Miracle-dz/UniFAR-FTUs huggingface dataset:
Optimization of a PEGylated Glucuronide-Monomethylauristatin E Linker for Antibody–Drug Conjugates

The emergence of antibody–drug conjugates (ADC), such as brentuximab vedotin and ado-trastuzumab emtansine, has led to increased efforts to identify new payloads and develop improved drug-linker technologies. Most antibody payloads impart significant hydrophobicity to the ADC, resulting in accelerated plasma clearance and suboptimal in vivo activity, particularly for conjugates with high drug-to-antibody ratios (DAR). We recently reported on the incorporation of a discrete PEG24 polymer as a side chain in a β-glucuronidase-cleavable monomethylauristatin E (MMAE) linker to provide homogeneous DAR 8 conjugates with decreased plasma clearance and increased antitumor activity in xenograft models relative to a non-PEGylated control. In this work, we optimized the drug-linker by minimizing the size of the PEG side chain and incorporating a self-stabilizing maleimide to prevent payload de-conjugation in vivo. Multiple PEG-glucuronide-MMAE linkers were prepared with PEG size up to 24 ethylene oxide units, and homogeneous DAR 8 ADCs were evaluated. A clear relationship was observed between PEG length and conjugate pharmacology when tested in vivo. Longer PEG chains resulted in slower clearance, with a threshold length of PEG8 beyond which clearance was not impacted. Conjugates bearing PEG of sufficient length to minimize plasma clearance provided a wider therapeutic window relative to faster clearing conjugates bearing shorter PEGs. A lead PEGylated glucuronide-MMAE linker was identified incorporating a self-stabilizing maleimide and a PEG12 side chain emerged from these efforts, enabling highly potent, homogeneous DAR 8 conjugates and is under consideration for future ADC programs. Mol Cancer Ther; 16(1); 116–23. ©2016 AACR.
Cardiovascular and Neuropsychiatric Events after Varenicline Use for Smoking Cessation

Rationale: Varenicline aids in smoking cessation but has also been associated with serious adverse events. Objectives: The aim of this study was to determine the risks of cardiovascular and neuropsychiatric events after varenicline receipt in a real‐world setting. Methods: A population‐based, self‐controlled risk interval study using linked universal health administrative data from the diverse, multicultural population of Ontario, Canada, was conducted. In two separate analyses, new varenicline users between September 1, 2011 and February 15, 2014 were observed from 1 year before to 1 year after varenicline receipt. The relative incidences of cardiovascular and neuropsychiatric hospitalizations and emergency department visits in the 12 weeks after varenicline receipt (the risk interval) compared with the remaining observation period (the control interval) were estimated in two separate fixed‐effect conditional Poisson regressions. Sensitivity analyses tested the robustness of the results. Measurements and Main Results: Among 56,851 new users of varenicline, 6,317 cardiovascular and 10,041 neuropsychiatric hospitalizations and emergency department visits occurred from 1 year before to 1 year after receipt. The incidence of cardiovascular events was 34% higher in the risk compared with the control interval (relative incidence, 1.34; 95% confidence interval, 1.25–1.44). Findings were consistent in sensitivity analyses, most notably in those without any history of previous cardiovascular disease. The relative incidence of neuropsychiatric events was marginally significant in the primary (relative incidence, 1.06; 95% confidence interval, 1.00–1.13) but not all sensitivity analyses. Conclusions: Varenicline appears to be associated with an increased risk of cardiovascular but not neuropsychiatric events.
Squamous cell carcinoma of buccal mucosa: An analysis of prognostic factors

Abstract Introduction: Carcinoma of the buccal mucosa is the most common oral cavity cancer in the Indian subcontinent. The aim of this study was to analyze the outcome and evaluate prognostic factors in surgically treated buccal mucosa squamous cell carcinoma (BMSCC) patients. Materials and Methods: A retrospective study was performed by reviewing the medical records of 409 pathologically proven buccal mucosa cancer patients, who were diagnosed and surgically treated in Tata Memorial Hospital between January 1, 2006, and December 31, 2008. Results: The overall 5-year survival of the cohort was found to be 54.1%. The stage-wise survival rate for tumor, node, metastasis (TNM) Stage I, II, III, and IV patients was found to be 85.2%, 82.9%, 56.3%, and 42.6% (P < 0.00), respectively. On multivariate Cox proportional hazard analysis, the presence of comorbidity, histological tumor size, pathological lymph node status, tumor differentiation, perineural invasion, and extracapsular spread were found to be independently associated with overall survival. Conclusion: BMSCC is an aggressive malignant tumor. In addition to TNM classification, other clinical and pathological factors also have a significant role in BMSCC prognostication. Hence, there is a need to move beyond TNM and develop a more inclusive, flexible, and easy to use prognostic system.
Lung glutathione and oxidative stress: implications in cigarette smoke-induced airway disease.

