tbuckley/cabot-search huggingface dataset:
USE OF INTRAVENOUS IMMUNOGLOBULIN TO PREVENT OR TREAT INFECTIONS IN PERSONS WITH IMMUNE DEFICIENCY
Authors: Martin L. Lee, PhD, CStat, Robert Peter Gale, MD, PhD, Peng Lee Yap, MD
Journal: Annual Review of Medicine (1997)

Intravenous immunoglobulin (IVIG) concentrates were originally developed as replacement therapy for individuals with primary deficiencies of the immune system. However, in various well-designed, controlled clinical trials, the ability of IVIG to prevent and possibly treat infections in patients with secondary immune deficiencies has also been considered. In this review, we briefly consider these different applications and suggest whether the data are sufficient to employ IVIG in these clinical settings.
Gene Conversion and DNA Sequence Polymorphism in the Sex-Determination Gene fog-2 and Its Paralog ftr-1 in Caenorhabditis elegans
Authors: H. S. Rane, J. M. Smith, U. Bergthorsson, V. Katju
Journal: Molecular Biology and Evolution (2010)

Gene conversion, a form of concerted evolution, bears enormous potential to shape the trajectory of sequence and functional divergence of gene paralogs subsequent to duplication events. fog-2, a sex-determination gene unique to Caenorhabditis elegans and implicated in the origin of hermaphroditism in this species, resulted from the duplication of ftr-1, an upstream gene of unknown function. Synonymous sequence divergence in regions of fog-2 and ftr-1 (excluding recent gene conversion tracts) suggests that the duplication occurred 46 million generations ago. Gene conversion between fog-2 and ftr-1 was previously discovered in experimental fog-2 knockout lines of C. elegans, whereby hermaphroditism was restored in mutant obligately outcrossing male–female populations. We analyzed DNA-sequence variation in fog-2 and ftr-1 within 40 isolates of C. elegans from diverse geographic locations in order to evaluate the contribution of gene conversion to genetic variation in the two gene paralogs. The analysis shows that gene conversion contributes significantly to DNA-sequence diversity in fog-2 and ftr-1 (22% and 34%, respectively) and may have the potential to alter sexual phenotypes in natural populations. A radical amino acid change in a conserved region of the F-box domain of fog-2 was found in natural isolates of C. elegans with significantly lower fecundity. We hypothesize that the lowered fecundity is due to reduced masculinization and less sperm production and that amino acid replacement substitutions and gene conversion in fog-2 may contribute significantly to variation in the degree of inbreeding and outcrossing in natural populations.
Methylation of p16 in EBUS-TBNA samples as a predictor of advanced disease in lung cancer
Authors: Laura Millares, Laia Setó, Felipe Andreo, Jose Sanz, Mireia Serra, Concepcion Monton, Eduard Monsó
Journal: European Respiratory Journal (2013)

Introduction  Aberrant methylation of DNA results in gene silencing and is frequently observed in tumour samples from patients with lung cancer. Epigenetic changes significantly contribute to tumour progression allowing cancer cells to disseminate from the primary tumour and metastasize to and survive at a distant site. Thus, the detection of methylation in the draining lymph nodes may be important to assess the prognosis of the disease.  Objective  To determine the relationship between the methylation status of 5 genes in samples of lymph nodes obtained by endobronchial ultrasound with real-time guided transbronchial needle aspiration (EBUS-TBNA) and the presence of an advanced stage of lung cancer.  Methods  Nodal samples obtained with EBUS-TBNA were flash-frozen with N2. After DNA extraction, DNA was chemically modified and the methylation status of DAPK, p16, RASSF1, APC and CDH-13 genes was determined by methylation-sensitive high resolution melting  Results  Fifty four samples were obtained from patients with NSCLC (age 70 SD 8 years). Forty nodal samples show malignancy (23 adenocarcinoma, 13 squamous and 4 undifferentiated carcinoma) and 14 samples were non-metastatic nodes. P16 gene appeared methylated in significantly more samples from patients with advanced stage of lung cancer, 7/24 (29%) IIIb- V stage vs 2/30 (7%) I-IIIa stage, p= 0.027, χ2 test. The other 4 tested genes did not show statistical differences (p>0.05) between early and more advanced stage of cancer.  Conclusion  Methylation of p16 gene in cells obtained from lymph nodes accessible to EBUS-TBNA is a predictor of advanced disease in NSCLC and may be important in the management of patients with lung cancer  Funded by FIS 09/01612 and FUCAP.
Hypothermic stress leads to activation of Ras-Erk signaling
Authors: Edmond Y.W. Chan, Stacey L. Stang, Drell A. Bottorff, James C. Stone
Journal: Journal of Clinical Investigation (1999)

