Noninvasive amino acid turnover predicts human embryo aneuploidy.

Assisted reproduction technology has two significant problems: low success rates and multiple pregnancies. Because of these problems, the priority in IVF clinics is to develop a potential diagnostic test that can be used to select the embryos with the ultimate developmental competence. Aneuploidy screening as embryo selection criteria will ensure that the transferred embryos are euploid and high implantation rate. We hypothesize that aneuploidy in human preimplantation embryos could be discriminated by their amino acid metabolism profile in the spent culture media. Preimplantation genetic testing for aneuploidy results and spent embryo culture medium amino acid content were analyzed for 58 couples. The next-generation sequencing technique was used and coupled with TE biopsy. Forty euploid and 71 aneuploid blastocysts were evaluated. Embryos were cultured individually until day 5 or 6 of embryo development. Spent culture medium was collected after finishing the culture. There was no statistical difference between D3 and D5 embryo morphology between euploid and aneuploid embryos (p > .05). Eight amino acids, including SER, GLY, HIS, ARG, THR, ALA, PRO, and TYR, were detected in the culture medium from the blank control group, euploid group, and aneuploid group. Only TYR amino acid concentration was found significantly higher in the aneuploid group compared to the euploid group (p < .003). Tyrosine amino acid levels equal to and above 76.38 µmol/L could be considered aneuploid. Aneuploid embryos demonstrate altered amino acid turnover in vitro relative to euploid counterparts. A noninvasive method of amino acid profiling will be of value as a tool for routine preimplantation embryo selection among all patient groups.

Combining locoregional CAR-T cells, autologous + allogeneic tumor lysate vaccination and levamisole in treatment of glioblastoma.

Glioblastoma multiforme (GBM) is an aggressive brain malignancy and harbors a microenvironment limiting immune cells activity. CAR-T cells are being tested in the treatment of cancers and there exist reports which demonstrate dramatic regression of multicentric GBMs following intrathecal treatment with CAR-T cells. In this article, a triple approach for immune treatment of GBM is proposed. First, GBM tumor specimens for each patient will be saved and cultured to obtain tumor lysates. Then, levamisole will be applied, which possesses immunostimulating, anti-glycolytic, and anti-angiogenic features. Following priming the immune system, GBM patients will be injected with lysates of their own tumor cells plus lysates from a GBM cell line, U251. After 3 months of this treatment, CAR-T cells (transduced with IL13Rα2-CAR) will be applied via intratumoral approach. As such, genetically-modified and native immunocytes may 'meet' in the vicinity of deeply-invading tumor cells and demonstrate greater efficacy via cell-cell interactions. By this, a self-propagating cyclic process - a cancer-immunity cycle - may be initiated to eradicate cancer cells.

Erucic acid, a nutritional PPARδ-ligand may influence Huntington's disease pathogenesis.

Increasing recent evidence suggests a key role of oligodendroglial injury and demyelination in the pathophysiology of Huntington's Disease (HD) and the transcription factor PPARδ is critical for oligodendroglial regeneration and myelination. PPARδ directly involves in the pathogenesis of HD and treatment with a brain-permeable PPARδ-agonist (KD3010) alleviates its severity in mice. Erucic acid (EA) is also a PPARδ-ligand ω9 fatty acid which is highly consumed in Asian countries through ingesting cruciferous vegetables such as rapeseed (Brassica napus) and indian mustard (Brassica juncea). EA is also an ingredient of Lorenzo's oil employed in the medical treatment of adrenoleukodystrophy and can be converted to nervonic acid, a component of myelin. HD pathogenesis also involves oxidative and inflammatory injury and EA exerts antioxidative and antiinflammatory efficacies including inhibition of thrombin and elastase. Consumption of rapeseed, indian mustard, and Canola oils (containing EA) improves cognitive parameters in animal models, as well as treatment with pure EA. Moreover, erucamide, an endogenous EA-amide derivative regulating angiogenesis and water balance, exerts antidepressive and anxiolytic effects in mice. Hitherto, no study has investigated the therapeutic potential of EA in HD and we believe that it strongly merits to be studied in animal models of HD as a potential therapeutic.

