Clinical application of the UroLift® prostatic urethral lift in Spain: consensus on the treatment of lower urinary tract symptoms associated with urinary flow obstruction and secondary to benign prostatic hyperplasia (BPH).

Benign prostatic hyperplasia (BPH) is an increasingly common pathology in the adult male. BPH increases after the age of 40-45 years, and its management consumes an enormous amount of resources. The UroLift® System is an approved technology designed to treat lower urinary tract symptoms (LUTS) secondary to BPH and is used to perform the prostatic urethral lift (PUL) procedure. Various urology specialists in Spain with experience in PUL have prepared this consensus document. Endorsed by the Spanish Urology Association, its information is based on the most recent findings. The main objective of this document is to disseminate the consensus recommendations among all professionals treating patients with LUTS/BPH. Both primary care physicians and urologists can assess and offer PUL as an effective, minimally invasive treatment.

Replacing middle colic artery arising from the splenic artery-an arterial variety in a patient undergoing total pancreatoduodenectomy.

Knowledge of variations in arterial vascular supply is crucial in HPB and general surgery. Although the arterial configuration of the coeliac trunk and the superior mesenteric artery had been investigated, there are still arterial branching patterns to be described. We herein present the case of an 84-year-old male patient who underwent total pancreatectomy due to a not specified pancreas head tumor with a replacing right hepatic artery according to Michel's classification III and a replacing middle colic artery arising from the splenic artery and running on the ventral side of the pancreas. To the best of our knowledge, this arterial branching pattern has never been described so far. In this case, two arterial variations had been presented with a type III arterial supply according to Michel's classification, and a replacing middle colic artery arising from the SA.

Is Conduction System Pacing Going to Be the New Gold Standard for Cardiac Resynchronization Therapy?

The current gold standard in device therapy for advanced heart failure (HF), which has been firmly established in HF management for more than 25 years, is classical biventricular pacing (BiV-CRT). In the last decade, a new pacing modality called conduction system pacing (CSP) has emerged as a variant for advanced cardiac device therapy. It provides pacing with preserved intrinsic cardiac activation by direct stimulation of the specific cardiac conduction system. The term CSP integrates the modalities of HIS bundle pacing (HBP) and left bundle branch area pacing (LBBAP), both of which have provided convincing data in smaller randomized and big non-randomized studies for the prevention of pacemaker-induced cardiomyopathy and for providing effective cardiac resynchronization therapy in patients with classical CRT-indication (primary approach or after failed CRT). Recent American guidelines proposed the term "cardiac physiological pacing" (CPP), which summarizes CSP including left ventricular septal pacing (LVSP), a technical variant of LBBAP together with classical BiV-CRT. The terms HOT-CRT (HIS-optimized CRT) and LOT-CRT (LBBP-optimized CRT) describe hybrid technologies that combine CSP with an additional coronary-sinus electrode, which is sometimes useful in patients with advanced HF and diffuse interventricular conduction delay. If CSP continues providing promising data that can be confirmed in big, randomized trials, it is likely to become the new gold standard for patients with an expected high percentage of pacing (>20%), possibly also for cardiac resynchronization therapy. CSP is a sophisticated new treatment option that has the potential to raise the term "cardiac resynchronization therapy" to a new level. The aim of this review is to provide basic technical, anatomical, and functional knowledge of these new pacemaker techniques in order to facilitate the understanding of the different modalities, as well as to provide an up-to-date overview of the existing randomized and non-randomized evidence, particularly in direct comparison to right ventricular and classical biventricular pacing.

The use of echocardiography compared to electrocardiogram when screening for left ventricular hypertrophy in hypertensive patients: A cross-sectional study.

