tbuckley/cabot-search huggingface dataset:
Abstract 664: Amanitin-based antibody-drug conjugates targeting the prostate-specific membrane antigen
Authors: Torsten Hechler, Michael Kulke, Christoph Mueller, Andreas Pahl, Jan Anderl
Journal: Cancer Research (2014)

Abstract Antitumoral activity of monoclonal antibodies can be dramatically enhanced by conjugation to toxic small molecules. Beside the recent approval of Kadcyla (T-DM1) and Adcetris (SGN-35) more than 30 antibody-drug conjugates (ADC) have entered clinical trials, promising to strengthen the therapeutic capabilities for cancer treatment in the next decade. Surprisingly most ADCs are based on one of few toxic compounds only and on an even smaller number of toxicity mechanisms: Most antibodies are coupled to the microtubuli-targeting auristatins and maytansines. Toxins that operate through such a mechanism could suffer from limited activity in different cancer indications and in cells expressing resistance mechanisms. Accordingly the use of new drugs that function via alternative toxicity mechanisms could enhance the therapeutic potential of ADCs. In the present study we evaluated the antitumoral potency of a monoclonal antibody targeting the prostate-specific membrane antigen (PSMA) conjugated to small molecules from the amatoxin family. PSMA is a membrane antigen overexpressed in prostate cancer and an attractive target for an ADC approach, as it shows low expression by most normal tissues and sufficient internalization after antibody binding. Amanitin, the most well-known toxin of the amatoxin family, binds to the eukaryotic RNA pol II and thereby inhibits the cellular transcription at very low concentrations. In our experiments, we tested several random- and site-specific strategies to covalently conjugate amanitin to the antibody and generated conjugates with low aggregation and high affinity for the target antigen. Using a series of PSMA-expressing cells we compared the cytotoxic activity of stable and cleavable linker ADCs and the stability of such constructs in plasma. Overall we observed picomolar activity of ADCs after incubation for three to five days with PSMA-positive prostate cancer cells independent of the hormone-sensitivity status. Moreover we demonstrated high activity of amanitin-based anti-PSMA ADCs in prostate cancer xenograft models. The data encourage the evaluation of these agents in a clinical advanced prostate cancer study. Note: This abstract was not presented at the meeting. Citation Format: Torsten Hechler, Michael Kulke, Christoph Mueller, Andreas Pahl, Jan Anderl. Amanitin-based antibody-drug conjugates targeting the prostate-specific membrane antigen. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 664. doi:10.1158/1538-7445.AM2014-664
A STATISTICAL STUDY OF ONE HUNDRED NEUROPSYCHIATRIC CASUALTIES FROM THE NORMANDY CAMPAIGN
Authors: WILLIAM NEEDLES
Journal: American Journal of Psychiatry (1945)

1. A comparative study of 100 neuropsychiatric combat casualties and of 100 control cases is reported. 2. There was a slight preponderance of older men in the neurosis group. 3. The incidence of poor family background and early environment was about twice as great in the neurosis group. 4. The average number of neurotic traits was higher in the neurosis group. 5. Many more cases in the neurosis group gave a history of treatment for some nervous condition in civilian life and in the Army prior to combat. 6. The application of (4) and (5) for screening purposes would have eliminated 52 men of the neurosis group from combat, 12 of the control group. 7. The potential neuropsychiatric casualty shows a tendency to be more nervous, inclined to worry, dependent and seclusive than the sturdy soldier. 8. Conflicts with the law and alcoholic habits were more frequent in the control group. 9. Religious tendencies were more prevalent in the neurosis group. 10. Discontent with society and with the Army was slightly more in evidence in the neurosis group. 11. Physically wounded soldiers showed less reluctance to discuss their experiences than the psychically wounded. 12. The limitations of the present study and reasons for considering its conclusions tentative until further tested are discussed.
Saúde de mães e crianças no Brasil: progressos e desafios
Authors: Cesar Gomes Victora, Estela Maria Motta Lima Leão de Aquino, Maria do Carmo Leal, Carlos Augusto Monteiro, Fernando Celso Lopes Fernandes de Barros, Celia Landmann Szwarcwald
Journal: The Lancet (2011)
Infections and risk factors in entrants to Irish prisons
Authors: S. Singh
Journal: BMJ (2002)

Editor—Long et al report a high prevalence of viral and other sexually transmitted diseases in Irish prisons and conclude that use of injecting drugs could be the single most important factor for the high infection with hepatitis C virus there.1 They suggest that increased infection control and harm reduction measures are needed in Irish prisons. But they fail to acknowledge other, similar reports, particularly from the countries where HIV infection is highly epidemic.

