HIF-1α and MIF enhance neutrophil-driven type 3 immunity and chondrogenesis in a murine spondyloarthritis model.

The hallmarks of spondyloarthritis (SpA) are type 3 immunity-driven inflammation and new bone formation (NBF). Macrophage migration inhibitory factor (MIF) was found to be a key driver of the pathogenesis of SpA by amplifying type 3 immunity, yet MIF-interacting molecules and networks remain elusive. Herein, we identified hypoxia-inducible factor-1 alpha (HIF1A) as an interacting partner molecule of MIF that drives SpA pathologies, including inflammation and NBF. HIF1A expression was increased in the joint tissues and synovial fluid of SpA patients and curdlan-injected SKG (curdlan-SKG) mice compared to the respective controls. Under hypoxic conditions in which HIF1A was stabilized, human and mouse neutrophils exhibited substantially increased expression of MIF and IL-23, an upstream type 3 immunity-related cytokine. Similar to MIF, systemic overexpression of IL-23 induced SpA pathology in SKG mice, while the injection of a HIF1A-selective inhibitor (PX-478) into curdlan-SKG mice prevented or attenuated SpA pathology, as indicated by a marked reduction in the expression of MIF and IL-23. Furthermore, genetic deletion of MIF or HIF1A inhibition with PX-478 in IL-23-overexpressing SKG mice did not induce evident arthritis or NBF, despite the presence of psoriasis-like dermatitis and blepharitis. We also found that MIF- and IL-23-expressing neutrophils infiltrated areas of the NBF in curdlan-SKG mice. These neutrophils potentially increased chondrogenesis and cell proliferation via the upregulation of STAT3 in periosteal cells and ligamental cells during endochondral ossification. Together, these results provide supporting evidence for an MIF/HIF1A regulatory network, and inhibition of HIF1A may be a novel therapeutic approach for SpA by suppressing type 3 immunity-mediated inflammation and NBF.

Cyperus rotundus L.: Invasive weed plant with insecticidal potential against Aphis craccivora Koch and Planococcus lilacinus (Cockerell).

Cyperus rotundus L. is a widely distributed invasive weed plant with vast traditional medicinal uses. Herein, the methanolic root extract of C. rotundus and its fractions (n-hexane, chloroform, n-butanol, and aqueous) were evaluated for insecticidal activity against nymphs of Aphis craccivora Koch and crawlers of Planococcus lilacinus (Cockerell) to find promising lead (s). In contact topical assay, among extract/fractions, n-hexane fraction exhibited more toxicity against A. craccivora (LD50 = 1.12 µg/insect) and P. lilacinus (LD50 = 0.94 µg/insect). The chemical analysis of n-hexane fraction revealed a volatile composition similar to that of the essential oil (EO) of C. rotundus roots. Hence, EO was extracted using water and deep eutectic solvents (DESs) as cosolvent, which revealed enhancement in EO yield (from 0.28 to 0.46% w/w) on implementing DESs. A total of 35 diverse volatile metabolites were identified in all EO samples, accounting for 85.0 to 91.8% of chemical composition, having cyperotundone, cyperene mustakone, isolongifolen-5-one, boronia butenal as major constituents. The EO obtained with DES-7 [choline chloride: ethylene glycol (1:4)] and DES-6 [choline chloride: lactic acid (1:3)] were found effective against A. craccivora (LD50 = 0.62-0.87 µg/insect) and P. lilacinus (LD50= 0.59-0.67 µg/insect) after 96 h. NMR analysis of EO revealed cyperotundone as a major compound, which was isolated along with cyperene and cyperene epoxide. All the molecules were found effective against P. lilacinus, whereas against A. craccivora cyperotundone, cyperene and cyperene epoxide showed promising toxicity (LD50 = 0.74-0.86 µg/insect). Extract/fractions, EO, and isolated molecules showed a significant reproductive inhibition rate of A. craccivora at higher concentrations. All the tested concentrations of cyperotundone showed significant inhibition of acetylcholinesterase (AChE) and glutathione-S-transferase (GST) in A. craccivora and P. lilacinus. Based upon the present study, C. rotundus can be recommended to control targeted insects in the greenhouse/field conditions after performing bio-efficacy and phytotoxicity studies.

High-throughput virtual screening of potential inhibitors of GPR52 using docking and biased sampling method for Huntington's disease therapy.

