tbuckley/cabot-search huggingface dataset:
COQ2 Nephropathy
Authors: Francesca Diomedi-Camassei, Silvia Di Giandomenico, Filippo M. Santorelli, Gianluca Caridi, Fiorella Piemonte, Giovanni Montini, Gian Marco Ghiggeri, Luisa Murer, Laura Barisoni, Anna Pastore, Andrea Onetti Muda, Maria Luisa Valente, Enrico Bertini, Francesco Emma
Journal: Journal of the American Society of Nephrology (2007)

Primary coenzyme Q(10) (CoQ(10)) deficiency includes a group of rare autosomal recessive disorders primarily characterized by neurological and muscular symptoms. Rarely, glomerular involvement has been reported. The COQ2 gene encodes the para-hydroxybenzoate-polyprenyl-transferase enzyme of the CoQ(10) synthesis pathway. We identified two patients with early-onset glomerular lesions that harbored mutations in the COQ2 gene. The first patient presented with steroid-resistant nephrotic syndrome at the age of 18 months as a result of collapsing glomerulopathy, with no extrarenal symptoms. The second patient presented at five days of life with oliguria, had severe extracapillary proliferation on renal biopsy, rapidly developed end-stage renal disease, and died at the age of 6 months after a course complicated by progressive epileptic encephalopathy. Ultrastructural examination of renal specimens from these cases, as well as from two previously reported patients, showed an increased number of dysmorphic mitochondria in glomerular cells. Biochemical analyses demonstrated decreased activities of respiratory chain complexes [II+III] and decreased CoQ(10) concentrations in skeletal muscle and renal cortex. In conclusion, we suggest that inherited COQ2 mutations cause a primary glomerular disease with renal lesions that vary in severity and are not necessarily associated with neurological signs. COQ2 nephropathy should be suspected when electron microscopy shows an increased number of abnormal mitochondria in podocytes and other glomerular cells.
Overcoming cisplatin resistance by mTOR inhibitor in lung cancer
Authors: Chunjing Wu, Medhi Wangpaichitr, Lynn Feun, Marcus Tien Kuo, Carlos Robles, Theodore Lampidis, Niramol Savaraj
Journal: Molecular Cancer (2005)

Abstract Background Cisplatin resistance is complex and involves several different mechanisms. Employing cDNA microarray analysis, we have found that cisplatin resistant cells share the common characteristic of increase in ribosomal proteins and elongation factors. We hypothesize that in order to survive cisplatin treatment, cells have to synthesize DNA repair proteins, antiapoptotic proteins and growth-stimulating proteins. Thus, by blocking the translation of these proteins, one should be able to restore cisplatin sensitivity. We have studied the role of CCI-779, an ester analog of rapamycin which is known to inhibit translation by disabling mTOR, in restoring cisplatin sensitivity in a panel of cisplatin resistant cell lines. We have also determined the role of CCI-779 in P-gp1 and MRP1 mediated resistance. Results Our data show that CCI-779 possess antiproliferative effects in both cisplatin sensitive and resistant cell lines, but shows no effect in P-gp1 and MRP1 overexpressing cell lines. Importantly, CCI-779 at 10 ng/ml (less that 10% of the growth inhibitory effect) can increase the growth inhibition of cisplatin by 2.5–6 fold. Moreover, CCI-779 also enhances the apoptotic effect of cisplatin in cisplatin resistant cell lines. In these resistant cells, adding CCI-779 decreases the amount of 4E-BP phosphorylation and p-70S6 kinase phosphorylation as well as lower the amount of elongation factor while cisplatin alone has no effect. However, CCI-779 can only reverse P-gp mediated drug resistance at a higher dose(1 ug/ml). Conclusion We conclude that CCI-779 is able to restore cisplatin sensitivity in small cell lung cancer cell lines selected for cisplatin resistance as well as cell lines derived from patients who failed cisplatin. These findings can be further explored for future clinical use. On the other hand, CCI-779 at achievable clinical concentration, has no growth inhibitory effect in P-gp1 or MRP1 overexpressing cells. Furthermore, CCI-779 also appears to be a weak MDR1 reversal agent. Thus, it is not a candidate to use in MDR1 or MRP1 overexpressing cells.
Renal Function and Outcome From Coronary Artery Bypass Grafting
Authors: Graham S. Hillis, Bernie L. Croal, Keith G. Buchan, Hussein El-Shafei, George Gibson, Robert R. Jeffrey, Colin G.M. Millar, Gordon J. Prescott, Brian H. Cuthbertson
Journal: Circulation (2006)

