Insights into medicinal attributes of imidazo[1,2-a]pyridine derivatives as anticancer agents.

Cancer ranks among the most life-threatening diseases worldwide and is continuously affecting all age groups. Consequently, many research studies are being carried out to develop new cancer treatments, but many of them experience resistance and cause severe toxicity to the patients. Therefore, there is a continuous need to design novel anticancer agents that are target-based, have a higher potency, and have minimal toxicity. The imidazo[1,2-a]pyridine (IP) pharmacophore has been found to be a prominent moiety in the field of medicinal chemistry due to its vast biological properties. Also, it holds immense potential for combating cancer with minimal side effects, depending on the substitution patterns of the core structure. IPs exhibit significant capability in regulating various cellular pathways, offering possibilities for targeted anticancer effects. The present review summarizes the anticancer profile of numerous IP derivatives synthesized and developed by various researchers from 2016 till now, as inhibitors of phosphoinositide-3-kinase/mammalian target of rapamycin (PI3K/mTOR), protein kinase B/mammalian target of rapamycin (Akt/mTOR), aldehyde dehydrogenase (ALDH), and tubulin polymerization. This review provides a comprehensive analysis of the anticancer activity afforded by the discussed IP compounds, emphasizing the structure-activity-relationships (SARs). The aim is also to underscore the potential therapeutic future of the IP moiety as a potent partial structure for upcoming cancer drug development and to aid researchers in the field of rational drug design.

Revolutionizing pediatric neuroblastoma treatment: unraveling new molecular targets for precision interventions.

Neuroblastoma (NB) is the most frequent solid tumor in pediatric cases, contributing to around 15% of childhood cancer-related deaths. The wide-ranging genetic, morphological, and clinical diversity within NB complicates the success of current treatment methods. Acquiring an in-depth understanding of genetic alterations implicated in the development of NB is essential for creating safer and more efficient therapies for this severe condition. Several molecular signatures are being studied as potential targets for developing new treatments for NB patients. In this article, we have examined the molecular factors and genetic irregularities, including those within insulin gene enhancer binding protein 1 (ISL1), dihydropyrimidinase-like 3 (DPYSL3), receptor tyrosine kinase-like orphan receptor 1 (ROR1) and murine double minute 2-tumor protein 53 (MDM2-P53) that play an essential role in the development of NB. A thorough summary of the molecular targeted treatments currently being studied in pre-clinical and clinical trials has been described. Recent studies of immunotherapeutic agents used in NB are also studied in this article. Moreover, we explore potential future directions to discover new targets and treatments to enhance existing therapies and ultimately improve treatment outcomes and survival rates for NB patients.

Computational insights into KRAS G12C inhibition: exploring possible repurposing of Azacitidine and Ribavirin.

Kirsten rat sarcoma (KRAS) stands out as the most prevalent mutated oncogene, playing a crucial role in the initiation and progression of various cancer types, including colorectal, lung and pancreatic cancer. The oncogenic modifications of KRAS are intricately linked to tumor development and are identified in 22% of cancer patients. This has spurred the necessity to explore inhibition mechanisms, with the aim of investigating and repurposing existing drugs for diagnosing cancers dependent on KRAS G12C In this investigation, 26 nucleoside-based drugs were collected from literature to assess their effectiveness against KRAS G12C. The study incorporates in-silico molecular simulations and molecular docking examinations of these nucleoside-derived drugs with the KRAS G12C protein using Protein Data Bank (PDB) ID: 5V71. The docking outcomes indicated that two drugs, Azacitidine and Ribavirin, exhibited substantial binding affinities of -8.7 and -8.3 kcal/mol, respectively. These drugs demonstrated stability in binding to the active site of the protein during simulation studies. Root mean square deviation (RMSD) analyses indicated that the complexes closely adhered to an equilibrium RMSD value ranging from 0.17 to 0.2 nm. Additionally, % occupancies, bond angles and the length of hydrogen bonds were calculated. These findings suggest that Azacitidine and Ribavirin may potentially serve as candidates for repurposing in individuals with KRAS-dependent cancers.Communicated by Ramaswamy H. Sarma.

Systematic evaluation of the Precision ID GlobalFiler™ NGS STR panel v2 using single-source samples of various quantity and quality and mixed DNA samples.

