Metabolic remodeling contributes towards an immune-suppressive phenotype in glioblastoma.

Glioblastoma (GBM) is one of the most aggressive tumors. Numerous studies in the field of immunotherapy have focused their efforts on identifying various pathways linked with tumor-induced immunosuppression. Recent research has demonstrated that metabolic reprogramming in a tumor can contribute towards immune tolerance. To begin to understand the interface between metabolic remodeling and the immune-suppressive state in GBM, we performed a focused, integrative analysis coupling metabolomics with gene-expression profiling in patient-derived GBM (n = 80) and compared them to low-grade astrocytoma (LGA; n = 28). Metabolic intermediates of tryptophan, arginine, prostaglandin, and adenosine emerged as immuno-metabolic nodes in GBM specific to the mesenchymal and classical molecular subtypes of GBM. Integrative analyses emphasized the importance of downstream metabolism of several of these metabolic pathways in GBM. Using CIBERSORT to analyze immune components from the transcriptional profiles of individual tumors, we demonstrated that tryptophan and adenosine metabolism resulted in an accumulation of Tregs and M2 macrophages, respectively, and was recapitulated in mouse models. Furthermore, we extended these findings to preclinical models to determine their potential utility in defining the biologic and/or immunologic consequences of the identified metabolic programs. Collectively, through integrative analysis, we uncovered multifaceted ways by which metabolic reprogramming may contribute towards immune tolerance in GBM, providing the framework for further investigations designed to determine the specific immunologic consequence of these metabolic programs and their therapeutic potential.

A multicenter phase II study of temozolomide plus disulfiram and copper for recurrent temozolomide-resistant glioblastoma.

PURPOSE: Preclinical studies have suggested promising activity for the combination of disulfiram and copper (DSF/Cu) against glioblastoma (GBM) including re-sensitization to temozolomide (TMZ). A previous phase I study demonstrated the safety of combining DSF/Cu with adjuvant TMZ for newly diagnosed GBM. This phase II study aimed to estimate the potential effectiveness of DSF/Cu to re-sensitize recurrent GBM to TMZ. METHODS: This open-label, single-arm phase II study treated recurrent TMZ-resistant GBM patients with standard monthly TMZ plus concurrent daily DSF 80 mg PO TID and Cu 1.5 mg PO TID. Eligible patients must have progressed after standard chemoradiotherapy and within 3 months of the last dose of TMZ. Known isocitrate dehydrogenase (IDH) mutant or secondary GBMs were excluded. The primary endpoint was objective response rate (ORR), and the secondary endpoints included progression-free survival (PFS), overall survival (OS), clinical benefit (response or stable disease for at least 6 months), and safety. RESULTS: From March 2017 to January 2018, 23 recurrent TMZ-resistant GBM patients were enrolled across seven centers, and 21 patients were evaluable for response. The median duration of DSF/Cu was 1.6 cycles (range: 0.1-12.0). The ORR was 0%, but 14% had clinical benefit. Median PFS was 1.7 months, and median OS was 7.1 months. Only one patient (4%) had dose-limiting toxicity (grade three elevated alanine transaminase). CONCLUSIONS: Addition of DSF/Cu to TMZ for TMZ-resistant IDH-wild type GBM appears well tolerated but has limited activity for unselected population.

Improving dosimetric outcome for hippocampus and cochlea sparing whole brain radiotherapy using spot-scanning proton arc therapy.

This feasibility study shows that Spot-scanning Proton Arc therapy (SPArc) is able to significantly reduce the dose to the hippocampus and cochlea compared to both Volumetric Modulated Arc Photon Therapy (VMAT) and the robust optimized Intensity Modulated Proton Therapy (ro-IMPT) plans in whole brain radiotherapy. Furthermore, SPArc not only improves plan robustness but could potentially deliver a treatment as efficient as ro-IMPT when proton system's energy layer switch time is less than 1 s.

Practice patterns and survival outcomes of intracranial germinoma: an analysis of the National Cancer Database.

