Recognition of diabetic retinopathy and macular edema using deep learning.

Diabetic retinopathy (DR) and diabetic macular edema (DME) are both serious eye conditions associated with diabetes and if left untreated, and they can lead to permanent blindness. Traditional methods for screening these conditions rely on manual image analysis by experts, which can be time-consuming and costly due to the scarcity of such experts. To overcome the aforementioned challenges, we present the Modified CornerNet approach with DenseNet-100. This system aims to localize and classify lesions associated with DR and DME. To train our model, we first generate annotations for input samples. These annotations likely include information about the location and type of lesions within the retinal images. DenseNet-100 is a deep CNN used for feature extraction, and CornerNet is a one-stage object detection model. CornerNet is known for its ability to accurately localize small objects, which makes it suitable for detecting lesions in retinal images. We assessed our technique on two challenging datasets, EyePACS and IDRiD. These datasets contain a diverse range of retinal images, which is important to estimate the performance of our model. Further, the proposed model is also tested in the cross-corpus scenario on two challenging datasets named APTOS-2019 and Diaretdb1 to assess the generalizability of our system. According to the accomplished analysis, our method outperformed the latest approaches in terms of both qualitative and quantitative results. The ability to effectively localize small abnormalities and handle over-fitted challenges is highlighted as a key strength of the suggested framework which can assist the practitioners in the timely recognition of such eye ailments.

A systematic review on understanding the mechanistic pathways and clinical aspects of natural CDK inhibitors on cancer progression.: Unlocking cellular and biochemical mechanisms.

Cell division, differentiation, and controlled cell death are all regulated by phosphorylation, a key biological function. This mechanism is controlled by a variety of enzymes, with cyclin-dependent kinases (CDKs) being particularly important in phosphorylating proteins at serine and threonine sites. CDKs, which contain 20 unique components, serve an important role in regulating vital physiological functions such as cell cycle progression and gene transcription. Methodologically, an extensive literature search was performed using reputable databases such as PubMed, Google Scholar, Scopus, and Web of Science. Keywords encompassed "cyclin kinase," "cyclin dependent kinase inhibitors," "CDK inhibitors," "natural products," and "cancer therapy." The inclusion criteria, focused on relevance, publication date, and language, ensured a thorough representation of the most recent research in the field, encompassing articles published from January 2015 to September 2023. Categorization of CDKs into those regulating transcription and those orchestrating cell cycle phases provides a comprehensive understanding of their diverse functions. Ongoing clinical trials featuring CDK inhibitors, notably CDK7 and CDK4/6 inhibitors, illuminate their promising potential in various cancer treatments. This review undertakes a thorough investigation of CDK inhibitors derived from natural (marine, terrestrial, and peptide) sources. The aim of this study is to provide a comprehensive comprehension of the chemical classifications, origins, target CDKs, associated cancer types, and therapeutic applications.

Molecular modeling of novel 2-aminopyridine derivatives as potential JAK2 inhibitors: a rational strategy for promising anticancer agents.

Janus kinase 2(JAK2) is a potential target for anticancer drugs in the treatment of numerous myeloproliferative diseases due to its central role in the JAK/STAT signaling cascade. In this study, the binding behavior of 2 amino-pyridine derivatives as JAK2 inhibitors was investigated by using multifaceted strategies including 3D-QSAR, molecular docking, Fingerprint analysis, MD simulations, and MM-PBSA calculations. A credible COMFA (q2 = 0.606 and r2 = 0.919) and COMSIA (q2 = 0.641 and r2 = 0.992) model was developed, where the internal and external validation revealed that the obtained 3D-QSAR models could be capable of predicting bioactivities of JAK2 inhibitors. The structural criteria provided by the contour maps of model were used to computationally develop more potent 100 new JAK2 inhibitors. Docking studies were conducted on the model data set and newly developed compounds (in-house library) to demonstrate their binding mechanism and highlight the key interacting residues within JAK2 active site. The selected docked complexes underwent MD simulation (100 ns), which contributed in the further study of the binding interactions. Binding free energy analyses (MMGB/PBSA) revealed that key residues such as Glu930, Leu932 (hinge region), Asp939 (solvent accessible region), Arg980, Asn981and Asp994 (catalytic site) have a significantly facilitate ligand-protein interactions through H-bonding and van der Waals interactions. The preliminary in-silico ADMET evaluation revealed encouraging results for all the modeled and in-house library compounds. The findings of this research have the potential to offer valuable recommendations for the advancement of novel, potent, and efficacious JAK2 inhibitors. Overall, this work has successfully employed a wide range of computer-based methodologies to understand the interaction dynamics between 2-amino-pyridine derivatives and the JAK2 enzyme, which is a crucial target in myeloproliferative disorders.Communicated by Ramaswamy H. Sarma.

