An overview of RAF kinases and their inhibitors (2019-2023).

Protein kinases (PKs) including RAF, perform a principal role in regulating countless cellular events such as cell growth, differentiation, and angiogenesis. Overexpression and mutation of RAF kinases are significant contributors to the development and spread of cancer. Therefore, RAF kinase inhibitors show promising outcomes as anti-cancer small molecules by suppressing the expression of RAF protein, blocking RAS/RAF interaction, or inhibiting RAF enzymes. Currently, there are insufficient reports about approving drugs with minimal degree of toxicity. Therefore, it is an urgent need to develop new RAF kinase inhibitors correlated with increased anticancer activity and lower cytotoxicity. This review outlines reported RAF kinase inhibitors for cancer treatment in patents and literature from 2019 to 2023. It highlights the available inhibitors by shedding light on their chemical structures, biochemical profiles, and current status. Additionally, we highlighted the hinge region-binding moiety of the reported compounds by showing the hydrogen bond patterns of representative inhibitors with the hinge region for each class. In recent years, RAF kinase inhibitors have gained considerable attention in cancer research and drug development due to their potential to be studied under clinical trials and their demonstration of various degrees of efficacy and safety profiles across different cancer types. However, addressing challenges related to drug resistance and safety represents a major avenue for the optimization and enhancement of RAF kinase inhibitors. Strategies to overcome such obstacles were discussed such as developing novel pan-RAF inhibitors, RAF dimer inhibitors, and combination treatments.

Thymoquinone, artemisinin, and thymol attenuate proliferation of lung cancer cells as Sphingosine kinase 1 inhibitors.

Sphingosine-1-phosphate (S1P) formed via catalytic actions of sphingosine kinase 1 (SphK1) behaves as a pro-survival substance and activates downstream target molecules associated with various pathologies, including initiation, inflammation, and progression of cancer. Here, we aimed to investigate the SphK1 inhibitory potentials of thymoquinone (TQ), Artemisinin (AR), and Thymol (TM) for the therapeutic management of lung cancer. We implemented docking, molecular dynamics (MD) simulations, enzyme inhibition assay, and fluorescence measurement studies to estimate binding affinity and SphK1 inhibitory potential of TQ, AR, and TM. We further investigated the anti-cancer potential of these compounds on non-small cell lung cancer (NSCLC) cell lines (H1299 and A549), followed by estimation of mitochondrial ROS, mitochondrial membrane potential depolarization, and cleavage of DNA by comet assay. Enzyme activity and fluorescence binding studies suggest that TQ, AR, and TM significantly inhibit the activity of SphK1 with IC50 values of 35.52 µM, 42.81 µM, and 53.68 µM, respectively, and have an excellent binding affinity. TQ shows cytotoxic effect and anti-proliferative potentials on H1299 and A549 with an IC50 value of 27.96 µM and 54.43 µM, respectively. Detection of mitochondrial ROS and mitochondrial membrane potential depolarization shows promising TQ-induced oxidative stress on H1299 and A549 cell lines. Comet assay shows promising TQ-induced oxidative DNA damage. In conclusion, TQ, AR, and TM act as potential inhibitors for SphK1, with a strong binding affinity. In addition, the cytotoxicity of TQ is linked to oxidative stress due to mitochondrial ROS generation. Overall, our study suggests that TQ is a promising inhibitor of SphK1 targeting lung cancer therapy.

Serum calgranulin C as a non-invasive predictor of activity among inflammatory bowel disease.

Inflammatory bowel disease is a chronic immune-mediated disorder with a relapsing and remitting course. It leads to disabling gastrointestinal symptoms, low quality of life, and a significant burden for healthcare utilization and associated costs. Therefore, non-invasive biomarkers are needed for early diagnosis and follow up to avoid the complications of invasive diagnostic procedures. Calgranulin C is a calcium binding protein with proinflammatory properties. The aim of this study was to evaluate the role of serum calgranulin C as a non-invasive biomarker for diagnosis and prediction of activity in comparison to different biomarkers and endoscopic activity scores in inflammatory bowel disease. The study included 80 inflammatory bowel disease patients (50 Ulcerative colitis and 30 Chron's patients) and 20 normal controls. Complete blood picture, C-reactive protein, erythrocyte sedimentation rate, fecal calprotectin and serum calgranulin C were measured. Colonoscopies with histopathological examination were done and different activity scoring systems assessed. Among ulcerative colitis group, serum calgranulin C was statistically significantly higher in comparison to control group [723.640±529.055 ng/ml versus 80.850±24.416 ng/ml]. Depending on the American college of gastroenterology ulcerative colitis activity index, fecal calprotectin and serum calgranulin C were statistically significantly higher among moderate to severe ulcerative colitis than those with mild activity and those in remission (p < 0.001, for both). Regarding Crohn's disease group, serum calgranulin C was statistically significantly higher in comparison to control group [759.233±797.963 ng/ml versus 80.850±24.416 ng/mL]. Depending on Crohn's disease activity index, both serum calgranulin C and fecal calprotectin were statistically significantly higher among active disease than those in remission (p < 0.001, for both). In conclusion, serum calgranulin C could be used as a non-invasive marker to predict activity and severity and to ensure remission among inflammatory bowel disease patients.

