Molecular characterization and survival analysis of a cohort of glioblastoma, IDH-wildtype.

Glioblastoma, IDH-wild type, the most common malignant primary central nervous system tumor, represents a formidable challenge in clinical management due to its poor prognosis and limited therapeutic responses. With an evolving understanding of its underlying biology, there is an urgent need to identify prognostic molecular groups that can be subject to targeted therapy. This study established a cohort of 124 sequential glioblastomas from a tertiary hospital and aimed to find correlations between molecular features and survival outcomes. Comprehensive molecular characterization of the cohort revealed prevalent alterations as previously described, such as TERT promoter mutations and involvement of the PI3K-Akt-mTOR, CK4/6-CDKN2A/B-RB1, and p14ARF-MDM2-MDM4-p53 pathways. MGMT promoter methylation is a significant predictor of improved overall survival, aligned with previous data. Conversely, age showed a marginal association with higher mortality. Multivariate analysis to account for the effect of MGMT promoter methylation and age showed that, in contrast to other published series, this cohort demonstrated improved survival for tumors harboring PTEN mutations, and that there was no observed difference for most other molecular alterations, including EGFR amplification, RB1 loss, or the coexistence of EGFR amplification and deletion/exon skipping (EGFRvIII). Despite limitations in sample size, this study contributes data to the molecular landscape of glioblastomas, prompting further investigations to examine these findings more closely in larger cohorts.

Helicobacter pylori Exposure in Nausea and Vomiting of Pregnancy Increases Risk of Preterm Delivery.

Background: Hyperemesis gravidarum (HG), a severe form of nausea and vomiting in pregnancy (NVP), is a leading indication for hospitalization in the first trimester. NVP and HG are associated with Helicobacter pylori (HP) infection in non-United States cohorts. How HP exposure and NVP interact to affect metabolic disturbance and pregnancy outcomes is not known. Materials and Methods: We designed a retrospective cohort study relating HP and NVP to serum electrolyte laboratory results, preterm delivery, and infant birth weight. Single academic institution discovery and independent multi-institutional validation cohorts included pregnant subjects with an HP test result. Associations of HP, NVP, and pregnancy outcomes were assessed with odds ratio calculations, Student's t-tests, and multivariate logistic regression. Results: Among subjects with positive HP test results, the prevalence of hyperemesis gravidarum (HG) was 0.025 (66 of 2671) and NVP was 0.27 (710 of 2671). Subjects with negative HP had prevalence of HG 0.015 (165 of 10,960) and NVP 0.22 (2392 of 10,960). History of HP exposure increased risk of NVP, including HG (odds ratio 1.3, 95% CI 1.1-1.4). Patients with HP exposure had lower serum potassium (mean difference 0.1 mEq/L) and bicarbonate (mean difference 0.3 mEq/L) during pregnancy than HP-negative patients (p < 0.01). Serum potassium was lowest in subjects with both NVP and HP exposure (mean 3.5 mEq/L [3.4-3.6], p < 0.0001). HP exposure alone carried increased risk for preterm delivery (OR 1.3 [1.1-1.4]). NVP alone increased risk of preterm delivery (OR 2.8 [2.5-3.1]) including second trimester delivery (OR 2.2 [1.7-2.8]). In multivariate analysis, HP exposure in the setting of NVP further increased risk of preterm delivery (adjusted OR 1.4 [1.0-1.9], p = 0.03). Conclusions: H. pylori exposure and diagnosis of NVP are individually associated with metabolic disturbances and adverse pregnancy outcomes such as preterm labor and delivery, and their combination further increases risk in US populations.

Manipulation of Redox Metabolism Using Pharmacologic Ascorbate Opens a Therapeutic Window for Radio-Sensitization by ATM Inhibitors in Colorectal Cancer.

