tbuckley/cabot-search huggingface dataset:
Long-term Rescue of a Lethal Murine Model of Methylmalonic Acidemia Using Adeno associated Viral Gene Therapy
Authors: Randy J Chandler, Charles P Venditti
Journal: Molecular Therapy (2009)

Methylmalonic acidemia (MMA) is an organic acidemia caused by deficient activity of the mitochondrial enzyme methylmalonyl-CoA mutase (MUT). This disorder is associated with lethal metabolic instability and carries a poor prognosis for long-term survival. A murine model of MMA that replicates a severe clinical phenotype was used to examine the efficacy of recombinant adeno-associated virus (rAAV) serotype 8 gene therapy as a treatment for MMA. Lifespan extension, body weight, circulating metabolites, transgene expression, and whole animal propionate oxidation were examined as outcome parameters after gene therapy. One-hundred percent of the untreated Mut−/− mice (n = 58) died by day of life (DOL) 72, whereas >95% of the adeno-associated virus–treated Mut−/− mice (n = 27) have survived for ≥1 year. Despite a gradual loss of transgene expression and elevated circulating metabolites in the treated Mut−/− mice, the animals are indistinguishable from unaffected control littermates in size and activity levels. These experiments provide the first definitive evidence that gene therapy will have clinical utility in the treatment of MMA and support the development of gene therapy for other organic acidemias. Methylmalonic acidemia (MMA) is an organic acidemia caused by deficient activity of the mitochondrial enzyme methylmalonyl-CoA mutase (MUT). This disorder is associated with lethal metabolic instability and carries a poor prognosis for long-term survival. A murine model of MMA that replicates a severe clinical phenotype was used to examine the efficacy of recombinant adeno-associated virus (rAAV) serotype 8 gene therapy as a treatment for MMA. Lifespan extension, body weight, circulating metabolites, transgene expression, and whole animal propionate oxidation were examined as outcome parameters after gene therapy. One-hundred percent of the untreated Mut−/− mice (n = 58) died by day of life (DOL) 72, whereas >95% of the adeno-associated virus–treated Mut−/− mice (n = 27) have survived for ≥1 year. Despite a gradual loss of transgene expression and elevated circulating metabolites in the treated Mut−/− mice, the animals are indistinguishable from unaffected control littermates in size and activity levels. These experiments provide the first definitive evidence that gene therapy will have clinical utility in the treatment of MMA and support the development of gene therapy for other organic acidemias.
A Mode of Employing Pressure in Cases of Inflammatory Enlargement
Authors: S. M. Bradley
Journal: BMJ (1874)

Sept. 26, I874.or adjacent softening.In its centre were two calcareous masses, irregular in shape, each about the size of a bean.The microscopic characters were most nearly those of a glioma.No structural lesion could be found elsewhere in the brain.REMARKS.-That the tumour was the cause, direct or indirect, of the convulsive attacks must be regarded as highly probable.It was the only cause discoverable.Its duration was evidently considerable, and may well have corresponded with the duration of the symptoms.Cal- careous nodules of such a size rarely form in a tumour of that character,
“Normal” liver stiffness measure (LSM) values are higher in both lean and obese individuals: A population-based study from a developing country
Authors: Kausik Das, Rajib Sarkar, Sk. Mahiuddin Ahmed, Asit R. Mridha, Partha S. Mukherjee, Kshaunish Das, Gopal K. Dhali, Amal Santra, Abhijit Chowdhury
Journal: Hepatology (2011)

