Case Studies of Two Classical Imprinting Growth Disorders: Silver-Russell and Beckwith-Wiedemann Syndromes.

The genetic influences on human growth are being increasingly deciphered. Silver-Russell and Beckwith-Wiedemann syndromes (SRS; BWS) are two relatively common genetic syndromes with under- and overgrowth-related issues being the reason for referral. Aberration in genomic imprinting is the underlying genetic pathomechanism behind these syndromes. Herein, we described a series of children with these two growth disorders and give an orientation to the reader of the concept of imprinting as well as the genetic testing strategy and counseling to be offered in these syndromes.

Severity Scoring Cutoff for MLPA and Its Diagnostic Yield in 332 North Indian Children with Developmental Delay.

Chromosomal aberrations/rearrangements are the most common cause of intellectual disability (ID), developmental delay (DD), and congenital malformations. Traditionally, karyotyping has been the investigation of choice in such cases, with the advantage of being cheap and easily accessible, but with the caveat of the inability to detect copy number variations of sizes less than 5 Mb. Chromosomal microarray can solve this problem, but again the problems of expense and poor availability are major challenges in developing countries. The purpose of this study is to find the utility of multiplex ligation-dependent probe amplification (MLPA) as a middle ground, in a resource-limited setting. We also attempted to establish an optimum cutoff for the de Vries score, to enable physicians to decide between these tests on a case-to-case basis, using only clinical data. A total of 332 children with DD/ID with or without facial dysmorphism and congenital malformations were studied by MLPA probe sets P245. Assessment of clinical variables concerning birth history, facial dysmorphism, congenital malformations, and family history was done. We also scored the de Vries scoring for all the patients to find a suitable cutoff for MLPA screening. In our study, the overall detection rate of MLPA was 13.5% (45/332). The majority of patients were DiGeorge's syndrome with probe deletion in 22q11.21 in 3.3% (11/332) followed by 15q11.2 del in 3.6% (12/332, split between Angelman's and Prader-Willi's syndromes). Also, 3.0% (10/332) of patients were positive for Williams-Beuren's syndrome 7q11.23, 1.8% (6/332) for Wolf--Hirschhorn's syndrome 4p16.3, 1.2% (4/332) for 1p36 deletion, and 1% for each trichorhinophalangeal syndrome type I 8q23.3 duplication syndrome and cri du chat syndrome. The optimum cutoff of de Vries score for MLPA testing in children with ID and/or dysmorphism came out to be 2.5 (rounded off to 3) with a sensitivity of 82.2% and specificity of 66.7%. This is the largest study from India for the detection of chromosomal aberrations using MLPA common microdeletion kit P245. Our study suggests that de Vries score with a cutoff of 3 or more can be used to offer MLPA as the first tier test for patients with unexplained ID, with or without facial dysmorphism and congenital malformations.

Pattern Recognition of Common Multiple Congenital Malformation Syndromes with Underlying Chromatinopathy.

Chromatinopathy is an emerging category of multiple malformation syndromes caused by disruption in global transcriptional regulation with imbalances in the chromatin states (i.e., open or closed chromatin). These syndromes are caused by pathogenic variants in genes coding for the writers, erasers, readers, and remodelers of the epigenetic machinery. Majority of these disorders (93%) show neurological dysfunction in the form of intellectual disability. Other overlapping features are growth abnormalities, limb deformities, and immune dysfunction. In this study, we describe a series of children with six common chromatinopathy syndromes with an aim to develop pattern recognition of this emerging category of multiple malformation syndromes.

Impaired Fibroblast Growth Factor 21 (FGF21) Associated with Visceral Adiposity Leads to Insulin Resistance: The Core Defect in Diabetes Mellitus.

