Direct Versus Indirect Revascularization for Moyamoya: a Large Multicenter Study.

BACKGROUND: Moyamoya is a chronic occlusive cerebrovascular disease of unknown etiology causing neovascularization of the lenticulostriate collaterals at the base of the brain. Although revascularization surgery is the most effective treatment for moyamoya, there is still no consensus on the best surgical treatment modality as different studies provide different outcomes. OBJECTIVE: In this large case series, we compare the outcomes of direct (DR) and indirect revascularisation (IR) and compare our results to the literature in order to reflect on the best revascularization modality for moyamoya. METHODS: We conducted a multicenter retrospective study in accordance with the Strengthening the Reporting of Observational studies in Epidemiology guidelines of moyamoya affected hemispheres treated with DR and IR surgeries across 13 academic institutions predominantly in North America. All patients who underwent surgical revascularization of their moyamoya-affected hemispheres were included in the study. The primary outcome of the study was the rate of symptomatic strokes. RESULTS: The rates of symptomatic strokes across 515 disease-affected hemispheres were comparable between the two cohorts (11.6% in the DR cohort vs 9.6% in the IR cohort, OR 1.238 (95% CI 0.651 to 2.354), p=0.514). The rate of total perioperative strokes was slightly higher in the DR cohort (6.1% for DR vs 2.0% for IR, OR 3.129 (95% CI 0.991 to 9.875), p=0.052). The rate of total follow-up strokes was slightly higher in the IR cohort (8.1% vs 6.6%, OR 0.799 (95% CI 0.374 to 1.709) p=0.563). CONCLUSION: Since both modalities showed comparable rates of overall total strokes, both modalities of revascularization can be performed depending on the patient's risk assessment.

Unveiling Discrepant and Rare Dihydropyrimidine Dehydrogenase (DPYD) Results Using an In-House Genotyping Test: A Case Series.

Fluoropyrimidine chemotherapy is a primary component of many solid tumor treatment regimens, particularly those for gastrointestinal malignancies. Approximately one-third of patients receiving fluoropyrimidine-based chemotherapies experience serious adverse effects. This risk is substantially higher in patients carrying DPYD genetic variants, which cause reduced fluoropyrimidine metabolism and inactivation (ie, dihydropyridine dehydrogenase [DPD] deficiency). Despite the known relationship between DPD deficiency and severe toxicity risk, including drug-related fatalities, pretreatment DPYD testing is not standard of care in the United States. We developed an in-house DPYD genotyping test that detects 5 clinically actionable variants associated with DPD deficiency, and genotyped 827 patients receiving fluoropyrimidines, of which 49 (6%) were identified as heterozygous carriers. We highlight 3 unique cases: (1) a patient with a false-negative result from a commercial laboratory that only tested for the c.1905 + 1G>A (*2A) variant, (2) a White patient in whom the c.557A>G variant (typically observed in people of African ancestry) was detected, and (3) a patient with the rare c.1679T>G (*13) variant. Lastly, we evaluated which DPYD variants are detected by commercial laboratories offering DPYD genotyping in the United States and found 6 of 13 (46%) did not test for all 5 variants included on our panel. We estimated that 20.4% to 81.6% of DPYD heterozygous carriers identified on our panel would have had a false-negative result if tested by 1 of these 6 laboratories. The sensitivity and negative predictive value of the diagnostic tests from these laboratories ranged from 18.4% to 79.6% and 95.1% to 98.7%, respectively. These cases underscore the importance of comprehensive DPYD genotyping to accurately identify patients with DPD deficiency who may require lower fluoropyrimidine doses to mitigate severe toxicities and hospitalizations. Clinicians should be aware of test limitations and variability in variant detection by commercial laboratories, and seek assistance by pharmacogenetic experts or available resources for test selection and result interpretation.

Serum apelin-12 and obesity-related markers in Egyptian children with Down syndrome.