I and colleagues from the Indian subcontinent conducted a study in 1998 among Indian prisoners.2 Altogether 240 male and nine female prison inmates in a district prison near Delhi were screened for sexually transmitted and bloodborne diseases including HIV, syphilis, and hepatitis B and C viral infections. The inmates were aged 15-50 (mean (SD) 24.8 (0.11)). Of the 240 male prisoners, 115 were married and 184 gave a history of penetrative sex. Of the 184, 53 were homosexual or bisexual and the remainder had sex with women only.

Sixty of 131 prisoners were faithful to their partners, while 124 gave a history of having multiple sexual partners and 100 of them had unprotected sex. Eighty three of these 100 had had sex with commercial sex workers. Altogether 126 were addicted to alcohol and 44 to smack/charas; only eight had a history of injecting drug use.

On examination 28 of the 240 had active hepatitis with or without a history of jaundice in the past two years, 25 had active pulmonary tuberculosis, and 11 had syphilitic ulcers on the penis. Four fifths of the teenagers confined to a particular barrack had moderate to severe scabies. Three male prisoners (1%) were positive for HIV-1 (confirmed by western blotting) while 28 (11%) male and two (22%) female prisoners were positive for hepatitis B surface antigen. Twelve (5%) male but no female prisoners were positive for antibodies to hepatitis C virus. Of the three HIV positive prisoners, one was an injecting drug user, one was a drug user and frequent commercial sex worker, and the third was homosexual.

This study showed that sexually transmitted and bloodborne infections are highly prevalent in prisons in India and may spread rapidly because of injecting drug use and homosexuality. Interestingly, unlike Long et al we found more hepatitis B than hepatitis C infection. Injecting drug use was less frequent than in Irish prisons, and homosexuality was probably the most important risk factor in Indian prisons. The study emphasised that more awareness about HIV and hepatitis virus infection is needed in Indian prisons.
A Genome-Wide View of the <i>In vitro</i> Response to <scp>l</scp>-Asparaginase in Acute Lymphoblastic Leukemia
Authors: Bernard M. Fine, Gertjan J.L. Kaspers, Minh Ho, Anne H. Loonen, Linda M. Boxer
Journal: Cancer Research (2005)

To investigate the effect of l-asparaginase on acute lymphoblastic leukemia (ALL), we used cDNA microarrays to obtain a genome-wide view of gene expression both at baseline and after in vitro exposure to l-asparaginase in cell lines and pediatric ALL samples. In 16 cell lines, a baseline gene expression pattern distinguished l-asparaginase sensitivity from resistance. However, for 28 pediatric ALL samples, no consistent baseline expression pattern was associated with sensitivity to l-asparaginase. In particular, baseline expression of asparagine synthetase (ASNS) was not predictive of response to l-asparaginase. After exposure to l-asparaginase, 5 cell lines and 10 clinical samples exhibited very similar changes in the expression of a large number of genes. However, the gene expression changes occurred more slowly in the clinical samples. These changes included a consistent increase in expression of tRNA synthetases and solute transporters and activating transcription factor and CCAAT/enhancer binding protein family members, a response similar to that observed with amino acid starvation. There was also a consistent decrease in many genes associated with proliferation. Taken together, the changes seem to reflect a consistent coordinated response to asparagine starvation in both cell lines and clinical samples. Importantly, in the clinical samples, increased expression of ASNS after l-asparaginase exposure was not associated with in vitro resistance to l-asparaginase, indicating that ASNS-independent mechanisms of in vitro l-asparaginase resistance are common in ALL. These results suggest that targeting particular genes involved in the response to amino acid starvation in ALL cells may provide a novel way to overcome l-asparaginase resistance.
Correlation of molecular alterations with efficacy of everolimus in hormone-receptor–positive (HR+), HER2-negative advanced breast cancer: Preliminary results from BOLERO-2.
Authors: Gabriel N. Hortobagyi, Martine J. Piccart-Gebhart, Hope S. Rugo, Howard A. Burris, Mario Campone, Shinzaburo Noguchi, Alejandra T. Perez, Ines Deleu, Mikhail Shtivelband, Louise Provencher, Norikazu Masuda, Shaker R. Dakhil, Ian Anderson, David Chen, Amy Damask, Alan Huang, Robert McDonald, Tanya Taran, Tarek Sahmoud, José Baselga
Journal: Journal of Clinical Oncology (2013)

