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A significant change in the dispersion relation of low frequency electromagnetic Alfven modes occurs when ion beam interacts with a magnetized plasma, depending on plasma and the beam parameters. The growth rates and dispersion relation of pure and shear Alfven modes have been estimated. Pure Alfven wave suffers a cyclotron damping when it interacts with the charged particles of beam via linear cyclotron interaction. Only when the beam ions travel in the opposite direction from the shear Alfven wave via fast cyclotron interaction can destabilize the left-hand polarized shear Alfven mode. The Alfven wave dispersion characteristics change due to collisions between plasma components and result in damping of the waves by acting as a stabilizing influence. The growth rate and the frequency of generated Alfven waves get affected differently for right-hand and left-hand polarized Alfven modes due to the collisions between beam ions and plasma components. The growth rate has smaller values in the presence of collisions which show a collisional damping of pure and shear modes in the beam plasma system. [ABSTRACT FROM AUTHOR]

Wolfram syndrome is a rare genetic disease caused by mutations in the WFS1 or CISD2 gene. A primary defect in Wolfram syndrome involves poor ER Ca2+ handling, but how this disturbance leads to the disease is not known. The current study, performed in primary neurons, the most affected and disease-relevant cells, involving both Wolfram syndrome genes, explains how the disturbed ER Ca2+ handling compromises mitochondrial function and affects neuronal health. Loss of ER Ca2+ content and impaired ER-mitochondrial contact sites in the WFS1- or CISD2-deficient neurons is associated with lower IP3R-mediated Ca2+ transfer from ER to mitochondria and decreased mitochondrial Ca2+ uptake. In turn, reduced mitochondrial Ca2+ content inhibits mitochondrial ATP production leading to an increased NADH/NAD+ ratio. The resulting bioenergetic deficit and reductive stress compromise the health of the neurons. Our work also identifies pharmacological targets and compounds that restore Ca2+ homeostasis, enhance mitochondrial function and improve neuronal health. Wolfram syndrome, caused by WFS1 or CISD2 gene mutations, disrupts ER Ca2+ regulation in neurons. Here, the authors show how these mutations impair ER-mitochondria interactions, compromise Ca2+ transfer and mitochondrial function, and lead to bioenergetic deficits and oxidative stress. [ABSTRACT FROM AUTHOR]

Aims: To study the association of pro-inflammatory markers with incident diabetes in India. Methods: We did a nested case–control study within the CARRS (Centre for Ardiometabolic Risk Reduction in South Asia) cohort. Of the 5739 diabetes-free individuals at the baseline, 216 participants with incident diabetes and 432 age-, gender- and city-matched controls at 2-year follow-up were included. We measured high sensitive C-reactive protein (hsCRP), interleukin-6 (IL-6), tumor necrosis factor-α (TNF-α), monocyte chemoattractant protein-1 (MCP-1), adiponectin, leptin and fetuin-A in the stored baseline blood samples. We did multivariate conditional logistic regression to estimate association of inflammatory markers (as quartiles) and incident diabetes. Covariates were baseline fasting plasma glucose (FPG) and lipids, body mass index (BMI), family history of diabetes, smoking and alcohol use. Results: Baseline hsCRP and TNF-α were higher, and IL-6 and adiponectin were lower among cases vs. controls. In multivariate conditional logistic regression models, only quartile-3 (odds ratio [OR]: 2.96 [95% CI:1.39, 6.30]) and quartile-4 (OR: 2.58 [95% CI: 1.15, 5.79]) of TNF-α and quartile-4 of MCP-1 (OR: 2.55 [95% CI: 1.06, 6.16]) were positively associated with diabetes after adjusting for baseline FPG and BMI. These associations did not remain after adjusting for family history. High level (quartile-4) of IL-6 was negatively associated with diabetes after adjusting for all factors (OR: 0.18 [95% CI: 0.06, 0.55]). Conclusions: Higher TNF-α and MCP-1 levels and lower IL-6 were associated with higher risk of developing diabetes. Better understanding and potential methods of addressing these biomarkers, especially in relation to family history, are needed to address diabetes in South Asians. [ABSTRACT FROM AUTHOR]

