tbuckley/cabot-search huggingface dataset:
Combination therapy with pentostatin and cyclophosphamide for advanced refractory cutaneous T cell lymphoma (CTCL)
Authors: Y. Ji, F. Foss
Journal: Journal of Clinical Oncology (2004)

6713 Background: CTCL comprises a spectrum of diseases of mature CD4+ T-lymphocytes. While a number of therapies, including cytokines, retinoids, and IL-2 receptor targeted agents, have demonstrated activity in patients with advanced and refractory disease, response durations have been short and no therapy has thus far demonstrated a survival benefit. Single agent therapy with purine analogs in patients with advanced disease has been reported, with response rates ranging from 20–30% for fludarabine and cladribine to 50–60% with pentostatin. Recent studies have demonstrated that the combination of alkylating agents with purine analogs is tolerable and may be associated with enhanced efficacy in patients with B-CLL and low grade B-NHL. Methods: We conducted a pilot study of the combination of pentostatin (3 mg/m2 daily x 3) with cyclophosphamide (600 mg/m2 on day 1) every 21 days in patients with advanced and refractory CTCL. Of six patients enrolled, all had failed multiple therapies including denileukin diftitox and bexarotene. Three had tumor stage disease (IIB), two had diffuse erythroderma (IIIB), and one had visceral involvement with a lung nodule (IVB). Three of these patients had Sezary syndrome. Results: Four of six patients responded, with three complete and one partial response. One patient had progressive disease and one discontinued therapy after two cycles due to dyspnea possibly related to pentostatin. Two of the patients with Sezary syndrome had complete and partial response, respectively, while the third had progressive disease. Response durations in the complete responders were 17 months, 29+ months, and 10 months in one patient who was consolidated with an allogeneic bone marrow transplant while in remission. The regimen was well-tolerated and no patient experienced grade IV hematologic toxicity. Conclusions: The combination of pentostatin and cyclophosphamide is active and well-tolerated in patients with advanced and refractory CTCL. This regimen should be further investigated in a phase II trial. No significant financial relationships to disclose.
NEUTRALIZING ANTIVIRAL B CELL RESPONSES
Authors: Martin F. Bachmann, Rolf M. Zinkernagel
Journal: Annual Review of Immunology (1997)

▪ Abstract Neutralizing antiviral B cell responses differ in various aspects from the many usually measured B cell responses specific for protein in adjuvants. In particular, such neutralizing antiviral B cell responses are more rapidly induced, reach higher titers, are longer lived, and are efficiently generated without adjuvants. Evidence is summarized here that the repetitiveness of many viral antigens is a key factor responsible for the efficiency of these B cell responses, amplifying B cells early and rapidly for potent IgM responses and also for efficient switching to IgG. The data reviewed indicate that B cells discriminate antigen patterns via the degree of surface Ig-cross-linking and use antigen repetitiveness as a self/nonself discriminator.
Matrix Metalloproteinase-3 Genotype Contributes to Age-Related Aortic Stiffening Through Modulation of Gene and Protein Expression
Authors: Tanya L. Medley, Bronwyn A. Kingwell, Christoph D. Gatzka, Prakash Pillay, Timothy J. Cole
Journal: Circulation Research (2003)

Matrix metalloproteinases (MMPs) include most major constituents of the arterial wall as substrates. A common promotor polymorphism (5A/6A) is associated with differences in MMP-3 (stromelysin-1) activity, and associations with certain forms of vascular disease have been shown. This study investigated whether the MMP-3 5A/6A promoter polymorphism contributes to age-related large artery stiffening. MMP-3 5A/6A genotype was determined in 203 (135 male) low cardiovascular risk, unmedicated individuals who were divided prospectively into two groups (30 to 60 years, n=126; ≥61 years, n=77). Noninvasive large artery stiffness was measured as ascending aortic input impedance from brachial blood pressure, carotid tonometry, and Doppler ascending aortic blood flow. In the older group, homozygotes had higher aortic input ( P &lt;0.01) and characteristic ( P &lt;0.01) impedance, ie, higher stiffness, than heterozygotes after correction for the effects of age, gender, and mean arterial pressure. There was no such difference in the younger group. Gene expression was subsequently investigated in dermal biopsies in randomly selected older men from the same cohort with real-time PCR (n=40). In 5A homozygotes, gene expression was 4-fold higher ( P &lt;0.05), and in 6A homozygotes, 2-fold lower ( P &lt;0.05) compared with the heterozygotes. Differences in gene expression were associated with corresponding significant changes in MMP-3 protein levels. Concordance between dermal and aortic gene and protein expression was shown in a separate cohort of postmortem aortic samples (n=7). We conclude that MMP-3 genotype may be an important determinant of vascular remodeling and age-related arterial stiffening, with the heterozygote having the optimal balance between matrix accumulation and deposition.
TA-19, a Novel Protein Antigen of<i>Trichosporon asahii</i>, in Summer-type Hypersensitivity Pneumonitis
Authors: Yasujiro Matsunaga, Yutaka Usui, Yasuyuki Yoshizawa
Journal: American Journal of Respiratory and Critical Care Medicine (2003)