Children with Down syndrome (DS) exhibit higher overweight/obesity rates than their typically developing peers. Apelin-12 is a bioactive adipokine that exerts vital roles in obesity-related cardiometabolic comorbidities. To date, apelin-12 has not been investigated in obese-DS. This study aimed to explore the possible association between serum apelin-12 and obesity-related markers and to evaluate the efficiency of apelin-12 in the prediction of metabolic syndrome (MetS) in obese-DS compared to BMI Z-score matched obese-control. The cross-sectional study included 150 prepubertal children classified into three groups; obese-DS (n = 50), obese-control (n = 50), and normal-weight-control (n = 50). Anthropometric parameters, body adiposity, fasting serum levels of blood glucose (FBG), insulin, lipid profile, and apelin-12 were evaluated. Homeostasis model assessment of insulin resistance (HOMA-IR) was calculated from FBG and insulin. MetS was defined using Adult Treatment Panel III criteria modified for the pediatric age group. ROC curves were analyzed to evaluate the efficiency of apelin-12 in predicting MetS in obesity groups. Obese-DS exhibited higher body adiposity with marked central fat distribution, atherogenic lipid profile, and higher HOMA-IR compared to obese-control. Apelin-12 was significantly higher in obese-DS and obese-DS with MetS compared to obese-control and obese-control with MetS respectively (p < 0.001). The increase in apelin-12 with higher obesity grades was pronounced in obese-DS. Apelin-12 strongly correlated with body adiposity, several MetS risk factors, and HOMA-IR in obese-DS. Significantly higher AUC for apelin-12 in the diagnosis of MetS among obese-DS than obese-control (AUC = 0.948 vs. AUC = 0.807; p = 0.04). CONCLUSIONS:  The current study supports the crucial role of apelin-12 in obesity-related clinical and biochemical markers and in MetS in obese-DS and obese-control. Serum apelin-12 is a potential diagnostic biomarker for MetS with greater performance in obese-DS than obese-control raising its potential for clinical and therapeutic applications. WHAT IS KNOWN: • Obese-DS children displayed excess body adiposity, Pronounced central fat distribution, atherogenic lipid profile, higher HOMA-IR, and higher prevalence of MetS than obese-control. WHAT IS NEW: • Higher serum apelin-12 was observed in obese-DS and obese-DS with MetS than obese-control and obese-control with MetS respectively. The increase in apelin-12 level with increasing obesity grades was more pronounced in obese-DS. • Apelin-12 strongly correlated with obesity-related markers and MetS components in obese-DS. Apelin-12 performed better as a diagnostic biomarker for MetS in obese-DS than obese-control.

Impact of helical elongation of symmetric oxa[n]helicenes on their structural, photophysical, and chiroptical characteristics.

The adjustment of the main helical scaffold in helicenes is a fundamental strategy for modulating their optical features, thereby enhancing their potential for diverse applications. This work explores the influence of helical elongation (n = 5-9) on the structural, photophysical, and chiroptical features of symmetric oxa[n]helicenes. Crystal structure analyses revealed structural variations with helical extension, impacting torsion angles, helical pitch, and packing arrangements. Through theoretical investigations using density functional theory (DFT) calculations, the impact of helical extension on aromaticity, planarity distortion, and heightened chiral stability were discussed. Photophysical features were studied through spectrophotometric analysis, with insights gained through time-dependent DFT (TD-DFT) calculations. Following optical resolution via chiral high-performance liquid chromatography (HPLC), the chiroptical properties of both enantiomers of oxa[7]helicene and oxa[9]helicene were investigated. A slight variation in the main helical scaffold of oxa[n]helicenes from [7] to [9] induced an approximately three-fold increase in dissymmetry factors with the biggest values of|glum| of oxa[9]helicene (2.2 × 10-3) compared to|glum|of oxa[7]helicene (0.8 × 10-3), findings discussed and supported by TD-DFT calculations.

Risk Factor Analysis for 30-day Mortality After Surgery for Infective Endocarditis.

BACKGROUND: Infective endocarditis (IE) remains a challenging disease associated with high mortality. Several scores have been suggested to assess surgical risk. None was sufficiently adequate. We therefore analyzed risk factors for 30-day mortality. METHODS: A total of 438 consecutive patients had surgery for IE in our department between 2002 and 2020. Patients were divided into two groups, one consisting of 30-day survivors (362 patients; 82.6%) and one of nonsurvivors (76 patients; 17.4%). Logistic regression analysis on pre- and intraoperative risk factors was performed and the groups were compared by univariable analyses. RESULTS: Patients in mortality group were older (69 [58, 77] vs. 63 [50, 72] years; p < 0.001), EuroSCORE II was higher (24.5 [12.1, 49.0] vs. 8.95 [3.7, 21.2]; p < 0.001) and there were more females. More frequently left ventricular function (below 30%), preoperative acute renal insufficiency, chronic dialysis, insulin-dependent diabetes mellitus, NYHA-class IV (New York Heart Association heart failure class IV), and cardiogenic shock occurred. Patients in the mortality group were often intensive care unit patients (40.8 vs. 22.4%; p < 0.001) or had a preoperative stroke (26.3 vs. 16.0%; p = 0.033). In the nonsurvivor group Staphylococcus aureus was prevalent. Streptococcus viridans was common in the survivor group as was isolated aortic valve endocarditis (32.9 vs. 17.1%; p = 0.006). Prosthetic valve endocarditis (PVE) and abscesses occurred more often in nonsurvivors. In the logistic regression analysis, female gender, chronic dialysis, cardiogenic shock, and NYHA IV and from intraoperative variables PVE, cardiopulmonary bypass time, and mitral valve surgery were the strongest predictors for 30-day mortality. CONCLUSION: This study indeed clearly indicates that significant risk factors for 30-day mortality cannot be changed. Nevertheless, they should be taken into account for preoperative counselling, and they will alert the surgical team for an even more careful management.

