tbuckley/cabot-search huggingface dataset:
Mechanisms of tolerance and potential therapeutic interventions in Alopecia Areata
Authors: Gabriel Skogberg, Sonya Jackson, Annika Åstrand
Journal: Pharmacology & Therapeutics (2017)

This review aims to address the mechanisms of compromised immune tolerance contributing to the development and maintenance of Alopecia Areata (AA). Our goal is to also highlight future treatment opportunities and therapeutics that will safely and efficiently restore hair growth and maintain patients in remission. AA is a presumptive autoimmune disorder that coincides and genetically clusters to several other autoimmune diseases. In this review, we pay attention to the learnings from the mechanistic research and drug development in these other autoimmune conditions. Interestingly, most of these diseases have been linked to compromised central and peripheral tolerance, and increased intestinal inflammation with enhanced gut permeability. Break of tolerance and priming of the autoreactive T-cells to attack antigenic epitopes in the hair follicle most likely requires several steps which include escape from negative selection and compromised peripheral tolerance. Local skin-related changes are also of importance due to the patchy manifestation of the skin areas with loss of hair, particularly in the early disease. Here, we discuss the defective mechanisms of tolerance, both central and peripheral, and hypothesize that the disease is driven by areas of tolerance break, and that these could be targeted for successful therapeutic interventions.
A first-in-human phase I study of the oral p38 MAPK inhibitor LY2228820 dimesylate in patients with advanced cancer.
Authors: Matthew P. Goetz, Anthony W. Tolcher, Paul Haluska, Kyriakos P. Papadopoulos, Charles Erlichman, Muralidhar Beeram, Janet Lensing, Drew Warren Rasco, Julian R. Molina, Rebecca Arcos, Peipei SHI, Palaniappan Kulanthaivel, Celine Pitou, Lynette Mulle, Edward Michael Chan, Amita Patnaik
Journal: Journal of Clinical Oncology (2012)

3001 Background: p38 MAPK regulates production of cytokines by the tumor microenvironment and its activation enables cancer cells to survive in the presence of oncogenic stress, radiation, chemotherapy, and targeted therapies. LY2228820 is a selective small-molecule inhibitor of p38 MAPK and preclinical studies demonstrate antitumor activity as a single agent and in combination with standard agents. We performed a phase I study to determine the maximum tolerated dose (MTD) and dose-limiting toxicity (DLT) of LY2228820 and to characterize its pharmacokinetics and pharmacodynamics. Methods: Dose escalation was performed in a 3+3 design. LY2228820 was taken orally every 12 hours on days 1-14 of a 28-day cycle. Results: 54 patients received either capsules at 8 dose levels (10, 20, 40, 65, 90, 120, 160, and 200mg) or tablets at 5 dose levels (160, 200, 300, 420, and 560mg). For both formulations, Cmax and AUC increased in a dose-dependent manner. LY2228820 inhibited p38 MAPK induced phosphorylation of MAPKAP-K2 in peripheral blood with dose-dependent maximum inhibition from 10 to 70% across the dose range 10-200mg. The most common drug-related adverse events included fatigue, nausea, rash, constipation, vomiting, and pruritus. 1 patient (200mg) had DLT of erythema multiforme (Gr3) and 2 patients (560mg) had DLT of ataxia (Gr3) and dizziness (Gr2), respectively. Although the MTD was 420mg, the frequency of Gr1/2 adverse events (mainly rash, dizziness, and tremor) and observation of clinical activity at lower dose levels led to a recommended dose of 300mg (mean AUC 0-24 = 11.7ug-hr/ml at steady state). Early clinical activity has been observed in ovary, breast, and kidney cancers. One patient with metastatic clear cell carcinoma of the kidney refractory to sorafenib, sunitinib, and temsirolimus had confirmed near partial response (29% decrease) after 8 cycles and remains on therapy. 15 patients (28%) achieved best overall response of stable disease, which in 12 patients (22%) was prolonged (≥4 cycles). Conclusions: LY2228820 demonstrates acceptable pharmacokinetics, safety, and early clinical activity as a single agent in advanced cancer. A phase II study for patients with ovary cancer is planned.
Expression of Five Neuroblastoma Genes in Bone Marrow or Blood of Patients with Relapsed/Refractory Neuroblastoma Provides a New Biomarker for Disease and Prognosis
Authors: Araz Marachelian, Judith G. Villablanca, Cathy W. Liu, Betty Liu, Fariba Goodarzian, Hollie A. Lai, Hiroyuki Shimada, Hung C. Tran, Jaime A. Parra, Richard Gallego, Nora Bedrossian, Sabrina Young, Scarlett Czarnecki, Rebekah Kennedy, Brian D. Weiss, Kelly Goldsmith, Meaghan Granger, Katherine K. Matthay, Susan Groshen, Shahab Asgharzadeh, Richard Sposto, Robert C. Seeger
Journal: Clinical Cancer Research (2017)

