tbuckley/cabot-search huggingface dataset:
Preclinical safety testing of an affinity-optimised MAGE-A10 T cell receptor for adoptive T cell therapy
Authors: Andrew Gerry, Joseph Sanderson, Manoj Saini, Barbara Tavano, Roslin Docta, Nicholas Pumphrey, Miguel Maroto, Ellen Border, Alan Bennett, Gwendolyn Binder-Scholl, Tom Holdich, Lini Pandite, Rafael Amado, Bent Jakobsen
Journal: Journal for ImmunoTherapy of Cancer (2015)

Meeting abstracts Preclinical safety testing for adoptive immunotherapies utilising T cell receptor-(TCR) engineered T cells relies on stringent target validation and a robust pre-clinical specificity testing strategy. Specific safety concerns include on-target off-tumour toxicity and off-target
Topical resiquimod can induce disease regression and enhance T-cell effector functions in cutaneous T-cell lymphoma
Authors: Alain H. Rook, Joel M. Gelfand, Maria Wysocka, Andrea B. Troxel, Bernice Benoit, Christian Surber, Rosalie Elenitsas, Marie A. Buchanan, Deborah S. Leahy, Rei Watanabe, Ilan R. Kirsch, Ellen J. Kim, Rachael A. Clark
Journal: Blood (2015)
Abstract 19387: Targeted Deletion of Mmp9 Mitigates Autophagy Mediated Contractile Dysfunction in Insulin2 Mutant Diabetic Mice
Authors: Paras Kumar Mishra, Vishalakshi Chavali, Naira Metreveli, Suresh C Tyagi
Journal: Circulation (2012)

Insulin mediated activation of MMP9 and myocardial autophagy fosters pathological cardiac remodeling, and targeted deletion of MMP9 improves contractility. We hypothesize that ablation of MMP9 mitigates autophagy mediated contractile dysfunction in diabetes. To test the hypothesis, we created Ins2+/- /MMP9-/- mice, where MMP9 gene is deleted from diabetic Ins2+/-. We measured the levels of LC3B-II and Atg3 (autophagy markers) in C57BL/6J, Ins2+/- and Ins2+/- /MMP9-/- hearts. The results revealed induction of both LC3B-II and Atg3 in Ins2+/-, which is mitigated in Ins2+/-/MMP9-/- (fold change in C57BL/6J, Ins2+/-, Ins2+/- /MMP9-/- for LC3B-II: 1; 4.5 ±0.3, 3.0± 0.2, and Atg3: 1, 2.5±0.2, 1±0.3, respectively). The down regulation of autophagy in Ins2+/-/MMP9-/- suggests that targeted deletion of MMP9 attenuates autophagy in diabetes. To assess the specific role of autophagy in contractility, we administered Mdivi-1 (autophagy blocker) into C57BL/6J (control) and Ins2+/- mice (50mg/Kg, i.p) for 7 days and determined the improvement in contractility (±dL/dt) of cardiomyocytes by Ion-Optics device. We found no significant difference in the rate of contraction (dL/dt) and relaxation (-dL/dt) in C57BL/6J untreated (dL/dt=160±13 and -dL/dt= -165± 15) and treated (dL/dt= 170±20 and -dL/dt= -165± 21) groups. However, there was significant improvement in ±dL/dt in Ins2+/- (untreated: dL/dt=100±10 and -dL/dt= -95± 12) and treated (dL/dt= 185± 17 and -dL/dt= -180± 14). These elicit a novel regulatory role of MMP9 in autophagy in diabetes. It also suggests that inhibition of autophagy improves contractility in diabetic hearts. In conclusion, targeted deletion of MMP9 mitigates autophagy mediated contractile dysfunction in diabetes.
Incorporating High-Dose IV Methotrexate Into Initial Therapy Results In Lower Rates Of Central Nervous System (CNS) Relapse In Patients With High-Risk Diffuse Large B-Cell Lymphoma (DLBCL)
Authors: Chan Y Cheah, Kirsten Herbert, Kacey O'Rourke, Glen Kennedy, Anupkumar George, Pasquale Fedele, Shuh Ying Tan, Stephen Opat, Kate Burbury, Max Wolf, Elchanan H. Januszewicz, Michael J. Dickinson, David A Westerman, H. Miles Prince, Dennis A Carney, Simon J. Harrison, Constantine S. Tam, John F Seymour
Journal: Blood (2013)
A phase II study of gemcitabine (G) and capecitabine (C) in patients with metastatic renal cell cancer (mRCC): A report of Cancer and Leukemia Group B #90008
Authors: W. M. Stadler, S. Halabi, M. S. Ernstoff, R. Barrier, E. Davila, J. Picus, E. J. Small
Journal: Journal of Clinical Oncology (2004)