The most common form of hypersensitivity pneumonitis in Japan is summer-type hypersensitivity pneumonitis (SHP), which is caused by the inhalation of Trichosporon asahii or Trichosporon mucoides. To seek protein antigens relevant to the immunopathogenesis of SHP, we constructed a cDNA expression library of T. asahii, a major causative yeast species of SHP. Using the immunoscreening method, we identified and cloned a novel gene encoding a 19-kD protein, named TA-19, which proved to be specifically recognized in the bronchoalveolar lavage (BAL) fluids and sera of patients with SHP. IgG, IgA, and IgM antibodies to the recombinant TA-19 protein were significantly elevated in the sera as well as in the BAL fluids from SHP patients compared with those from non-SHP groups. This protein also induced SHP-specific proliferation of the mononuclear cells from both the peripheral blood and BAL. These results reveal that TA-19 derived from T. asahii may play a relevant role in specific cellular and humoral immune responses in patients with SHP.
Effect of long-term primary aerosolized pentamidine prophylaxis on breakthrough Pneumocystis carinii pneumonia
Authors: S Ewig, H Schafer, JK Rockstroh, A Pickenhain, B Luderitz
Journal: European Respiratory Journal (1996)

Aerosolized pentamide is a well-tolerated primary prophylaxis regimen for Pneumocystis carinii pneumonia (PCP) in human immunodeficiency virus (HIV)-infected patients. It is now commonly administered for prolonged periods. We therefore studied the effect of long-term inhalation on breakthrough PCP. We recorded clinical, immunological, radiological and microbiological data, as well as therapy and clinical course of all episodes with confirmed PCP diagnosed at our institution between January 1, 1990 and June 30, 1995. Furthermore, data of all patients on primary aerosolized pentamidine since May 1, 1989 were retrieved. Prophylaxis failures were subdivided into "early" (< or = 12 months of inhalation time) and "late" (> 12 months of inhalation time) failures and were compared with episodes without any prophylaxis. Thirty patients without any prophylaxis, six with early and 14 with late failures represented the study population. Mean +/- SD inhalation times were 4.9 +/- 4.8 and 26.3 +/- 14.1 months, respectively. No significant differences could be detected with regard to clinical presentation, severity of PCP, and in-hospital as well as long term outcome. Early as well as late prophylaxis failures had a higher incidence of upper lobe infiltrates on chest radiography (50% without prophylaxis versus 100% with early and 83% with late failure, respectively; p < 0.05). No extrapulmonary or disseminated pneumocystosis was observed in either group. The sensitivity of site-directed bronchoalveolar lavage was conserved after long-term inhalation (86% versus 100% without prophylaxis and 97% in early failure; p = NS). The severity and outcome of Pneumocystis carinii pneumonia is not altered by long-term primary aerosolized pentamidine prophylaxis. Presentation with upper lobe infiltrates is a radiographic pattern also of late failures. Bronchoalveolar lavage should, therefore, be performed using the site-directed technique in this setting.
MicroRNA-125a-5p Is an Independent Prognostic Factor in Gastric Cancer and Inhibits the Proliferation of Human Gastric Cancer Cells in Combination with Trastuzumab
Authors: Naohiro Nishida, Koshi Mimori, Muller Fabbri, Takehiko Yokobori, Tomoya Sudo, Fumiaki Tanaka, Kohei Shibata, Hideshi Ishii, Yuichiro Doki, Masaki Mori
Journal: Clinical Cancer Research (2011)

