Validation and identification of promising gene specific markers governing foliar disease resistance in groundnut (Arachis hypogaea L.).

BACKGROUND: Groundnut is vulnerable to the major foliar fungal disease viz., late leaf spot (LLS) and rust in kharif season, which results in severe yield losses. Until now, LLS and rust resistance linked markers were developed based on GPBD 4 as a major donor source and were validated in its derivatives only, which restricted their use in marker assisted selection (MAS) involving other donors. METHODS AND RESULTS: The current study focused to validate LLS and rust resistance linked markers employing advanced breeding lines of F6 generation, derived from nine different crosses involving nine diverse parents, to identify potential markers for marker-assisted breeding of LLS and rust resistance in groundnut. Out of 28-trait linked markers used for validation, 8 were polymorphic (28.57%). Marker-trait association (MTA) and Single Marker Analysis (SMA) revealed that the SSR marker pPGPseq5D05 is significantly associated with both LLS (15.8% PVE) and rust (17.5% PVE) resistance, whereas, the marker IPAHM103 is tightly linked with rust resistance (26.8% PVE) alone. In silico analysis revealed that the marker gene for IPAHM103 is a zinc finger protein and the marker gene for pPGPseq5D05 is an ADP-ribosylation factor GTPase-activating protein. Both these protein products impart resistance or tolerance to biotic stress in crop plants. Two other markers namely, GMLQ975 and pPGPseq13A10 were also found to be associated with LLS resistance explaining MTA up to 60%. CONCLUSION: These gene specific markers will enable us to screen more number of germplasm lines or newly developed lines in MAS schemes for LLS and rust resistance using a wide range of resistant sources.

Increasing Eligibility to Transplant Through the Selective Cytopheretic Device: A Review of Case Reports Across Multiple Clinical Conditions.

A stable, minimum physiological health status is required for patients to qualify for transplant or artificial organ support eligibility to ensure the recipient has enough reserve to survive the perioperative transplant period. Herein, we present a novel strategy to stabilize and improve patient clinical status through extracorporeal immunomodulation of systemic hyperinflammation with impact on multiple organ systems to increase eligibility and feasibility for transplant/device implantation. This involves treatment with the selective cytopheretic device (SCD), a cell-directed extracorporeal therapy shown to adhere and immunomodulate activated neutrophils and monocytes toward resolution of systemic inflammation. In this overview, we describe a case series of successful transition of pediatric and adult patients with multiorgan failure to successful transplant/device implantation procedures by treatment with the SCD in the following clinical situations: pediatric hemophagocytic lymphohistiocytosis, and adult hepatorenal and cardiorenal syndromes. Application of the SCD in these cases may represent a novel paradigm in increasing clinical eligibility of patients to successful transplant outcomes.

WT1 Cancer Vaccine in Advanced Pancreatic Cancer: A Systematic Review.

Advanced pancreatic cancer is one of the prominent contributors to cancer-related mortality globally. Chemotherapy, especially gemcitabine, is generally used for the treatment of advanced pancreatic cancer. Despite the treatment, the fatality rate for advanced pancreatic cancer is alarmingly high. Thus, the dire need for better treatment alternatives has drawn focus to cancer vaccinations. The Wilms tumor gene (WT1), typically associated with Wilms tumor, is found to be excessively expressed in some cancers, such as pancreatic cancer. This characteristic feature is harvested to develop cancer vaccines against WT1. This review aims to systematically summarize the clinical trials investigating the efficacy and safety of WT1 vaccines in patients with advanced pancreatic cancer. An extensive literature search was conducted on databases Medline, Web of Science, ScienceDirect, and Google Scholar using the keywords "Advanced pancreatic cancer," "Cancer vaccines," "WT1 vaccines," and "Pulsed DC vaccines," and the results were exclusively studied to construct this review. WT1 vaccines work by introducing peptides from the WT1 protein to trigger an immune response involving cytotoxic T lymphocytes via antigen-presenting cells. Upon activation, these lymphocytes induce apoptosis in cancer cells by specifically targeting those with increased WT1 levels. WT1 vaccinations, which are usually given in addition to chemotherapy, have demonstrated clinically positive results and minimal side effects. However, there are several challenges to their widespread use, such as the immunosuppressive nature of tumors and heterogeneity in expression. Despite these limitations, the risk-benefit profile of cancer vaccines is encouraging, especially for the WT1 vaccine in the treatment of advanced pancreatic cancer. Considering the fledgling status of their development, large multicentric, variables-matched, extensive analysis across diverse demographics is considered essential.

