Modern-Day Therapeutics and Ongoing Clinical Trials against Type 2 Diabetes Mellitus: A Narrative Review.

OBJECTIVES: Diabetes Mellitus (DM) is a global health concern that affects millions of people globally. The present review aims to narrate the clinical guidelines and therapeutic interventions for Type 2 Diabetes Mellitus (T2DM) patients. Furthermore, the present work summarizes the ongoing phase 1/2/3 and clinical trials against T2DM. METHODS: A meticulous and comprehensive literature review was performed using various databases, such as PubMed, MEDLINE, Clinical trials database (https://clinicaltrials.gov/), and Google Scholar, to include various clinical trials and therapeutic interventions against T2DM. RESULTS: Based on our findings, we concluded that most T2DM-associated clinical trials are interventional. Anti-diabetic therapeutics, including insulin, metformin, Dipeptidyl Peptidase-4 (DPP-4) inhibitors, Glucagon-Like Peptide-1 Receptor Agonists (GLP-1RAs), and Sodium- Glucose cotransporter-2 (SGLT-2) inhibitors are frontline therapeutics being clinically investigated. Currently, the therapeutics in phase IV clinical trials are mostly SGLT-2 inhibitors, implicating their critical contribution to the clinical management of T2DM. CONCLUSION: Despite the success of T2DM treatments, a surge in innovative treatment options to reduce diabetic consequences and improve glycemic control is currently ongoing. More emphasis needs to be on exploring novel targeted drug candidates that can offer more sustained glycemic control.

Retrieval of high-resolution aerosol optical depth (AOD) using Landsat 8 imageries over different LULC classes over a city along Indo-Gangetic Plain, India.

Aerosol optical depth (AOD) serves as a crucial indicator for assessing regional air quality. To address regional and urban pollution issues, there is a requirement for high-resolution AOD products, as the existing data is of very coarse resolution. To address this issue, we retrieved high-resolution AOD over Kanpur (26.4499°N, 80.3319°E), located in the Indo-Gangetic Plain (IGP) region using Landsat 8 imageries and implemented the algorithm SEMARA, which combines SARA (Simplified Aerosol Retrieval Algorithm) and SREM (Simplified and Robust Surface Reflectance Estimation). Our approach leveraged the green band of the Landsat 8, resulting in an impressive spatial resolution of 30 m of AOD and rigorously validated with available AERONET observations. The retrieved AOD is in good agreement with high correlation coefficients (r) of 0.997, a low root mean squared error of 0.035, and root mean bias of - 4.91%. We evaluated the retrieved AOD with downscaled MODIS (MCD19A2) AOD products across various land classes for cropped and harvested period of agriculture cycle over the study region. It is noticed that over the built-up region of Kanpur, the SEMARA algorithm exhibits a stronger correlation with the MODIS AOD product compared to vegetation, barren areas and water bodies. The SEMARA approach proved to be more effective for AOD retrieval over the barren and built-up land categories for harvested period compared with the cropping period. This study offers a first comparative examination of SEMARA-retrieved high-resolution AOD and MODIS AOD product over a station of IGP.

Emerging trends in gastrointestinal cancers: Targeting developmental pathways in carcinogenesis and tumor progression.

Gastrointestinal carcinomas are a group of cancers associated with the digestive system and its accessory organs. The most prevalent cancers related to the gastrointestinal tract are colorectal, gall bladder, gastric, hepatocellular, and esophageal cancers, respectively. Molecular aberrations in different signaling pathways, such as signal transduction systems or developmental pathways are the chief triggering mechanisms in different cancers Though a massive advancement in diagnostic and therapeutic interventions results in improved survival of patients with gastrointestinal cancer; the lower malignancy stages of these carcinomas are comparatively asymptomatic. Various gastrointestinal-related cancers are detected at advanced stages, leading to deplorable prognoses and increased rates of recurrence. Recent molecular studies have elucidated the imperative roles of several signaling pathways, namely Wnt, Hedgehog, and Notch signaling pathways, play in the progression, therapeutic responsiveness, and metastasis of gastrointestinal-related cancers. This book chapter gives an interesting update on recent findings on the involvement of developmental signaling pathways their mechanistic insight in gastrointestinalcancer. Subsequently, evidences supporting the exploration of gastrointestinal cancer related molecular mechanisms have also been discussed for developing novel therapeutic strategies against these debilitating carcinomas.

