LKB1/STK11 is a tumor suppressor and a negative regulator of mammalian target of rapamycin signaling. It is inactivated in 30% of lung cancer cell lines but only 5-15% of primary lung ...adenocarcinomas. There is evidence that homozygous deletion (HD) of chromosome 19p at the LKB locus contributes to the inactivation of the gene in primary human lung cancers. Here, we used several complementary genetic approaches to assess the LKB1 locus in primary non-small cell lung cancers (NSCLCs). We first analyzed 124 NSCLC cases for allelic imbalance using eight microsatellite markers on chromosome 19p, which revealed an overall rate of 65% (80 of 124) loss of heterozygosity (LOH). We next used chromogenic in situ hybridization (CISH) to directly examine the chromosomal status of the LKB1 locus. In all, 65 of 124 LOH tested samples were available for CISH and 58 of those (89%) showed either loss of one copy of chromosome 19p (LOH, 40 of 65 cases, 62%) or both copies (HD 18 of 65 cases, 28%). The occurrence of HD was significantly more frequent in Caucasian (35%) than in African-American patients (6%) (P=0.04). A total of 62 of 124 samples with LOH at one or both markers immediately flanking the LKB1 gene were further analyzed by directly sequencing the complete coding region, which identified 7 of 62 (11%) tumors with somatic mutations in the gene. Jointly, our data identified total inactivation of the LKB1 gene by either HD or LOH with somatic mutation in 39% of tested samples, whereas loss of chromosome 19p region by HD or LOH at the LKB1 region occured in 90% of NSCLC.
Background Price forecasting of perishable crop like vegetables has importance implications to the farmers, traders as well as consumers. Timely and accurate forecast of the price helps the farmers ...switch between the alternative nearby markets to sale their produce and getting good prices. The farmers can use the information to make choices around the timing of marketing. For forecasting price of agricultural commodities, several statistical models have been applied in past but those models have their own limitations in terms of assumptions. Methods In recent times, Machine Learning (ML) techniques have been much successful in modeling time series data. Though, numerous empirical studies have shown that ML approaches outperform time series models in forecasting time series, but their application in forecasting vegetables prices in India is scared. In the present investigation, an attempt has been made to explore efficient ML algorithms e.g. Generalized Neural Network (GRNN), Support Vector Regression (SVR), Random Forest (RF) and Gradient Boosting Machine (GBM) for forecasting wholesale price of Brinjal in seventeen major markets of Odisha, India. Results An empirical comparison of the predictive accuracies of different models with that of the usual stochastic model i.e. Autoregressive integrated moving average (ARIMA) model is carried out and it is observed that ML techniques particularly GRNN performs better in most of the cases. The superiority of the models is established by means of Model Confidence Set (MCS), and other accuracy measures such as Mean Error (ME), Root Mean Square Error (RMSE), Mean Absolute Error (MAE) and Mean Absolute Prediction Error (MAPE). To this end, Diebold-Mariano test is performed to test for the significant differences in predictive accuracy of different models. Conclusions Among the machine learning techniques, GRNN performs better in all the seventeen markets as compared to other techniques. RF performs at par with GRNN in four markets. The accuracies of other techniques such as SVR, GBM and ARIMA are not up to the mark.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
The sensitivity of heterogeneous energetic (HE) materials (propellants, explosives, and pyrotechnics) is critically dependent on their microstructure. Initiation of chemical reactions occurs at hot ...spots due to energy localization at sites of porosities and other defects. Emerging multi-scale predictive models of HE response to loads account for the physics at the meso-scale, i.e. at the scale of statistically representative clusters of particles and other features in the microstructure. Meso-scale physics is infused in machine-learned closure models informed by resolved meso-scale simulations. Since microstructures are stochastic, ensembles of meso-scale simulations are required to quantify hot spot ignition and growth and to develop models for microstructure-dependent energy deposition rates. We propose utilizing generative adversarial networks (GAN) to spawn ensembles of synthetic heterogeneous energetic material microstructures. The method generates qualitatively and quantitatively realistic microstructures by learning from images of HE microstructures. We show that the proposed GAN method also permits the generation of new morphologies, where the porosity distribution can be controlled and spatially manipulated. Such control paves the way for the design of novel microstructures to engineer HE materials for targeted performance in a materials-by-design framework.