New aspects of femtosecond laser ablation of Si in water: a material perspective.

We report a study of the role of material's conductivity in determining the morphology of nanoparticles and nanostructures produced by ultrafast laser ablation of solids. Nanoparticles and textured surfaces formed by laser ablation display a wide variation in size and morphology depending on the material. In general, these qualities can be grouped as to material type, insulator, semiconductor, or metal; although each has many other different material properties that make it difficult to identify the critical material factor. In this report, we study these nanoparticle/surface structural characteristics as a function of silicon (Si) resistivity, thus honing-in on this critical parameter and its effects. The results show variations in morphology, optical, and nonlinear properties of Si nanoparticles. The yield of colloidal Si nanoparticles increased with an increase in the conductivity of Si. Laser-induced periodic surface structures formed on ablated substrates are also found to be sensitive to the initial conductivity of the material. Further, the laser ablation of Gamma-irradiated Si has been investigated to verify the influence of altered conductivity on the formation of Si nanoparticles. These observations are interpreted using the basic mechanisms of the laser ablation process in a liquid and its intricate relation with the initial density of states and thermal conductivities of the target material.

Cytogenetic and Molecular Associations with Outcomes in Higher-Risk Myelodysplastic Syndromes Treated with Hypomethylating Agents plus Venetoclax.

PURPOSE: Hypomethylating agents (HMA) combined with venetoclax are an emerging therapeutic strategy for higher-risk myelodysplastic syndromes (HR-MDS). The cytogenetic and molecular factors associated with outcomes with this combination for HR-MDS are incompletely understood. EXPERIMENTAL DESIGN: We pooled patient data from 3 prospective trials evaluating HMA-venetoclax in HR-MDS to study associations between cytogenetic and molecular factors and overall response rate (ORR), overall survival (OS), and event-free survival (EFS). The Kaplan-Meier method was used to estimate time-to-event endpoints. Univariate and multivariate analyses using logistic regression (for ORR) or the Cox proportional hazards model (for OS and EFS) were used to identify associations between clinical, cytogenetic, and molecular factors and outcomes. RESULTS: A total of 80 patients (52 HMA-naïve, 28 HMA-failure) were included. ORR was 90% in HMA-naïve and 57% in HMA-failure. Median OS was 28.2 and 8.3 months in HMA-naïve and HMA-failure, respectively. Median EFS was 17.9 and 5.5 months in HMA-naïve and HMA-failure, respectively. In addition, 24/52 (46%) of the HMA-naïve and 3/28 (11%) of the HMA-failure patients proceeded to allogeneic stem cell transplantation (SCT). Factors associated with inferior outcomes were prior HMA failure, complex cytogenetics, trisomy 8, TP53 mutations, and RAS pathway mutations. Mutations in RNA splicing, DNA methylation, and ASXL1 appeared favorable. Blast percentage was not predictive of outcomes. CONCLUSIONS: Knowledge of cytogenetic and molecular alterations may help identify which patients with HR-MDS benefit the most from venetoclax.

Rationale and Design of NEUTRALIZE-AKI: A Multicenter, Randomized, Controlled, Pivotal Study to Assess the Safety and Efficacy of a Selective Cytopheretic Device in Patients with Acute Kidney Injury Requiring Continuous Kidney Replacement Therapy.