In this work, a problem based on fluid theory of parametric decay of a lower hybrid wave in a magnetized relativistic beam-plasma system has been studied. The non-linear coupling of lower hybrid wave via beam mode excitation is numerically analysed. The lower-hybrid wave ( ω p , k p ) imparts energy and momentum to the electrons of the target plasma. The density fluctuation associated with the electron beam mode interacts with electron velocity and generates a non-linear current, driving sideband ( ω s , k s ), where ω s = ω p - ω B , k s = k p - k B on account of the pump wave. The excited sideband wave interacts with the pump wave, exerting a ponderomotive force on plasma electrons. This coupling drives the beam mode (the low frequency mode at ω B , k B ). The beam driven instability’s growth rate in different beam density regions has been obtained with the dependency of parametric instabilities on the local plasma parameters. This finding suggests that the beam coupling that leads to parametric instability of the LH wave is mostly determined by electron dynamics. [ABSTRACT FROM AUTHOR]

HER2-positive breast cancer is an aggressive subtype of breast cancer with five-year survival rates of 30% for the advanced stage. The development of anti-HER2 treatments has led to a paradigm shift in the management and clinical outcomes of advanced HER2-positive breast cancer patients. The standard first-line treatment consists of taxane-based chemotherapy plus dual anti-HER2 therapies with trastuzumab and pertuzumab. The antibody-drug conjugate (ADC) ado-trastuzumab emtansine (T-DM1) has been a second-line therapeutic standard, but the second-line treatment approach is rapidly evolving. Given a substantial advantage of another ADC, Fam-trastuzumab deruxtecan (T-DXd), compared to T-DM1 in a recent randomized trial in the second-line setting, T-DXd is currently the preferred second-line option. Optimal third-line treatment strategies are still not established, and multiple approaches have been used including combinations based on capecitabine, trastuzumab, or both with oral anti-HER2 tyrosine kinase inhibitors. Tucatinib plus capecitabine and trastuzumab, lapatinib plus trastuzumab, neratinib or lapatinib plus capecitabine are some of the FDA approved combinations. Another newer agent approved for third- or later-line therapy in the metastatic setting is margetuximab, an Fc-engineered anti-HER2 monoclonal antibody, in combination with chemotherapy. Other novel agents currently under clinical trials are the drugs that indirectly target HER2, including immune cell cycle inhibitors, PI3K/mTOR inhibitors, and immunotherapy agents. [ABSTRACT FROM AUTHOR]

Background: Docosahexaenoic acid (DHA) is an important structural component of human brain and retina. Evidence exists linking nutritional status of pregnant mothers and cognitive functions of their born infants. The DHANI (Maternal DHA Supplementation and Offspring Neurodevelopment in India) trial was implemented to evaluate the effect of maternal supplementation with DHA during pregnancy and for 6 months following delivery on motor and mental development of infants at 1 and 12 months. We describe here the standardization and validation of an assay for measurement of selected omega-3 and omega-6 fatty acids from the phospholipid fraction of red blood cells to assess their status in mothers at baseline, delivery and 6 months post-delivery and for infants in cord blood and at 1 and 12 months of age. The validated method has been used for the analysis of samples for DHANI. Methods: Lipids were extracted from a pool of red blood cells, separated using thin layer chromatography. The phospholipid fraction was esterified, and fatty acids were separated by gas chromatography using a flame ionization detector. Result: The method accuracy for DHA was between 97 - 98% and between 91 - 95% for arachidonic acid (AA) at three different concentrations. The intra-assay and inter-assay coefficient of variation for the fatty acids ranged from 1.19 to 5.7% and 0.78 to 13.0% respectively. Intraclass correlation (ICC), as a measure of reproducibility, ranged between 0.689 and 0.996. A good linearity was observed for all the fatty acids between concentrations of 0.2–4 μg/ml. Conclusion: The standardized and validated method is suitable for implementation in large epidemiological studies for evaluation of fatty acids and in nutritional trials for assessment of fatty acid content of various lipid classes. [ABSTRACT FROM AUTHOR]

Coronavirus disease 2019 is caused by severe acute respiratory syndrome coronavirus 2. Primarily an infection of the lower respiratory tract, it is now well known to cause multisystem abnormalities. Hematologic manifestations constitute a significant area of concern. Severe acute respiratory syndrome coronavirus 2 infects monocytes and endothelial cells leading to a complex downstream cascade, cytokine storm, and eventual intravascular thrombosis. Coronavirus disease 2019 causes lymphopenia, neutrophilia, and thrombocytopenia. Prophylactic anticoagulation is vital in patients with coronavirus disease 2019, as its effect on the coagulation system is associated with significant morbidity and mortality. The disease can cause both arterial and venous thromboses, especially pulmonary embolism and pulmonary microthrombi. A high index of suspicion is indispensable in recognizing these complications, and timely institution of therapeutic anticoagulation is vital in treating them. Virus-induced disseminated intravascular coagulation is uncommon but shares some similarities to sepsis-induced disseminated intravascular coagulation. Marked elevations in hematologic biomarkers such as lactate dehydrogenase, D-dimer, ferritin, and C-reactive protein are associated with worse outcomes. Understanding the pathophysiology and recognizing factors associated with poor prognosis are crucial in improving patient outcomes with coronavirus disease 2019. [ABSTRACT FROM AUTHOR]