The liver stiffness measure (LSM) needs to be explored in ethnically and anthropometrically diverse healthy subjects (to derive an acceptable normal range) and also in patients with liver disease. In view of this objective, LSM was performed by transient elastography (TE) using FibroScan in 437 healthy subjects with normal alanine aminotransferase (ALT) levels, recruited from a free-living population of the Birbhum Population Project (BIRPOP; www.shds.in), a Health and Demographic Surveillance System (HDSS), and from 274 patients with liver disease attending the Hepatology Clinic of the School of Digestive and Liver Diseases (SDLD; Institute of Post Graduate Medical Education & Research [IPGME&R], Kolkata, India) including 188 with nonalcoholic fatty liver disease (NAFLD) and 86 with chronic hepatitis of viral and other etiologies. Liver biopsy was performed in 125 patients. The range of normal values for LSM, defined by 5th and 95th percentile values in healthy subjects, was 3.2 and 8.5 kPa, respectively. Healthy subjects with a lower body mass index (BMI; < <18.5 kg/m(2)) had a higher LSM compared with subjects who had a normal BMI; this LSM value was comparable to that of obese subjects (6.05 ± 1.78 versus 5.51 ± 1.59 and 6.60 ± 1.21, P = 0.016 and 0.349, respectively). Liver disease patients without histologic fibrosis had significantly higher LSM values compared with healthy subjects (7.52 ± 5.49 versus 5.63 ± 1.64, P < 0.001). Among the histologic variables, stage of fibrosis was the only predictor for LSM. LSM did not correlate with inflammatory activity and ALT in both NAFLD and chronic hepatitis groups.LSM varies between 3.2 and 8.5 kPa in healthy subjects of South Asian origin. Both lean and obese healthy subjects have higher LSM values compared with subjects with normal BMI. Liver stiffness begins to increase even before fibrosis appears in patients with liver disease.
Safety, Efficacy, Pharmacokinetics, and Pharmacodynamics of the Combination of Sorafenib and Tanespimycin
Authors: Ulka N. Vaishampayan, Angelika M. Burger, Edward A. Sausville, Lance K. Heilbrun, Jing Li, M. Naomi Horiba, Merrill J. Egorin, Percy Ivy, Simon Pacey, Patricia M. LoRusso
Journal: Clinical Cancer Research (2010)

Heat shock protein (Hsp) 90 inhibition affects the Raf kinase signaling pathway and could enhance antitumor effects of sorafenib, a Raf kinase inhibitor. The combination of sorafenib and tanespimycin [17-allyl-amino-geldanamycin (17-AAG); NSC 330507/KOS-953] was evaluated in a phase I trial with the primary objective of defining a phase II dose.The dose cohorts consisted of fixed continuous oral dosing of 400 mg sorafenib twice daily, starting at 14 days before tanespimycin, which was administered intravenously at escalating doses (starting at 300 mg/m,(2) with 50 mg/m(2) increments), on days 1, 8, and 15 in a 28-day cycle. Toxicity was assessed weekly, and response was evaluated every two cycles.Twenty-seven toxicity-evaluable patients were enrolled and treated at four dose levels. Predominant primary malignancies were renal cancer (12), melanoma (6), and colorectal cancer (4). Dose-limiting toxicities of grade 4 transaminitis and grade 3 hand-foot syndrome in one patient each were observed at 450 mg/m(2) of tanespimycin. One hundred fourteen cycles were administered with a median of four cycles (range 1-17 cycles). Plasma concentrations of sorafenib and metabolites reached steady state after 7 days. Tanespimycin did not alter sorafenib concentrations. Pharmacodynamics showed a decrease in Hsp90 levels and induction of Hsp70. Clinical efficacy was observed in 9 of 12 renal cancer patients and 4 of 6 melanoma patientsRecommended phase II doses of this combination are 400 mg sorafenib twice daily and 400 mg/m(2) tanespimycin on days 1, 8, and 15, every 28 days. Clinical and pharmacodynamic activity was observed in kidney cancer and melanoma.
Philadelphia‐positive acute myelomonocytic leukemia with inversion of chromosome 16 and eosinobasophils
Authors: Cristina Mecucci, Lucien Noens, Ana Aventin, Nicoletta Testoni, Herman Van Den Berghe
Journal: American Journal of Hematology (1988)

Abstract Cytogenetic studies in a case of acute nonlymphocytic leukemia, type M4‐FAB with eosinophilia, showed an acquired abnormal karyotype characterized by both a t(9;22) Philadelphia translocation and a pericentric Inversion of chromosome 16, inv(16)(p13q22). This unique case shows that the previously described association between inversion of chromosome 16 and myelomonocytic leukemia with bone marrow eosinophilia is true also in Philadelphia‐positive disorders. The present findings are consistent with the existence of a group of chromosome anomalies, namely t(15;17) and inv(16), which are specifically associated with one single stage of morphological differentiation of myeloid leukemic cells.
Action of cholecystokinin and cholinergic agents on membrane-bound calcium in dispersed pancreatic acinar cells.
Authors: H T Shelby, L P Gross, P Lichty, J D Gardner
Journal: Journal of Clinical Investigation (1976)