INTRODUCTION: NEUTRALIZE-AKI is a pivotal study to evaluate the safety and effectiveness of the selective cytopheretic device (SCD) in adult patients with acute kidney injury (AKI) requiring continuous kidney replacement therapy (CKRT). METHODS/DESIGN: This is a two-arm, randomized, open-label, controlled multi-center pivotal US study which will enroll 200 adult patients (age 18-80 years) in the intensive care unit with acute kidney injury requiring CKRT and at least one additional organ failure across 30 clinical centers. Eligible patients will be randomized to CKRT plus SCD therapy versus CKRT alone. Therapy will be administered for up to 10 days, with the hypothesis that the CKRT plus SCD group will demonstrate a lower mortality rate or better rate of renal recovery than the CKRT alone group by day 90. The primary outcome is a composite of dialysis dependence or all-cause mortality at day 90. CONCLUSION: The SCD is a cell-directed extracorporeal therapy that targets and deactivates pro-inflammatory neutrophils and monocytes, with evidence of efficacy across a variety of critically ill patient populations. Knowledge and experience from many of those studies and other AKI trials were incorporated into the design of this pivotal study, with the aim to investigate the role of effector cell immunomodulation in the intervention of AKI.

Sub-70†nm surface structures on femtosecond laser irradiated GaAs in distilled water and sensing application.

This study reveals the possibility of distinct ablation mechanisms at different radial positions of the ablated track on GaAs when ablated with femtosecond pulses in distilled water. From the center to the edges of the ablated track, fascinating features such as micron-sized cones, nano-pores, and nano-ripple trenches (average size of 60-70 nm) were observed. The requirement for simulations incorporating the variations in a Gaussian beam fluence and dynamics of the melt flow/surrounding media is discussed. Deep-subwavelength structures, i.e., nano-ripple trenches with a ripple size of ∼λ/11 are achieved on the GaAs surface in this study. Further, these GaAs surface structures acted as excellent hybrid surface-enhanced Raman spectroscopy platforms upon gold coating.

Safety Summary of the Selective Cytopheretic Device: A Review of Safety Data Across Multiple Clinical Trials in ICU Patients With Acute Kidney Injury and Multiple Organ Failure.

OBJECTIVES: Acute kidney injury (AKI) requiring continuous kidney replacement therapy is a significant complication in ICU patients with mortality rates exceeding 50%. A dysregulated immune response can lead to systemic inflammation caused by hyperactivity of pro-inflammatory neutrophils and monocytes leading to tissue damage. The selective cytopheretic device (SCD) is an investigational medical device in a new class of cell-directed extracorporeal therapies distinct from cytokine adsorbers or filters, as it targets activated leukocytes. These leukocytes are the cellular sources driving this hyperinflammatory process. The objective of this report is to summarize the safety experience from clinical studies of the SCD in ICU patients with AKI or acute respiratory distress syndrome (ARDS) and multiple organ dysfunction (MOD). DATA SOURCES AND STUDY SELECTION: The studies included in this report represent all relevant trials of the SCD conducted in patients with AKI or ARDS and MOD. Adverse event data, clinical laboratory data and mortality rates were described and summarized in this report. DATA EXTRACTION AND DATA SYNTHESIS: Five clinical studies were included in this report, including four adult studies of AKI and/or ARDS and one pediatric AKI study, which involved 151 patients treated with the SCD in an ICU setting. Over 800 SCD sessions were deployed with an estimated 19,000 exposure hours with no device-related infections or attributable serious adverse events. Furthermore, there were no safety signals of leukopenia, thrombocytopenia, or other indications of immunodepletion or immunosuppression. CONCLUSIONS: The SCD has shown to be a promising extracorporeal therapy with promising clinical results and a favorable safety profile. These studies support that the SCD can be added as a therapeutic intervention in critically ill AKI patient populations with multiple organ failure without adding additional safety risks.

