Zinc(II) Complexes of SIRTi1/2 Analogues Transmetallating with Copper Ions and Inducing ROS Mediated Paraptosis.

As the SIRTi analogue series (HL1-HL6) show potent antitumor activity in vitro, we synthesized their corresponding zinc(II) complexes (ZnL1-ZnL6) and investigated their potential as anticancer agents. The Zn(II) complexes showed substantially greater cytotoxicity than HL1-HL6 alone in several cancer cell-types. Notably, distinct structure-activity relationships confirmed the significance of tert-butyl (ZnL2) pharmacophore inclusion in their activity. ZnL2 complexes were found to transmetalate with copper ions inside cells, causing the formation of redox-active copper complexes that induced reactive oxygen species (ROS) production, mitochondrial membrane depolarization, ATP decay, and cell death. This is the first study to exhibit Zn(II) complexes that mediate their activity via transmetalation with copper ions to undergo paraptosis cell death pathway. To further confirm if the SIRT1/2 inhibitory property of SIRTi analogues is conserved, a docking simulation study is performed. The binding affinity and specific interactions of the Cu(II) complex obtained after transmetalation with ZnL2 were found to be higher for SIRT2 (K i = 0.06 µM) compared to SIRT1 (K i = 0.25 µM). Thus, the concurrent regulation of several biological targets using a single drug has been shown to have synergistic therapeutic effects, which are crucial for the effective treatment of cancer.

Posterior Leaflet of Mitral Valve-Is it Really Tri-scalloped? -A Morphological and Morphometric Study in North Indian Cadaveric Hearts.

Background: Maintaining normal left ventricular geometry and function depends on the mitral valve's normal integrity. Irreparable damage to the mitral valve calls for its replacement using either a valve made up of biological tissue or metal, pyrolytic carbon, and similar materials. Materials and Methods: The material consists of 50 formalin-fixed adults, seemingly normal cadaveric hearts of either sex which were received from the Department of Anatomy of various institutes in the north region. These hearts were cut open to access the mitral valve in the left ventricle. Results: In this study, the posterior leaflet was semi-oval in shape being 3.72 cm wide at the base. Usually said to be tri-scalloped, interestingly, it was found so only in 56% of the hearts; being bi-scalloped in 20% and single-cusped in 16% of the hearts. Even four scallops and six scallops were observed in three (6%) and one (2%) hearts, respectively. Conclusions: To conclude, notable variation has been seen in the scallops of posterolateral cusps in the present study. The number of scallops varies greatly as single, double, three, four, or tetra-scalloped and most significant six or hexa-scalloped which has never been reported in the previous studies. To understand the rationale behind each unique architectural layout, such noticeable variations are crucial for scientists around the world. Cardiothoracic surgeons could find this information valuable for mitral valve surgery repair.

Concurrent Cu(II)-initiated Fenton-like reaction and glutathione depletion to escalate chemodynamic therapy.

Chemodynamic therapy is an evolving therapeutic strategy but there are certain limitations associated with its treatment. Herein, we present de novo synthesis and mechanistic evaluation of HL1-HL8 ligands and their corresponding CuII(L1)2-CuII(L8)2. The most active Cu(L2)2 (IC50 = 5.3 µM, MCF-7) complex exclusively depletes glutathione while simultaneously promoting ROS production. Cu(L2)2 also affects other macromolecules like the mitochondrial membrane and DNA while activating the unfolded protein response cascade.

Prebiotics: Ignored player in the fight against cancer.

BACKGROUND: Prebiotics is a relatively neglected area in cancer research, despite evidence suggesting that it plays a key role in suppressing tumour growth and improving immune function. RECENT FINDINGS: Including prebiotics in the diet has been shown to strengthen the immune system and can better slow down or prevent the growth of tumours. It has also been strongly indicated in various scientific studies that prebiotics can contribute to the sustenance of a healthy microbiome, which in turn plays an important role in increasing the effectiveness and reducing the side effects of cancer treatments. CONCLUSION: In the present review article we highlight the mechanisms by which prebiotics like inulin, fructooligosaccharide (FOS), ß-glucan, pectin, and xylooligosaccharide (XOS) function. Furthermore, the beneficial effect of incorporating prebiotics during cancer therapy to improvise gut health and prevent/reverse the damage caused to patients due to chemotherapy has also been elaborated.