Left ventricular hypertrophy (LVH) is often used as an indicator to assess hypertension-mediated organ damage (HMOD), alongside hypertensive retinopathy (HR) and nephropathy. Assessment of HMOD is crucial when making decisions about treatment optimization. Despite longstanding debate over its reliability to detect LVH, it is common practice to perform an electrocardiogram (ECG) instead of directly assessing left ventricular mass with echocardiography. In this study, the presence of LVH was evaluated using both ECG and echocardiography among consecutive patients suspected of therapy-resistant hypertension or secondary hypertension in the outpatient clinic of the Department of Internal Medicine at the Diakonessen Hospital, Utrecht, the Netherlands, between July 15, 2017, and July 31, 2020. The primary endpoints were the specificity and sensitivity of ECG as a diagnostic tool for LVH, with echocardiography serving as the reference method. Among the 329 participants, we identified 70 individuals (21.3%) with true LVH based on echocardiography. The ECG displayed a sensitivity of 47.9% and a specificity of 75.3%. Moreover, the area under the receiver operating characteristics curve was 0.604. In conclusion, ECG demonstrates limited value in identifying LVH. Considering the importance of accurately assessing HMOD for treatment optimization of hypertension, the role of ECG as a diagnostic tool for LVH is, therefore, questionable. Instead, we recommend employing standard echocardiography as a more reliable diagnostic.

Muscle-specific lack of Gfpt1 triggers ER stress to alleviate misfolded protein accumulation.

Pathogenic variants in GFPT1, encoding a key enzyme to synthesize UDP-N-acetylglucosamine (UDP-GlcNAc), cause congenital myasthenic syndrome (CMS). We made a knock-in (KI) mouse model carrying a frameshift variant in Gfpt1 exon 9, simulating that found in a patient with CMS. As Gfpt1 exon 9 is exclusively expressed in striated muscles, Gfpt1-KI mice were deficient for Gfpt1 only in skeletal muscles. In Gfpt1-KI mice, (1) UDP-HexNAc, CMP-NeuAc and protein O-GlcNAcylation were reduced in skeletal muscles; (2) aged Gfpt1-KI mice showed poor exercise performance and abnormal neuromuscular junction structures; and (3) markers of the unfolded protein response (UPR) were elevated in skeletal muscles. Denervation-mediated enhancement of endoplasmic reticulum (ER) stress in Gfpt1-KI mice facilitated protein folding, ubiquitin-proteasome degradation and apoptosis, whereas autophagy was not induced and protein aggregates were markedly increased. Lack of autophagy was accounted for by enhanced degradation of FoxO1 by increased Xbp1-s/u proteins. Similarly, in Gfpt1-silenced C2C12 myotubes, ER stress exacerbated protein aggregates and activated apoptosis, but autophagy was attenuated. In both skeletal muscles in Gfpt1-KI mice and Gfpt1-silenced C2C12 myotubes, maladaptive UPR failed to eliminate protein aggregates and provoked apoptosis.

The metabolic landscape of the bacteria Rhodococcus erythropolis used in the biodesulfurization of petroleum products: an emphasis on 2-hydroxybiphenyl.

Microorganisms produce diverse classes of metabolites under various physiological conditions. Many bacterial strains have been reported to carry out the process of desulfurization in a cost-effective manner by converting dibenzothiophene (DBT) into 2-hydroxybiphenyl (2-HBP) and then using the 2-HBP as a carbon source for growth and development. Key rate-limiting factors and an increased concentration of 2HBP (400 µM) affect the biodesulfurization activity of bacteria through the produced metabolites. Thus, this study was designed to explore the nature of the metabolites produced by Rhodococcus erythropolis in the presence of DBT and 2HBP supplemented with a culture medium. A total of 330 metabolites were detected, and the key metabolites identified were 11Z-eicosaenoyl-EA, 1-carboxyethylisoleucine, 1(3)-glyceryl-PGF2alpha, taurine, 2-hydroxynicotinic acid, 4,4-dimethyl-14alpha-hydroxymethyl-5alpha-cholest-8-en-3beta-ol, and 10-nitrooleic acid. The supplementation of DBT and DBT-2HBP resulted in the differential regulation of these metabolites, either through downregulation or overexpression. Furthermore, at high concentrations of 2-HBP, 1-carboxyethylisoleucine, taurine, 2-hydroxynicotinic acid, and nicotinic acid were upregulated. This work proposes that the identified metabolites may play a role in bacteria-mediated desulphurization and could be beneficial in developing a cost-effective method of desulphurization for refining petroleum.

Antecubital vein combined with femoral vein pathway could shorten the learning curve of simultaneous bilateral adrenal vein sampling.