4515 Background: Low but consistent responses have been observed in mRCC patients (pts) treated with 5FU, G, or the combination. A phase II multi-center study to assess the activity of G plus the oral 5FU analog C was thus conducted. Methods: Pts with adequate performance status (PS), normal organ function, measurable disease, and no prior nucleoside analog therapy were treated with G at 1000 mg/m2 day 1, 8, 15 and C at 830 mg/m2 twice daily, days 1–21 on a 28 day cycle. Dose reductions for estimated creatinine clearance of 30–50 ml/min, hand/foot syndrome, myelosuppression, hepatic toxicity, and gastrointestinal toxicity were specified. A null hypothesis of a 5% response rate versus an alternative of 15% was assumed, with type I and type II error rates of 7% and 14%, respectively. Results: Sixty pts from 18 institutions were accrued over 19 weeks. In 55 pts with complete data, characteristics included PS 0/1/2 in 20/27/8, prior nephrectomy in 45, prior systemic therapy in 42, greater than 2 metastatic sites in 23, median and interquartile hemoglobin of 12.4 (10.3 –14.5) g/dl. Partial responses were observed in 8 out of 55 pts for a response rate of 15% (95% CI: 7 –27%). Median duration of response was 7.1 (4.0 –7.1) months (mo). Median time to progression was 5.1 (3.2 –7.8) mo. With a median follow-up of 5.5 mo, median survival has not been reached. Grade 3,4 toxicities included neutropenia (40%) with febrile neutropenia in 1 pt, anemia (15%), thrombocytopenia (6%), nausea (11%), fatigue (7%), diarrhea (7%), and hand/foot syndrome and stomatitis (2% each). Grade 1,2 toxicities included leukopenia (49%), fatigue (62%), nausea (42%), stomatitis (29%), diarrhea (27%), and hand/foot syndrome (36%). Conclusions: GC has modest activity in mRCC and met the protocol specified level of activity for further evaluation. Toxicity suggests that additional study of this regimen would require a dose modification. Author Disclosure Employment or Leadership Consultant or Advisory Stock Ownership Honoraria Research Funding Expert Testimony Other Remuneration Lilly Lilly
ヒストンデメチラーゼJMJD1Aの阻害により,抗脈管形成療法が向上し,腫瘍関連マクロファージが減少する
Authors: Osawa Tsuyoshi, Tsuchida Rika, Muramatsu Masashi, Shimamura Teppei, Wang Feng, Suehiro Jun-ichi, Kanki Yasuharu, Wada Youichiro, Yuasa Yasuhito, Aburatani Hiroyuki, Miyano Satoru, Minami Takashi, Kodama Tatsuhiko, Shibuya Masabumi
Journal: Cancer Research (2013)
Both EphA2 and EphA1 are sufficient in mediating suppression of Erk activity in MEFs
Authors: Jarnail Singh, Emhonta Johnson, Bingcheng Wang
Journal: Cancer Research (2005)