The small GTPase Ras is converted to the active, GTP-bound state during exposure of vertebrate cells to hypothermic stress. This activation occurs more rapidly than can be accounted for by spontaneous nucleotide exchange. Ras-guanyl nucleotide exchange factors and Ras GTPase-activating proteins have significant activity at 0 degrees C in vitro, leading to the hypothesis that normal Ras regulators influence the relative amounts of Ras-GTP and Ras-GDP at low temperatures in vivo. When hypothermic cells are warmed to 37 degrees C, the Raf-Mek-Erk protein kinase cascade is activated. After prolonged hypothermic stress, followed by warming to physiologic temperature, cultured fibroblasts assume a rounded morphology, detach from the substratum, and die. All of these biologic responses are attenuated by pharmacologic inhibition of Mek. Previously, it had been found that low temperature blocks acute growth factor signaling to Erk. In the present study, we found that this block occurs at the level of Raf activation. Temperature regulation of Ras signaling could help animal cells respond appropriately to hypothermic stress, and Ras-Erk signaling can be manipulated to improve the survival of cells in cold storage.
Inflammatory response to fine particulate air pollution exposure: Neutrophil versus monocyte
Authors: Xiaohua Xu, Silis Jiang, Yuntao Bai, Aixia Wang, Mianhua Zhong, Lung-Chi Chen, Qinghua Sun
Journal: European Respiratory Journal (2014)

Introduction: Studies have shown that chronic exposure to ambient fine particulate matter (less than 2.5 mm in aerodynamic diameter, PM2.5) pollution induces insulin resistance through alterations in inflammatory pathways. It is critical to study how the immune system responds to this stimulant, which has been linked to cardiovascular and autoimmune diseases, but few studies have been focused on such involvement of both neutrophils and monocytes in a timely manner. We hypothesized that the neutrophil was involved in the inflammatory response to air pollution.  Methods and Results: C57BL/6 mice were exposed to PM2.5 or filtered air (6 hours/day, 5 days/week) for 5, 14, and 21 days, respectively, in Columbus, OH. At the end of each of the exposure periods, we investigated the inflammatory response through flow cytometry, histology, intravital microscopy, and real-time PCR. PM2.5-exposed mice demonstrated a significant inflammatory response after 5 days of exposure. In the lung tissue and bronchoalveolar lavage fluid, monocytes/macrophages showed a transient response, while neutrophils showed a cumulative response. In addition, exposure to PM2.5 resulted in elevation of the monocyte chemoattractant protein 1 (MCP-1) cytokine, a monocyte/macrophage attractant in blood, at an early stage of exposure.  Conclusions: These findings suggest that PM2.5 exposure induces the inflammatory responses from both macrophages and neutrophils involvement.
Randomized Trial of Lapatinib Versus Placebo Added to Paclitaxel in the Treatment of Human Epidermal Growth Factor Receptor 2–Overexpressing Metastatic Breast Cancer
Authors: Zhongzhen Guan, Binghe Xu, Michelle L. DeSilvio, Zhenzhou Shen, Wichit Arpornwirat, Zhongsheng Tong, Vicharn Lorvidhaya, Zefei Jiang, Junlan Yang, Anatoly Makhson, Wai Lim Leung, Mark W. Russo, Beth Newstat, Li Wang, George Chen, Cristina Oliva, Henry Gomez
Journal: Journal of Clinical Oncology (2013)