Huntington's disease (HD) is a rare and progressive neurodegenerative disorder caused by polyglutamine (poly-Q) mutations of the huntingtin (HTT) gene resulting in chorea, cognitive, and psychiatric dysfunctions. Being a monogenic condition, reducing the levels of the mutated huntingtin protein (mHTT) holds promise as an effective therapeutic approach. GPR52, an orphan G-protein coupled receptor (GPCR), enriched in the striatum, is a novel target for slowing down the progression of HD by lowering the mHTT levels. Therefore, the study focuses on identifying potent small-molecule inhibitors for GPR52 using a combination of robust high-throughput virtual screening (HTVS) and pharmacokinetics profiling followed by fast pulling of ligand (FPL) and umbrella sampling (US) simulations. Initially, screening a library of 2,36,545 compounds was done against the binding pocket of GPR52. Based on binding affinity, stereochemical and non-bonded interactions, and pharmacokinetic profiling, 50 compounds were shortlisted. Selected hit compounds 1, 2, and 3 were subjected to FPL simulations with applied external bias potential to investigate their unique dissociation pathways and intermolecular interactions over time. Subsequently, the US simulations were performed on the selected hit compounds to estimate their binding free energy (ΔG). The analysis of the trajectories obtained from simulations revealed that the residues TYR34, TYR185, GLY187, ASP188, ILE189, SER299, PHE300, and THR303 within the active site of GPR52 were significant for efficient ligand binding through the formation of various hydrogen bond interactions and hydrophobic contacts. Out of the three hit compounds, compound 3 had the lowest ΔG of - 20.82 ± 0.44 kcal/mol. The study identified compounds 1, 2, and 3 as potential molecules that can be developed as GPR52 inhibitors holding promise for lowering mHTT levels.

Identification of prognostic markers and potential therapeutic targets using gene expression profiling and simulation studies in pancreatic cancer.

BACKGROUND: Pancreatic ductal adenocarcinoma (PDAC) has a 5-year relative survival rate of less than 10% making it one of the most fatal cancers. A lack of early measures of prognosis, challenges in molecular targeted therapy, ineffective adjuvant chemotherapy, and strong resistance to chemotherapy cumulatively make pancreatic cancer challenging to manage. OBJECTIVE: The present study aims to enhance understanding of the disease mechanism and its progression by identifying prognostic biomarkers, potential drug targets, and candidate drugs that can be used for therapy in pancreatic cancer. METHODS: Gene expression profiles from the GEO database were analyzed to identify reliable prognostic markers and potential drug targets. The disease's molecular mechanism and biological pathways were studied by investigating gene ontologies, KEGG pathways, and survival analysis to understand the strong prognostic power of key DEGs. FDA-approved anti-cancer drugs were screened through cell line databases, and docking studies were performed to identify drugs with high affinity for ARNTL2 and PIK3C2A. Molecular dynamic simulations of drug targets ARNTL2 and PIK3C2A in their native state and complex with nilotinib were carried out for 100 ns to validate their therapeutic potential in PDAC. RESULTS: Differentially expressed genes that are crucial regulators, including SUN1, PSMG3, PIK3C2A, SCRN1, and TRIAP1, were identified. Nilotinib as a candidate drug was screened using sensitivity analysis on CCLE and GDSC pancreatic cancer cell lines. Molecular dynamics simulations revealed the underlying mechanism of the binding of nilotinib with ARNTL2 and PIK3C2A and the dynamic perturbations. It validated nilotinib as a promising drug for pancreatic cancer. CONCLUSION: This study accounts for prognostic markers, drug targets, and repurposed anti-cancer drugs to highlight their usefulness for translational research on developing novel therapies. Our results revealed potential and prospective clinical applications in drug targets ARNTL2, EGFR, and PI3KC2A for pancreatic cancer therapy.

Hard and Soft Tissue Relapse After Different Genioplasty Procedures: A Scoping Review.

The chin is a crucial component of facial aesthetics, and 20% of craniofacial problems require repair of the chin size, shape, and position. Genioplasty is used to treat irregularities in all three planes of the chin. Specific hard and soft tissue relapses following various genioplasty techniques have not been adequately studied in the literature to date. The purpose of this scoping review was to investigate the stability of hard and soft tissue changes achieved by different genioplasty procedures, six months after the procedure. A literature search was performed on PubMed, Web of Science, Embase, Wiley Online, Scopus, Google Scholar, Science Direct, and Cochrane databases from January 1, 2011 to October 31, 2022. Prospective and retrospective cohorts, case-control studies, observational studies, and randomized control trials, with at least 10 patients, which were written in English and evaluated the stability of different genioplasty procedures, with a follow-up period of at least six months were included. The manual and electronic search yielded 523 articles, and after complete screening, seven articles were selected (five with advancement genioplasty and two with reduction genioplasty) that met the eligibility criteria for review. The patients undergoing reduction genioplasty had a mean age of 24.15 years, compared to 20.5 years for augmentation genioplasty. The average follow-up period was 18.64 months for augmentation genioplasty and 10.5 months for reduction genioplasty technique. The relapse was assessed at pogonion, and it was noted that the average surgical advancement at hard tissue pogonion was 7.04 mm with a relapse of 0.69 mm after six months post-treatment. The average vertical movement of the hard tissue pogonion was 1.8 mm with a relapse of 0.74 mm. The average reduction at hard tissue pogonion was 3.2 mm in the vertical direction with a relapse of 0.2 mm and 0.8 mm reduction in soft tissue pogonion with a relapse of 0.3 mm. The soft to hard tissue ratio mentioned in the different studies ranged from 0.89 to 0.97. Both reduction and augmentation genioplasty are stable and reliable for altering the chin position for aesthetic purposes. The recommended mode of fixation is rigid fixation.