The goal of the study is to examine the practice pattern and survival outcome of adult and pediatric patients with intracranial germinoma. Patients from the National Cancer Database (NCDB) brain tumor registry between the years 2004-2014 with intracranial germinoma were extracted for analysis. Patients who had distant metastasis, received no treatments, or only surgery/chemotherapy alone were excluded. An age cutoff of > 21 years old was used to define the pediatric population. Patients were stratified by the treatments radiation therapy alone (RT) and chemotherapy followed by radiation therapy (C + RT). 445 patients with intracranial germinoma meeting our inclusion criteria were identified. Of the adult patients, 65.7% received RT and 34.3% received C + RT, compared to the pediatric patients, where 31.8% received RT and 68.2% received C + RT. Those patients who received C + RT had a lower radiation dose compared to the RT group (p < 0.001). The 5 and 10 year overall survival (OS) for the entire cohort was 92.6 and 87.9%, respectively. Univariate analysis demonstrated improved OS with younger age, private insurance, C + RT treatment, and pediatric patients. Only age and insurance type remained significant on multivariate analysis. The 5 year OS was 92.6% (RT) versus 97.2% (C + RT) (p = 0.307) and 83.4% (RT) versus 95.4% (C + RT) (p = 0.122) in the pediatric and adult patients, respectively. There is a higher use of C + RT with an accompanied reduction in RT dose in the treatment of intracranial germinoma. There is no difference in survival between the treatment approaches of RT or C + RT in the NCDB patient cohort.

Pharmaceutical products as emerging contaminant in water: relevance for developing nations and identification of critical compounds for Indian environment.

Pharmaceuticals and personal care products (PPCPs) are contaminants of emerging concern and have been detected worldwide in water bodies in trace concentrations. Most of these emerging contaminants are not regulated in water quality standards except a few in the developed countries. In the case of developing countries, research in this direction is at a nascent stage. For the effective management of Pharmaceutical contaminants (PC) in developing countries, the relevance of PCs as an emerging contaminant has to be analyzed followed by regular monitoring of the environment. Considering the resource constraints, this could be accomplished by identifying the priority compounds which is again region specific and dependent on consumption behavior and pattern. In this work, relevance of pharmaceutical compound as emerging contaminant in water for a developing country like India is examined by considering the data pertaining to pharmaceutical consumption data. To identify the critical Pharmaceutical Contaminants to be monitored in the Indian environment, priority compounds from selected prioritization methods were screened with the compounds listed in National List of Essential Medicine (NLEM), India. Further, information on the number of publications on the compound as an emerging contaminant, data on monitoring studies in India and the number of brands marketing the compound in India were also analyzed. It is found that out of 195 compounds from different prioritization techniques, only 77 compounds were found relevant to India based on NLEM sorting.

Immunotherapy and radiation in glioblastoma.

Radiation therapy plays a central role in the management of glioblastoma. Although primarily thought of as modality to provide local tumor control through DNA damage, the capacity of ionizing radiation to modulate tumor immune response has long been recognized. The recent emergence of clinically active immunotherapies offers exciting potential for harnessing the immune modulatory effects or radiation through combinatorial strategies designed to enhance clinical outcomes. In this Review, we provide background describing the unique immune environment within the central nervous system, how ionizing radiation may modulate the tumor immune response, preclinical and clinical data testing the combination of radiation and immune modulating agents, and highlight some of the current challenges in extending these findings clinically.

p75 neurotrophin receptor cleavage by α- and γ-secretases is required for neurotrophin-mediated proliferation of brain tumor-initiating cells.

Malignant gliomas are highly invasive, proliferative, and resistant to treatment. Previously, we have shown that p75 neurotrophin receptor (p75NTR) is a novel mediator of invasion of human glioma cells. However, the role of p75NTR in glioma proliferation is unknown. Here we used brain tumor-initiating cells (BTICs) and show that BTICs express neurotrophin receptors (p75NTR, TrkA, TrkB, and TrkC) and their ligands (NGF, brain-derived neurotrophic factor, and neurotrophin 3) and secrete NGF. Down-regulation of p75NTR significantly decreased proliferation of BTICs. Conversely, exogenouous NGF stimulated BTIC proliferation through α- and γ-secretase-mediated p75NTR cleavage and release of its intracellular domain (ICD). In contrast, overexpression of the p75NTR ICD induced proliferation. Interestingly, inhibition of Trk signaling blocked NGF-stimulated BTIC proliferation and p75NTR cleavage, indicating a role of Trk in p75NTR signaling. Further, blocking p75NTR cleavage attenuated Akt activation in BTICs, suggesting role of Akt in p75NTR-mediated proliferation. We also found that p75NTR, α-secretases, and the four subunits of the γ-secretase enzyme were elevated in glioblastoma multiformes patients. Importantly, the ICD of p75NTR was commonly found in malignant glioma patient specimens, suggesting that the receptor is activated and cleaved in patient tumors. These results suggest that p75NTR proteolysis is required for BTIC proliferation and is a novel potential clinical target.