Lapatinib is an oral small-molecule tyrosine kinase inhibitor of both epidermal growth factor receptor and human epidermal growth factor receptor 2 (HER2). This study is designed to test whether the addition of lapatinib to paclitaxel improves overall survival (OS) compared with placebo plus paclitaxel in patients with HER2-overexpressing metastatic breast cancer (MBC).This phase III, randomized, double-blind study assessed the efficacy and safety of lapatinib plus paclitaxel compared with placebo plus paclitaxel in patients with newly diagnosed HER2-positive MBC. The primary end point was OS. Secondary end points included progression-free survival (PFS), overall response rate (ORR), clinical benefit rate, and safety.The addition of lapatinib to paclitaxel significantly improved OS versus paclitaxel (treatment hazard ratio [HR], 0.74; 95% CI, 0.58 to 0.94; P = .0124); median OS was 27.8 versus 20.5 months, respectively. Median PFS was prolonged by 3.2 months, from 6.5 months with placebo plus paclitaxel to 9.7 months with lapatinib plus paclitaxel (HR, 0.52; 95% CI, 0.42 to 0.64; stratified log-rank P < .001). ORR was significantly higher with lapatinib plus paclitaxel compared with placebo plus paclitaxel (69% v 50%, respectively; P < .001). The incidence of grades 3 and 4 diarrhea and neutropenia was higher in the lapatinib plus paclitaxel arm. Only 4% of patients in this group reported febrile neutropenia. Cardiac events were low grade, asymptomatic, and mostly reversible. The incidence of hepatic events was similar in both arms. There were no fatal adverse events in the lapatinib plus paclitaxel arm.This trial demonstrated that lapatinib combined with paclitaxel offers a significant and clinically meaningful survival advantage over paclitaxel alone in patients with HER2-positive MBC.
Induction of unresponsiveness and impaired T cell expansion by staphylococcal enterotoxin B in CD28-deficient mice.
Authors: H W Mittrücker, A Shahinian, D Bouchard, T M Kündig, T W Mak
Journal: The Journal of Experimental Medicine (1996)

We used CD28-deficient mice to analyze the importance of CD28 costimulation for the response against Staphylococcal enterotoxin B (SEB) in vivo. CD28 was necessary for the strong expansion of V beta 8+ T cells, but not for deletion. The lack of expansion was not due to a failure of SEB to activate V beta 8+ T cells, as V beta 8+ T cells from both CD28-/- and CD28+/+ mice showed similar phenotypic changes within the first 24 h after SEB injection and cell cycle analysis showed that an equal percentage of V beta 8+ T cells started to proliferate. However, the phenotype and the state of proliferation of V beta 8+ T cells was different at later time points. Furthermore, in CD28-/- mice injection with SEB led to rapid induction of unresponsiveness in SEB responsive T cells, indicated by a drastic reduction of proliferation after secondary SEB stimulation in vitro. Unresponsiveness could also be demonstrated in vivo, as CD28-/- mice produced only marginal amounts of TNF alpha after rechallenge with SEB. In addition CD28-/- mice were protected against a lethal toxic shock induced by a second injection with SEB. Our results indicate that CD28 costimulation is crucial for the T cell-mediated toxicity of SEB and demonstrate that T cell stimulation in the absence of CD28 costimulation induces unresponsiveness in vivo.
A phase II trial of temozolomide and vinorelbine for patients with recurrent brain metastases
Authors: F. M. Iwamoto, A. M. Omuro, J. J. Raizer, C. P. Nolan, A. Hormigo, A. B. Lassman, I. T. Gavrilovic, L. E. Abrey
Journal: Journal of Clinical Oncology (2007)

