tbuckley/cabot-search huggingface dataset:
NAD<sup>+</sup>‐Dependent DNA Ligase: A novel target waiting for the right inhibitor
Authors: Namrata Dwivedi, Divya Dube, Jyoti Pandey, Biswajit Singh, Vandna Kukshal, Ravishankar Ramachandran, Rama Pati Tripathi
Journal: Medicinal Research Reviews (2007)

DNA ligases (EC.6.5.1.1) are key enzymes that catalyze the formation of phosphodiester bonds at single stranded or double stranded breaks between adjacent 5' phosphoryl and 3' hydroxyl groups of DNA. These enzymes are important for survival because they are involved in major cellular processes like DNA replication/repair and recombination. DNA ligases can be classified into two groups on the basis of their cofactor specificities. NAD(+)-dependent DNA ligases are present in bacteria, some entomopox viruses and mimi virus while ATP-dependent DNA ligases are ubiquitous. The former have recently been drawing a lot of attention as novel targets for antibiotics to overcome current drug resistance issues. Currently a diverse range of inhibitors have been identified. There are several issues to be addressed in the quest for optimized inhibitors of the enzyme. In the first part of the review we summarize current structural work on these enzymes. Subsequently we describe the currently available classes of inhibitors. We also address modalities to improve the specificity and potencies of new inhibitors identified using protein structure based rational approaches. In conclusion, NAD(+)-dependent ligases show great promise and represent a novel drug target whose time has come.
Improvements in skin reactions to insulin, produced by a highly purified preparation
Authors: PETER DAGGETT, B.E. MUSTAFFA, J.D.N. NABARRO
Journal: British Journal of Dermatology (1977)

A group of 14 patients with skin reactions to insulin have been treated with highly purified insulin over a period of 5–14 months while continuing to inject into the abnormal areas. Fat atrophy improved in all cases, coincident with a reduction in insulin requirement and insulin binding capacity. The response of patients with fat hypertrophy was less predictable, but there was an improvement in 3 out of 6 cases. Measurements of insulin binding capacity of the plasma suggested that fat atrophy and hypertrophy are immunologically distinct and some explanations for this are discussed. It is concluded that highly purified insulin benefits some patients with skin reactions to insulin.
DIRECT EVIDENCE FOR HAGEMAN FACTOR (FACTOR XII) ACTIVATION BY BACTERIAL LIPOPOLYSACCHARIDES (ENDOTOXINS)
Authors: David C. Morrison, Charles G. Cochrane
Journal: The Journal of Experimental Medicine (1974)

Purified precursor Hageman factor has been demonstrated to bind to soluble bacterial lipopolysaccharide (LPS, endotoxin) isolated from Escherichia coli 0111:B4, and this complex has been shown to have the capacity to convert prekallikrein to its active form. In addition, LPS-activated Hageman factor substantially reduces clotting times in XII-deficient plasma. The capacity to activate Hageman factor has been demonstrated to reside in the lipid A region of the LPS molecule. Activation of Hageman factor by LPS contrasts with fluid-phase activation (e.g., by kallikrein or trypsin) in that no cleavage to lower molecular weight fragments occurs. High concentrations of LPS inhibit the activity of Hageman factor, probably by a direct LPS-Hageman factor interaction.
Alterations of Left Ventricular Hypertrophy in and Survival of Patients Receiving Hemodialysis
Authors: Gérard M. London, Bruno Pannier, Alain P. Guerin, Jacques Blacher, Sylvain J. Marchais, Bernadette Darne, Fabien Metivier, Hassan Adda, Michel E. Safar
Journal: Journal of the American Society of Nephrology (2001)