LINAC-based stereotactic radiosurgery to the brain with concurrent vemurafenib for melanoma metastases.

While selective BRAF inhibitors have demonstrated improved outcomes in patients with metastatic BRAF V600E mutant melanoma, management of brain metastases prior to and during therapy presents challenges. Stereotactic radiosurgery (SRS) is an effective treatment for melanoma brain metastases, but there is limited safety and efficacy data on the use of SRS during BRAF therapy. An analysis was performed of patients with metastatic melanoma and brain metastases treated with SRS while on vemurafenib. MRI scans were reviewed post-SRS to evaluate local control (LC) as well as distant control. We identified 80 metastatic melanoma brain lesions treated in 24 patients. The median planning target volume was 0.28 cm(3) (range 0.05-4.19 cm(3)), and lesions were treated to a median dose of 24 Gy (range 15-24 Gy). The median follow up was 5.1 months (range 2-25.2 months). Eight (10 %) lesions showed progression at a median of 6.1 months (range 2-20.1 months) following SRS. Kaplan-Meier LC estimates at 6 and 12 months were 92 and 75 %, respectively. Fourteen (58 %) patients were noted to have distant brain failure at a median of 3.4 months (range 1.9-16.1 months) following treatment with SRS. Median overall (OS) from the date of SRS was 7.2 months (range 1.5-26.8 months) with a median of 11.9 months (range 1.5-28.5 months) since the date of brain metastases diagnosis. There was no evidence of increased toxicity with the combination of SRS and vemurafenib. SRS to brain metastases appears to be both safe and effective for patients treated concurrently with BRAF inhibitors.

Microenvironmental variables must influence intrinsic phenotypic parameters of cancer stem cells to affect tumourigenicity.

Since the discovery of tumour initiating cells (TICs) in solid tumours, studies focussing on their role in cancer initiation and progression have abounded. The biological interrogation of these cells continues to yield volumes of information on their pro-tumourigenic behaviour, but actionable generalised conclusions have been scarce. Further, new information suggesting a dependence of tumour composition and growth on the microenvironment has yet to be studied theoretically. To address this point, we created a hybrid, discrete/continuous computational cellular automaton model of a generalised stem-cell driven tissue with a simple microenvironment. Using the model we explored the phenotypic traits inherent to the tumour initiating cells and the effect of the microenvironment on tissue growth. We identify the regions in phenotype parameter space where TICs are able to cause a disruption in homeostasis, leading to tissue overgrowth and tumour maintenance. As our parameters and model are non-specific, they could apply to any tissue TIC and do not assume specific genetic mutations. Targeting these phenotypic traits could represent a generalizable therapeutic strategy across cancer types. Further, we find that the microenvironmental variable does not strongly affect the outcomes, suggesting a need for direct feedback from the microenvironment onto stem-cell behaviour in future modelling endeavours.

Radiation-induced autophagy potentiates immunotherapy of cancer via up-regulation of mannose 6-phosphate receptor on tumor cells in mice.

There is a significant body of evidence demonstrating that radiation therapy (XRT) enhances the effect of immune therapy. However, the precise mechanisms by which XRT potentiates the immunotherapy of cancer remain elusive. Here, we report that XRT potentiates the effect of immune therapy via induction of autophagy and resultant trafficking of mannose-6-phopsphate receptor (MPR) to the cell surface. Irradiation of different tumor cells caused substantial up-regulation of MPR on the cell surface in vitro and in vivo. Down-regulation of MPR in tumor cells with shRNA completely abrogated the combined effect of XRT and immunotherapy (CTLA4 antibody) in B16F10-bearing mice without changes in the tumor-specific responses of T cells. Radiation-induced MPR up-regulation was the result of redistribution of the receptor to the cell surface. This effect was caused by autophagy with redirection of MPR to autophagosomes in a clathrin-dependent manner. In autophagosomes, MPR lost its natural ligands, which resulted in subsequent trafficking of empty receptor(s) back to the surface. Together, our data demonstrated a novel mechanism by which XRT can enhance the effect of immunotherapy and the molecular mechanism of this process.