Middle meningeal artery patency after surgical evacuation for chronic subdural hematoma.

BACKGROUND: Chronic subdural hematoma (CSDH) often requires surgical evacuation, but recurrence rates remain high. Middle meningeal artery (MMA) embolization (MMAE) has been proposed as an alternative or adjunct treatment. There is concern that prior surgery might limit patency, access, penetration, and efficacy of MMAE, such that some recent trials excluded patients with prior craniotomy. However, the impact of prior open surgery on MMA patency has not been studied. METHODS: A retrospective analysis was conducted on patients who underwent MMAE for cSDH (2019-2022), after prior surgical evacuation or not. MMA patency was assessed using a six-point grading scale. RESULTS: Of the 109 MMAEs (84 patients, median age 72 years, 20.2% females), 58.7% were upfront MMAEs, while 41.3% were after prior surgery (20 craniotomies, 25 burr holes). Median hematoma thickness was 14 mm and midline shift 3 mm. Hematoma thickness reduction, surgical rescue, and functional outcome did not differ between MMAE subgroups and were not affected by MMA patency or total area of craniotomy or burr-holes. MMA patency was reduced in the craniotomy group only, specifically in the distal portion of the anterior division (p = 0.005), and correlated with craniotomy area (p < 0.001). CONCLUSION: MMA remains relatively patent after burr-hole evacuation of cSDH, while craniotomy typically only affects the frontal-distal division. However, MMA patency, evacuation method, and total area do not affect outcomes. These findings support the use of MMAE regardless of prior surgery and may influence future trial inclusion/exclusion criteria. Further studies are needed to optimize the timing and techniques for MMAE in cSDH management.

Dual Layer vs Single Layer Woven EndoBridge Device in the Treatment of Intracranial Aneurysms: A Propensity Score-Matched Analysis.

BACKGROUND: The Woven EndoBridge (WEB) devices have been used for treating wide neck bifurcation aneurysms (WNBAs) with several generational enhancements to improve clinical outcomes. The original device dual-layer (WEB DL) was replaced by a single-layer (WEB SL) device in 2013. This study aimed to compare the effectiveness and safety of these devices in managing intracranial aneurysms. METHODS: A multicenter cohort study was conducted, and data from 1,289 patients with intracranial aneurysms treated with either the WEB SL or WEB DL devices were retrospectively analyzed. Propensity score matching was utilized to balance the baseline characteristics between the two groups. Outcomes assessed included immediate occlusion rate, complete occlusion at last follow-up, retreatment rate, device compaction, and aneurysmal rupture. RESULTS: Before propensity score matching, patients treated with the WEB SL had a significantly higher rate of complete occlusion at the last follow-up and a lower rate of retreatment. After matching, there was no significant difference in immediate occlusion rate, retreatment rate, or device compaction between the WEB SL and DL groups. However, the SL group maintained a higher rate of complete occlusion at the final follow-up. Regression analysis showed that SL was associated with higher rates of complete occlusion (OR: 0.19; CI: 0.04 to 0.8, p = 0.029) and lower rates of retreatment (OR: 0.12; CI: 0 to 4.12, p = 0.23). CONCLUSION: The WEB SL and DL devices demonstrated similar performances in immediate occlusion rates and retreatment requirements for intracranial aneurysms. The SL device showed a higher rate of complete occlusion at the final follow-up.

A Survey of Burnout Among Neurocritical Care Practitioners.