In dispersed acinar cells prepared from guinea pig pancreas, cellular uptake of 45Ca was moderately rapid and reached a steady state by 60 min. At the steady state, 69% of total cellular 45Ca was membrane-bound. In acinar cells preloaded with 45Ca and then incubated with COOH-terminal octapeptide of cholecystokinin (CCK-OP) or carbamylcholine, total cellular 45Ca decreased by approximately 40% within 5-10 min and then steadily increased to control values by 60 min. Under identical conditions, membrane-bound 45Ca decreased by 40% within 5-10 min and remained constant for the duration of the incubation. Free cellular 45Ca did not change during the initial 30 min but then increased steadily to values three times those in control cells by 60 min. In cells preloaded with 45Ca and then incubated with EDTA, the loss of total cellular radioactivity stimulated by CCK-OP could be accounted for by loss of membrane-bound 45Ca. CCK-OP failed to alter total cellular uptake of 45Ca when both tracer and peptide were added at the beginning of the incubation. Under identical conditions, membrane-bound 45Ca was not altered by CCK-OP during the first 30 min of incubation but was significantly below control values after this time. The effect of CCK-OP on free cellular 45Ca was the same as in cells preloaded with the tracer. These results suggest that CCK-OP causes release of 45Ca from a membrane-bound compartment that equilibrates slowly with extracellular fluid and that the change in free cellular 45Ca is a secondary effect.
Relative efficiencies of the maximum-likelihood, neighbor-joining, and maximum-parsimony methods when substitution rate varies with site.
Authors: Y Tateno, N Takezaki, M Nei
Journal: Molecular Biology and Evolution (1994)

The relative efficiencies of the maximum-likelihood (ML), neighbor-joining (NJ), and maximum-parsimony (MP) methods in obtaining the correct topology and in estimating the branch lengths for the case of four DNA sequences were studied by computer simulation, under the assumption either that there is variation in substitution rate among different nucleotide sites or that there is no variation. For the NJ method, several different distance measures (Jukes-Cantor, Kimura two-parameter, and gamma distances) were used, whereas for the ML method three different transition/transversion ratios (R) were used. For the MP method, both the standard unweighted parsimony and the dynamically weighted parsimony methods were used. The results obtained are as follows: (1) When the R value is high, dynamically weighted parsimony is more efficient than unweighted parsimony in obtaining the correct topology. (2) However, both weighted and unweighted parsimony methods are generally less efficient than the NJ and ML methods even in the case where the MP method gives a consistent tree. (3) When all the assumptions of the ML method are satisfied, this method is slightly more efficient than the NJ method. However, when the assumptions are not satisfied, the NJ method with gamma distances is slightly better in obtaining the correct topology than is the ML method. In general, the two methods show more or less the same performance. The NJ method may give a correct topology even when the distance measures used are not unbiased estimators of nucleotide substitutions. (4) Branch length estimates of a tree with the correct topology are affected more easily than topology by violation of the assumptions of the mathematical model used, for both the ML and the NJ methods. Under certain conditions, branch lengths are seriously overestimated or underestimated. The MP method often gives serious underestimates for certain branches. (5) Distance measures that generate the correct topology, with high probability, do not necessarily give good estimates of branch lengths. (6) The likelihood-ratio test and the confidence-limit test, in Felsenstein's DNAML, for examining the statistical of branch length estimates are quite sensitive to violation of the assumptions and are generally too liberal to be used for actual data. Rzhetsky and Nei's branch length test is less sensitive to violation of the assumptions than is Felsenstein's test. (7) When the extent of sequence divergence is < or = 5% and when > or = 1,000 nucleotides are used, all three methods show essentially the same efficiency in obtaining the correct topology and in estimating branch lengths.(ABSTRACT TRUNCATED AT 400 WORDS)
Evidence for an association between the aetiology of cirrhosis and pattern of hepatocellular carcinoma development
Authors: L Benvegnu
Journal: Gut (2001)