Running-related injuries have been associated with excessive foot pronation and high vertical loading rates. Traditional plaster-molded (TPM) foot orthoses are commonly prescribed to minimize these ...atypical biomechanical patterns. Recently, 3D printed (3DP) orthoses have become popular, yet the functional difference between these two types of orthoses remains unknown. Therefore, this study compared running biomechanics and perceived comfort during treadmill running in three orthotic conditions: 3DP orthoses, TPM orthoses, and a no-orthoses control condition (CON). Thirteen female asymptomatic runners with excessive foot pronation were recruited. Rearfoot eversion angle and velocity (at initial contact and peak) during stance, vertical loading rates, and perceived comfort were compared. Results showed lower peak rearfoot eversion angles during running with TPM (p=0.001, d=0.38) or 3DP orthoses (p=0.002, d=0.24) than CON. No differences were observed in other biomechanical parameters among the three conditions (p>0.05). Running with TPM (p≤0.001, d=1.74-1.82) and 3DP orthoses (p<0.003, d=1.06-1.34) resulted in better perceived comfort in "medial-lateral control" and "heel cushioning" than CON. There were no statistical differences in all parameters between TPM and 3DP orthoses. The present findings indicate improved comfort during running with TPM or 3DP orthoses, which hinted 3DP orthoses could be a viable alternative to TPM orthoses for clinical practice.
Emerging evidence suggests that cancer cell metabolism can be regulated by cancer-associated fibroblasts (CAFs), but the mechanisms are poorly defined. Here we show that CAFs regulate malignant cell ...metabolism through pathways under the control of FAK. In breast and pancreatic cancer patients we find that low FAK expression, specifically in the stromal compartment, predicts reduced overall survival. In mice, depletion of FAK in a subpopulation of CAFs regulates paracrine signals that increase malignant cell glycolysis and tumour growth. Proteomic and phosphoproteomic analysis in our mouse model identifies metabolic alterations which are reflected at the transcriptomic level in patients with low stromal FAK. Mechanistically we demonstrate that FAK-depletion in CAFs increases chemokine production, which via CCR1/CCR2 on cancer cells, activate protein kinase A, leading to enhanced malignant cell glycolysis. Our data uncover mechanisms whereby stromal fibroblasts regulate cancer cell metabolism independent of genetic mutations in cancer cells.
Abstract
Context:
The increased use of diagnostic and therapeutic procedures that involve radiation raises concerns about radiation effects, particularly in children and the radiosensitive thyroid ...gland.
Objectives:
Evaluation of relative risk (RR) trends for thyroid radiation doses <0.2 gray (Gy); evidence of a threshold dose; and possible modifiers of the dose-response, e.g., sex, age at exposure, time since exposure.
Design and Setting:
Pooled data from nine cohort studies of childhood external radiation exposure and thyroid cancer with individualized dose estimates, ≥1000 irradiated subjects or ≥10 thyroid cancer cases, with data limited to individuals receiving doses <0.2 Gy.
Participants:
Cohorts included the following: childhood cancer survivors (n = 2); children treated for benign diseases (n = 6); and children who survived the atomic bombings in Japan (n = 1). There were 252 cases and 2,588,559 person-years in irradiated individuals and 142 cases and 1,865,957 person-years in nonirradiated individuals.
Intervention:
There were no interventions.
Main Outcome Measure:
Incident thyroid cancers.
Results:
For both <0.2 and <0.1 Gy, RRs increased with thyroid dose (P < 0.01), without significant departure from linearity (P = 0.77 and P = 0.66, respectively). Estimates of threshold dose ranged from 0.0 to 0.03 Gy, with an upper 95% confidence bound of 0.04 Gy. The increasing dose–response trend persisted >45 years after exposure, was greater at younger age at exposure and younger attained age, and was similar by sex and number of treatments.
Conclusions:
Our analyses reaffirmed linearity of the dose response as the most plausible relationship for “as low as reasonably achievable” assessments for pediatric low-dose radiation-associated thyroid cancer risk.
A pooling of nine cohort studies of childhood external radiation exposure revealed a linear increase in risk of thyroid cancer and reaffirmed the “as low as reasonably achievable” principal for pediatric low dose radiation.
•Only few in vivo toxicity and epidemiological studies focused specifically on non-exhaust sources.•Further experiments are needed to better separate individual contributions and health effects.•Need ...of understanding of the interaction between road surface texture, moisture, chemistry, dust load and dust emission.•Poor emission inventorying on resuspension and heavy metals.•The optimal mitigation strategy for each climatic region is still unknown.