Management of Osteomyelitis in Autosomal Dominant Osteopetrosis: A Rare Case Report.

Albers-Schönberg disease, also known as osteopetrosis or marble bone disease, is a rare genetic disorder characterised by increased cortical bone mass due to dysfunctional osteoclast cells. This case report presents a 34-year-old male with autosomal dominant osteopetrosis (ADO), who was referred for evaluation and treatment of a chronic mandibular abscess with associated osteomyelitis and fistula. The patient's medical history included multiple fractures necessitating open reduction and internal fixation. Radiological examinations revealed the presence of chronic osteomyelitis in the mandible, marked by an increase in bone density and obliteration of medullary spaces. The treatment approach included surgical debridement, extraction of adjacent teeth, sequestrectomy, and antibiotic therapy. Notably, Enterobacter cloacae bacteria were identified through culture, leading to a tailored antibiotic regimen. Follow-up assessments, including clinical photographs and postoperative CT scans, were conducted to monitor the patient's progress. Histopathological examination confirmed osteomyelitis showing both viable and non-viable bone, surrounded by significant inflammatory infiltrate. This case underscores the complexity of managing osteomyelitis in patients with osteopetrosis and highlights the importance of early diagnosis, particularly before dental extractions, to prevent disease exacerbation. The rarity of this condition emphasises the need for further research and awareness among healthcare providers for optimal patient care.

An unmet need: Pancreatic beta cell replacement.

Diabetes mellitus (DM) is a growing public health concern in South Africa (SA) and poses a substantial economic burden on healthcare globally. A century has passed since the discovery of insulin, and despite advances in diabetes management, exogenous insulin remains a primary treatment for type 1 DM, posing challenges of hyperglycaemia and hypoglycaemia. Pancreas transplantation should be considered a treatment for insulin-deficient DM, offering sustained euglycaemia and preventing complications associated with the disease. However, there has been a global decrease in the number of transplants performed. In SA, only a few pancreas transplants have been performed, primarily because of surgical risks and the need for immunosuppression. Islet transplantation is an alternative but faces limitations due to donor scarcity and immunosuppression requirements. This review explores recent progress in pancreas and islet transplants for DM, with the aim of providing insights into expanding treatment options for people with insulin-deficient DM.

Renoprotective effects of apocynin and/or umbelliferone against acrylamide-induced acute kidney injury in rats: role of the NLRP3 inflammasome and Nrf-2/HO-1 signaling pathways.

Acrylamide (ACR) is a toxic, probably carcinogenic compound commonly found in fried foods and used in the production of many industrial consumer products. ACR-induced acute kidney injury is mediated through several signals. In this research, we investigated, for the first time, the therapeutic effects of phytochemicals apocynin (APO) and/or umbelliferone (UMB) against ACR-induced nephrotoxicity in rats and emphasized the underlying molecular mechanism. To achieve this goal, five groups of rats were randomly assigned: the control group received vehicle (0.5% CMC; 1 ml/rat), ACR (40 mg/kg, i.p.), ACR + APO (100 mg/kg, P.O.), ACR + UMB (50 mg/kg, P.O.), and combination group for 10 days. In ACR-intoxicated rats, there was a significant reduction in weight gain while the levels of blood urea, uric acid, creatinine, and Kim-1 were elevated, indicating renal injury. Histopathological injury was also observed in the kidneys of ACR-intoxicated rats, confirming the biochemical data. Moreover, MDA, TNF-α, and IL-1ß levels were raised; and GSH and SOD levels were decreased. In contrast, treatment with APO, UMB, and their combination significantly reduced the kidney function biomarkers, prevented tissue damage, and decreased inflammatory cytokines and MDA. Mechanistically, it suppressed the expression of NLRP-3, ASC, GSDMD, caspase-1, and IL-1ß, while it upregulated Nrf-2 and HO-1 in the kidneys of ACR-intoxicated rats. In conclusion, APO, UMB, and their combination prevented ACR-induced nephrotoxicity in rats by attenuating oxidative injury and inflammation, suppressing NLRP-3 inflammasome signaling, enhancing antioxidants, and upregulating Nrf-2 and HO-1 in the kidneys of ACR-induced rats.

