A major rate-limiting step in developing more effective immunotherapies for GBM is our inadequate understanding of the cellular complexity and the molecular heterogeneity of immune infiltrates in ...gliomas. Here, we report an integrated analysis of 201,986 human glioma, immune, and other stromal cells at the single cell level. In doing so, we discover extensive spatial and molecular heterogeneity in immune infiltrates. We identify molecular signatures for nine distinct myeloid cell subtypes, of which five are independent prognostic indicators of glioma patient survival. Furthermore, we identify S100A4 as a regulator of immune suppressive T and myeloid cells in GBM and demonstrate that deleting S100a4 in non-cancer cells is sufficient to reprogram the immune landscape and significantly improve survival. This study provides insights into spatial, molecular, and functional heterogeneity of glioma and glioma-associated immune cells and demonstrates the utility of this dataset for discovering therapeutic targets for this poorly immunogenic cancer.
Emerging data indicate that gut-derived endotoxin (metabolic endotoxemia) may contribute to low-grade systemic inflammation in insulin-resistant states. Specific gut bacteria seem to serve as ...lipopolysaccharide (LPS) sources and several reports claim a role for increased intestinal permeability in the genesis of metabolic disorders. Therefore, we investigated the serum levels of LPS and zonulin (ZO-1, a marker of gut permeability) along with systemic levels of tumor necrosis factor-α (TNF-α) and Interleukin-6 (IL-6) in patients with type 2 diabetes mellitus (T2DM) compared to control subjects. Study subjects were recruited from the Chennai Urban Rural Epidemiology Study CURES, Chennai, India. Study group (
n
= 45 each) comprised of a) subjects with normal glucose tolerance (NGT) and (b) patients with T2DM. LPS, ZO-1, TNF-α, and IL-6 levels were measured by ELISA. Serum levels of LPS
p
< 0.05, LPS activity
p
< 0.001, ZO-1
p
< 0.001, TNFα
p
< 0.001, and IL-6
p
< 0.001 were significantly increased in patients with T2DM compared to control subjects. Pearson correlation analysis revealed that LPS activity was significantly and positively correlated with ZO-1, fasting plasma glucose, 2 h post glucose, HbA1c, serum triglycerides, TNF-α, IL-6, and negatively correlated with HDL cholesterol. Regression analysis showed that increased LPS levels were significantly associated with type 2 diabetes odds ratio (OR) 13.43, 95 % CI 1.998–18.9;
p
= 0.003. In Asian Indians who are considered highly insulin resistant, the circulatory LPS levels, LPS activity, and ZO-1 were significantly increased in patients with type 2 diabetes and showed positive correlation with inflammatory markers and poor glycemic/lipid control.
Delayed sowing of maize hybrids could exacerbate the capability of maximizing the yield potential through poor crop stand, root proliferation, nutrient uptake, and dry matter accumulation coupled ...with the inadequate partitioning of the assimilates. This study appraised the performance of five recent maize hybrids viz., PMH-1, PJHM-1, AH-4158, AH-4271, and AH-8181 under timely and late sown conditions of the irrigated semi-arid ecologies. Timely sowing had the grain and stover yields advantage of 16-19% and 12-25%, respectively over the late sown maize hybrids. The advanced hybrids AH-4271 and AH-4158 had higher grain yields than the others. During the post-anthesis period, a greater dry matter accumulation and contribution to the grain yield to the tune of 16% and 10.2%, respectively, was observed under timely sown conditions. Furthermore, the nutrient acquisition and use efficiencies also improved under the timely sown. The nutrient and dry matter remobilization varied among the hybrids with AH-4271 and PMH-1 registering greater values. The grain yield stability index (0.85) was highest with AH-4158 apart from the least yield reduction (15.2%) and stress susceptibility index (0.81), while the maximum geometric mean productivity was recorded with the AH-4271 (5.46 Mg ha
). The hybrids AH-4271 and PJHM-1 exhibited improved root morphological traits, such as root length, biomass, root length density, root volume at the V5 stage (20 days after sowing, DAS) and 50% flowering (53 DAS). It is thus evident that the timely sowing and appropriate hybrids based on stress tolerance indices resulted in greater yields and better utilization of resources.
Abstract
Background
Treatment options for patients with melanoma brain metastasis (MBM) have changed significantly in the last decade. Few studies have evaluated changes in outcomes and factors ...associated with survival in MBM patients over time. The aim of this study is to evaluate changes in clinical features and overall survival (OS) for MBM patients.
