tbuckley/cabot-search huggingface dataset:
Abstract 2347: Multiplexed quantitative assessment and prognostic value of TIL subtypes in non-small cell lung cancer
Authors: Kurt A. Schalper, Cliff Hoyt, Chichung Wang, David Rimm
Journal: Cancer Research (2015)

Abstract Background: The presence of high levels of tumor-infiltrating lymphocytes (TILs) is associated with favorable outcome in diverse human neoplasms including non-small cell lung cancer (NSCLC). Previous studies suggest that different TIL subtypes have distinct biological roles in cancer progression and their contribution to prognosis remains unclear. Here, we simultaneously quantified TIL subtypes using 2 different automated, objective methods in human NSCLC and determined their association with tumor characteristics and outcome. Methods: Using a sequential multiplexed immunofluorescence staining protocol with tyramide signal amplification and heat-inactivation steps, we simultaneously visualized all cell nuclei (DAPI), epithelial cells (Cytokeratin AE1/AE3, Dako), T helper cells (CD4-368, Leica), Cytotoxic T cells (CD8, C8/144B, Dako), B-lymphocytes (CD20, L26, Leica) and Regulatory T cells [Tregs], (Foxp3, D608R, CST) in 202 stages I-IV NSCLC represented in tissue microarray format. The preparations were digitalized and the number of each TIL subpopulation was counted using multispectral fluorescence analysis and a trainable tissue/cell image segmentation algorithm with the inForm software (PerkinElmer). Markers were also measured using the AQUA method of quantitative immunofluorescence (QIF). Results: NSCLC samples show a highly variable TIL content ranging from 0 to 2717 lymphocytes per tumor histospot. The median TIL content was 23.9 T-helper cells, 55.8 Cytotoxic T cells, 59.7 B-lymphocytes and 6.1 Tregs. Although the amount of CD4+, CD8+ and CD20+ cells was comparable between the histological NSCLC subtypes, the average number of Tregs (CD4+/Foxp3+ cells) was significantly higher in squamous cell carcinomas than in adenocarcinomas (10.4 and 4.9 cells per histospot, respectively, P = 0.03). Increased numbers of CD8+ or CD20+ TILs were significantly associated with longer overall survival (log-rank P&amp;lt;0.05), but the amount of CD4+ and Foxp3+ cells were not. Correlations were seen between multiplexed counting methods and QIF. Conclusions: This strategy allows simultaneous and objective quantification of diverse TIL subpopulations in lung tumor samples. Our results indicate that increased Cytotoxic T cells and B-lymphocytes, but not T helper cells or Tregs have prognostic value in NSCLC. Accurate quantification of TIL subpopulations in the tumor microenvironment could be useful to predict response and study the local effects of novel anti-cancer immunostimulatory therapies. Citation Format: Kurt A. Schalper, Cliff Hoyt, Chichung Wang, David Rimm. Multiplexed quantitative assessment and prognostic value of TIL subtypes in non-small cell lung cancer. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 2347. doi:10.1158/1538-7445.AM2015-2347
Corrigendum to “A method of lyophilizing vaccines containing aluminum salts into a dry powder without causing particle aggregation or decreasing the immunogenicity following reconstitution” [J. Control. Release 204 (2015) 38–50]
Authors: Xinran Li, Sachin G. Thakkar, Tinashe B. Ruwona, Robert O. Williams, Zhengrong Cui
Journal: Journal of Controlled Release (2015)
Pathological T0 Following Cisplatin-Based Neoadjuvant Chemotherapy for Muscle-Invasive Bladder Cancer: A Network Meta-analysis
Authors: Hyung Suk Kim, Chang Wook Jeong, Cheol Kwak, Hyeon Hoe Kim, Ja Hyeon Ku
Journal: Clinical Cancer Research (2015)