2050 Background: Temozolomide has shown modest efficacy in the treatment of recurrent brain metastases. We designed a regimen combining temozolomide with vinorelbine, a lipophilic agent that crosses the blood-brain barrier, trying to improve efficacy. Methods: This is a phase II trial with 28-day cycles using temozolomide (150 mg/m 2 , days 1–7 and 15–21) and vinorelbine on days 1 and 8. We previously reported a phase I trial that established an MTD of 30 mg/m 2 of vinorelbine in this combination, but the dose was decreased to 25 mg/m 2 in this phase II trial. The phase II component was planned as a two-stage clinical trial. Since two or more responses were observed after the 20 initial patients, 15 more assessable patients were required. This design had a 91% probability to detect a true response rate of 20% or more. The primary endpoint was objective radiographic response. Secondary endpoints include OS, PFS and toxicity. Patients = 18 years old with KPS = 60, adequate organ function and progressive or recurrent brain metastases were eligible. Results: Thirty-six patients (13 men, 23 women) with a median age of 56 years (range, 38–76) and median KPS of 80 were enrolled. The primary tumor sites were lung (n=19), breast (n=11), colon (n=2), bladder (n=1), endometrium (n=1), head/neck (n=1) and kidney (n=1). Prior therapies included whole-brain radiation therapy (81%), chemotherapy (97%), radiosurgery (42%) and brain metastasis resection (47%). Objective radiographic response was 7% (1 CR and 1 minor response); 4 patients had SD and 23 PD. Three patients withdrew consent and did not undergo follow-up scans, 2 patients did not receive the planned treatment and 2 patients recently began treatment and have not been assessed. The median follow-up was 12.3 weeks and 72% of patients have died. Median PFS and OS were 8.3 weeks and 5 months, respectively. Grade 3/4 toxicities were mainly hematological and 3 patients were removed from the study due to myelosuppression. Conclusions: In this heavily pretreated population of patients with brain metastases, adding vinorelbine to temozolomide does not seem to improve response rates as compared to temozolomide alone. Single-agent temozolomide also has a more favorable toxicity profile. [Table: see text]
Voided Midstream Urine Culture and Acute Cystitis in Premenopausal Women
Authors: Thomas M. Hooton, Pacita L. Roberts, Marsha E. Cox, Ann E. Stapleton
Journal: New England Journal of Medicine (2013)

The cause of acute uncomplicated cystitis is determined on the basis of cultures of voided midstream urine, but few data guide the interpretation of such results, especially when gram-positive bacteria grow.Women from 18 to 49 years of age with symptoms of cystitis provided specimens of midstream urine, after which we collected urine by means of a urethral catheter for culture (catheter urine). We compared microbial species and colony counts in the paired specimens. The primary outcome was a comparison of positive predictive values and negative predictive values of organisms grown in midstream urine, with the presence or absence of the organism in catheter urine used as the reference.The analysis of 236 episodes of cystitis in 226 women yielded 202 paired specimens of midstream urine and catheter urine that could be evaluated. Cultures were positive for uropathogens in 142 catheter specimens (70%), 4 of which had more than one uropathogen, and in 157 midstream specimens (78%). The presence of Escherichia coli in midstream urine was highly predictive of bladder bacteriuria even at very low counts, with a positive predictive value of 10(2) colony-forming units (CFU) per milliliter of 93% (Spearman's r=0.944). In contrast, in midstream urine, enterococci (in 10% of cultures) and group B streptococci (in 12% of cultures) were not predictive of bladder bacteriuria at any colony count (Spearman's r=0.322 for enterococci and 0.272 for group B streptococci). Among 41 episodes in which enterococcus, group B streptococci, or both were found in midstream urine, E. coli grew from catheter urine cultures in 61%.Cultures of voided midstream urine in healthy premenopausal women with acute uncomplicated cystitis accurately showed evidence of bladder E. coli but not of enterococci or group B streptococci, which are often isolated with E. coli but appear to rarely cause cystitis by themselves. (Funded by the National Institute of Diabetes and Digestive and Kidney Diseases.).
Distribution of collagenous colitis: utility of flexible sigmoidoscopy.
Authors: M Tanaka, G Mazzoleni, R H Riddell
Journal: Gut (1992)