Purpose: We determined whether quantifying neuroblastoma-associated mRNAs (NB-mRNAs) in bone marrow and blood improves assessment of disease and prediction of disease progression in patients with relapsed/refractory neuroblastoma.Experimental Design: mRNA for CHGA, DCX, DDC, PHOX2B, and TH was quantified in bone marrow and blood from 101 patients concurrently with clinical disease evaluations. Correlation between NB-mRNA (delta cycle threshold, ΔCt, for the geometric mean of genes from the TaqMan Low Density Array NB5 assay) and morphologically defined tumor cell percentage in bone marrow, 123I-meta-iodobenzylguanidine (MIBG) Curie score, and CT/MRI-defined tumor longest diameter was determined. Time-dependent covariate Cox regression was used to analyze the relationship between ΔCt and progression-free survival (PFS).Results: NB-mRNA was detectable in 83% of bone marrow (185/223) and 63% (89/142) of blood specimens, and their ΔCt values were correlated (Spearman r = 0.67, P < 0.0001), although bone marrow Ct was 7.9 ± 0.5 Ct stronger than blood Ct When bone marrow morphology, MIBG, or CT/MRI were positive, NB-mRNA was detected in 99% (99/100), 88% (100/113), and 81% (82/101) of bone marrow samples. When all three were negative, NB-mRNA was detected in 55% (11/20) of bone marrow samples. Bone marrow NB-mRNA correlated with bone marrow morphology or MIBG positivity (P < 0.0001 and P = 0.007). Bone marrow and blood ΔCt values correlated with PFS (P < 0.001; P = 0.001) even when bone marrow was morphologically negative (P = 0.001; P = 0.014). Multivariate analysis showed that bone marrow and blood ΔCt values were associated with PFS independently of clinical disease and MYCN gene status (P < 0.001; P = 0.055).Conclusions: This five-gene NB5 assay for NB-mRNA improves definition of disease status and correlates independently with PFS in relapsed/refractory neuroblastoma. Clin Cancer Res; 23(18); 5374-83. ©2017 AACR.
Anti-denatured collagen antibody D93: An extra-cellular matrix approach to treatment of solid tumors and metastasis
Authors: Flavia M. Pernasetti, Jeffrey Nickel, Derek Clark, Dennis Van Epps, Bruce Freimark
Journal: Cancer Research (2006)

Proc Amer Assoc Cancer Res, Volume 47, 2006

236 

The extracellular matrix (ECM) is an interconnected molecular network comprised mostly of collagen, which provides mechanical support for cells and tissues and regulates processes such as adhesion, migration, invasion, cell-cycle progression, proliferation, and survival. Structural remodeling of collagen by proteolytic enzymes secreted by tumor and endothelial cells during angiogenesis results in the exposure of cryptic sites that may play a role in angiogenesis and cell growth. Monoclonal antibodies that bind to cryptic sites on denatured (dn) collagen have been generated. Prior reports have demonstrated that the humanized anti-dn collagen monoclonal antibody D93 specifically binds to dn collagen and significantly inhibits tumor growth in M21 melanoma and MDA-MB-231 breast cancer models. Here we report studies in the MDA-MB-435 human breast orthotopic staged murine model, where D93 (5 mg/kg, b.i.w., i.v.) inhibited tumor growth up to 52%; increasing the total weekly dose did not further inhibit tumor growth. When D93 was combined with Taxol, greater inhibition of tumor growth was observed than with either treatment alone. Immunohistochemical evaluation of tumors and organs collected from D93 treated mice demonstrated that D93 targets to tumor vasculature. In an initial study using the human pancreatic BxPC3-GFP orthotopic staged murine model, D93 significantly inhibited tumor growth as well as metastasis to the lymph nodes by 50% and to the abdominal cavity (diaphragm) by 86%, compared to vehicle-treated animals. In non-human primates, the pharmacokinetic half-life of D93 was ∼10 days, and no significant toxicity was noted after administration of multiple doses of D93 based on gross observation, ECG, serum chemistry profiles and urine analyses. Conclusion: D93 significantly inhibits tumor growth in preclinical models of human melanoma, breast, or pancreatic cancer. In the MDA-MB-435 breast cancer model, tumor inhibitory effect of D93 is enhanced when in combination with Taxol beyond D93 and Taxol treatments alone. D93 also reduced metastasis to the abdominal cavity and lymph nodes in a pancreatic model. The specificity of D93 binding to cryptic sites exposed on collagen during angiogenesis and tumor growth may contribute to the selective localization of D93 in tumor vasculature of treated animals. D93 appears to be well tolerated in mice or non-human primates.
Mutation analysis of PI3 kinase pathway genes in bladder cancer
Authors: Fiona Platt, Tara Stanton, Johanna Lowery, Claire Taylor, Carolyn Hurst, Margaret Knowles
Journal: Cancer Research (2007)