Streptomyces enissocaesilis L-82 has broad-spectrum antibacterial activity and promotes growth for Carassius auratus.

Aeromonas is the main pathogen causing bacterial diseases in fish. The disadvantages of chemical drugs to control fish diseases have been highlighted, and it is urgent to find an eco-friendly control method. In this study, an actinomycete strain with antibacterial activity against fish pathogenic bacteria was screened from soil samples. Combined with morphological characteristics, physiological and biochemical characteristics, and gyrB gene and whole genome comparison analysis, it was identified as a new strain of Streptomyces enissocaesilis, named Streptomyces enissocaesilis L-82. The strain has broad-spectrum antibacterial activity against fish pathogens. A substance with a mass-to-charge ratio of 227.20 [M + H] + was isolated and purified by high-performance liquid chromatography and mass spectrometry. It was presumed to be a derivative of 5-dimethylallylindole-3-acetonitrile. The strain is safe and non-toxic to crucian carp, and can stably colonize crucian carp and inhibit the proliferation of A. hydrophila. After feeding the feed containing 1 × 108 CFU/mL strain concentration, the weight growth rate and specific growth rate of crucian carp increased, the activity of ACP and SOD in serum increased, and the survival rate of crucian carp increased after challenge. Genome-wide analysis showed that the strain had strong ability to metabolize and tolerate extreme environments. And has a strong potential for disease resistance. Therefore, the strain is expected to be developed as a feed additive for fish farming. KEY POINTS: • The new Streptomyces enissocaesilis L-82 has a broad spectrum and stable antibacterial activity and meets the safety standards of feed additives. • Strain L-82 can colonize crucian carp, improve the growth, antioxidant, and immune performance of the host, and improve the survival rate after being infected with A. hydrophila. • Genome-wide analysis suggests that the strain has great disease resistance potential and is expected to be developed as a feed additive for fish culture.

Comparative pharmacokinetic evaluation of glimepiride orodispersable and conventional tablets in rabbits.

OBJECTIVES: Glimepiride Orodispersable Tablets (ODT) were prepared with the goal to have rapid onset of action and higher bioavailability with ease administration to individuals with swallowing difficulty to ameliorate patient compliance. SIGNIFICANCE: Glimepiride is a contemporary hypoglycemic medication that belongs to the family of sulfonylurea derivatives. It is used in type 2 diabetes mellitus. Compliance adherence remains one of the limitations with the conventional drug delivery system especially in pediatric, geriatric, psychiatric, and traveling patients, for such population ODT provides a good alternate dosage form compared with Commercial Tablets. METHOD: The Comparative in vivo pharmacokinetic parameters of the prepared ODT and conventional tablets (CT) were evaluated using an animal model. The plasma concentration of Glimepiride after oral administration of a single dose was determined at predetermined time intervals with HPLC. The pharmacokinetic parameters were calculated using PK Solutions 2.0 from Summit PK® software. RESULTS: The Cmax obtained with ODT (22.08 µg/ml) was significantly (p = 0.006) high, a lower tmax of 3.0 hr was achieved with the orodispersable formulation of the drug. The ODT showed 104.34% relative bioavailability as compared to CT and left shift of tmax as well. CONCLUSION: As per findings of the in vivo investigation, the Glimepiride ODT would be beneficial in terms of patient compliance, quick onset of action, and increased bioavailability.

