Using Machine Learning and miRNA for the Diagnosis of Esophageal Cancer.

BACKGROUND: Esophageal cancer (EC) remains a global health challenge, often diagnosed at advanced stages, leading to high mortality rates. Current diagnostic tools for EC are limited in their efficacy. This study aims to harness the potential of microRNAs (miRNAs) as novel, noninvasive diagnostic biomarkers for EC. Our objective was to determine the diagnostic accuracy of miRNAs, particularly in distinguishing miRNAs associated with EC from control miRNAs. METHODS: We applied machine learning (ML) techniques in WEKA (Waikato Environment for Knowledge Analysis) and TensorFlow Keras to a dataset of miRNA sequences and gene targets, assessing the predictive power of several classifiers: naïve Bayes, multilayer perceptron, Hoeffding tree, random forest, and random tree. The data were further subjected to InfoGain feature selection to identify the most informative miRNA sequence and gene target descriptors. The ML models' abilities to distinguish between miRNA implicated in EC and control group miRNA was then tested. RESULTS: Of the tested WEKA classifiers, the top 3 performing ones were random forest, Hoeffding tree, and naïve Bayes. The TensorFlow Keras neural network model was subsequently trained and tested, the model's predictive power was further validated using an independent dataset. The TensorFlow Keras gave an accuracy 0.91. The WEKA best algorithm (naïve Bayes) model yielded an accuracy of 0.94. CONCLUSIONS: The results demonstrate the potential of ML-based miRNA classifiers in diagnosing EC. However, further studies are necessary to validate these findings and explore the full clinical potential of this approach.

Molecular and Phenotypic Characterization of the RORB-Related Disorder.

BACKGROUND AND OBJECTIVES: Heterozygous variants in RAR-related orphan receptor B (RORB) have recently been associated with susceptibility to idiopathic generalized epilepsy. However, few reports have been published so far describing pathogenic variants of this gene in patients with epilepsy and intellectual disability (ID). In this study, we aimed to delineate the epilepsy phenotype associated with RORB pathogenic variants and to provide arguments in favor of the pathogenicity of variants. METHODS: Through an international collaboration, we analyzed seizure characteristics, EEG data, and genotypes of a cohort of patients with heterozygous variants in RORB. To gain insight into disease mechanisms, we performed ex vivo cortical electroporation in mouse embryos of 5 selected variants, 2 truncating and 3 missense, and evaluated on expression and quantified changes in axonal morphology. RESULTS: We identified 35 patients (17 male, median age 10 years, range 2.5-23 years) carrying 32 different heterozygous variants in RORB, including 28 single-nucleotide variants or small insertions/deletions (12 missense, 12 frameshift or nonsense, 2 splice-site variants, and 2 in-frame deletions), and 4 microdeletions; de novo in 18 patients and inherited in 10. Seizures were reported in 31/35 (89%) patients, with a median age at onset of 3 years (range 4 months-12 years). Absence seizures occurred in 25 patients with epilepsy (81%). Nineteen patients experienced a single seizure type: absences, myoclonic absences, or absences with eyelid myoclonia and focal seizures. Nine patients had absence seizures combined with other generalized seizure types. One patient had presented with absences associated with photosensitive occipital seizures. Three other patients had generalized tonic-clonic seizures without absences. ID of variable degree was observed in 85% of the patients. Expression studies in cultured neurons showed shorter axons for the 5 tested variants, both truncating and missense variants, supporting an impaired protein function. DISCUSSION: In most patients, the phenotype of the RORB-related disorder associates absence seizures with mild-to-moderate ID. In silico and in vitro evaluation of the variants in our cohort, including axonal morphogenetic experiments in cultured neurons, supports their pathogenicity, showing a hypomorphic effect.

Investigating Electronic, Optical, Thermodynamic, and Thermoelectric Properties of SrO and SrO2 Phases: A Density Functional Theory Approach.

