Search

Aerobic glycolysis supports proliferation through unresolved mechanisms. We have previously shown that aerobic glycolysis is required for the regulated proliferation of cerebellar granule neuron progenitors (CGNP) and for the growth of CGNP-derived medulloblastoma. Blocking the initiation of glycolysis via deletion of hexokinase-2 (Hk2) disrupts CGNP proliferation and restricts medulloblastoma growth. Here, we assessed whether disrupting pyruvate kinase-M (Pkm), an enzyme that acts in the terminal steps of glycolysis, would alter CGNP metabolism, proliferation, and tumorigenesis. We observed a dichotomous pattern of PKM expression, in which postmitotic neurons throughout the brain expressed the constitutively active PKM1 isoform, while neural progenitors and medulloblastomas exclusively expressed the less active PKM2. Isoform-specific Pkm2 deletion in CGNPs blocked all Pkm expression. Pkm2-deleted CGNPs showed reduced lactate production and increased SHH-driven proliferation. 13C-flux analysis showed that Pkm2 deletion reduced the flow of glucose carbons into lactate and glutamate without markedly increasing glucose-to-ribose flux. Pkm2 deletion accelerated tumor formation in medulloblastoma-prone ND2:SmoA1 mice, indicating the disrupting PKM releases CGNPs from a tumor-suppressive effect. These findings show that distal and proximal disruptions of glycolysis have opposite effects on proliferation, and that efforts to block the oncogenic effect of aerobic glycolysis must target reactions upstream of PKM. Cancer Res; 77(12); 3217–30. ©2017 AACR.

Immunofluorescence for PKM1 and PCNA demonstrates that PKM1+ cells within medulloblastomas are PCNA-.

Rates of change of select media metabolites in 24 hour cultures of CGNPs, with and without Pkm2 deletion

Supplementary Materials and Methods, including NMR, LC-MS and RNA-seq methods

Statement of Significance According to the World Health Organization (WHO), a third of health issues for women aged 15 and 44 years are sexual and reproductive health problems with unsafe sex practices being a major risk factor.1 Additionally, “every day in 2017, approximately 810 women died from preventable causes related to pregnancy and childbirth.”2 Although there have been improvements in prenatal and postpartum care, these benefits do not extend worldwide. Cervical and breast cancer represent additional issues in women’s health wherein adequate preventative medicine can dramatically improve patient outcomes. Our findings provide insight into the use of accessible contraception, preventive screenings, and cesarean deliveries based on the self-reported experience of a rural population near Guanajuato, Mexico. The results stand to inform future research and public health efforts in the region aiming to improve knowledge and use of contraception, investigate increasing cesarean delivery rates, and improve screening rates for cervical and breast cancer. Background: The objective of this study was to evaluate preventative screening for breast and cervical cancer, contraceptive practices, and cesarean section rates for women in rural Guanajuato Mexico. Understanding this data is important because such accessibility and healthcare practices can influence the safety of this population’s lives as well as provide insight to the impact of public healthcare programs. Methods: A twenty-one question oral survey was administered to both male and female participants of health fairs and screenings in seven rural communities around the cities of Juventino Rosas and San Miguel de Allende. The survey covered diet and exercise habits as well as women’s health topics for participants who self-identified as female. Women’s health topics included questions about mammography & Papanicolaou test (Pap test) history as well as contraception use and cesarean section history. Results: A total of 155 participants. Mean respondent age was 46 years and a majority of respondents were female (81%, n = 155). Of female respondents, almost half reported a previous cesarean section. More women in the younger cohort (aged 50 years), but not at a level of statistical significance. Almost half of the women of childbearing age denied contraception utilization. Most women (72%, n = 110) reported a Pap test within the past five years and about a third had one within the past year. Of the women aged >40 years, almost half had not received mammography. Conclusions: Younger women appeared more likely to have had at least one cesarean delivery than older women, but the sample size provided inadequate power for statistical significance. Access to contraception did not appear to be a barrier to contraception utilization in this region, an important finding for future investigations of associated topics, such as rates of unplanned pregnancies or the spread of communicable sexual diseases. Though the Pap test rates were comparable to that of the United States, mammogram rates lagged. Further studies should investigate increasing cesarean delivery rates in rural Guanajuato, Mexico, strategies to increase education regarding contraceptive modalities, and approaches to improve screening and treatment of cervical and breast cancer.

This cross-sectional study assess online preoperative and postoperative patient information regarding the potential risks of severe acute respiratory syndrome coronavirus 2 nasopharyngeal swab testing for those with a history of sinus or skull-base surgery.

Aerobic glycolysis supports proliferation through unresolved mechanisms. We have previously shown that aerobic glycolysis is required for the regulated proliferation of cerebellar granule neuron progenitors (CGNP) and for the growth of CGNP-derived medulloblastoma. Blocking the initiation of glycolysis via deletion of hexokinase-2 (Hk2) disrupts CGNP proliferation and restricts medulloblastoma growth. Here, we assessed whether disrupting pyruvate kinase-M (Pkm), an enzyme that acts in the terminal steps of glycolysis, would alter CGNP metabolism, proliferation, and tumorigenesis. We observed a dichotomous pattern of PKM expression, in which postmitotic neurons throughout the brain expressed the constitutively active PKM1 isoform, while neural progenitors and medulloblastomas exclusively expressed the less active PKM2. Isoform-specific Pkm2 deletion in CGNPs blocked all Pkm expression. Pkm2-deleted CGNPs showed reduced lactate production and increased SHH-driven proliferation. 13C-flux analysis showed that Pkm2 deletion reduced the flow of glucose carbons into lactate and glutamate without markedly increasing glucose-to-ribose flux. Pkm2 deletion accelerated tumor formation in medulloblastoma-prone ND2:SmoA1 mice, indicating the disrupting PKM releases CGNPs from a tumor-suppressive effect. These findings show that distal and proximal disruptions of glycolysis have opposite effects on proliferation, and that efforts to block the oncogenic effect of aerobic glycolysis must target reactions upstream of PKM. Cancer Res; 77(12); 3217–30. ©2017 AACR.