LBA509 The full, final text of this abstract will be available at abstract.asco.org at 7:30 AM (EDT) on Monday, June, 3, 2013, and in the Annual Meeting Proceedings online supplement to the June 20, 2013, issue of Journal of Clinical Oncology. Onsite at the Meeting, this abstract will be printed in the Monday edition of ASCO Daily News.
Longitudinal validation of clinical COPD phenotypes identified by cluster analysis
Authors: Pierre-Régis Burgel, Jean-Louis Paillasseur, Denis Caillaud, Isabelle Tillie-Leblond, Pascal Chanez, Roger Escamilla, Isabelle Court-Fortune, Thierry Perez, Philippe Carré, Nicolas Roche
Journal: European Respiratory Journal (2011)

Because FEV 1  is a poor descriptor of COPD heterogeneity, a great interest has emerged regarding the identification of clinically relevant COPD phenotypes. Using principal component and cluster analyses on multiple clinical variables, we described 4 COPD phenotypes (Burgel, P.R. et al. Eur Resp J 2010; 36: 531-9):  Phenotype 1: young subjects with severe respiratory disease.  Phenotype 2: older subjects with mild respiratory disease and few comorbidities.  Phenotype 3: young subjects with moderate to severe respiratory disease and few comorbidities.  Phenotype 4: older subjects with moderate to severe respiratory disease and major comorbidities.   Methods:  Data regarding vital status of the 322 COPD subjects included in our previous analyses were systematically requested. Cox proportional hazards model was performed to examine whether mortality was different among phenotypes.   Results:  Data were available for 303/322 (94.1%) subjects and median [IQR] follow-up was 3.35 [2.01; 4.25] yr. During prospective follow-up, 60/303 (19.8%) died. Differential mortality among phenotypes is shown in Table 1. Interestingly, the highest mortality rate was found among the youngest subjects (Phenotype 1).   Conclusion:  These data provide strong evidence that our previously identified phenotypes have different natural history.
Violence associated with phencyclidine abuse
Authors: M A Fauman, B J Fauman
Journal: American Journal of Psychiatry (1979)

Violence associated with chronic phencyclidine (PCP) abuse was investigated by administering a structured interview to 16 chronic PCP abusers. A more intensive study was done of another individual who committed murder and self-mutilation under the influence of PCP. The results suggest that there is no consistent association between PCP-related violence and a history of violence not related to drug or alcohol abuse. The author defines four types of violence associated with chronic PCP abuse.
Chromosomal Patterns of Irradiated Leukemic and Nonleukemic C57BL/6J Mice&lt;xref ref-type="fn" rid="FN1"&gt;2&lt;/xref&gt;
Authors: Charles F. Nadler
Journal: JNCI Journal of the National Cancer Institute (1963)

Chromosomes of 17 C57BL/6J mice receiving 600 r total-body X irradiation were analyzed and compared to chromosomes of 6 normal mice. Seven mice developed leukemia and 10 did not. Chromosomes of 4 leukemic mice were examined. Mouse #1 (generalized leukemia) had cells with a mode of 40, variation above the mode, and a large marker chromosome. Mouse #2 (localized thymic leukemia) had 2 hyperdiploid modes of 41 and 42 in thymic tissue, but normal chromosomes were in the spleen and marrow. Mouse #3 (generalized leukemia) had modes of 40 and 41 in the thymus, spleen, and marrow. Mouse #4 (localized thymic leukemia) had a modal number of 41 with variation about the mode. One of the 10 irradiated nonleukemic mice had some cells with a pseudodiploid karyotype containing a minute chromosome, and another had a questionable abnormality consisting of increased variation about the mode. The remaining 8 mice had normal chromosomes. Aneuploidy in irradiated nonleukemic mice may be due to preleukemia or to persistent X-ray induced aberrations. The possibility of persistent chromosomal alterations after X ray suggests irradiation leukemias are not ideal for evaluation of the significance of aneuploidy in mouse preleukemia or leukemia.
HER-2/neu gene amplification characterized by fluorescence in situ hybridization: poor prognosis in node-negative breast carcinomas.
Authors: M F Press, L Bernstein, P A Thomas, L F Meisner, J Y Zhou, Y Ma, G Hung, R A Robinson, C Harris, A El-Naggar, D J Slamon, R N Phillips, J S Ross, S R Wolman, K J Flom
Journal: Journal of Clinical Oncology (1997)