Phase I study of bendamustine with concurrent whole brain radiation therapy in patients with brain metastases from solid tumors.

A phase I study was conducted to evaluate the dose-limiting toxicities (DLTs) and to determine the maximum tolerated dose (MTD)/recommended phase II dose of bendamustine with concurrent whole brain radiation (WBR) in patients with brain metastases (BM) from solid tumors. Four doses of intravenous weekly bendamustine were administered with 3 weeks of WBR at three dose levels (60, 80, and 100 mg/m(2)) according to a standard 3 + 3 phase I design. A total of 12 patients with solid tumor BM were enrolled in the study (six with non-small cell lung cancer, four with melanoma, one with breast cancer, and one with neuroendocrine carcinoma). The first two dose levels had three patients each, and the third dose level had six total patients. Plasma pharmacokinetic studies of bendamustine demonstrated no significant differences from pharmacokinetic characteristics of bendamustine in other studies. No DLTs were noted at any dose levels, and no grade 4 toxicities occurred. The MTD of weekly bendamustine with concurrent WBR was 100 mg/m(2). The majority of trial patients died from progressive systemic disease rather than their brain disease. The combination of weekly bendamustine with concurrent WBR was acceptably tolerated. The efficacy of this combination may be evaluated in a phase II trial with stratification by histologies.

Fractionated stereotactic radiotherapy to the post-operative cavity for radioresistant and radiosensitive brain metastases.

Following surgical resection for brain metastases, fractionated stereotactic radiotherapy (FSRT) has been used as an alternative to single dose treatment for large cavities and to reduce risks of late toxicity. The purpose of this study was to evaluate the outcomes of patients treated with FSRT to the post-operative bed for both radioresistant and radiosensitive brain metastases. Between December 2009 and May 2013 a total of 65 patients with newly diagnosed brain metastases were treated with resection followed by FSRT. Patients were treated to a total dose of 20-30 Gy in five fractions. Median planning target volume (PTV) was 16.88 cm(3) (range 4.87-128.43 cm(3)). The median follow-up for all patients was 8.5 months (range 1.1-28.6 months) with a median of 12.9 months for living patients. One and two year Kaplan-Meier estimates of local control were 87.0 and 70.0 %, respectively. Local control at 1 year was 85.6 and 88.0% for radioresistant and radiosensitive tumors, respectively (p = 0.44). A PTV ≥17 cm(3), was associated with local failure, HR 8.63 ((1.44-164.78); p = 0.02). One and two year distant control rates were 50.9 and 46.2%, respectively with six patients (9.2%) experiencing leptomeningeal disease. OS rates at 1 and 2 years were 65.2 and 47.5%, respectively. Survival was significantly associated with recursive partitioning analysis class (p = 0.001) and graded prognostic assessment score (p = 0.005). One case of radionecrosis was noted on follow-up imaging. FSRT in five fractions offers excellent local control in both radiosensitive and radioresistant tumors with minimal toxicity.

Class I histone deacetylases localize to the endoplasmic reticulum and modulate the unfolded protein response.

Post-translational modification through protein acetylation is emerging as an important mode of cellular regulation. We have previously demonstrated the role that glucose-regulated protein 78 kDa (GRP78) acetylation and subsequent activation of the unfolded protein response (UPR) play in the antitumor activity of class I histone deacetylase (HDAC) inhibitors, which primarily target class I HDACs. In this study, we explored the contributory role these class I HDACs may play in UPR regulation. Binding studies were performed using immunoprecipitation/immunoblotting following dual-transfection with HA-tagged GRP78 and FLAG-tagged HDACs. Subcellular localization was performed using Western blot of fractionated cell lysates and confocal microscopy. Individual HDACs were inhibited using RNA interference. We identified the potential of HDACs 1, 2, and 3 to bind to GRP78. These HDACs colocalized with GRP78 in the endoplasmic reticulum (ER). Inhibition of individual HDACs resulted in GRP78 acetylation and selective activation of the UPR. Although traditionally viewed as nuclear enzymes, we demonstrate that Class I HDACs localize to the ER, bind to GRP78, and selectively activate the UPR, representing a novel mode of UPR regulation and mechanism of action of HDAC inhibitors.