Severe renal dysfunction is associated with a worse outcome after coronary artery bypass graft surgery (CABG). Less is known about the effects of milder degrees of renal impairment, and previous studies have relied on levels of serum creatinine, an insensitive indicator of renal function. Recent studies have suggested that estimated glomerular filtration rate (eGFR) is a more discriminatory measure. However, data on the utility of eGFR in predicting outcome from CABG are limited.We studied 2067 consecutive patients undergoing CABG. Demographic and clinical data were collected preoperatively, and patients were followed up a median of 2.3 years after surgery. Estimated GFR was calculated from the Modification of Diet in Renal Disease equation. The primary outcome was all-cause mortality. Mean+/-SD eGFR was 57.9+/-17.6 mL/min per 1.73 m2 in the 158 patients who died during follow-up compared with 64.7+/-13.8 mL/min per 1.73 m2 in survivors (hazard ratio [HR], 0.71 per 10 mL/min per 1.73 m2; 95% CI, 0.64 to 0.80; P<0.001). Estimated GFR was an independent predictor of mortality in both models with other individual univariable predictors (HR, 0.80 per 10 mL/min per 1.73 m2; 95% CI, 0.72 to 0.89; P<0.001) and the European system for cardiac operative risk evaluation (HR, 0.88 per 10 mL/min per 1.73 m2; 95% CI, 0.78 to 0.98; P=0.02).Estimated GFR is a powerful and independent predictor of mortality after CABG.
LIM Kinase 1 Promotes Endothelial Barrier Disruption and Neutrophil Infiltration in Mouse Lungs
Authors: Matvey Gorovoy, Jingyan Han, Haiyun Pan, Emily Welch, Radu Neamu, Zhengping Jia, Dan Predescu, Stephen Vogel, Richard D. Minshall, Richard D. Ye, Asrar B. Malik, Tatyana Voyno-Yasenetskaya
Journal: Circulation Research (2009)

Rationale: Disruption of endothelial barrier function and neutrophil-mediated injury are two major mechanisms underlying the pathophysiology of sepsis-induced acute lung injury (ALI). Recently we reported that endotoxin induced activation of RhoA in mice lungs that led to the disruption of endothelial barrier and lung edema formation; however, the molecular mechanism of this phenomenon remained unknown. Objective: We reasoned that LIMK1, which participates in the regulation of endothelial cell contractility and is activated by RhoA/Rho kinase pathway, could mediate RhoA-dependent disruption of endothelial barrier function in mouse lungs during ALI. And if that is the case, then attenuation of endothelial cell contractility by downregulating LIMK1 may lead to the enhancement of endothelial barrier function, which could protect mice from endotoxin-induced ALI. Methods and Results: Here we report that LIMK1 deficiency in mice significantly reduced mortality induced by endotoxin. Data showed that lung edema formation, lung microvascular permeability, and neutrophil infiltration into the lungs were suppressed in limk1 −/− mice. Conclusions: We identified that improvement of endothelial barrier function along with impaired neutrophil chemotaxis were the underlying mechanisms that reduced severity of ALI in limk1 −/− mice, pointing to a new therapeutic target for diseases associated with acute inflammation of the lungs.
Concordant fetal hemoglobin response to hydroxyurea in siblings with sickle cell disease
Authors: Martin H. Steinberg, Ersi Voskaridou, Abdullah Kutlar, Dimitris Loukopoulos, Mabel Koshy, Samir K. Ballas, Oswaldo Castro, Franca Barton
Journal: American Journal of Hematology (2003)