Glutathione (GSH), a ubiquitous tripeptide thiol, is a vital intra- and extracellular protective antioxidant in the lungs. The rate-limiting enzyme in GSH synthesis is γ-glutamylcysteine synthetase (γ-GCS). The promoter (5'-flanking) region of the human γ-GCS heavy and light subunits are regulated by activator protein-1 and antioxidant response elements. Both GSH and γ -GCS expression are modulated by oxidants, phenolic antioxidants, and inflammatory and anti-inflammatory agents in lung cells. γ-GCS is regulated at both the transcriptional and posttranscriptional levels. GSH plays a key role in maintaining oxidant-induced lung epithelial cell function and also in the control of proinflammatory processes. Alterations in alveolar and lung GSH metabolism are widely recognized as a central feature of many inflammatory lung diseases including chronic obstructive pulmonary disease (COPD). Cigarette smoking, the major factor in the pathogenesis of COPD, increases GSH in the lung epithelial lining fluid of chronic smokers, whereas in acute smoking, the levels are depleted. These changes in GSH may result from altered gene expression of γ -GCS in the lungs. The mechanism of regulation of GSH in the epithelial lining fluid in the lungs of smokers and patients with COPD is not known. Knowledge of the mechanisms of GSH regulation in the lungs could lead to the development of novel therapies based on the pharmacological or genetic manipulation of the production of this important antioxidant in lung inflammation and injury. This review outlines 1) the regulation of cellular GSH levels and γ -GCS expression under oxidative stress and 2) the evidence for lung oxidant stress and the potential role of GSH in the pathogenesis of COPD.
Methylphenidate reduces energy intake and dietary fat intake in adults: a mechanism of reduced reinforcing value of food?

BACKGROUND Dopamine mediates the reinforcing value of food, and low concentrations of dopamine are related to increased feeding. Thus, administering a drug that increases dopamine may reduce energy intake, possibly by reducing food reinforcement. OBJECTIVES We tested whether short-acting methylphenidate (MPH), a drug that increases the availability of dopamine by blocking its reuptake, reduces energy intake and alters macronutrient preference and whether these effects are due to a mechanism of reduced hunger or food reinforcement. DESIGN Fourteen adults were given placebo or short-acting MPH (0.5 mg/kg) in a randomized, double-blind, placebo-controlled crossover fashion. One hour after ingestion, hunger and the relative reinforcing value of snack food were measured, followed immediately by energy intake and macronutrient preference during a buffet-style lunch. RESULTS MPH reduced energy intake by 11% (P = 0.024) as well as intake of fat by 17% (P = 0.003) relative to placebo. Despite similar levels of prebuffet hunger, subjects taking MPH reduced their energy and fat intakes more than did those taking placebo, which suggests that hunger may not mediate the effects of MPH on energy intake. MPH showed a trend toward reducing the reinforcing value of high-fat food relative to placebo, but reduced food reinforcement was not significantly correlated with energy intake. CONCLUSION MPH reduced overall energy intake with a selective reduction in dietary fat. Findings are consistent with a reward deficiency model of obesity whereby low brain dopamine predicts overeating and obesity, and administering agents that increase dopamine results in reduced feeding behavior.
Matrix metalloproteinase synthesis and expression in isolated LV myocyte preparations.