Biochemical, Toxicological, and in Silico Aspects of Trillium govanianum Wall. ex D.Don (Trilliaceae): A Rich Source of Natural Bioactive Compounds.

Trillium govanianum is a high-value medicinal herb, having multifunctional traditional and culinary uses. The present investigation was carried out to evaluate the phytochemical, biological and toxicological parameters of the T. govanianum Wall. ex D. Don (Family: Trilliaceae) roots collected from Azad Kashmir, Pakistan. Phytochemical profiling was achieved by determining total bioactive contents (total phenolic and flavonoid contents) and UHPLC-MS analysis. For biological evaluation, antioxidant activities (DPPH, ABTS, FRAP, CUPRAC, phosphomolybdenum, and metal chelation assays) and enzyme inhibition activities (against AChE, BChE, glucosidase, amylase, and tyrosinase) were performed. Moreover, cytotoxicity was assessed against three human carcinoma cell lines (MDA-MB-231, CaSki, and DU-145). The tested extract was found to contain higher total phenolics (7.56 mg GAE/g dry extract) as compared to flavonoid contents (0.45 mg RE/g dry extract). Likewise, for the antioxidant activity, higher CUPRAC activity was noted with 39.84 mg TE/g dry extract values. In the case of enzyme assays, higher activity was pointed out against the cholinesterase, glucosidase and tyrosinase enzymes. The plant extract displayed significant cytotoxicity against the cell lines examined. Moreover, the in-silico studies highlighted the interaction between the important phytochemicals and tested enzymes. To conclude, the assessed biological activity and the existence of bioactive phytochemicals in the studied plant extract may pave the way for the development of novel pharmaceuticals.

3D-QSAR, docking and molecular dynamics simulations of novel Pyrazolo-pyridazinone derivatives as covalent inhibitors of FGFR1: a scientific approach for possible anticancer agents.

Developing highly potent covalent inhibitors of Fibroblast growth factor receptors 1 (FGFR1) has always been a challenging task. In the current study, various computational techniques, such as 3D-QSAR, covalent docking, fingerprinting analysis, MD simulation followed by MMGB/PBSA, and per-residue energy decomposition analysis were used to explore the binding mechanism of pyrazolo[3,4-d]pyridazinone derivatives to FGFR1. The high q2 and r2 values for the CoMFA and CoMSIA models, suggest that the constructed 3D-QSAR models could reliably predict the bioactivities of FGFR1 inhibitors. The structural requirements revealed by the model's contour maps were strategically used to computationally create an in-house library of more than 100 new FGFR1 inhibitors using the R-group exploration technique implemented in the SparkTM software. The compounds from the in-house library were also mapped in the 3D-QSAR model that predicts comparable pIC50 values with the experimental values. A comparison between 3D-QSAR generated contours and molecular docking conformation of ligands was performed to reveal the fundamentals to design potent FGFR1 covalent inhibitors. The estimated binding free energies (MMGB/PBSA) for the selected compounds were in agreement with the experimental value ranking of their binding affinities towards FGFR1. Furthermore, per-residue energy decomposition analysis has identified Arg627 and Glu531 to contribute significantly in improved binding affinity of compound W16. During ADME analysis, the majority of in-house library compounds exhibited pharmacokinetic properties superior to those of experimentally produced compounds. These new compounds may help researchers better understand FGFR1 inhibition and lead to the creation of novel, potent FGFR1 inhibitors.Communicated by Ramaswamy H. Sarma.

Synthesis of novel nonsteroidal anti-inflammatory galloyl ß-sitosterol-loaded lignin-capped Ag-based drug.