Fetal hemoglobin (HbF) level and the HbF responses to hydroxyurea (HU) vary among patients with sickle cell disease and are, at least in part, genetically regulated. We hypothesized that siblings with sickle cell disease are likely to share the same parental beta-like globin gene clusters with their cis-acting regulatory sequences and therefore, if regulation of this response is linked to the beta-globin gene cluster, might have concordant HbF responses to HU. Accordingly, we studied 26 families (30 sib pairings), 20 with sickle cell anemia (three families had three siblings) and 6 families with HbS-beta-thalassemia (one family had three siblings, and one family consisted of monozygotic twins), to see if siblings with sickle cell disease had discordant or concordant changes in HbF during HU treatment. Intraclass correlation coefficients (r) showed a high, positive correlation between sibs for HbF levels before and during HU treatment and a concordant change in HbF response from baseline to treatment-associated levels. Changes in mean corpuscular volume (MCV) paralleled HbF levels, while the expected correlations between treatment-associated fall in leukocyte count and increase in MCV were also present. Our results provide additional evidence that some elements that regulate HbF expression are linked to the beta-globin gene cluster.
Survival After Pancreas Transplantation in Patients With Diabetes and Preserved Kidney Function
Authors: Jeffrey M. Venstrom, Maureen A. McBride, Kristina I. Rother, Boaz Hirshberg, Trevor J. Orchard, David M. Harlan
Journal: JAMA (2003)

ContextSolitary pancreas transplantation (ie, pancreas alone or pancreas-after-kidney) for diabetes mellitus remains controversial due to procedure-associated morbidity/mortality, toxicity of immunosuppression, expense, and unproven effects on the secondary complications of diabetes. Whether transplantation offers a survival advantage over conventional therapies for diabetes is unknown.ObjectiveTo determine the association between solitary pancreas transplantation and survival in patients with diabetes and preserved kidney function.Design, Setting, and PatientsRetrospective observational cohort study conducted at 124 transplant centers in the United States, in 11 572 patients with diabetes mellitus on the waiting list for pancreas transplantation (pancreas alone, pancreas-after-kidney, or simultaneous pancreas-kidney) at the United Network for Organ Sharing/Organ Procurement and Transplantation Network between January 1, 1995, and December 31, 2000. All patients receiving a multiorgan (other than simultaneous pancreas-kidney) transplant were excluded, as were those listed for solitary pancreas transplantation who had a serum creatinine level greater than 2 mg/dL (176.8 µmol/L) at time of listing, or who ultimately received a simultaneous pancreas-kidney transplant.Main Outcome MeasureAll-cause mortality within 4 years following transplantation (or within a comparable time on the waiting list for the group not undergoing transplantation).ResultsOverall relative risk of all-cause mortality for transplant recipients (compared with patients awaiting the same procedure) over 4 years of follow-up was 1.57 (95% confidence interval [CI], 0.98-2.53; P = .06) for pancreas transplant alone, 1.42 (95% CI, 1.03-1.94; P = .03) for pancreas-after-kidney transplant, and 0.43 (95% CI, 0.39-0.48) for simultaneous pancreas-kidney transplant. Transplant patient 1- and 4-year survival rates were 96.5% and 85.2% for pancreas transplant alone, respectively, and 95.3% and 84.5% for pancreas-after-kidney transplant, while 1- and 4-year survival rates for patients on the waiting list were 97.6% and 92.1% for pancreas transplant alone, respectively, and 97.1% and 88.1% for pancreas-after-kidney transplant.ConclusionFrom 1995-2000, survival for those with diabetes and preserved kidney function and receiving a solitary pancreas transplant was significantly worse compared with the survival of waiting-list patients receiving conventional therapy.
SIGNIFICANCE OF BLOOD GROUPS IN INOCULATION MALARIA
Authors: Irving M. Derby
Journal: American Journal of Psychiatry (1935)