In several cardiac disease states, alterations in myocyte and extracellular matrix (ECM) structure occur with left ventricular (LV) remodeling and are associated with changes in matrix metalloproteinase (MMP) activity. Although nonmyocyte cell types have been implicated as sites for synthesis and expression of MMPs within the ECM, whether the LV myocyte itself expresses specific types and active forms of MMPs remains unknown. Accordingly, isolated Ca2+-tolerant LV porcine myocytes (105 cells/ml) in which selective disaggregation and resuspension was performed (13 independent experiments) were plated on basement membrane substrates including Matrigel, collagen IV, laminin, and fibronectin as well as poly-l-lysine. After 24-h incubation, LV myocyte conditioned media were subjected to zymography, a specific MMP-2 proteolytic capture assay, immunoblotting, and ELISA for detection of MMP activity and relative content of the 72-kDa gelatinase MMP-2. Although robust zymographic activity [(pixels ⋅ mm2)/cell] was observed in conditioned media from LV myocytes plated on collagen IV (1,673 ± 297), fibronectin (1,530 ± 281), and poly-l-lysine (2,545 ± 560), proteolytic activity appeared to be lower in conditioned media from LV myocytes plated on Matrigel (842 ± 83) and laminin (1,329 ± 238). MMP-2 proteolytic activity was increased by approximately eightfold in conditioned media taken from LV myocytes plated on poly-l-lysine compared with that of Matrigel. With respect to each of the adhesion substrates, MMP-2 content was at least 50% lower in LV myocyte conditioned media taken from Matrigel and laminin. Immunofluorescent labeling of LV myocytes yielded a strong signal for MMP-2 within the myocyte and along the sarcolemmal surface. In conclusion, this study demonstrated for the first time that adult LV myocytes synthesize and express members of the MMP family and thus may potentially participate in the LV remodeling process through synthesis and secretion of MMPs.
Dietary and physical activity patterns in French children are related to overweight and socioeconomic status.

Sedentary behavior (SED) has already been identified as a risk factor of childhood overweight (OW) but less is known about the dietary patterns related to adiposity. Our objective was to investigate if lifestyle patterns combining overall diet and physical activity were associated with childhood OW and if they were involved in the reverse association between socioeconomic status (SES) and OW. Dietary intake was assessed using a 7-d food record in 748 French children aged 3-11 y from the 1998-1999 cross-sectional French Enquête Individuelle et Nationale sur les Consommations Alimentaires national food consumption survey. Weight and height, leisure time physical activity, SED (television viewing), and SES were reported by parents or children by answering questionnaires. Scores for lifestyle patterns were assessed with factor analysis and their relationship with OW was explored by logistic regression analysis. Two similar lifestyle patterns were identified in children aged 3-6 y and 7-11 y: "snacking and sedentary" and "varied food and physically active. " The snacking and sedentary pattern was positively associated with OW in the youngest children (P-trend = 0.0161) and partly mediated the negative association of SES to OW. The varied food and physically active pattern was inversely correlated with OW in the eldest children only (P-trend = 0.0401). A third pattern called "big eaters at main meals" was derived in children aged 7-11 y and was positively correlated with OW (P-trend = 0.0165). From a public health perspective, the combinations of identifiable dietary and physical activity behaviors may be useful as a basis for recommendations on preventing OW.
Phosphorylation of p70S6kcorrelates with increased skeletal muscle mass following resistance exercise.

High-resistance exercise training results in an increase in muscle wet mass and protein content. To begin to address the acute changes following a single bout of high-resistance exercise, a new model has been developed. Training rats twice a week for 6 wk resulted in 13.9 and 14.4% hypertrophy in the extensor digitorum longus (EDL) and tibialis anterior (TA) muscles, respectively. Polysome profiles after high-resistance lengthening contractions suggest that the rate of initiation is increased. The activity of the 70-kDa S6 protein kinase (p70S6k), a regulator of translation initiation, is also increased following high-resistance lengthening contractions (TA, 363 ± 29%; EDL, 353 ± 39%). Furthermore, the increase in p70S6k activity 6 h after exercise correlates with the percent change in muscle mass after 6 wk of training ( r = 0.998). The tight correlation between the activation of p70S6k and the long-term increase in muscle mass suggests that p70S6k phosphorylation may be a good marker for the phenotypic changes that characterize muscle hypertrophy and may play a role in load-induced skeletal muscle growth.
Study of Tool Electrode Wear in EDM Process

Technology of Electrical Discharge Machining (EDM) uses thermal energy in material removal, in which is the electrical energy transformed, generated between the electrodes (tool and workpiece). The material removal occurs through the rapid periodic repetitive electrical discharges in the presence of dielectric fluid. By the action of electrical discharges occurs to decline not only particles of a metal workpiece material, but also to decline in a certain proportion of metal particles in tool electrode. The paper deals with the diagnosis the size of the electrode wear of tools made from copper and graphite used in EDM machining.
Effects of intraduodenal glucose, fat, and protein on blood pressure, heart rate, and splanchnic blood flow in healthy older subjects.

