Miracle-dz/UniFAR-FTUs huggingface dataset:
Integrated Molecular and Clinical Analysis of AKT Activation in Metastatic Melanoma

Purpose: Activation of the phosphoinositide 3-kinase (PI3K)-AKT pathway has been implicated in melanoma based primarily on the prevalence of mutations in PTEN and NRAS. To improve our understanding of the regulation and clinical significance of the PI3K-AKT pathway in melanoma, we quantitatively measured the levels of phosphorylated AKT, its substrate GSK3α/β, and its negative regulator PTEN in clinical metastases. Results were compared with mutational status, clinical outcomes, and sites of metastasis. Experimental Design: DNA and protein were isolated from dissected frozen melanoma metastases (n = 96). Activating mutations of BRAF, NRAS, AKT, PIK3CA, and KIT were detected by mass spectroscopy genotyping. Phosphorylated AKT (Ser473 and Thr308), P-GSK3α/β, and PTEN protein expression were measured by reverse-phase protein array. A panel of human melanoma cells lines (n = 58) was analyzed for comparison. Results: BRAF-mutant tumors had higher levels of P-AKT-Ser473 (P = 0.01), P-AKT-Thr308 (P = 0.002), and P-GSK3α/β (P = 0.08) than NRAS-mutant tumors. Analysis of individual tumors showed that almost all tumors with elevated P-AKT had low PTEN levels; NRAS-mutant tumors had normal PTEN and lower P-AKT. Similar results were observed in melanoma cell lines. Stage III melanoma patients did not differ in overall survival based on activation status of the PI3K-AKT pathway. Brain metastases had significantly higher P-AKT and lower PTEN than lung or liver metastases. Conclusions: Quantitative interrogation of the PI3K-AKT pathway in melanoma reveals unexpected significant differences in AKT activation by NRAS mutation and PTEN loss, and hyperactivation of AKT in brain metastases. These findings have implications for the rational development of targeted therapy for this disease. (Clin Cancer Res 2009;15(24):7538–46)
The Role of the Primate Amygdala in Conditioned Reinforcement

Conditioned reinforcement refers to the capacity of a conditioned stimulus to support instrumental behavior by acquiring affective properties of the primary reinforcer with which it is associated. Conditioned reinforcers maintain behavior over protracted periods of time in the absence of, and potentially in conflict with, primary reinforcers and as such may play a fundamental role in complex social behavior. A relatively large body of evidence supports the view that the amygdala (and in particular the basolateral area) contributes to conditioned reinforcement by maintaining a representation of the affective value of conditioned stimuli. However, a recent study in primates (Malkova et al., 1997), using a second-order visual discrimination task, suggests that the amygdala is not critical for the conditioned reinforcement process. In the present study, excitotoxic lesions of the amygdala in a new world primate, the common marmoset, resulted in a progressive impairment in responding under a second-order schedule of food reinforcement. In addition, the responding of amygdala-lesioned animals was insensitive to the omission of the conditioned reinforcer, unlike that of control animals, for which responding was markedly reduced. In contrast, lesioned animals were unimpaired when responding on a progression of fixed-ratio schedules of primary reinforcement. These data confirm that the amygdala is critical for the conditioned reinforcement process in primates, and taken together with other recent work in monkeys, these results suggest that the contribution of the amygdala is to provide the affective value of specific reinforcers as accessed by associated conditioned stimuli.
Preservation of Physiological Responses to Hypoglycemia 2 Days After Antecedent Hypoglycemia in Patients With IDDM