Investigating Pyruvate Dehydrogenase Kinase 3 Inhibitory Potential of Myricetin Using Integrated Computational and Spectroscopic Approaches.

Protein kinases are involved in various diseases and currently represent potential targets for drug discovery. These kinases play major roles in regulating the cellular machinery and control growth, homeostasis, and cell signaling. Dysregulation of kinase expression is associated with various disorders such as cancer and neurodegeneration. Pyruvate dehydrogenase kinase 3 (PDK3) is implicated in cancer therapeutics as a potential drug target. In this current study, a molecular docking exhibited a strong binding affinity of myricetin to PDK3. Further, a 100 ns all-atom molecular dynamics (MD) simulation study provided insights into the structural dynamics and stability of the PDK3-myricetin complex, revealing the formation of a stable complex with minimal structural alterations upon ligand binding. Additionally, the actual affinity was ascertained by fluorescence binding studies, and myricetin showed appreciable binding affinity to PDK3. Further, the kinase inhibition assay suggested significant inhibition of PDK3 by myricetin, revealing an excellent inhibitory potential with an IC50 value of 3.3 µM. In conclusion, this study establishes myricetin as a potent PDK3 inhibitor that can be implicated in therapeutic targeting cancer and PDK3-associated diseases. In addition, this study underscores the efficacy of myricetin as a potential lead to drug discovery and provides valuable insights into the inhibition mechanism, enabling advancements in cancer therapeutics.

Verbena officinalis (VO) leaf extract as an anti-corrosion inhibitor for carbon steel in acidic environment.

In the present work, Verbena Officinalis (VO) leaf extract was used as potential corrosion inhibitor for the corrosion of carbon steel (CS) in 0.5 M H2SO4 medium. Further, the corrosion inhibiting nature of VO leaf extract towards the CS was evaluated using mass loss (ML), potentiodynamic polarization (PDP), electrical impedance spectroscopy (EIS) and surface morphological analyses using atomic force microscope (AFM) and X-ray photoelectron spectroscopy (XPS) techniques. Calculation of activation energy E a ∗ using Arrhenius equation shows the increase in activation energy when adding the VO leaf extract in 0.5 M H2SO4 medium and the maximum activation energy ( E a ∗ = 49.9 kJ mol-1) was observed for 1000 mg L-1 VO leaf extract in acid medium. The negative free energy values suggested the spontaneous and the stability of the adsorbed layer of VO leaf extract on the CS surface. Using EIS measurements, high percent inhibitory effectiveness of 91.1% for 1000 ppm solutions was achieved. With an increase in VO leaf extract dose, the double layer capacitance (Cdl) values fall while the values of charge transfer (Rct) increase. This showed that a protective layer of VO leaf extract on CS surface was formed. The polarization curves showed that the VO leaf extract acts as a mixed-type inhibitor. It is discovered that the adsorption of VO leaf extract molecules adhering to the CS surface followed the Langmuir isotherm. The anti-corrosion action of VO leaf extract is fully demonstrated by some surface techniques.

Effect of thermomechanical loading on fracture resistance and failure mode of new pressable zirconia-reinforced lithium disilicate onlay restoration.

Background: Insufficient information exists regarding the fracture resistance and failure pattern of newly developed zirconia-reinforced lithium disilicate (ZL, Vita Ambria) onlays. This in vitro study compared the fracture resistance of two types of onlays: monolithic lithium disilicate (LD) and monolithic ZL. Methods: Forty-eight ceramic onlay restorations were fabricated on epoxy dies using a maxillary first premolar model. The samples were divided into two main groups: LD and ZL. Half of each group was subjected to thermomechanical fatigue loading (TML) using a chewing simulator. All the samples were cemented with self-adhesive resin cement. Subsequently, they were loaded until failure in a universal testing machine, and the fracture patterns and resistance were recorded. Results: Before TML, ZL demonstrated the highest statistically significant mean fracture resistance (499.76±34.14N) compared to LD (470.40±27.38N). After TML, ZL showed the highest non-statistically significant mean fracture resistance (429.27±131.42N), while LD's mean fracture resistance decreased (377.31±62.18N). Conclusion: Monolithic zirconia-reinforced onlays demonstrated higher fracture resistance and a more favorable failure mode compared to LD. However, the impact of thermomechanical aging resulted in reduced fracture resistance for both materials, with a notable preference observed for ZL.