AACR Annual Meeting-- Apr 14-18, 2007; Los Angeles, CA

2947 

Genetic alterations affecting the PI3 kinase genes TSC1, PTEN and PIK3CA have previously been identified in bladder cancers, indicating that this pathway may play an important role in tumor development. Two other genes that regulate this pathway are also potential targets for genetic activation or inactivation. LKB1 acts as a tumor suppressor by regulating TSC2 through the AMP-dependent protein kinase. In addition to its role in the inherited condition Peutz-Jeghers syndrome, it is inactivated by mutation in some sporadic cancers. The TSC1/2 complex controls mTOR signalling via GTPase activity towards the small GTPase Rheb. Thus Rheb activation could provide an alternative mechanism for deregulating this pathway. We have carried out a comprehensive mutation screen of all coding exons of TSC1, PIK3CA, LKB1 and RHEB in a series of bladder tumors (n=92) and >30 bladder tumor cell lines. No mutations were found in LKB1 and RHEB. TSC1 mutations were identified in 3/33 (9 %) cell lines and 15/92 (16 %) tumors. These mutations comprised 10 nonsense, 4 missense and 4 frameshifts. The distribution of TSC1 mutations amongst tumors was 7/46 (15%) G1+2, 8/56 (14%) G3, 6/49 (12%) Ta, 7/29 (24%) T1 and 2/13 (15%) T2+. PIK3CA mutations were identified in 10/39 (25.6 %) cell lines and 26/92 (28%) tumors. This is the first comprehensive screen of all coding exons of PIK3CA in bladder cancer and the overall frequencies are similar to those described previously in colorectal and other cancers. Mutations were found in exons 2, 9, 12 and 20. Ten different missense mutations were identified, the majority affecting the known hotspots E542 and E545. PIK3CA mutations in the tumor panel were found in 16/46 (35%) G1+2, 10/56 (18%) G3, 16/49 (33%) Ta, 8/29(28%) T1 and 2/13 (15%) T2+ tumors. In some tumor types, PIK3CA shows genomic amplification. Array CGH of 162 bladder tumors (including 77 screened for mutations) and 42 cell lines showed some over-representation of the gene but no high level amplifications were detected. Mutations of PIK3CA and TSC1 were not mutually exclusive events and appeared to be distributed independently in this tumor series. These results indicate frequent genetic alteration of components of the PI3 kinase pathway in human bladder cancer. Currently we are assessing the status of PTEN and the relationship of these mutations to other known genetic events in the same tumor and cell line series.
The TH1 phenotype of follicular helper T cells indicates an IFN-γ–associated immune dysregulation in patients with CD21low common variable immunodeficiency
Authors: Susanne Unger, Maximilian Seidl, Pauline van Schouwenburg, Mirzokhid Rakhmanov, Alla Bulashevska, Natalie Frede, Bodo Grimbacher, Jens Pfeiffer, Klaudia Schrenk, Luis Munoz, Leif Hanitsch, Ina Stumpf, Fabian Kaiser, Oliver Hausmann, Florian Kollert, Sigune Goldacker, Mirjam van der Burg, Baerbel Keller, Klaus Warnatz
Journal: Journal of Allergy and Clinical Immunology (2017)
Heparin-Induced Thrombocytopenia Antibodies Inhibit PF4-Dependent Enhancement of Activated Protein C Formation by Binding to Antigenic Complexes Formed with the Chondroitin Sulfate Side-Chain of Thrombomodulin
Authors: M. Anna Kowalska, Lubica Rauova, Vincent Hayes, Douglas B. Cines, Daniel W. Bougie, Richard H. Aster, Sriram Krishnaswamy, Mortimer Poncz
Journal: Blood (2010)
The Src/c-Abl pathway is a potential therapeutic target in amyotrophic lateral sclerosis
Authors: Keiko Imamura, Yuishin Izumi, Akira Watanabe, Kayoko Tsukita, Knut Woltjen, Takuya Yamamoto, Akitsu Hotta, Takayuki Kondo, Shiho Kitaoka, Akira Ohta, Akito Tanaka, Dai Watanabe, Mitsuya Morita, Hiroshi Takuma, Akira Tamaoka, Tilo Kunath, Selina Wray, Hirokazu Furuya, Takumi Era, Kouki Makioka, Koichi Okamoto, Takao Fujisawa, Hideki Nishitoh, Kengo Homma, Hidenori Ichijo, Jean-Pierre Julien, Nanako Obata, Masato Hosokawa, Haruhiko Akiyama, Satoshi Kaneko, Takashi Ayaki, Hidefumi Ito, Ryuji Kaji, Ryosuke Takahashi, Shinya Yamanaka, Haruhisa Inoue
Journal: Science Translational Medicine (2017)