The significance of strontium oxide (SrO) and strontium peroxide (SrO2) is currently being investigated as one of the countless potential uses for green energy. However, few studies have examined the distinctive properties of several phases of SrO and SrO2. In order to fill this research gap, we have conducted a study on their various properties through "density functional theory (DFT)" under ideal conditions. This includes the study of electronic, optical, thermodynamic, and thermoelectric properties of the above-mentioned materials. For this study, the "Quantum Espresso" tool in DFT using Perdew-Burke-Ernzerhof-generalized-gradient approximation (PBE-GGA) as the exchange-correlation functional and "Optimized Norm-Conserving Vanderbilt (ONCV)" as the pseudopotential has been used. The face-centered cubic (FCC), body-centered cubic (BCC), hexagonal-1, and hexagonal-2 phases of SrO and the tetragonal and orthorhombic phases of SrO2 have been selected for the aforesaid study, for which some structural information has already been available. During this study, the energy band gap as an electronic property; the dielectric constant, refractive index, absorption coefficient, reflectivity, and energy loss function as optical properties; entropy, heat capacity, Debye temperature, and Debye sound velocity as thermodynamic properties; and the Seebeck coefficient, thermal conductivity, electrical conductivity, and figure of merit as thermoelectric properties have been investigated. In addition, phonon dispersion curves and formation energies have been used to confirm the dynamical stability and thermodynamic stability, respectively, for all of the materials mentioned above. The curve showed that the FCC, hexagonal-1, and hexagonal-2 phases of "SrO" are dynamically stable. These materials have good optoelectronic properties and can be used in ultraviolet sensors due to their intermediate band gap and highest material response in the ultraviolet range. In terms of thermoelectric property, the maximum value of "figure of merit" for the above material has been achieved up to 0.5. Satisfactory agreement has been found between the current findings and the known theoretical and experimental findings.

PEG-mediated synthesis, antibacterial, antifungal and antioxidant studies of some new 1,3,5-trisubstituted 2-pyrazolines.

A new series of 1,3,5-trisubstituted 2-pyrazoline derivatives (3a-l) are synthesized in good to excellent yields from the corresponding chalcones (1a-h) and acid hydrazides (2a-e) in polyethylene glycol-400 (PEG-400) as a green reaction medium. The newly synthesized 2-pyrazoline derivatives are screened for their antibacterial and antifungal activity. The synthesized trisubstituted pyrazolines displayed moderate to good antibacterial and antifungal properties as compared with the standard reference penicillin and fluconazole drugs. Additionally, the antioxidant potential of the 1,3,5-trisubstituted 2-pyrazolines is evaluated by OH and DPPH assay. The 1,3,5-trisubstituted 2-pyrazolines showed good radical scavenger activity and were found as good antioxidant agents.

An Unusual Case of Buerger's Disease in a Pregnant Female.

Thromboangitis obliterans or Buerger's disease is a segmental inflammatory condition of small and medium-sized arteries and veins. It is commonly seen in males with age under 45 years and with a current or recent history of tobacco use, and in smokers. It is sporadic in young women. This report describes a primigravida with dry gangrene in both upper and lower limbs because of Buerger's disease. The primary diagnosis of the disease occurred first time in pregnancy at the 17th week of gestation with the patient reporting dry gangrene and pain in the digits and confirmed with a non-invasive Doppler study. The patient was screened for autoimmune diseases, diabetes mellitus, and the presence of hypercoagulable disorders. Echocardiography and arteriography were performed to rule out any source of emboli. The case report aims to discuss a rare diagnostic and therapeutic dilemma in the case of a pregnant woman presenting with gangrene without any history of tobacco addiction.

A rare case of collision tumour of the ovary complicated by torsion.

Collision tumour is the coexistence of two adjacent, but histologically distinct tumours without histologic admixture. Collision tumours are rare in the ovary. It is mostly a histopathological diagnosis often missed in preoperative imaging. The radiologist, gynaecologists and pathologists should be aware of such a combination of tumours to avoid misdiagnosis. We describe the finding of a rare collision tumour, mature cystic teratoma and ovarian fibroma complicated by torsion.

Benign Pericardial Hemangioma-A Rare Cause of Cardiac Tamponade.