On the speech envelope in the cortical tracking of speech.

The synchronization between the speech envelope and neural activity in auditory regions, referred to as cortical tracking of speech (CTS), plays a key role in speech processing. The method selected for extracting the envelope is a crucial step in CTS measurement, and the absence of a consensus on best practices among the various methods can influence analysis outcomes and interpretation. Here, we systematically compare five standard envelope extraction methods the absolute value of Hilbert transform (absHilbert), gammatone filterbanks, heuristic approach, Bark scale, and vocalic energy), analyzing their impact on the CTS. We present performance metrics for each method based on the recording of brain activity from participants listening to speech in clear and noisy conditions, utilizing intracranial EEG, MEG and EEG data. As expected, we observed significant CTS in temporal brain regions below 10 Hz across all datasets, regardless of the extraction methods. In general, the gammatone filterbanks approach consistently demonstrated superior performance compared to other methods. Results from our study can guide scientists in the field to make informed decisions about the optimal analysis to extract the CTS, contributing to advancing the understanding of the neuronal mechanisms implicated in CTS.

Application of edible nanocomposites from chitosan/fenugreek seed mucilage/selenium nanoparticles for protecting lemon from green mold.

Green (Penicillium digitatum) mold can severely endanger the citrus fruits production and quality. Targeting the protection of lemon fruits from green mold infestations with nanobiotechnology approach, the fenugreek seed mucilage (FM) was extracted and exploited for biosynthesis of selenium (SeNPs) nanoparticles; their nanocomposites (NCs) with chitosan (CT) was constructed and employed as antifungal materials and edible coating (ECs) to protect lemon fruits against green mold. The nanoparticles formation and conjugations were verified by infrared (FTIR) analysis and electron microscopy. The FM-synthesized SeNPs had particles average of 8.35 nm, were the NCs of them with CT had size mean of 49.33 nm and charged with +22.8 mV. The CT/FM/SeNPs composite exhibited superior antifungal actions toward P. digitatum isolates, up to 32.2 mm inhibition diameter and 12.5 mg/mL inhibitory concentration, which exceeded the actions of imazilil. The microscopic screening of exposed P. digitatum to NCs clarified their mycelial destructive action within 30 h. The coating of infected lemons with fabricated NCs led to complete elimination of green mold development after 10 days of coating, without any infestation remarks. The innovative fabrication of NCs from CT/FM/SeNPs is strongly suggested to protect citrus crops from green mold and preserve fruits quality.

The Role of Epithelial Cell Adhesion Molecule Cancer Stem Cell Marker in Evaluation of Hepatocellular Carcinoma.

Background and Objectives: Hepatocellular carcinoma (HCC) is a prevalent form of malignancy that is characterized by high mortality rates and prognosis that remain suboptimal, largely due to treatment resistance mechanisms. Recent studies have implicated cancer stem cells (CSCs), particularly those expressing epithelial cell adhesion molecule (EpCAM), in HCC progression and resistance. In the present study, we sought to assess EpCAM expression in HCC patients and its correlation with various clinicopathological parameters. Materials and Methods: Tissue samples from 42 HCC patients were subjected to immunohistochemical staining to evaluate EpCAM expression. Clinicopathological data were obtained including the size, grade and stage of tumors, vascular invasion status, alpha-fetoprotein levels, and cirrhosis status. The Chi square and Fisher's exact tests were employed to assess the association between categorical groups. Independent Student-t test or Mann-Whitney U test was used to investigate the association between continuous patient characteristics and survival. Results: Immunohistochemical analysis revealed EpCAM expression in 52.5% of HCC cases. EpCAM-positive tumors exhibited characteristics indicative of aggressive disease, including larger tumor sizes (p = 0.006), greater tumor multiplicity (p = 0.004), higher grades (p = 0.002), more advanced stages (p = 0.003), vascular invasion (p = 0.023), elevated alpha-fetoprotein levels (p = 0.013), and cirrhosis (p = 0.052). Survival analysis demonstrated that EpCAM expression was significantly associated with lower overall rates of survival and higher rates of recurrence in HCC patients. Conclusions: Our findings suggest that EpCAM expression may serve as a prognostic biomarker for HCC with a potential role in patient management. Targeting EpCAM-positive CSCs may represent a promising approach to overcome treatment resistance and improve clinical outcomes in HCC. However, further investigation into the molecular mechanisms underlying EpCAM's role in HCC progression is warranted to facilitate the development of personalized therapeutic interventions.