Quality will determine the future of mass spectrometry imaging in clinical laboratories: the need for standardization.

Introduction: Mass Spectrometry Imaging (MSI) provides information about the spatial distributions of different analytes on tissue sections and requires no homogenization techniques or labeling. It has a wide spectrum of applications ranging from biomarker discovery to drug response studies. MSI can be adapted to the clinical settings due to its ability to combine mass spectrometry and histological data. Areas covered: The major obstacle to adapt MSI into clinical settings arises from the limited standardization in MSI experiments. We aimed to review the multi-site studies in MSI specifically focusing on reproducibility. Additionally, we emphasized the necessity of quality assessments in MSI for its potential usage in clinical settings. Expert opinion: We discuss how important it is to follow optimized and standardized workflows in MSI and conduct potential quality assessments at important stages in order to adapt MSI into clinical applications.

Noscapine, a Non-addictive Opioid and Microtubule-Inhibitor in Potential Treatment of Glioblastoma.

Noscapine is a phthalide isoquinoline alkaloid that easily traverses the blood brain barrier and has been used for years as an antitussive agent with high safety. Despite binding opioid receptors, noscapine lacks significant hypnotic and euphoric effects rendering it safe in terms of addictive potential. In 1954, Hans Lettré first described noscapine as a mitotic poison. The drug was later tested for cancer treatment in the early 1960's, yet no effect was observed likely as a result of its short biological half-life and limited water solubility. Since 1998, it has regained interest thanks to studies from Emory University, which showed its anticancer activity in animal models with negligible toxicity. In contrast to other microtubule-inhibitors, noscapine does not affect the total intracellular tubulin polymer mass. Instead, it forces the microtubules to spend an increased amount of time in a paused state leading to arrest in mitosis and subsequently inducing mitotic slippage/mitotic catastrophe/apoptosis. In experimental models, noscapine does not induce peripheral neuropathy, which is common with other microtubule inhibitors. Noscapine also inhibits tumor growth and enhances cancer chemosensitivity via selective blockage of NF-κB, an important transcription factor in glioblastoma pathogenesis. Due to their anticancer activities and high penetration through the blood-brain barrier, noscapine analogues strongly deserve further study in various animal models of glioblastoma as potential candidates for future patient therapy.

Acetylsalicylic acid and its metabolite gentisic acid may act as adjunctive agents in the treatment of psychiatric disorders.

Neuropsychiatric disorders place a very high burden on the global health and economy. The efficacies of currently available drugs in the psychiatric armamentarium are suboptimal and almost all of them target several neurotransmitter pathways. But it is more and more recognized that the neuroinflammation and associated oxidative pathways are important players in the etiopathogenesis of psychiatric disorders. In parallel to this new concept, recent investigations indicate that adjunction of acetylsalicylic acid (ASA) to the orthodox psychiatric treatments augments therapeutic efficacy in bipolar disorder and schizophrenia. Gentisic acid is a redox active quinonoid ASA metabolite and an endogenously produced siderophore with much more potent antioxidant effects than its parent compound. Moreover, it harbours molecular features that provide its selective conversion to even more potent anti-inflammatory quinonoid molecules within the inflammatory micromilieu. We believe that ASA alone and its combination with gentisic acid should be studied in animal models of psychiatric disorders to reveal their potential in regard to the augmentation of currently available treatments. If several animal studies prove their potential, clinical trials could easily be conducted, as both ASA and gentisic acid have a relatively high biosafety and a long history of clinical use.

Could hepatitis B vaccine act as an adjuvant to lower risk and relapses of cancer?