Patients with liver cirrhosis are at significant risk of hepatocellular carcinoma (HCC) that may develop as well defined nodular lesions or as more aggressive infiltrating tumours.To compare prospectively risk factors associated with nodular or infiltrating HCC in cirrhotic patients.We studied 370 patients with cirrhosis, followed prospectively by periodic ultrasound (US) of the liver, for a mean period of 74.6 (SD 32.4) months to define the incidence and patterns of HCC development. Patients who developed HCC were compared according to tumour pattern using univariate and multivariate analysis.Sixty one (16.5%) patients developed HCC: HCC was classified as nodular in 49 (80.3%) and infiltrating in 12 (19.7%) according to US and computerised tomography (CT) imaging. The five and 10 year cumulative probabilities were 8.1% (95% confidence interval (CI) 5. 2%-11%) and 25.2% (15.0-35.4%) for nodular HCC and 2.1% (0.5-3.7%) and 6.9% (2.1-11.7%) for infiltrating HCC. Patients with infiltrating HCC were younger than those with nodular HCC (59.5 v 66. 2 years, 95% CI 55.2-63.8 and 64.1-68.3 years; p=0.014). Using multivariate analysis, development of nodular HCC was associated with older age (p=0.0002; relative risk (RR) 3.1; 95% CI 1.6-5.2), longer duration (p=0.09; RR 2.6; 95% CI 1.8-3.4), and more advanced stage (p=0.002; RR 2.5; 95% CI 1.3-4.5) of cirrhosis but not with the aetiology of liver disease. In contrast, development of infiltrating HCC appeared to be unrelated to age or disease duration or stage, while it was associated with hepatitis B virus infection (p=0.07; RR 3.96; 95% CI 1.1-5.2) and with hepatitis B/hepatitis C virus coinfection (p=0.0007; RR 16.9; 95% CI 3.8-36.7).In liver cirrhosis, we identified two patterns of HCC developing with distinct risk factors. Nodular HCC was related to the cirrhotic process per se independent of aetiological factors and may depend on the proliferative activity within regenerative nodules, while the infiltrating form of HCC was linked to hepatitis B virus infection and may reflect more direct virus induced carcinogenesis.
Low Therapeutic Threshold for Hepatocyte Replacement in Murine Phenylketonuria
Authors: Kelly Hamman, Heather Clark, Eugenio Montini, Muhsen Al-Dhalimy, Markus Grompe, Milton Finegold, Cary O. Harding
Journal: Molecular Therapy (2005)

Phenylalanine homeostasis in mammals is primarily controlled by liver phenylalanine hydroxylase (PAH) activity. Inherited PAH deficiency (phenylketonuria or PKU) leads to hyperphenylalaninemia in both mice and humans. A low level of residual liver PAH activity ensures near-normal dietary protein tolerance with normal serum phenylalanine level, but the precise threshold for normal phenylalanine clearance is unknown. We employed hepatocyte transplantation under selective growth conditions to investigate the minimal number of PAH-expressing hepatocytes necessary to prevent hyperphenylalaninemia in mice. Serum phenylalanine levels remained normal in mice exhibiting nearly complete liver repopulation with PAH-deficient hepatocytes (<5% residual wild-type liver PAH activity). Conversely, transplantation of PAH-positive hepatocytes into PAH-deficient Pah(enu2) mice, a model of human PKU, yielded a significant decrease in serum phenylalanine (<700 muM) when liver repopulation exceeded approximately 5%. These data suggest that restoration of phenylalanine homeostasis requires PAH activity in only a minority of hepatocytes.
Experimental IgA nephropathy induced by oral immunization.
Authors: S N Emancipator, G R Gallo, M E Lamm
Journal: The Journal of Experimental Medicine (1983)

To test the hypothesis that IgA nephropathy can result from a mucosal immune response, mice were orally immunized with one of three protein antigens for 14 wk. Such mice exhibited an essentially pure mucosal antibody response characterized by specific IgA-producing plasma cells in exocrine sites and specific IgA antibodies in serum. Furthermore, 73% of immunized mice had IgA and 88% had immunogen deposited in the glomerular mesangium, and 64% of immunized mice examined ultrastructurally had electron-dense mesangial deposits. All three were present concurrently in 57% of the immunized mice. No differences in regard to IgG or IgM were observed between immunized and control mice for any of these parameters. Mucosal immunization therefore can result in a specific immune response that leads to mesangial deposition of immune complexes containing IgA antibody. In its fundamental features the experimental renal lesion resembles that seen in the human disease IgA nephropathy.
Effective induction of naive and recall T-cell responses by targeting antigen to human dendritic cells via a humanized anti–DC-SIGN antibody
Authors: Paul J. Tacken, I. Jolanda M. de Vries, Karlijn Gijzen, Ben Joosten, Dayang Wu, Russell P. Rother, Susan J. Faas, Cornelis J. A. Punt, Ruurd Torensma, Gosse J. Adema, Carl G. Figdor
Journal: Blood (2005)
Diabetes Self-Management: Self-reported recommendations and patterns in a large population
Authors: Laurie Ruggiero, Russell Glasgow, Janet M Dryfoos, Joseph S Rossi, James O Prochaska, C Tracy Orleans, Alexander V Prokhorov, Susan R Rossi, Geoffrey W Greene, Gabrielle R Reed, Kim Kelly, Lisa Chobanian, Suzann Johnson
Journal: Diabetes Care (1997)