Utilization of health insurance by patients admitted for dental surgical procedures at a tertiary care hospital in Coastal Karnataka: a retrospective study.

Background: There are various medical insurance options available in India. However, unlike many other countries, dental insurance plans are rare. The aim of this study was to assess the utilization of various government and private health insurance schemes by patients admitted for dental surgical procedures at a tertiary care hospital in coastal Karnataka, India. Methods: A study was conducted retrospectively to gather data on the socio-demographics, bill details, insurance, and benefits claimed by patients admitted to the Department of Oral and Maxillofacial Surgery at a tertiary care hospital from May 2016 to September 2022. Results: Out of 1750 patients, only 856 (48.9%) patients had availed of insurance, 395 patients (22.6%) utilized government health insurance policies, and 461 patients (26.3%) availed of private health insurance plans. Among Government schemes, primarily Ayushman Bharat-Arogya Karnataka was used by 262 (30.6%) patients, followed by Employees' State Insurance Scheme by 110 (12.9%) patients. Among private schemes, 212 (24.8%) patients used the policies purchased by them, 19 (2.2%) patients' medical expenses were paid by their employers, 105 (12.3%) patients utilized Manipal Arogya Suraksha and 124 (14.5%) patients used Medicare provided by the hospital. Bivariate linear regression confirmed that the total bill amount, out-of-pocket expenditure by the patient, and insurance amount reimbursed to the hospital were significantly associated with the type of insurance (government vs. private). The study noticed a gradual rise in insured patients every year. Conclusion: Greater utilization of health insurance should be encouraged because the cost of dental treatment has always hindered the use of oral health services worldwide. This study highlights that the benefit available to the patients were mainly through general health insurance schemes, not specifically dental health insurance. Insurance schemes covering dental must be promoted more aggressively in the media, highlighting their available benefits, merits, and demerits.

Fabrication and analysis of chitosan oligosaccharide based mucoadhesive patch for oromucosal drug delivery.

OBJECTIVE: Fabrication and analyses of mucoadhesive patches made from chitosan oligosaccharide for the purpose of oromucosal drug delivery. SIGNIFICANCE: The mucosal epithelium in the oral cavity, consisting of buccal and sublingual epithelium, has gained significant attention in the last decade as an alternative anatomical site for systemic drug delivery that could potentially minimize the challenges of solid oral dosage and parenteral delivery. In this study, we have fabricated and tested drug-loaded chitosan oligosaccharide-based patches for the oromucosal drug delivery. METHODS: The chitosan oligosaccharide (with and without alginate) based patches were fabricated using the conventional solvent casting method and were analyzed for their swelling capacity, hydrophilicity, anti-cancer activity, in vitro drug release, and in vivo drug release activity. The in-house developed artificial saliva was used for the swelling study. RESULTS: Alginate-containing patches showed lesser swelling ability compared to the bare chitosan oligosaccharide-based patches. The former was also found to be more hydrophobic compared to the latter one. Both the unloaded patches restricted the growth of epithelial cancer cells indicating their anti-cancer behavior. In vitro drug release indicated a super case II release pattern while in vivo study demonstrated the release of drug from the patch into the plasma indicating the purpose of the fabricated patch. CONCLUSIONS: The chitosan oligosaccharide-based mucoadhesive hydrogel patch fabricated in this study can be highly suitable for possible translational purposes.

Temporal variability of atmospheric particulate-bound polycyclic aromatic hydrocarbons (PAHs) over central east India: sources and carcinogenic risk assessment.