Laboratory evidence of injury to the plasmodium through mutilation of its erythrocyte host by incompatible serum may be readily demonstrated. In inoculation, when a number of parasites are disseminated from erythrocytes and their development thus disturbed, clinical results may appear as toxic phenomena, in a prolongation of incubation time—and, to a lesser degree—a frequency of tertian and mixed types of fever. Conversely, by the use of compatible blood in intravenous inoculation, there appears almost a stimulation to speeding up of plasmodial development reflected clinically by short incubation time and malignant and quotidian fever types. Clinical application of these concepts through donor selection varies between choice of a quickly appearing and possibly over-whelming infection, which may be controlled by judicious observation and intravenous quinine, and the selection of a slower developing type of less extreme fever. The latter utilizes incompatible donor blood which carries a minimal probability of embolic sequelæ. We may state that clinically similar results might be attained either by a stated amount of compatible blood or by the use of a larger dosage of incompatible blood. But large amounts of the latter may result in alarming symptoms which are difficult of control. Compatible donor blood also provides a better chance of over-coming relative immunity in cases previously treated with malaria; and its use guards against extended periods of incubation. The selection of incompatible blood apparently does not influence absolute failure of infection, and its effect on the entity known as primary fever has not appeared important. Despite the fact that blood type is an important individual constitutional factor and the possibility that it may play some role in immunity, there is no evidence sufficiently marked to state there is any relationship between blood type and clinical improvement following malarial therapy.
Pneumonitis induced by rifampicin
Authors: N Kunichika, N Miyahara, K Kotani, H Takeyama, M Harada, M Tanimoto
Journal: Thorax (2002)

An 81 year old man was admitted to hospital with pulmonary <i>Mycobacterium tuberculosis</i> infection and was treated with rifampicin (RFP), isoniazid (INH), and ethambutol (EB). On day 9 he developed fever and dyspnoea. Chest radiographs showed new infiltration shadows in the right lung. Bronchoalveolar lavage (BAL) was performed and increased numbers of lymphocytes were recovered. Drug induced pneumonitis was suspected so the antituberculous regimen was discontinued and methylprednisolone was administered. The symptoms and infiltration shadows improved. INH and EB were reintroduced without any recurrence of the abnormal shadows. T cell subsets in the BAL fluid and a positive lymphocyte stimulation test for RFP suggest that RFP induced pneumonitis may be related to a complex immunological response.
Retinoids and Apoptosis: Implications for Cancer Chemoprevention and Therapy
Authors: R. Lotan
Journal: JNCI Journal of the National Cancer Institute (1995)

Lung cancer in the United States leads other cancers in both incidence and mortality (1). The severe morbidity of lung cancer and the discouraging 15% overall 5-year survival rate have not improved despite advancements in treatment modalities. Furthermore, the incidence of lung cancer among women is increasing. Therefore, novel approaches to control this dreadful disease are urgently needed. Biological agents such as differentiati oninducing agents are being evaluated in clinical trials for their potential use for therapy and prevention of a variety of malignancies, including lung cancer (2,5). Among these novel agents are vitamin A analogues (retinoids) that modulate the growth and differentiation of a variety of normal and malignant celjs in vitro and in vivo (4). All-fra/w-retinoic acid (ATRA) was found to be effective in the treatment of patients with acute promyelocytic leukemia by inducing granulocytic differentiation of the leukemia cells in vivo (5). 13-c/s-Retinoic acid (13CRA) has demonstrated efficacy in suppressing premalignant oral lesions and in preventing the development of second primary cancers in the upper aerodigestive tract in patients with head and neck cancer (6). Likewise, retinyl palmitate was found
Association Between Age at Diagnosis and Disease-Specific Mortality Among Postmenopausal Women With Hormone Receptor–Positive Breast Cancer
Authors: Willemien van de Water, Christos Markopoulos, Cornelis J. H. van de Velde, Caroline Seynaeve, Annette Hasenburg, Daniel Rea, Hein Putter, Johan W. R. Nortier, Anton J. M. de Craen, Elysée T. M. Hille, Esther Bastiaannet, Peyman Hadji, Rudi G. J. Westendorp, Gerrit-Jan Liefers, Stephen E. Jones
Journal: JAMA (2012)