PURPOSE The HER-2/neu gene codes for a membrane receptor protein that is homologous, but distinct from the epidermal growth factor receptor. This investigation was performed to validate fluorescence in situ hybridization (FISH) as a sensitive and specific method for assessing HER-2/neu gene amplification in archival tissue and to test whether this alteration is associated with poor prognosis. MATERIALS AND METHODS HER-2/neu gene amplification was determined by FISH in 140 archival breast cancers, previously characterized for gene amplification by Southern hybridization or dot-blot hybridization, and for gene expression by Northern hybridization, Western immunoblot, or immunohistochemistry. A separate cohort of 324 node-negative breast cancers was assessed for amplification by FISH to determine the utility of HER-2/neu gene amplification. RESULTS Relative to solid-matrix blotting procedures, FISH analysis of HER-2/neu gene amplification showed a sensitivity of 98% and a specificity of 100% in 140 breast cancers. Among patients treated by surgery only, the relative risks (relative hazard) of early recurrence (recurrent disease within 24 months of diagnosis), recurrent disease (at any time), and disease-related death were statistically significantly associated with amplification. The prognostic information contributed by HER-2/neu amplification was independent of the other markers studied. CONCLUSION FISH was an alternative technique for determining gene amplification and had some distinct advantages over Southern hybridization. Our results demonstrate that HER-2/neu gene amplification in the absence of adjuvant therapy is an independent predictor of poor clinical outcome and is a stronger discriminant than tumor size. Women with small tumors that had gene amplification were at increased risk of recurrence and disease-related death.
Non-Hodgkin's lymphomas of childhood: an analysis of the histology, staging, and response to treatment of 338 cases at a single institution.
Authors: S B Murphy, D L Fairclough, R E Hutchison, C W Berard
Journal: Journal of Clinical Oncology (1989)

Between 1962 and 1986, a total of 338 consecutive newly diagnosed children and adolescents with non-Hodgkin's lymphomas (NHLs) were evaluated and treated at St Jude Children's Research Hospital (SJCRH). Median follow-up is 6.6 years (range, 1.8 to 23 years). The patients ranged in age from 7 months to 21 years (median, 10 years), and 71% were males. All cases were staged (I to IV) by a clinical staging system. Eighteen percent were stage I, 21% stage II, 43% stage III, and 18% stage IV. Cases frankly leukemic at diagnosis (ie, greater than 25% marrow blasts) were excluded from the analysis. Pathologic material from all cases was reviewed and classified according to the Working Formulation. The histologic distribution of cases was as follows: 38.8% diffuse small non-cleaved cell (undifferentiated, Burkitt's and non-Burkitt's); 26.3% diffuse large-cell, mainly immunoblastic; 28.1% lymphoblastic; and 6.8% other. Treatment policy evolved over time to a stage- and histology-specific strategy for treatment assignment, and overall results significantly improved by era from 37% (+/- 5%) 2-year event-free survival (EFS) for patients treated before 1975 to 77% (+/- 4%) since 1978. By univariate and multivariate Cox regression analyses, the era of treatment (hence, the protocol-specific treatment itself), the stage, and the log of the initial serum lactic dehydrogenase (LDH) emerged as the most powerful prognostic indicators, while histology per se was not significantly related to outcome. For the 154 patients treated since 1978, the 2-year EFS by stage was 97% (+/- 3%) for stage I, 86% (+/- 6%) for stage II, 73% (+/- 6%) for stage III, and 47% (+/- 11%) for stage IV (P less than .0001). Compared with our previous experience, we conclude that the cure rate of childhood NHL has doubled in the last decade with modern management.
3H-thymidine-labeling index as a prognostic indicator in node-positive breast cancer.
Authors: R Silvestrini, M G Daidone, P Valagussa, G Di Fronzo, G Mezzanotte, L Mariani, G Bonadonna
Journal: Journal of Clinical Oncology (1990)

The prognostic relevance of 3H-thymidine-labeling index (3H-TdR-LI) was retrospectively evaluated in 523 women with resectable node-positive breast cancer given adjuvant combination chemotherapy consisting of cyclophosphamide, methotrexate, and fluorouracil (CMF) +/- Adriamycin (doxorubicin; Farmitalia, Carlo Ezba, Italy). The 5-year relapse-free survival (RFS) and overall survival (OS) rates were significantly higher for patients with slowly proliferating tumors (3H-TdR-LI less than or equal to 2.8%) compared with rapidly proliferating tumors (RFS, 66% v 50%, P = .0007; OS, 85% v 73%, P = .0012). In the analysis of RFS, 3H-TdR-LI provided prognostic information independent of axillary node involvement, tumor size, and estrogen receptor (ER) status, with an estimated lower hazard ratio compared with the degree of nodal involvement, but equivalent to that of the other indicators. Conversely, nodal involvement was found to interact with 3H-TdR-LI and receptors on survival. Present findings confirm that tumor cell kinetics represents a prognostic indicator also in an adjuvant situation. 3H-TdR-LI can substantially contribute to a more precise definition of high-risk patients within subsets having the traditionally favorable prognostic characteristics.
Flurbiprofen does not affect elastase-induced bronchial secretory cell metaplasia in hamsters
Authors: H M Nields, G L Snider, T G Christensen
Journal: European Respiratory Journal (1991)