Bipolar fracture of clavicle mimicking fracture dislocation of sternoclavicular joint: A case report.

INTRODUCTION AND IMPORTANCE: Bipolar fractures involving segmental fractures of the lateral and proximal clavicles are exceptionally rare, with only isolated cases documented in the literature. Such fractures may easily be overlooked during the initial presentation. CASE PRESENTATION: We present the case of a 35-year-old male with deformation in the middle segment of the clavicle following a road traffic accident (RTA). On radiography, the injury was initially thought to be a lateral clavicle fracture combined with sternoclavicular joint dislocation but was later changed to a bipolar clavicle fracture intraoperatively. The patient had an uneventful postoperative course with excellent functional outcomes 14 months after surgery. CLINICAL DISCUSSION: A bipolar clavicle fracture is the result of direct trauma to the shoulder region commonly following RTA. Bipolar injuries can be diagnosed based on clinical findings and radiographic evaluation using plain X-rays and aided by computed tomography (CT) scans in doubtful scenarios. With a paucity of guidelines regarding the management of bipolar clavicle fractures most reported cases have been managed operatively with open reduction and internal fixation using locking plates and screws. CONCLUSIONS: Due to its rarity, bipolar clavicle fractures can be easily missed, necessitating a high index of suspicion and detailed evaluation of suspected cases. Appropriate initial and definitive management through operative fixation can lead to optimal outcomes.

Angiokeratoma of tongue in the pediatric age group: a rare presentation.

BACKGROUND: Angiokeratoma is a rare cutaneous presentation with unknown etiology. CASE PRESENTATION: A case of a 10-year male, who was presented to the ENT OPD with a swelling over the posterior aspect of the tongue. The chief complaints included growth on the right side of the posterior third of the tongue which was extending up to the base of the tongue on the same side. CONCLUSION: Excisional biopsy was taken and sent for histopathology which was suggestive of inflamed angiokeratoma. Post-excision there is no recurrence till date.

Targeting NF-κB signaling cascades of glioblastoma by a natural benzophenone, garcinol, via in vitro and molecular docking approaches.

Glioblastoma multiforme (GBM) is regarded as the most aggressive form of brain tumor delineated by high cellular heterogeneity; it is resistant to conventional therapeutic regimens. In this study, the anti-cancer potential of garcinol, a naturally derived benzophenone, was assessed against GBM. During the analysis, we observed a reduction in the viability of rat glioblastoma C6 cells at a concentration of 30 µM of the extract (p < 0.001). Exposure to garcinol also induced nuclear fragmentation and condensation, as evidenced by DAPI-stained photomicrographs of C6 cells. The dissipation of mitochondrial membrane potential in a dose-dependent fashion was linked to the activation of caspases. Furthermore, it was observed that garcinol mediated the inhibition of NF-κB (p < 0.001) and decreased the expression of genes associated with cell survival (Bcl-XL, Bcl-2, and survivin) and proliferation (cyclin D1). Moreover, garcinol showed interaction with NF-κB through some important amino acid residues, such as Pro275, Trp258, Glu225, and Gly259 during molecular docking analysis. Comparative analysis with positive control (temozolomide) was also performed. We found that garcinol induced apoptotic cell death via inhibiting NF-κB activity in C6 cells, thus implicating it as a plausible therapeutic agent for GBM.

A Systematic Narrative Review on ADIPOQ Gene Variants and its Association with T2DM in the Indian Population.