In addition to classic tumor-related prognostic factors, patient characteristics may be associated with breast cancer outcome.To assess the association between age at diagnosis and breast cancer outcome in postmenopausal women with hormone receptor-positive breast cancer.Study analysis of 9766 patients enrolled in the TEAM (Tamoxifen Exemestane Adjuvant Multinational) randomized clinical trial between January 2001 and January 2006. Age at diagnosis was categorized as younger than 65 years (n=5349), 65 to 74 years (n=3060), and 75 years or older (n=1357).Primary end point was disease-specific mortality; secondary end points were other-cause mortality and breast cancer relapse.During median follow-up of approximately 5.1 years, there were a total of 1043 deaths. Disease-specific mortality, as a proportion of all-cause mortality, decreased with categorical age group (78% [<65 years], 56% [65-74 years], and 36% [≥75 years]; P < .001). In multivariable analyses, compared with patients younger than 65 years, disease-specific mortality increased with age for patients aged 65 to 74 years (hazard ratio [HR], 1.25; 95% CI, 1.01-1.54); and patients aged 75 years or older (HR, 1.63; 95% CI, 1.23-2.16) (P < .001). Similarly, breast cancer relapse increased with age for patients aged 65-74 years (HR, 1.07; 95% CI, 0.91-1.25 and patients aged 75 years or older (HR, 1.29; 95% CI, 1.05-1.60) (P = .06). Other-cause mortality increased with age in patients aged 65 to 74 years (HR, 2.66; 95% CI, 1.96-3.63) and patients aged 75 years or older (HR, 7.30; 95% CI, 5.29-10.07) (P < .001).Among postmenopausal women with hormone receptor-positive breast cancer, increasing age was associated with a higher disease-specific mortality.
Synchronous double primary lung cancers of squamous and neuroendocrine type associated with cryptogenic fibrosing alveolitis.
Authors: J W Seo, J G Im, Y W Kim, J H Kim, M N Sheppard
Journal: Thorax (1991)

A 72 year old man with simultaneously occurring squamous cell and neuroendocrine carcinomas in association with cryptogenic fibrosing alveolitis is reported. The tumours were separate and both were in the fibrotic area of the right lower lobe.
Atg7 Induces Basal Autophagy and Rescues Autophagic Deficiency in CryAB <sup>R120G</sup> Cardiomyocytes
Authors: J. Scott Pattison, Hanna Osinska, Jeffrey Robbins
Journal: Circulation Research (2011)