Quinazoline Derivatives as Targeted Chemotherapeutic Agents.

Most of the current chemotherapeutic medications are extremely toxic, exhibit little selectivity, and contribute to the emergence of treatment resistance. Consequently, the discovery of targeted chemotherapy drugs with high selectivity and low side effects is necessary for cancer treatment. The quinazoline system has a broad range and a long history of biological activities. Numerous quinazoline derivatives have been used to treat different types of cancer by working on various molecular targets. This review presents various chemical information, including molecular structure, design, and biological activity of some reported quinazolines that function by inhibiting four types of important molecular targets: dihydrofolate reductase, breast cancer resistant protein, poly-(ADP-ribose)-polymerase, and tubulin polymerization.

Impact of Embolisate Penetration, Type, and Technique on Results After Standalone Middle Meningeal Artery Embolization for Chronic Subdural Hematoma.

BACKGROUND AND OBJECTIVES: Middle meningeal artery embolization (MMAE) has emerged as a promising modality for chronic/subacute subdural hematoma treatment; however, consensus regarding embolization technique and embolisate has not been achieved. We thus sought to compare the efficacy of distinct MMAE techniques and embolisate. METHODS: An institutional registry was reviewed to identify patients undergoing standalone MMAE for symptomatic chronic/subacute subdural hematoma. Surgical rescue rate and time preceding 50% hematoma resolution were evaluated across 3 technical groups: aggressive penetration (AP), nonaggressive penetration with proximal coil embolization (NP-PC), and nonaggressive penetration alone (NP). Effect sizes were adjusted for demographic, neurological and radiological features through multivariable logistic and Cox regression. RESULTS: Among 117 procedures, 33.3% achieved AP, 36.8% had NP-PC, and 29.9% had NP. The rate of surgical rescue was 2.6% after AP, 9.3% for NP-PC, and 11.4% for NP. In patients not undergoing rescue surgery, 82.4% achieved hematoma resolution ≥50% at a median imaging follow-up of 56 days; AP or NP-PC were each statistically significantly associated with enhanced hematoma resolution as compared with NP (P = .02). Similarly, sensitivity analysis within medium-size hematoma and antiplatelet/anticoagulation-at-admission subgroups revealed a superiority of resolution after AP or NP-PC. A unique, comparative secondary analysis of liquid embolisate (Onyx vs n-butyl cyanoacrylate) revealed no impact on rate of surgical rescue or hematoma resolution. CONCLUSION: AP was associated with the lowest rate of surgical rescue, while both AP and NP-PC were associated with improved rates of hematoma resolution.

Distal Medium Vessel Occlusion Strokes: Understanding the Present and Paving the Way for a Better Future.

Distal medium vessel occlusions (DMVOs) are thought to cause as many as 25% to 40% of all acute ischemic strokes and may result in substantial disability amongst survivors. Although intravenous thrombolysis (IVT) is more effective for distal than proximal vessel occlusions, the overall efficacy of IVT remains limited in DMVO with less than 50% of patients achieving reperfusion and about 1/3 to 1/4 of the patients failing to achieve functional independence. Data regarding mechanical thrombectomy (MT) among these patients remains limited. The smaller, thinner, and more tortuous vessels involved in DMVO are presumably associated with higher procedural risks whereas a lower benefit might be expected given the smaller amount of tissue territory at risk. Recent advances in technology have shown promising results in endovascular treatment of DMVOs with room for future improvement. In this review, we discuss some of the key technical and clinical considerations in DMVO treatment including the anatomical and clinical terminology, diagnostic modalities, the role of IVT and MT, existing technology, and technical challenges as well as the contemporary evidence and future treatment directions.

Effects of dietary supplementation with benthic diatom Amphora coffeaeformis on blood biochemistry, steroid hormone levels and seed production efficiency of Nile tilapia Oreochromis niloticus broodstock.