BACKGROUND: The prevalence of diabetes is rapidly increasing in India, even among young adult individuals. Rare adiponectin gene (ADIPOQ) variants may be predominantly present in Indians and decrease the circulatory levels of APN (Adiponectin). Studies reported that ADIPOQ gene variants were associated with type 2 diabetes mellitus (T2DM) and its complications in the Indian population. OBJECTIVES: To review the association of specific ADIPOQ gene variants with T2DM and its associated complications. MATERIALS & METHODS: A search of Pubmed, Chinhal, Medline, Scopus, Web of Science databases, and Google Scholar search engine was performed to retrieve articles by using the following keywords; "ADIPOQ and T2DM", "ADIPOQ and India," "ADIPOQ gene variants and T2DM", "ADIPOQ gene variants and T2DM and India", "SNPs of ADIPOQ gene and T2DM", "SNPs of ADIPOQ gene and India," SNPs of ADIPOQ gene and T2DM and India". Eligibility criteria for the inclusion of articles: Original, Case-Control Study, and Full-Text articles were published in the English language till the end of April 2023. RESULTS: A total of 540 articles were retrieved. Out of this, only 18 articles were found suitable to include in this systematic narrative review. The most studied ADIPOQ gene variants were found to be +10211T/G (rs17846866), +45T/G (rs2241766), and +276G/T (rs1501299) in different Indian populations. CONCLUSION: It was reviewed that ADIPOQ gene variants +10211T/G (rs17846866), +45T/G (rs2241766), and +276G/T (rs1501299) were predominantly present in the Indian population, and decreasing the circulatory levels of APN and significantly associated with T2DM and its complications.

Biosubstitutes for dural closure: Unveiling research, application, and future prospects of dura mater alternatives.

The dura mater, as the crucial outermost protective layer of the meninges, plays a vital role in safeguarding the underlying brain tissue. Neurosurgeons face significant challenges in dealing with trauma or large defects in the dura mater, as they must address the potential complications, such as wound infections, pseudomeningocele formation, cerebrospinal fluid leakage, and cerebral herniation. Therefore, the development of dural substitutes for repairing or reconstructing the damaged dura mater holds clinical significance. In this review we highlight the progress in the development of dural substitutes, encompassing autologous, allogeneic, and xenogeneic replacements, as well as the polymeric-based dural substitutes fabricated through various scaffolding techniques. In particular, we explore the development of composite materials that exhibit improved physical and biological properties for advanced dural substitutes. Furthermore, we address the challenges and prospects associated with developing clinically relevant alternatives to the dura mater.

Protective Assessment of Novel (Bncs Formulation) against Brain Tumor.

BACKGROUND: Oxidative stress refers to non-homeostatic elevation within intracellular reactive oxygen species (ROS) levels and is associated with several neuro-related pathological conditions. Diclofenac is a commonly prescribed non-steroidal anti-inflammatory drug (NSAID) for treating aches and pain by reducing inflammation. Diclofenac is also associated with the induction of apoptotic cell death by altering the homeostatic balance within mitochondria. In the present report, the neuroprotective effects of BNC formulation constituted by Bacopa monnieri leaves, Nigella sativa and Curcuma longa rhizome seeds were investigated. METHODS: The synthesized formulation was characterized using FT-IR and LC-MS along with organoleptic evaluation. Thereafter neuroprotective efficacy of BNC formulation was subsequently investigated against Diclofenac-induced oxidative stress in SH-SY5Y cells. The cells were pretreated with synthesized formulation and subsequently evaluated for amelioration in Diclofenac-induced cytotoxicity, and ROS augmentation. The neuroprotective effect of synthesized formulation was further explored by evaluating the changes in nuclear morphology, and apoptosis alleviation with concomitant regulatory effects on caspase-3 and -9 activation. RESULTS: Diclofenac was found to be considerably cytotoxic against human neuroblastoma SHSY5Y cells. Intriguingly, Diclofenac-mediated toxicity was reduced significantly in SH-SY5Y cells pretreated with BNC formulation. Augmented ROS levels within Diclofenac-treated SHSY5Y cells were also reduced in the BNC formulation pretreated SH-SY5Y cells. Furthermore, BNC formulation pretreated SH-SY5Y cells also exhibited reduced dissipation of mitochondrial membrane potential, caspase-3 and -9, along with apoptosis after Diclofenac treatment. CONCLUSION: These findings indicated that, indeed, Diclofenac induces considerable ROSmediated apoptosis in SH-SY5Y cells, which further intriguingly ameliorated Diclofenacmediated cytotoxic effects on SH-SY5Y cells. This manuscript further collected information about available National and International patents published or granted in preparation of and thereof applications against motor and non-motor brain dysfunctions.

Excess Mortality Risk Due to Heat Stress in Different Climatic Zones of India.