BACKGROUND Postprandial hypotension frequently occurs in the elderly. The hypotensive response to a meal is triggered by the interaction of nutrients with the small intestine; information relating to the effects of different macronutrients on blood pressure (BP) is limited and inconsistent. OBJECTIVE The objective of the study was to determine the effects of intraduodenal glucose, fat, and protein on BP, heart rate (HR), and superior mesenteric artery (SMA) blood flow in healthy older subjects. DESIGN Eight subjects received intraduodenal glucose (64 g), fat (10% oil emulsion), protein (72 g whey), or saline (0.9%) at a rate of 2.7 mL/min for 90 min, followed by intraduodenal saline for 30 min. BP, HR, and SMA blood flow were measured. RESULTS The falls in systolic BP during infusions of glucose, fat, and protein did not differ significantly (P=0.97); however, the fall occurred significantly earlier during the glucose infusion; (18+/-3.0 min) than during the fat (46+/-11.0 min; P=0.02) and protein 33+/-7 min; P=0.04) infusions. The increases in HR during glucose, fat, and protein infusions (P<0.0001 for all) did not differ significantly. SMA blood flow increased significantly after all infusions (P<0.001 for all), but the increase was significantly (P<0.05) lower after protein than after the other infusions. CONCLUSIONS Intraduodenal glucose, fat, and protein decrease systolic BP in healthy older subjects, but the onset of the hypotensive response is earlier after glucose, and the effect of protein on SMA blood flow is less than that of the other nutrients.
Renal growth and development in mice lacking AT1A receptors for angiotensin II.

To examine the role of the type 1A (AT1A) angiotensin receptor in renal growth and development, we analyzed F2 progeny from a series of crosses between F1 mice that were heterozygous for a targeted disruption of the AT1Areceptor gene [ Agtr1A-(+/-)]. Among 21-day-old weanling F2 mice, we found that 194 (32%) were homozygous for the wild-type allele Agtr1A-(+/+), 299 (49%) were Agtr1A-(+/-), and 119 (19%) were Agtr1A-(-/-). This differed significantly from the proportions predicted by Mendelian genetics ( P = 0.01), suggesting that the complete absence of AT1Areceptors is associated with a mild survival disadvantage. Agtr1A-(-/-) mice grew normally, and we found no significant differences in body weight or heart and kidney weights in Agtr1A-(+/+) and Agtr1A-(-/-) mice examined at 21, 60, and 100 days. Protein and DNA content of kidneys and hearts were also similar in weanling or adult Agtr1A-(+/+) and Agtr1A-(-/-) mice. By light microscopy with immunohistochemistry, kidneys from Agtr1A-(-/-) were essentially normal, with two exceptions: 1) there was marked hypertrophy of the juxtaglomerular apparatus (JGA) and proximal expansion of renin-producing cells along the afferent arterioles, and 2) some glomeruli showed evidence of mesangial expansion. We did not find the severe renal vascular lesions or papillary atrophy that have been observed in angiotensinogen- or angiotensin converting enzyme-deficient animals. We conclude that the AT1A receptor is not essential for the normal organogenesis of the kidney; however, its absence is associated with mild mesangial expansion and JGA hypertrophy.
Putative domal microbial structures in fluvial siliciclastic facies of the Mesoproterozoic (1.09 Ga) Copper Harbor Conglomerate, Upper Peninsula of Michigan, USA