Left ventricular (LV) hypertrophy (LVH) is a risk factor for mortality in patients with end-stage renal disease (ESRD). Whether the attenuation of LVH has a positive effect on survival of patients with ESRD has not been documented. The aim of this study was to determine the effect of parallel treatment of hypertension and anemia on LV mass (LVM) and to determine the effect of LVM changes on survival. A cohort of 153 patients receiving hemodialysis was studied. The duration of follow-up was 54 +/- 37 mo. All patients had echocardiographic determination of LV dimensions and LVM at baseline and regular intervals until the end of the follow-up period. During the study, BP decreased from (mean +/- SD) 169.4 +/- 29.7/90.2 +/- 15.6 to 146.7 +/- 29/78 +/- 14.1 mmHg (P < 0.001), and hemoglobin increased from 8.65 +/- 1.65 to 10.5 +/- 1.45 g/dl (P < 0.001). The LV end-diastolic diameter and mean wall thickness decreased from 56.6 +/- 6.5 to 54.8 +/- 6.5 mm (P < 0.001), and from 10.4 +/- 1.6 to 10.2 +/- 1.6 mm (P < 0.05), respectively. The LVM decreased from 290 +/- 80 to 264 +/- 86 g (P < 0.01). Fifty-eight deaths occurred, 38 attributed to cardiovascular (CV) disease and 20 attributed to non-CV causes. According to Cox analyses after adjustment for age, gender, diabetes, history of CV disease, and all nonspecific CV risk factors, LVM regression positively affected the survival. The hazard risk ratio associated with a 10% LVM decrease was 0.78 (95% confidence interval, 0.63 to 0.92) for all-causes mortality and 0.72 (95% confidence interval, 0.51 to 0.90) for mortality due to CV disease. These results show that a partial LVH regression in patients with ESRD had a favorable and independent effect on patients' all-cause and CV survival.
C3b covalently bound to IgG demonstrates a reduced rate of inactivation by factors H and I.
Authors: L F Fries, T A Gaither, C H Hammer, M M Frank
Journal: The Journal of Experimental Medicine (1984)

We have prepared C3b covalently linked to IgG via a hydroxylamine-sensitive bond between the C3b alpha' chain and sites predominantly, but not exclusively, located in the IgG heavy chain. This C3b species displays relative resistance to inactivation by factors H and I when compared with free C3b. This resistance appears to be due entirely to reduced affinity of C3b-IgG for factor H. Resistance to inactivation is not conferred on C3b by binding to another serum glycoprotein of similar size, ceruloplasmin, and may be a special property of IgG. C3b-IgG demonstrates an enhanced capacity to consume serum C3 relative to C3b. These alterations of the behavior of C3b when bound to IgG may in part explain the augmentation of alternative pathway activity by IgG. In addition, IgG-induced protection of C3b might influence both complement-mediated killing and phagocytosis of bacteria, as well as modify the in vivo handling of IgG-containing soluble immune complexes.
Hepatitis C virus and B-cell non-Hodgkin lymphomas: an Italian multicenter case-control study
Authors: Alfonso Mele, Alessandro Pulsoni, Elvira Bianco, Pellegrino Musto, Andrè Szklo, Maria Grazia Sanpaolo, Emilio Iannitto, Amalia De Renzo, Bruno Martino, Vincenzo Liso, Cristina Andrizzi, Simona Pusterla, Fausto Dore, Maddalena Maresca, Maria Rapicetta, Fabrizio Marcucci, Franco Mandelli, Silvia Franceschi
Journal: Blood (2003)
What do working-memory tests really measure?
Authors: Michael J. Kane, Andrew R. A. Conway, Randall W. Engle
Journal: Behavioral and Brain Sciences (1999)

Individuals may differ in the general-attention executive component or in the subordinate domain-specific “slave” components of working memory. Tasks requiring sustained memory representations across attention shifts are reliable, valid indices of executive abilities. Measures emphasizing specific processing skills may increase reliability within restricted samples but will not reflect the attention component responsible for the broad predictive validity of span tasks.
Benzodiazepine drug use and adverse respiratory outcomes among older adults with COPD
Authors: Nicholas T. Vozoris, Hadas D. Fischer, Xuesong Wang, Anne L. Stephenson, Andrea S. Gershon, Andrea Gruneir, Peter C. Austin, Geoffrey M. Anderson, Chaim M. Bell, Sudeep S. Gill, Paula A. Rochon
Journal: European Respiratory Journal (2014)