In this review article, we hypothesize that Hepatitis B Virus Vaccine (HBV-V) and certain antigens of Hepatitis B Virus (HBV) could act as anticancer immunoadjuvants in addition to their role of preventing HBV-associated liver cancer. Evidence suggests that in animal breast cancer and melanoma models, combining hepatitis B-surface antigen (HBsAg) with other cancer antigens resulted in enhanced antitumour activity. HBsAg shares antigenic mimicry with healthy and malignant cells including squamous epithelia, thymic epithelia, bladder- and colon cancer cells. There exist anecdotal reports and small case series about spontaneous remission of leukaemias and neuroblastoma following acute HBV-infection. Recent studies also exist showing HBV-carrier state is a good prognostic factor for intrahepatic cholangiocarcinoma. Further epidemiological studies and animal experiments are necessary whether HBV-Vs exert additional immunoadjuvant benefits besides lowering the risk of liver cancer.

Methenamine's journey of 160 years: Repurposal of an old urinary antiseptic for treatment and hypoxic radiosensitization of cancers and glioblastoma.

Methenamine (hexamethylenetetramine, hexamine, urotropine) is a compound discovered in 1859, which is still currently being used as a urinary antiseptic. Methenamine is highly soluble in water and polar solvents, and its molecular constitution is similar to adamantane compounds with tetrahedral cage like structure. In acidic conditions, methenamine decomposes to formaldehyde and ammonia. Recently, methenamine has gained a renewal of interest due to antibiotic-resistant bacteria urinary tract infections; interestingly, bacteria cannot gain resistance to formaldehyde. In 1968, David and Burkitt reported remarkable regression of four Burkitt Lymphoma patients in eight subjects who were treated with septicemine (a solution containing 6.3 g of methenamine iodomethylate and 1 g of methenamine sodium benzoate in 100 cc distilled water). Unfortunately, these striking observations did not gain interest in the medical community; despite experimental models that showed that methenamine synergized with hyperthermia, radiation, and chemotherapy to block cancer growth. As the hypoxic core of tumours have an acidic pH, it would be plausible to expect that methenamine would selectively target dormant, non-proliferative, and treatment-resistant cancer clones in large tumours. Moreover, previous data suggests that methenamine can be safely used intravenously and for treatment of infections of the central nervous system. It may therefore be an effective adjuvant in treatment of systemic cancers and glioblastoma.

From epidemiology and neurometabolism to treatment: Vitamin D in pathogenesis of glioblastoma Multiforme (GBM) and a proposal for Vitamin D + all-trans retinoic acid + Temozolomide combination in treatment of GBM.

Here we review tumoricidal efficacy of Vitamin D analogues in glioblastoma multiforme (GBM) and potential synergisms with retinoic acid and temozolomide based on epidemiological and cellular studies. Epidemiological data suggest that winter birth is associated with higher risk of GBM, and GBM debulking in the winter enhanced mortality, which may relate with lower exposure to sunlight essential to convert cholecalciferol to Vitamin D. Comparative studies on blood bank specimens revealed that higher prediagnosis levels of calcidiol are associated with lower risk of GBM in elderly men. Supplemental Vitamin D reduced mortality in GBM patients in comparison to nonusers. Expression of Vitamin D Receptor is associated with a good prognosis in GBM. Conversely, Vitamin D increases glial tumor synthesis of neutrophins NGF and NT-3, the low affinity neurotrophin receptor p75NTR, IL-6 and VEGF, which may enhance glioma growth. Antitumor synergisms between temozolomide and Vitamin D and Vitamin D with Vitamin A derivatives were observed. Hence, we hypothesize that Calcitriol + ATRA (All-Trans Retinoic Acid) + Temozolomide - CAT combination might be a safer approach to benefit from Vitamin D in the management of high-grade glial tumors. Adding acetazolomide to this protocol may reduce the risk of pseudotumor cerebri, as both Vitamin D and Vitamin A excess may cause intracranial hypertension; this approach may provide further benefit as acetazolomide also exhibits anticancer activity.

Reproductive epidemiology of glial tumors may reveal novel treatments: high-dose progestins or progesterone antagonists as endocrino-immune modifiers against glioma.