Background: Despite treatment with abiraterone acetate and prednisone (AA/P), most patients with metastatic hormone sensitive prostate cancer (mHSPC) will develop castration-resistant disease (metastatic castration-resistant prostate cancer [mCRPC]). The early identification of who will progress on AA/P is limited. Objective: This study investigates the role of prostate surface antigen (PSA) kinetics as a predictor of progression in mHSPC patients treated with AA/P. Patients and Methods: All patients with mHSPC who initiated androgen deprivation therapy (ADT) and AA/P from June 2017 to February 2019 at the Cleveland Clinic were eligible. PSA-mCRPC was defined as a PSA rise at two consecutive time points. Patients were followed until first mCRPC or last contact after AA/P. Patterns of PSA change were evaluated using a longitudinal mixed model at time 0, 3, 6, 9, and 12 months from AA/P initiation. The association between PSA profile at 3 months and PSA-mCRPC was examined using survival analysis. Radiographic progression (Rad-mCRPC) was also analyzed. Results: A total of 130 men with follow-up were included. The median (interquartile range [IQR]) follow-up time was 15.3 (10.5, 22.5) months. Eighty-two percent were Caucasian (median age 68.5 years); participants had a median (IQR) PSA of 16.8 (5.3, 48.0) ng/mL. Half of the patients had de novo disease, and 46.2% had high-risk disease (61% had a Gleason score ≥ 8, 16% had visceral disease, and 54% had three or more bony lesions). The greatest PSA percentage reduction from baseline after AA/P initiation occurred at the first 3 months (median 98.3%). The reduction at 6–12 months from baseline was small (99.7–100%). Patients without PSA-mCRPC had a significantly greater 3-month reduction of PSA values compared to patients who developed PSA-mCRPC (p interaction = 0.0002). 50.8% of patients were able to achieve a non-detectable PSA (median 13.1 months). PSA-mCRPC (n = 20) was observed from 4 to 24 months after AA/P, with the majority of events occurring within the first 12 months. Patients with PSA < 0.3 ng/mL (12-month PSA-mCRPC–free 94.5% vs. 69.4%, p = 0.0004) or a ≥ 98% reduction (94.9% vs. 68.0%, p = 0.0002) at 3 months had better PSA-mCRPC–free survival compared to their counterparts. Absolute reduction at 3 months was not associated with PSA-mCRPC. Similar PSA patterns were seen in those who had Rad-mCRPC compared to no Rad-mCRPC (p interaction < 0.05). Conclusion: The degree of PSA decline at 3 months predicted serologic progression to mCRPC. Those who developed castration-resistant disease had higher PSA and a lower percentage reduction by 3 months. Tracking early PSA pattern changes may alert clinicians to poor treatment effect and potential progression; they should consider frequent PSA measurement and imaging, as well as the initiation of sequential therapy. [ABSTRACT FROM AUTHOR]

Background: The lemongrass (LG) leaves could be a useful source of cellulose after its oil extraction, which is still either dumped or burned, not considered as a cost-effective approach. The synthesis of cellulose nanofibers (CNF) from LG waste has emerged as a beneficial alternative in the value-added applications. The non-toxicity, biodegradability, and biocompatibility of CNF have raised the interest in its manufacturing. Method: In the present study, we have isolated and characterized CNFs using enzymatic hydrolysis. We also explored the cytotoxic properties of the final material. The obtained products were characterized using dynamic light scattering (DLS), fourier transform infrared spectroscopy (FT-IR), scanning electron microscopy (SEM), transmission electron microscopy (TEM), x-ray diffraction (XRD), and thermogravimetric/differential thermal gravimetric analysis (TG/DTG). The cytotoxicity of CNF was assessed by 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyl tetrazolium bromide (MTT) assay against three different cancer cell lines NCIH460, PA1, and L132 cells. Results: The FT-IR results showed that the resulting sample was of cellulose species, and CNF was found free from the non-cellulosic components like lignin and hemicellulose. The SEM micrographs of the cellulose showed a bundle like structure. The TEM micrographs of CNF showed diverse long fibers structure with 105.7 nm particle size analysed using DLS. The TGA analysis revealed that the thermal stability was slightly lower, compared to cellulose. Additionally, CNF did not show the cytotoxic effect at the tested concentrations (~10-1000 μg/ml) in any of the cell lines. Conclusion: Overall, the results concluded that LG waste-derived CNF is a potential sustainable material and could be employed as a favourable reinforcing agent or nanocarriers in diverse areas, mainly in food and drug delivery sectors. [ABSTRACT FROM AUTHOR]