During our previous bilateral adrenal vein sampling (AVS) procedure, the authors observed that accessing the left adrenal vein through the antecubital vein was more feasible than the conventional femoral vein. Meanwhile, the femoral vein pathway facilitated access to the right adrenal vein than the antecubital vein pathway. Therefore, the authors hypothesized that simultaneous bilateral AVS via the antecubital combined with the femoral vein pathway could improve the success rate. A total of 94 cases of AVS via the antecubital combined with the femoral vein pathway were performed, while the remaining 20 cases employed the antecubital vein pathway at our center between August 2020 and April 2023. Furthermore, a meta-analysis was conducted in this study using 15 selected articles to determine the success rate of AVS in each center and pathway. The success rate of ACTH-stimulated simultaneous bilateral AVS via the antecubital vein combined with the femoral vein pathway was 92.85% (P = .503) on the right and 95.00% (P < .001) on the left. In the antecubital vein pathway, the success rates were only 25.00% (P < .001) on the right side and 80.00% (P = .289) on the left side. The results of meta-analysis demonstrated a success rate of 78.16% on the right and 94.98% on the left for ACTH-stimulated AVS via the femoral vein pathway. Based on our center's experience, simultaneous bilateral adrenal vein sampling via the combined pathway could improve the success rate of AVS in the short term and shorten the learning curve.

Psychometric evaluation of a novel tool for assessing gestational diabetes and hypertension care: knowledge, attitudes, and practices of midwives and nurses.

While standardized assessment of knowledge, attitudes, and practices (KAP) related to gestational diabetes and hypertension is possible with a valid tool, existing research remains limited. This prospective validation study aimed to develop and validate a novel tool to assess the KAP of midwives and obstetric nurses. We included 125 midwives and obstetric nurses who routinely care for patients with gestational diabetes and hypertension. The tool demonstrated good internal consistency (Cronbach's alpha): knowledge (0.729, 95% CI, 0.654-0.776), attitude (0.756, 95% CI, 0.690-0.814), and practices (0.925, 95% CI, 0.905-0.943). Difficulty indices (d) ranged from 0.38 to 0.99 (knowledge), 0.41 to 0.99 (attitudes), and 0.41 to 0.93 (practices), indicating appropriate item difficulty. Discrimination indices (D) confirmed items could differentiate between respondents with low and high knowledge levels (D range: 0.02-0.77 for knowledge, 0.06-0.64 for attitudes, 0.20-0.84 for practices). The robust psychometric properties of this tool support its use in future research on KAP related to diabetes and gestational hypertension management in midwives and nurses. This instrument has the potential to be valuable in various settings, including baseline assessment before educational programs or evaluation of learning outcomes after interventions.

Skraban-Deardorff intellectual disability syndrome-associated mutations in WDR26 impair CTLH E3 complex assembly.

Patients with Skraban-Deardorff syndrome (SKDEAS), a neurodevelopmental syndrome associated with a spectrum of developmental and intellectual delays and disabilities, harbor diverse mutations in WDR26, encoding a subunit of the multiprotein CTLH E3 ubiquitin ligase complex. Structural studies revealed that homodimers of WDR26 bridge two core-CTLH E3 complexes to generate giant, hollow oval-shaped supramolecular CTLH E3 assemblies. Additionally, WDR26 mediates CTLH E3 complex binding to subunit YPEL5 and functions as substrate receptor for the transcriptional repressor HBP1. Here, we mapped SKDEAS-associated mutations on a WDR26 structural model and tested their functionality in complementation studies using genetically engineered human cells lacking CTLH E3 supramolecular assemblies. Despite the diversity of mutations, 15 of 16 tested mutants impaired at least one CTLH E3 complex function contributing to complex assembly and interactions, thus providing first mechanistic insights into SKDEAS pathology.

Surgical versus medical management of patients with primary hyperaldosteronism and indeterminate adrenal vein sampling: A 10-year experience of the Cleveland Clinic.

