tbuckley/cabot-search huggingface dataset:
Identification of potentially targetable kinases by concurrent high-throughput functional kinomics and RNA-sequencing (seq) of muscle-invasive bladder cancer (MIBC).
Authors: Christopher Douglas Willey, Michael Crowley, Dongquan Chen, Joshua Anderson, Okechukwu Nwakile Mgbemena, David Crossman, Gurudatta Naik, William E. Grizzle, Guru Sonpavde
Journal: Journal of Clinical Oncology (2014)

4553 Background: Interrogation of kinases in tumor and matched normal tissue by concurrent kinomic activity profiling and RNA-seq might identify the most relevant kinases and inform the development of agents for MIBC. We report the first such analysis followed by supportive analysis of the TCGA (The Cancer Genome Atlas). Methods: We performed kinomic profiling and RNA-seq of frozen tumor samples and matched adjacent normal bladder from 6 pts with MIBC. Kinomic profiling was performed using the PamStation 12 high-content phosphopeptide substrate microarray system (PamGene International). Protein tyrosine and serine/threonine kinome PamChips were used to measure global kinase activity by detecting phosphorylation of peptide substrates through FITC-labeled antibodies. Upstream kinase prediction was determined by a scoring algorithm derived from the phosphonet database. RNA-seq libraries were prepared using standard techniques and were sequenced on the Illumina HiSeq2000 platform. RNA-seq of kinases from 59 pts with MIBC and complete pathologic staging information were compared with 16 normal bladder controls from TCGA. Pathway analysis was conducted for kinases with gene expression changes concordant between the TCGA dataset and the 6 UAB pts. Results: Kinomic activity profiling identified increased tumor (vs. matched normal) kinase activity corresponding to BRK, FAK, PYK2, ZAP70 and CTK target peptides. Interestingly, kinase gene expression showed no concordance with activity. Among 529 kinase genes, 124 genes were significantly altered in tumor v. matched normal, of which 28 overlapped with the TCGA dataset. The top 5 up-regulated tumor kinases from both sets were CIT, CDK4, PRKD2, IKBKE, and EPHB2. Pathway analysis revealed significant involvement of post-translational modification and survival signaling. Conclusions: Comprehensive kinase analyses of MIBC using kinomic activity profiling and RNA-seq identified multiple potential therapeutic targets. Preclinical validation of agents targeting these kinases and pathways is warranted and will facilitate integration of kinomic and transcriptomic data.
The Puzzle of Huntington Disease Phenocopies
Authors: Nicolas Dupré, Guy Rouleau
Journal: JAMA Neurology (2016)

Our website uses cookies to enhance your experience. By continuing to use our site, or clicking "Continue," you are agreeing to our Cookie Policy | Continue JAMA Neurology HomeNew OnlineCurrent IssueFor Authors Podcast Publications JAMA JAMA Network Open JAMA Cardiology JAMA Dermatology JAMA Health Forum JAMA Internal Medicine JAMA Neurology JAMA Oncology JAMA Ophthalmology JAMA Otolaryngology–Head & Neck Surgery JAMA Pediatrics JAMA Psychiatry JAMA Surgery Archives of Neurology & Psychiatry (1919-1959) JN Learning / CMESubscribeJobsInstitutions / LibrariansReprints & Permissions Terms of Use | Privacy Policy | Accessibility Statement 2023 American Medical Association. All Rights Reserved Search All JAMA JAMA Network Open JAMA Cardiology JAMA Dermatology JAMA Forum Archive JAMA Health Forum JAMA Internal Medicine JAMA Neurology JAMA Oncology JAMA Ophthalmology JAMA Otolaryngology–Head & Neck Surgery JAMA Pediatrics JAMA Psychiatry JAMA Surgery Archives of Neurology & Psychiatry Input Search Term Sign In Individual Sign In Sign inCreate an Account Access through your institution Sign In Purchase Options: Buy this article Rent this article Subscribe to the JAMA Neurology journal
Pathological complete response (pCR) rates after carboplatin-containing neoadjuvant chemotherapy in patients with germline <i>BRCA</i> (g<i>BRCA</i>) mutation and triple-negative breast cancer (TNBC): Results from GeparSixto.
Authors: Gunter Von Minckwitz, Eric Hahnen, Peter A. Fasching, Jan Hauke, Andreas Schneeweiss, Christoph Salat, Mahdi Rezai, Jens U. Blohmer, Dirk Michael Zahm, Christian Jackisch, Bernd Gerber, Peter Klare, Sherko Kummel, Holger Eidtmann, Stefan Paepke, Valentina Nekljudova, Sibylle Loibl, Michael Untch, Rita K. Schmutzler
Journal: Journal of Clinical Oncology (2014)