To systematically assess and compare the relationship between various neoadjuvant chemotherapy regimens and pCR in patients with muscle-invasive bladder cancer.We performed a literature search of PubMed, Embase, and the Cochrane Library for all articles published before March 2015 and according to the Preferred Reporting Items for Systematic Review and Meta-analysis (PRISMA) guidelines. There were 17 articles that met the study eligibility criteria and were selected for the final analysis. A direct pair-wise meta-analysis was performed for studies that compared the same regimen. Finally, a Bayesian network meta-analysis was used to indirectly compare the regimens.In a pair-wise meta-analysis, the methotrexate/vinblastine/Adriamycin/cisplatin [MVAC; OR, 4.36; 95% confidence interval (CI), 2.71-7.02] and gemcitabine/cisplatin (GC) regimens (OR, 4.92; 95% CI, 2.93-8.24) were significantly associated with a better pCR than RC alone. In a network meta-analysis, there was no significant difference in terms of pCR achievement between the GC and MVAC regimens (OR, 1.14; 95% CI; 0.85-1.70). However, in a subgroup network meta-analysis that only included prospective randomized trials, the MVAC regimen was significantly correlated with a higher rate of pCR (OR, 5.75; 95% CI, 1.96-24.18).The results of this meta-analysis suggest that a GC regimen was associated with a pCR rate that was similar to that of a MVAC regimen based on retrospective data, but only the MVAC regimen was proven to achieve pCR in prospective randomized trials. Additional prospective randomized trials comparing both regimens will be necessary to establish the optimal neoadjuvant chemotherapy regimen.
Schistosomiasis in travellers returning from sub-Saharan Africa
Authors: P Jordan, G Webbe
Journal: BMJ (1996)

The beneficial characteristics of the dihydro- pyridine calcium blockers, including the absence of negative inotropism and the neutral effect on lipids and insulin sensitivity, have rendered them popular first line agents in managing hypertension.Like other antihypertensives, appropriate cost-benefit analyses of their various actions are required before they are prescribed.However, inappropriate extrapolation from small, highly selected and methodologically flawed statistics should not preclude their use.
FOLFIRI vs FOLFOX in the general practice for metastatic colorectal carcinoma (MCRC) - Impact of 1st-line or 2nd-line treatment
Authors: B. Melosky, C. Lohrisch, C. Kollmannsberger, S. Gill, H. Kennecke, V. Bernstein, C. Fitzgerald, J. Yun, A. Shah
Journal: Journal of Clinical Oncology (2005)

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BRMS1 binding proteins mSDS3 and RBBP1 serve distinct roles in BRMS1 function
Authors: Alexandra Silveira, Yi Xie, Kedar Vaidya, Danny Welch
Journal: Cancer Research (2007)