BACKGROUND: Burnout is a growing problem among medical professionals, reaching a crisis proportion. It is defined by emotional exhaustion, cynicism, and career dissatisfaction and is triggered by a mismatch between the values of the person and the demands of the workplace. Burnout has not previously been examined thoroughly in the Neurocritical Care Society (NCS). The purpose of this study is to assess the prevalence, contributing factors, and potential interventions to reduce burnout within the NCS. METHODS: A cross-sectional study of burnout was conducted using a survey distributed to members of the NCS. The electronic survey included personal and professional characteristic questions and the Maslach Burnout Inventory Human Services Survey for Medical Personnel (MBI). This validated measure assesses for emotional exhaustion (EE), depersonalization (DP), and personal achievement (PA). These subscales are scored as high, moderate, or low. Burnout (MBI) was defined as a high score in either EE or DP or a low score in PA. A Likert scale (0-6) was added to the MBI (which contained 22 questions) to provide summary data for the frequencies of each particular feeling. Categorical variables were compared using χ2 tests, and continuous variables were compared using t-tests. RESULTS: A total of 82% (204 of 248) of participants completed the entire questionnaire; 61% (124 of 204) were burned out by MBI criteria. A high score in EE was present in 46% (94 of 204), a high score in DP was present in 42% (85 of 204), and a low score in PA was present in 29% (60 of 204). The variables feeling burned out now, feeling burned out in the past, not having an effective/responsive supervisor, thinking about leaving one's job due to burnout, and leaving one's job due to burnout were significantly associated with burnout (MBI) (p < 0.05). Burnout (MBI) was also higher among respondents early in practice (currently training/post training 0-5 years) than among respondents post training 21 or more years. In addition, insufficient support staff contributed to burnout, whereas improved workplace autonomy was the most protective factor. CONCLUSIONS: Our study is the first to characterize burnout among a cross-section of physicians, pharmacists, nurses, and other practitioners in the NCS. A call to action and a genuine commitment by the hospital, organizational, local, and federal governmental leaders and society as a whole is essential to advocate for interventions to ameliorate burnout and care for our health care professionals.

New prospective insecticidal agents based on thiazolo[4,5-b]quinoxaline derivatives against cotton leafworm Spodoptera litura (Fabricius): Design, synthesis, toxicological, morphology, histological, and biomedical studies.

In this study, a new series of thiazolo[4,5-b]quinoxaline derivatives 3-8 were synthesized by treating 2,3-dichloroquinoxaline with thiosemicarbazone and thiourea derivatives under reflux conditions. The chemical structure of the newly designed derivatives was conducted using spectroscopic techniques. The insecticidal bioassay of the designed derivatives was evaluated against the 2nd and 4th larvae of S. litura after five days as toxicity agents via median lethal concentration (LC50) and the lethal time values (LT50). The results indicated that all the tested compounds had insecticidal effects against both instar larvae of S. litura with variable values. Among them, thiazolo[4,5-b]quinoxaline derivative 3 was the most toxic, with LC50 = 261.88 and 433.68 ppm against 2nd and 4th instar larvae, respectively. Moreover, the thiazolo[4,5-b]quinoxaline derivative 3 required the least time to kill the 50% population (LT50) of 2nd larvae were 20.88, 13.2, and 15.84 hs with 625, 1250, and 2500 ppm, respectively, while for the 4th larval instar were 2.75, 2.08, and 1.76 days with concentrations of 625, 1250, and 2500 ppm, respectively. Larvae's morphological and histological studies for the most active derivative 3 were investigated. According to SEM analysis, the exterior morphology of the cuticle and head capsule was affected. In addition, there were some histological alterations in the cuticle layers and the midgut tissues. Columnar cells began breaking down, and vacuolization occurred in the peritrophic membrane. Moreover, treating 4th S litura larvae hemolymph with compound 3 showed significant changes in biochemical analysis, such as total proteins, GPT, GOT, acetylcholinesterase (AChE), and alkaline phosphatase (AlP). Finally, the toxicity prediction of the most active derivative revealed non-corrosive, non-irritant to the eye, non-respiratory toxicity, non-sensitivity to the skin, non-hepatotoxic, and don't have toxicity on minnow toxicity and T. pyriformis indicating a good toxicity profile for human.

Explore new quinoxaline pharmacophore tethered sulfonamide fragments as in vitro α-glucosidase, α-amylase, and acetylcholinesterase inhibitors with ADMET and molecular modeling simulation.

A new series of quinoxaline-sulfonamide derivatives 3-12 were synthesized using fragment-based drug design by reaction of quinoxaline sulfonyl chloride (QSC) with different amines and hydrazines. The quinoxaline-sulfonamide derivatives were evaluated for antidiabetic and anti-Alzheimer's potential against α-glucosidase, α-amylase, and acetylcholinesterase enzymes. These derivatives showed good to moderate potency against α-amylase and α-glucosidase with inhibitory percentages between 24.34 ± 0.01%-63.09 ± 0.02% and 28.95 ± 0.04%-75.36 ± 0.01%, respectively. Surprisingly, bis-sulfonamide quinoxaline derivative 4 revealed the most potent activity with inhibitory percentages of 75.36 ± 0.01% and 63.09 ± 0.02% against α-glucosidase and α-amylase compared to acarbose (IP = 57.79 ± 0.01% and 67.33 ± 0.01%), respectively. Moreover, the quinoxaline derivative 3 exhibited potency as α-glucosidase and α-amylase inhibitory with a minute decline from compound 4 and acarbose with inhibitory percentages of 44.93 ± 0.01% and 38.95 ± 0.01%. Additionally, in vitro acetylcholinesterase inhibitory activity for designed derivatives exhibited weak to moderate activity. Still, sulfonamide-quinoxaline derivative 3 emerged as the most active member with inhibitory percentage of 41.92 ± 0.02% compared with donepezil (IP = 67.27 ± 0.60%). The DFT calculations, docking simulation, target prediction, and ADMET analysis were performed and discussed in detail.