4496  Eph receptors are the largest family of membrane bound receptor tyrosine kinases (RTKs) that have been implicated in various developmental processes as well as tumorigenesis. But the role of Eph kinases in tumor progression is controversial since on one hand it has been shown to inhibit or attenuate growth factors dependent MAPK activity and on the other hand, they are overexpressed and in some cases mutated in various types of tumors. However, in contrast to other RTKs, activation of Eph receptors fails to promote cell proliferation, or to transform rodent fibroblasts, indicating that Eph kinases may initiate signaling pathways that are distinct from those transmitted by other RTKs. We have previously reported that activation of EphA kinases by their ligand ephrinA1 inhibits the ras/Erk signaling cascade(Nature Cell Biology;3;p527). To characterize further regarding which EphA kinase/s are involved in this regulation, we established primary mouse embryonic fibroblasts (MEFs) from the EphA2 knock out (KO) mice. Here we show that disruption of EphA2 abolishes the inhibitory effect of ephrinA1 on Erk1/2 activity. More importantly, restoration of EphA2 expression rescued the inhibitory effect of ephrinA1 on Erk1/2 activity. In addition, deletion and site directed mutation analysis revealed that catalytic activity of kinase domain of EphA2 is required for Erk1/2 inhibition. Furthermore, we demonstrate that ephrinA1 is also capable of mediating EphA1 activation induced Erk1/2 inhibition. In summary, our data establishes that EphA1 and EphA2 are sufficient in mediating suppression of Erk1/2 activity in MEFs, and suggest that this activation of EphA kinases can be attractive targets for cancer therapy.
Ebola outbreak in west Africa is officially over
Authors: Anne Gulland
Journal: BMJ (2016)

The World Health Organization has declared the outbreak of Ebola virus disease in west Africa officially over, more than two years after it began.

Liberia is the last of the three west African countries worst affected by the virus to mark 42 days since the last patient tested negative for the disease. Liberia was first declared free of the virus in May 2015 but has had two flare ups of the virus since then. Sierra Leone was declared free of transmission on 7 November last year, and Guinea was declared free …
Breast cancer and neuroendocrine tumor can pose a diagnostic challenge
Authors: G. Lopes, L. Negret, G. Fernandez, M. Jorda, J. Hurley, J. Powell, O. Silva
Journal: Journal of Clinical Oncology (2004)

868 Background: Neuroendocrine differentiation of breast carcinomas has been well described, but its clinical significance is still unclear. The classical presentation is an isolated breast mass that histologically resembles a neuroendocrine tumor (NET) but stains as a breast carcinoma. Rarely, presentation consists of metastatic disease without a palpable breast mass. Also, NET may metastasize to the breast. Methods: Case series Results: We report four cases of patients with unusual presentations of breast cancer and NET. Two of the patients were initially misdiagnosed with widespread NET based on histologic appearance. Neither woman had a palpable breast mass on presentation. Both were later determined to have metastatic breast cancer by immunohistochemistry (IH). Another patient, intially diagnosed with metastatic breast cancer, was determined instead to have both a locally advanced breast cancer and a primary pulmonary NET. Finally, a fourth patient with a breast mass was ultimately diagnosed with a primary NET metastatic to the breast. Discussion: The pathologic presentations of NET involving the breast are diverse. Undifferentiated small cell carcinomas, carcinoid tumors, and invasive ductal and lobular carcinomas with neuroendocrine differentiation have all been reported. Papotti et al described seven different types on a review of 43 cases. Moreover, in a review of 81 cases of adenocarcinoma of the breast, Yao et al described the presence of neuroendocrine cells and hormone products in 21% and 17.6% of the samples, respectively. Among the patients reported with metastatic carcinoma of the breast with neuroendocrine differentiation, most have been treated with breast cancer directed therapy. In one case, the patient was treated with both octreotide and tamoxifen. Conclusion: The cases we describe reveal a potential diagnostic challenge between NET and breast cancer with neuroendocrine differentiation. To clarify the diagnosis, women presenting with “metastatic NET” should be considered for the possibility of breast cancer. This work-up should include IH staining for ER, PR, and Her-2-Neu. Making this distinction has major prognostic and therapeutic implications. No significant financial relationships to disclose.
Novel (Hetero)arylalkenyl propargylamine compounds are protective in toxin-induced models of Parkinson’s disease
Authors: Mária Baranyi, Pier Francesca Porceddu, Flóra Gölöncsér, Szabina Kulcsár, Lilla Otrokocsi, Ágnes Kittel, Annalisa Pinna, Lucia Frau, Paul B. Huleatt, Mui-Ling Khoo, Christina L. L. Chai, Petra Dunkel, Peter Mátyus, Micaela Morelli, Beáta Sperlágh
Journal: Molecular Neurodegeneration (2016)