Biocompatible anti-inflammatory lignin-capped Ag (LCAg) nanoparticles (NPs) were synthesized for the delivery of galloyl ß-sitosterol (Galloyl-BS). ß-Sitosterol (BS) is effective against inflammatory responses, like cancer-induced inflammations. BS was modified via gallic acid esterification to enhance its anti-inflammatory potential. LCAg NPs were synthesized by a green method and loaded with galloyl-BS. For comparison, pure BS was also loaded onto LCAg NPs in a separate assembly. The antioxidant potential of Galloyl-BS was greater (IC50 177 µM) than pure BS. Materials were characterized by FT-IR, SEM, XRD, and Zeta potential. Using UV-Vis spectroscopy, drug release experiments were performed by varying pH, time, concentration, and temperature. Maximum drug release was observed after 18 h at pH 6 and 40 °C. Galloyl-BS showed improved drug loading efficiency, release %age, and antioxidant activity compared to pure BS when loaded onto LCAg NPs. DLCAg exhibited excellent anti-inflammatory activity in rat models. These findings indicate that galloyl-BS (drug)-loaded LCAg (DLCAg) NPs have the potential as an anti-inflammatory agent without any prior release and scavenging in normal cells.

Integrated computational approaches for designing potent pyrimidine-based CDK9 inhibitors: 3D-QSAR, docking, and molecular dynamics simulations.

CDK9 is an emerging target for the development of anticancer drugs. The development of CDK9 inhibitors with significant potency had consistently posed a formidable challenge. In the current research, a number of computational methodologies, such as, 3D-QSAR, molecular docking, fingerprint analysis, molecular dynamic (MD) simulations followed by MMGB/PBSA and ADMET studies were used systemically to uncover the binding mechanism of pyrimidine derivatives against CDK9. The CoMFA and CoMSIA models having high q2 (0.53, 0.54) and r2 values (0.96, 0.93) respectively indicating that model could accurately predict the bioactivities of CDK9 inhibitors. Using the R-group exploration technique implemented by the Spark™ by Cresset group, the structural requirements revealed by the contour maps of model were utilized strategically to create an in-house library of 100 new CDK9 inhibitors. Additionally, the compounds from the in-house library were mapped into 3D-QSAR model which predicted pIC50 values comparable to the experimental values. A comparison between 3D-QSAR generated contours and molecular docking conformation of ligands was performed to elucidate the essentials of CDK9 inhibitor design. MD simulations (100 ns) were performed on the selected docked complexes A21, A14 and D98 which contributed in validating the binding interactions. According to the findings of binding free energy analysis (MMGB/PBSA), It was observed that residues CYS106 and GLU107 had a considerable tendency to facilitate ligand-protein interactions via H-bond interactions. The aforementioned findings have the potential to enhance researchers comprehension of the mechanism underlying CDK9 inhibition and may be utilized in the development of innovative and efficacious CDK9 inhibitors.

Unravelling the secrets of lesser florican: a study of their home range and habitat use in Gujarat, India.

The home range of a species is determined by a complex interplay of extrinsic and intrinsic factors, which can have profound impacts on the species' resource use. Understanding these dynamics is especially important for conserving critically endangered species. In this study, we used satellite telemetry to investigate the home range of the critically endangered lesser florican (Sypheotides indicus) in Gujarat, India. We analysed GPS locations from 10 lesser floricans deployed with GPS/GSM transmitters between 2020 and 2022. The average home range size (95% KDE) was 10.73 ± 10.70 km2 (mean ± SD), while the average core area (50% KDE) was 1.95 ± 1.56 km2 (mean ± SD). The monthly and daily distances covered were 286.29 ± 599.42 km and 10.11 ± 19.78 km, respectively. Our analysis indicated that suitable habitats and movement patterns were the most important factors explaining the variation in home range size. Specifically, our results suggest that lesser floricans prefer multi-use agro-grassland habitat systems with heterogeneous structures to accommodate different life history requirements. This preference may reflect the depletion and degradation of grasslands across the species' range. Therefore, managing grassland habitats amidst croplands should be one of the key conservation strategies for the lesser florican.