OBJECTIVE To assess the effects of short-term antecedent hypoglycemia on responses to further hypoglycemia 2 days later in patients with IDDM. RESEARCH DESIGN AND METHODS We studied eight type I diabetic patients without hypoglycemia unawareness or autonomic neuropathy during two periods at least 4 weeks apart. On day 1, 2 h of either clamped hyperinsulinemic (60 mU · m−2 · min−1) hypoglycemia at 2.8 mmol/l or euglycemia at 5.0 mmol/l were induced. Hyperinsulinemic hypoglycemia was induced 2 days later with 40 min glucose steps of 5.0, 4.0, 3.5, 3.0, and 2.5 mmol/l. Catecholamine levels and symptomatic and physiological responses were measured every 10–20 min. RESULTS When compared with the responses measured following euglycemia, the responses of norepinephrine 2 days after hypoglycemia were reduced (peak, 1.4 ± 0.4 [mean ± SE] vs.1.0 ± 0.3 nmol/l [P < 0.05]; threshold, 3.4 ± 0.1 vs. 2.9 ± 0.1 mmol/l glucose [P < 0.01]). The responses of epinephrine (peak, 4.0 ± 1.4 vs. 3.5 ± 0.8 nmol/l [P = 0.84]; threshold, 3.8 ± 0.1 vs. 3.6 ± 0.1 mmol/l glucose [P = 0.38]), water loss (peak, 194 ± 34 vs. 179 ± 47 g−1 · m−2 · h−1 [P = 0.73]; threshold, 2.9 ± 0.2 vs. 2.9 ± 0.2 mmol/l glucose [P = 0.90]), tremor (peak, 0.28 ± 0.05 vs. 0.37 ± 0.06 root mean square volts (RMS V) [P = 0.19]; threshold, 3.2 ± 0.2 vs. 3.1 ± 0.2 mmol/l glucose [P = 0.70]), total symptom scores (peak, 10.6 ± 2.1 vs. 10.8 ± 1.9 [P = 0.95]; threshold, 3.3 ± 0.2 vs. 3.6 ± 0.1 mmol/l glucose [P = 0.15]), and cognitive function (four-choice reaction time: threshold, 2.9 ± 0.2 vs. 3.0 ± 0.2 mmol/l glucose [P = 0.69]) were unaffected. CONCLUSIONS The effect on hypoglycemic physiological responses of 2 h of experimental hypoglycemia lasts for 1–2 days in these patients with IDDM . The pathophysiological effect of antecedent hypoglycemia may be of shorter duration in IDDM patients, compared with nondiabetic subjects.
Donor NK cell licensing in control of malignancy in hematopoietic stem cell transplant recipients

Among cancers treated with allogeneic hematopoietic stem‐cell transplantation (HSCT), some are sensitive to natural killer (NK) cell reactivity, described as the “missing self” recognition effect. However, this model disregarded the NK cell licensing effect, which highly increases the NK cell reactivity against tumor and is dependent on the coexpression of inhibitory killer cell immunoglobulin‐like receptor (iKIR) and its corresponding HLA Class I ligand. We assessed clinical data, HLA and donor iKIR genotyping in 283 patients with myelo‐ and lymphoproliferative malignancies who underwent HSCT from unrelated donors. We found dramatically reduced overall survival (OS), progression free survival (PFS), and time to progression (TTP) among patients with malignant diseases with the lack of HLA ligand cognate with this iKIR involved in NK cell licensing in corresponding donor (events 83.3% vs. 39.8%, P = 0.0010; 91.6% vs. 47.7%, P = 0.00010; and 30.0% vs. 17.3%, P = 0.013, for OS, PFS, and TTP, respectively). The extremely adverse PFS have withstand the correction when patient group was restricted to HLA mismatched donor‐recipient pairs. The incidence of aGvHD was comparable in two groups of patients. In malignant patients after HSCT the missing HLA ligand for iKIR involved in NK cell licensing in corresponding donor (“missing licensing proof”) induced extremely adverse survival of the patients due to the progression of malignancy and not to the aGvHD. Avoiding the selection of HSCT donors with the “missing licensing proof” in the malignant patient is strongly advisable.Am. J. Hematol. 89:E176–E183, 2014. © 2014 Wiley Periodicals, Inc.
Do Macro Variables, Asset Markets or Surveys Forecast Inflation Better?

Surveys do! We examine the forecasting power of four alternative methods of forecasting U.S. inflation out-of-sample: time series ARIMA models; regressions using real activity measures motivated from the Phillips curve; term structure models that include linear, non-linear, and arbitrage-free specifications; and survey-based measures. We also investigate several optimal methods of combining forecasts. Our results show that surveys outperform the other forecasting methods and that the term structure specifications perform relatively poorly. We find little evidence that combining forecasts using means or medians, or using optimal weights with prior information produces superior forecasts to survey information alone. When combining forecasts, the data consistently places the highest weights on survey information.
Measuring health-related quality of life in Singapore: normal values for the English and Chinese SF-36 Health Survey.