485   The mechanism by which Breast Cancer Metastasis Suppressor 1 (BRMS1) blocks metastasis has yet to be fully elucidated. However, it is known that BRMS1 represses transcription as a core member of mSin3-HDAC chromatin remodeling complexes. Yeast two-hybrid studies show that BRMS1 binds two other core proteins of the same mSin3/HDAC complexes, Rb-Binding Protein 1 (RBBP1/ARID4a) and the BRMS1 family member Mammalian Suppressor of Defective Silencing (mSDS3/SAP45; 24% identity and 50% similarity to BRMS1). We hypothesized that mSDS3 either complements BRMS1 as a family member or that mSDS3 plays a unique role in BRMS1-mediated biological changes as compared to RBBP1. To examine complementation, mSDS3 was overexpressed in the BRMS1-deficient breast cancer lines MDA-MB-231 and MDA-MB-435. Overexpression did not consistently diminish metastasis, suggesting that mSDS3 cannot fully complement BRMS1 function. To define a role for the BRMS1 interactors mSDS3 and RBBP1, sites of interaction were identified and then binding was disrupted to examine effects on BRMS1-mediated functions. BRMS1:RBBP1 interaction was specifically disrupted through mutation of the L174 residue (BRMS1 L174D ) in a yeast two-hybrid system. BRMS1:mSDS3 interaction was disrupted through deletion of BRMS1 amino acids 7-137, 137-248, or either coiled-coil domain (delCC1; del61-92 and delCC2; del130-187). Deletion of CC1 did not disrupt BRMS1:RBBP1 interaction but did disrupt direct binding of BRMS1 to mSDS3, suggesting that mSDS3 and RBBP1 bind to BRMS1 at unique sites rather than competitively binding the same site. Further studies addressed the role of these interactors in BRMS1-mediated down-regulation of EGFR and PtdIns(4,5) 2 . Similar to BRMS1 WT , both BRMS1 L174D  and BRMS1 delCC1  down-regulated EGFR when expressed in MDA-MB-435 cells. In contrast, PtdIns(4,5) 2  levels were decreased by BRMS1 L174D  but not by BRMS1 delCC1 . These data suggest that neither mSDS3 nor RBBP1 are necessary for BRMS1-mediated EGFR regulation and that RBBP1 does not play a necessary role in the regulation of PtdIns(4,5) 2 .  In conclusion, we show that mSDS3 and RBBP1 bind BRMS1 at different sites to selectively regulate BRMS1-mediated biological functions including gene expression and metastasis suppression. These studies further define the role of RBBP1, BRMS1, and mSDS3 protein-protein interactions in mediating the specificity of mSin3A:HDAC complexes.  Support: C87728, National Foundation for Cancer Research, Susan G. Komen Breast Cancer Foundation PDF0122660.
Congenital Nystagmus Gene FRMD7 Is Necessary for Establishing a Neuronal Circuit Asymmetry for Direction Selectivity
Authors: Keisuke Yonehara, Michele Fiscella, Antonia Drinnenberg, Federico Esposti, Stuart Trenholm, Jacek Krol, Felix Franke, Brigitte Gross Scherf, Akos Kusnyerik, Jan Müller, Arnold Szabo, Josephine Jüttner, Francisco Cordoba, Ashrithpal Police Reddy, János Németh, Zoltán Zsolt Nagy, Francis Munier, Andreas Hierlemann, Botond Roska
Journal: Neuron (2015)

Neuronal circuit asymmetries are important components of brain circuits, but the molecular pathways leading to their establishment remain unknown. Here we found that the mutation of FRMD7, a gene that is defective in human congenital nystagmus, leads to the selective loss of the horizontal optokinetic reflex in mice, as it does in humans. This is accompanied by the selective loss of horizontal direction selectivity in retinal ganglion cells and the transition from asymmetric to symmetric inhibitory input to horizontal direction-selective ganglion cells. In wild-type retinas, we found FRMD7 specifically expressed in starburst amacrine cells, the interneuron type that provides asymmetric inhibition to direction-selective retinal ganglion cells. This work identifies FRMD7 as a key regulator in establishing a neuronal circuit asymmetry, and it suggests the involvement of a specific inhibitory neuron type in the pathophysiology of a neurological disease.Video AbstracteyJraWQiOiI4ZjUxYWNhY2IzYjhiNjNlNzFlYmIzYWFmYTU5NmZmYyIsImFsZyI6IlJTMjU2In0.eyJzdWIiOiIzMmUzNGJkNWNlNDFiZDEyNzJiYThlZDEzMzdkMTU1MCIsImtpZCI6IjhmNTFhY2FjYjNiOGI2M2U3MWViYjNhYWZhNTk2ZmZjIiwiZXhwIjoxNjc4NjUxMTk0fQ.c7cbIpedz5yPxIls2CJule0S7s6X07WWKZAWW5_ordQ9xIgRHZwKIH3L1LsPim7D3ZdOUHyIu2CI1Ub7QaxeGVUcSenZXjDHETUUra1xVz2f_HgGO8UHUgnuBirxb75GxNOka35b4u2G57Q6jiyu3X8emPXluNYdGbVDNDAuJuedSAoZbkaxut5PQs3W6W1HLuiB04Wfa5If5fSqeZnY_rBEcsww7nAnRqHvVKAKX8i7x93F_jjt-UFu0iX1EByCmWT8j_jBO08kCtmNrJ_qVPTnC0Kr8v1hFcEVKYHgJuwmw3VHjxhCLTokdwqkuUmJWpKp_dUeHFNjmi4vR_gbaQ(mp4, (47.53 MB) Download video
Does physiotherapy diagnosis of shoulder pathology compare to arthroscopic findings?
Authors: Mary Elizabeth Magarey, Mark Alan Jones, Chad E Cook, Michael George Hayes
Journal: British Journal of Sports Medicine (2015)