Massively parallel sequencing (MPS) techniques were developed approximately 15 years ago. Meanwhile, several MPS kits for forensic identification, phenotypic information, ancestry, and mitochondrial DNA analysis have been developed and their use has been established. Sequencing short tandem repeats (STRs) has certain advantages over the currently used length-based genotyping methods, which are based on PCR amplification followed by capillary electrophoresis (CE). MPS is more discriminative and includes the possibility of testing high numbers of targets (> 100), different types of markers [STRs and single nucleotide polymorphisms (SNPs)], as well as the use of smaller amplicons (< 300 bp). This study evaluated in 24 experimental runs the Precision ID GlobalFiler™ NGS STR panel v2 from ThermoFisher, which targets 31 autosomal STRs, amelogenin, and three Y-markers (one STR, SRY, and Yindel). Single-source samples were used in 18 experimental runs, for systematic evaluation. These included assessing library preparation benchmark conditions, limited DNA input, as well as testing repeatability, number of samples per run, and degraded DNA samples. Full profiles were consistently obtained from as little as 50 pg DNA input. Using the optional recovery PCR method improved outcomes for samples with low DNA input. Full profiles were also obtained from severely degraded DNA samples with degradation indices (DI) of > 60. In addition, six experimental runs were performed testing various two-person mixtures with mixture ratios ranging from 1:20 to 20:1. Major and minor contributors were distinguishable by their read counts (coverage), because less DNA input yielded lower read counts, analogous to the traditional CE technology, where less DNA produces lower peak heights. Mixture ratios of approximately 1:1 were indistinguishable, while a greater imbalance, i.e., higher mixture ratios, made the mixture more distinguishable between major and minor contributors. Based on this information, the highest success rate of correctly deconvoluted four-allelic loci was from mixtures with 1:3 ratios. At higher mixture ratios, the drop-out rate of the minor contributor increased, reducing the number of four-allelic loci.

Short Stature for Age in Children of 5 to 16 Years: The First Research from the Northern Himalayan Region of India.

Introduction: Anthropometric parameters play vital role in monitoring growth in pediatrics. Many etiological factors lead to short stature. So, before assessing the etiological factors short stature needs to be addressed. This study aimed to screen short stature for age in school-going children aged 5 to 16 years in Uttarakhand. Material and Methods: In this cross-sectional observational study, the height (through stadiometer) and weight (through weight machine) of 4189 students of government and private school in Rishikesh (Uttarakhand) aged 5-16 years were measured after the verbal assent of the students and individual's height is in the 3rd percentile for the mean height of a given age, sex, and population group and was considered short stature. The data collection was performed from October 2019 to July 2021. The data were categorized according to different age groups to 5-8 years, 9-12 years, and 13-16 years. The data were recorded in Microsoft (MS) Excel spreadsheet program. Statistical Package for the Social Sciences (SPSS) v23 (IBM Corp.) was used for data analysis. Descriptive statistics were elaborated in the form of means or standard deviations and medians or Interquartile range IQRs for continuous variables and frequencies and percentages for categorical variables. The Chi-square test was used for group comparisons for categorical data. Results: 7.1% of children were short stature (height 143.16 ± 15.09 cm) in the Himalayan belt, and males were more prone to short stature at age of 9-12 years. Conclusion: In the growing phase of children, the etiology of short stature has to be rectified, so the children can achieve such proper growth. Parents and physicians have to assess and monitor the growth of children timely. This study can be a stepping stone for further epidemiological studies.

Intraconal Retroorbital Cavernous Hemangioma - A Case Report.

Cavernous hemangioma of orbit is a benign, noninfiltrative, slowly progressive vascular neoplasm. It is usually asymptomatic but patients may present with proptosis and diminished vision due to compression of second cranial nerve, optic nerve. This can be usually diagnosed with the help of clinical examination and computed tomography (CT) or magnetic resonance imaging (MRI). Small sized tumours are worth wait and watch while large ones need surgical excision. In our case report, A 65-year-old male patient presented to the head and neck surgery with proptosis of left eye since 5 years along with decreased vision since 4 years. MDCT scan (orbits plain) suggestive of large solid retroocular, intraconal mass in left orbit leading to proptosis of left eyeball. The patient underwent excision of tumour through a transnasal endoscopic approach. Histopathological examination of the tumour identified as cavernous hemangioma. It is safe and effective way to access and excise the orbital tumours through the transnasal endoscopic approach. It is essential to have experienced surgeon in endoscopic procedures. The patient had satisfactory results at three months follow up and showed no symptoms or relapse on CT scans of orbital region. Supplementary Information: The online version contains supplementary material available at 10.1007/s12070-023-03984-y.