Methods
Patients diagnosed with MBMs from 1/1/2009 to 12/31/2013 (Prior Era; PE) and 1/1/2014 to 12/31/2018 (Current Era; CE) at The University of Texas MD Anderson Cancer Center were included in this retrospective analysis. The primary outcome measure was OS. Log-rank test assessed differences between groups; multivariable analyses were performed with Cox proportional hazards models and recursive partitioning analysis (RPA).
Results
A total of 791 MBM patients (PE, n = 332; CE, n = 459) were included in analysis. Median OS from MBM diagnosis was 10.3 months (95% CI, 8.9–12.4) and improved in the CE vs PE (14.4 vs 10.3 months, P < .001). Elevated serum lactate dehydrogenase (LDH) was the only factor associated with worse OS in both PE and CE patients. Factors associated with survival in CE MBM patients included patient age, primary tumor Breslow thickness, prior immunotherapy, leptomeningeal disease, symptomatic MBMs, and whole brain radiation therapy. Several factors associated with OS in the PE were not significant in the CE. RPA demonstrated that elevated serum LDH and prior immunotherapy treatment are the most important determinants of survival in CE MBM patients.
Conclusions
OS and factors associated with OS have changed for MBM patients. This information can inform contemporary patient management and clinical investigations.
The accurate grading of malignant astrocytomas has significant prognostic and therapeutic implications. Traditional histopathological grading can be challenging due to regional tumor heterogeneity, ...especially in scenarios where small amounts of tissue are available for pathologic review. Here, we hypothesized that a critical tumor resection volume is needed for correct grading of astrocytomas by histopathology. For insufficient tissue sampling, IDH1 molecular testing can act as a complementary marker to improve diagnostic accuracy. Volumetric analyses were obtained using preoperative and postoperative MRI images. Histological specimens were gathered from 403 patients with malignant astrocytoma who underwent craniotomy. IDH1 status was assessed by immunohistochemistry and sequencing. Patients with >20 cubic centimeters (cc) of the total tumor volume resected on MRI have higher rate of GBM diagnosis compared to <20 cc odds ratio (OR) 2.57, 95 % confidence interval (CI) 1.6–4.06,
P
< 0.0001. The rate of IDH1 status remained constant regardless of the tumor volume resected (OR 0.81, 95 % CI 0.48–1.36,
P
< 0.43). The rate of GBM diagnosis is twofold greater for individual surgical specimen >10 cc than those of lower volume (OR 2.48, 95 % CI 1.88–3.28,
P
< 0.0001). Overall survival for AA patients with >20 cc tumor resection on MRI is significantly better than those with <20 cc tumor resected (
P
< 0.05). No volume-dependent differences were observed in patients with GBM (
P
< 0.4), IDH1 wild type (
P
< 0.1) or IDH1 mutation (
P
< 0.88). IDH1 status should be considered when total resection volume is <20 cc based on MRI analysis and for surgical specimen <10 cc to complement histopathologic diagnosis of malignant astrocytomas. In these specimens, under-diagnosis of GBM may occur when analysis is restricted to histopathology alone.
Shifting from chemical-intensive practices to organic-based farming within the rice-wheat rotation (RWR) is crucial for its long-term sustainability. This highly productive system holds a significant ...carbon (C) sequestration potential if managed efficiently. The dynamics of soil organic-C profoundly impacts the global climate change and crops’ productivity, necessitating the continuous monitoring of organic carbon to ensure soil vitality. Hence, we have evaluated the long-term (twenty-one years) impact of organic amendments on yields of the RWR, soil properties and C-dynamics. After 21 years, we observed that organic-based amendments increased the rice and wheat grain yields by 33.4–52.5% and 20–42.8%, respectively, over the control (no organics). On an average, in top 0.0–0.15 m soil layer, the organic-manured plots had 21.6%, 21.3% and 23.4% greater available nitrogen (N), phosphorous (P) and potassium (K) over the control plot, respectively. Furthermore, such organic-manured plots recorded 32.9–50.8% and 6.04–32.3% greater microbial biomass carbon (MBC) and dehydrogenase activity (DHA) over the control. Also, the use of organic amendments had a significant (p≤0.05) and positive impact on the soil carbon dynamics (0.0–0.45 m). In 0.0–0.45 m soil depth, the organic-manured treatments registered a 25.9–44.2% greater total organic carbon (TOC) than the control. These treatments improved the active (labile, very labile) and recalcitrant (less labile, non-labile)-C pools especially in upper soil layers. In summary, the synergistic use of Sesbania green manure, Leucaena leucocephala leaf manuring, farmyard manure, and biofertilizers (blue-green algae/Azotobacter etc.) proves effective in restoring soil health and enhancing crop productivity by increasing soil organic carbon and ensuring nutrients availability. Thus, these organic amendment treatments can be advocated to farmers to sustain the productivity of the rice-wheat ecosystems.