Female gender, contraceptives, and menopausal hormone replacement treatments containing progesterone analogues associate with higher risk of meningiomas yet with lower risk of gliomas. Progesterone receptor (PR) expression and mifepristone treatment was highly discussed for meningiomas. However, much less is known in regard to progesterone actions in gliomas despite PR expression strongly correlates with their grade. Meningiomas and gliomas may grow faster during gestation; but paradoxically, parousity reduces lifetime risk of gliomas which can be explained with dichotomous cell growth-stimulating and inhibitory actions of progesterone at low versus high levels. Progesterone levels gradually increase in gestation up to 200-fold and the incidence of highly angiogenic brain tumors decreases in the last trimester. Indeed, progesterone stimulates glial tumor cell growth at low doses (10 nM) while induces cell kill at higher doses. During gestation, some immune pathways are activated to protect the mother and the fetus against microbial pathogens. In parallel, high-dose medroxyprogesterone acetate (MPA) used in treatment of endometrial carcinoma decreases tumoral expression of PR-B and increases infiltration of cytotoxic T lymphocytes and natural killer cells. MPA also synergies with IL-2 in clinical treatment of renal cancer. In both glioma and meningioma, the dominant cytosolic PR is PR-B which increases cell growth, while PR-A limits cell growth. This seems also paradoxical at the first glance due to opposite behavior of these tumors in diverse endocrine conditions. High-dose progestins may inhibit brain tumor growth by downregulating PR-B, yet the dosage thresholds may differ between glial and meningeal tumors due to higher total PR expression in meningiomas. Supporting this proposal, certain progestins were reported to stimulate meningioma growth in anecdotal reports, but same agents at much higher doses reduced meningioma cell proliferation in pilot clinical studies. PR antagonist mifepristone reduced meningioma growth in some clinical studies, but lacked efficacy in others. In fact, mifepristone also has partial PR agonist efficacy and acts in synergy with MPA to block EC growth. Hence, a similar mechanism of receptor downregulation may also account for mifepristone. Both MPA and mifepristone also harbor myeloprotective features against chemotherapy. Ulipristal is another contraceptive PR antagonist and exerts promising anticancer activity on drug-resistant ovarian cancer and BRCA1-mutant breast cancer cells, which can be tested in animal glioblastoma models. We propose that progestins strongly deserve to be investigated in experimental models of glioblastoma alone and in combination with immunostimulating agents.

Neuroprotective and tumoricidal activities of cardiac glycosides. Could oleandrin be a new weapon against stroke and glioblastoma?

Cardiac glycosides induce a strong immunological cancer cell cytotoxicity, in which the released intracellular components of dying tumor cells (e.g. calreticulin, HMGB1 and ATP) stimulate immunity and help in eradicating cancer. Among the cardiac glycosides, oleandrin is an inhibitor of P-glycoprotein expression and exerts excellent penetration through the blood-brain barrier which also harbors neuroprotective and anti-glioma efficacies. Cardiac glycosides also exert neuroprotective activities, one explanation for such an action is the metabolic arrest as a defense strategy against hypoxia. Recently, it was also shown that oleandrin increases survival of glioma-implanted mice alone and in synergy with temozolomide, which also associated with the release of brain derived neurotrophic factor and activation of its receptor TrkB. In conclusion, oleandrin strongly deserves to be studied as a candidate molecule in treatment of neurodegenerative and neurooncological diseases.

Clinical applications of MALDI imaging technologies in cancer and neurodegenerative diseases.

Matrix-assisted laser desorption/ionization (MALDI) time-of-flight (TOF) imaging mass spectrometry (IMS) enables localization of analytes of interest along with histology. More specifically, MALDI-IMS identifies the distributions of proteins, peptides, small molecules, lipids, and drugs and their metabolites in tissues, with high spatial resolution. This unique capacity to directly analyze tissue samples without the need for lengthy sample preparation reduces technical variability and renders MALDI-IMS ideal for the identification of potential diagnostic and prognostic biomarkers and disease gradation. MALDI-IMS has evolved rapidly over the last decade and has been successfully used in both medical and basic research by scientists worldwide. In this review, we explore the clinical applications of MALDI-IMS, focusing on the major cancer types and neurodegenerative diseases. In particular, we re-emphasize the diagnostic potential of IMS and the challenges that must be confronted when conducting MALDI-IMS in clinical settings. This article is part of a Special Issue entitled: MALDI Imaging, edited by Dr. Corinna Henkel and Prof. Peter Hoffmann.