MicroRNA 125a-5p (miR-125a-5p) has been reported to be a tumor suppressor in malignancies of the breast, ovary, lung, and central nervous system. However, the clinical significance of miR-125a-5p in human gastrointestinal cancer has not been explored. We investigated a tumor inhibitory effect of miR-125a-5p in gastric cancer, focusing in particular on the miR-125a-ERBB2 (HER2, HER-2/neu) pathway.Quantitative RT-PCR was used to evaluate miR-125a-5p expression in 87 gastric cancer cases to determine the clinicopathologic significance of miR-125a-5p expression. The regulation of ERBB2 by miR-125a-5p was examined with precursor miR-125a-transfected cells. Furthermore, we investigated whether miR-125a-5p suppresses proliferation of gastric cancer cells in combination with trastuzumab, a monoclonal antibody against ERBB2.Low expression levels of miR-125a-5p were associated with enhanced malignant potential such as tumor size (P = 0.0068), tumor invasion (P = 0.031), liver metastasis (P = 0.029), and poor prognosis (P = 0.0069). Multivariate analysis indicated that low miR-125a-5p expression was an independent prognostic factor for survival. In vitro assays showed that ERBB2 is a direct target of miR-125a-5p, which potently suppressed the proliferation of gastric cancer cells, and, interestingly, the growth inhibitory effect was enhanced in combination with trastuzumab.miR-125a-5p is a meaningful prognostic marker. Furthermore, miR-125a-5p mimic alone or in combination with trastuzumab could be a novel therapeutic approach against gastric cancer.
Metabolic Syndrome in Men With Prostate Cancer Undergoing Long-Term Androgen-Deprivation Therapy
Authors: Milena Braga-Basaria, Adrian S. Dobs, Denis C. Muller, Michael A. Carducci, Majnu John, Josephine Egan, Shehzad Basaria
Journal: Journal of Clinical Oncology (2006)

Purpose Prostate cancer (PCa) is one of the most common cancers in men. Men with recurrent or metastatic PCa are treated with androgen-deprivation therapy (ADT), resulting in profound hypogonadism. Because male hypogonadism is a risk factor for metabolic syndrome and men with PCa have high cardiovascular mortality, we evaluated the prevalence of metabolic syndrome in men undergoing long-term ADT. Patients and Methods This was a cross-sectional study. We evaluated 58 men, including 20 with PCa undergoing ADT for at least 12 months (ADT group), 18 age-matched men with nonmetastatic PCa who had received local treatment and were recently found to have an increasing prostate-specific antigen (non-ADT group), and 20 age-matched controls (control group). Men in the non-ADT and control groups were eugonadal. Metabolic syndrome was defined according to the Adult Treatment Panel III criteria. Results Mean age was similar among the groups. Men on ADT had significantly higher body mass index and lower total and free testosterone levels. The prevalence of metabolic syndrome was higher in the ADT group compared with the non-ADT (P &lt; .01) and control (P = .03) groups. Among the components of metabolic syndrome, men on ADT had a higher prevalence of abdominal obesity and hyperglycemia. Androgen-deprived men also had elevated triglycerides compared with controls (P = .02). The prevalence of hypertension and low high-density lipoprotein levels were similar. Conclusion These data suggest that metabolic syndrome was present in more than 50% of the men undergoing long-term ADT, predisposing them to higher cardiovascular risk. Abdominal obesity and hyperglycemia were responsible for this higher prevalence. We recommend prospective studies to further delineate this association.
High Frequency of Hereditary Colorectal Cancer in Newfoundland Likely Involves Novel Susceptibility Genes
Authors: Michael O. Woods, Angela J. Hyde, Fiona K. Curtis, Susan Stuckless, Jane S. Green, Aaron F. Pollett, J. Desmond Robb, Roger C. Green, Marina E. Croitoru, Amanda Careen, Jason A.W. Chaulk, Jegan Jegathesan, John R. McLaughlin, Steven S. Gallinger, H. Banfield Younghusband, Bharati V. Bapat, Patrick S. Parfrey
Journal: Clinical Cancer Research (2005)

Abstract Purpose: Newfoundland has one of the highest rates of colorectal cancer in North America. The most common hereditary form of colorectal cancer is hereditary nonpolyposis colorectal cancer caused by mutations in genes involved in mismatch repair. Our purpose was to determine the proportion of hereditary colorectal cancer and to determine the genetic basis of disease in both population and clinically referred cohorts from Newfoundland. Experimental Design: Seventy-eight colorectal cancer patients were accrued over a 2-year period from the Avalon Peninsula of Newfoundland. We also examined 31 hereditary nonpolyposis colorectal cancer–like families, which had been referred to the Provincial Medical Genetics Program. Tumors from probands were tested by immunohistochemistry for deficiencies in MLH1, MSH2, and MSH6 proteins and tested for DNA microsatellite instability. Mutation analyses of MLH1, MSH2, and MSH6 were undertaken by direct sequencing and an assay to detect deletions, amplifications, and rearrangements in MSH2 and MLH1. Results: We identified eight population-based families that fulfill the Amsterdam I or II criteria, 4 (50%) of which seem to have hereditary cancer not attributable to the most commonly mutated mismatch repair genes. In addition, in 16 of 21 (76%) referred families fulfilling Amsterdam I or II criteria, no mutations were found in the three most commonly altered mismatch repair genes, and tumor analyses corroborated these findings. Conclusions: It seems that strong and novel genetic causes of hereditary colorectal cancer are responsible for a high proportion of colorectal cancer in this population. Conditions are suitable for the identification of these genes by linkage studies of large Newfoundland cancer families.
Genetic basis for increased intestinal permeability in families with Crohn's disease: role of CARD15 3020insC mutation?
Authors: S Buhner
Journal: Gut (2005)