We investigated the distribution of the collagen band in 33 patients with collagenous colitis to estimate the likelihood of the disease being diagnosed in biopsy specimens from the left side of the colon, such as those obtained using flexible sigmoidoscopy. To be included in this study patients had a subepithelial collagen band greater than or equal to 10 microns, an increase in chronic inflammatory cells in the same specimen, and diarrhoea for which there was no other apparent cause. In 17 patients undergoing full colonoscopy with a thickened collagen band, collagenous colitis was frequently patchy, even though overall the thickened collagen band was almost equally distributed throughout the colon. Rectal biopsy specimens showed a normal collagen band in 73% of patients, while a thickened collagen band was found in 82% of patients in at least one specimen from the left side of the colon. Three patients had a thickened collagen band only in the caecum. In three of eight rectal biopsy specimens with a normal collagen band there was no mucosal inflammation to raise the possibility of proximal disease, although all but one specimen with a normal collagen band from the sigmoid and descending colon were inflamed. Rectal biopsy alone is therefore a relatively poor method of making the diagnosis. Flexible sigmoidoscopy with multiple biopsy specimens from several sites is a reasonable initial investigation but not sufficient to exclude collagenous colitis when based on the presence of a thickened collagen band alone. Should left sided biopsy specimens show a normal collagen band but an inflamed mucosa, total colonoscopy with multiple specimens including the caecum may be required to establish the diagnosis.
In vitro models of carcinogenesis: expression of recessive genes by chromosomal mutations.
Authors: J B Little
Journal: Environmental Health Perspectives (1989)

There has been considerable recent interest in the mechanisms by which recessive mutations involving cancer genes may be expressed. We have developed an in vitro model to study this phenomenon in an endogenous autosomal gene in human cells. We have analyzed the molecular structural changes that lead to loss of heterozygosity at the thymidine kinase (tk) locus. The results indicate that expression of a recessive allele frequently occurs by loss of heterozygosity at that locus. Over 90% of spontaneous mutants at the tk locus arose by allele loss. The fraction of induced mutants that arose by this mechanism depended upon the inducing agent. Loss of the active tk allele was often accompanied by loss of linked genetic loci on the long arm of chromosome 17. These results suggest that large-scale chromosomal mutations resulting from events such as deletion or mitotic recombination may be an important mechanism for the expression of activated or mutated recessive genes in human cells. Such recessive mutations could involve oncogenes or other growth regulatory genes important in carcinogenesis.
The effects of alpha 2-adrenergic and serotonergic receptor antagonists on cyclic blood flow alterations in stenosed canine coronary arteries.
Authors: L R Bush, W B Campbell, K Kern, G D Tilton, P Apprill, J Ashton, J Schmitz, L M Buja, J T Willerson
Journal: Circulation Research (1984)