OBJECTIVE To determine norms for assessing Health-related Quality of Life (HRQOL) in Singapore using the Short Form 36 Health Survey (SF-36). MATERIALS AND METHODS Mean SF-36 scores were calculated for 24 population subgroups (categorised by age, gender, ethnicity and questionnaire language) and for subjects with self-reported co-morbid conditions using data from a community-based survey in Singapore. RESULTS The English and Chinese SF-36 was completed by 4122 and 1381 subjects, respectively, 58% (n = 3188) of whom had self-reported co-morbid conditions. SF-36 scores varied in subgroups differing in age, gender and ethnicity. In general, subjects with self-reported co-morbid conditions had lower SF-36 scores than those without these conditions, the magnitude of which exceeded 20 points in several instances. A method for calculation of SF-36 scores adjusted for age, gender, ethnicity and questionnaire language is described. CONCLUSION We present norms for English and Chinese SF-36 versions in Singapore and describe potential uses for these data in assessing HRQOL in Singapore.
Primary adrenal nodular lymphocyte-predominant Hodgkin lymphoma: A case report and review of the literature

Nodular lymphocyte-predominant Hodgkin lymphoma (NLPHL) is a subtype of Hodgkin lymphoma (HL), and is a rare disease manifestation in the adrenal gland, which is difficult to be diagnosed and treated. In the present study, we report a case of primary adrenal NLPHL in a 36-year-old male patient. The patient was without specific clinical signs and the definitive diagnosis was achieved by histological study. The patient underwent a laparoscopic left adrenalectomy and chemotherapy regimen of doxorubicin, bleomycin, vinblastine and dacarbazine (ABVD). There is no standard treatment for adrenal NLPHL and therefore, treatment is based on that for other types of NLPHL, which includes radiotherapy and ABVD chemotherapy. Given the rarity of this disease, there are limited experiences with regard to its diagnosis and treatment. This study is useful for the differential diagnosis and treatment of adrenal masses.
Total parenteral nutrition with glutamine dipeptide after major abdominal surgery: a randomized, double-blind, controlled study.

OBJECTIVE To assess the efficacy of glutamine (Gln) dipeptide-enriched total parenteral nutrition (TPN) on selected metabolic, immunologic, and clinical variables in surgical patients. SUMMARY BACKGROUND DATA Depletion of Gln stores might lead to severe clinical complications. Recent studies indicate that the parenteral provision of Gln or Gln-containing dipeptides improves nitrogen balance, maintains the intracellular Gln pool, preserves intestinal permeability and absorption, and shortens hospital stay. METHODS Twenty-eight patients (age range, 42-86 years, mean 68 years) undergoing elective abdominal surgery were allocated, after randomization, to two groups to receive isonitrogenous (0.24 g nitrogen kg(-1) day(-1)) and isoenergetic (29 kcal/122 kJ kg(-1) day(-1)) TPN over 5 days. Controls received 1.5 g of amino acids kg(-1) day(-1), and the test group received 1.2 g of amino acids and 0.3 g of L-alanyl-L-glutamine (Ala-Gln) kg(-1) day(-1). Venous heparinized blood samples were obtained before surgery and on days 1, 3, and 6 after surgery for routine clinical chemistry and for the measurement of plasma free amino acids. Lymphocytes were counted and the generation of cysteinyl-leukotrienes from polymorphonuclear neutrophil granulocytes was analyzed before surgery and on days 1 and 6 after surgery. Nitrogen balances were calculated postoperatively on days 2, 3, 4, and 5. RESULTS No side effects or complaints were noted. Patients receiving Gln dipeptide revealed improved nitrogen balances (cumulative balance over 5 days: -7.9 +/- 3.6 vs. -23.0 +/- 2.6 g nitrogen), improved lymphocyte recovery on day 6 (2.41 +/- 0.27 vs. 1.52 +/- 0.17 lymphocytes/nL) and improved generation of cysteinyl-leukotrienes from polymorphonuclear neutrophil granulocytes (25.7 +/- 4.89 vs. 5.03 +/- 3.11 ng/mL). Postoperative hospital stay was 6.2 days shorter in the dipeptide-supplemented group. CONCLUSION We confirm the beneficial effects of Gln dipeptide-supplemented TPN on nitrogen economy, maintenance of plasma Gln concentration, lymphocyte recovery, cysteinyl-leukotriene generation, and shortened hospital stay in surgical patients.
Single-crystal indicators of fatigue and plastic deformation damage