1005 Background: We previously showed in participants with TNBC of the neoadjuvant phase II GeparSixto study (NCT01426880) that the addition of carboplatin can substantially improve the pCR rates from 36.9% with weekly paclitaxel/non-pegylated liposomal doxorubicin (PM) to 53.2% with PM plus weekly carboplatin (AUC2) (PMCb) (von Minckwitz et al, Proc ASCO 2013). We aimed to assess how far this benefit is correlated with gBRCA mutation or with a family history for breast or ovarian cancer. Methods: Full blood samples with sufficient amount of DNA were available in 295 (94%) out of 315 participants of GeparSixto with TNBC. We searched for gBRCA mutations by MLPA and Fluidigm screening for recurrent pathogenic BRCA1/2 alterations. In combination, both methods enable us to detect approximately 60% of all expected mutation carriers. Participants with so far undetected mutations are currently under investigation by employing next generation sequencing (NGS) techniques to detect additional pathogenic germline alterations in BRCA1/2 or other breast cancer predisposing genes. Results: At total of 38 mutation carriers (35 BRCA 1, 3 BRCA 2) have so far been identified (31 by central testing and 7 known results from local testing). Additional 78 patients have a known family breast cancer history. 179 patients have so far neither a mutation nor a family history. Overall pCR (ypT0 ypN0) rate increased from 40.2% in patients with no identified risk, to 44.9% in patients with family history only, to 57.9% for patients with gBRCA mutation. Adding carboplatin to PM increased the pCR rate by 14% (odds ratio, OR 1.79) in patients without increased risk, by 20% (OR 2.29) in patients with family history only, and by 25% (OR 2.75) for patients with gBRCA mutation. Conclusions: gBRCA mutation and family history are predictors for higher pCR rates after neoadjuvant anthracycline/taxane based chemotherapy in TNBC. Additive effect of carboplatin is most prominent in patients with gBRCA mutation. Updated results after complete gBRCA mutation analysis will be presented at the meeting. Clinical trial information: NCT 01426880.
Neoadjuvant <i>nab</i>-paclitaxel and gemcitabine (AG) in borderline resectable (BR) or unresectable (UR) locally advanced pancreatic adenocarcinoma (LAPC) in patients ineligible for FOLFIRINOX.
Authors: Shawn Peterson, Arturo Loaiza-Bonilla, Edgar Ben-Josef, Jeffrey A. Drebin, Colleen Westendorf-Overley, Lowell Brian Anthony, Philip A. DeSimone, Gaurav Goel, Mahesh R. Kudrimoti, Sean Patrick Dineen, Ching-Wei David Tzeng, Peter J Hosein
Journal: Journal of Clinical Oncology (2016)