About 400,000 premature adult deaths attributable to air pollution occur each year in the European Region. Road transport emissions account for a significant share of this burden. While important technological improvements have been made for reducing particulate matter (PM) emissions from motor exhausts, no actions are currently in place to reduce the non-exhaust part of emissions such as those from brake wear, road wear, tyre wear and road dust resuspension. These “non-exhaust” sources contribute easily as much and often more than the tailpipe exhaust to the ambient air PM concentrations in cities, and their relative contribution to ambient PM is destined to increase in the future, posing obvious research and policy challenges.
This review highlights the major and more recent research findings in four complementary fields of research and seeks to identify the current gaps in research and policy with regard to non-exhaust emissions. The objective of this article is to encourage and direct future research towards an improved understanding on the relationship between emissions, concentrations, exposure and health impact and on the effectiveness of potential remediation measures in the urban environment.
The Giant Metrewave Radio Telescope (GMRT) is today a frontline international facility for low-frequency radio astronomy, that has produced several exciting and important new results in the 15 years ...that it has been operational. To keep the GMRT competitive in the global arena in the future, a major upgrade of the observatory is nearing completion that will increase its sensitivity by up to three times and make it a more powerful and versatile facility. We describe the main goals of this upgrade, highlight the technical features and challenges, outline the science potential and update the current status of this venture.
Celotno besedilo
Dostopno za:
BFBNIB, DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, UILJ, UKNU, UL, UM, UPUK
Tumors are thought to be sustained by a reservoir of self-renewing cells, termed tumor-initiating cells or cancer stem cells. Osteosarcomas are high-grade sarcomas derived from osteoblast progenitor ...cells and are the most common pediatric bone malignancy. In this report we show that the stem cell transcription factor Sox2 is highly expressed in human and murine osteosarcoma (mOS) cell lines as well as in the tumor samples. Osteosarcoma cells have increased ability to grow in suspension as osteospheres, that are greatly enriched in expression of Sox2 and the stem cell marker, Sca-1. Depletion of Sox2 by short-hairpin RNAs in independent mOS-derived cells drastically reduces their transformed properties in vitro and their ability to form tumors. Sox2-depleted osteosarcoma cells can no longer form osteospheres and differentiate into mature osteoblasts. Concomitantly, they exhibit decreased Sca-1 expression and upregulation of the Wnt signaling pathway. Thus, despite other mutations, these cells maintain a requirement for Sox2 for tumorigenicity. Our data indicate that Sox2 is required for osteosarcoma cell self renewal, and that Sox2 antagonizes the pro-differentiation Wnt pathway that can in turn reduce Sox2 expression. These studies define Sox2 as a survival factor and a novel biomarker of self renewal in osteosarcomas, and support a tumor suppressive role for the Wnt pathway in tumors of mesenchymal origin. Our findings could provide the basis for novel therapeutic strategies based on inhibiting Sox2 or enhancing Wnt signaling for the treatment of osteosarcomas.
To investigate the safety and efficacy of subretinal injection of human Wharton's Jelly-derived mesenchymal stem cells (hWJ-MSCs) on retinal structure and function in Royal College of Surgeons (RCS) ...rats.
RCS rats were divided into 2 groups: hWJ-MSCs treated group (n = 8) and placebo control group (n = 8). In the treatment group, hWJ-MSCs from healthy donors were injected into the subretinal space in one eye of each rat at day 21. Control group received saline injection of the same volume. Additional 3 animals were injected with nanogold-labelled stem cells for in vivo tracking of cells localisation using a micro-computed tomography (microCT). Retinal function was assessed by electroretinography (ERG) 3 days before the injection and repeated at days 15, 30 and 70 after the injection. Eyes were collected at day 70 for histology, cellular and molecular studies.
No retinal tumor formation was detected by histology during the study period. MicroCT scans showed that hWJ-MSCs stayed localised in the eye with no systemic migration. Transmission electron microscopy showed that nanogold-labelled cells were located within the subretinal space. Histology showed preservation of the outer nuclear layer (ONL) in the treated group but not in the control group. However, there were no significant differences in the ERG responses between the groups. Confocal microscopy showed evidence of hWJ-MSCs expressing markers for photoreceptor, Müller cells and bipolar cells.
Subretinal injection of hWJ-MSCs delay the loss of the ONL in RCS rats. hWJ-MSCs appears to be safe and has potential to differentiate into retinal-like cells. The potential of this cell-based therapy for the treatment of retinal dystrophies warrants further studies.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
PDF