Summary: Background Despite definitive local therapy, patients with high-risk prostate cancer have a significant risk for local and distant failure. To date, no systemic therapy given prior to surgery has been shown to improve outcomes. The phosphatidilinositol 3-kinase/AKT/mTOR pathway is commonly dysregulated in men with prostate cancer. We sought to determine the clinical efficacy and safety of the mTOR/TORC1 inhibitor everolimus in men with high-risk prostate cancer undergoing radical prostatectomy. Methods This is a randomized phase II study of everolimus at two different doses (5 and 10 mg daily) given orally for 8 weeks before radical prostatectomy in men with high-risk prostate cancer. The primary endpoint was the pathologic response (histologic P0, margin status, extraprostatic extension) and surgical outcomes. Secondary endpoints included changes in serum PSA level and treatment effects on levels of expression of mTOR, p4EBP1, pS6 and pAKT. Results Seventeen patients were enrolled: nine at 10 mg dose and eight at 5 mg dose. No pathologic complete responses were observed and the majority of patients (88%) had an increase in their PSA values leading to this study being terminated early due to lack of clinical efficacy. Treatment-related adverse events were similar to those previously reported with the use of everolimus in other solid tumors and no additional surgical complications were observed. A significant decrease in the expression of p4EBP1 was noted in prostatectomy samples following treatment. Conclusions Neoadjuvant everolimus given at 5 mg or 10 mg daily for 8 weeks prior to radical prostatectomy did not impact pathologic responses and surgical outcomes of patients with high-risk prostate cancer. Trial registration NCT00526591. [ABSTRACT FROM AUTHOR]

Summary: Background Mammalian target of rapamycin (mTOR) pathway and angiogenesis through vascular endothelial growth factor (VEGF) have been shown to play important roles in prostate cancer progression. Preclinical data in prostate cancer has suggested the potential additive effect dual inhibition of VEGF and mTOR pathways. In this phase I/II trial we assessed the safety and efficacy of bevacizumab in combination with temsirolimus for the treatment of men with metastatic castration-resistant prostate cancer (mCRPC). Methods In the phase I portion, eligible patients received temsirolimus (20 mg or 25 mg IV weekly) in combination with a fixed dose of IV bevacizumab (10 mg/kg every 2 weeks). The primary endpoint for the phase II portion was objective response measured by either PSA or RECIST criteria. Exploratory endpoints included changes in circulating tumor cells (CTC) and their correlation with PSA response to treatment. Results Twenty-one patients, median age 64 (53–82), with pre-treatment PSA of 205.3 (11.1–1801.0), previously treated with a median of 2 (0–5) lines of therapy for mCRPC received the combination of temsirolimus weekly at 20 mg (n = 4) or 25 mg (n = 17) with bevacizumab 10 mg/kg every 2 weeks (n = 21). Median time to progression was 2.6 months (95% CI, 1.2–3.9) and the median best PSA change from baseline to 12 weeks was a 32% increase (−40–632%) which met the predefined futility rule and led to early termination of the study. Nine patients (43%) had ≥ grade 3 toxicity that included fatigue (24%), anorexia (10%), nausea/vomiting (5%) and lymphopenia (5%). In exploratory analysis, a decrease in CTC levels was observed in 9 out of 11 patients. No association between PSA levels and CTC levels was detected. Conclusions The combination of temsirolimus and bevacizumab showed limited clinical activity in mCRPC patients previously treated with chemotherapy and was associated with significant adverse events (AEs). Transient decrease in CTC levels was independent from PSA response. NCT01083368. [ABSTRACT FROM AUTHOR]