•Organic amendments had significant positive impact on rice (33.4–52.5 %) and wheat (20–42.8 %) yields over the control.•Organic-manured improved the active (labile, very labile) and recalcitrant (less labile, non-labile)-C pools.•Also, the use of organic amendments significantly improved soil microbial properties besides available nutrients.•Organic amendments enhanced the stability for C-sequestration and accessibility of vital plant nutrients
Conservation agriculture (CA) coupled with the integrated crop management (ICM)-practices based on a whole-farm approach could preserve the agroecosystems to achieve the soil-related Sustainable ...Development Goals (SDGs). Hence, eight conventional and CA-based ICM practices have been evaluated for 6 years in a direct seeded rice-zero till wheat rotation; wherein, ICM1&2- conventional (CT) rice followed by (fb) flatbed wheat, ICM3&4- CT direct seeded rice (DSR) fb raised-bed wheat, ICM5&6- CA-based zero tilled (ZT) DSR fb ZT wheat with the wheat and rice residues, and ICM7&8- CA-based ZTDSR fb ZT wheat with the wheat, mungbean, and rice residues. The CA-based ICM7–8 practices outperformed the traditional (CT)-based ICM1–4 practices in terms of wheat equivalent yields (WEY) (10.8–14.7%) and sustainable yield indices (SYI) of rice (10.8–21.7%) and wheat (12.9–16.1%) crops, demonstrating the greater sustainability of RWR. Additionally, the ICM techniques led to a substantial (p < 0.05) improvement in the properties governing soil quality throughout 0.0–0.45 m soil depth. The ICM7–8 practices improved the soil quality index (SQI) by 24.7% and 56.2% compared to the ICM5–6 and ICM1–4 practices, respectively. The results showed that the SQI indicators including total carbon (TC), alkaline phosphatase (APA), urease (UA), nitrogen (N), and water-stable aggregates (WSA, 0.2 mm) were all improved. CA-based ICM5–8 practices substantially reduced the carbon footprints in terms of kg CO2-eq. ha−1 ranging from 9.1% to 47% compared to the CT-based ICM1–4 practices. In contrast, carbon efficiency (7.38% ± 0.06), and carbon sustainability index (CSI) (6.38 ± 0.06) were superior in the CT-derived ICM2&4 practices. Thus, the CA-based ICM practices proved to be environmentally more safe and clean and can thus sustain the food and soil security of the extensive rice-wheat rotation under the South Asian ecologies.
●Residue retained CA-based ICM7&8 practices had a positive impact on the system wheat equivalent yields.●Also, ICM7&8 practices enriched the soil quality index (SQI) by 24.7% and 56.2% than the ICM5–6 and ICM1–4, respectively.●Total carbon, alkaline phosphatase, nitrogen, and water-stable aggregates are identified as key indicators of SQI.●CA-based ICM5-8 substantially reduces the carbon footprint in terms of CO2 eq. kg ha-1 ranging from 9.1-47% than ICM1-4.●Synergistic effects of the CA-based ICMs are also reflected in improving soil's properties.
This study investigates the effect of adding TeO2 instead of B2O3 in a glass system containing a fixed amount of Al2O3, MoO3, and SrO as modifiers. The present work included the impact of the ...addition of TeO2 on radiation and mechanical properties theoretically. The shielding properties were calculated based on XCOM data, and mechanical properties were computed based Makishima-Mackenzie’s model. The addition of TeO2 reduced the packing density gradually. Besides, Young’s longitudinal, shear, and bulk moduli showed the same behavior. In contrast, the density and shielding properties enhanced progressively with increasing TeO2 instead B2O3, like mass attenuation coefficient, transmission factor, effective atomic number, radiation protection efficiency, charged particle range, etc. It can be concluded that adding TeO2 reduced the glass elasticity and enhanced radiation shielding features, leading to potential utilization in the gamma and charged particle shielding scope.
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