Rice biofortification: breeding and genomic approaches for genetic enhancement of grain zinc and iron contents.

Rice is a highly consumed staple cereal cultivated predominantly in Asian countries, which share 90% of global rice production. Rice is a primary calorie provider for more than 3.5 billion people across the world. Preference and consumption of polished rice have increased manifold, which resulted in the loss of inherent nutrition. The prevalence of micronutrient deficiencies (Zn and Fe) are major human health challenges in the 21st century. Biofortification of staples is a sustainable approach to alleviating malnutrition. Globally, significant progress has been made in rice for enhancing grain Zn, Fe, and protein. To date, 37 biofortified Fe, Zn, Protein and Provitamin A rich rice varieties are available for commercial cultivation (16 from India and 21 from the rest of the world; Fe > 10 mg/kg, Zn > 24 mg/kg, protein > 10% in polished rice as India target while Zn > 28 mg/kg in polished rice as international target). However, understanding the micronutrient genetics, mechanisms of uptake, translocation, and bioavailability are the prime areas that need to be strengthened. The successful development of these lines through integrated-genomic technologies can accelerate deployment and scaling in future breeding programs to address the key challenges of malnutrition and hidden hunger.

"Flipped Lid" Fracture of the Lateral Tibial Plateau with Dislocated Lateral Meniscus: A Case Report.

CASE: We present a rare "flipped lid" type of fracture of the lateral tibial plateau with dislocation of the lateral meniscus into the notch with intact roots. This was fixed using headless screws through arthrotomy and peripheral suturing of the meniscus. At the 1-year follow-up, although there was terminal restriction of 10° flexion with redislocation of the lateral meniscus, the patient was able to perform all daily activities and declined further surgery. CONCLUSION: Flipped lid-type fracture is rare and results in good outcome when fixed early. Meniscal dislocation repair requires close monitoring to detect failure.

Memojis Pain Scale: A novel pain assessment tool.

BACKGROUND: Dental pain exerts a considerable impact on the psychosocial well-being of children; reliable management of pain depends on the ability to assess pain intensity. AIM: To validate and compare a new memojis pain assessment scale with the Faces Pain Scale-Revised (FPS-R) and Wong-Baker FACES Pain Rating Scale (WBFPS) in assessing dental pain experienced by children. DESIGN: Two hundred and fifty healthy children aged 5-9 years without any past dental experience and requiring local anaesthesia (LA) administration were recruited. Three different scales [FPS-R, WBFPS and Memojis Pain Scale (MPS)] were applied to assess the children's pain during LA administration. The preferences of each child based on the ease of understanding the faces were recorded. RESULTS: Pearson correlation test was performed to determine the correlation between MPS with WBFPS and MPS with FPS-R. A strong correlation was seen when comparing MPS with WBFPS (r = .966; p < .001) and MPS with FPS-R (r = .969; p < .001), and 81.6% of the children preferred MPS. CONCLUSION: The Memojis Pain Scale was an effective pain assessment tool. It can be employed as an alternative scale for pain assessment in children.

Characterization of actinobacteria from wheat seeds for plant growth promoting traits and protection against fungal pathogens.

Seeds harbor naturally occurring microbial endophytes that proliferate during seedling development; playing crucial roles in seedling growth, establishment, and protection against fungal pathogens. Resilient actinobacteria of wheat seeds have been explored in this study for their beneficial traits. Ten actinobacteria isolated from the surface-sterilized seeds of wheat variety HD3117 were identified as nine species of Streptomyces and one of Nocardiopsis. Most isolates could grow at 42°C, 5% NaCl, and 10% poly ethylene glycol (PEG); exhibited variable hydrolytic enzyme production for amylase, cellulase, and protease. Few isolates produced indole acetic acid (9.0-18.9 µg ml-1 ) and could solubilize P (11.3-85.2 µg ml-1 ). The isolates were antagonistic against one or more fungal pathogens under test (Fusarium graminearum, Bipolaris sorokiniana, Alternaria sp., and Tilletia indica), of which Streptomyces sampsonii WSA20 inhibited all in dual culture assay. Priming of wheat seeds with the efficient isolate WSA20 led to effective colonization in the root zone and significantly improved germination, shoot and root length in seed germination assay. Significant protection was recorded in microcosm experiment where no symptoms of disease were observed. This study shows the significance of actinobacterial endophytes of wheat seeds in influencing seed germination and seedling growth while protecting from soil-borne pathogens. It is original and suggests that the seed inhabiting efficient actinobacteria may be developed as efficient bioinoculant for sustainable farming system.