The Copper Harbor Conglomerate is a Mesoproterozoic (1.09 Ga) freshwater sedimentary sequence that outcrops in the Upper Peninsula of Michigan. The formation was deposited during infilling of the failed Midcontinent Rift and contains fluvial, lacustrine, and alluvial fan facies. This study describes and analyzes the formation of small domal structures preserved in fluvial sandstone facies within the lower portion of the formation. These domal structures range from millimeters to several centimeters in diameter and height, and are preserved in convex epirelief on fine‐grained sandstone beds. The structures have a pustulose texture and a patchy distribution on bedding planes. Slabs containing the structures were collected in the field and analyzed in the laboratory through inspection of cut slabs, petrographic thin sections, X‐radiographs, and RAMAN spectroscopy. Results of these analyses reveal that the domal structures often contain weak, wavy horizontal bedding and laminae, and lack any vertical structures. These results support a biogenic origin of the domal structures instead of through abiogenic processes such as loading, sand volcanoes, or adhesion warts. These structures are akin to what were traditionally labeled as ‘sand stromatolites’, but are now known as ‘domal sand structures’. Along with previous descriptions of carbonate stromatolites, organic‐rich paleosols, and microbial sand structures, our findings provide further evidence that mat‐forming microbial communities thrived in the late Mesoproterozoic freshwater systems of the Midcontinent Rift.
Oral ferrous sulfate supplements increase the free radical-generating capacity of feces from healthy volunteers.

BACKGROUND Most dietary iron remains unabsorbed and hence may be available to participate in Fenton-driven free radical generation in conjunction with the colonic microflora, leading to the production of carcinogens or direct damage to colonocytes. OBJECTIVE Our aims were to measure the proportion of fecal iron available to participate in free radical generation and to determine the effect of an oral supplement of ferrous sulfate on free radical generation. DESIGN Eighteen healthy volunteers recorded their food intake and collected fecal samples before, during, and after 2 wk of supplementation (19 mg elemental Fe/d). Total, free, and weakly chelated fecal iron were measured and free radical production was determined by using an in vitro assay with dimethyl sulfoxide as a free radical trap. RESULTS Fecal iron increased significantly during the period of supplementation and returned to baseline within 2 wk. The concentration of weakly bound iron in feces (approximately 1.3% of total fecal iron) increased from 60 micromol/L before to 300 micromol/L during supplementation, and the production of free radicals increased significantly (approximately 40%). Higher-carbohydrate diets were associated with reduced free radical generation. CONCLUSION Unabsorbed dietary iron may increase free radical production in the colon to a level that could cause mucosal cell damage or increased production of carcinogens.
Age, sex, ethnicity, body composition, and resting energy expenditure of obese African American and white children and adolescents.

BACKGROUND African Americans may have a lower resting energy expenditure (REE) than do whites, although the data are limited for obese children and adolescents and for boys. Differences in bone density and trunk lean body mass may account for some of these measured differences in REE. OBJECTIVE We assessed the REE and body composition of obese African American and white children and adolescents. DESIGN Obese, 5-17-y-old children and adolescents were evaluated (n = 203). Body composition was assessed by dual-energy X-ray absorptiometry. REE was measured by open-circuit calorimetry. African American and white children were compared. The relation between REE and the independent variables (age, sex, ethnic group, fat mass, and fat-free mass or lean tissue mass) was assessed. RESULTS Of those evaluated, 66% were girls and 34% were African American. Age, sex, pubertal status, and body composition did not differ significantly by ethnic group. All the independent variables were significantly associated with REE. Using lean tissue mass to account for differences in bone density did not significantly alter the results. REE decreased with age and was lower in the girls than in the boys and in the African Americans than in the whites. When trunk fat-free mass was included in the model in place of whole-body fat-free mass, the ethnic difference in REE decreased. CONCLUSIONS Adjustment for trunk lean tissue mass partially explains the lower REE of obese African American children and adolescents. The lower relative REE of older obese children suggests the importance of early intervention in the prevention of childhood obesity. The lower REE of girls and of African Americans may contribute to the difficulty in weight management in these groups.
RF CMOS and SOI Technology: Status quo,Recent Advances and Future Trends

With recent fast growth in the RF (Radio-Frequency) wireless communications market, the demand for high performance but low cost RF solutions is rising. Recent advances in SOI (Silicon on Insulator) and complementary metal oxide semiconductor (CMOS) processing, continuous scaling of gate length, and progress in silicon on insulator have stirred serious discussions on the suitability of metal-oxide semiconductor field-effect transistors (MOSFETs) for RF/microwave applications. The scale down of CMOS-SOI technologies has challenged toward the deep-submicron minimum feature size. This leads to great expectations for CMOS RF applications. This paper covers the recent advances and current status of mainstream CMOS and SOI as the dominating technologies in very large scale integration, future trends of RF MOSFETs, and applications of MOSFETs in RF electronics.