Analysis of ALS patient iPSC-derived motor neurons indicates that Src/c-Abl inhibitors may have potential for treating ALS.
Temporal changes in treatment exposures in the Childhood Cancer Survivor Study (CCSS).
Authors: Ann Mertens, John Whitton, Joseph Philip Neglia, Daniel M. Green, Todd M. Gibson, Marilyn Stovall, Melissa M. Hudson, Leslie L. Robison, Gregory T. Armstrong, Yutaka Yasui, Wendy M. Leisenring
Journal: Journal of Clinical Oncology (2015)

10074 Background: Well-designed epidemiologic investigations of pediatric cancer survivors inform clinical practice guidelines and future clinical trials. Expansion of the CCSS cohort to include survivors diagnosed across three decades (1970-99) affords the opportunity to evaluate associations between key temporal changes in survivor and treatment characteristics and risk for subsequent adverse health outcomes. Methods: We analyzed cancer and treatment characteristics of 24,000 CCSS participants. Treatment exposures were abstracted from medical records. Trends across 5 year intervals were evaluated using logistic regression models with weights to account for sampling probabilities. Results: Within the expanded CCSS, the use of chemotherapy significantly increased overall (Table, T1-T6) for all diagnoses except leukemia which was always 100%. Exposure to radiation (RT) decreased overall and for all diagnoses except soft tissue sarcoma. Overall, chest RT exposure was reduced and notably, exposures of ≥ 30 Gy declined from 85% to 6% (T1 to T6) for Hodgkin lymphoma. Alkylating agent use increased by 15% overall, and among leukemia, lymphoma and sarcoma patients proportions were on the order of 40% higher at T6 than at T1. Use of anthracyclines (ANT) increased significantly, predominantly for doses lower than 250 mg/m2. Conclusions: The expansion of the CCSS cohort provides a unique resource to evaluate the impact of historical changes in primary cancer therapy, including reduction of therapeutic intensity for low- and standard-risk populations, as well as intensification of specific therapies for high-risk populations on health and psychosocial outcomes. % With Characteristic T1 1970-74 T2 1975-79 T3 1980-84 T4 1985-89 T5 1990-94 T6 1995-99 Any RT* 79 75 64 50 40 34 RT to brain* 30 36 32 24 18 16 RT to neck* 24 19 16 9 7 7 RT to abdomen* 28 22 19 12 8 9 RT to chest ≥ 30 Gy* 21 13 8 4 1 1 Any Chemotherapy* 75 81 81 85 86 87 Any alkylating agents* 45 49 55 57 58 60 ANT 1-250 mg/m2* 3 12 18 34 45 52 ANT >250 mg/m2* 11 24 24 23 17 14 Any epipodophyllotoxins* 1 4 9 25 34 36 Platinum* <1 2 7 12 14 17 *Trend p-value <0.0001.
Abstract 104: Effects of Pinacidil and Ca <sup>2</sup> + on Sodium-loaded Rat Heart Mitochondria
Authors: Sergey M Korotkov, Vladimir P Nesterov, Irina V Brailovskaya, Larisa V Emelyanova, Svetlana A Konovalova, Victor V Furaev
Journal: Circulation Research (2013)