The Central nervous system (CNS) is the prime regulator of signaling pathways whose function includes regulation of food intake (consumption), energy expenditure, and other metabolic responses like glycolysis, gluconeogenesis, fatty acid oxidation, and thermogenesis that have been implicated in chronic inflammatory disorders. Type 2 diabetes mellitus (T2DM) and obesity are two metabolic disorders that are linked together and have become an epidemic worldwide, thus raising significant public health concerns. Fibroblast growth factor 21 (FGF21) is an endocrine hormone with pleiotropic metabolic effects that increase insulin sensitivity and energy expenditure by elevating thermogenesis in brown or beige adipocytes, thus reducing body weight and sugar intake. In contrast, during starvation conditions, FGF21 induces its expression in the liver to initiate glucose homeostasis. Insulin resistance is one of the main anomalies caused by impaired FGF21 signaling, which also causes abnormal regulation of other signaling pathways. Tumor necrosis factor alpha (TNF-α), the cytokine released by adipocytes and inflammatory cells in response to chronic inflammation, is regarded major factor that reduces the expression of FGF21 and modulates underlying insulin resistance that causes imbalanced glucose homeostasis. This review aims to shed light on the mechanisms underlying the development of insulin resistance in obese individuals as well as the fundamental flaw in type 2 diabetes, which is malfunctioning obese adipose tissue.

RiTe conjugate mediated corneal collagen crosslinking, a novel therapeutic intervention for keratoconus - in vitro and in vivo study.

Corneal collagen crosslinking (CXL) is an effective method to halt the disease progression of keratoconus, a progressive corneal dystrophy leading to cone shaped cornea. Despite the efficacy of standard protocol, the concerning step of this procedure is epithelial debridement performed to facilitate the entry of riboflavin drug. Riboflavin, a key molecule in CXL protocol, is a sparsely permeable hydrophilic drug in corneal tissues. The present study has employed cell penetrating peptide (CPP), Tat2, to enhance the penetration of riboflavin molecule, and thereby improve currently followed CXL protocol. This study demonstrates approximately two-fold enhanced uptake of CPP riboflavin conjugate, Tat2riboflavin-5'Phosphate (RiTe conjugate), both in vitro and in vivo. Two different CXL protocols (Epi ON and Epi OFF) have been introduced and implemented in rabbit corneas using RiTe conjugate in the present study. The standard and RiTe conjugate mediated CXL procedures exhibited an equivalent extent of crosslinking in both the methods. Reduced keratocyte loss and no endothelial damage in RiTe conjugate mediated CXL further ascertains the safety of the proposed CXL protocols. Therefore, RiTe conjugate mediated CXL protocols present as potential alternatives to the standard keratoconus treatment in providing equally effective, less invasive and patient compliant treatment modality.

Estrogen Receptor 1 Gene Polymorphism and its Association with Idiopathic Short Stature in North Indian Population.

Background: In the hypothalamic-pituitary-gonadotrophin (HPG) axis, estrogen plays a key role in the bone maturation regulation and growth plates closure. This study was designed to explore the link between single nucleotide polymorphisms (SNPs) in estrogen receptor 1 (ESR1) gene with idiopathic short stature (ISS) susceptibility in the North Indian population. Methods: Four SNPs of the ESR1 gene (rs543650, rs6557177, rs2234693 and rs9340799) were genotyped by Sanger sequencing in 52 ISS patients and 68 controls. Linkage disequilibrium (LD) and haplotyping were done by SNPstat and SHESISplus softwares. Extent of LD was determined by calculating D' and r2 values in SNPs paired combinations. Results: A significant positive association was found between rs6557177 and rs543650 genotype and ISS susceptibility as compared to controls. The frequencies of the rs6557177 CC genotype (p=0.030; OR=0.13; 95% CI:0.01-1.10) and rs543650 genotype TT (p =0.043; OR=0.29; 95% CI: 0.09-0.92) were observed to be increased in ISS group as compared with the control group. However, no significant correlation was observed between clinical parameters of patients and these SNPs. rs543650 shown strong LD with rs2234693 and rs9340799, similarly rs2234693 and rs9340799. Conclusion: Our study showed that CC genotype at rs6557177 and TT genotype of rs543650 of ESR1 constitutes risk factor for developing ISS in North Indian children. In the future, these findings may lead to a better understanding of the SNPs associated with ISS susceptibility.

Chromosomal Duplication Syndromes: A Case Series.

Chromosomal deletion and duplication syndromes can lead to intellectual disability, autism, microcephaly, and poor growth. Usually manifestations of duplication syndromes are milder than that of the deletion syndromes. With the availability of tests for analysis of copy number variants, it is possible to identify the deletion and duplication syndromes with greater ease. We report 32 cases of chromosomal duplication syndromes, identified in children presenting with developmental delay, intellectual disability, or microcephaly and/or additional features, at a tertiary care center on karyotyping or microarray analysis. Seven were isolated duplications, and one child had an additional smaller pathogenic deletion. Thus, duplication syndromes can have milder presentations with spectrum of dysmorphism, behavioral problems, and intellectual disability, but it is possible to diagnose easily with latest emerging high-throughput technologies.