PURPOSE: Ataxia telangiectasia mutated kinase (ATM) inhibitors are potent radiosensitizers that regulate DNA damage responses and redox metabolism, but they have not been translated clinically because of the potential for excess normal tissue toxicity. Pharmacologic ascorbate (P-AscH-; intravenous administration achieving mM plasma concentrations) selectively enhances H2O2-induced oxidative stress and radiosensitization in tumors while acting as an antioxidant and mitigating radiation damage in normal tissues including the bowel. We hypothesized that P-AscH- could enhance the therapeutic index of ATM inhibitor-based chemoradiation by simultaneously enhancing the intended effects of ATM inhibitors in tumors and mitigating off-target effects in adjacent normal tissues. METHODS AND MATERIALS: Clonogenic survival was assessed in human (human colon tumor [HCT]116, SW480, HT29) and murine (CT26, MC38) colorectal tumor lines and normal cells (human umbilical vein endothelial cell, FHs74) after radiation ± DNA repair inhibitors ± P-AscH-. Tumor growth delay was assessed in mice with HCT116 or MC38 tumors after fractionated radiation (5 Gy × 3) ± the ATM inhibitor KU60019 ± P-AscH-. Intestinal injury, oxidative damage, and transforming growth factor ß immunoreactivity were quantified using immunohistochemistry after whole abdominal radiation (10 Gy) ± KU60019 ± P-AscH-. Cell cycle distribution and ATM subcellular localization were assessed using flow cytometry and immunohistochemistry. The role of intracellular H2O2 fluxes was assessed using a stably expressed doxycycline-inducible catalase transgene. RESULTS: KU60019 with P-AscH- enhanced radiosensitization in colorectal cancer models in vitro and in vivo by H2O2-dependent oxidative damage to proteins and enhanced DNA damage, abrogation of the postradiation G2 cell cycle checkpoint, and inhibition of ATM nuclear localization. In contrast, concurrent P-AscH- markedly reduced intestinal toxicity and oxidative damage with KU60019. CONCLUSIONS: We provide evidence that redox modulating drugs, such as P-AscH-, may facilitate the clinical translation of ATM inhibitors by enhancing tumor radiosensitization while simultaneously protecting normal tissues.

Hyperbaric oxygen exposure alleviate metabolic side-effects of olanzapine treatment and is associated with Langerhans islet proliferation in rats.

Introduction: Olanzapine (OLZ) is one of the second-generation antipsychotics drugs (APDs) used to treat several psychiatric illnesses. Olanzapine treatment is often associated with many metabolic side effects in a dose dependent manner such as obesity, dyslipidemia and insulin resistance, induction of type II diabetes and acute pancreatitis in some patients. Methods: Hyperbaric Oxygen therapy (HBOT) was investigated as a tool to mitigate olanzapine metabolic side effects in rats. Thirty-six female Sprague Dawley (SD) rats were divided into 4 groups; rats on olanzapine treatment either exposed to hyperbaric oxygen therapy (HBOOLZ) or left without exposure (OLZ) then non-treated rats that either exposed to hyperbaric oxygen therapy or left without exposure (control). Rats received Hyperbaric Oxygen therapy for 35 days at 2.4 atmospheres absolute (ATA) for 2.5 h daily followed by intraperitoneal injection of olanzapine at 10 mg/kg or placebo. Results: Rats on either hyperbaric oxygen therapy or olanzapine had a significant loss in body weight. Olanzapine treatment showed a decrease in serum insulin level, triglyceride, highdensity lipoprotein (HDL) cholesterol, and lipase level but an increase in fasting blood sugar (FBS), insulin resistance index (HOMA-IR) and amylase, while rats' exposure to hyperbaric oxygen therapy reversed these effects. The Pancreatic Langerhans islets were up-regulated in both hyperbaric oxygen therapy and olanzapine treatments but the combination (HBOOLZ) doubled these islets number. Discussion: This study advocated that hyperbaric oxygen therapy can be an alternative approach to control or reverse many metabolic disorders (MDs) associatedwith olanzapine treatment. In addition, it seems that hyperbaric oxygen therapy positively affect the pancreatic Langerhans cells activity and architecture.

TIMAP Upregulation Correlates Negatively with Survival in HER2- Negative Subtypes of Breast Cancer.

OBJECTIVE: TIMAP expression is regulated by transforming growth factor beta 1 (TGFß1); known for its role in breast cancer development and metastasis. Nevertheless, data on TIMAP protein expression and its association with breast cancer development are lacking. In this study, we aimed to investigate the variation in TIMAP protein expression in breast cancer tissue and its correlation with various clinicopathological characteristics of breast cancer patients and overall survival rate. METHODS: A total of 159 paraffin-embedded tissue blocks from women diagnosed with four breast cancer subtypes (49 HER2-only, 33 Luminal A, 39 Luminal B, and 38 triple negative) were used to construct tissue microarray (TMA), followed by TIMAP immunohistochemistry (IHC). TIMAP expression was scored by two pathologists and categorized as weak (1-33% expression), moderate (34-66%), and strong (67-100%). Chi-square test and Kaplan Meier survival test were performed to determine the association between TIMAP expression and clinicopathological features and overall survival rate, respectively. RESULTS: TIMAP protein was strongly expressed in 46 (93.9%) HER2-only, 32 (97%) luminal A, 37 (94.9%) luminal B, and 29 (76.3%) triple negative. TIMAP expression negatively associated with ER/PR expression (P=0.03), and it negatively impacted the overall survival in HER2 negative group (P=0.02). CONCLUSION: Our findings suggest that TIMAP protein expression is upregulated in all breast cancer subtypes. However, its prognostic role is exclusively observed in HER2- negative group, suggesting a potential of targeting TIMAP in future therapeutic strategies in this group.