Aquafeed additive quality and quantity remain pivotal factors that constrain the sustainability and progress of aquaculture feed development. This study investigates the impact of incorporating the benthic diatom Amphora coffeaeformis into the diet of Nile tilapia (Oreochromis niloticus) broodstock, on the blood biochemistry, steroid hormone (SH) levels and seed production efficiency. Broodstock females displaying mature ovary indications were initially combined with males at a ratio of three females to one male. A total of 384 adult Nile tilapia (288 females and 96 males) were used, with 32 fish (24 females and eight males) assigned to each of 12 concrete tanks (8 m³; 2 m × 4 m × 1 m), with three replicate tanks for each dietary treatment, throughout a 14-day spawning cycle until egg harvest. Fish were fed one of four different dietary treatments: AM0% (control diet), and AM2%, AM4% and AM6% enriched with the diatom A. coffeaeformis at levels of 20, 40 and 60 g/kg of diet respectively. At the trial's conclusion, total protein, albumin, triglyceride and creatinine), SHs (follicle-stimulating hormone, luteinizing hormone, free testosterone, total testosterone, progesterone and prolactin) and seeds production efficiency of Nile tilapia improved significantly (p < 0.05) in alignment with the increment of A. coffeaeformis supplementation. The findings propose that including A. coffeaeformis at levels ranging from 4% to 6% could be effectively employed as a feed additive during the Nile tilapia broodstock's spawning season.

Mode of Onset Modifies the Effect of Time to Endovascular Reperfusion on Clinical Outcomes after Acute Ischemic Stroke: An Analysis of the DAWN Trial.

OBJECTIVE: We aimed to assess the impact of time to endovascular thrombectomy (EVT) on clinical outcomes in the DAWN trial, while also exploring the potential effect modification of mode of stroke onset on this relationship. METHODS: The association between every 1-h treatment delay with 90-day functional independence (modified Rankin Scale [mRS] score 0-2), symptomatic intracranial hemorrhage, and 90-day mortality was explored in the overall population and in three modes of onset subgroups (wake-up vs. witnessed vs. unwitnessed). RESULTS: Out of the 205 patients, 98 (47.8%) and 107 (52.2%) presented in the 6 to 12 hours and 12 to 24 hours time window, respectively. Considering all three modes of onset together, there was no statistically significant association between time last seen well to randomization with either functional independence or mortality at 90 days in either the endovascular thrombectomy (mRS 0-2 1-hour delay OR 1.07; 95% CI 0.93-1.24; mRS 6 OR 0.84; 95% CI 0.65-1.03) or medical management (mRS 0-2 1-hour delay OR 0.98; 95% CI 0.80-1.14; mRS 6 1-hour delay OR 0.94; 95% CI 0.79-1.09) groups. Moreover, there was no significant interaction between treatment effect and time (p = 0.439 and p = 0.421 for mRS 0-2 and 6, respectively). However, within the thrombectomy group, the models that tested the association between time last seen well to successful reperfusion (modified Treatment in Cerebral Infarction ≥2b) and 90-day functional independence showed a significant interaction with mode of presentation (p = 0.013). This appeared to be driven by a nominally positive slope for both witnessed and unwitnessed strokes versus a significantly (p = 0.018) negative slope in wake-up patients. There was no association between treatment times and symptomatic intracranial hemorrhage. INTERPRETATION: Mode of onset modifies the effect of time to reperfusion on thrombectomy outcomes, and should be considered when exploring different treatment paradigms in the extended window. ANN NEUROL 2024;96:356-364.

Comprehensive machine learning models for predicting therapeutic targets in type 2 diabetes utilizing molecular and biochemical features in rats.

Introduction: With the increasing prevalence of type 2 diabetes mellitus (T2DM), there is an urgent need to discover effective therapeutic targets for this complex condition. Coding and non-coding RNAs, with traditional biochemical parameters, have shown promise as viable targets for therapy. Machine learning (ML) techniques have emerged as powerful tools for predicting drug responses. Method: In this study, we developed an ML-based model to identify the most influential features for drug response in the treatment of type 2 diabetes using three medicinal plant-based drugs (Rosavin, Caffeic acid, and Isorhamnetin), and a probiotics drug (Z-biotic), at different doses. A hundred rats were randomly assigned to ten groups, including a normal group, a streptozotocin-induced diabetic group, and eight treated groups. Serum samples were collected for biochemical analysis, while liver tissues (L) and adipose tissues (A) underwent histopathological examination and molecular biomarker extraction using quantitative PCR. Utilizing five machine learning algorithms, we integrated 32 molecular features and 12 biochemical features to select the most predictive targets for each model and the combined model. Results and discussion: Our results indicated that high doses of the selected drugs effectively mitigated liver inflammation, reduced insulin resistance, and improved lipid profiles and renal function biomarkers. The machine learning model identified 13 molecular features, 10 biochemical features, and 20 combined features with an accuracy of 80% and AUC (0.894, 0.93, and 0.896), respectively. This study presents an ML model that accurately identifies effective therapeutic targets implicated in the molecular pathways associated with T2DM pathogenesis.