India is at a high risk of heat stress-induced health impacts and economic losses owing to its tropical climate, high population density, and inadequate adaptive planning. The health impacts of heat stress across climate zones in India have not been adequately explored. Here, we examine and report the vulnerability to heat stress in India using 42 years (1979-2020) of meteorological data from ERA-5 and developed climate-zone-specific percentile-based human comfort class thresholds. We found that the heat stress is usually 1-4 °C higher on heatwave (HW) days than on nonheatwave (NHW) days. However, the stress on NHW days remains considerable and cannot be neglected. We then showed the association of a newly formulated India heat index (IHI) with daily all-cause mortality in three cities - Delhi (semiarid), Varanasi (humid subtropical), and Chennai (tropical wet and dry), using a semiparametric quasi-Poisson regression model, adjusted for nonlinear confounding effects of time and PM2.5. The all-cause mortality risk was enhanced by 8.1% (95% confidence interval, CI: 6.0-10.3), 5.9% (4.6-7.2), and 8.0% (1.7-14.2) during "sweltering" days in Varanasi, Delhi, and Chennai, respectively, relative to "comfortable" days. Across four age groups, the impact was more severe in Varanasi (ranging from a 3.2 to 7.5% increase in mortality risk for a unit rise in IHI) than in Delhi (2.6-4.2% higher risk) and Chennai (0.9-5.7% higher risk). We observed a 3-6 days lag effect of heat stress on mortality in these cities. Our results reveal heterogeneity in heat stress impact across diverse climate zones in India and call for developing an early warning system keeping in mind these regional variations.

Methotrexate-conjugated zinc oxide nanoparticles exert a substantially improved cytotoxic effect on lung cancer cells by inducing apoptosis.

In the current study, we report the synthesis of methotrexate-conjugated zinc oxide nanoparticles (MTX-ZnONPs) and their high efficacy against lung cancer cells. Conjugation of MTX with ZnONPs was authenticated by UV-vis spectroscopy, dynamic light scattering (DLS), Fourier-transform infrared (FTIR) spectroscopy, and transmission electron microscopy (TEM). This drug-nanoconjugate also showed high drug-loading efficiency. The therapeutic efficacy of MTX-ZnONPs was further tested in vitro against A549 cells, and the results of MTT and LDH release assays showed that MTX-ZnONPs, in addition to free MTX, were efficient in exerting cytotoxic effect on A549 cells; however, the effectiveness of MTX-ZnONPs was found to be considerably enhanced at very low doses compared to that of free MTX. Moreover, ZnONPs alone significantly inhibited the cell viability of A549 cells at a much higher concentration compared to MTX-ZnONPs and MTX. Furthermore, the cytomorphology of A549 cells was characterized by cellular shrinkage and detachment from the surface in all the treatment groups. Similarly, A549 cells, in all the treatment groups, showed fragmented and condensed nuclei, indicating the initiation of apoptosis. Mitochondrial membrane potential (ψm) in A549 cells showed a gradual loss in all the treatment groups. Results of the qualitative and quantitative analyses depicted increased reactive oxygen species (ROS) levels in A549 cells. The results of the caspase activity assay showed that MTX-ZnONPs andfree MTX caused significant activation of caspase-9, -8, and -3 in A549 cells; however, the effect of MTX-ZnONPs was more profound at very low doses compared to that of free MTX. Thus, our results showed high efficacy of MTX-ZnONPs, suggesting efficient intracellular delivery of the drug by ZnONPs as nanocarriers.

Advancing Treatment Frontiers: Radiofrequency Ablation for Small Renal Mass-Intermediate-Term Results.

Our study aims to discern the immediate and intermediate-term oncological outcomes of the patients with small renal mass and who were surgically unfit or were having a bilateral tumor and underwent radiofrequency ablation (RFA) of the mass. We retrospectively and prospectively analyzed the status of the patients who were diagnosed to have small renal masses and were biopsy-proven renal cell carcinoma (RCC) cases, who underwent RFA at our institute from the year 2013 to 2022. Patients were followed-up for 3 years. Data regarding complications were analyzed for all patients who underwent renal RFA along with the 3-year recurrence-free survival (RFS) rate. A total of 28 patients were eligible for the study based on our inclusion and exclusion criteria. Their renal function was recorded. They underwent RFA and were followed-up for a period of 3 years for RFS. Four patients out of the total had immediate complications, out of which two developed a hematoma. Three-year-follow-ups showed six recurrences, overall having 78.6% RFS. Post-procedural renal function was stable as documented by Estimated glomerular filtration rate. Oncological results of RFA in patients with small renal masses who are surgically unfit are associated with a low risk of immediate and intermediate-term deterioration of renal function.