Pericardial tumors are very rare. It can be primary or secondary, of which secondary tumors are more common. Pericardial hemangiomas are extremely rare primary neoplasms and there are only very few cases published in the literature. These patients can be asymptomatic. When symptomatic, they present with dyspnea, palpitation, or atypical chest pain. Severity of symptoms depends on the size and location of the tumor. Pericardial effusion with features of cardiac tamponade can lead to a life-threatening situation. Here, we report a case of pericardial hemangioma in a patient who presented with breathlessness and tamponade which was diagnosed preoperatively with computed tomography.

Role of Imaging in a Case of Toxoplasmosis Presenting as Generalized Lymphadenopathy.

Toxoplasmosis is caused by Toxoplasma gondii an obligate protozoan intracellular parasite. The disease has variable prevalence globally and is usually asymptomatic. Pregnant and immunocompromised people are at risk of getting infected. Enlarged lymph nodes are the most frequently observed clinical form of Toxoplasma in humans, mostly affecting posterior cervical nodes. Other organs usually affected are the brain and eyes. We present a case of toxoplasmosis with generalized lymphadenopathy mimicking metastasis in a lady with a previous history of operated pancreatic neoplasm.

Microwave prompted solvent-free synthesis of new series of heterocyclic tagged 7-arylidene indanone hybrids and their computational, antifungal, antioxidant, and cytotoxicity study.

In this study, we report the expeditious synthesis of ten new antifungal and antioxidant agents containing heterocyclic linked 7-arylidene indanone moiety. The solvent-free microwave technique, ample substrate scope, superfast synthesis, and very simple operation are noteworthy features of this protocol. Antifungal activities of the newly synthesized compounds were evaluated against four fungal strains namely Rhizophus oryzae, Mucor mucido, Aspergillus niger, and Candida albicans. Most of the compounds were shown strong inhibition of the investigated fungal agents. In vitro, antioxidant potential against DPPH and OH radicals affirmed that the synthesized compounds are good to excellent radicals scavenging agents. The cytotoxicity data of the synthesized compounds towards HL-60 cells uncovered that the synthesized compounds display very low to negligible cytotoxicity. The structural and quantum chemical parameters of the synthesized compounds were explored by employing density functional theory (DFT) at B3LYP functional using 6-311G(d,p) basis set. The compound 3a is discussed in detail for the theoretical and experimental correlation. Time-dependent density functional theory (TD-DFT) at CAM-B3LYP functional with 6-311G(d,p) basis set was used for the electronic absorption study in the gas phase and indichloromethane and benzene solvents. The UV-Visible absorption peaks and fundamental vibrational wavenumbers were computed and a good agreement between observed and theoretical results has been achieved. From the DFT and antifungal activity correlation, it has been found that the 7-heteroarylidene indanones with more stabilized LUMO energy levels display good antifungal potential.

Incorporation of grape seed extract towards wound care product development.

Naturally derived ingredients are becoming more prevalent in therapeutic drug formulations due to consumers' concerns about chemical side effects. In the context of wound care, despite the impressive progress in therapeutic product development, drugs dispensed to treat impaired healing challenged by biofilms; excessive inflammation and oxidation are not yet really effective. Thus, the hunts for improved drug formulations preferably using natural ingredients that are cost-effective in accelerating the wound-healing process are of constant demand. The grape seed extract is extensively studied and is reported to be rich in phenolic compounds, unsaturated fatty acids and vitamins which exhibit numerous therapeutic benefits owing to their anti-inflammatory, anti-microbial, and anti-oxidative properties that support its potential use in the development of wound-healing products. We conducted a literature study using Scopus, PubMed, and Google Scholar including the keywords "grape seed extract" and "wound healing". We also scanned all the references cited by the retrieved articles. Accordingly, this review is aimed to (i) explore the various phytochemical constituents found in grape seed extracts along with their mechanism of action that instigate wound healing, (ii) to highlight the latest pre-clinical and clinical assessments of grape seed extract in wound models, and (iii) to encourage innovation scientists in the field to address current limitations and to effectively develop grape seed extract-based wound care product formulations for commercialization.