Identification of sources of coarse mode aerosol particles (PM10) using ATR-FTIR and SEM-EDX spectroscopy over the Himalayan Region of India.

This study attempts to examine the morphological, elemental and physical characteristics of PM10 over the Indian Himalayan Region (IHR) using FTIR and scanning electron microscopy-energy dispersive X-ray (SEM-EDX) analysis. The study aimed at source identification of PM10 by exploring the inorganic ions, organic functional groups, morphology and elemental characteristics. The pollution load of PM10 was estimated as 63 ± 22 µg m-3; 53 ± 16 µg m-3; 67 ± 26 µg m-3 and 55 ± 11 µg m-3 over Mohal-Kullu, Almora, Nainital and Darjeeling, respectively. ATR-FTIR spectrum analysis revealed the existence of inorganic ions (SiO44-, TiO2, SO42-, SO3-, NO3-, NO2-, CO32-, HCO3-, NH4+) and organic functional groups (C-C, C-H, C=C, C≡C, C=O, N-H, C≡N, C=N, O-H, cyclic rings, aromatic compounds and some heterogeneous groups) in PM10 which may arise from geogenic, biogenic and anthropogenic sources. The morphological and elemental characterization was performed by SEM-EDX, inferring for geogenic origin (Al, Na, K, Ca, Mg and Fe) due to the presence of different morphologies (irregular, spherical, cluster, sheet-like solid deposition and columnar). In contrast, particles having biogenic and anthropogenic origins (K, S and Ba) have primarily spherical with few irregular particles at all the study sites. Also, the statistical analysis ANOVA depicts that among all the detected elements, Na, Al, Si, S and K are site-specific in nature as their mean of aw% significantly varied for all the sites. The trajectory analysis revealed that the Uttarakhand, Jammu and Kashmir, the Thar Desert, Himachal Pradesh, Pakistan, Afghanistan, Nepal, Sikkim, the Indo-Gangetic Plain (IGP) and the Bay of Bengal (BoB) contribute to the increased loading of atmospheric pollutants in various locations within the IHR.

Neurofibromatosis type 1: Clinical characteristics and mutation spectrum in a North Indian cohort.

Background: Neurofibromatosis type 1 (NF1) is a unique, highly penetrant neuro-cutaneous disorder with a wide range of manifestations. Though the clinical diagnosis of NF1 is straight forward, there can be other disorders which mimic NF1, especially its cutaneous features. Here we describe the clinical and mutation spectrum of a series of individuals whose primary diagnosis was NF1 or NF1 related disorders. Methods: We have screened 29 unrelated individuals who fulfilled the clinical criteria of NF1. Whole exome sequencing (WES) was done in all individuals except one with suspected microdeletion syndrome with NF1 in whom Cytogenetic microarray (CMA) was done. Results: Out of 29 suspected patients, 25 had germline pathogenic/likely pathogenic variants involving NF1 gene. Five novel and 20 known variants in coding and non-coding regions were identified, among them 7 variants were deletions (28%), 7 nonsense (28%), 3 splice-site (12%), 4 missense (16%), 2 duplications (8%) and 2 (8%) were contiguous deletions. In those where NF1 variants were not detected, 3 had neurofibromatosis type 2 (NF2) and 1 rare autosomal recessive form of Elher Danlos syndrome. Conclusion: We hereby present the wide range of manifestations in different age groups and the mutation spectrum ranging from small scale variants to contiguous gene deletion syndromes involving NF1 gene. We highlight the usefulness of molecular testing and its importance in tumor surveillance and genetic counseling in this disorder.

Influence of forkhead box protein 3 gene polymorphisms in recurrent pregnancy loss: A meta-analysis.