Impact of fermented organic formulations combined with inorganic fertilizers on broccoli (Brassica oleracea L. var. italica Plenck) cv. Palam Samridhi.

A two-year field experiment (2018-19 and 2019-20) was laid out in a randomized complete block design (RCBD) with a spacing of 60 × 45 cm involving three replications with ten treatments having cow manurial amendments along with integrated nutrient management in a plot size of 3.0 m × 1.8 m. The effect of the integration of cow manurial amendments and mineral fertilizers on soil fertility, nutrient uptake, yield, and economics of broccoli was studied. The experiment was laid out during the rabi season in the mid-hills of Himachal Pradesh. T8 [90% RDN (112.5 N: 67.5 P: 46.8 K kg/ha) + 5% jeevamrit (1.5 l/m2) + 5% jeevamrit foliar spray] obtained the greatest organic carbon (20.93 g kg-1), available N (375.13 kg ha-1), P (48.46 kg ha-1), K (260.53 kg ha-1) in the soil as well as more uptake of N (60.58 kg ha-1), P (7.25 kg ha-1) and K (37.88 g ha-1) by the plants. Further, this treatment obtained the greatest value for yield (186.77 q ha-1 and 12.44 kg plot-1), net income (₹ 245840) and cost-benefit ratio (1.93). Outcomes of this investigation suggested that combined usage of cow manure, jeevamrit, beejamrit, and ghanjeevamrit with inorganic fertilizers proved to be useful for enhancing soil health, increasing nutrient uptake, and ensuring sustainable production of broccoli.

Potentials of genotypes, morpho-physio-biochemical traits, and growing media on shelf life and future prospects of gene editing in tomatoes.

Background: To study the genetic basis of the impact of genotypes and morpho-physio-biochemical traits under different organic and inorganic fertilizer doses on the shelf life attribute of tomatoes, field experiments were conducted in randomized block designs during the rabi seasons of 2018-2019 and 2019-2020. The experiment comprised three diverse nutrient environments [T1-organic; T2-inorganic; T3-control (without any fertilizers)] and five tomato genotypes with variable growth habits, specifically Angoorlata (Indeterminate), Avinash-3 (semi-determinate), Swaraksha (semi-determinate), Pusa Sheetal (semi-determinate), and Pusa Rohini (determinate). Results: The different tomato genotypes behaved apparently differently from each other in terms of shelf life. All the genotypes had maximum shelf life when grown in organic environments. However, the Pusa Sheetal had a maximum shelf life of 8.35 days when grown in an organic environment and showed an increase of 12% over the control. The genotype Pusa Sheetal, organic environment and biochemical trait Anthocyanin provides a promise as potential contributor to improve the keeping quality of tomatoes. Conclusion: The genotype Pusa Sheetal a novel source for shelf life, organic environment, and anthocyanin have shown promises for extended shelf life in tomatoes. Thus, the identified trait and genotype can be utilized in tomato improvement programs. Furthermore, this identified trait can also be targeted for its quantitative enhancement in order to increase tomato shelf life through a genome editing approach. A generalized genome editing mechanism is consequently suggested.

Comparison between peripheral nerve stimulator-guided serratus anterior plane block versus transversus abdominis plane block for postoperative analgesia in laparoscopic cholecystectomy under general anaesthesia: A double-blind randomised controlled trial.

Background and Aims: Laparoscopic cholecystectomy (LC) is a widely accepted surgical procedure associated with postoperative pain. This study was done to compare peripheral nerve stimulator (PNS)-guided serratus anterior plane block (SAP) and transversus abdominis plane (TAP) block for postoperative analgesia for patients undergoing LC. Methods: Following approval from the ethical committee, 70 patients for LC were randomly assigned to Group S: SAP block and Group T: TAP block. The blocks were performed under PNS guidance, and 20 ml of 0.375% ropivacaine was administered. The severity of pain was measured using a visual analogue scale (VAS). The study's primary objective was the evaluation of the postoperative VAS score. The time of the first dose of rescue analgesia and total tramadol consumption for 24 h postoperatively were secondary objectives. All the statistical calculation was done using statistical analyses for Social Sciences for Windows version 23.0 (IBM Corp, NY, USA). Results: Lower VAS score was seen in patients of TAP block at rest as well as movement at 6 h (P = 0.001), 12 h (P = 0.001) and 18 h (P = 0.001) postoperatively compared with SAP. The TAP group showed a significantly increased time of first rescue analgesic compared to the SAP group (7.97 ± 0.51 vs. 5.89 ± 1.45, P = 0.001). Tramadol usage was significantly higher in the SAP group than in the TAP group (128.9 ± 36.22 vs. 72.43 ± 44.80, P = 0.001). Conclusion: TAP block guided by the PNS improves postoperative pain with less tramadol consumption and during the postoperative period without significant complications.