Comparison of Disintegrant-addition Methods on the Compounding of Orodispersible Tablets.

Orodispersible tablets disintegrate rapidly (within 3 minutes) in the oral cavity and release the medicament before swallowing. The mode of disintegrant addition might affect the properties of orodispersible tablets. The objective of this study was to formulate and evaluate orodispersible tablets by studying different modes of disintegration addition with varying concentrations of disintegrants. The wet granulation method was used to produce the orodispersible tablets. Two methods of disintegration addition were compared (i.e., intragranular, extragranular). Three disintegrants (i.e., cornstarch, sodium starch glycolate, crospovidone) were used at three levels (5%, 10%, and 15%) in the study. The formulations were tested for the powder flowability (angle of repose) and characterized physically (hardness, weight, thickness, friability, disintegration time). The mangosteen pericarp extract was used as a model active pharmaceutical ingredient to be incorporated into the optimum formulation. It was observed that the extragranular method produced granules with better flowability compared to that of the intragranular method. Crospovidone was found as the most efficient disintegrant among the three. The optimum formulation selected was one with the highest concentration of crospovidone (15%), which showed the fastest disintegration time. The mode of disintegrant addition into the orodispersible tablets formulation was found to show a marked difference in the disintegration, as well as other physical characteristics of the orodispersible tablets where the extragranular mode of addition showed better property, which caused the orodispersible tablets to disintegrate the fastest.

A Rare Case of Grey Zone Lymphoma Successfully Treated with Brentuximab Vedotin and R-CHP Chemotherapy.

INTRODUCTION: The diagnosis of B-cell lymphoma, unclassifiable, with features intermediate between diffuse large B-cell lymphoma (DLBCL) and classical Hodgkin's lymphoma (cHL), also referred to as grey zone lymphoma (GZL), is a challenging diagnosis. There are no standardized guidelines; however, evidence strongly suggests that DLBCL-based regimens are effective in the treatment of GZL. Brentuximab vedotin (BV) is an anti-CD30 antibody drug conjugate that has established efficacy in relapsed/refractory Hodgkin and some T-cell lymphomas. There is some evidence that BV has a positive response in non-Hodgkin lymphoma (NHL) with a wide range of CD30 expressions-including GZL. CASE: We present a case of a patient initially diagnosed with cHL who underwent repeat biopsy which was revealed to be GZL. Based on PET scanning and immunohistochemical studies, she was classified as a stage IIIA CD20+/CD30+ GZL patient. Given her strong CD30 expression, she underwent 6 cycles of R-BV-CHP (rituximab, brentuximab vedotin, cyclophosphamide, doxorubicin, and prednisone) chemotherapy and achieved complete response (CR) both clinically and radiographically. DISCUSSION: Given the rarity of GZL, this case illustrates the immense challenges in making the diagnosis, discusses the current treatment options, and suggests that BV may be a viable therapeutic candidate in the treatment of GZL.

Genotype-phenotype specificity in Menke-Hennekam syndrome caused by missense variants in exon 30 or 31 of CREBBP.

CREBBP loss-of function variants cause Rubinstein-Taybi syndrome (RTS). There have been two separate reports of patients with missense variants in exon 30 or 31 of CREBBP in individuals lacking the characteristic facial and limb dysmorphism associated with RTS. Frequent features in this condition include variable intellectual disability, short stature, autistic behavior, microcephaly, feeding problems, epilepsy, recurrent upper airway infections, and mild hearing impairment. We report three further patients with de novo exon 31 CREBBP missense variants. The first individual has a c.5357G>A p. (Arg1786His) variant affecting the same codon as one of the previously described patients. Both these patients could be recognized by clinicians as mild RTS. Our second patient has a c.5602C>T p.(Arg1868Trp) variant that has been described in five other individuals who all share a strikingly similar phenotype. The third individual has a novel c.5354G>A p.(Cys1785Try) variant. Our reports expand the clinical spectrum to include ventriculomegaly, absent corpus callosum, staphyloma, cochlear malformations, and exomphalos. These additional cases also help to establish genotype-phenotype correlations in this disorder. After the first and last authors of the previous two reports, we propose to call this disorder "Menke-Hennekam syndrome" to establish it as a clinical entity distinct from RTS and to provide a satisfactory name for adoption by parents and professionals, thus facilitating appropriate clinical management and research.