In patients with primary hyperaldosteronism (PA), adrenal vein sampling (AVS) can identify patients suitable for unilateral adrenalectomy. However, in AVS with an indeterminate aldosterone-to-cortisol lateralization (ACL) ratio of 3.0-4.0, clinical guidance is unclear. The authors screened all patients undergoing AVS at the Cleveland Clinic from October 2010 to January 2021 and identified 18 patients with indeterminate ACL results. Ten underwent adrenalectomy and eight continued medical management. The surgical group was younger (58.5 vs. 68 years, p = .17), and more likely to have a unilateral imaging adrenal abnormality (90% vs. 38%, p = .043) and a lower contralateral suppression index (0.63 vs. 1.1, p = .14). Post-treatment, the surgical group had a significant reduction in diastolic blood pressure (-5.5 mmHg, p = .043) and aldosterone (4.40 vs. 35.80 ng/mL, p = .035) and required fewer anti-hypertensive medications (2 vs. 3, p = .015). These findings may support the benefit of adrenalectomy in a select group of patients with indeterminate ACL.

Surface enhanced Raman spectroscopy for the characterization of the metabolites of the biodesulfurization of dibenzothiophene carried out by Tsukamurella paurometabola.

Large amount of sulphur is released by the combustion of fossil fuels in the form of SoX which affects human health and leads to acid rain. To overcome this issue, it is essential to eliminate sulphur moieties from heterocyclic organo-sulphur compounds like Dibenzothiophene (DBT) present in the petrol. In this study Surface enhanced Raman scattering (SERS) spectroscopy is used to analyze the desulfurizing activity of Tsukamurella paurometabola bacterial strain. The most prominent SERS peaks observed at 791, 837, 944 and 1032 cm-1, associated to C-S stretching, are solely observed in dibenzothiophene and its metabolite-I (DBTS) but absent in 2-Hydroxybiphenyl (metabolite-II) and extraction sample of supernatant as a result of biodesulfurization. Moreover, the SERS peaks observed at 974 (characteristic peak of benzene ring) and 1015 cm-1 is associated to C-C ring breathing while 1642 and 1655 cm-1 assigned to CC bonds of aromatic ring. These peaks are only observed in 2-Hydroxybiphenyl (metabolite-II) and extraction sample of supernatant as a result of biodesulfurization. Notably, these peaks are absent in the Dibenzothiophene and its metabolite-I which indicate that aromatic ring is carrying sulfur in this fraction. Moreover, multivariate data analytical tools like principal component analysis (PCA) and PCA-loadings are applied to further differentiate between dibenzothiophene and its metabolites that are Dibenzothiophene sulphone (metabolite-I) and 2-Hydroxybiphenyl (metabolite-II).

Inadvertent septal perforation during conduction system pacing device implant: a case report.

Background: There has been recent growing interest in the use of conduction system pacing (CSP) for both bradycardia and heart failure indications. There remains a paucity of data, however, regarding complications related to the intraventricular septum associated with CSP implant and the management of these events. Case summary: We present a case of a patient with non-ischemic dilated cardiomyopathy presenting for cardiac resynchronization therapy in whom left bundle branch area pacing was complicated with interventricular septal perforation and managed intra-procedurally with repositioning of the lead to provide His bundle pacing (HBP) for QRS correction of underlying left bundle branch block. Post-procedure echocardiography did not show persistent ventricular septal defect. Left ventricular ejection fraction improved from 13% four months before implant to 30% at 32 months post-implant. Corrective HBP pacing thresholds showed a rise at 3-year follow-up. Discussion: Interventricular septal perforation during CSP is a possible complication during lead fixation. Pre-operative septal assessment with imaging can be helpful to provide important septal anatomical features. Septal perforation can be managed appropriately with lead repositioning intra-procedurally and close follow-up.

O-GlcNAc of STING mediates antiviral innate immunity.