328 Background: AG is superior to gemcitabine in patients with advanced pancreas cancer. There are limited data on the use of AG in BR or UR LAPC. Although FOLFIRINOX (5-fluorouracil, leucovorin, irinotecan and oxaliplatin) is an option for such patients, many are not eligible due to age, poor performance status (PS) or comorbidities. Herein, we report our experience with neoadjuvant AG for BR/UR LAPC in patients ineligible for FOLFIRINOX. Methods: In this retrospective series, we included patients with BR/UR LAPC who received neoadjuvant AG. The treatment algorithm included AG for 3-4 months followed by radiation, then re-evaluation for surgery. The published AG regimen doses were modified based on patient tolerance. The primary outcome measure was R0 resection rate. Secondary outcomes were response rate, tolerability, and overall survival (OS). Results: Between 10/2013-9/2015, 20 patients (14 BR, 6 UR) at two institutions were treated with this approach. Median age was 69 years (range 44-90); 11/20 were female; PS ranged from 0-3; 14 patients have completed therapy and 6 remain on treatment. Five were converted to resectability by imaging and subsequently underwent operation; 4 had R0 resections (29% of patients who have finished therapy). To date, 6 patients died from progressive disease (PD), 2 are alive with PD and 12 remain alive on therapy or surveillance. All patients who achieved R0 resections are alive and disease free. The best response to AG was a partial response in 4 patients (20%), stable disease in 11, and progression in 2 with 3 patients still pending re-evaluation. Mean dose intensity was 77% for AG. Toxicities were similar to the published AG regimen. Conclusions: In this small series, both the R0 resection rate and the response rate were at least 20%, despite frequent dose reductions and relatively low dose intensity. Elderly and/or poor PS patients with LAPC have been historically excluded from curative-intent strategies. Our data suggest that these patients may now have a possibility for cure with the use of neoadjuvant AG.
High pathologic response rate of hepatic colorectal cancer metastases (HCRM) following neoadjuvant bevacizumab (Bev)-based treatment (tx).
Authors: Filippo Pietrantonio, Jorgelina Clara Coppa, Rosalba Miceli, Massimo Milione, Federica Perrone, Giuseppe Fanetti, Cotsoglou Christian, Flavia Melotti, Maria Di Bartolomeo, Vincenzo Mazzaferro, Luigi Mariani, Alessio Pellegrinelli, Claudia Bertan, Pamela Biondani, Filippo G. De Braud
Journal: Journal of Clinical Oncology (2013)

529 Background: Pathologic response of HCRM to neoadjuvant tx is associated to better outcome. In retrospective analyses Bev-based tx improved tumor regression grade (TRG), while cetuximab (Cmab) increased RECIST response and R0 resections in prospective studies. The aim of this analysis was to assess the effect of Bev vs Cmab-based tx in terms of HCRM pathological response and outcome. Methods: Fifty-eight pts with HCRM were resected at National cancer Institute of Milan from 2007 to 2012 following Bev (n=30) or Cmab (n=28) based neoadjuvant tx. Pathological response was classified from TRG 1 for pathological complete response (pCR), to TRG5 for no response; TRG 1-3, for histological response; TRG 4-5 for scarce/no response (Rubbia-Brandt L, Ann Oncol 2007). Results: KRAS missing in 9 pts (3 Bev/6 Cmab), mutated in 18 pts (60%) in Bev vs 4 (14%) in Cmab group.Median number of resected metastases: 4.6 vs 3.9; mean TRG: 2.9 (2.2-4) in Bev vs 3.8 (3-5) in Cmab group (p=0.04 at Kruskal-Wallis test). Pathological response rate was higher for Bev vs Cmab (70% vs 39%; p=0.037 at Chi-square test). Bev also increased pCRs (20% vs 0%, p=0.024 at Fisher’s test). With generalized estimating equation for all resected nodules, mean TRG was lower in Bev vs Cmab group: 2.6 (2-4) vs 3.7 (3-4), p&lt;0.001. At univariate analysis, no PFS and OS difference was observed according to tx. Multivariable Cox models shown below: Conclusions: Bev-based tx obtained an excellent pathological response rate, despite the high proportion of KRAS mutated tumors, and further prospective confirmation of these data is planned. [Table: see text]
Communication and understanding of prognosis among stage IV lung and GI cancer patients
Authors: L. Lehmann, S. Shaykevich, J. C. Weeks
Journal: Journal of Clinical Oncology (2007)