Perchlorate levels found in tap water collected from several cities in Turkey.

Perchlorate is an inorganic anion that inhibits iodide transport to the thyroid by sodium-iodide transporters. Because perchlorate is highly soluble, stable, and mobile in water, drinking water is a potential source of perchlorate exposure. When exposed to perchlorate, thyroid dysfunction can be observed in sensitive populations (pregnant woman, infants, and children), especially those with iodide deficiency. The aim of this study was to determine the perchlorate levels in tap water from five cities in Turkey. Perchlorate concentrations of 145 tap water samples collected from Ankara, Isparta, Istanbul, Kayseri, and Sakarya were determined by liquid chromatography-tandem mass spectrometry. Mean and median values were found to be 0.15 and 0.07 µg/L, respectively. The median values (25-75 % percentile) of Istanbul, Ankara, Sakarya, Isparta, and Kayseri were 0.08 µg/L (0.04-0.09 µg/L), 0.07 µg/L (0.07-0.21 µg/L), 0.04 µg/L (0.04-0.04 µg/L), 0.03 µg/L (0.02-0.07 µg/L), and 0.25 µg/L (0.23-0.31 µg/L), respectively. The median perchlorate level observed in Kayseri was significantly higher than those found at other cities (p < 0.05). Perchlorate concentrations in water samples were lower than the interim drinking water health advisory level (15 µg/L) determined by the US Environmental Protection Agency. This study showed that perchlorate in drinking water is not the main source of exposure in these cities. Future studies should be performed to determine perchlorate levels in other potential sources, such as food products.

Perchlorate Exposure Through Water and Milk in Istanbul.

Perchlorate is a chemical pollutant that inhibits iodide uptake and may possibly impair thyroid function. Our previous study found widespread perchlorate exposure in non-pregnant, non-lactating, healthy women residing in Istanbul. The aim of this study is to assess the relative amounts of perchlorate exposure attributable to consumption of municipal water, bottled water and boxed milk available in Istanbul. Only trace levels of perchlorate were found in treated municipal water (58 % detectable, mean = 0.13 µg/L, maximum = 0.75 µg/L) and bottled water (7.4 % detectable, mean = 

Post-translational modifications of transthyretin affect the triiodonine-binding potential.

Transthyretin (TTR) is a visceral protein, which facilitates the transport of thyroid hormones in blood and cerebrospinal fluid. The homotetrameric structure of TTR enables the simultaneous binding of two thyroid hormones per molecule. Each TTR subunit provides a single cysteine residue (Cys10 ), which is frequently affected by oxidative post-translational modifications. As Cys10 is part of the thyroid hormone-binding channel within the TTR molecule, PTM of Cys10 may influence the binding of thyroid hormones. Therefore, we analysed the effects of Cys10 modification with sulphonic acid, cysteine, cysteinylglycine and glutathione on binding of triiodothyronine (T3) by molecular modelling. Furthermore, we determined the PTM pattern of TTR in serum of patients with thyroid disease by immunoprecipitation and mass spectrometry to evaluate this association in vivo. The in silico assays demonstrated that oxidative PTM of TTR resulted in substantial reorganization of the intramolecular interactions and also affected the binding of T3 in a chemotype- and site-specific manner with S-glutathionylation as the most potent modulator of T3 binding. These findings were supported by the in vivo results, which indicated thyroid function-specific patterns of TTR with a substantial decrease in S-sulphonated, S-cysteinylglycinated and S-glutathionylated TTR in hypothyroid patients. In conclusion, this study provides evidence that oxidative modifications of Cys10 seem to affect binding of T3 to TTR probably because of the introduction of a sterical hindrance and induction of conformational changes. As oxidative modifications can be dynamically regulated, this may represent a sensitive mechanism to adjust thyroid hormone availability.

Oxamate targeting aggressive cancers with special emphasis to brain tumors.