MeCP2 Deficiency Leads to Loss of Glial Kir4.1.

Rett syndrome (RTT) is an X-linked neurodevelopmental disorder usually caused by mutations in methyl-CpG-binding protein 2 (MeCP2). RTT is typified by apparently normal development until 6-18 mo of age, when motor and communicative skills regress and hand stereotypies, autonomic symptoms, and seizures present. Restoration of MeCP2 function selectively to astrocytes reversed several deficits in a murine model of RTT, but the mechanism of this rescue is unknown. Astrocytes carry out many essential functions required for normal brain functioning, including extracellular K+ buffering. Kir4.1, an inwardly rectifying K+ channel, is largely responsible for the channel-mediated K+ regulation by astrocytes. Loss-of-function mutations in Kir4.1 in human patients result in a severe neurodevelopmental disorder termed EAST or SESAME syndrome. Here, we evaluated astrocytic Kir4.1 expression in a murine model of Rett syndrome. We demonstrate by chromatin immunoprecipitation analysis that Kir4.1 is a direct molecular target of MeCP2. Astrocytes from Mecp2-deficient mice express significantly less Kir4.1 mRNA and protein, which translates into a >50% deficiency in Ba2+-sensitive Kir4.1-mediated currents, and impaired extracellular potassium dynamics. By examining astrocytes in isolation, we demonstrate that loss of Kir4.1 is cell autonomous. Assessment through postnatal development revealed that Kir4.1 expression in Mecp2-deficient animals never reaches adult, wild-type levels, consistent with a neurodevelopmental disorder. These are the first data implicating a direct MeCP2 molecular target in astrocytes and provide novel mechanistic insight explaining a potential mechanism by which astrocytic dysfunction may contribute to RTT.

The role of glial-specific Kir4.1 in normal and pathological states of the CNS.

Kir4.1 is an inwardly rectifying K(+) channel expressed exclusively in glial cells in the central nervous system. In glia, Kir4.1 is implicated in several functions including extracellular K(+) homeostasis, maintenance of astrocyte resting membrane potential, cell volume regulation, and facilitation of glutamate uptake. Knockout of Kir4.1 in rodent models leads to severe neurological deficits, including ataxia, seizures, sensorineural deafness, and early postnatal death. Accumulating evidence indicates that Kir4.1 plays an integral role in the central nervous system, prompting many laboratories to study the potential role that Kir4.1 plays in human disease. In this article, we review the growing evidence implicating Kir4.1 in a wide array of neurological disease. Recent literature suggests Kir4.1 dysfunction facilitates neuronal hyperexcitability and may contribute to epilepsy. Genetic screens demonstrate that mutations of KCNJ10, the gene encoding Kir4.1, causes SeSAME/EAST syndrome, which is characterized by early onset seizures, compromised verbal and motor skills, profound cognitive deficits, and salt-wasting. KCNJ10 has also been linked to developmental disorders including autism. Cerebral trauma, ischemia, and inflammation are all associated with decreased astrocytic Kir4.1 current amplitude and astrocytic dysfunction. Additionally, neurodegenerative diseases such as Alzheimer disease and amyotrophic lateral sclerosis demonstrate loss of Kir4.1. This is particularly exciting in the context of Huntington disease, another neurodegenerative disorder in which restoration of Kir4.1 ameliorated motor deficits, decreased medium spiny neuron hyperexcitability, and extended survival in mouse models. Understanding the expression and regulation of Kir4.1 will be critical in determining if this channel can be exploited for therapeutic benefit.

GABAergic disinhibition and impaired KCC2 cotransporter activity underlie tumor-associated epilepsy.