Effect of different intraoral scanning strategies on the marginal and internal fit of CAD-CAM inlay restorations: An in vitro study.

STATEMENT OF PROBLEM: Whether the scanning strategy of intraoral scanners (IOSs) affects the accuracy of the digital recording for an indirect ceramic inlay restoration is unclear. Furthermore, which strategy would be optimal and most effective is uncertain. PURPOSE: The purpose of this in vitro study was to evaluate the impact of 3 different scanning strategies using the Carestream CS 3700 IOS on the marginal and internal fit of a mesio-occluso-distal (MOD) ceramic inlay restoration. MATERIAL AND METHODS: A typodont master model (ANA-4 VCER; Frasaco) was used with a standardized preprepared MOD inlay maxillary first molar typodont tooth (ANA-4 ZP16 CER99-008; Frasaco) (N=30). These inlay preparations were scanned with the CS 3700 IOS using 3 different scanning strategies: linear, wave, and S-figure scanning strategies. Each scan strategy group was scanned 10 times for all groups to obtain 30 standard tessellation language (STL) files. Thirty restorations were milled from lithium disilicate CAD blocks (IPS e.max; Ivoclar AG) and cemented into their typodont-prepared inlay cavities. A single examiner used a stereomicroscope to measure the marginal and internal gaps at the predetermined points. A 1-way ANOVA was used for the statistical analysis, followed by the Tukey post hoc test with Bonferroni adjustment. All tests were 2-tailed (α=.05). RESULTS: All scanning strategy groups demonstrated statistically significant differences for the marginal and internal fit of the inlay restorations (P<.001). Overall, the linear scanning strategy showed the lowest mean marginal and internal gap values (29.2 ±3.6 µm and 39.0 ±6.4 µm), followed by the wave scanning strategy, which had comparable mean marginal and internal gap values: 49.1 ±3.6 µm and 48.2 ±6.0 µm, respectively. The S-figure scan strategy had the highest mean marginal and internal gap values: 50.2 ±12.6 µm and 71.3 ±7.7 µm, respectively. CONCLUSIONS: Inlay restorations scanned by the linear scan strategy had the best marginal and internal fit when scanned with the CS 3700 IOS.

Synthesis and Structural and Optical Behavior of Dehydrohelicene-Containing Polycyclic Compounds.

Dehydrohelicene-based molecules stand out as highly promising scaffolds and captivating chiroptical materials, characterized by their unique chirality. Their quasi-helical π-conjugated molecular architecture, featuring successively ortho-annulated aromatic rings, endows them with remarkable thermal stability and optical properties. Over the past decade, diverse approaches have emerged for synthesizing these scaffolds, reinvigorating this field, with anticipated increased attention in the coming years. This review provides a comprehensive overview of the historical evolution of dehydrohelicene chemistry since the pioneering work of Zander and Franke in 1969 and highlights recent advancements in the synthesis of various molecules incorporating dehydrohelicene motifs. We elucidate the intriguing structural features and optical merits of these molecules, occasionally drawing comparisons with their helicene or circulene analogs to underscore the significance of the bond between the helical termini.

Modulatory effects of dietary prickly pear (Opuntia ficus-indica) peel on high salinity tolerance, growth rate, immunity and antioxidant capacity of Nile tilapia (Oreochromis niloticus).