Exploring the potential of combined B-mode features and color Doppler ultrasound in the diagnosis of ureteric stone as an alternative to ionizing radiation exposure by computed tomography.

OBJECTIVE: To assess the diagnostic efficacy of integrating B-mode and color Doppler capabilities of ultrasound (US) to establish a robust standalone diagnostic tool for the diagnosis of ureteric stones as an alternative to non-contrast-enhanced computed tomography (NCCT). METHODS: A total of 140 consecutive patients diagnosed with ureteric stones using NCCT were enrolled. On the same day, US in both B-mode and Color Doppler was performed by an experienced radiologist who was blinded to the NCCT scan results. The diagnostic rate of US for stone detection was recorded. Additionally, baseline patient and stone characteristics were analyzed for their association with the accuracy of stone detection using US. RESULTS: US exhibited a high sensitivity of 91.43%, detecting 128 out of 140 stone foci. Notably, ureteric stones in the proximal and uretero-vesical junction (UVJ) segments were readily identifiable compared to those in the pelvic region (p = 0.0003). Additionally, hydronephrosis enhanced the US's ability to detect stones (p < 0.0001). Conversely, abdominal gases and obesity adversely affected US capabilities (p < 0.0001 and p = 0.009, respectively). Stone side, size, and density showed no statistically significant impact (p > 0.05). CONCLUSIONS: US with its color Doppler capabilities could serve as a reliable and safe alternative imaging modality in the diagnostic work up of patients with ureterolithiasis. Factors including stone location, Hydronephrosis, weight and abdominal gases significantly influenced its accuracy.

Prevalence of Diabetes, Ketosis, and Ketoacidosis and Their Correlation With Mortality in Critical COVID-19 Patients: A Single-Center Retrospective Study.

Aim We aimed to find out the prevalence of diabetes, ketosis, and ketoacidosis in coronavirus disease 2019 (COVID-19) critically ill patients and to explore the clinical impact of the development of ketosis and ketoacidosis on the outcome of COVID-19 critically ill patients and identify them as potential risk factors for these patients. Methods We collected data on COVID-19 patients admitted to the intensive care unit (ICU) retrospectively. The study population will be classified into two groups based on the presence of diabetes or ketosis. Results The study comprises data on 253 ICU patients admitted with COVID-19 pneumonia. Two hundred patients (79.05%) had diabetes or prediabetes on admission. Seventy-six patients (30%) presented with ketosis. Nine patients had progressed to diabetic ketoacidosis during their ICU stay. Concerning the outcome, among 150 patients who died (59.3%), there was significantly higher mortality among the ketotic patients (69.7%) compared to nonketotic patients (54.8%) with a P-value < 0.027. We noted that the peak blood glucose level during ICU stay was statistically significantly higher in nonsurvivors (mean 345 mg/dl) compared to survivors (mean 298 mg/dl) with a P-value of 0.006. Our data showed that peak serum levels of lactate, procalcitonin (PCT), C-reactive protein, white blood cells (WBC), D dimer, and lactate dehydrogenase strongly positively correlated to the length of ICU stay. We used the ROC curve (receiver operating characteristic curve) to assess the relation between many laboratories and mortality. We noted that uncontrolled hyperglycemia and other laboratory variables are significant predictors of mortality of COVID-19 patients (e.g., peak blood glucose (P = 0.004), PCT (P = 0.047), and P < 0.001 of other laboratories (e.g. lactate, PH, WBC, D dimer, ferritin). Conclusion We reported a high prevalence of diabetes and ketosis among COVID-19 patients admitted to the ICU. Ketosis is associated with an increased mortality risk. Uncontrolled hyperglycemia is a significant predictor of mortality in critically ill COVID-19 patients.