Preparation of Tamsulosin Hydrochloride-Loaded Mucoadhesive In Situ Gelling Polymeric Formulation for Nasal Delivery in Geriatrics.

This study aimed to prepare tamsulosin hydrochloride (HCl)-loaded in situ gelling formulation by using hydroxypropyl methylcellulose (HPMC), gellan gum, poloxamer 188, and benzalkonium chloride. Physicochemical evaluation of formulations included determination of pH, viscosity, gelation time, gel strength, drug content, and sterility. In silico study was performed to analyze interactions between polymers, drug, and mucin glycoprotein. In vitro degradation time, drug release, ex vivo mucoadhesion time, permeation, in vivo pharmacokinetics, and stability studies were performed to assess the formulation. Formulations were transparent and displayed acceptable physicochemical attributes. Tamsulosin HCl and polymers interacted via non-covalent interactions. HPMC formed hydrogen bonds, hydrophobic and van der Waals interactions with mucin protein while the drug formed hydrogen bonds only. Gel formulation degraded in simulated nasal fluid within 24 h. In situ gelling formulation showed 83.8 ± 1.7% drug release and remained adhered to the mucosa for 24.5 ± 1 h. A higher (~ 1.85 times) drug permeation was recorded through mucosa within 6 h by in situ gelling formulation when compared to control counterparts (aqueous solution of drug and in situ gelling formulation without poloxamer 188). Nasal administration of tamsulosin HCl by using in situ gelling formulation led to a ~ 3.3 and ~ 3.5 times, respectively, higher Cmax (maximum plasma concentration) and AUCtotal (total area under the curve) than the orally administered aqueous solution. Relative bioavailability of drug delivered by nasal in situ gelling formulation was 3.5 times the oral counterpart. These results indicated that the prepared in situ gelling formulation can act as a promising candidate for systemic administration of tamsulosin HCl.

TumorDetNet: A unified deep learning model for brain tumor detection and classification.

Accurate diagnosis of the brain tumor type at an earlier stage is crucial for the treatment process and helps to save the lives of a large number of people worldwide. Because they are non-invasive and spare patients from having an unpleasant biopsy, magnetic resonance imaging (MRI) scans are frequently employed to identify tumors. The manual identification of tumors is difficult and requires considerable time due to the large number of three-dimensional images that an MRI scan of one patient's brain produces from various angles. Moreover, the variations in location, size, and shape of the brain tumor also make it challenging to detect and classify different types of tumors. Thus, computer-aided diagnostics (CAD) systems have been proposed for the detection of brain tumors. In this paper, we proposed a novel unified end-to-end deep learning model named TumorDetNet for brain tumor detection and classification. Our TumorDetNet framework employs 48 convolution layers with leaky ReLU (LReLU) and ReLU activation functions to compute the most distinctive deep feature maps. Moreover, average pooling and a dropout layer are also used to learn distinctive patterns and reduce overfitting. Finally, one fully connected and a softmax layer are employed to detect and classify the brain tumor into multiple types. We assessed the performance of our method on six standard Kaggle brain tumor MRI datasets for brain tumor detection and classification into (malignant and benign), and (glioma, pituitary, and meningioma). Our model successfully identified brain tumors with remarkable accuracy of 99.83%, classified benign and malignant brain tumors with an ideal accuracy of 100%, and meningiomas, pituitary, and gliomas tumors with an accuracy of 99.27%. These outcomes demonstrate the potency of the suggested methodology for the reliable identification and categorization of brain tumors.

Aicardi syndrome in a Nigerian female child: A case report and literature review of a rare neuro-developmental disorder from North-Western Nigeria.