BACKGROUND: O-GlcNAcylation modification affects multiple physiological and pathophysiolocal functions of cells. Altered O-GlcNAcylation was reported to participate in antivirus response. Stimulator of interferon genes (STING) is an adaptor mediating DNA virus-induced innate immune response. Whether STING is able to be modified by O-GlcNAcylation and how O-GlcNAcylation affects STING-mediated anti-DNA virus response remain unknown. METHODS: Metabolomics analysis was used for detecting metabolic alterations in HSV-1 infection cells. Succinylated wheat germ agglutinin (sWGA), co-immunoprecipitation, and pull-down assay were employed for determining O-GlcNAcylation. Mutagenesis PCR was applied for the generation of STING mutants. WT and Sting1-/- C57BL/6 mice (KOCMP-72512-Sting1-B6NVA) were infected with HSV-1 and treated with O-GlcNAcylation inhibitor for validating the role of STING O-GlcNAcylation in antiviral response. RESULTS: STING was functionally activated by O-GlcNAcylation in host cells challenged with HSV-1. We demonstrated that this signaling event was initiated by virus infection-enhanced hexosamine biosynthesis pathway (HBP). HSV-1 (or viral DNA mimics) promotes glucose metabolism of host cells with a marked increase in HBP, which provides donor glucosamine for O-GlcNAcylation. STING was O-GlcNAcylated on threonine 229, which led to lysine 63-linked ubiquitination of STING and activation of antiviral immune responses. Mutation of STING T229 to alanine abrogated STING activation and reduced HSV-1 stimulated production of interferon (IFN). Application of 6-diazo-5-oxonorleucine (DON), an agent that blocks the production of UDP-GlcNAc and inhibits O-GlcNAcylation, markedly attenuated the removal of HSV-1 in wild type C57BL/6 mice, leading to an increased viral retention, elevated infiltration of inflammatory cells, and worsened tissue damages to those displayed in STING gene knockout mice. Together, our data suggest that STING is O-GlcNAcylated in HSV-1, which is crucial for an effective antiviral innate immune response. CONCLUSION: HSV-1 infection activates the generation of UDP-Glc-NAc by upregulating the HBP metabolism. Elevated UDP-Glc-NAc promotes the O-GlcNAcylation of STING, which mediates the anti-viral function of STING. Targeting O-GlcNAcylation of STING could be a useful strategy for antiviral innate immunity.

AZU1: a new promising marker for infection in orthopedic and trauma patients?

Early and reliable detection of infection is vital for successful treatment. Serum markers such as C-reactive protein (CRP) and procalcitonin (PCT) are known to increase with a time lag. Azurocidin 1 (AZU1) has emerged as a promising marker for septic patients, but its diagnostic value in orthopedic and trauma patients remains unexplored. Between July 2020 and August 2023, all patients necessitating inpatient treatment for periprosthetic joint infection (PJI), peri-implant infection (II), soft tissue infection, chronic osteomyelitis, septic arthrodesis, bone non-union with and without infection were enrolled. Patients undergoing elective total joint arthroplasty (TJA) served as the control group. Blood samples were collected and analyzed for CRP, white blood cell count (WBC), PCT, and AZU1. Based on the inclusion and exclusion criteria 222 patients were included in the study (trauma = 38, soft tissue infection = 75, TJA = 33, PJI/II = 39, others = 37). While sensitivity and specificity were comparably high for AZU1 (0.734/0.833), CRP and PCT had higher specificity (0.542/1 and 0.431/1, respectively), and WBC a slightly higher sensitivity (0.814/0.455) for septic conditions. Taken together, the area under the curve (AUC) showed the highest accuracy for AZU1 (0.790), followed by CRP (0.776), WBC (0.641), and PCT (0.656). The Youden-Index was 0.57 for AZU1, 0.54 for CRP, 0.27 for WBC, and 0.43 for PCT. Elevated AZU1 levels effectively distinguished patients with a healthy condition from those suffering from infection. However, there is evidence suggesting that trauma may influence the release of AZU1. Additional research is needed to validate the diagnostic value of this new biomarker and further explore its potential clinical applications.

Multiple radiologist review of adrenal CT still frequently misses lateralized surgical primary aldosteronism.

Patients with primary aldosteronism (PA) have increased morbidity and mortality compared to those with essential hypertension. Accurate detection of lateralized PA is important so that affected patients can receive potentially curative adrenalectomy. However, around 40% of patients with lateralized PA have "normal" adrenal glands on computed tomography (CT). Additional independent review of imaging has been shown to improve diagnostic accuracy in many areas of imaging. Therefore, the authors sought to establish if multi-reader re-assessment of previously reported normal CT scans would result in increased detection of surgically remediable disease. The authors found that re-assessment of CT imaging by one, two, or three additional radiologists (or a combination thereof) slightly increased the detection of lateralized disease, but these differences were not statistically significant (p > .05). Readers had low inter-observer agreement (kappa = 0.17). If detection of a discrete nodule on CT was made a prerequisite for adrenal vein sampling (AVS), a second read by another reviewer would still result in an excess of missed cases (84.2%, 36.8%, and 65.8%, respectively, for each of the three independent reviewers). Therefore, a "normal" CT does not preclude the possibility of lateralized PA. Adrenal vein sampling should still be strongly considered wherever available and whenever surgery is considered for treatment of PA, irrespective of CT findings.