Specially prepared thin single-crystal plates rigidly fastened to the sample surface area are shown to be effective as sensor elements (indicators and detectors) of the deformation damage of multi-phase commercial alloys under fatigue and static loading. It is proposed to estimate the lifetime and the strain of basic material by monitoring the geometric characteristics of band patterns on the detector surface. It is shown that density, direction of deformation bands and fractal dimension of band patterns on surfaces of indicators correlate with the number of cycles, maximum applied stress (fatigue loading) and plastic strain, temperature (static loading).
Dissecting Rotavirus Particle-Raft Interaction with Small Interfering RNAs: Insights into Rotavirus Transit through the Secretory Pathway

ABSTRACT Studies of rotavirus morphogenesis, transport, and release have shown that although these viruses are released from the apical surface of polarized intestinal cells before cellular lysis, they do not follow the classic exocytic pathway. Furthermore, increasing evidence suggests that lipid rafts actively participate in the exit of rotavirus from the infected cell. In this study, we silenced the expression of VP4, VP7, and NSP4 by using small interfering RNAs (siRNAs) and evaluated the effect of shutting down the expression of these proteins on rotavirus-raft interactions. Silencing of VP4 and NSP4 reduced the association of rotavirus particles with rafts; in contrast, inhibition of VP7 synthesis slightly affected the migration of virions into rafts. We found that inhibition of rotavirus migration into lipid rafts, by either siRNAs or tunicamycin, also specifically blocked the targeting of VP4 to rafts, suggesting that the association of VP4 with rafts is mostly mediated by the formation of viral particles in the endoplasmic reticulum (ER). We showed that two populations of VP4 exist, one small population that is independently targeted to rafts and a second large pool of VP4 whose association with rafts is mediated by particle formation in the ER. We also present evidence to support the hypothesis that assembly of VP4 into mature virions takes place in the late stages of transit through the ER. Finally, we analyzed the progression of rotavirus proteins in the exocytic pathway and found that VP4 and virion-assembled VP7 colocalized with ERGIC-53, suggesting that rotavirus particles transit through the intermediate compartment between the ER and the Golgi complex.
Experimental and Theoretical Study on Shear Flow Behavior of Polypropylene/Layered Silicate Nanocomposites

Polypropylene/layered silicate nanocomposites containing maleic anhydride grafted polypropylene were prepared by melt compounding and their rheological behavior was investigated in shear flow. Transient and steady shear flows were simulated numerically by using the K-BKZ integral constitutive equation along with experimentally determined damping functions under dynamic oscillatory and step strain shear flows. Nonlinear shear responses were predicted with the K-BKZ constitutive equation using two different damping functions such as the Wagner and PSM models. It was observed that PP-g-MAH compatibilized PP/layered silicate nanocomposites have stronger and earlier shear thinning and higher steady shear viscosity than pure PP resin or uncompatibilized nanocomposites at low shear rate regions. Strong damping behavior of the PP/layered silicate nanocomposite was predicted under large step shear strain and considered as a result of the strain-induced orientation of the organoclay in the shear flow. Steady shear viscosity of the pure PP and uncompatibilized nanocomposite predicted by the K-BKZ model was in good agreement with the experimental results at all shear rate regions. However, the model was inadequate to predict the steady shear viscosity of PP-g-MAH compatibilized nanocomposites quantitatively because the K-BKZ model overestimates strain-softening damping behavior for PP/layered silicate nanocomposites.
Mechanism of B-box 2 domain-mediated higher-order assembly of the retroviral restriction factor TRIM5α

Restriction factors and pattern recognition receptors are important components of intrinsic cellular defenses against viral infection. Mammalian TRIM5α proteins are restriction factors and receptors that target the capsid cores of retroviruses and activate ubiquitin-dependent antiviral responses upon capsid recognition. Here, we report crystallographic and functional studies of the TRIM5α B-box 2 domain, which mediates higher-order assembly of TRIM5 proteins. The B-box can form both dimers and trimers, and the trimers can link multiple TRIM5α proteins into a hexagonal net that matches the lattice arrangement of capsid subunits and enables avid capsid binding. Two modes of conformational flexibility allow TRIM5α to accommodate the variable curvature of retroviral capsids. B-box mediated interactions also modulate TRIM5α’s E3 ubiquitin ligase activity, by stereochemically restricting how the N-terminal RING domain can dimerize. Overall, these studies define important molecular details of cellular recognition of retroviruses, and how recognition links to downstream processes to disable the virus. DOI: http://dx.doi. org/10.7554/eLife.16309. 001
Design and Evaluation of a Novel Fixation Mechanism for a Transcatheter Pacemaker