Cancer is one of the main causes of human mortality and brain tumors, including invasive pituitary adenomas, medulloblastomas and glioblastomas are common brain malignancies with poor prognosis. Therefore, the development of innovative management strategies for refractory cancers and brain tumors is important. In states of mitochondrial dysfunction - commonly encountered in malignant cells - cells mostly shift to anaerobic glycolysis by increasing the expression of LDHA (Lactate Dehydrogenase-A) gene. Oxamate, an isosteric form of pyruvate, blocks LDHA activity by competing with pyruvate. By blocking LDHA, it inhibits protumorigenic cascades and also induces ROS (reactive oxygen species)-induced mitochondrial apoptosis of cancer cells. In preclinical studies, oxamate blocked the growth of invasive pituitary adenomas, medulloblastomas and glioblastomas. Oxamate also increases temozolomide and radiotherapy sensitivity of glioblastomas. Oxamate is highly polar, which may preclude its clinical utilization due to low penetrance through cell membranes. However, this obstacle could be overcome with nanoliposomes. Moreover, different oxamate analogs were developed which inhibit LDHC4, an enzyme also involved in cancer progression and germ cell physiology. Lastly, phenformin, an antidiabetic agent, exerts anticancer effects via complex I inhibition in the mitochondria and leading the overproduction of ROS. Oxamate combination with phenformin reduces the lactic acidosis-causing side effect of phenformin while inducing synergistic anticancer efficacy. In sum, oxamate as a single agent and more efficiently with phenformin has high potential to slow the progression of aggressive cancers with special emphasis to brain tumors.

Immunomodifying and neuroprotective effects of noscapine: Implications for multiple sclerosis, neurodegenerative, and psychiatric disorders.

Noscapine is a phthalide isoquinoline alkaloid with antitussive activity. Noscapine protects oligodendroglia from ischemic and chemical injury, binds to bitter taste receptors, antagonizes the bradykinin and histaminergic systems, which may be of benefit in treatment of multiple sclerosis. Noscapine normalizes axonal transport and exerts significant therapeutic efficacy in animal models of Parkinson's Disease and Amyotrophic Lateral Sclerosis. Noscapine exerts neuroprotective effects on oxygen- and glucose-deprived fetal cortical neuronal cells and reduces ischemic brain damage in neonatal rat pups. Pilot clinical studies indicated some beneficial effects of noscapine in stroke. Noscapine harbours anxiolytic activity and methyl-noscapine blocks small conductance SK channels, which is beneficial in alleviating anxiety and depression. Noscapine exerts anticholinesterase activity and acts inhibitory on the inflammatory transcription factor NF-κB, which may be harnessed in treatment of Alzheimer's Disease. With its blood-brain barrier traversing features and versatile actions, noscapine may be a promising agent in the armamentarium against neurodegenerative and psychiatric diseases.

Maternal omega-3 polyunsaturated fatty acids supplementation in pregnancy decreases MMP-1 levels in breastmilk: a cross-sectional study.

INTRODUCTION: Anti-inflammatory properties of fish-oil are well known and suggested during pregnancy. MMP-1 is involved in inflammation and tissue remodelling. There have been studies focused on anti-inflammatory effect of maternal omega use on human milk while little is known about the effect of omega use on breastmilk proteases. Leptin is an important hormone that influences MMP levels in various tissues and exerts its metabolic effects. In our study we assessed the levels of MMP-1, TIMP-1, leptin, IL-6 and FA's including PUFA in breastmilk from women who used omega-3. MATERIALS AND METHODS: Our study was a cross-sectional study included 67(Group 1, n = 32, omega user; Group 2 n = 35, non-user)lactating women and their infan MMP-1, TIMP-1, leptin, IL-6 and FA's were evaluated in breastmilk of both groups. MMP-1, TIMP-1, IL-6 and leptin were measured by enzyme-linked immunoabsorbent assay (ELISA) method. Breastmilk fatty acids were measured by gas chromatography flame ionisation detector (GC-FID). RESULTS: Matrix metalloproteinase-1 (MMP-1) levels in breastmilk were significantly lower in breastmilk from omega users (mean ± SD, 0.455 ± 0.1) than non-users (mean ± SD, 0.677 ± 0.289) (p=.0001). MMP-1 and omega 6:3 ratio were positively correlated (r: 0.301, p=.01). MMP levels were correlated with IL-6 (Pearson's r: 0.411, p<.001). MMP-1 and leptin levels were positively correlated (r: .388, p=.001). CONCLUSION: MMP-1 levels in breastmilk, may be modified by maternal omega use in pregnancy which may help to redirect extracellular matrix remodelling and metabolic programming in early infancy.