BACKGROUND: Treg cells play an important role in development of tolerance in maternal immune system against the semi-allogenic embryo. Human forkhead box protein 3 (FOXP3) gene, is the major transcription factor responsible for the regulation of Treg function during pregnancy. Single nucleotide polymorphisms (SNPs) of FOXP3 gene have been reported as a risk factor for Recurrent Pregnancy Loss (RPL), however, results from previous studies are inconsistent. METHODOLOGY: We have collected data from different studies to investigate the overall association of FOXP3 SNPs with risk of RPL. PubMed, Google Scholar, Elsevier, and Cochrane databases were searched to identify eligible studies. Odds Ratio (OR) and 95 % Confidence Interval (CI), calculated via fixed effect or random effect models, were used to evaluate strength of association. This meta-analysis included 11 studies (1383 RPL cases and 1413 controls) of 6 SNPs: rs3761548 A/C, rs2232365 A/G, rs2294021 T/C, 2280883 T/C, rs5902434del/ATT and rs141704699C/T, with ≥2 studies per SNPs and at least 1 significant result. RESULTS: We observed that FOXP3 polymorphism was predominantly present in Asian women with history of RPL. rs2232365 A/G, rs3761548 A/C, rs2294021 T/C, rs2280883 T/C and rs5902434del/ATT polymorphisms were significantly associated with risk of RPL in Indian population. Further, among the most commonly seen polymorphism, rs3761548 A/C was significantly associated with risk of RPL in women from Kazakhstan, China and Gaza, Palestine; rs2232365 A/G in populations of Kazakhstan, Egypt, Iran and Gaza, Palestine. Results of this study indicates that FOXP3 polymorphism is significantly associated with risk of RPL, especially in Asians.

Biallelic novel variants in ZNF469 causing Brittle Cornea Syndrome 1: a detailed report of an Indian patient.

BACKGROUND: Variations in ZNF469 have been associated with Brittle Cornea Syndrome that presents with bluish sclera, loss of vision after trivial trauma, arachnodactyly, and joint laxity. MATERIALS AND METHODS: Detailed medical and family history, physical examination, and molecular analysis. RESULTS: A 21-year-old female presented with bluish discoloration of sclera, diminution of vision following trivial trauma in childhood along with hearing loss and systemic features of arachnodactyly and joint laxity. Clinical diagnosis of brittle cornea syndrome was made which was molecularly proven using next-generation sequencing which identified compound heterozygosity in ZNF469 for pathogenic and likely pathogenic nonsense variants. One variant namely NM_001367624.2:c.5882dup was identified in the exon 3 which was novel and classified as likely pathogenic according to American College of Medical Genetics (ACMG) criteria for variant classification. Another variant NM_001367624.2:c.8992C>T in the exon 2 was classified as pathogenic for Brittle Cornea Syndrome 1. CONCLUSIONS: The report adds to the allelic heterogeneity in ZNF469 causative of Brittle Cornea Syndrome 1 and shall acquaint the physicians about this potentially vision threatening, underdiagnosed, rare syndrome.

Individualized Homeopathic Medicines in the Management of Symptomatic Adenotonsillar Hypertrophy in Children: A Prospective Observational Study.

BACKGROUND: Globally, adenotonsillar hypertrophy (ATH) is one of the most prevalent upper respiratory tract disorders of children, with associated troublesome symptoms such as sleep apnea and cognitive disturbances. In this study, we evaluated the potential role of individualized homeopathic medicines in the management of symptomatic ATH in children. METHODS: A multicenter prospective observational study was conducted at five institutes under the Central Council for Research in Homoeopathy, India. Primary and secondary outcomes (symptom score for adenoids, other symptoms of ATH, Mallampati score, tonsillar size, Sleep-Related Breathing Disorder of the Paediatric Sleep Questionnaire [SRBD-PSQ]) were assessed through standardized questionnaires at baseline and at 3, 6, 9 and 12 months. Radiological investigations for assessing the adenoid/nasopharyngeal (A/N) ratio were carried out at baseline, 6 and 12 months. All analyses were carried out using an intention-to-treat approach. RESULTS: A total of 340 children were screened and 202 children suffering from ATH were enrolled and followed up monthly for 12 months. Each patient received individualized homeopathic treatment based on the totality of symptoms. Statistically significant reductions in adenoid symptom score, Mallampati score (including tonsillar size), SRBD-PSQ sleep quality assessment and A/N ratio were found over time up to 12 months (p < 0.001). Homeopathic medicines frequently indicated were Calcarea carbonicum, Phosphorus, Silicea, Sulphur, Calcarea phosphoricum, Pulsatilla, Lycopodium and Tuberculinum. No serious adverse events were recorded during the study period. CONCLUSION: This study suggests that homeopathic medicines may play a beneficial role in the management of symptomatic ATH in children. Well-designed comparative trials are warranted.