This study evaluated the effects of prickly pear (Opuntia ficus-indica) peel (PPP) on salinity tolerance, growth, feed utilization, digestive enzymes, antioxidant capacity, and immunity of Nile tilapia (Oreochromis niloticus). PPP was incorporated into four iso-nitrogenous (280 g kg-1 protein) and iso-energetic (18.62 MJ kg-1) diets at 0 (PPP0), 1 (PPP1), 2 (PPP2), and 4 (PPP4) g kg-1. Fish (9.69 ± 0.2 g) (mean ± SD) were fed the diets for 75 days. Following the feeding experiment, fish were exposed to a salinity challenge (25‰) for 24 h. Fish survival was not affected by the dietary PPP inclusion either before or after the salinity challenge. Fish fed the PPP-supplemented diets showed lower aspartate aminotransferase, alanine aminotransferase, cortisol, and glucose levels compared to PPP0, with the lowest values being observed in PPP1. Fish fed dietary PPP had higher growth rates and feed utilization than PPP0. Quadratic regression analysis revealed that the best weight gain was obtained at 2.13 g PPP kg-1 diet. The highest activities of protease and lipase enzymes were recorded in PPP1, while the best value of amylase was recorded in PPP2, and all PPP values were higher than PPP0. Similarly, PPP1 showed higher activities of lysozyme, alternative complement, phagocytic cells, respiratory burst, superoxide dismutase, glutathione peroxidase and catalase, and lower activity of malondialdehyde than in PPP0. Further increases in PPP levels above 2 g kg-1 diet led to significant retardation in the immune and antioxidant parameters. Thus, the inclusion of PPP at about 1 to or 2 g kg-1 diet can improve stress tolerance, immunity, and antioxidant capacity in Nile tilapia.

Principal component analysis of phenotypic and breeding value data for semen traits in Egyptian buffalo bulls.

Buffalo bull semen traits are economically important traits that influence farm fertility and profitability. Genetic improvement of semen characteristics is an important detail of the genetic improvement. This study was conducted to assess the relationship between the breeding values as well as the phenotypic values for semen traits (VOL, MM, LS, AS and CONC) of the Egyptian buffalo bulls. A total of 7761 normal semen ejaculates were collected and characterized at ILMTC laboratory from 26 bulls from 2009 to 2019. For VOL, MM, LS, AS, and CONC, the actual means were 3.89 mL, 62.37%, 60.64%, 3.94%, and 0.67 × 109 sperm/mL, respectively. The prediction of breeding values for semen traits was estimated using a Bayesian procedure. The estimated standardized EBVs and phenotypic values were used in the principal component analysis (PCA). Of five PCs, one PC (PC1) had > 1 eigenvalues that was responsible for 87.19% of the total variation of SEBV, and two PCs had > 1 eigenvalues that were responsible for 59.61% and 21.35% of the total variation of the phenotypic values. Together, PC1 and PC2 accounted for 97.97% of the total variance of SEBV and 80.96% of the total variance of phenotypic values. A graphs of the first two components showed the traits separated into two different directions by group. This indicates each group was under similar genetic influence. Therefore, selection can be done separately for each group without influencing the other. Principal component analysis reduced variables to describe the key information in buffalo semen data.

Deciphering the role of wound healing genes in skin cutaneous melanoma: Insights into expression, methylation, mutations, and therapeutic implications.

Skin Cutaneous Melanoma (SKCM) is a form of cancer that originates in the pigment-producing cells, known as melanocytes, of the skin. Delay wound healing is often correlated with the occurrence of and progression of SKCM. In this comprehensive study, we investigated the intricate roles of two important wound healing genes in SKCM, including Matrix Metalloproteinase-2 (MMP2) and Matrix Metalloproteinase-9 (MMP9). Through a multi-faceted approach, we collected clinical samples, conducted molecular experiments, including RT-qPCR, bisulphite sequencing, cell culture, cell Counting Kit-8, colony formation, and wound healing assays. Beside this, we also used various other databases/tools/approaches for additional analysis including, UALCAN, GEPIA, HPA, MEXPRESS, cBioPortal, KM plotter, DrugBank, and molecular docking. Our results revealed a significant up-regulation of MMP2 and MMP9 in SKCM tissues compared to normal counterparts. Moreover, promoter methylation analysis suggested an epigenetic regulatory mechanism. Validations using TCGA datasets and immunohistochemistry emphasized the clinical relevance of MMP2 and MMP9 dysregulation. Functional assays demonstrated their synergistic impact on proliferation and migration in SKCM cells. Furthermore, we identified potential therapeutic candidates, Estradiol and Calcitriol, through drug prediction and molecular docking analyses. These compounds exhibited binding affinities, suggesting their potential as MMP2/MMP9 inhibitors. Overall, our study elucidates the diagnostic, prognostic, and therapeutic implications of MMP2 and MMP9 in SKCM, shedding light on their complex interplay in SKCM occurrence and progression.

RNA-Seq analysis of the pyloric caecum, liver, and muscle reveals molecular mechanisms regulating fillet color in rainbow trout.

