL-1b, TNFa, IL-6+TNFa) showed that the main inducer of LCN-2 was IL-1β. Conclusions: Single dose liver irradiation, induces a fast and significant increase of LCN-2 serum level. Hepatocytes are the major producers of LCN-2 in oxidative stress conditions. LCN-2 may represent a new serum-biomarker when the liver is hit by irradiation.
Significance of Conducting 2 Types of Fecal Tests in Patients With Ulcerative Colitis
Authors: Makoto Naganuma, Taku Kobayashi, Masanao Nasuno, Satoshi Motoya, Shingo Kato, Katsuyoshi Matsuoka, Ryota Hokari, Chikako Watanabe, Hirotsugu Sakamoto, Hironori Yamamoto, Makoto Sasaki, Kenji Watanabe, Hideki Iijima, Yutaka Endo, Hitoshi Ichikawa, Keiji Ozeki, Satoshi Tanida, Nobuhiro Ueno, Mikihiro Fujiya, Minako Sako, Ken Takeuchi, Shinya Sugimoto, Takayuki Abe, Toshifumi Hibi, Yasuo Suzuki, Takanori Kanai
Journal: Clinical Gastroenterology and Hepatology (2019)

We compared the diagnostic accuracy of the fecal calprotectin (FCP) test vs the fecal immunochemical blood test (FIT) in determining the endoscopic severity and predicting outcomes of patients with ulcerative colitis (UC).We performed a nationwide study of 879 patients with UC, enrolled at medical centers across Japan, from March 2015 to March 2017. We collected data on fecal biomarkers, endoscopic severities, and other clinical indices from Cohort 1 (n = 427) and assessed the diagnostic accuracy of FCP measurement and FIT results in determining clinical severity, based on Mayo score, and endoscopic remission, based on Mayo endoscopic sub-score (MES) or UC endoscopic index of severity. We also followed 452 patients in clinical remission from UC (Cohort 2) for 12 months and evaluated the associations of FCP levels and FIT results with clinical recurrence.The levels of FCP and FIT each correlated with the MES and UC endoscopic index of severity. There were no significant differences in the areas under the curve of FCP vs FIT in distinguishing patients with MES≤1 from those with MES≥2 (P = .394) or in distinguishing patients with MES=0 from those with MES≥1 (P = .178). Among 405 patients in clinical remission at baseline, 38 (9.4%) had UC recurrences within 3 months and 90 (22.2%) had recurrences within 12 months. FCP≥146 mg/kg (hazard ratio [HR], 4.83; 95% confidence interval [CI], 2.80-8.33) and FIT≥77 ng/mL (HR, 2.92; 95% CI, 1.76-4.83) were independently associated with clinical recurrence within 12 months. UC recurred within 12 months in 69% of patients with levels of FCP≥146 mg/kg and FIT ≥77 ng/mL; this value was significantly higher than the rate of recurrence in patients with levels of FCP≥146 mg/kg and FIT <77 ng/mL (31.5%, P < .001) or patients with levels of FCP<146 mg/kg and FIT ≥77 ng/mL (30.0%, P < .001).In a nationwide study of patients with UC in Japan, we found that the level of FCP and FIT could each identify patients with endoscopic markers of disease severity (MES≥2). The combination of FCP and FIT results can identify patients in remission who are at risk for disease recurrence. Clinical Trials Registry no: UMIN000017650 (http://www.umin.ac.jp/ctr/).
TDP-43 regulates early-phase insulin secretion via CaV1.2-mediated exocytosis in islets
Authors: Kunihiko Araki, Amane Araki, Daiyu Honda, Takako Izumoto, Atsushi Hashizume, Yasuhiro Hijikata, Shinichiro Yamada, Yohei Iguchi, Akitoshi Hara, Kazuhiro Ikumi, Kaori Kawai, Shinsuke Ishigaki, Yoko Nakamichi, Shin Tsunekawa, Yusuke Seino, Akiko Yamamoto, Yasunori Takayama, Shihomi Hidaka, Makoto Tominaga, Mica Ohara-Imaizumi, Atsushi Suzuki, Hiroshi Ishiguro, Atsushi Enomoto, Mari Yoshida, Hiroshi Arima, Shin-ichi Muramatsu, Gen Sobue, Masahisa Katsuno
Journal: Journal of Clinical Investigation (2019)

TAR DNA-binding protein 43 kDa (TDP-43), encoded by TARDBP, is an RNA-binding protein, the nuclear depletion of which is the histopathological hallmark of amyotrophic lateral sclerosis (ALS), a fatal neurodegenerative disorder affecting both upper and lower motor neurons. Besides motor symptoms, patients with ALS often develop nonneuronal signs including glucose intolerance, but the underlying pathomechanism is still controversial, i.e., whether it is impaired insulin secretion and/or insulin resistance. Here, we showed that ALS subjects reduced early-phase insulin secretion and that the nuclear localization of TDP-43 was lost in the islets of autopsied ALS pancreas. Loss of TDP-43 inhibited exocytosis by downregulating CaV1.2 calcium channels, thereby reducing early-phase insulin secretion in a cultured β cell line (MIN6) and β cell-specific Tardbp knockout mice. Overexpression of CaV1.2 restored early-phase insulin secretion in Tardbp knocked-down MIN6 cells. Our findings suggest that TDP-43 regulates cellular exocytosis mediated by L-type voltage-dependent calcium channels and thus plays an important role in the early phase of insulin secretion by pancreatic islets. Thus, nuclear loss of TDP-43 is implicated in not only the selective loss of motor neurons but also in glucose intolerance due to impaired insulin secretion at an early stage of ALS.