Quinolinate promotes macrophage-induced immune tolerance in glioblastoma through the NMDAR/PPARγ signaling axis.

There has been considerable scientific effort dedicated to understanding the biologic consequence and therapeutic implications of aberrant tryptophan metabolism in brain tumors and neurodegenerative diseases. A majority of this work has focused on the upstream metabolism of tryptophan; however, this has resulted in limited clinical application. Using global metabolomic profiling of patient-derived brain tumors, we identify the downstream metabolism of tryptophan and accumulation of quinolinate (QA) as a metabolic node in glioblastoma and demonstrate its critical role in promoting immune tolerance. QA acts as a metabolic checkpoint in glioblastoma by inducing NMDA receptor activation and Foxo1/PPARγ signaling in macrophages, resulting in a tumor supportive phenotype. Using a genetically-engineered mouse model designed to inhibit production of QA, we identify kynureninase as a promising therapeutic target to revert the potent immune suppressive microenvironment in glioblastoma. These findings offer an opportunity to revisit the biologic consequence of this pathway as it relates to oncogenesis and neurodegenerative disease and a framework for developing immune modulatory agents to further clinical gains in these otherwise incurable diseases.

Metabolomic Profiles of Human Glioma Inform Patient Survival.

Aims: Targeting tumor metabolism may improve the outcomes for patients with glioblastoma (GBM). To further preclinical efforts targeting metabolism in GBM, we tested the hypothesis that brain tumors can be stratified into distinct metabolic groups with different patient outcomes. Therefore, to determine if tumor metabolites relate to patient survival, we profiled the metabolomes of human gliomas and correlated metabolic information with clinical data. Results: We found that isocitrate dehydrogenase-wildtype (IDHwt) GBMs are metabolically distinguishable from IDH mutated (IDHmut) astrocytomas and oligodendrogliomas. Survival of patients with IDHmut gliomas was expectedly more favorable than those with IDHwt GBM, and metabolic signatures can stratify IDHwt GBMs subtypes with varying prognoses. Patients whose GBMs were enriched in amino acids had improved survival, while those whose tumors were enriched for nucleotides, redox molecules, and lipid metabolites fared more poorly. These findings were recapitulated in validation cohorts using both metabolomic and transcriptomic data. Innovation: Our results suggest the existence of metabolic subtypes of GBM with differing prognoses, and further support the concept that metabolism may drive the aggressiveness of human gliomas. Conclusions: Our data show that metabolic signatures of human gliomas can inform patient survival. These findings may be used clinically to tailor novel metabolically targeted agents for GBM patients with different metabolic phenotypes. Antioxid. Redox Signal. 39, 942-956.

The Influence of the Ketogenic Diet on the Immune Tolerant Microenvironment in Glioblastoma.

Glioblastoma (GBM) represents an aggressive and immune-resistant cancer. Preclinical investigations have identified anti-tumor activity of a ketogenic diet (KD) potentially being used to target GBM's glycolytic phenotype. Since immune cells in the microenvironment have a similar reliance upon nutrients to perform their individual functions, we sought to determine if KD influenced the immune landscape of GBM. Consistent with previous publications, KD improved survival in GBM in an immune-competent murine model. Immunophenotyping of tumors identified KD-influenced macrophage polarization, with a paradoxical 50% increase in immune-suppressive M2-like-macrophages and a decrease in pro-inflammatory M1-like-macrophages. We recapitulated KD in vitro using a modified cell culture based on metabolomic profiling of serum in KD-fed mice, mechanistically linking the observed changes in macrophage polarization to PPARγ-activation. We hypothesized that parallel increases in M2-macrophage polarization tempered the therapeutic benefit of KD in GBM. To test this, we performed investigations combining KD with the CSF-1R inhibitor (BLZ945), which influences macrophage polarization. The combination demonstrated a striking improvement in survival and correlative studies confirmed BLZ945 normalized KD-induced changes in macrophage polarization. Overall, KD demonstrates antitumor activity in GBM; however, its efficacy is attenuated by promoting an immunosuppressive phenotype in macrophages. Combinatorial strategies designed to modulate macrophage polarization represent a rational approach to improve the anti-tumor activity of KD in GBM.