Deterioration of the contractile parameters of the heart muscle caused by ischemia and followed reperfusion is known as the main postoperative complication which is related to Ca 2+ and Na + overload in cardiomyocytes and mitochondria. Pinacidil reduced the overload in ischemia/reperfusion experiments. The mechanism of this phenomenon is still not clear. We hypothesized that increased ion permeability of the inner mitochondrial membrane (IMM) followed drop of electrochemical potential (ΔΨ mito ) can reduce the calcium. The aim of the study was to elucidate the effect of pinacidil (100 μM) and Ca 2+ (100 μM ) on swelling, oxygen consumption and ΔΨ mito of isolated sodium-loaded rat heart mitochondria (RHM(Na)) energized glutamate and malate. Pinacidil significantly enchanced the permeability of IMM to protons in ammonium nitrate medium. Also increased swelling of RHM(Na) energized with substrates in potassium acetate medium revealed that pinacidil increased potassium transport into matrix. Pinacidil stimulated oxygen consumption of RHM(Na) in State 4 and detained Ca 2+ -induced dissipation of ΔΨ mito . Under condition of Ca 2+ and Na + overload simulating ischemia/reperfusion, RHM(Na) oxygen consumption was not affected with pinacidil in State 3 and in the presence of 2,4-dinitrophenol. Cyclosporin A and ADP, the inhibitors of mitochondrial permeability transition pore (MPTP), markedly decreased Ca 2+ - induced swelling of RHM(Na) in nitrate ammonium or potassium acetate medium in the presence of pinacidil. Carboxyatractyloside, an inhibitor of cytosolic side-specific adenine nucleotide translocase, eliminated a pinacidil-stimulated oxygen consumption of succinate-energized RHMNa in State 4 regardless of the presence of Ca 2+ . Pinacidil was also concluded to accelerat potassium flux into energized RHM(Na) and promot MPTP opening in the low conduction state. Based on our data we suggested that the effect of pharmacological preconditioning induced by pinacidil could be due to it’s direct effect on mitochondria which is connected with above stimulation of the potassium permeability of the inner mitochondrial membrane and following reduce of the ΔΨ mito that thus prevent calcium overload of cardiomyocytes after ischemia/reperfusion in turn.
Racial Disparities in Risks of Stroke
Authors: Wilson Nadruz, Brian Claggett, Mir Henglin, Amil M Shah, Hicham Skali, Wayne D Rosamond, Aaron R Folsom, Scott D Solomon, Susan Cheng
Journal: New England Journal of Medicine (2017)

In the Atherosclerosis Risk in Communities cohort of four U.S. communities, risk factors for stroke declined from 66% to 34% among whites and from 84% to 63% among blacks from 1990 through 2010. The main driver of the difference was a smaller reduction in hypertension among blacks.
Factors associated with post-concussion syndrome in high school student-athletes
Authors: Zachary, Y Kerr, Erin, B Wasserman, Scott, L Zuckerman, Aaron, M Yengo-Kahn, Thomas, P Dompier
Journal: British Journal of Sports Medicine (2017)

Objective This study examined factors predictive of post-concussion syndrome (PCS; i.e., concussion-related symptoms lasting ≥4 weeks) among high school (HS) student-athletes during the 2011/12-2013/14 academic years. Design Prospective cohort. Setting Concussion data originated from the National Athletic Trainers Injury and Outcomes Network (NATION), a nationwide surveillance program comprised of a convenience sample of 127 HS. All concussions were diagnosed and reported by athletic trainers and team physicians. Subjects Our sample included 1846 concussed HS student-athletes from 22 sports (73.7% male). For student-athletes with multiple concussions, only the most recent concussion was considered. Intervention Factors potentially related to PCS (i.e., sex, sport contact level, recurrent concussion, presence of symptoms) were examined. Outcome measures The 215 concussed student-athletes with PCS were compared to 1119 concussed student-athletes with symptoms lasting &lt;2 weeks. Those with symptoms lasting 2-4 weeks were excluded (n=512). Logistic regression predicted the odds of PCS. Results In multivariate analysis, concussion symptoms associated with increased odds of PCS were somatic symptoms including: disorientation [odds ratio (OR)=1.86, 95% confidence interval (CI):1.04–3.33]; balance issues (OR=1.76, 95% CI: 1.00–3.10); visual impairments (OR=2.21, 95% CI: 1.23–3.97); noise sensitivity (OR=1.80, 95% CI: 1.02–3.17); and cognitive symptoms including: retrograde amnesia (OR=3.01, 95% CI: 1.31–6.91); and difficulty concentrating (OR=2.72, 95% CI:1.56–4.77). Sex, sport contact level, and recurrent concussion were not associated with PCS. Conclusions As in previous research, various somatic and cognitive symptoms were associated with PCS. The identification of risk factors potentially associated with PCS may assist clinicians in providing timely interventions to shorten symptom resolution and recovery time. Competing interests None
Abstract 20388: Impact of Changes in Cardiorespiratory Fitness on Incidence of Atrial Fibrillation/Flutter
Authors: Nasir Hussain, Bernard J Gersh, Stephanie A Joppa, Francisco Lopez-Jimenez, Stephen L Kopecky, Randal J Thomas, Thomas G Allison
Journal: Circulation (2016)

Background: The benefits of regular exercise in improving cardiovascular health are well recognized; however, the impact of changes in cardiorespiratory fitness on the incidence of atrial fibrillat...