The anti-inflammatory drug flurbiprofen speeds the repair of cigarette smoke-induced bronchial secretory cell metaplasia (SCM) in rats. We tested whether flurbiprofen would prevent or mitigate the development of elastase-induced bronchial SCM in hamsters. Twice daily injections of flurbiprofen (4 or 6 mg.kg-1.day-1) were begun immediately after intertracheal instillation of porcine pancreatic elastase (PPE) or its vehicle, saline. At 3 wks, the bronchi of these animals were compared to those of animals receiving PPE or saline. PPE-treated hamsters, with or without flurbiprofen, developed moderate to severe SCM. Control hamsters had normal airways. Flurbiprofen had no effect on the neutrophilic pulmonary infiltrate seen 2 h after PPE instillation. We conclude that the development of elastase-induced SCM in hamsters is not affected by a flurbiprofen regimen begun directly after elastase instillation. The pathogenesis of this lesion may involve factors which are insensitive to flurbiprofen or which trigger the lesion immediately upon exposure to the enzyme.
Perspectives of pediatricians and general practitioners on definition and important outcomes in bronchiolitis
Authors: Ricardo M. Fernandes, Daisy Abreu, Maria Gabriela Andrade, Carolina Constant, Duarte Malveiro, Manuel Magalhães, Inês Azevedo, Eduarda Sousa, Rizério Salgado, Teresa Bandeira
Journal: European Respiratory Journal (2014)

We assessed the perspectives of pediatricians (Peds) and general practitioners (GPs) on definition and clinically important outcomes in bronchiolitis.  The ABBA study was a nationwide online survey with members of the Portuguese Society of Pediatrics and of GPs9 mailing lists.The questionnaire evaluated agreement with statements on bronchiolitis definition,and importance given to different outcomes.We used principal component analysis (PCA) to explore dimensions underlying disease definition,and MANOVA to explore their determinants.  514 Peds and 165 GPs participated (59% specialists).On definition,most Peds agreed with preceding coryza (93%),wheezing (93%) and rales/crepitations (90%),and disagreed with sudden onset (68%),but varied on nr of episodes (1st: 32%,  Physician definitions of bronchiolitis have considerable variability and often mismatch those of clinical trials.Rating of important outcomes was consistent.Our results contribute to rational study design and interpretation of evidence,and inform a core outcome set in this field.
High-Dose Chemotherapy With Autologous Hematopoietic Stem-Cell Transplantation for Advanced Soft Tissue Sarcoma in Adults
Authors: J-Y. Blay, D. Bouhour, I. Ray-Coquard, C. Dumontet, T. Philip, P. Biron
Journal: Journal of Clinical Oncology (2000)

PURPOSE: Patients with metastatic or locally advanced, unresectable soft tissue sarcoma (ASTS) are seldom curable, with 5-year survival rates of less than 10% in all large series. The role of high-dose chemotherapy (HDCT) with hematopoietic stem-cell support in this disease is not established. PATIENTS AND METHODS: Between 1988 and 1994, 30 patients with ASTS who responded to a standard chemotherapy regimen were included in a prospective pilot study of HDCT as consolidation therapy using ifosfamide (12 g/m 2 ), etoposide (800 mg/m 2 ), and cisplatin (200 mg/m 2 ) (VIC). RESULTS: The median duration of grade 4 neutropenia and thrombocytopenia was 14 and 10 days, respectively. Nineteen patients (63%) experienced grade 1 or higher renal toxicity. All eight patients in complete remission (CR) before HDCT were still in CR at day 60. Of the 22 patients in partial remission (PR) or with a minor response to conventional chemotherapy, CR, PR, and stable disease were achieved in four (18%), three (13%), and 12 patients (54%), respectively, by day 60, while three patients (14%) progressed. With a median follow-up of 94 months, overall and progression-free survival rates at 5 years after HDCT were 23% and 21%, respectively. Patients in CR before HDCT had a significantly superior 5-year overall survival rate compared with other patients (75% v 5%; P = .001). CONCLUSION: Despite the toxicity of the VIC regimen, a high survival rate was observed in HDCT-treated patients who were in CR after conventional chemotherapy. A phase III randomized trial is required to establish the role of HDCT in ASTS.