Rationale: Increasing evidence suggests that misfolded proteins and intracellular aggregates contribute to cardiac disease and heart failure. Several cardiomyopathies, including the αB-crystallin R120G mutation (CryAB R120G ) model of desmin-related cardiomyopathy, accumulate cytotoxic misfolded proteins in the form of preamyloid oligomers and aggresomes. Impaired autophagic function is a potential cause of misfolded protein accumulations, cytoplasmic aggregate loads, and cardiac disease. Atg7, a mediator of autophagosomal biogenesis, is a putative regulator of autophagic function. Objective: To determine whether autophagic induction by Atg7 is sufficient to reduce misfolded protein and aggregate content in protein misfolding-stressed cardiomyocytes. Methods and Results: To define the gain and loss of function effects of Atg7 expression on CryAB R120G protein misfolding and aggregates, neonatal rat cardiomyocytes were infected with adenoviruses expressing either wild-type CryAB or CryAB R120G and coinfected with Atg7 adenovirus or with Atg7 silencing siRNAs to produce gain-of or loss-of Atg7 function. Atg7 overexpression effectively induced basal autophagy with no detrimental effects on cell survival, suggesting that Atg7 can activate autophagy with no apparent cytotoxic effects. Autophagic flux assays on CryAB R120G -expressing cardiomyocytes revealed reduced autophagic function, which probably contributed to the failure of misfolded proteins and aggregates to be cleared. Coexpression of Atg7 and CryAB R120G significantly reduced preamyloid oligomer staining, aggregate content, and cardiomyocyte cytotoxicity. Conversely, Atg7 silencing in the CryAB R120G background significantly inhibited the already reduced rate of autophagy and increased CryAB R120G aggregate content and cytotoxicity. Conclusions: Atg7 induces basal autophagy, rescues the CryAB R120G autophagic deficiency, and attenuates the accumulation of misfolded proteins and aggregates in cardiomyocytes.
Mesenchymal stem cells as carriers and amplifiers in CRAd delivery to tumors
Authors: Xi Xia, Teng Ji, Pingbo Chen, Xiao Li, Yong Fang, Qinglei Gao, Shujie Liao, Lanying You, Hongbin Xu, Quanfu Ma, Peng Wu, Wencheng Hu, Mingfu Wu, Li Cao, Kezhen Li, Yanjie Weng, Zhiqiang Han, Junchen Wei, Ronghua Liu, Shixuan Wang, Gang Xu, Daowen Wang, Jianfeng Zhou, Ding Ma
Journal: Molecular Cancer (2011)

Abstract Background Mesenchymal stem cells (MSCs) have been considered to be the attractive vehicles for delivering therapeutic agents toward various tumor diseases. This study was to explore the distribution pattern, kinetic delivery of adenovirus, and therapeutic efficacy of the MSC loading of E1A mutant conditionally replicative adenovirus Adv-Stat3(-) which selectively replicated and expressed high levels of anti-sense Stat3 complementary DNA in breast cancer and melanoma cells. Methods We assessed the release ability of conditionally replicative adenovirus (CRAd) from MSC using crystal violet staining, TCID 50 assay, and quantitative PCR. In vitro killing competence of MSCs carrying Adv-Stat3(-) toward breast cancer and melanoma was performed using co-culture system of transwell plates. We examined tumor tropism of MSC by Prussian blue staining and immunofluorescence. In vivo killing competence of MSCs carrying Adv-Stat3(-) toward breast tumor was analyzed by comparison of tumor volumes and survival periods. Results Adv-Stat3(-) amplified in MSCs and were released 4 days after infection. MSCs carrying Adv-Stat3(-) caused viral amplification, depletion of Stat3 and its downstream proteins, and led to significant apoptosis in breast cancer and melanoma cell lines. In vivo experiments confirmed the preferential localization of MSCs in the tumor periphery 24 hours after tail vein injection, and this localization was mainly detected in the tumor parenchyma after 72 hours. Intravenous injection of MSCs carrying Adv-Stat3(-) suppressed the Stat3 pathway, down-regulated Ki67 expression, and recruited CD11b-positive cells in the local tumor, inhibiting tumor growth and increasing the survival of tumor-bearing mice. Conclusions These results indicate that MSCs migrate to the tumor site in a time-dependent manner and could be an effective platform for the targeted delivery of CRAd and the amplification of tumor killing effects.
Interhemispheric correlations of slow spontaneous neuronal fluctuations revealed in human sensory cortex
Authors: Yuval Nir, Roy Mukamel, Ilan Dinstein, Eran Privman, Michal Harel, Lior Fisch, Hagar Gelbard-Sagiv, Svetlana Kipervasser, Fani Andelman, Miri Y Neufeld, Uri Kramer, Amos Arieli, Itzhak Fried, Rafael Malach
Journal: Nature Neuroscience (2008)