Our purpose was to evaluate the association of new benzodiazepine use relative to non-use with adverse clinical respiratory outcomes among older adults with chronic obstructive pulmonary disease (COPD). This was a retrospective population-based cohort study of Ontario, Canada, residents between 2003 and 2010. A validated algorithm was applied to health administrative data to identify adults aged 66 years and older with COPD. Relative risks (RRs) of several clinically important respiratory outcomes were examined within 30 days of incident benzodiazepine use compared with non-use, applying propensity score matching. New benzodiazepine users were at significantly higher risk for outpatient respiratory exacerbations (RR 1.45, 95% CI 1.36-1.54) and emergency room visits for COPD or pneumonia (RR 1.92, 95% CI 1.69-2.18) compared to non-users. Risk of hospitalisation for COPD or pneumonia was also increased in benzodiazepine users, but was nonsignificant (RR 1.09, 95% CI 1.00-1.20). There were no significant differences in intensive care unit admissions between the two groups and all-cause mortality was slightly lower among new versus non-users. Benzodiazepines were associated with increased risk for several serious adverse respiratory outcomes among older adults with COPD. The findings suggest that decisions to use benzodiazepines in older patients with COPD need to consider potential adverse respiratory outcomes.
Cognitive impairments in psychotic disorders: common mechanisms and measurement
Authors: Deanna M. Barch, Julia M. Sheffield
Journal: World Psychiatry (2014)

Decades of research have provided robust evidence of cognitive impairments in psychotic disorders. Individuals with schizophrenia appear to be impaired on the majority of neuropsychological tasks, leading some researchers to argue for a "generalized deficit", in which the multitude of cognitive impairments are the result of a common neurobiological source. One such common mechanism may be an inability to actively represent goal information in working memory as a means to guide behavior, with the associated neurobiological impairment being a disturbance in the function of the dorsolateral prefrontal cortex. Here, we provide a discussion of the evidence for such impairment in schizophrenia, and how it manifests in domains typically referred to as cognitive control, working memory and episodic memory. We also briefly discuss cognitive impairment in affective psychoses, reporting that the degree of impairment is worse in schizophrenia than in bipolar disorder and psychotic major depression, but the profile of impairment is similar, possibly reflecting common mechanisms at the neural level. Given the recent release of the DSM-5, we end with a brief discussion on assessing cognition in the context of diagnosis and treatment planning in psychotic disorders.
West Nile Virus: A Primer for the Clinician
Authors: Lyle R. Petersen, Anthony A. Marfin
Journal: Annals of Internal Medicine (2002)