Assessment of thermal and temporal stability of SARS-CoV-2 samples using real-time qRT-PCR.

BACKGROUND: As per the guidelines of the Indian Council of Medical Research, nasopharyngeal and oropharyngeal swabs in viral transport medium (VTM) are to be stored at 4 °C for less than 5 days and for more than 5 days at -70 °C. Samples are not transported or stored as per prescribed conditions because of the limitations, resulting in an apprehensive diagnosis. The aim of the study was to test the stability of the SARS-CoV-2 sample stored in VTM at different temperatures. METHODS: In this study, the stability of 21 positive and 9 negative samples for SARS-CoV-2 was evaluated in commercial VTM at different temperatures (-80 °C, -20 °C, 4 °C, and 25 to 30 °C). Stability was checked for up to 50 days in the above storage conditions at different intervals. PathoDetect™ and Hi-PCR® kits were used for the detection of the four genes of SARS-CoV-2. The Cycle Threshold (Ct) value for determining the positivity of samples for PathoDetect™ was < 40 and for Hi-PCR® was < 38. RESULTS: The SARS-CoV-2 confirmatory genes (RdRp and E genes) and the internal housekeeping gene remained detectable even on the 50th day of the study. The Ct of the RdRp and E genes were found to increase with storage duration, but all positive samples remained positive till the end of the study, or the Ct value remained below the cut-off level. The negative samples gave consistent results until the end of the study. When the differences in Ct values were compared between the days in a set of experiments, they were not significantly different except in a few samples. CONCLUSION: The SARS-CoV-2 genetic materials in commercial VTM were stable at room temperature to -80 °C for 50 days.

A liposomal radionanoformulation for targeted drug delivery and real time monitoring by radionuclide imaging for HER2 overexpressing cancers.

Liposomal formulations carrying chemotherapeutic drugs have demonstrated great potential as effective drug delivery systems. Smart nanoformulations decorated with targeting agents and probes are desired for site specific delivery of drugs and real time monitoring. In this study, we aimed to develop liposomal formulation loaded with doxorubicin and tagged with trastuzumab antibody (Ab) for targeting human epidermal growth factor receptor 2 (HER2) positive tumors. Liposomes were prepared by ethanol injection method using modified lipids to conjugate trastuzumab and radiolabel with Tc-99m radioisotope using DTPA for imaging by single photon emission computed tomography (SPECT). Doxorubicin was loaded using the active pH gradient method. The conjugation of Ab to liposomes was validated by SDS-PAGE and MALDI-MS. 99m Tc labeled liposomes encapsulating doxorubicin conjugated with antibody (99m Tc-Lip-Ab-Dox) and 99m Tc labeled liposomes encapsulating doxorubicin (99m Tc-Lip-Dox) were found to be stable in blood plasma and saline using chromatography method. The specificity of 99m Tc-Lip-Ab-Dox against HER2 receptor was evident from cell uptake and inhibition studies. Results also corroborated with confocal microscopy studies. In vivo studies in tumor bearing severe combined immunodeficient mice by SPECT imaging and biodistribution studies revealed higher uptake of 99m Tc-Lip-Ab-Dox in tumor and less accumulation in the liver compared to 99m Tc-Lip-Dox. In conclusion, liposomal nanoformulation for immunotargeting and monitoring of drug delivery was successfully formulated and evaluated. Encouraging results in preclinical studies were obtained with the radioformulation. Such smart radioformulations will not only serve the purpose of site-specific controlled release of drugs at the target site but also aid in optimizing the drug doses and schedule of cancer treatment by monitoring pharmacokinetics.