HBP1 promotes chicken preadipocyte proliferation via directly repressing SOCS3 transcription.

Preadipocyte proliferation is an essential process in adipose development. During proliferation of preadipocytes, transcription factors play crucial roles. HMG-box protein 1 (HBP1) is an important transcription factor of cellular proliferation. However, the function and underlying mechanisms of HBP1 in the proliferation of preadipocytes remain unclear. Here, we found that the expression level of HBP1 decreased first and then increased during the proliferation of chicken preadipocytes. Knockout of HBP1 could inhibit the proliferation of preadipocytes, while overexpression of HBP1 could promote the proliferation of preadipocytes. ChIP-seq data showed that HBP1 had the unique DNA binding motif in chicken preadipocytes. By integrating ChIP-Seq and RNA-Seq, we revealed a total of 3 candidate target genes of HBP1. Furthermore, the results of ChIP-qPCR, RT-qPCR, luciferase reporter assay and EMSA showed that HBP1 could inhibit the transcription of suppressor of cytokine signaling 3 (SOCS3) by binding to its promoter. Moreover, we confirmed that SOCS3 can mediate the regulation of HBP1 on the proliferation of preadipocytes through RNAi and rescue experiments. Altogether, these data demonstrated that HBP1 directly targets SOCS3 to regulate chicken preadipocyte proliferation. Our findings expand the transcriptional regulatory network of preadipocyte proliferation, and they will be helpful in formulating a molecular breeding scheme to control excessive abdominal fat deposition and to improve meat quality in chickens.

miR-29c-3p acts as a tumor promoter by regulating ß-catenin signaling through suppressing DNMT3A, TET1 and HBP1 in ovarian carcinoma.

Ovarian Carcinoma (OvCa) is characterized by rapid and sustained growth, activated invasion and metastasis. Studies have shown that microRNAs recruit and alter the expression of key regulators to modulate carcinogenesis. Here, we find that miR-29c-3p is increased in benign OvCa and malignant OvCa compared to normal ovary. Univariate and multivariate analyses report that miR-29c-3p overexpression is associated with poor prognosis in OvCa. Furthermore, we investigate that expression of miR-29c-3p is inversely correlated to DNA methyltransferase (DNMT) 3 A and Ten-Eleven-Translocation enzyme TET1. The high-throughput mRNA sequencing, bioinformatics analysis and pharmacological studies confirm that aberrant miR-29c-3p modulates tumorigenesis in OvCa cells, including epithelial-mesenchymal transition (EMT), proliferation, migration, and invasion. This modulation occurs through the regulation of ß-catenin signaling by directly targeting 3'UTR of DNMT3A, TET1 and the HMG box transcription factor HBP1 and suppressing their expression. The further 3D spheres assay clearly shows the regulatory effects of miR-29c-3p on OvCa tumorigenesis. Additionally, the receiver operating characteristic (ROC) curve analysis of miR-29c-3p and the clinical detection/diagnostic biomarker CA125 suggests that miR-29c-3p may be conducive for clinical diagnosis or co-diagnosis of OvCa. These findings support miR-29c-3p functions as a tumor promoter by targeting its functional targets, providing new potential biomarker (s) for precision medicine strategies in OvCa.

Nutlin-3a induces KRAS mutant/p53 wild type lung cancer specific methuosis-like cell death that is dependent on GFPT2.