BACKGROUND: The characteristic pink-reddish color in the salmonids fillet is an important, appealing quality trait for consumers and producers. The color results from diet supplementation with carotenoids, which accounts for up to 20-30% of the feed cost. Pigment retention in the muscle is a highly variable phenotype. In this study, we aimed to understand the molecular basis for the variation in fillet color when rainbow trout (Oncorhynchus mykiss) fish families were fed an Astaxanthin-supplemented diet. We used RNA-Seq to study the transcriptome profile in the pyloric caecum, liver, and muscle from fish families with pink-reddish fillet coloration (red) versus those with lighter pale coloration (white). RESULTS: More DEGs were identified in the muscle (5,148) and liver (3,180) than in the pyloric caecum (272). Genes involved in lipid/carotenoid metabolism and transport, ribosomal activities, mitochondrial functions, and stress homeostasis were uniquely enriched in the muscle and liver. For instance, the two beta carotene genes (BCO1 and BCO2) were significantly under-represented in the muscle of the red fillet group favoring more carotenoid retention. Enriched genes in the pyloric caecum were involved in intestinal absorption and transport of carotenoids and lipids. In addition, the analysis revealed the modulation of several genes with immune functions in the pyloric caecum, liver, and muscle. CONCLUSION: The results from this study deepen our understanding of carotenoid dynamics in rainbow trout and can guide us on strategies to improve Astaxanthin retention in the rainbow trout fillet.

Higher cytotoxic activities of CD8+ T cells and natural killer cells from peripheral blood of early diagnosed lung cancer patients.

INTRODUCTION: Cytotoxic (CD8+) and natural killer (NK) cells play critical roles in anti-tumor immunity. Dysfunction in these cells is considered as one of the extrinsic mechanisms for tumor relapse. AIM: We aimed in this study to assess cytotoxic activities of CD8 + T and NK cells in the peripheral blood from lung cancer patients before and after induction of chemotherapy. SUBJECTS AND METHODS: Healthy (n = 5) volunteers and lung cancer patients (n = 15:5 before, 5 during, and 5 after induction of chemotherapy) were recruited. Flow cytometry was used to analyze the numbers of CD8 + T cells, NK and CD56+T cells and their intracellular expression of granzyme B (GzB) in fresh peripheral blood mononuclear cells (PBMCs) and after 72 h of their culture in vitro and stimulation with 5 µg/ml Concanavalin A (Con A) and 50ng/ml IL-2). In addition, the plasma levels of inflammatory cytokines were measured using luminex. RESULTS: After culture, significant increases in the number of GzB expressing cells gated on CD3+, CD4+, CD8 + and NKCD8 + T cells in the PBMCs from lung cancer patients before induction of chemotherapy as compared to control individuals as well as patients during and after induction of chemotherapy. Serum levels of IL-1 and CXCL8 in patients before induction of chemotherapy showed 37- and 40-fold increases, respectively, as compared to control individuals. Both GzB expression and cytokines levels in patients during and after chemotherapy were similar. CONCLUSION: Polyclonal stimulation of PBMCs can restore the cytolytic activities of cytotoxic CD8 and NK cells from lung cancer patients even after chemotherapy.

Middle Meningeal Artery Embolization for Chronic Subdural Hematoma: Predictors of Clinical and Radiographic Failure from 636 Embolizations.

Background Knowledge regarding predictors of clinical and radiographic failures of middle meningeal artery (MMA) embolization (MMAE) treatment for chronic subdural hematoma (CSDH) is limited. Purpose To identify predictors of MMAE treatment failure for CSDH. Materials and Methods In this retrospective study, consecutive patients who underwent MMAE for CSDH from February 2018 to April 2022 at 13 U.S. centers were included. Clinical failure was defined as hematoma reaccumulation and/or neurologic deterioration requiring rescue surgery. Radiographic failure was defined as a maximal hematoma thickness reduction less than 50% at last imaging (minimum 2 weeks of head CT follow-up). Multivariable logistic regression models were constructed to identify independent failure predictors, controlling for age, sex, concurrent surgical evacuation, midline shift, hematoma thickness, and pretreatment baseline antiplatelet and anticoagulation therapy. Results Overall, 530 patients (mean age, 71.9 years ± 12.8 [SD]; 386 men; 106 with bilateral lesions) underwent 636 MMAE procedures. At presentation, the median CSDH thickness was 15 mm and 31.3% (166 of 530) and 21.7% (115 of 530) of patients were receiving antiplatelet and anticoagulation medications, respectively. Clinical failure occurred in 36 of 530 patients (6.8%, over a median follow-up of 4.1 months) and radiographic failure occurred in 26.3% (137 of 522) of procedures. At multivariable analysis, independent predictors of clinical failure were pretreatment anticoagulation therapy (odds ratio [OR], 3.23; P = .007) and an MMA diameter less than 1.5 mm (OR, 2.52; P = .027), while liquid embolic agents were associated with nonfailure (OR, 0.32; P = .011). For radiographic failure, female sex (OR, 0.36; P = .001), concurrent surgical evacuation (OR, 0.43; P = .009), and a longer imaging follow-up time were associated with nonfailure. Conversely, MMA diameter less than 1.5 mm (OR, 1.7; P = .044), midline shift (OR, 1.1; P = .02), and superselective MMA catheterization (without targeting the main MMA trunk) (OR, 2; P = .029) were associated with radiographic failure. Sensitivity analyses retained these associations. Conclusion Multiple independent predictors of failure of MMAE treatment for chronic subdural hematomas were identified, with small diameter (<1.5 mm) being the only factor independently associated with both clinical and radiographic failures. © RSNA, 2023 Supplemental material is available for this article. See also the editorial by Chaudhary and Gemmete in this issue.