9024 Background: Patients' understanding of prognosis is essential to informed decision making about treatment options. There is little data on what prognostic information oncologists communicate to patients and what patients actually understand about their prognosis. Methods: We audio taped consultations between 90 newly diagnosed stage IV non small cell lung cancer patients and stage IV GI cancer patients and medical oncologists at academic teaching hospitals. Interactions were audio taped until patients arrived at a treatment decision. Audiotapes were digitized, coded and analyzed using the RIAS system. All conversation relating to prognosis was blocked, coded and analyzed. After meeting with an oncologist patients were surveyed about their understanding of prognosis and desire for information about life expectancy. Results: 276 patients were contacted of whom 190 consented to participate. 87 patients were ineligible, 13 patients withdrew from the study, and complete data were obtained on 90 patients. The mean age of participants was 62 years (±11), 65% were women. Analysis of the audiotapes revealed that in 78% of cases oncologists told patients that their cancer was not curable. When patients were surveyed, however, only 32% of those who were told that their cancer was not curable actually understood that there was no cure for their cancer (CI 0.19–0.45). Patients’ age, gender, education, and marital status were not associated with an understanding of prognosis. Patient factors associated with understanding of prognosis included a desire for good and bad medical information (CI 0.75–0.99; p&lt;0.0001), an interest in knowing the likelihood that treatment would cure their disease (CI 0.54–0.94; p&lt;0.01), and a belief that information about life expectancy would influence their medical decisions (CI 0.56–0.94; p&lt;0.01). Conclusion: In a majority of cases oncologists actually told patients that their cancer is not curable. Most patients, however, did not understand what was communicated. Patients’ understanding of prognosis is determined not only by what oncologists communicate, but also by patients’ desire for prognostic information. No significant financial relationships to disclose.
Case of small intestinal double hit lymphoma forming cutaneous fistula between intestinal lumen in Western patients
Authors: Yasuko Miyahara, Chihiro Kojima, Akifumi Oba, Norihiro Kawabata, Yoshihito Horisawa, Yuta Goto, Masashi Matsui, Mitsuru Itoh
Journal: Annals of Oncology (2015)
Risk-Adapted Dosing of Melphalan for Systemic AL Amyloidosis (AL) Lowers Treatment-Related Mortality: Early Death but Not Post-3 Month Survival Is Linked to Cardiac Involvement.
Authors: Raymond L. Comenzo, Ping Zhou, Hani Hassoun, Tarun Kewalramani, Virginia Klimek, Adam D. Cohen, Susane K. Ferrand, Madhav Dhodapkar, Julie Teruya-Feldstein, Martin Fleisher, Stephen D. Nimer
Journal: Blood (2005)
Catastrophic Antiphospholipid Syndrome: Candidate Therapies for a Potentially Lethal Disease
Authors: Ozan Unlu, Doruk Erkan
Journal: Annual Review of Medicine (2017)

Catastrophic antiphospholipid syndrome (CAPS) is a potentially lethal disease that presents with rapidly progressive multiple organ thromboses. Anticoagulation, corticosteroids, intravenous immunoglobulin, and plasma exchange are the most commonly used treatments for CAPS patients. However, the high mortality despite these medications necessitates new treatment strategies. Following a brief review of current diagnostic and management strategies, we discuss the candidate therapies, i.e., hydroxychloroquine, rituximab, eculizumab, sirolimus, and defibrotide, that can be considered in CAPS patients refractory to traditional treatment.
Clustered cases of leptospirosis in Rochefort, France, June 2001
Authors: A Perra, V Servas, G Terrier, D Postic, G Baranton, G André-Fontaine, V Vaillant, I Capek
Journal: Eurosurveillance (2002)

Five clustered cases of leptospirosis were diagnosed in the area of Rochefort, France, in June 2001, among teenagers who had swum in the Genouillé canal. The symptoms included fever, headache, abdominal pain and vomiting, chills and myalgia. Three cases were confirmed by PCR and serology. The mean cumulative duration of bathing was significantly higher in cases (23.8 hours) compared to controls (14.4 hours). No other particular risk factor was observed. The environmental investigation revealed the presence of rodents excreting of leptospires near the bathing area. For all antigens considered, the occurence of seropositive rodents was 30.8%, L. icterohaemorrhagiae being the predominant serogroup (23,1%).
Canada’s new assisted dying law faces legal challenge
Authors: Owen Dyer
Journal: BMJ (2016)

After just 11 days Canada’s controversial new law on physician assisted dying has been challenged on constitutional grounds by a young woman with a degenerative wasting disease who is ineligible for assistance.