This paper provides the clinician with an understanding of the epidemiologic and biological characteristics of West Nile virus in North America, as well as useful information on the diagnosis, reporting, and management of patients with suspected West Nile virus infection and on advising patients about prevention. Information was gathered from the medical literature and from national surveillance data through May 2002. Since the identification of West Nile virus in New York City in 1999, enzootic activity has been documented in 27 states and the District of Columbia. Continued geographic expansion is likely. Overall, one in 150 infections results in severe neurologic illness. Advanced age is by far the most important risk factor for neurologic disease and, once disease develops, for worse clinical outcome. Surveillance has identified 149 persons with West Nile virus–related illness in 10 states. Encephalitis is more commonly reported than meningitis, and concomitant muscle weakness and flaccid paralysis may provide a clinical clue to the presence of West Nile virus infection. Peak incidence occurs in late summer, although onset has occurred from July through December. Immunoglobulin M antibody testing of serum specimens and cerebrospinal fluid is the most efficient method of diagnosis, although cross-reactions are possible in patients recently vaccinated against or recently infected with related flaviviruses. Testing can be arranged through local, state, or provincial (in Canada) health departments. Prevention rests on elimination of mosquito breeding sites; judicious use of pesticides; and avoidance of mosquito bites, including mosquito repellent use.
Identification of ATPAF1 as a novel candidate gene for asthma in children
Authors: Eric M. Schauberger, Susan L. Ewart, Syed H. Arshad, Marianne Huebner, Wilfried Karmaus, John W. Holloway, Karen H. Friderici, Julie T. Ziegler, Hongmei Zhang, Matthew J. Rose-Zerilli, Sheila J. Barton, Stephen T. Holgate, Jeffrey R. Kilpatrick, John B. Harley, Stephane Lajoie-Kadoch, Isaac T.W. Harley, Qutayba Hamid, Ramesh J. Kurukulaaratchy, Max A. Seibold, Pedro C. Avila, William Rodriguez-Cintrón, Jose R. Rodriguez-Santana, Donglei Hu, Christopher Gignoux, Isabelle Romieu, Stephanie J. London, Esteban G. Burchard, Carl D. Langefeld, Marsha Wills-Karp
Journal: Journal of Allergy and Clinical Immunology (2011)
Neosquamous Epithelium Does Not Typically Arise from Barrett's Epithelium
Authors: Thomas G. Paulson, Lianjun Xu, Carissa Sanchez, Patricia L. Blount, Kamran Ayub, Robert D. Odze, Brian J. Reid
Journal: Clinical Cancer Research (2006)

Abstract Purpose: Neosquamous epithelium (NSE) can arise within Barrett's esophagus as a consequence of medical or surgical acid reduction therapy, as well as after endoscopic ablation. Morphologic studies have suggested that NSE can develop from adjacent squamous epithelium, submucosal gland ducts, or multipotent progenitor cell(s) that can give rise to either squamous or Barrett's epithelium, depending on the luminal environment. The cells responsible for Barrett's epithelium self-renewal are frequently mutated during neoplastic progression. If NSE arises from the same cells that self-renew the Barrett's epithelium, the two tissues should be clonally related and share genetic alterations; if NSE does not originate in the self-renewing Barrett's, NSE and Barrett's esophagus should be genetically independent. Experimental Design: We isolated islands of NSE and the surrounding Barrett's epithelium from 20 patients by microdissection and evaluated each tissue for genetic alterations in exon 2 of CDKN2A or exons 5 to 9 of the TP53 gene. Nine patients had p16 mutations and 11 had TP53 mutations within the Barrett's epithelium. Results: In 1 of 20 patients, a focus of NSE had a 146 bp deletion in p16 identical to that found in surrounding Barrett's epithelium. The NSE in the remaining 19 patients was wild-type for p16 or TP53. Conclusion: Our mutational data support the hypothesis that, in most circumstances, NSE originates in cells different from those responsible for self-renewal of Barrett's epithelium. However, in one case, NSE and Barrett's epithelium seem to have arisen from a progenitor cell that was capable of differentiating into either intestinal metaplasia or NSE.
Chylothorax complicating repair of a left diaphragmatic hernia in a neonate.
Authors: Z Czerniak, Z Dreznik, Y Neuman, I Wolfstein
Journal: Thorax (1981)

We describe here a case of chylothorax complicating repair of a left posterolateral diaphragmatic hernia.Successful treatment consisted of continuous drainage of the pleural cavity, combined with parenteral hyperalimentation. Case reportA 2500 g term female baby developed severe respiratory distress shortly after birth.A chest radiograph established the diagnosis of a left diaphragmatic hernia (fig 1).She
PSYCHIATRIC ILLNESS IN THE PHYSICIAN'S WIFE
Authors: JAMES L. EVANS
Journal: American Journal of Psychiatry (1965)