An integrated pipeline for prediction of Clostridioides difficile infection.

With the expansion of electronic health records(EHR)-linked genomic data comes the development of machine learning-enable models. There is a pressing need to develop robust pipelines to evaluate the performance of integrated models and minimize systemic bias. We developed a prediction model of symptomatic Clostridioides difficile infection(CDI) by integrating common EHR-based and genetic risk factors(rs2227306/IL8). Our pipeline includes (1) leveraging phenotyping algorithm to minimize temporal bias, (2) performing simulation studies to determine the predictive power in samples without genetic information, (3) propensity score matching to control for the confoundings, (4) selecting machine learning algorithms to capture complex feature interactions, (5) performing oversampling to address data imbalance, and (6) optimizing models and ensuring proper bias-variance trade-off. We evaluate the performance of prediction models of CDI when including common clinical risk factors and the benefit of incorporating genetic feature(s) into the models. We emphasize the importance of building a robust integrated pipeline to avoid systemic bias and thoroughly evaluating genetic features when integrated into the prediction models in the general population and subgroups.

Comparison of Mechanical Properties, Physical Properties, and Biocompatibility of Four Different Denture Base Resins: An In vitro Study.

Four new dental replacement base tars were evaluated in vitro to determine their mechanical qualities, authentic properties, and biocompatibility. Materials and Methods: In this experiment, we employed SR Triplet HOT (a fiber-developed heat fix tar), Sunflex (a multipurpose force fix sap), Trevalon-Hello (a high-impact heat fix tar), DPI (a digital pigment imaging system), and a variety of other pigments and inks (normal power fix tar). For these models, the ISO specification 1567 for dental substitute base gums called for testing of flexural strength, hardness, impact strength, water sorption and dissolvability, and cytotoxicity. Results: All the strength and mechanical properties tested had a statistically significant difference when intergroup analysis was performed. Conclusion: The exceptional physical and mechanical capabilities of the Sunflex denture base resin, together with its biocompatibility with oral tissues, make it a good candidate for use as a denture base material in routine clinical practice.

Point-of-Care Serum Amyloid A as a Diagnostic Marker for Neonatal Sepsis.

OBJECTIVES: To evaluate diagnostic accuracy of point-of-care Serum Amyloid A (POC-SAA) and its comparison with procalcitonin for diagnosis of neonatal sepsis. METHODS: The present diagnostic accuracy study consecutively recruited neonates with suspected sepsis. Blood samples for sepsis screen, culture, high sensitivity C-reactive protein (CRP) (hs-CRP, as a part of sepsis screen), procalcitonin and POC-SAA were collected before starting antibiotics. The optimum cut-off level of biomarkers (POC-SAA and procalcitonin) was determined by receiver-operating-characteristics curve (ROC) analysis. Sensitivity, specificity, positive predictive value (PPV) and negative predictive value (NPV) of POC-SAA and procalcitonin were derived for 'clinical sepsis (neonates with suspected sepsis and either positive sepsis screen and/or blood culture)' and 'culture positive sepsis' (neonates with suspected sepsis and positive blood culture). RESULTS: Seventy-four neonates with mean±SD gestational age of 32.8±3.7 wk were evaluated for suspected sepsis, of which the proportion of 'clinical sepsis' and 'culture positive sepsis' was 37.8% had 16.2%, respectively. At a cut-off of 25.4 mg/L, POC-SAA had sensitivity, specificity, PPV and NPV of 53.6%, 80.4%, 62.5% and 74.0%, respectively for diagnosis of clinical sepsis. The sensitivity, specificity, PPV and NPV of POC-SAA for detection of culture positive sepsis were 83.3%, 61.3%, 29.4% and 95.0%, respectively at a cut-off of 10.3 mg/L. There was no significant difference in the diagnostic accuracy of biomarkers for detection of culture positive sepsis (area under the curve, AUC of POC-SAA vs. procalcitonin vs. hs-CRP: 0.72 vs. 0.85 vs. 0.85; p = 0.21). CONCLUSIONS: POC-SAA is comparable to procalcitonin and hs-CRP for diagnosis of neonatal sepsis.