Seizures frequently accompany gliomas and often escalate to peritumoral epilepsy. Previous work revealed the importance of tumor-derived excitatory glutamate (Glu) release mediated by the cystine-glutamate transporter (SXC) in epileptogenesis. We now show a novel contribution of GABAergic disinhibition to disease pathophysiology. In a validated mouse glioma model, we found that peritumoral parvalbumin-positive GABAergic inhibitory interneurons are significantly reduced, corresponding with deficits in spontaneous and evoked inhibitory neurotransmission. Most remaining peritumoral neurons exhibit elevated intracellular Cl(-) concentration ([Cl(-) ]i ) and consequently depolarizing, excitatory gamma-aminobutyric acid (GABA) responses. In these neurons, the plasmalemmal expression of KCC2, which establishes the low [Cl(-) ]i required for GABAA R-mediated inhibition, is significantly decreased. Interestingly, reductions in inhibition are independent of Glu release, but the presence of both decreased inhibition and decreased SXC expression is required for epileptogenesis. We suggest GABAergic disinhibition renders peritumoral neuronal networks hyper-excitable and susceptible to seizures triggered by excitatory stimuli, and propose KCC2 as a therapeutic target.

Particle numbers of lipoprotein subclasses and arterial stiffness among middle-aged men from the ERA JUMP study.

We examined the association between serum lipoprotein subclasses and the three measures of arterial stiffness, that is, (i) carotid-femoral pulse wave velocity (cfPWV), which is a gold standard measure of central arterial stiffness, (ii) brachial-ankle PWV (baPWV), which is emerging as a combined measure of central and peripheral arterial stiffness and (iii) femoral-ankle PWV (faPWV), which is a measure of peripheral arterial stiffness. Among a population-based sample of 701 apparently healthy Caucasian, Japanese American and Korean men aged 40-49 years, concentrations of lipoprotein particles were assessed by nuclear magnetic resonance (NMR) spectroscopy, and the PWV was assessed with an automated waveform analyzer (VP2000, Omron, Japan). Multiple linear regressions were performed to analyse the association between each NMR lipoprotein subclasses and PWV measures, after adjusting for cardiovascular risk factors and other confounders. A cutoff of P<0.01 was used for determining significance. All PWV measures had significant correlations with total and small low-density lipoprotein particle number (LDL-P) (all P<0.0001) but not LDL cholesterol (LDL-C) (all P>0.1), independent of race and age. In multivariate regression analysis, no NMR lipoprotein subclass was significantly associated with cfPWV (all P>0.01). However, most NMR lipoprotein subclasses had significant associations with both baPWV and faPWV (P<0.01). In this study of healthy middle-aged men, as compared with cfPWV, both baPWV and faPWV had stronger associations with particle numbers of lipoprotein subclasses. Our results may suggest that both baPWV and faPWV are related to arterial stiffness and atherosclerosis, whereas cfPWV may represent arterial stiffness alone.

Comparative pharmacokinetic studies of fast dissolving film and oral solution of ondansetron in rats.

Ondansetron, selective serotonin (5-HT3) receptor blocker, is used in treating chemotherapy induced nausea and vomiting in cancer patients. Mouth dissolving films containing ondansetron were developed to have better onset and patient compliances. The drug content of prepared films was within 85%-115%. The films were found to be stable for 4 months when stored at 40 %°C and 75% RH. In-vitro dissolution studies suggested a rapid disintegration, in which most of ondansetron was released (91.5±3.4%) within 90 sec. Subsequently, Sprague-Dawley rats were used to compare pharmacokinetic parameters of the formulated films with oral administration of pure drug solution. Pharmacokinetic parameters were similar between the two groups in which AUC0-t (ng h/ml), AUC0-∞ (ng h/ml), Cmax (ng/ml), Tmax (min), Kel (h(-1)) and t1/2 (h) of reference was 109.091±15.73, 130.32±18.56, 28.5±4.053, 60, 0.1860±0.0226, and 3.771±0.498 respectively; and for formulated film 113.663±16.64, 151.79±16.54, 30±3.51, 60, 0.1521±0.0310 and 4.755±0.653 respectively. These results suggest that the fast dissolving film containing ondansetron is likely to become one of the choices to treat chemotherapy induced nausea and vomiting.