Insecticidal and Detoxification Enzyme Inhibition Activities of Essential Oils for the Control of Pulse Beetle, Callosobruchus maculatus (F.) and Callosobruchus chinensis (L.) (Coleoptera: Bruchidae).

Pulse beetle is the most harmful pest attacking stored grains and affecting quality and marketability. Continuous use of chemical-based pesticides against pulse beetle led to the development of insecticidal resistance; essential oils (EOs) can be an effective natural alternative against this pest. The main objective was to study the chemical composition of seven EOs viz., Acorus calamus, Hedychium spicatum, Lavandula angustifolia, Juniperus recurva, Juniperus communis, Cedrus deodara and Pinus wallichiana, their insecticidal and enzyme inhibition activities against pulse beetle. The primary compounds present in these EOs were cis-asarone, 1,8-cineole, linalyl isobutyrate, 2-ß-pinene, camphene, α-dehydro-ar-himachalene and camphene. A. calamus oil showed promising fumigant toxicity to Callosobruchus maculatus and C. chinensis (LC50 = 1357.86 and 1379.54 µL/L, respectively). A combination of A. calamus + L. angustifolia was effective against C. maculatus and C. chinensis (LC50 = 108.58 and 92.18 µL/L, respectively). All the combinations of EOs showed synergistic activity. In the repellency study, A. calamus showed more repellence to C. maculatus and C. chinensis (RC50 = 53.98 and 118.91 µL/L, respectively). A. calamus and L. angustifolia oil at 2500, 5000 and 10,000 µL/L significantly inhibited the AChE and GST enzymes in C. maculatus and C. chinensis after 24 and 48 h.

Phase II trial of a novel chemotherapy regimen CVEP (cyclophosphamide, vinblastine, etoposide and prednisolone) for acquired immunodeficiency syndrome (AIDS)-associated lymphomas.

Management of acquired immunodeficiency syndrome (AIDS)-related diffuse large B-cell (DLBCL) and plasmablastic lymphomas (PBL) poses significant challenges. The evidence supports use of dose-adjusted EPOCH (etoposide, prednisone, vincristine, cyclophosphamide and doxorubicin) with or without rituximab as first-line therapy. The need for central venous access, growth factors and significant toxicities limits its use in resource-constrained settings. To address these challenges, we have developed a novel regimen, CVEP (cyclophosphamide, vinblastine, etoposide, and prednisolone) based on the pharmacodynamic principles of dose-adjusted EPOCH. This single-centre phase II study evaluated the efficacy and safety of CVEP regimen in patients with de novo systemic AIDS-related DLBCL and PBL. The primary objective was complete response (CR) rates as assessed by positron emission tomography-computed tomography. The secondary objectives were incidence of Grade 3/4 toxicities, toxicities requiring hospitalisation, and disease-free survival. From May 2011 to February 2017, 42 patients were enrolled. At the end of therapy the CR rates were 69% (29/42) in the intention-to-treat population and 80.5% (29/36) in evaluable patients. At a median follow-up of 69 months, the 5-year disease-free survival was 65.3%. Out of 217 cycles administered, febrile neutropenia occurred in 19.3% and hospitalisation was required in 18.3% of cycles. There were two treatment-related deaths. The CVEP regimen is an active and safe regimen for AIDS-related DLBCL and PBL.

The current treatment approach to adolescents and young adults with acute lymphoblastic leukemia (AYA-ALL): challenges and considerations.

INTRODUCTION: AYA-ALL differs from pediatric ALL in terms of clinical, biological, psychosocial factors and access to care and has an inferior outcome. It is now being recognized that pediatric-inspired protocols are superior to adult protocols for this cohort, but given the lack of randomized trials, several questions remain unanswered. AREAS COVERED: In this review, we discuss how AYA-ALL is different from the pediatric ALL population, compare AYA-ALL with ALL in middle and older age adults, review the studies that have enrolled the AYA cohort, summarize risk-stratified and response-adapted approaches, describe the biological subtypes, and review the novel agents/approaches under evaluation. EXPERT OPINION: AYA-ALL is a complex and challenging disease that needs multidisciplinary and focused care. Well-designed clinical trials that focus on this cohort are needed to further improve the outcomes.

