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Nearly 10% of patients with adult diffuse glioma develop clinically significant myelotoxicity while on temozolomide (TMZ) leading to treatment interruptions. This study aimed to assess single nucleotide polymorphisms (SNPs) in the OThis study assessed 33 adults treated with TMZ for diffuse glioma who developed ≥ grade 2 thrombocytopenia and/or ≥ grade 3 neutropenia. Genomic DNA was extracted from peripheral blood cells for MGMT SNP analysis after written informed consent. TMZ-induced severe myelotoxicity (≥ grade 3) was correlated with three specified SNPs commonly seen in the MGMT gene (L84F, I143V/K178R) using chi-square test or Fischer's exact test as appropriate.Of the 33 adults, 24 (72.7%) experienced ≥ grade 3 thrombocytopenia and/or neutropenia, while 9 (27.3%) developed grade 2 thrombocytopenia only. The variant T allele of L84F was expressed in 28.7% (19/66) of analyzed alleles, which was substantially higher than previously reported for South Asian ancestry. The variant G allele of I143V/K178R was expressed in 9.3% (6/64) of analyzed alleles. Of which 3 patients showed statistically significant association with prolonged myelosuppression for 2 months (p = 0.03). No significant correlation was established between the mentioned SNPs and severe myelotoxicity.There is substantially higher frequency of variant T allele (L84F) in Indian patients than previously reported for South Asians. The presence of specific SNPs in the MGMT gene correlates with prolonged duration but not severity of TMZ-induced myelotoxicity.

According to the current consensus, neural stem cells (NSCs) apically contacting the lateral ventricle generate differentiated progenitors by rare asymmetric divisions or by relocating to the basal side of the ventricular-subventricular zone V-SVZ. Both processes will then ultimately lead to the generation of adult-born olfactory bulb (OB) interneurons. In contrast to this view, we here found that adult-born OB interneurons largely derive from an additional NSC type resident in the basal V-SVZ. Despite being both capable of self-renewal and long-term quiescence, apical and basal NSCs differ in Nestin expression, primary cilia extension and frequency of cell division. The expression of Notch-related genes also differed between the two NSC groups and Notch-activation was greatest in apical NSCs. Apical downregulation of Notch-effector Hes1 decreased Notch activation while increasing proliferation across the niche and neurogenesis from apical NSCs. Underscoring their different roles in neurogenesis, lactation-dependent increase in neurogenesis was paralleled by extra activation of basal but not apical NSCs. Thus, basal NSCs support OB neurogenesis whereas apical NSCs impart Notch-mediated lateral inhibition across the V-SVZ.

e14032 Background: Polymorphisms in MGMT gene have been implicated in temozolomide (TMZ)-induced hematological toxicity in patients with adult diffuse gliomas. We aimed to investigate the association of three single nucleotide polymorphisms (SNPs) in the MGMT gene viz. L84F, I143V/K178R with severe hematological toxicity in patients of adult diffuse glioma treated with TMZ at an academic neuro-oncology unit of a tertiary-care comprehensive cancer centre from India. Methods: Thirty-three patients of adult diffuse glioma treated with multi-modality adjuvant therapy including TMZ who developed CTCAE V5.0 grade 2-4 hematological toxicity were included after written informed consent. Genomic DNA was extracted from peripheral blood mononuclear cells for SNP analysis. Correlation of MGMT SNP with patient demographics and hematological toxicity was assessed using the Chi-square and Fisher’s exact test. Results: Twenty-four patients (72.7%) developed grade 3-4 hematological toxicity with TMZ with a distinct female predilection. The variant T allele of L84F was expressed in 28.7% of the total 66 analyzed alleles which was markedly higher than previously reported in the general population of South Asian ancestry. The variant G allele of I43V/K178R was expressed in 9.3% (6/64) of 64 analyzed alleles. Persistent myelosuppression lasting beyond 2 months after cessation of TMZ correlated with I143V/K178R hetero/homozygous compared to wild type allele (p = 0.03). However, no significant correlation could be seen between any of the tested MGMT SNPs and grade of hematological toxicity. Conclusions: There is a higher prevalence of the L84F polymorphism in Indian patients with severe hematological toxicity than previously reported in the literature. The variant G allele of I143V/K178R is associated with prolonged and persistent myelosuppression induced by TMZ. A larger case-control is being planned to further elucidate the causal relationship between MGMT gene polymorphisms and TMZ-induced severe hematological toxicity.

The glycoprotein Prominin-1 and the carbohydrate Lewis X stage-specific embryonic antigen 1 (LeX-SSEA1) both have been extensively used as cell surface markers to purify neural stem cells (NSCs). While Prominin-1 labels a specialized membrane region in NSCs and ependymal cells, the specificity of LeX-SSEA1 expression and its biological significance are still unknown. To address these issues, we have here monitored the expression of the carbohydrate in neonatal and adult NSCs and in their progeny. Our results show that the percentage of immunopositive cells and the levels of LeX-SSEA1 immunoreactivity both increase with postnatal age across all stages of the neural lineage. This is associated with decreased proliferation in precursors including NSCs, which accumulate the carbohydrate at the cell surface while remaining quiescent. Exposure of precursors to bone morphogenetic protein (BMP) increases LEX-SSEA1 expression, which promotes cell cycle withdrawal by a mechanism involving LeX-SSEA1-mediated interaction at the cell surface. Conversely, interference with either BMP signaling or with LeX-SSEA1 promotes proliferation to a similar degree. Thus, in the postnatal germinal niche, the expression of LeX-SSEA1 increases with age and exposure to BMP signaling, thereby downregulating the proliferation of subependymal zone precursors including NSCs.

Neural stem cells (NSCs) generate new neurons in vivo and in vitro throughout adulthood and therefore are physiologically and clinically relevant. Unveiling the mechanisms regulating the lineage progression from NSCs to newborn neurons is critical for the transition from basic research to clinical application. However, the direct analysis of NSCs and their progeny is still elusive due to the problematic identification of the cells. We here describe the isolation of highly purified genetically unaltered NSCs and transit-amplifying precursors (TAPs) from the adult subependymal zone (SEZ). Using this approach we show that a primary cilium and high levels of epidermal growth factor receptor (EGFR) at the cell membrane characterize quiescent and cycling NSCs, respectively. However, we also observed non-ciliated quiescent NSCs and NSCs progressing into the cell cycle without up-regulating EGFR expression. Thus, the existence of NSCs displaying distinct molecular and structural conformations provides more flexibility to the regulation of quiescence and cell cycle progression.