Evaluation of Nanostructured NiS2 Thin Films from a Single-Source Precursor for Flexible Memristive Devices.

Herein, we report the first demonstration of a single-step, in situ growth of NiS2 nanostructures from a single-source precursor onto a flexible substrate as a versatile platform for an effective nonvolatile memristor. The low temperature, solution-processed deposition of NiS2 thin films exhibits a wide band gap range, spherical-flower-like morphology with high surface area and porosity, and negligible surface roughness. Moreover, the fabricated Au/NiS2/ITO/PET memristor device reveals reproducible bipolar resistive switching (RS) at low operational voltages under both flat and bending conditions. The flexible device shows stable RS behavior for multiple cycles with a good memory window (∼102) and data retention of up to 104 s. The switching of a device between a high-resistance state and a low-resistance state is attributed to the filamentary conduction based on sulfur ion migration and sulfur vacancies and plays a key role in the outstanding memristive performance of the device. Consequently, this work provides a simple, scalable, solution-processed route to fabricate a flexible device with potential applications in next-generation neuromorphic computing and wearable electronics.

A Phase II Study of Azacitidine, Venetoclax, and Trametinib in Relapsed or Refractory Acute Myeloid Leukemia Harboring RAS Pathway-Activating Mutations.

INTRODUCTION: RAS pathway mutations are common mechanisms of resistance to acute myeloid leukemia (AML) therapies. Trametinib, an oral MEK inhibitor, has been shown to have single-agent activity in relapsed/refractory AML and preclinical synergy with venetoclax. METHODS: We conducted a single-center, open-label, phase 2 trial of the combination of azacitidine, venetoclax, and trametinib in patients with relapsed or refractory AML harboring a RAS pathway-activating mutation. RESULTS: Sixteen patients were treated. The patients were heavily pretreated with a median number of 4 prior therapies; 13 (81%) had received a prior hypomethylating agent (HMA) with venetoclax, and 8 (50%) had undergone prior stem cell transplant. Four patients (25%) responded (CR, n = 1; CRi, n = 1; MLFS, n = 2). Two of the 3 patients (67%) who had not previously received HMA plus venetoclax responded; in contrast, only 2 of the 13 patients (15%) who had previously received HMA plus venetoclax responded. The median OS was 2.4 months, and the 6-month OS rate was 31%. Related grade 3-4 adverse events occurred in 50% of patients, and 50% of patients required a dose adjustment of trametinib. CONCLUSIONS: The combination of azacitidine, venetoclax, and trametinib had only modest activity in patients with relapsed/refractory AML, with a response rate that was similar to previous reports of trametinib monotherapy. Substantial toxicity was observed with this combination. Given the established role of RAS pathway mutations in mediating resistance to AML therapies, future studies of better tolerated, more active inhibitors of this pathway are still needed.

Resistance to targeted therapies: delving into FLT3 and IDH.

Recent advances in FLT3 and IDH targeted inhibition have improved response rates and overall survival in patients with mutations affecting these respective proteins. Despite this success, resistance mechanisms have arisen including mutations that disrupt inhibitor-target interaction, mutations impacting alternate pathways, and changes in the microenvironment. Here we review the role of these proteins in leukemogenesis, their respective inhibitors, mechanisms of resistance, and briefly ongoing studies aimed at overcoming resistance.