Aims To explore the ability of a physiotherapist, using a standardised musculoskeletal physiotherapy assessment protocol, to accurately identify the structures potentially responsible for shoulder symptoms against a standardised arthroscopic shoulder diagnostic assessment, and to determine the physiotherapists’ ability to influence post-test diagnostic accuracy. Study design Consecutive case-based cohort study. Subject selection All participants were selected by two orthopaedic surgeons for arthroscopic investigation during a 6-month period. Setting Private orthopaedic clinic. Method All consenting participants selected for arthroscopic investigation were examined by the physiotherapist prior to arthroscopy. Presence and priority of impairments/diagnoses were recorded on a standardised form. Inter and intra-rater reliability and diagnostic accuracy were tabulated. Statistical analysis Proportional agreement on diagnostic incidence (broad) and priority (strict) using 2×2 contingency tables for sensitivity, specificity, positive and negative predictive value and positive and negative likelihood ratios were calculated. Post-test probabilities were analysed to determine the influence of a positive or a negative finding. Results 211 participants, aged 14–79 years were included. Overall prevalence of subacromial pathology was (77%) and, disorders of the passive restraints (29%). For both negative and positive findings, post-test probabilities were not notably altered; although positive findings yielded greater value in the decision-making modelling. The physiotherapist's ability to identify individual pathology (eg, tendon rupture vs tendinopathy, capsular vs labral) was lower than recognition of pathology within the broader diagnostic category. Conclusions The physiotherapist's ability to diagnose individual pathologies was inconsistent. Indirectly, this raises the issue of whether signs and symptoms identified under arthroscopic surgery are reflective of a lesion/pathology reflective of a specific tissue.
Abstract MP07: Rising Incidence and Prevalence of Atrial Fibrillation from 2004 to 2013: A Community-Based Study Using Electronic Medical Records
Authors: Brent Williams, Peter Berger
Journal: Circulation (2015)

Introduction: Atrial fibrillation (AF) is the most common cardiac arrhythmia observed in clinical practice and is associated with an elevated risk of stroke and mortality. Evaluating community-level temporal trends in AF incidence and prevalence serve to describe the evolving public health and clinical burden of AF, however recent studies describing AF trends in community-based settings have been inconsistent, with no recent data evaluating trends among individuals under 65 years of age. Accordingly, this study sought to describe community-level trends in AF incidence and prevalence from 2004 to 2013 using the electronic medical records (EMR) of a single, large health care system. Methods: This study includes 329,634 patients receiving primary care and other health care services through the Geisinger Health System (Geisinger) over at least a two-year period. Geisinger consists of over 40 outpatient and seven inpatient facilities spread throughout central and northeastern Pennsylvania. Geisinger’s extensive EMR data repository contains information on demographics, vital signs, social history, diagnoses, medical history, problem lists, medications, procedures, laboratory results, and billing information from all Geisinger encounters since 2001. Incident and prevalent AF were identified by ICD-9 codes observed within any EMR domain. For incident AF, cases had no AF ICD-9 code in the EMR for at least two years prior to the diagnosis. Incidence and prevalence rates were age- and sex-adjusted to the 2010 US census and reported per 1000 person-years (persons). Stratified rates are reported across age groups (&lt;45, 45-54, ¼, &gt;85) and sex. Results: Age- and sex-adjusted AF incidence rates remained relatively stable from 2004 to 2008, but increased sharply thereafter. Incidence rates were 5.0, 5.2, and 8.4 cases per 1000 person-years in 2004, 2008, and 2013, respectively. The overall annual increase was 5.5% per year (95% CI: 4.8, 6.3%). Incidence rates increased significantly in all age and gender groups, with the largest relative increase observed among patients &lt;45 years of age (annual increase in males: 10.8%, females: 11.6%). Prevalence rates increased consistently throughout the entire 10-year period from 23.5 to 39.2 AF cases per 1000 persons from 2004 to 2013 (6.0% annual increase; 95% CI: 5.7, 6.4%). Conclusions: AF incidence and prevalence have been increasing in the community over the last 10 years. Increases were observed in all age and gender groups, with notable increases in the very young. Prevailing trends may be attributable to increased application of AF diagnostics in an aging population and/or an increased clinical recognition of AF due to the recent availability of novel oral anticoagulants for stroke prevention. A mature EMR system functioning within a large health care system can be a powerful tool for performing epidemiologic studies and disease surveillance.
TISSUE CULTURE STUDIES ON BACTERIAL HYPERSENSITIVITY
Authors: Johannes K. Moen
Journal: The Journal of Experimental Medicine (1936)