Julia Lamb, 25, the new face of the right-to-die movement in Canada, does not qualify for physician assistance in dying under the new legislation but would be eligible under the Supreme Court ruling that forced the government to draw up the legislation.

Canada’s …
Targeting CD26 with Humanized Monoclonal Antibody, As a Novel Approach to Inhibit Human Osteoclast Differentiation and Subsequent Bone Resorption
Authors: Hiroko Nishida, Hiroko Madokoro, Hiroshi Suzuki, Michiie Sakamoto, Chikao Morimoto, Taketo Yamada
Journal: Blood (2012)
Caloric Restriction Mimetics Enhance Anticancer Immunosurveillance
Authors: Federico Pietrocola, Jonathan Pol, Erika Vacchelli, Shuan Rao, David P. Enot, Elisa E. Baracco, Sarah Levesque, Francesca Castoldi, Nicolas Jacquelot, Takahiro Yamazaki, Laura Senovilla, Guillermo Marino, Fernando Aranda, Sylvère Durand, Valentina Sica, Alexis Chery, Sylvie Lachkar, Verena Sigl, Norma Bloy, Aitziber Buque, Simonetta Falzoni, Bernhard Ryffel, Lionel Apetoh, Francesco Di Virgilio, Frank Madeo, Maria Chiara Maiuri, Laurence Zitvogel, Beth Levine, Josef M. Penninger, Guido Kroemer
Journal: Cancer Cell (2016)
P2-012: Analysis of XPD gene Lys751Gln polymorphism as predisposing factor for non-small cell lung cancer (NSCLC) development
Authors: Amelia Szymanowska, Ewa Jassem, Sabine Zoechbauer-Mueller, Krzysztof Konopa, Witold Rzyman, Grazyna Kobierska-Gulida, Christoph C. Zielinski, Jacek Jassem
Journal: Journal of Thoracic Oncology (2007)
Complete human CD1a deficiency on Langerhans cells due to a rare point mutation in the coding sequence
Authors: Daniela Cerny, Duyen Huynh Thi Le, Trung Dinh The, Roland Zuest, Srinivasan KG, Sumathy Velumani, Chiea Chuen Khor, Lucia Mori, Cameron P. Simmons, Michael Poidinger, Francesca Zolezzi, Florent Ginhoux, Muzlifah Haniffa, Bridget Wills, Katja Fink
Journal: Journal of Allergy and Clinical Immunology (2016)
General hospitals and the severely mentally ill: changing patterns of diagnosis
Authors: M Olfson
Journal: American Journal of Psychiatry (1991)

The author's goal is to determine whether there has been a recent change in the number and proportion of severely ill psychiatric patients treated in general hospitals.He analyzed the discharge data from the National Hospital Discharge Survey for the years between 1970 and 1987, focusing particularly on the discharges of patients with psychiatric versus nonpsychiatric diagnoses. The number and proportion of discharges of patients with psychiatric diagnoses in four major diagnostic groups (depression, bipolar spectrum disorders, schizophrenia, and other psychoses) were determined.Between 1970 and 1987, discharges of patients with psychiatric diagnoses from general hospitals increased by a factor of 0.8. The percentage of discharges of patients with the diagnoses of depression (18.0%-22.7%), schizophrenia (9.4%-13.6%), and paranoid or other nonorganic psychoses (3.1%-4.0%) remained relatively constant. The percentage of discharges of patients with the diagnosis of nondepressed bipolar disorder increased from 0.6% in 1970 to 3.2% in 1987.Although there has been a recent absolute increase in the number of general hospital patients with severe psychiatric diagnoses, the increase has been tempered by a concomitant increase in the number of patients with nonsevere diagnoses. Changes in classification systems (DSM-II or ICDA-8 to DSM-III or ICD-9-CM) and questions regarding the rigor with which the nosologic changes have been incorporated into practice complicate the interpretation of these findings.
Gut microbiota translocation to the pancreatic lymph nodes triggers NOD2 activation and contributes to T1D onset
Authors: Frederico R.C. Costa, Marcela C.S. Françozo, Gabriela G. de Oliveira, Aline Ignacio, Angela Castoldi, Dario S. Zamboni, Simone G. Ramos, Niels O. Câmara, Marcel R. de Zoete, Noah W. Palm, Richard A. Flavell, João S. Silva, Daniela Carlos
Journal: The Journal of Experimental Medicine (2016)