BACKGROUND: Oncogenic KRAS mutation, the most frequent mutation in non-small cell lung cancer (NSCLC), is an aggressiveness risk factor and leads to the metabolic reprogramming of cancer cells by promoting glucose, glutamine, and fatty acid absorption and glycolysis. Lately, sotorasib was approved by the FDA as a first-in-class KRAS-G12C inhibitor. However, sotorasib still has a derivative barrier, which is not effective for other KRAS mutation types, except for G12C. Additionally, resistance to sotorasib is likely to develop, demanding the need for alternative therapeutic strategies. METHODS: KRAS mutant, and wildtype NSCLC cells were used in vitro cell analyses. Cell viability, proliferation, and death were measured by MTT, cell counting, colony analyses, and annexin V staining for FACS. Cell tracker dyes were used to investigate cell morphology, which was examined by holotomograpy, and confocal microscopes. RNA sequencing was performed to identify key target molecule or pathway, which was confirmed by qRT-PCR, western blotting, and metabolite analyses by UHPLC-MS/MS. Zebrafish and mouse xenograft model were used for in vivo analysis. RESULTS: In this study, we found that nutlin-3a, an MDM2 antagonist, inhibited the KRAS-PI3K/Akt-mTOR pathway and disrupted the fusion of both autophagosomes and macropinosomes with lysosomes. This further elucidated non-apoptotic and catastrophic macropinocytosis associated methuosis-like cell death, which was found to be dependent on GFPT2 of the hexosamine biosynthetic pathway, specifically in KRAS mutant /p53 wild type NSCLC cells. CONCLUSION: These results indicate the potential of nutlin-3a as an alternative agent for treating KRAS mutant/p53 wild type NSCLC cells.

Predictive power of isolated high home systolic blood pressure for cardiovascular outcomes in individuals with type 2 diabetes mellitus: KAMOGAWA-HBP study.

AIMS/INTRODUCTION: Isolated high home systolic blood pressure (IHHSBP) is a risk for cardiovascular disease (CVD). However, no study has shown an association between IHHSBP and CVD in diabetes. We examined the association between IHHSBP and CVD in type 2 diabetes. MATERIALS AND METHODS: This retrospective cohort study included 1082 individuals with type 2 diabetes, aged 20 to 90 years, without a history of macrovascular complications. Home blood pressure (HBP) was measured three times every morning and evening for 14 days. Cox proportional hazards models were used to examine the relationship between IHHSBP and CVD incidence. RESULTS: With the normal HBP group as the reference, the adjusted hazard ratio (HR) (95% confidence interval [CI]) for CVD was 1.58 (1.02-2.43) in the IHHSBP group. Correcting for antihypertensive medication use did not change HR. Based on sex, the adjusted HR (95% CI) for CVD was 1.25 (0.74-2.13) in males and 2.28 (1.01-5.15) in females. CONCLUSIONS: In individuals with type 2 diabetes, those with IHHSBP had a higher HR for cardiovascular disease than those with normal HBP. But, Isolated high home diastolic blood pressure and high HBP were not. The association between IHHSBP and CVD was stronger in females than in males.

Inhibition of O-GlcNAcylation Reduces Cell Viability and Autophagy and Increases Sensitivity to Chemotherapeutic Temozolomide in Glioblastoma.

Glioblastoma (GB) is the most aggressive primary malignant brain tumor and is associated with short survival. O-GlcNAcylation is an intracellular glycosylation that regulates protein function, enzymatic activity, protein stability, and subcellular localization. Aberrant O-GlcNAcylation is related to the tumorigenesis of different tumors, and mounting evidence supports O-GlcNAc transferase (OGT) as a potential therapeutic target. Here, we used two human GB cell lines alongside primary human astrocytes as a non-tumoral control to investigate the role of O-GlcNAcylation in cell proliferation, cell cycle, autophagy, and cell death. We observed that hyper O-GlcNAcylation promoted increased cellular proliferation, independent of alterations in the cell cycle, through the activation of autophagy. On the other hand, hypo O-GlcNAcylation inhibited autophagy, promoted cell death by apoptosis, and reduced cell proliferation. In addition, the decrease in O-GlcNAcylation sensitized GB cells to the chemotherapeutic temozolomide (TMZ) without affecting human astrocytes. Combined, these results indicated a role for O-GlcNAcylation in governing cell proliferation, autophagy, cell death, and TMZ response, thereby indicating possible therapeutic implications for treating GB. These findings pave the way for further research and the development of novel treatment approaches which may contribute to improved outcomes and increased survival rates for patients facing this challenging disease.