1. Guinea pigs infected with naturally pathogenic hemolytic streptococci (group C-Lancefield) develop a low grade chronic type of disease characterized chiefly by purulent lymphadenitis. 2. Cutaneous hyperreactivity to a crude streptococcal extract invariably occurred during the course of this infection. 3. Production of antibodies (precipitins and agglutinins) was studied. 4. The hemolytic streptococcal extract had a specific toxic effect, when tested in vitro, on cells from infected animals; this was shown by microscopic evidence of cellular injury, and by quantitative inhibition of cellular migration and growth. The specificity of the reaction was proven by testing with other cytotoxic substances. 5. There was no parallelism between skin hypersensitivity and humoral antibody titer. 6. There was no correlation between the degree of skin reactivity to the bacterial extract and the degree of sensitivity of splenic cells to the toxic action of the same extract in vitro. 7. Comparison of cellular sensitivity to tuberculin with cellular sensitivity to streptococcal extract in cultures of guinea pig tissues showed that the former was more intense and was more persistent on prolonged growth in vitro.
Transformed Diffuse Large B-Cell Lymphoma (DLBCL) Patients Treated With Salvage Rituximab, Ifosfamide, Carboplatin and Etoposide (R-ICE) Have Superior Overall Survival Than Patients With De Novo DLBCL
Authors: Kathleen B Fenner, Lisa Rybicki, Deepa Jagadeesh, Robert M Dean, Brad Pohlman, Mitchell R Smith, Brian T. Hill
Journal: Blood (2013)
Antileukemic effects of novel immunomodulatory agent lenalinomide (L) with or without rituximab (R) in patients (pts) with relapsed (rel) or refractory (ref) chronic lymphocytic leukemia (CLL). Encouraging preliminary results of an ongoing phase II clinical study
Authors: K. C. Miller, M. S. Czuczman, L. Dimiceli, P. McCarthy, Z. P. Bernstein, J. B. Zeldis, A. Mohr, A. A. Chanan-Khan
Journal: Journal of Clinical Oncology (2005)