Aicardi syndrome is a very rare neurodevelopmental disorder, inherited as an X-linked dominant condition with a triad of infantile spasm, partial or complete agenesis of the corpus callosum, and chorio-retinal "lacunae." We report a case of a female infant with the classical triad of Aicardi syndrome. A female infant presented to the Paediatric Neurology Clinic of the Federal Medical Centre Birnin-Kebbi, North-western Nigeria, at the age of two months with complaints of recurrent afebrile convulsions typical for infantile spasms. The patient was delivered at term with normal Apgar scores and anthropometry. Examination revealed an infant with no dysmorphic features and normal systemic examination. Magnetic Resonance Imaging (MRI) of the brain however, showed complete agenesis of the corpus callosum and dilatation of the posterior horn of the lateral and third ventricles. Fundoscopy showed multiple yellowish spots along the vascular arcades in the right eye. The left eye had a one-disc diameter lacuna in the superior nasal quadrant adjacent to the optic disc with multiple yellowish spots. A diagnosis of Aicardi syndrome was made. The child was placed on oral phenobarbital and followed up. At the age of 18 months, the child can only sit without support, hold an object in each hand, smile socially, and babble. The frequency of the seizures had also reduced from >100 episodes per day to 2-3 episodes per day, but the child had developed right-sided spastic hemiparesis. The patient was commenced on physiotherapy and the anti-epileptic drugs were maintained. We recommend clinicians consider Aicardi syndrome in the differential diagnosis of any child presenting with infantile spasms.

Transition metal doped CeO2 for photocatalytic removal of 2-chlorophenol in the exposure of indoor white light and antifungal activity.

Besides natural sunlight and expensive artificial lights, economical indoor white light can play a significant role in activating a catalyst for photocatalytic removal of organic toxins from contaminated water. In the current effort, CeO2 has been modified with Ni, Cu, and Fe through doping methodology to study the removal of 2-chlorophenol (2-CP) in the illumination of 70 W indoor LED white light. The absence of additional diffractions due to the dopants and few changes such as reduction in peaks' height, minor peak shift at 2θ (28.525°) and peaks' broadening in XRD patterns of modified CeO2 verifies the successful doping of CeO2. The solid-state absorption spectra revealed higher absorbance of Cu-doped CeO2 whereas a lower absorption response was observed for Ni-doped CeO2. An interesting observation regarding the lowering of indirect bandgap energy of Fe-doped CeO2 (∼2.7 eV) and an increase in Ni-doped CeO2 (∼3.0 eV) in comparison to pristine CeO2 (∼2.9 eV) was noticed. The process of e -- h + recombination in the synthesized photocatalysts was also investigated through photoluminescence spectroscopy. The photocatalytic studies revealed the greater photocatalytic activity of Fe-doped CeO2 with a higher rate (∼3.9 × 10-3 min-1) among all other materials. Moreover, kinetic studies also revealed the validation of the Langmuir-Hinshelwood kinetic model (R2 = 0.9839) while removing 2-CP in the exposure of indoor light with a Fe-doped CeO2 photocatalyst. The XPS analysis revealed the existence of Fe3+, Cu2+ and Ni2+ core levels in doped CeO2. Using the agar well-diffusion method, the antifungal activity was assessed against the fungus M. fructicola and F. oxysporum. Compared to CeO2, Ni-doped CeO2, and Cu-doped CeO2 nanoparticles, the Fe-doped CeO2 nanoparticles have outstanding antifungal properties.

Rapidly Progressive Glomerulonephritis: A COVID-19 Case Report.