Platelets possess alpha 2-adrenergic and serotonergic (5-hydroxytryptamine) receptors which are thought to mediate the in vitro proaggregatory effects of epinephrine and serotonin, respectively. However, their importance in platelet aggregation in vivo is uncertain. In the present study, we evaluate the ability of yohimbine and ketanserin, relatively selective alpha 2-adrenergic and serotonin antagonists, respectively, to alter cyclic flow reductions in stenosed coronary arteries in open-chest, anesthetized dogs. These cyclic flow reductions, characterized by progressive declines in coronary blood flow interrupted by abrupt and, often spontaneous, restorations of flow, were produced by cylindrical constrictors placed on the left anterior descending coronary artery. A pulsed Doppler flow probe, placed proximal to the constrictor, was used to measure coronary blood flow. Regional myocardial blood flow was measured with 15-micron radiolabeled microspheres before coronary constriction and when coronary blood flow appeared to be at its nadir and zenith during cyclic flow reductions. After the cyclic flow reductions had been observed for 1 hour, yohimbine (1-2 mg/kg), ketanserin (0.25 or 0.5 mg/kg), or saline was given, and coronary blood flow and hemodynamics were monitored for another hour. The frequency of cyclic flow reductions and the mean of the three lowest nadirs of coronary blood flow (mean +/- SE) were compared between the first and second hours. Ketanserin, at doses of 0.25 and 0.50 mg/kg, virtually abolished cyclic flow reductions in all dogs tested. Yohimbine [1 mg/kg ( n = 14)] was partially effective in reducing the frequency (9.6 vs. 5.5 cyclic flow reductions/hr) and severity of cyclic flow reductions (nadirs of coronary blood flow = 6.2 +/- 2.4 vs. 20.9 +/- 6.1% of control). A higher dose of yohimbine [2 mg/kg (n = 7)] was no more effective. The frequency (9.3 +/- 0.9 vs. 9.3 +/- 1.0 CFR/hr) and severity (17.4 +/- 5.4 vs. 12.4 +/- 3.9% of control coronary blood flow) of cyclic flow reductions were not changed by saline. The relatively selective alpha 1-adrenergic antagonist, prazosin (0.01 mg/kg, iv), and the beta-adrenergic antagonist, propranolol (1-2 mg/kg, iv), did not affect the frequency or severity of cyclic flow reductions. Thus, the abilities of yohimbine to inhibit and ketanserin to abolish cyclic flow reductions in stenosed canine coronary arteries suggest that serotonin and, possibly, alpha 2-adrenergic agonists may influence cyclic flow alterations importantly in this model.
Vasopressin Directly Regulates Cyst Growth in Polycystic Kidney Disease
Authors: Xiaofang Wang, Yanhong Wu, Christopher J. Ward, Peter C. Harris, Vicente E. Torres
Journal: Journal of the American Society of Nephrology (2007)

The polycystic kidney diseases (PKD) are a group of genetic disorders causing renal failure and death from infancy to adulthood. Arginine vasopressin (AVP) V2 receptor antagonists inhibit cystogenesis in animal models of cystic kidney diseases, presumably by downregulating cAMP signaling, cell proliferation, and chloride-driven fluid secretion. For confirmation that the protective effect of these drugs is due to antagonism of AVP, PCK (Pkhd1(-/-)) and Brattleboro (AVP(-/-)) rats were crossed to generate rats with PKD and varying amounts of AVP. At 10 and 20 weeks of age, PCK AVP(-/-) rats had lower renal cAMP and almost complete inhibition of cystogenesis compared with PCK AVP(+/+) and PCK AVP(+/-) rats. The V2 receptor agonist 1-deamino-8-d-arginine vasopressin increased renal cAMP and recovered the full cystic phenotype of PCK AVP(-/-) rats and aggravated the cystic disease of PCK AVP(+/+) rats but did not induce cystic changes in wild-type rats. These observations indicate that AVP is a powerful modulator of cystogenesis and provide further support for clinical trials of V2 receptor antagonists in PKD.
Pharmacokinetic and safety study of subcutaneously administered weekly ING-1, a human engineered™ monoclonal antibody targeting human EpCAM, in patients with advanced solid tumors
Authors: S. Goel, R.J. Bauer, K. Desai, A. Bulgaru, T. Iqbal, B.-K. Strachan, G. Kim, A. Kaubisch, G.F. Vanhove, G. Goldberg, S. Mani
Journal: Annals of Oncology (2007)
EphA4-Dependent Axon Guidance Is Mediated by the RacGAP α2-Chimaerin
Authors: Heike Wegmeyer, Joaquim Egea, Nadine Rabe, Henrik Gezelius, Alessandro Filosa, Anders Enjin, Frederique Varoqueaux, Katrin Deininger, Frank Schnütgen, Nils Brose, Rüdiger Klein, Klas Kullander, Andrea Betz
Journal: Neuron (2007)