6557 Introduction: Tumor microenvironment (ME) and cytokine milieu play an important role in CLL cell survival, growth and resistance to therapy. VEGFR-1 and VEGFR-2 are over expressed on CLL cells. Both VEGF and TNF-α are thought to play an important role in CLL pathogenesis. L (Revlimid™) is an immunomodulatory agent that can downregulate VEGF and TNF-α. The anti-tumor effect of L in CLL is unknown. We hypothesized that targeting CLL tumor ME by down regulation of key regulatory cytokines with L will predispose these cells to undergo apoptosis. Method: All pts with rel or ref CLL were eligible. L was given at 25mg PO QD x 21 days followed by 7 days rest on a 28 day cycle. Absolute lymphocyte count (ALC) at Day 0, 7 and 30 were done to determine direct anti-CLL effect of L. Response was assessed at day 30 and then monthly using the NCI-WG criteria. Pts with stable disease or better response will be continued on therapy for 6 months while those with progressive disease (PD) will receive R (375mg/m2) added to L. Results: Nine pts (6M, 1F; median age 66 years, range 58–74; median stage III, range I-IV) have been enrolled to date. Median baseline ALC was 46k (8–106). Of the pts who completed 30 days of L (n=7), all pts are available for toxicity and 5 for response evaluation. The most common side effect was fatigue and rash (6 pts). A flare reaction (tender swelling of lymph nodes) and tumor lysis syndrome was noted in 1 pt each. Six of the 7 (85.7%) pts responded at day 30 (median decrease in ALC; 61%, Range; 55–70%) with 1 CR and 5 PR while 1 pt withdrew consent and is not evaluable for response. None of the pts have PD yet and therefore have not received R. Conclusion: This is the first experience with L in pts with CLL. In our experience single agent L is reasonably well tolerated with rapid anti-CLL effects, noted as early as day 7 of treatment. Toxicity profile so far is predictable and manageable. Further follow-up will ascertain the durability of these responses and establish the role of L in treatment of pts with CLL. Accrual is ongoing and updated results of this phase II study will be presented at the meeting. Author Disclosure Employment or Leadership Consultant or Advisory Role Stock Ownership Honoraria Research Funding Expert Testimony Other Remuneration Celgene Celgene
Counterfeit antiepileptic drugs threaten community services in Guinea-Bissau and Nigeria
Authors: Willem M Otte, Eric van Diessen, Pieter van Eijsden, Frank van der Maas, Philip N Patsalos, Paul N Newton, Inácio C Alvarenga, Kees P Braun, Josemir W Sander
Journal: The Lancet Neurology (2015)
Ulcerative Colitis
Authors: F. Frankel
Journal: BMJ (1954)

It is the purpose of this paper to review some of the literature on ulcerative colitis, and to present the case report of a patient with this disease in whom a success- ful outcome was obtained by psychotherapeutic means.Review of Literature Murray (1930a) investigated the life histories and mental attitudes of 12 patients suffering from ulcerative colitis, and found a close association in time between the emergence of a difficult emotional situation and the onset of symptoms.Mental conflicts concerned with marriage were more com- monly found than other types of situations which might evoke anxiety.Murray felt that the outstanding trait in colitis patients, besides fearfulness, was their emotional im- maturity, and stressed the childish elements in the make-up of his patients.In his seven male patients the onset of symptoms was associated with the conflict between the mother attachment and the desire for marriage.Of the five female patients in his series, three were involved in marriages of a significant nature, the husbands being obvious father-substitutes, one was engaged but could not marry on account of her colitis, and the fifth was unapproachable on the subject of marriage.In a later publication Murray (1930b) dealt with the analysis of a patient with ulcerative colitis and pointed to the fact that the character and sexuality of his patient corresponded quite closely to the so-called anal level described by Freud, and the masochistic and sadistic components which are so generally associated with anal temperament were very conspicuous in this patient.In 1936 Sullivan drew attention to the long-recognized association of emotion and diarrhoea, and pointed out that psychotherapy had been astonishingly successful in the treatment of ulcerative colitis.Bargen et al. (1939) discussed pregnancy associated with ulcerative colitis in a series of 17 women sufferers with colitis who had 18 deliveries and 4 miscarriages among them.They concluded that the effect of pregnancy on ulcerative colitis was variable.In 1942 Daniels, in a review of 14 cases of ulcerative colitis, was of the opinion that these patients were apt to be too dependent on some member of the family, usually the mother, and conflict developed in situations threatening this dependence, especially engagement and marriage.The emotional con- flict in these patients was held responsible for the appearance of colitis symptoms.He found childbirth another frequent precipitating factor.Lindemann (1945), in a review of 45 patients with ulcer- ative colitis, maintained that various forms of bereavement were the most import-.ntprecipitating factors in the illness, and for 26 of the 45 patients a close time relationship existed between the loss of an important person and the onset of the illness.He felt that rewarding patterns of