Utilising BC observations to estimate CO contributions from fossil fuel and biomass burning in the Central Himalayan region.

The Himalayan region is adversely affected by the increasing anthropogenic emissions from the adjacent Indo-Gangetic plain. However, source apportionment studies for the Himalayan region that are crucial for estimating CO concentration, are grossly insufficient, to say the least. It is in this context that our study reported here assumes significance. This study utilizes five years (2014-2018) of ground-based observations of eBC and multiple linear regression framework (MLR) to estimate CO and segregate its fossil fuel and biomass emission fractions at a high-altitude (1958 m) site in the Central Himalayas. The results show that MERRA2 always underestimates the observed CO; MOPITT has a high monthly difference ranging from -32% to +57% while WRF-Chem simulations underestimate CO from February to June and overestimate in other months. In contrast, CO estimated from MLR replicates diurnal and monthly variations and estimates CO with an r2 > 0.8 for 2014-2017. The CO predicted during 2018 closely follows the observed variations, and its mixing ratios lie within ±17% of the observed CO. The results reveal a unimodal diurnal variation of CO, COff (ff: fossil fuel) and CObb (bb: biomass burning) governed by the boundary layer evolution and upslope winds. COff has a higher diurnal amplitude (39.1-67.8 ppb) than CObb (5.7-33.5 ppb). Overall, COff is the major contributor (27%) in CO after its background fraction (58%). CObb fraction reaches a maximum (28%) during spring, a period of increased agricultural and forest fires in Northern India. In comparison, WRF-Chem tracer runs underestimate CObb (-38% to -98%) while they overestimate the anthropogenic CO during monsoon. This study thus attempts to address the lack of continuous CO monitoring and the need to segregate its fossil fuel and biomass sources, specifically over the Central Himalayas, by employing a methodology that utilizes the existing network of eBC observations.

SHOX Variations in Idiopathic Short Stature in North India and a Review of Cases from Asian Countries

Objective: Short stature homeobox (SHOX) haploinsufficiency underlies idiopathic short stature (ISS) and Leri-Weill dyschondrosteosis. The worldwide prevalence of SHOX variations in ISS varies from 2.5% to 15.0%. The aim of this study was to assess the implication of SHOX variation in ISS in North Indians and compare this with other cases of SHOX variations from Asian population. Methods: SHOX gene analysis was carried out by multiplex ligation-dependent probe amplification followed by Sanger sequencing in 54 patients with variable phenotypes. Comparison with other reports in a meta-analysis comprising the current study and 11 previous studies (n=979) was performed. Results: SHOX analysis resulted in 12.9% positivity (7.4% deletions and 5.5% duplications). SHOX association was seen significantly related to gender, with predominance in females (p=0.047). Short arms and forearms were the only significantly associated trait seen in 51.9% of children. The overall prevalence of SHOX variation was 15.2% in Asians with ISS. No significant difference was found in geographical region-specific analysis. Conclusion: This study summarises findings from the last decade and provides an updated picture of the prevalence of SHOX variations in Asians, emphasizing their potential as therapeutic targets in ISS patients. Further high quality, large investigations including functional validation is warranted to validate this association.

Current Insights of Nanocarrier-Mediated Gene Therapeutics to Treat Potential Impairment of Amyloid Beta Protein and Tau Protein in Alzheimer's Disease.

Alzheimer's disease (AD), is the major type of dementia and most progressive, irreversible widespread neurodegenerative disorder affecting the elderly worldwide. The prime hallmarks of Alzheimer's disease (AD) are beta-amyloid plaques (Aß) and neurofibrillary tangles (NFT). In spite of recent advances and developments in targeting the hallmarks of AD, symptomatic medications that promise neuroprotective activity against AD are currently unable to treat degenerating brain clinically or therapeutically and show little efficacy. The extensive progress of AD therapies over time has resulted in the advent of disease-modifying medications with the potential to alleviate AD. However, due to the presence of a defensive connection between the vascular system and the neural tissues known as the blood-brain barrier (BBB), directing these medications to the site of action in the degenerating brain is the key problem. BBB acts as a highly selective semipermeable membrane that prevents any type of foreign substance from entering the microenvironment of neurons. To overcome this limitation, the revolutionary approach of nanoparticle(NP)/nanocarrier-mediated drug delivery system has marked the era with its unique property to cross, avoid, or disrupt the defensive BBB efficiently and release the modified drug at the target site of action. After comprehensive data mining, this review focuses on the detailed understanding of different types of nanoparticle(NP)/nanocarrier-mediated drug delivery system like liposomes, micelles, gold nanoparticles(NP), polymeric NPs, etc. which have promising potential in carrying the desired drug(cargo) to the location in the degenerated brain thus mitigating the Alzheimer's disease.

