Glioblastoma is a challenge in neuro-oncology, with survival significantly influenced mainly by extent of resection and molecular markers. Despite advancements, the prognosis for IDH-wildtype glioblastoma remains poor, particularly when surgical resection is not possible. However, some patients exhibit unexpectedly extended survival despite the extent of resection. This study aims to analyze the determinants that contribute to these atypical survival rates among glioblastoma patients who have had solely biopsy procedures. We conducted a retrospective analysis of patients diagnosed with IDH- wildtype glioblastomas at our institution from 2017 to 2021, who underwent biopsy only. The study focused on evaluating the impact of demographic characteristics, clinical features, molecular markers and treatment modalities on survival outcomes (Overall Survival (OS) and Progression-Free Survival (PFS)). Statistical analyses included survival analysis and logistic regression for evaluating associations between OS and preoperative characteristics and postoperative treatments. The cohort included 99 patients, with a median age at diagnosis of 65.5 years. Median OS and PFS were 6.0 and 3.6 months, respectively. The multivariate analysis revealed that higher KPS scores before biopsy, no contrast uptake on imaging and any adjuvant therapy, particularly the use of bevacizumab, were independently associated to increased OS (HR=0.97, p=0.009. HR=0.7, p=0.015; HR=0.27, p=0.002, respectively). Out of 99 patients, 77.8% survived past the 3-month threshold, with 87.0% of this receiving adjuvant treatment. Only 8% of patients survived past 24 months, and in this group of patients, MGMT Methylation was observed in just 25% of cases. Kaplan-Meier analysis indicated a better prognosis with any type of adjuvant therapy across all patients, particularly so in those with KPS ≥70. Age did not significantly affect survival outcomes (OR=1.00, p=0.835). Our findings reveal that any adjuvant treatment, no contrast uptake on imaging and higher preoperative KPS are key determinants of survival in IDH wildtype glioblastoma and should therefore be considered when deciding whether to perform a biopsy.

Leukemia represents as one of the most common primary malignancies of the hematologic system in both children’s and adults and remains a largely incurable or relapse disease. The elucidation of disease subtypes based on mutational profiling, has not improved clinical outcomes. IDH1/2 are key enzymes of TCA cycle that produces α-ketoglutarate (αKG), however their mutated version, are well reported in various cancer types including leukemia, produces D-2 hydroxyglutarate (D-2HG), an oncometabolite. Recently, some studies have shown that wild type IDH1 is highly expressed in non-small cell lung carcinoma (NSCLC), primary glioblastomas (GBM) and several hematological malignancies and corelates with disease progression. In this work, we have showed treatment of wild type IDH1 leukemia cells with specific IDH1 inhibitor switched leukemic cells towards gly-colysis from oxidative phosphorylation (OXPHOS) phenotype. We also noticed reduction in αKG in treated cells possible suggesting inhibition of IDH1 enzymatic activity. Further, we found that IDH1 inhibition reduces the metabolites related to one carbon metabolism, essential to maintain global methylation in leukemic cells. Finally, we observed that metabolic alteration in IDH1 inhibitor treated leukemic cells promotes reactive oxygen species (ROS) formation along with loss of mito-chondrial membrane potential, leading towards apoptosis in leukemic cells. Overall, we showed that wild type IDH1 targeting in leukemic cells promote metabolic alterations that can be exploited for combination therapies for better outcome.

Relapses and resistance to therapeutic agents are major barriers for treatment of acute myeloid leukemia (AML) patients. This unfavorable circumstance emphasizes the need for new strategies targeting drug-resistant cells. As IDH mutation is present in the preleukemic stem cells and systematically conserved at relapse, targeting mutant IDH cells would be essential to achieve a long-term remission in the AML subgroup with IDH mutation. Here, using a panel of human AML cell lines and primary AML patient specimens harboring IDH mutation, we showed that the presence of IDH mutation through the production of an oncometabolite (R)-2-HG induces vitamin D receptor related transcriptional programs, priming these AML cells to differentiate with pharmacological doses of ATRA or/and VD. This activation occurs in a CEBP-dependent manner. Accordingly, our findings illuminate potent and cooperative effects of IDH mutation and vitamin D pathway to differentiate in AML, revealing a novel therapeutic approach easily transferable/immediately applicable in clinics for this subgroup of AML patients.