The records of 50 wives of physicians admitted to a private psychiatric hospital have been reviewed. Despite a high level of adaptation in the early years of marriage, they later developed severe psychiatric illnesses requiring repeated hospitalizations. A precipitating factor in many of these cases appeared to be a feeling of increasing exclusion from the husband's life, as he became more and more involved in his profession. Symptoms of depression, somatization and addiction were prevalent and were related dynamically and empirically to the profession of the husband.
Intratumoral Injection of INGN 241, a Nonreplicating Adenovector Expressing the Melanoma-Differentiation Associated Gene-7 (mda-7/IL24): Biologic Outcome in Advanced Cancer Patients
Authors: Alex W. Tong, John Nemunaitis, Dan Su, Yuan Zhang, Casey Cunningham, Neil Senzer, George Netto, Dawn Rich, Abner Mhashilkar, Karen Parker, Keith Coffee, Rajagopal Ramesh, Suhendan Ekmekcioglu, Elizabeth A. Grimm, Jill van Wart Hood, James Merritt, Sunil Chada
Journal: Molecular Therapy (2004)

The mda-7 gene (approved gene symbol IL24) is a novel tumor suppressor gene with tumor-apoptotic and immune-activating properties. We completed a Phase I dose-escalation clinical trial, in which a nonreplicating adenoviral construct expressing the mda-7 transgene (INGN 241; Ad-mda7) was administered intratumorally to 22 patients with advanced cancer. Excised tumors were evaluated for vector-specific DNA and RNA, transgenic MDA-7 expression, and biological effects. Successful gene transfer as assessed by DNA- and RT-PCR was demonstrated in 100% of patients evaluated. DNA analyses demonstrated a dose-dependent penetration of INGN 241 (up to 4 × 108 copies/μg DNA at the 2 × 1012 vp dose). A parallel distribution of vector DNA, vector RNA, MDA-7 protein expression, and apoptosis induction was observed in all tumors, with signals decreasing with distance away from the injection site. Additional evidence for bioactivity of INGN 241 was illustrated via regulation of the MDA-7 target genes β-catenin, iNOS, and CD31. Transient increases (up to 20-fold) of serum IL-6, IL-10, and TNF-α were observed. Significantly higher elevations of IL-6 and TNF-α were observed in patients who responded clinically to INGN 241. Patients also showed marked increases of CD3+CD8+ T cells posttreatment, suggesting that INGN 241 increased systemic TH1 cytokine production and mobilized CD8+ T cells. Intratumoral delivery of INGN 241 induced apoptosis in a large volume of tumor and elicited tumor-regulatory and immune-activating events that are consistent with the preclinical features of MDA-7/IL-24.
Soluble E-cadherin: a novel cutaneous disease marker
Authors: N. MATSUYOSHI, T. TANAKA, K. TODA, H. OKAMOTO, F. FURUKAWA, S. IMAMURA
Journal: British Journal of Dermatology (2006)

E-cadherin is a major homophilic cell-cell adhesion molecule of the skin. There are two forms of E-cadherin--membrane and soluble types. Although various abnormalities of the former type have been identified in some cutaneous diseases, information relating to the latter is sparse. We measured the concentrations of soluble E-cadherin in several cutaneous diseases, and found higher levels in sera from patients with bullous pemphigoid, pemphigus vulgaris, psoriasis vulgaris and inflammatory skin diseases, compared with controls. In psoriasis vulgaris the levels of soluble E-cadherin in sera correlated with the PASI score. In normal individuals, levels in suction blister fluid were double those in sera. These findings suggest that changes occur in circulating levels of soluble E-cadherin in skin disease, possibly reflecting increased turnover and/or proteolysis of cell-surface molecules in the epidermis.
Metabolic response of glioma to dichloroacetate measured in vivo by hyperpolarized 13C magnetic resonance spectroscopic imaging
Authors: J. M. Park, L. D. Recht, S. Josan, M. Merchant, T. Jang, Y.-F. Yen, R. E. Hurd, D. M. Spielman, D. Mayer
Journal: Neuro-Oncology (2013)