Alginic acid-functionalized silver nanoparticles: A rapid monitoring tool for detecting the technology-critical element tellurium.

The increasing global demand for tellurium, driven by its critical role in alloys, photovoltaic devices, and electronics, has raised concerns about its environmental pollution and neurotoxicity. In response, the potential of alginic acid (AA), a renewable, low-cost, and sustainable biopolymer, was explored for the biosynthesis of ultra-small silver nanoparticles (AgNPs) and their application in the detection of tellurium (Te(IV)). The effect of key synthesis parameters on desired physicochemical properties and yield of AgNPs was established to ensure high specificity and sensitivity towards Te(IV). The purified AgNPs with AA surface ligands were utilized to demonstrate a ratiometric absorbance sensor that exhibits excellent linearity and nanomolar-level affinity. This approach achieved a high correlation coefficient of ∼ 0.982, with a low detection limit of about 22 nM. Further investigations into the effect of pH, ionic strength, and organic molecules were conducted to elucidate detection performance and molecular understanding. The detection mechanism relies on the coordination between Te(IV) ions and the carboxylate groups of AA, which initiates aggregation-induced plasmon coupling in adjacent AgNPs. The capability of this analytical method to monitor Te(IV) in real-world water samples features its rapidity, user-friendliness, and suitability for point-of-care monitoring, making it a promising alternative to more complex techniques.

Verbal-analytical rather than visuo-spatial Raven's puzzle solving favors Raven's-like puzzle generation.

Raven's advanced progressive matrices (APM) comprise two types of representational codes, namely visuo-spatial and verbal-analytical, that are used to solve APM puzzles. Studies using analytical, behavioral, and imaging methods have supported the multidimensional perspectives of APM puzzles. The visuo-spatial code is expected to recruit operations more responsive to the visual perception tasks. In contrast, the verbal-analytical code is expected to use operations more responsive to the logical reasoning task and may entail different cognitive strategies. Acknowledging different representational codes used in APM puzzle-solving is critical for a better understanding of APM's performance and their relationship with other tasks, especially creative reasoning. We used the eye-tracking method to investigate the role of two representational codes, visuo-spatial and verbal-analytical, in strategies involved in solving APM puzzles and in generating an APM-like puzzle by using a creative-reasoning task (CRT). Participants took longer time to complete the verbal-analytical than visuo-spatial puzzles. In addition, visuo-analytical than visual-spatial puzzles showed higher progressive and regressive saccade counts, suggesting the use of more response elimination than constructive matching strategies employed while solving verbal-analytical than visuo-spatial puzzles. We observed higher CRT scores when it followed verbal-analytical (Mdn = 84) than visuo-spatial (Mdn = 73) APM puzzles, suggesting puzzle-solving specific strategies affect puzzle-creating task performance. The advantage of verbal-analytical over visuo-spatial puzzle-solving has been discussed in light of shared cognitive processing between APM puzzle-solving and APM-like puzzle-creating task performance.

Enduring Efficacy and Clinical Outcomes of Combined Palliative Chemotherapy With Gefitinib, Methotrexate, and Cyclophosphamide in Advanced Oral Cancer: A 3.5-Year Case Study of Carcinoma in the Buccal Mucosa and Hard Palate.