<b>Background and aim:</b> A genetically impaired intestinal barrier function has long been suspected to be a predisposing factor for Crohn’s disease (CD). Recently, mutations of the capsase recruitment domain family, member 15 (<i>CARD15</i>) gene have been identified and associated with CD. We hypothesise that a <i>CARD15</i> mutation may be associated with an impaired intestinal barrier. <b>Methods:</b> We studied 128 patients with quiescent CD, 129 first degree relatives (CD-R), 66 non-related household members (CD-NR), and 96 healthy controls. The three most common <i>CARD15</i> polymorphisms (R702W, G908R, and 3020insC) were analysed and intestinal permeability was determined by the lactulose/mannitol ratio. <b>Results:</b> Intestinal permeability was significantly increased in CD and CD-R groups compared with CD-NR and controls. Values above the normal range were seen in 44% of CD and 26% of CD-R but only in 6% of CD-NR, and in none of the controls. A household community with CD patients, representing a common environment, was not associated with increased intestinal permeability in family members. However, 40% of CD first degree relatives carrying a <i>CARD15</i> 3020insC mutation and 75% (3/4) of those CD-R with combined 3020insC and R702W mutations had increased intestinal permeability compared with only 15% of wild-types, indicating a genetic influence on barrier function. R702W and G908R mutations were not associated with high permeability. <b>Conclusions:</b> In healthy first degree relatives, high mucosal permeability is associated with the presence of a <i>CARD15</i> 3020insC mutation. This indicates that genetic factors may be involved in impairment of intestinal barrier function in families with IBD.
Dynamics of normal and ischemic canine papillary muscles.
Authors: S C Rayhill, G T Daughters, L J Castro, M A Niczyporuk, M R Moon, N B Ingels, M L Stadius, G C Derby, A F Bolger, D C Miller
Journal: Circulation Research (1994)

This investigation was designed to elucidate the dynamics of the left ventricular (LV) papillary muscles. Miniature tantalum myocardial markers were placed on the tip and base of each papillary muscle in six dogs. Markers were also implanted into the LV myocardium to define two orthogonal equatorial diameters and the long-axis dimension. Two weeks later, after recovery from thoracotomy, markers were visualized by biplane fluoroscopy, and video images were recorded during control conditions, after autonomic blockade, after inotropic stimulation with calcium, after methoxamine infusion (to increase afterload), and after blood volume augmentation (to increase preload). Two days later, radiographic recordings were made before and after occlusion of the left circumflex coronary artery. Computer-aided analysis of the video recordings was used to determine three-dimensional coordinates of the markers. It was found that before circumflex coronary occlusion, the dynamics of both papillary muscles closely mimicked the dynamics of the LV as a whole. The papillary muscles shortened during ejection and lengthened during diastole. Their lengths changed minimally during the isovolumic periods, and this behavior was not altered by any of the interventions except coronary occlusion. During circumflex coronary artery occlusion, the ischemic posterior papillary muscle lengthened during isovolumic contraction and most of ejection and shortened only when LV pressure began to fall. Hence, we believe that previous studies demonstrating papillary muscle lengthening during isovolumic contraction and shortening during isovolumic relaxation may have been confounded by coexistent myocardial ischemia or stunning.
Challenging the roles of CD44 and lipolysis stimulated lipoprotein receptor in conveying Clostridium perfringens iota toxin cytotoxicity in breast cancer
Authors: Katerina D Fagan-Solis, Denise K Reaves, M Cristina Rangel, Michel R Popoff, Bradley G Stiles, Jodie M Fleming
Journal: Molecular Cancer (2014)