Type 1 diabetes (T1D) is an autoimmune disease that is triggered by both genetic and environmental factors, resulting in the destruction of pancreatic β cells. The disruption of the intestinal epithelial barrier and consequent escape of microbial products may be one of these environmental triggers. However, the immune receptors that are activated in this context remain elusive. We show here that during streptozotocin (STZ)-induced T1D, the nucleotide-binding oligomerization domain containing 2 (NOD2), but not NOD1, participates in the pathogenesis of the disease by inducing T helper 1 (Th1) and Th17 cells in the pancreatic LNs (PLNs) and pancreas. Additionally, STZ-injected wild-type (WT) diabetic mice displayed an altered gut microbiota compared with vehicle-injected WT mice, together with the translocation of bacteria to the PLNs. Interestingly, WT mice treated with broad-spectrum antibiotics (Abx) were fully protected from STZ-induced T1D, which correlated with the abrogation of bacterial translocation to the PLNs. Notably, when Abx-treated STZ-injected WT mice received the NOD2 ligand muramyl dipeptide, both hyperglycemia and the proinflammatory immune response were restored. Our results demonstrate that the recognition of bacterial products by NOD2 inside the PLNs contributes to T1D development, establishing a new putative target for intervention during the early stages of the disease.
Real-world self-reported adherence to endocrine therapy in a large longitudinal cohort of breast cancer patients.
Authors: Raina Mahajan Ferzoco, Emily J. Hallberg, Sithara Vivek, Jodie A. Cogswell, Jamie L. Hinton, Patricia J. Marshman, Curtis L. Olswold, Matthew P. Goetz, Susan L. Slager, Janet E. Olson, Fergus J. Couch, Kathryn Jean Ruddy
Journal: Journal of Clinical Oncology (2015)

e20630 Background: Endocrine therapy plays an important role in the treatment of estrogen receptor (ER) -positive breast cancer. Multiple prior studies have shown poor adherence to oral endocrine treatment in part due to side effects. We aimed to assess adherence in a large cohort of breast cancer survivors seen at an academic institution. Methods: We surveyed survivors of breast cancer (at least 18 months after diagnosis), who had been seen at Mayo Clinic in Rochester, MN. Surveys included questions about endocrine therapies, adherence, and side effects. We analyzed rates and predictors of adherence amongst these survivors. Clinical data were collected via medical record review and from the Mayo Clinic Tumor Registry. Multivariate models were used to assess for predictors of adherence. High adherence was defined as responding “very consistently” to “How consistently did you take endocrine therapy while you were on it?“. Side effects were self-reported as present vs. absent. Results: 2105 breast cancer patients were surveyed, of whom1782 (85%) women responded. Median time since diagnosis was 3 years. 98% were white, and 50% had had mastectomy. 18% of tumors were Stage 0, 41% Stage I, 28% Stage II, 7% Stage III, 1% Stage IV, and 5% had missing stage. 65% took endocrine therapy. 86% of those taking tamoxifen, 96% taking letrozole, 89% taking exemestane, and 92% taking anastrozole reported being highly adherent. See Table 1 for frequency of side effects from each drug. In a multivariate analysis, patients with less pain had greater adherence to aromatase inhibitors (OR 0.39; 95% CI (0.16-0.96) p=0.032). We found no independent predictors of adherence to tamoxifen. Conclusions: Among women followed at a tertiary academic insitution,self- reported adherence rates were substantially higher than those currently in the literature. Recall bias or social desirability bias may have impacted these results. Percent of patients who had taken each drug who reported specific side effects related to the medication. Symptom Tamoxifen Letrozole Exemestane Anastrozole Hot flashes GI side effects Pain Weakness /Fatigue 79 7 37 45 48 15 58 50 47 13 56 46 53 15 63 53