This case report outlines the diagnostic and treatment experience of a 50-year-old male diagnosed with moderately differentiated squamous cell carcinoma (SCC) in the right lower alveolus. It underscores the challenges of oral squamous cell carcinoma (OSCC) diagnosis and management, emphasizing the need for comprehensive multidisciplinary approaches. The patient's initial presentation with persistent mandibular pain highlighted the complexities of diagnosing oral and maxillofacial pathologies. A detailed clinical examination revealed unique ulceroproliferative growth, showcasing the importance of meticulous clinical assessment. Histopathological confirmation solidified the diagnosis. Treatment involved surgery, adjuvant radiotherapy, and concurrent chemotherapy. Post-chemotherapy, the patient responded positively, underlining treatment efficacy. Transitioning to oral chemotherapy demonstrated adaptability. Vigilant follow-up, exemplified by detecting non-healing ulcers and erosions, is crucial for early intervention. This case informs oral squamous cell carcinoma management. Integrated therapy's success underscores the value of combining surgery, chemotherapy, and radiotherapy. The patient's response to gefitinib, cyclophosphamide, and methotrexate suggests promise for targeted therapies. Patient-centered care, interdisciplinary collaboration, and adaptability are vital. This case report illustrates oral squamous cell carcinoma eradication through multidimensional treatment. The patient's journey highlights accurate diagnosis, adaptable therapy, and vigilant follow-up. It informs the field and fosters further research and innovation.

CD40 gene polymorphism and its expression in children with Kawasaki disease from North India: a preliminary case-control study and meta-analysis.

Introduction: CD40 gene single-nucleotide polymorphisms (SNPs) have been associated with susceptibility and development of coronary artery abnormalities (CAAs) in children with Kawasaki disease (KD) in Japanese, Chinese, and Taiwanese populations. However, data on SNPs of the CD40 gene in patients with KD from the Indian subcontinent are not available. We studied the CD40 gene polymorphisms and its expression in children with KD from North India. Methods: SNPs of the CD40 gene (rs4810485, rs1535045) were studied using Sanger sequencing. CD40 expression was studied by flow cytometry. Meta-analysis was carried out to assess the role of both SNPs of the CD40 gene in KD. GRADEpro GDT software (v.3.2) was used to assess the "certainty of evidence." Results: Forty-one patients with KD and 41 age-, sex-matched febrile controls were enrolled. However, none of the alleles and genotypes of the CD40 gene were found to be associated with KD. CD40 expression was higher in KD and in KD with CAAs compared to controls, but it failed to reach statistical significance. In a meta-analysis, the T allele of rs153045 was found to be significantly associated with KD (OR = 1.28; 95% confidence interval (: 1.09-1.50; p = 0.002). The GRADE of evidence for this outcome, however, is of " very low certainty." Conclusion: The present study found no association between SNPs (rs4810485 and rs153045) and susceptibility to KD. This could be a reflection of a modest sample size. CD40 expression was higher in KD and in KD with CAAs. In the meta-analysis, the T allele of rs153045 was significantly associated with KD. Our study confirms a significant genetic heterogeneity in KD among different ethnicities.

Vitamin D Receptor Antagonist MeTC7 Inhibits PD-L1.

Small-molecule inhibitors of PD-L1 are postulated to control immune evasion in tumors similar to antibodies that target the PD-L1/PD-1 immune checkpoint axis. However, the identity of targetable PD-L1 inducers is required to develop small-molecule PD-L1 inhibitors. In this study, using chromatin immunoprecipitation (ChIP) assay and siRNA, we demonstrate that vitamin D/VDR regulates PD-L1 expression in acute myeloid leukemia (AML) and myelodysplastic syndrome (MDS) cells. We have examined whether a VDR antagonist, MeTC7, can inhibit PD-L1. To ensure that MeTC7 inhibits VDR/PD-L1 without off-target effects, we examined competitive inhibition of VDR by MeTC7, utilizing ligand-dependent dimerization of VDR-RXR, RXR-RXR, and VDR-coactivators in a mammalian 2-hybrid (M2H) assay. MeTC7 inhibits VDR selectively, suppresses PD-L1 expression sparing PD-L2, and inhibits the cell viability, clonogenicity, and xenograft growth of AML cells. MeTC7 blocks AML/mesenchymal stem cells (MSCs) adhesion and increases the efferocytotic efficiency of THP-1 AML cells. Additionally, utilizing a syngeneic colorectal cancer model in which VDR/PD-L1 co-upregulation occurs in vivo under radiation therapy (RT), MeTC7 inhibits PD-L1 and enhances intra-tumoral CD8+T cells expressing lymphoid activation antigen-CD69. Taken together, MeTC7 is a promising small-molecule inhibitor of PD-L1 with clinical potential.