The metabolic phenotype that derives disproportionate energy via glycolysis in solid tumors, including glioma, leads to elevated lactate labeling in metabolic imaging using hyperpolarized [1-13C]pyruvate. Although the pyruvate dehydrogenase (PDH)–mediated flux from pyruvate to acetyl coenzyme A can be indirectly measured through the detection of carbon-13 (13C)-labeled bicarbonate, it has proven difficult to visualize 13C-bicarbonate at high enough levels from injected [1-13C]pyruvate for quantitative analysis in brain. The aim of this study is to improve the detection of 13C-labeled metabolites, in particular bicarbonate, in glioma and normal brain in vivo and to measure the metabolic response to dichloroacetate, which upregulates PDH activity. An optimized protocol for chemical shift imaging and high concentration of hyperpolarized [1-13C]pyruvate were used to improve measurements of lactate and bicarbonate in C6 glioma-transplanted rat brains. Hyperpolarized [1-13C]pyruvate was injected before and 45 min after dichloroacetate infusion. Metabolite ratios of lactate to bicarbonate were calculated to provide improved metrics for characterizing tumor metabolism. Glioma and normal brain were well differentiated by lactate-to-bicarbonate ratio (P = .002, n = 5) as well as bicarbonate (P = .0002) and lactate (P = .001), and a stronger response to dichloroacetate was observed in glioma than in normal brain. Our results clearly demonstrate for the first time the feasibility of quantitatively detecting 13C-bicarbonate in tumor-bearing rat brain in vivo, permitting the measurement of dichloroacetate-modulated changes in PDH flux. The simultaneous detection of lactate and bicarbonate provides a tool for a more comprehensive analysis of glioma metabolism and the assessment of metabolic agents as anti-brain cancer drugs.
Targeting Breast Cancer Stem Cells
Authors: Suling Liu, Max S. Wicha
Journal: Journal of Clinical Oncology (2010)

There is increasing evidence that many cancers, including breast cancer, contain populations of cells that display stem-cell properties. These breast cancer stem cells, by virtue of their relative resistance to radiation and cytotoxic chemotherapy, may contribute to treatment resistance and relapse. The elucidation of pathways that regulate these cells has led to the identification of potential therapeutic targets. A number of agents capable of targeting breast cancer stem cells in preclinical models are currently entering clinical trials. Assessment of the efficacy of the agents will require development of innovative clinical trial designs with appropriate biologic and clinical end points. The effective targeting of breast cancer stem cells has the potential to significantly improve outcome for women with both early-stage and advanced breast cancer.
Periportal and sinusoidal liver dendritic cells suppressing T helper type 1-mediated hepatitis
Authors: T. Watanabe, H. Katsukura, T. Chiba, T. Kita, Y. Wakatsuki
Journal: Gut (2007)

<b>Background:</b> Recently, we found that portal vein tolerance is associated with generation of Th2 cells and apoptosis of Th1 cells in the liver, which is regulated by antigen (Ag)-presenting dendritic cells (DCs) in the periportal area and sinusoids. <b>Aim:</b> In this study, we tested whether the periportal and sinusoidal DCs, which were loaded with an Ag in vivo, can inhibit liver injury caused by Th1 cells activated by the Ag administered systemically. <b>Methods:</b> Ag-specific hepatitis model was created by adoptively transferring ovalbumin (OVA)-specific CD4<sup>+</sup> T cells to BALB/c mice and venous injection of OVA-containing liposomes. Liver CD11c<sup>+</sup> cells obtained from mice fed OVA were then transferred into these mice. <b>Results:</b> The transfer of liver CD11c<sup>+</sup> cells from OVA-fed mice completely inhibited hepatic injury, which was associated with apoptosis of OVA-specific CD4<sup>+</sup> T cells and emergence of Th2 cells in the liver. Transfer of CD11c<sup>+</sup> cells and subcutaneous OVA challenge led to enhancement of OVA-specific IgE Ab as well as Th2 cytokine responses in the recipient mice. <b>Conclusions:</b> Periportal and sinusoidal DCs loaded with an Ag in the portal vein can induce Th2 response in the liver and prevent hepatic injury caused by Th1 cells.