Expression and Role of ß3-Adrenergic Receptor during the Differentiation of 3T3-L1 Preadipocytes into Adipocytes.

ß3-adrenergic receptor (ß3-AR) is expressed predominantly in mature white and brown/beige adipocytes. Although the lipolytic and thermogenic role of ß3-AR in brown/beige adipocytes is well defined, the adipogenic role of ß3-AR in white adipocytes remains unclear at present. In this study, we investigated the expression and function of ß3-AR in differentiating 3T3-L1 cells, murine white preadipocytes. Of note, the expression of ß3-AR at the protein and mRNA levels was highly induced in a time-dependent manner during 3T3-L1 preadipocyte differentiation. Interestingly, the results of the pharmacological inhibition study demonstrated the roles of p38 MAPK and PKC in the induction of ß3-AR expression in differentiating 3T3-L1 cells. Knockdown of ß3-AR led to less lipid accumulation and triglyceride (TG) content during 3T3-L1 preadipocyte differentiation with no cytotoxicity. Furthermore, knockdown of ß3-AR resulted in a decrease in not only expression levels of CCAAT/enhancer-binding protein-α (C/EBP-α), peroxisome proliferator-activated receptor-γ (PPAR-γ), fatty acid synthase (FASN), perilipin A, and leptin but also phosphorylation levels of signal transducer and activator of transcription-5 (STAT-5) during 3T3-L1 preadipocyte differentiation. In summary, these results demonstrate firstly that ß3-AR expression is highly up-regulated in p38 MAPK and PKC-dependent manners, and the up-regulated ß3-AR plays a crucial role in lipid accumulation in differentiating 3T3-L1 cells, which is mediated through control of expression and phosphorylation levels of C/EBP-α, PPAR-γ, STAT-5, FASN, and perilipin A.

BTK inhibitor selection for chronic lymphocytic leukemia: which drug for which patient?

INTRODUCTION: The development of BTK inhibitors has revolutionized the management of CLL. Currently, there are 3 BTK inhibitors available to treat CLL: ibrutinib, acalabrutinib, and zanubrutinib (the latter not yet approved for this disease but included in the NCCN guidelines). In this review, we will elucidate our approach to the selection of BTK inhibitor and provide insight into the future of BTK directed therapy. AREAS COVERED: This review utilizes data from published prospective trials, specifically RESONATE, RESONATE-2, ELEVATE-TN, ASCEND, ELEVATE-RR, and the ongoing FLAIR, SEQUOIA, and ALPINE trials. EXPERT OPINION: The choice of BTK inhibitor is guided by the setting (frontline vs relapsed) in conjunction with patient disease characteristics and comorbidities. In this review, we will elucidate our approach to the selection of BTK inhibitor and provide insight into the future of BTK directed therapy.

Advances in Immunology: A Cornerstone in Diagnosis and Therapy of Merkel Cell Carcinoma.

Merkel cell cancer (MCC) is a rare cutaneous malignancy arising from neuroendocrine cells. This rare but lethal malignancy (mortality greater than 30%) has also tripled in incidence over the last two decades. The role of immunodeficiency in pathogenesis of this rare malignancy is well established, with elucidation of viral pathogenesis by Merkel cell polyoma virus (MCPyV), a novel polyoma virus, in a majority of patients. Viral neoantigens while playing an important role in oncogenesis can also aid in early immunologic detection of recurrent disease. Viral neoantigens can also be targets for immunotherapy. Immune checkpoint inhibitors (ICI) have established role in frontline therapy in addition to recurrence of metastatic MCC. ICI therapy is being explored in adjuvant and neoadjuvant settings as well. We would like to illustrate curative potential of early diagnosis of recurrence and prompt use of ICI in treatment of oligometastatic disease in our case presentation.