Background: Glioblastomas (GBM) is generally burdened, to date, by a dismal prognosis, although Long Term Survivors have a relatively significant incidence. Our specific aim was to determine the exact impact of many surgery-, patient- and tumor-related variable on Survival parameters. Methods: The surgical, radiological and clinical outcomes of patients have been retrospectively reviewed for the present study. All the patients have been operated on in our Institution and classified according their Overall Survival in LTS (Long Term Survivors) and STS (Short Term Survivors). A thorough Review of our surgical series was conducted to compare the oncologic results of the patients in regards to 1. Surgical , 2. Molecular, and 3.Treatment related features. Results: A total of 177 patients were included in the final cohort. Extensive statistical analysis by means of univariate, multivariate and survival analyses disclosed a survival advantage for patients presenting a younger age, a smaller lesion and a better functional status at presentation. From the Histochemical point of view, Ki67(%) was the strongest predictor of better oncologic outcomes. A stepwise analysis of variance outlines the existence of 8 prognostic subgroups according to the molecular patterns of Ki67 overexpression and EGFR, p53 and IDH mutations. Conclusions: On the ground of our statistical analyses we can affirm that the following factors were significant predictors of survival advantage: KPS, Age, Volume of the lesion, Motor disorder at presentation, a Ki67 overexpression. A fine molecular profiling is feasible to precisely stratify the prognosis of GBM patients.

Excessive high fat diet (HFD) consumption can induce food addiction which is believed to involve the communication between the hypothalamus and mesolimbic dopaminergic neurons, originating in the ventral tegmental area (VTA) and projecting to the nucleus accumbens (NAc). These brain regions are densely populated with opioid receptors, raising the possibility that these receptors, and particularly mu opioid receptors (MORs), are involved in mediating reward induced by palatable foods. This study sought to investigate the involvement of MORs in high fat diet (HFD)-induced reward and if there is any difference between male and female subjects in this response. We also assessed if exposure to HFD would potentiate the rewarding action of oxycodone, a relatively selective MOR agonist. The place conditioning paradigm was used to determine if conditioning for a short time (STC, 2 h) or long time (LTC, 16 h) with HFD induces reward or alters the rewarding action of oxycodone. Male and female C57BL/6J mice as well as MOR knockout and wildtype mice of both sexes were tested for basal place preference on day 1 and then conditioned with HFD in one chamber and regular chow diet (RCD) in another chamber and tested for place preference again after three sets of STC and again after a set of LTC. Each set consisted of two conditioning with RCD and two conditioning with HFD. Controls were conditioned with RCD in both conditioning chambers. Following the last place preference test, mice were treated with oxycodone and conditioned in the HFD-paired chamber and saline in the RCD-paired chamber for one hour once a day to explore the possibility if the HFD could alter oxycodone reward. The result showed that HFD induced conditioned place preference (CPP) in both male and female subjects following the LTC. This response was further potentiated after oxycodone conditioning. The latter response was mediated via MORs, as it was blunted in MOR knockout mice. However, HFD-induced CPP was observed following LTC in only female MOR knockout mice, suggesting for sexual dimorphism in this response.

As variants of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) continue to emerge, assessment of vaccine immunogenicity remains a critical factor to support continued vaccination. To this end, an in vitro microneutralization (MN50) assay was validated to quantitate SARS-CoV-2 neutralizing antibodies against ancestral and variant strains (Beta, Delta, Omicron BA.1, Omicron BA.5 and XBB.1.5) in human serum. For ancestral strain, the MN50 assay met acceptance criteria for inter-/intra-assay precision, specificity, linearity, and selectivity. The assay was robust against changes to virus/serum incubation time, cell seeding density, virus content per well, cell passage number, and serum interference. Analyte in serum samples was stable up to 5 freeze/thaw cycles and for up to 12 months of storage at –80 ± 10 °C. Similar results were observed for the variant-adapted MN50 assays. The conversion factor to convert assay result units to WHO international standard units (IU/mL) was determined to be 0.62 for the ancestral prototype strain. This MN50 assay will be useful for vaccine immunogenicity analyses in clinical trial samples, enabling assessment of vaccine immunogenicity for ancestral and variant strains as variant-adapted vaccines are developed.