Mitochondrial dysfunction, oxidative stress and their interplay are core pathological features of Parkinson's disease. In dopaminergic neurons, monoamines and their metabolites provide an additional source of reactive free radicals during their breakdown by monoamine oxidase or auto-oxidation. Moreover, mitochondrial dysfunction and oxidative stress have a supraadditive impact on the pathological, cytoplasmic accumulation of dopamine and its subsequent release. Here we report the effects of a novel series of potent and selective MAO-B inhibitory (hetero)arylalkenylpropargylamine compounds having protective properties against the supraadditive effect of mitochondrial dysfunction and oxidative stress. The (hetero)arylalkenylpropargylamines were tested in vitro, on acute rat striatal slices, pretreated with the complex I inhibitor rotenone and in vivo, using the 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) induced acute, subchronic, and chronic experimental models of Parkinson's disease in mice. The compounds exhibited consistent protective effects against i) in vitro oxidative stress induced pathological dopamine release and the formation of toxic dopamine quinone in the rat striatum and rescued tyrosine hydroxylase positive neurons in the substantia nigra after rotenone treatment; ii) in vivo MPTP-induced striatal dopamine depletion and motor dysfunction in mice using acute and subchronic, delayed application protocols. One compound (SZV558) was also examined and proved to be protective in a chronic mouse model of MPTP plus probenecid (MPTPp) administration, which induces a progressive loss of nigrostriatal dopaminergic neurons. Simultaneous inhibition of MAO-B and oxidative stress induced pathological dopamine release by the novel propargylamines is protective in animal models and seems a plausible strategy to combat Parkinson's disease.
Interstitial renal fibrosis due to multiple cisplatin treatments is ameliorated by semicarbazide-sensitive amine oxidase inhibition
Authors: Daisuke Katagiri, Yoshifumi Hamasaki, Kent Doi, Kousuke Negishi, Takeshi Sugaya, Masaomi Nangaku, Eisei Noiri
Journal: Kidney International (2015)

Elucidation of acute kidney diseases and disorders (AKD), including acute kidney injury (AKI), is important to prevent their progression to chronic kidney disease. Current animal AKI models are often too severe for use in evaluating human AKI. Therefore, new animal models of mild kidney injury are needed. Here a new clinically relevant animal model using multiple low doses of cisplatin (CP) was used to evaluate AKD. When 10 mg/kg CP was administered intraperitoneally once weekly for three times to L-type fatty acid-binding protein (L-FABP) transgenic mice, moderate renal interstitial fibrosis and tubule dilatation occurred, accompanied by brush-border loss. Urinary L-FABP, a promising biomarker of AKI, changed more drastically than blood urea nitrogen or creatinine. Preventing fibrosis in organs was also studied. Oral administration of a recently reported selective semicarbazide-sensitive amine oxidase inhibitor, PXS-4728A, for 1 week attenuated kidney injury and interstitial fibrosis compared with vehicle. Inhibition of renal lipid accumulation in semicarbazide-sensitive amine oxidase inhibitor-treated mice, together with reduced oxidative stress and L-FABP suppression in proximal tubules, suggested an antifibrotic effect of semicarbazide-sensitive amine oxidase inhibition in this CP-AKD model, a representative onco-nephrology. Thus, semicarbazide-sensitive amine oxidase inhibitors may be promising candidates for the prevention of chronic kidney disease in patients using CP to treat malignancy.
The Four-Arm Cooperative Study (FACS) for advanced non-small-cell lung cancer (NSCLC)
Authors: K. Kubota, Y. Nishiwaki, Y. Ohashi, N. Saijo, Y. Ohe, T. Tamura, S. Negoro, Y. Ariyoshi, K. Nakagawa, M. Fukuoka
Journal: Journal of Clinical Oncology (2004)