Bortezomib and rituximab in de novo adolescent/adult CD20-positive, Ph-negative pre-B-cell acute lymphoblastic leukemia.

The expression of CD20 in precursor B-cell acute lymphoblastic leukemia (B-ALL) is associated with poor outcomes. The addition of rituximab to intensive chemotherapy in CD20+ ALL has led to improved outcomes in several studies. However, there is no clear evidence regarding the optimal number of doses and its benefit without an allogeneic stem cell transplant. Achieving measurable residual disease (MRD)-negative status postinduction would reduce the requirement for a transplant. Novel approaches are needed to induce a higher proportion of MRD-negative complete remission in patients with high-risk ALL. Given bortezomib's activity in relapsed ALL and its synergism with rituximab in B-cell lymphomas, the addition of bortezomib to rituximab and chemotherapy may provide an incremental benefit in CD20+ precursor B-ALL. We conducted a phase 2 study to test the activity of bortezomib and rituximab in combination with a pediatric-inspired regimen during induction therapy in newly diagnosed adolescents and adults (aged >14 years) with CD20+, Philadelphia-negative precursor B-ALL; bone marrow MRD negativity at the end of induction was the primary end point. From December 2017 through August 2019, a total of 35 patients were enrolled. End-of-induction MRD-negative status was achieved in 70.9% of patients, as opposed to 51.7% in the historical cohort treated with chemotherapy alone. MRD-negative rates improved to 87.5% post-consolidation. At a median follow-up of 21 months, event-free survival and overall survival rates were 78.8% (95% confidence interval, 66-94) and 78.7% (95% confidence interval, 65.8-94), respectively. There was no significant increase in toxicity with bortezomib and rituximab compared with the historical cohort. The incidence of neuropathy was 26% (all less than grade 3). The combination of bortezomib, rituximab, and a pediatric-inspired ALL regimen was active and well tolerated in de novo CD20+ Philadelphia-negative precursor B-ALL. This trial was registered with the Clinical Trials Registry-India as CTRI/2017/04/008393(http://ctri.nic.in/Clinicaltrials).

Signature of strong localization and crossover conduction processes in doped ZnO thin films: synergetic effect of doping fraction and dense electronic excitations.

GaxZn1-xO thin films with varying Ga fraction within the solubility limit were irradiated with high-energy heavy ions to induce electronic excitations. The films show good transmittance in the visible region and a reduction of about 20% in transmittance was observed for irradiated films at higher ion fluences. The Urbach energy was estimated and showed an augmenting response upon increase in doping fraction and ion irradiation, this divulges an enhancement of localized states in the bandgap or disorder in the films. The evolution of such localized states plays a vital role in charge transport and thus the temperature dependent electrical conductivity of irradiated thin films was studied to elucidate the dominant conduction mechanisms. The detailed analysis unfolds that in the high-temperature regime (180 K

Defect-induced photoluminescence from gallium-doped zinc oxide thin films: influence of doping and energetic ion irradiation.

Herein, we present defect-induced photoluminescence behavior of Ga-doped ZnO (GZO) thin films with varying doping (Ga) concentrations and energetic ion irradiation. The Ga-doped ZnO thin films were prepared by a sol-gel spin-coating method. Micro-photoluminescence (µ-PL) was carried out to investigate the defect-related emission with the variation of doping concentration and ion irradiation. The PL spectra revealed that all films showed near-band-edge (NBE) emission along with a broad visible emission band, consisting of violet, blue, green, and yellow emission bands. The intensity of these emission bands was found to be strongly dependent on the Ga doping concentration and ion irradiation. Interestingly, a pronounced violet emission band around 2.99 eV (415 nm) was observed for the Ga-doped ZnO thin films with high Ga doping concentration, whereas an irradiated film with high ion fluence exhibited a strong green emission around 2.39 eV (519 nm); however, we concluded that the violet emission might have originated from zinc interstitial defects (Zni), and the concentration of Zni increased with the increasing doping concentration. The green emission is ascribed to the oxygen vacancies (VO), and the concentration of the VO defects increases with the increasing ion fluence. Thus, the µ-PL spectra of the irradiated films with emission dominating in the blue and green regions could be attributed to the formation of extended defects such as clusters and ionizing centers of Zni and VO. Herein, an in-depth understanding of the variation in defects related to the emission bands from these films is reported and correlated with the transport properties of these films for their possible optoelectronic applications.