Atmospheric polycyclic aromatic hydrocarbons (PAHs) are of significant interest owing to their high potential health effects, including mutagenicity and carcinogenicity. We report 16 PAHs measured in ambient PM2.5 from June 2018 to May 2019 over three different sites located in central east India. The annual average PM2.5 mass concentrations of 97.3 ± 18.1 µg m-3, 101.9 ± 19.4 µg m-3, and 93.9 ± 20.3 µg m-3 were measured at RCI (Ranchi), GHY (Gamharia), and BKR (Bokaro), respectively. The mass concentrations at all sampling sites are relatively higher than the annual average concentration of the National Ambient Air Quality Standard. Total annual PAH concentrations (ng m-3) are found to be comparable at BKR (797.9 ± 39.1 ng m-3) and RCI (887.7 ± 38.8 ng m-3); however, a relatively higher average is observed over GHY (1015.1 ± 42.7 ng m-3). Using PAH diagnostic ratios and principal component analysis (PCA), their major sources were attributed to coal and wood combustion as well as vehicular emission of diesel and gasoline at all sampling sites. Significant seasonal variability is observed for PAH composition and mainly attributed to change in emission sources. Summer and winter compositions were found to be impacted by the transport from Indo-Gangetic Plains (IGP). However, ambient level PAHs during the post-monsoon season were impacted by mixed sources from Indo-Gangetic Plain and eastern India. These observations are supported by the analysis of back-trajectory and fire count data. The excess life time cancer risk (ELCR) values estimated for the study sites are within acceptable limits suggesting acceptable risk levels at BKR, GHY, and RCI. This study highlights the significance of ambient aerosol concentration for health risks in the pre-COVID-19 scenario.

Implementing a Functional Precision Medicine Tumor Board for Acute Myeloid Leukemia.

We generated ex vivo drug-response and multiomics profiling data for a prospective series of 252 samples from 186 patients with acute myeloid leukemia (AML). A functional precision medicine tumor board (FPMTB) integrated clinical, molecular, and functional data for application in clinical treatment decisions. Actionable drugs were found for 97% of patients with AML, and the recommendations were clinically implemented in 37 relapsed or refractory patients. We report a 59% objective response rate for the individually tailored therapies, including 13 complete responses, as well as bridging five patients with AML to allogeneic hematopoietic stem cell transplantation. Data integration across all cases enabled the identification of drug response biomarkers, such as the association of IL15 overexpression with resistance to FLT3 inhibitors. Integration of molecular profiling and large-scale drug response data across many patients will enable continuous improvement of the FPMTB recommendations, providing a paradigm for individualized implementation of functional precision cancer medicine. SIGNIFICANCE: Oncogenomics data can guide clinical treatment decisions, but often such data are neither actionable nor predictive. Functional ex vivo drug testing contributes significant additional, clinically actionable therapeutic insights for individual patients with AML. Such data can be generated in four days, enabling rapid translation through FPMTB.See related commentary by Letai, p. 290.This article is highlighted in the In This Issue feature, p. 275.

Intratympanic Dexamethasone in Sudden Sensorineural Hearing Loss.

Sudden sensorineural hearing loss can be a frightening experience for the sufferer and needs immediate treatment. Systemic steroid therapy has been the mainstay of treatment of this condition but concerns about their side effects has led to their use by intratympanic injection. We studied the results of intratympanic dexamethasone (IT-Dexa) both as a primary therapy and as salvage treatment after failure of oral steroids. A total of 39 patients of SSNHL were studied prospectively. Of these 23 were given oral steroids. Ten of these showed no response and were treated with IT-Dexa 4 mg/ml twice a week for two weeks. In addition, 16 patients who reported later than two weeks or had concomitant medical disorders like diabetes and/or hypertension were treated with IT-Dexa. While oral steroids showed hearing improvement (≥ 10 dB) in 56.5% patients, the recovery rate was 62.5% and 80% in those treated primarily with IT-Dexa and as salvage therapy respectively. There was a negative correlation of delay in institution of treatment with hearing recovery. Conclusion: intratympanic dexamethasone is a safe and effective treatment and should be offered to patients as a primary treatment modality and also as salvage therapy after failure of oral steroids. For best results the treatment should be started at the earliest.