The present study reports the Agrobacterium rhizogenes-mediated hairy root induction in of an ethno-medicinally significant herb -Boerhaavia diffusa L., for elucidating the underlying competence regarding its biosynthetic (i.e. boeravinone B and eupalitin) and bioactivity (antibacterial, antioxidant and anti-inflammatory) potentials. Host plant-specific receptiveness towards A. rhizogenes strains and disparity in compatibility threshold of leaf and nodal explants were evident. Only leaf explants responded, attaining hairy root induction with the ATCC 15834 followed by A4 and SA79 strains in reducing order of transformation efficiency. The growth behaviours differed amongst independent rhizoclones, and two clones of A4 (RBH) and ATCC 15834 (RBT8) origin demonstrated higher growth potentials. Polymerase chain reaction amplification of rol genes confirmed their transformed nature. Optimization of the appropriate solvent and reverse phase high-performance liquid chromatography parameters relating to the targeted metabolite production in the selected RBH and RBT8 clones revealed higher accumulation of eupalitin with the RBH clone having the best result of 1.44 times greater yield over the control root. Compared to the selected rhizoclones, the control roots however showed higher boeravinone B content. Devising a modified 'stirred-tank' reactor through equipping with marine impellers and ring spargers facilitated high-density RBH root biomass yield with 6.1-fold and 1.15-fold yield increment of the boeravinone B and eupalitin respectively compared to shake-flask cultures. Considering the control roots, the RBH clone revealed analogous antioxidant/antibacterial activities with improved anti-inflammatory potential. The hairy root mediated higher production of boeravinone B and eupalitin could be achieved for the first time in bioreactor. [ABSTRACT FROM AUTHOR]

Betulinic acid (BA), a pentacyclic triterpenoid, is gaining unmatched attention owing to its unique anti-cancer activity with selective melanoma growth inhibition without damaging normal cells. It is also well-known for its multifaceted pharmacokinetics, entailing antibacterial, antimalarial, anti-HIV and antioxidant merits. Considering the escalating demand with diminishing bioresource of this molecule, the present study was undertaken that revealed the untapped potentials of Ocimum calli, contrasting to that in the in vitro derived leaves, as effective production alternative of BA in three out of four tested species (i.e. Ocimum basilicum, Ocimum kilimandscharicum, Ocimum sanctum excluding Ocimum grattisimum) . Callus inductions were obtained in all the four species with different 2,4-dichlorophenoxyacetic acid (2,4-D)/α-naphthaleneacetic acid (NAA) concentrations with kinetin. Notably, 2,4-D favoured maximum callus growth in all whereas NAA proved beneficial for the highest metabolite yield in the calli of each BA-producing species. The O. basilicum calli demonstrated the maximum growth (growth index (GI) 678.7 ± 24.47) and BA yield (2.59 ± 0.55 % dry weight [DW]), whereas those in O. kilimandscharicum (GI 533.33 ± 15.87; BA 1.87 ± 0.6 % DW) and O. sanctum (GI 448 ± 16.07; BA 0.39 ± 0.12 % DW) followed a descending order. The O. gratissimum calli revealed minimum growth (GI 159 ± 13.25) with no BA accumulation. Elicitation with methyl jasmonate at 200-μM concentration after 48-h exposure doubled the BA yield (5.10 ± 0.18 % DW) in NAA-grown O. basilicum calli compared to that in the untreated counterpart (2.61 ± 0.19 % DW), which further enthused its future application. [ABSTRACT FROM AUTHOR]

Objective: To Compare performance of combined creatinine and cystatin C-based equation with equations based on either cystatin C or creatinine alone, in early chronic kidney disease. Design: Diagnostic accuracy study. Setting: Tertiary-care hospital. Patients: One hundred children with chronic kidney disease who underwent 99mTc diethylenetriamine pentaacetic acid (DTPA) glomerular filtration rate measurement. Methods: Estimating equations for glomerular filtration rate (GFR) based on serum cystatin C alone and in combination with serum creatinine were generated using regression analyses. These equations and the creatinine-based equation [0.42 × height/creatinine] were validated in 42 children with glomerular filteration rate between 60 and 90 mL/min/1.73 m. Bias, precision and accuracy of estimating equations using DTPA glomerular filteration rate as gold standard. Results: Cystatin C-based equation (GFR=96.9-30.4 x cystatin) overestimated while the combined cystatin C-and creatininebased equation [GFR=11.45 x (height/creatinine) 0.356 x (1/cystatin) 0.188] underestimated the measured GFR. Cystatin Cbased equation had less bias (1.9 vs. 12.4 ml/min/1.73 m), and higher precision (13.1 vs. 25.6 mL/min/1.73 m) and accuracy (92.1% vs. 75.7%) than creatinine-based equation. The combined cystatin C and creatinine equation had bias (−1.4 mL/ min/1.73 m) precision (15.2 mL/min/1.73 m) and accuracy (91.2%) similar to cystatin C-based equation. Conclusions: Cystatin C-based equation has a better performance in estimating glomerular filtration rate than creatinine-based equation in children with early chronic kidney disease. Addition of creatinine equation does not improve the performance of the cystatin C-based equation. [ABSTRACT FROM AUTHOR]