Introduce a rotational robust optimization framework for spot-scanning proton arc (SPArc) therapy.

Objective. Proton dosimetric uncertainties resulting from the patient's daily setup errors in rotational directions exist even with advanced image-guided radiotherapy techniques. Thus, we developed a new rotational robust optimization SPArc algorithm (SPArcrot) to mitigate the dosimetric impact of the rotational setup error in Raystation ver. 6.02 (RaySearch Laboratory AB, Stockholm, Sweden).Approach.The initial planning CT was rotated ±5° simulating the worst-case setup error in the roll direction. The SPArcrotuses a multi-CT robust optimization framework by taking into account of such rotational setup errors. Five cases representing different disease sites were evaluated. Both SPArcoriginaland SPArcrotplans were generated using the same translational robust optimized parameters. To quantitatively investigate the mitigation effect from the rotational setup errors, all plans were recalculated using a series of pseudo-CT with rotational setup error (±1°/±2°/±3°/±5°). Dosimetric metrics such as D98% of CTV, and 3D gamma analysis were used to assess the dose distribution changes in the target and OARs.Main results.The magnitudes of dosimetric changes in the targets due to rotational setup error were significantly reduced by the SPArcrotcompared to SPArc in all cases. The uncertainties of the max dose to the OARs, such as brainstem, spinal cord and esophagus were significantly reduced using SPArcrot. The uncertainties of the mean dose to the OARs such as liver and oral cavity, parotid were comparable between the two planning techniques. The gamma passing rate (3%/3 mm) was significantly improved for CTV of all tumor sites through SPArcrot.Significance.Rotational setup error is one of the major issues which could lead to significant dose perturbations. SPArcrotplanning approach can consider such rotational error from patient setup or gantry rotation error by effectively mitigating the dose uncertainties to the target and in the adjunct series OARs.

Redefine the Role of Spot-Scanning Proton Beam Therapy for the Single Brain Metastasis Stereotactic Radiosurgery.

Purpose: To explore the role of using Pencil Beam Scanning (PBS) proton beam therapy in single lesion brain stereotactic radiosurgery (SRS), we developed and validated a dosimetric in silico model to assist in the selection of an optimal treatment approach among the conventional Volumetric Modulated Arc Therapy (VMAT), Intensity Modulated Proton Therapy (IMPT) and Spot-scanning Proton Arc (SPArc). Material and Methods: A patient's head CT data set was used as an in silico model. A series of targets (volume range from 0.3 cc to 33.03 cc) were inserted in the deep central and peripheral region, simulating targets with different sizes and locations. Three planning groups: IMPT, VMAT, and SPArc were created for dosimetric comparison purposes and a decision tree was built based on this in silico model. Nine patients with single brain metastases were retrospectively selected for validation. Multiple dosimetric metrics were analyzed to assess the plan quality, such as dose Conformity Index (CI) (ratio of the target volume to 100% prescription isodose volume); R50 (ratio of 50% prescription isodose volume to the target volume); V12Gy (volume of brain tissue minus GTV receiving 12 Gy), and mean dose of the normal brain. Normal tissue complication probability (NTCP) of brain radionecrosis (RN) was calculated using the Lyman-Kutcher-Burman (LKB) model and total treatment delivery time was calculated. Six physicians from different institutions participated in the blind survey to evaluate the plan quality and rank their choices. Results: The study showed that SPArc has a dosimetric advantage in the V12Gy and R50 with target volumes > 9.00 cc compared to VMAT and IMPT. A significant clinical benefit can be found in deep centrally located lesions larger than 20.00 cc using SPArc because of the superior dose conformity and mean dose reduction in healthy brain tissue. Nine retrospective clinical cases and the blind survey showed good agreement with the in silico dosimetric model and decision tree. Additionally, SPArc significantly reduced the treatment delivery time compared to VMAT (SPArc 184.46 ± 59.51s vs. VMAT: 1574.78 ± 213.65s). Conclusion: The study demonstrated the feasibility of using Proton beam therapy for single brain metastasis patients utilizing the SPArc technique. At the current stage of technological development, VMAT remains the current standard modality of choice for single lesion brain SRS. The in silico dosimetric model and decision tree presented here could be used as a practical clinical decision tool to assist the selection of the optimal treatment modality among VMAT, IMPT, and SPArc in centers that have both photon and proton capabilities.