FLT3-ITD allelic ratio and HLF expression predict FLT3 inhibitor efficacy in adult AML.

FLT3 internal tandem duplication (FLT3-ITD) is a frequent mutation in acute myeloid leukemia (AML) and remains a strong prognostic factor due to high rate of disease recurrence. Several FLT3-targeted agents have been developed, but determinants of variable responses to these agents remain understudied. Here, we investigated the role FLT3-ITD allelic ratio (ITD-AR), ITD length, and associated gene expression signatures on FLT3 inhibitor response in adult AML. We performed fragment analysis, ex vivo drug testing, and next generation sequencing (RNA, exome) to 119 samples from 87 AML patients and 13 healthy bone marrow controls. We found that ex vivo response to FLT3 inhibitors is significantly associated with ITD-AR, but not with ITD length. Interestingly, we found that the HLF gene is overexpressed in FLT3-ITD+ AML and associated with ITD-AR. The retrospective analysis of AML patients treated with FLT3 inhibitor sorafenib showed that patients with high HLF expression and ITD-AR had better clinical response to therapy compared to those with low ITD-AR and HLF expression. Thus, our findings suggest that FLT3 ITD-AR together with increased HLF expression play a role in variable FLT3 inhibitor responses observed in FLT3-ITD+ AML patients.

Graphene oxide based electrochemical immunosensor for rapid detection of groundnut bud necrosis orthotospovirus in agricultural crops.

Groundnut bud necrosis orthotospovirus (GBNV) is one of the causative plant viruses responsible for the outbreak of many viral epidemics in food crops across India and other south-Asian countries. Its management is a major challenge due to fast vector transmission, and the non-availability of appropriate agrochemical treatment. The timely detection of GBNV becomes indispensable for the effective management of viral infection and the periodic monitoring of plant health. We report the fabrication of graphene oxide (GO) based electrochemical immunosensor for the rapid and sensitive detection of GBNV. The immunoelectrode is prepared by depositing GO onto indium-tin oxide (ITO) coated glass substrates and functionalized by anti-GBNV antibodies using N-ethyl-N'-(3- dimethylaminopropyl) carbodiimide hydrochloride and N-hydroxysuccinimide (EDC-NHS) conjugation chemistry. The response measurements of the immunoelectrodes revealed a sensitivity of 221 ± 1 µA µg-1 mL-1(n = 3) and limit of detection (LOD) of 5.7 ± 0.7 ng mL-1(n = 3) for the standard concentrations of GBNV antigen. Further, the GBNV detection was carried out in infected leaf extracts of three different host plants i.e., Tomato, Cowpea, and N. benthamiana, and the results have been compared with the conventionally used direct antigen coated enzyme-linked immunosorbent assay (DAC-ELISA) technique. The comparable results obtained for the detection of GBNV in infected plants using electrochemical immunosensing and DAC-ELISA techniques advocated the immense potential of GO based immunosensor as a point-of-care sensing device that is poised to overcome the limitations of the traditional methods of virus detection in field conditions and may transform the diagnostics in agriculture.

Comparison of Structural and Short Variants Detected by Linked-Read and Whole-Exome Sequencing in Multiple Myeloma.

Linked-read sequencing was developed to aid the detection of large structural variants (SVs) from short-read sequencing efforts. We performed a systematic evaluation to determine if linked-read exome sequencing provides more comprehensive and clinically relevant information than whole-exome sequencing (WES) when applied to the same set of multiple myeloma patient samples. We report that linked-read sequencing detected a higher number of SVs (n = 18,455) than WES (n = 4065). However, linked-read predictions were dominated by inversions (92.4%), leading to poor detection of other types of SVs. In contrast, WES detected 56.3% deletions, 32.6% insertions, 6.7% translocations, 3.3% duplications and 1.2% inversions. Surprisingly, the quantitative performance assessment suggested a higher performance for WES (AUC = 0.791) compared to linked-read sequencing (AUC = 0.766) for detecting clinically validated cytogenetic alterations. We also found that linked-read sequencing detected more short variants (n = 704) compared to WES (n = 109). WES detected somatic mutations in all MM-related genes while linked-read sequencing failed to detect certain mutations. The comparison of somatic mutations detected using linked-read, WES and RNA-seq revealed that WES and RNA-seq detected more mutations than linked-read sequencing. These data indicate that WES outperforms and is more efficient than linked-read sequencing for detecting clinically relevant SVs and MM-specific short variants.