A comparative transcriptomics and eQTL approach identifies SlWD40 as a tomato fruit ripening regulator.

Although multiple vital genes with strong effects on the tomato (Solanum lycopersicum) ripening process have been identified via the positional cloning of ripening mutants and cloning of ripening-related transcription factors (TFs), recent studies suggest that it is unlikely that we have fully characterized the gene regulatory networks underpinning this process. Here, combining comparative transcriptomics and expression QTLs, we identified 16 candidate genes involved in tomato fruit ripening and validated them through virus-induced gene silencing analysis. To further confirm the accuracy of the approach, one potential ripening regulator, SlWD40 (WD-40 repeats), was chosen for in-depth analysis. Co-expression network analysis indicated that master regulators such as RIN (ripening inhibitor) and NOR (nonripening) as well as vital TFs including FUL1 (FRUITFUL1), SlNAC4 (NAM, ATAF1,2, and CUC2 4), and AP2a (Activating enhancer binding Protein 2 alpha) strongly co-expressed with SlWD40. Furthermore, SlWD40 overexpression and RNAi lines exhibited substantially accelerated and delayed ripening phenotypes compared with the wild type, respectively. Moreover, transcriptome analysis of these transgenics revealed that expression patterns of ethylene biosynthesis genes, phytoene synthase, pectate lyase, and branched chain amino transferase 2, in SlWD40-RNAi lines were similar to those of rin and nor fruits, which further demonstrated that SlWD40 may act as an important ripening regulator in conjunction with RIN and NOR. These results are discussed in the context of current models of ripening and in terms of the use of comparative genomics and transcriptomics as an effective route for isolating causal genes underlying differences in genotypes.

Postoperative de novo epilepsy after resection of brain arteriovenous malformations: A national database study of 536 patients.

OBJECTIVE: We aimed to assess the incidence and risk factors for de novo epilepsy after arteriovenous malformation (AVM) resection and compare them with a nonresection cohort after propensity score matching, utilizing a national database. METHODS: Utilizing the TriNetX Research Network, we queried cases from January 1, 2004 to March 1, 2022. We included patients of all ages who underwent supratentorial AVM resection, presenting without seizures on or before surgery and without being on antiseizure medications at least 1 day before surgery. The primary outcome was seizures manifesting at least 6 weeks after surgery. Patient characteristics and outcomes were compared between the cohorts with and without postoperative epilepsy. Further cohorts were created to compare cohorts with and without embolization or rupture. After propensity score matching, we compared an additional cohort of patients with an AVM diagnosis who did not undergo resection. RESULTS: Of the 536 patients (mean age = 38.9 ± 19.6, 52% females) presenting without seizure who underwent AVM resection, 99 (18.5%) developed de novo epilepsy, with a 1-year cumulative incidence of 13.8%. Patients with epilepsy had higher rates of intracerebral hemorrhage, and intracerebral hemorrhage was less common in the embolization cohort. Patients in the ruptured cohort were older and more often males. After propensity score matching with 18 588 patients with AVM diagnosis but no resection, each group consisted of 529 patients, and de novo epilepsy at 1 year was significantly higher in the AVM resection cohort compared to the nonresection cohort (11.5% vs. 3.4%, p < .001). SIGNIFICANCE: This analysis of 536 patients provides evidence that de novo epilepsy after brain AVM resection occurs at a 1-year cumulative incidence of 13.8%, with a total of 19.4% developing de novo epilepsy. Intracerebral hemorrhage was inconsistently associated with postoperative de novo epilepsy. De novo epilepsy was significantly less frequent after AVM diagnosis without resection.