Goal: The purpose of this paper was to evaluate a nitinol tine fixation design for a transcatheter pacemaker in order to determine if the tines could be easily deployed and safely removed from the myocardium, enable low, stable pacing thresholds, and minimize the potential for dislodgment. Methods: The penetration properties of 13 human hearts were compared to the deployment and fixation energy of the tines to determine if the tines could be easily deployed and removed from the myocardium. The safety factor for dislodgement was calculated by comparing the kinetic energy of the device to the fixation energy of the tines. The fixation stability was tested in 113 chronic implants across 89 animals via pacing threshold measurements or evidence of dislodgement at necropsy. Results: Based on the tine fixation and tissue energy analysis, the tines can easily penetrate the heart. The tines can be safely removed from the myocardium based on the increased tine surface area during retraction. There were no dislodgements observed in the animals and the mean pacing threshold at implant was 0.59 +/- 0.21 V and at termination was 0.65 +/- 0.36 V. The safety factor for dislodgement was determined to be 15X during simulated exercise conditions. Conclusion: The nitinol tine fixation design enabled the implant of a self-contained pacemaker within the right ventricle and was effective in meeting the design requirements. Significance: This fixation technology provides a novel solution to enable the attachment of a transcatheter pacemaker directly within the heart.
Bone graft in the shape of human mandibular condyle reconstruction via seeding marrow-derived osteoblasts into porous coral in a nude mice model.

PURPOSE The purpose of this study was to develop a tissue-engineered bone graft model in the shape of a human mandibular condyle. MATERIALS AND METHODS Natural coral with a pore size of 150 to 220 microm and porosity of about 36% was molded into the shape of a human mandibular condyle. Culture-expanded rabbit marrow mesenchymal stem cells were induced by recombinant human bone morphogenetic protein-2 (rhBMP2) to improve osteoblastic phenotype. Then marrow-derived osteoblasts were seeded into natural coral at a density of 2 x 10(8)/mL and incubated in vitro for 3 days before implantation. The cell-coral complexes were implanted subcutaneously into the backs of nude mice and incubated in vivo for 2 months before harvesting. Implantation of coral alone acted as control. The specimens were processed for gross inspection, radiographic examination, and histologic and scanning electronic microscopic observation. RESULTS The results showed that new bone grafts in the shape of a human mandibular condyle were successfully developed 2 months after implantation and maintained the initial shape of the natural coral scaffold. New bone could be observed histologically on the surface and in the pores of natural coral in all specimens in the cell-seeding group (6 of 6), whereas in the control group there was no evidence of osteogenesis process (0 of 4). CONCLUSION This study suggests the feasibility of using porous coral as scaffold material transplanted with marrow-derived osteoblasts to restore bone graft in the shape of human mandibular condyle and shows the potential of using this method for the reconstruction of bone defects.
Trends of tuberculin skin test positivity rate among schoolchildren in Attica, Greece

We sought to estimate the prevalence and temporal trends of tuberculin skin test (TST) positivity rate among schoolchildren, in a suburban area of Attica, Greece. We retrospectively analysed the prevalence of the TST positivity (forearm volar surface induration >10 mm) of schoolchildren, in the catchment area of the public primary healthcare centre of Vari, over a 16-y period (1990–2005). TSTs were performed in the context of a national, government-directed TB screening programme. We retrieved 11,105 records of TSTs performed on children aged 6 and 14 y. These tests referred to 7920 and 2969 BCG unvaccinated and vaccinated children, respectively, as well as 120 children who had close contact with a TB confirmed case, and 6 children with known active or latent TB. The prevalence of TST positivity among BCG unvaccinated children was 2.0% over the whole study period; this figure declined in the second compared to the first half of the study period (2.4% vs 1.4%, p<0.001). The gradual decline in TST positivity among BCG unvaccinated schoolchildren, despite the substantial rise in the number of immigrants in Greece, over our study period, may, at least in part, be attributed to relevant national screening and prevention measures.