Anti-neutrophil cytoplasmic antibody (ANCA) associated vasculitis is a systemic autoimmune disease that typically presents as a multi-organ manifesting disease of unclear etiology that can predispose to rapidly progressive glomerulonephritis (RPGN). If left untreated, ANCA-associated vasculitis can be fatal, and RPGN can progress to irreversible renal failure. Environmental and genetic factors have been implicated in the pathogenesis of this vasculitis. Coronavirus disease (COVID-19) has been noted to have various physiologic impacts on the body, with literature indicating possible autoimmune effects. We present a rare case of ANCA-associated vasculitis in an elderly male with no known autoimmune history after a recent illness with COVID-19. The patient had been seen as an outpatient with progressively declining renal function until he presented to the hospital with acute renal failure and pericarditis. Workup revealed elevated anti-myeloperoxidase antibody (MPO-AB) and perinuclear ANCA (p-ANCA) antibodies with a biopsy confirming focal cresenteric glomerulonephritis, and the patient was initiated on steroid therapy with notable improvement and a return to baseline kidney function.

Outcomes of gout in patients with cirrhosis: A national inpatient sample-based study.

BACKGROUND: Hyperuricemia is a prerequisite for the development of gout. Elevated serum uric acid (UA) levels result from either overproduction or decreased excretion. A positive correlation between serum UA levels, cirrhosis-related complications and the incidence of nonalcoholic fatty liver disease has been established, but it is unknown whether hyperuricemia results in worsening cirrhosis outcomes. We hypothesize that patients with cirrhosis will have poorer gout outcomes. AIM: To explore the link between cirrhosis and the incidence of gout-related complications. METHODS: This was a cross-sectional study. The national inpatient sample was used to identify patients hospitalized with gout, stratified based on a history of cirrhosis, from 2001 to 2013 via the International Classification of Diseases, Ninth Revision, Clinical Modification codes. Primary outcomes were mortality, gout complications and joint interventions. The χ 2 test and independent t-test were performed to assess categorical and continuous data, respectively. Multiple logistic regression was used to control for confounding variables. RESULTS: Patients without cirrhosis were older (70.37 ± 13.53 years vs 66.21 ± 12.325 years; P < 0.05). Most patients were male (74.63% in the cirrhosis group vs 66.83%; adjusted P < 0.05). Patients with cirrhosis had greater rates of mortality (5.49% vs 2.03%; adjusted P < 0.05), gout flare (2.89% vs 2.77%; adjusted P < 0.05) and tophi (0.97% vs 0.75%; adjusted P = 0.677). Patients without cirrhosis had higher rates of arthrocentesis (2.45% vs 2.21%; adjusted P < 0.05) and joint injections (0.72% vs 0.52%; adjusted P < 0.05). CONCLUSION: Gout complications were more common in cirrhosis. Those without cirrhosis had higher rates of interventions, possibly due to hesitancy with performing these interventions given the higher complication risk in cirrhosis.

Molecular modeling of pyrrolo-pyrimidine based analogs as potential FGFR1 inhibitors: a scientific approach for therapeutic drugs.

Fibroblast growth factor receptors 1 (FGFR1) is an emerging target for the development of anticancer drugs. Uncontrolled expression of FGFR1 is strongly associated with a number of different types of cancers. Apart from a few FGFR inhibitors, the FGFR family members have not been thoroughly studied to produce clinically effective anticancer drugs. The application of proper computational techniques may aid in understanding the mechanism of protein-ligand complex formation, which may provide a better notion for developing potent FGFR1 inhibitors. In this study, a variety of computational techniques, including 3D-QSAR, flexible docking and MD simulation followed by MMGB/PBSA, H-bonds and distance analysis, have been performed to systematically explore the binding mechanism of pyrrolo-pyrimidine derivatives against FGFR1. The 3D-QSAR model was generated to deduce the structural determinants of FGFR1 inhibition. The high q2 and r2 values for the CoMFA and CoMSIA models indicated that the created 3D-QSAR models could reliably predict the bioactivities of FGFR1 inhibitors. The computed binding free energies (MMGB/PBSA) for the selected compounds were consistent with the ranking of their experimental binding affinities against FGFR1. Furthermore, per-residue energy decomposition analysis revealed that the residues Lys514 in catalytic region, Asn568, Glu571 in solvent accessible portion and Asp641 in DFG motif exhibited a strong tendency to mediate ligand-protein interactions through the hydrogen bonding and Van Der Waals interactions. These findings may benefit researchers in gaining better knowledge of FGFR1 inhibition and may serve as a guideline for the development of novel and highly effective FGFR1 inhibitors.Communicated by Ramaswamy H. Sarma.