Sex differences in brain tumor glutamine metabolism reveal sex-specific vulnerabilities to treatment.

BACKGROUND: Brain cancer incidence and mortality rates are greater in males. Understanding the molecular mechanisms that underlie those sex differences could improve treatment strategies. Although sex differences in normal metabolism are well described, it is currently unknown whether they persist in cancerous tissue. METHODS: Using positron emission tomography (PET) imaging and mass spectrometry, we assessed sex differences in glioma metabolism in samples from affected individuals. We assessed the role of glutamine metabolism in male and female murine transformed astrocytes using isotope labeling, metabolic rescue experiments, and pharmacological and genetic perturbations to modulate pathway activity. FINDINGS: We found that male glioblastoma surgical specimens are enriched for amino acid metabolites, including glutamine. Fluoroglutamine PET imaging analyses showed that gliomas in affected male individuals exhibit significantly higher glutamine uptake. These sex differences were well modeled in murine transformed astrocytes, in which male cells imported and metabolized more glutamine and were more sensitive to glutaminase 1 (GLS1) inhibition. The sensitivity to GLS1 inhibition in males was driven by their dependence on glutamine-derived glutamate for α-ketoglutarate synthesis and tricarboxylic acid (TCA) cycle replenishment. Females were resistant to GLS1 inhibition through greater pyruvate carboxylase (PC)-mediated TCA cycle replenishment, and knockdown of PC sensitized females to GLS1 inhibition. CONCLUSION: Our results show that clinically important sex differences exist in targetable elements of metabolism. Recognition of sex-biased metabolism may improve treatments through further laboratory and clinical research. FUNDING: This work was supported by NIH grants, Joshua's Great Things, the Siteman Investment Program, and the Barnard Research Fund.

Novel organic assisted Ag-ZnO photocatalyst for atenolol and acetaminophen photocatalytic degradation under visible radiation: performance and reaction mechanism.

This study is on photocatalytic degradation of pharmaceutical residues of atenolol (ATL) and acetaminophen (ACT) present in secondary effluent under visible light irradiation stimulated by Ag doped ZnO (Ag-ZnO) photocatalyst. Lawsonia inermis leaf extract was used for reduction of Zinc sulphate to ZnO nanoparticles (NPs). Further, ZnO NPs were doped with Ag and characterized by XRD, FT-IR, SEM-EDX, surface area analyzer, UV-Vis, and photoluminescence spectrometry to analyze the structure, morphology, chemical composition, and optical property. FT-IR analysis revealed major functional groups such as OH, C=O, and SEM analysis depicted the polyhedron shape of the NPs with size range of 100 nm. Ag-ZnO NPs were used in the photocatalytic degradation of ATL and ACT, and its removal was evaluated by varying initial contaminant concentration, catalyst dosage, and initial pH. Findings indicate that Ag-ZnO NPs demonstrated relative narrow bandgap and efficient charge separation that resulted in enhanced photocatalytic activity under visible light illumination. The photocatalytic degradation of ATL and ACT fitted well with pseudo-first-order kinetic model. Further, it was found that under optimal conditions of 5 mg/L of contaminants, pH of 8.5, and catalyst dose of 1 g/L, degradation efficiency of 70.2% (ATL) and 90.8% (ACT) was achieved for a reaction time of 120 min. More than 60% reduction in TOC was observed for both contaminants and OH• pathway was found to be the major removal process. Ag-ZnO photocatalyst showed good recycling performance, and these findings indicate that it could be cost effectively employed for removing emerging contaminants under visible light radiation.