7006 Background: Platinum-containing regimens are the standard treatment for patients with advanced NSCLC. The purpose of FACS was to compare 3 platinum-based combination regimens with cisplatin (80mg/m2, day 1) plus irinotecan (60mg/m2, days 1, 8, 15) (IP, q4wks) as the reference arm. Methods: The experimental regimens included carboplatin (AUC 6, day 1) plus paclitaxel (200mg/m2, day 1) (TC, q3wks); cisplatin (80mg/m2, day 1) plus gemcitabine (1000mg/m2, day 1, 8) (GP, q3wks); cisplatin (80mg/m2, day 1) plus vinorelbine (25mg/m2, day 1, 8) (NP, q3wks). Sample size (n=600) was calculated based on non-inferiority study design. The estimated 1-year survival rate of the reference arm was 43% and the lower-side equivalence limit for 1-year survival rate was -10%. Each patient (pt) had to fulfill the following criteria: histologically and/or cytologically documented NSCLC, clinical stage IV or IIIB (malignant pleural effusion and/or metastasis in the same lobe), ECOG PS 0 or 1, age from 20 to 74 years, no prior chemotherapy, measurable lesion, adequate organ functions. Results: Between Oct. 2000 and June 2002, 602 pts were registered from 44 hospitals in Japan. Twenty-one pts were not eligible or evaluable and 581 pts were fully assessable (full analysis set; FAS). Pt demographics were well balanced across arms. Conclusions: Non-inferiority of the 3 experimental regimens compared with IP was not demonstrated in the analysis of FAS. One-year survival rate of 59.2% in the reference arm was higher than expected. Quality of life and second-line treatment data will be presented at 2004 ASCO. Author Disclosure Employment or Leadership Consultant or Advisory Stock Ownership Honoraria Research Funding Expert Testimony Other Remuneration Bristol Pharmaceuticals Y.K.; Eli Lilly Japan K.K.; Kyowa Hakko Kogyo Co.,LTD
Abstract 16938: Transcriptional Repression of Protein Kinase G during Ischemic-Reperfusion Injury in Stem Cells is Restored by Inhibition of Phosphodiesterase 5A with Long Acting Tadalafil
Authors: sanjay kumar, Motoi Okada, Wei Huang, Ibrahim Elmadbouh, W. Clark Bacon, Yi-Gang Wang, Muhammad Ashraf
Journal: Circulation (2012)

Background: PDE5A activity increases during ischemic reperfusion (IR) injury with concomitantly breakdown of cGMP and PKG deactivation. Pharmacological preconditioning with tadalafil, a PDE5A inhib...
Phase III study of standard triweekly versus dose-dense biweekly capecitabine (C) + oxaliplatin (O) + bevacizumab (B) as first-line treatment for metastatic colorectal cancer (mCRC): XELOX-A-DVS (dense versus standard): Interim analysis
Authors: H. Hurwitz, Y. Z. Patt, D. Henry, L. Garbo, E. P. Mitchell, J. Kohles, D. Spigel
Journal: Journal of Clinical Oncology (2009)