Dose-dependent efficacy of bevacizumab in recurrent glioblastoma.

BACKGROUND: Bevacizumab (BEV), at a standard dose of 10 mg/kg every 2 weeks is associated with prolonged progression-free survival (PFS) but no improvement in overall survival (OS) in recurrent glioblastoma (rGBM). Few studies have examined the potential dose-dependent efficacy of BEV. In Ontario, reimbursement for the costs of BEV varies, and as a result, our practice began to routinely use lower dose regimens. The main aim of this study was to ensure that there was no harm to patients who received the low dose protocol. METHODS: A single-center retrospective study of patients given BEV for rGBM between 2015 and 2020 was performed. Clinical and treatment data including BEV dose regimen [SD (10 mg/kg every 2 weeks) vs. LD (5 mg/kg every 2-3 weeks or 10 mg/kg every 3 weeks)] received at the time of rGBM diagnosis were captured. Overall survival (OS) and progression-free survival (PFS) on BEV were compared using the Kaplan-Meier product-limit method. Log-rank test was used to compare potential predictive factors. Cox regression model was performed for multivariable analysis of OS and PFS. RESULTS: A total of 96 patients were included with a median follow-up duration of 6.84 months (range 1.12-50.63 months) from the date of the first infusion. The LD group consisted of 55 of the 96 patients. By virtue of funding mechanisms for BEV, the median age in the LD group was significantly higher (62 vs. 54 years p = 0.009). There was no difference in MGMT status between the two groups (p = 0.60). The LD group had prolonged median PFS (5.89 months versus 3.22 months; p = 0.0112) and OS (10.23 months versus 6.28 months; p = 0.0010). Multivariable analysis including the dose of BEV, the extent of resection, gender, and age revealed that standard dose of BEV, subtotal resection, and female sex were associated with worse overall survival. Nine patients in the SD group vs. 18 patients in the LD group reported an adverse event related to BEV. CONCLUSION: For patients with recurrent GBM, we found that a low dose regimen of BEV was associated with prolonged OS and PFS compared to the standard dose regimen. Lower dose schedules may be a better and more cost-effective option for patients with rGBM. Lower costs might provide more equitable access to this very important palliative drug.

Fabrication and employment of cobalt-doped yttrium iron garnets for the electrochemical analysis of anti-diabetic, metformin in serum of type 2 diabetes mellitus patients.

Metformin (MET) is an anti-diabetic drug employed as the first-line therapy for patients of type II diabetes mellitus (T2DM). Overdosage of drugs leads to severe outcomes, and its monitoring in biofluids is vital. The present study develops cobalt-doped yttrium iron garnets and employs them as an electroactive material immobilized on a glassy carbon electrode (GCE) for the sensitive and selective detection of metformin via electroanalytical techniques. The fabrication procedure via the sol-gel method is facile and gives a good yield of nanoparticles. They are characterized by FTIR, UV, SEM, EDX, and XRD. Pristine yttrium iron garnet particles are also synthesized for comparison, where the electrochemical behaviors of varying electrodes are analyzed via cyclic voltammetry (CV). The activity of metformin at varying concentrations and pH is investigated via differential pulse voltammetry (DPV), and the sensor generates excellent results for metformin detection. Under optimum conditions and at a working potential of 0.85 V (vs. Ag/AgCl/3.0 M KCl), the linear range and limit of detection (LOD) obtained through the calibration curve are estimated as 0-60 µM and 0.04 µM, respectively. The fabricated sensor is selective for metformin and depicts a blind response toward interfering species. The optimized system is applied to directly measure MET in buffers and serum samples of T2DM patients.