Translational exploration of bacterial toxins has come to the forefront of research given their potential as a chemotherapeutic tool. Studies in select tissues have demonstrated that Clostridium perfringens iota toxin binds to CD44 and lipolysis stimulated lipoprotein receptor (LSR) cell-surface proteins. We recently demonstrated that LSR expression correlates with estrogen receptor positive breast cancers and that LSR signaling directs aggressive, tumor-initiating cell behaviors. Herein, we identify the mechanisms of iota toxin cytotoxicity in a tissue-specific, breast cancer model with the ultimate goal of laying the foundation for using iota toxin as a targeted breast cancer therapy. In vitro model systems were used to determine the cytotoxic effect of iota toxin on breast cancer intrinsic subtypes. The use of overexpression and knockdown technologies confirmed the roles of LSR and CD44 in regulating iota toxin endocytosis and induction of cell death. Lastly, cytotoxicity assays were used to demonstrate the effect of iota toxin on a validated set of tamoxifen resistant breast cancer cell lines. Treatment of 14 breast cancer cell lines revealed that LSR+/CD44- lines were highly sensitive, LSR+/CD44+ lines were slightly sensitive, and LSR-/CD44+ lines were resistant to iota cytotoxicity. Reduction in LSR expression resulted in a significant decrease in toxin sensitivity; however, overexpression of CD44 conveyed toxin resistance. CD44 overexpression was correlated with decreased toxin-stimulated lysosome formation and decreased cytosolic levels of iota toxin. These findings indicated that expression of CD44 drives iota toxin resistance through inhibition of endocytosis in breast cancer cells, a role not previously defined for CD44. Moreover, tamoxifen-resistant breast cancer cells exhibited robust expression of LSR and were highly sensitive to iota-induced cytotoxicity. Collectively, these data are the first to show that iota toxin has the potential to be an effective, targeted therapy for breast cancer.
Interchromosomal Segmental Duplications Explain the Unusual Structure of PRSS3, the Gene for an Inhibitor-Resistant Trypsinogen
Authors: Lee Rowen, Eleanor Williams, Gustavo Glusman, Elena Linardopoulou, Cynthia Friedman, Mary Ellen Ahearn, Jason Seto, Cecilie Boysen, Shizhen Qin, Kai Wang, Amardeep Kaur, Scott Bloom, Leroy Hood, Barbara J. Trask
Journal: Molecular Biology and Evolution (2005)

Homo sapiens possess several trypsinogen or trypsinogen-like genes of which three (PRSS1, PRSS2, and PRSS3) produce functional trypsins in the digestive tract. PRSS1 and PRSS2 are located on chromosome 7q35, while PRSS3 is found on chromosome 9p13. Here, we report a variation of the theme of new gene creation by duplication: the PRSS3 gene was formed by segmental duplications originating from chromosomes 7q35 and 11q24. As a result, PRSS3 transcripts display two variants of exon 1. The PRSS3 transcript whose gene organization most resembles PRSS1 and PRSS2 encodes a functional protein originally named mesotrypsinogen. The other variant is a fusion transcript, called trypsinogen IV. We show that the first exon of trypsinogen IV is derived from the noncoding first exon of LOC120224, a chromosome 11 gene. LOC120224 codes for a widely conserved transmembrane protein of unknown function. Comparative analyses suggest that these interchromosomal duplications occurred after the divergence of Old World monkeys and hominids. PRSS3 transcripts consist of a mixed population of mRNAs, some expressed in the pancreas and encoding an apparently functional trypsinogen and others of unknown function expressed in brain and a variety of other tissues. Analysis of the selection pressures acting on the trypsinogen gene family shows that, while the apparently functional genes are under mild to strong purifying selection overall, a few residues appear under positive selection. These residues could be involved in interactions with inhibitors.
Rheumatoid knee synovitis successfully treated with intra-articular rifamycin SV.
Authors: I Caruso, F Montrone, M Fumagalli, C Patrono, S Santandrea, M C Gandini
Journal: Annals of the Rheumatic Diseases (1982)

Thirty rheumatoid patients with persistent knee effusion were treated intra-articularly with rifamycin SV, 500 mg weekly, or with saline solution, 10 ml, in a double-blind study. A complete disappearance of effusion and an impressive clinical improvement was observed in the patients on rifamycin. The synovial fluid and membrane underwent some changes. In 2 patients the rifamycin caused a painful local reaction. After a follow-up of 5 years only one patient has experienced effusion relapse, 5 months after the termination of rifamycin SV treatment. The patients on saline showed no significant change. On the basis of the results obtained from the monoarthritis experimental model and from clinical trials it is tempting to consider that rifamycin has an antimitotic effect, impeding the synthesis of RNA and DNA polymerases in immunocompetent cells.