4078 Background: Every 3 week (Q3W) COB has been shown to be highly active and non-inferior to FOLFOX+B in first-line mCRC. Phase II data suggest that dose-dense every 2 week (Q2W) COB may be significantly more active and better tolerated than Q3W COB. Methods: XELOXA-DVS was a phase III, open-label study of 435 patients with chemonaive mCRC who met standard eligibility criteria. Patients were randomized to Q3W: C 850 mg/m 2 BID d1–14 + O 130 mg/m 2 d1 + B 7.5 mg/kg d1 or Q2W: C 1500 mg/m 2 BID d1–7 + O 85 mg/m 2 d1 + B 5 mg/kg d1 for up to 72 weeks. Complete surgical resection was allowed using pre-defined criteria. The primary endpoint, progression-free survival (PFS), was estimated using the Kaplan- Meier method, while the hazard ratio and 95% CI were estimated using Cox regression analysis, based on the intent-to-treat population. No formal statistical testing was conducted. Results: The median PFS was 8.4 months (Q2W) and 9.7 months (Q3W) (hazard ratio [HR]=0.84; 95% CI=0.62–1.13). The median PFS (on-treatment) was 9.1 months and 10.2 months, respectively (HR=0.81). Of the 72 and 73 patients with disease progression (DP), the median time to DP was 9.4 and 10.8 months, respectively (HR=0.86). The objective response rates were 21.7% vs 29.4%, respectively (HR=1.05). Patients in the Q2W vs Q3W group experienced higher rates of grade 3/4 diarrhea (29% vs 24%), hand-foot syndrome (12% vs 8%), and treatment discontinuation rates (40% vs 20%), respectively. Other grade 3/4 toxicities (&gt;5%, Q2W vs Q3W) included fatigue (13% vs 13%), dehydration (12% vs 10%), nausea (8% vs 9%), peripheral neuropathy (5% vs 9%), anorexia (5% vs 7%), and abdominal pain (5% vs 7%). Conclusions: At the dose and schedule used, dose-dense Q2W COB was not superior to standard Q3W COB. These data further confirm the activity and tolerability of Q3W COB. The activity and tolerability of a lower C dose Q2W, with more aggressive dose reduction, combined with B and O or irinotecan is currently being evaluated (X-BIO). [Table: see text]
25-Hydroxyvitamin D in Patients With Cognitive Decline—Reply
Authors: Joshua W. Miller, Ralph Green, Charles DeCarli
Journal: JAMA Neurology (2016)

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Hip pain after a fall
Authors: Michael P Barrett, Stephen M McDonnell
Journal: BMJ (2015)

<h3>Abstract</h3> <h3>Background</h3> Early and proper diagnosis of laryngeal lesions is necessary to begin treatment of the patient as soon as possible with the possibility of preserve organ functions. Imaging examinations are oft aided by artificial intelligence (AI) to improve quality and facilitate appropriate diagnosis. The aim of the study is to investigate of the diagnostic utility of AI in laryngeal endoscopy. <h3>Methods</h3> Five electronic databases (PubMed, Embase, Cochrane, Scopus, Web of Science) were searched for studies published before October 15, 2021 implementing artificial intelligence (AI) enhanced models assessing images of laryngeal lesions taken during laryngeal endoscopy. Outcomes were analyzed in terms of accuracy, sensitivity and specificity. <h3>Results</h3> All 13 included studies presented overall low risk of bias. The overall accuracy of AI models was very high (from 0.806 to 0.997) and the number of images used to build and evaluate the models ranged from 120 to 24,667. The accuracy was significantly higher in studies using larger database. The pooled sensitivity and specificity for identification of healthy laryngeal tissue (8 studies) was 0.91 (95% CI: 0.83-0.98) and 0.97 (95% CI: 0.96-0.99), respectively. The same values for differentiation between benign and malignant lesions (7 studies) were 0.91 (95% CI: 0.86-0.96) and 0.95 (95% CI: 0.90-0.99), respectively. The analysis was extended to a comparison of sensitivity and specificity of AI models assessing Narrow Band Imaging (3 studies) and white light endoscopy images (4 studies). The results were similar for both methods, no subgroup effect was revealed (p = 0.406 for sensitivity and p = 0.817 for specificity). <h3>Conclusions</h3> In assessing images of laryngeal lesions, AI demonstrates extraordinarily high accuracy, sensitivity, and specificity. AI enhanced diagnostic tools should be introduced into everyday clinical work. The performance of AI diagnoses increases efficacy with the size of the image database when using similar standards for evaluating images. The multicentre cooperation should concentrate on creation of huge database of laryngeal lesions images and implement their sharing, which allows building AI modes with the best performance, based on vast amount of images for learning and testing.