OBJECTIVE Diabetes self-management is the cornerstone of overall diabetes management. Yet many questions concerning self-management remain unanswered. The current study was designed to examine several questions about diabetes self-management: 1) What do individuals report being told to do? 2) What are their self-reported levels and patterns of self-care? 3) Are there differences on self-reported self-management recommendations and levels across various subgroups? RESEARCH DESIGN AND METHODS Mailed surveys were returned by 2,056 individuals (73.4% response rate). Of the total, 13.8% had IDDM and the remainder had NIDDM, with 65% of the NIDDM group using insulin. RESULTS The levels and patterns of self-management were consistent with those found in previous studies, i.e., individuals most regularly followed their prescribed medication regimen and least regularly followed recommendations for lifestyle changes of diet and exercise. There were significant differences on reported self-management recommendations across different subgroups. Comparisons on level of self-management across diabetes type revealed significant differences for diet and glucose testing. Differences were also found on self-management levels for a number of individual characteristics, including age, working status, and type of insurance, along with knowledge of the Diabetes Control and Complications Trial findings. CONCLUSIONS These findings provide important information on perceived self-management recommendations and the specific self-management levels and patterns in individuals with diabetes. The current findings may help health professionals better understand the levels and correlates of diabetes self-management and direct future research.
Plasma concentration of asymmetrical dimethylarginine and mortality in patients with end-stage renal disease: a prospective study
Authors: Carmine Zoccali, Stefanie M Bode-Böger, Francesca Mallamaci, Frank Antonio Benedetto, Giovanni Tripepi, Lorenzo Salvatore Malatino, Alessandro Cataliotti, Ignazio Bellanuova, Isabella Fermo, Jürgen C Frölich, Rainer H Böger
Journal: The Lancet (2001)
Meta-analysis: Dietary Fat Intake, Serum Estrogen Levels, and the Risk of Breast Cancer
Authors: A H Wu, M C Pike, D O Stram
Journal: JNCI Journal of the National Cancer Institute (1999)

BACKGROUND: There is compelling evidence that estrogens influence breast cancer risk. Since the mid-1980s, dietary fat intervention studies have been conducted to investigate the effect of fat intake on endogenous estrogen levels. To further our understanding of the possible relationship between dietary fat and breast cancer, we conducted a meta-analysis of dietary fat intervention studies that investigated serum estradiol levels, and we reviewed the nature of the evidence provided by prospective analytic studies of fat consumption and breast cancer risk. METHODS: A computerized search of the English language literature on estrogen/estradiol and dietary fat intervention studies published from January 1966 through June 1998 was conducted using the MEDLINE® database. Pooled estimates were derived from the change in estradiol levels associated with fat reduction from 13 studies. Analyses were conducted separately for premenopausal and postmenopausal women and in both groups combined. RESULTS AND CONCLUSIONS: Statistically significant reductions in serum estradiol levels of − 7.4% (95% confidence interval [CI] = − 11.7% to −2.9%) among premenopausal women and − 23.0% (95% CI = −27.7% to −18.1%) among postmenopausal women were observed, with an overall −13.4% (95% CI = −16.6% to −10.1%) reduction observed. The greatest reductions occurred in two studies in which dietary fat was reduced to 10%-12% of calories compared with 18%-25% of calories in the other studies. A statistically significant reduction in estradiol levels of −6.6% (95% CI = −10.3% to −2.7%) remained after exclusion of these two studies. Review of prospective analytic epidemiologic studies that allowed for dietary measurement error suggests that the possibility that reducing fat consumption below 20% of calories will reduce breast cancer risk cannot be excluded. IMPLICATIONS: Dietary fat reduction can result in a lowering of serum estradiol levels and such dietary modification may still offer an approach to breast cancer prevention.