Immunogenomic Landscape of Hematological Malignancies.

Understanding factors that shape the immune landscape across hematological malignancies is essential for immunotherapy development. We integrated over 8,000 transcriptomes and 2,000 samples with multilevel genomics of hematological cancers to investigate how immunological features are linked to cancer subtypes, genetic and epigenetic alterations, and patient survival, and validated key findings experimentally. Infiltration of cytotoxic lymphocytes was associated with TP53 and myelodysplasia-related changes in acute myeloid leukemia, and activated B cell-like phenotype and interferon-γ response in lymphoma. CIITA methylation regulating antigen presentation, cancer type-specific immune checkpoints, such as VISTA in myeloid malignancies, and variation in cancer antigen expression further contributed to immune heterogeneity and predicted survival. Our study provides a resource linking immunology with cancer subtypes and genomics in hematological malignancies.

Mutation accumulation in cancer genes relates to nonoptimal outcome in chronic myeloid leukemia.

Chronic myeloid leukemia (CML) is a myeloproliferative neoplasm accounting for ∼15% of all leukemia. Progress of the disease from an indolent chronic phase to the more aggressive accelerated phase or blast phase (BP) occurs in a minority of cases and is associated with an accumulation of somatic mutations. We performed genetic profiling of 85 samples and transcriptome profiling of 12 samples from 59 CML patients. We identified recurrent somatic mutations in ABL1 (37%), ASXL1 (26%), RUNX1 (16%), and BCOR (16%) in the BP and observed that mutation signatures in the BP resembled those of acute myeloid leukemia (AML). We found that mutation load differed between the indolent and aggressive phases and that nonoptimal responders had more nonsilent mutations than did optimal responders at the time of diagnosis, as well as in follow-up. Using RNA sequencing, we identified other than BCR-ABL1 cancer-associated hybrid genes in 6 of the 7 BP samples. Uncovered expression alterations were in turn associated with mechanisms and pathways that could be targeted in CML management and by which somatic alterations may emerge in CML. Last, we showed the value of genetic data in CML management in a personalized medicine setting.

Allelic Imbalance of Recurrently Mutated Genes in Acute Myeloid Leukaemia.

The patho-mechanism of somatic driver mutations in cancer usually involves transcription, but the proportion of mutations and wild-type alleles transcribed from DNA to RNA is largely unknown. We systematically compared the variant allele frequencies of recurrently mutated genes in DNA and RNA sequencing data of 246 acute myeloid leukaemia (AML) patients. We observed that 95% of all detected variants were transcribed while the rest were not detectable in RNA sequencing with a minimum read-depth cut-off (10x). Our analysis focusing on 11 genes harbouring recurring mutations demonstrated allelic imbalance (AI) in most patients. GATA2, RUNX1, TET2, SRSF2, IDH2, PTPN11, WT1, NPM1 and CEBPA showed significant AIs. While the effect size was small in general, GATA2 exhibited the largest allelic imbalance. By pooling heterogeneous data from three independent AML cohorts with paired DNA and RNA sequencing (N = 253), we could validate the preferential transcription of GATA2-mutated alleles. Differential expression analysis of the genes with significant AI showed no significant differential gene and isoform expression for the mutated genes, between mutated and wild-type patients. In conclusion, our analyses identified AI in nine out of eleven recurrently mutated genes. AI might be a common phenomenon in AML which potentially contributes to leukaemogenesis.