A hypothetical proposal to employ meperidine and tamoxifen in treatment of glioblastoma. Role of P-glycoprotein, ceramide and metabolic pathways.

Meperidine (pethidine) is a µ-opioid receptor (MOR) agonist widely used in the treatment of cancer pain. While MOR agonists in experimental models have demonstrated both pro- and antitumorigenic properties, meperidine has unique features which may be predominantly anticancer in nature. Meperidine both inhibits NMDA (N-methyl-D-Aspartate) receptors, which are involved in the progression of glioblastoma, and blocks NADH:Ubiquinone Oxidoreductase, which may hinder mitochondrial respiration. In the developing embryonic neural tissue, meperidine reduces cell proliferation around the neural tube and lowers the expression of the B RE (brain and reproductive organ-expressed). This is notable given that the B RE gene is implicated in cancer chemoresistance and gliomagenesis. Further, meperidine inhibits P-glycoprotein, which is involved in cancer multidrug resistance and the degradation of the sphingolipid backbone, ceramide. By enhancing the pro-autophagic and pro-apoptotic ceramide levels in cancer cells, meperidine stimulates cell death and reverses multidrug resistance. Tamoxifen, a safe medication employed in the treatment of breast cancer, directly blocks P-glycoprotein and boosts levels of ceramide both via inhibition of glycosylceramide synthase and ceramidase. Further, tamoxifen blocks NMDA-neurotoxicity and therefore it may act synergistically with meperidine in reducing glioblastoma progression associated with NMDA-activation. Finally, tamoxifen blocks glycolysis which may enhance the mitochondrial-blocking activity of meperidine to shut down energy metabolism of glioblastoma cells. Because of these properties, we believe that the combination of meperidine and tamoxifen merits study in cell culture and animal models to investigate a potential synergistic relationship in the treatment of glioblastoma.

The effect of reticulocyte hemoglobin content on the diagnosis of iron deficiency anemia: A meta-analysis study.

Background: Iron deficiency anemia (IDA) is the most common type of anemia worldwide and has many adverse effects on life quality. This meta-analysis study aims to show that reticulocyte hemoglobin content (CHr) is more effective than routinely used parameters in the diagnosis of IDA. Methods: Comprehensive and systematic research was done using international databases including PubMed, Web of Science, Cochrane Library, Science Direct, and Google Scholar, which contain all articles published on IDA until December 29, 2020. Seventeen articles were included in the meta-analysis. Results: The analyses found the Cohen's deffect size (Standardized Mean Difference) values of the parameters. Accordingly, CHr is 2.84 (95% CI 2.36 to 3.31), mean corpus volume (MCV) is 2.46 (95% CI 1.97 to 2.95), ferritin is 2.37 (95% CI 1.63 to 3.11), and transferrin saturation (TSAT) is 3.76 (95% CI 2.14 to 5.38). To diagnose IDA, the sensitivity value of the CHr concentration was found as 83.5% (95% CI 76.1 to 89.8), specificity value to be 91.8% (95% CI 85.5 to 96.4), and mean cut-off value as 28.2 pg. Conclusions: The results of our study reveal the findings that CHr is a better biomarker than MCV and ferritin used in determining IDA, and its efficacy is lower than TSAT. It is very important to use it routinely for the pre-diagnosis of IDA, which is very important for public health. The groups in the study are heterogeneous but contain bias. Therefore, meta-analyses of studies with less heterogeneity of CHr are needed.