Dysregulated Recruitment of the Histone Methyltransferase EZH2 to the Class II Transactivator (CIITA) Promoter IV in Breast Cancer Cells

One mechanism frequently utilized by tumor cells to escape immune system recognition and elimination is suppression of cell surface expression of Major Histocompatibility Class II (MHC II) molecules. Expression of MHC II is regulated primarily at the level of transcription by the Class II Transactivator, CIITA, and decreased CIITA expression is observed in multiple tumor types. We investigate here contributions of epigenetic modifications to transcriptional silencing of CIITA in variants of the human breast cancer cell line MDA MB 435. Significant increases in histone H3 lysine 27 trimethylation upon IFN-γ stimulation correlate with reductions in transcription factor recruitment to the interferon-γ inducible CIITA promoter, CIITApIV, and with significantly increased CIITApIV occupancy by the histone methyltransferase enhancer of zeste homolog 2 (EZH2). Most compelling is evidence that decreased expression of EZH2 in MDA MB 435 variants results in significant increases in CIITA and HLA-DRA mRNA expression, even in the absence of interferon-γ stimulation, as well as increased cell surface expression of MHC II. Together, these data add mechanistic insight to prior observations of increased EZH2 expression and decreased CIITA expression in multiple tumor types

Reproductive health crisis during waves one and two of the COVID-19 pandemic in India: incidence and deaths from severe maternal complications in more than 202000 hospital births

Background The SARS-CoV-2 pandemic in India has adversely affected many aspects of population health. We need detailed evidence of the impact on reproductive health in India so that lessons can be learnt. Methods Hospital-based repeated monthly survey of nine severe maternal complications and death in 15 hospitals across five states in India covering a total of 202,986 hospital births, December-2018 through to May-2021. We calculated incidence rates (with 95% confidence intervals (CIs)) per 1000 hospital births, case-fatality and rate ratios (RR) with 95% CIs. Linear regression was used to examine the association between the Government Response Stringency Index (GRSI) for India and changes in hospital births, incidence and case-fatality. Findings There was a significant decrease in hospital births per month during the pandemic period with a 4.8% decrease per 10% increase in the GRSI scores (p < 0.001). The overall incidence of severe complications in the pandemic period was not significantly different from the pre-pandemic period, but hospital admissions from septic abortion was 56% higher (RR=1.56; 95% CI=1.22–1.99; p < 0.001). The overall case-fatality of complications increased by 23% (RR=1.23; 95% CI=1.03–1.46; p = 0.022) and remained high across the different phases of the pandemic with a notable significant increase in deaths from heart failure in pregnancy. Interpretation Our study supports the legitimacy of the calls made to maintain sexual and reproductive health services as essential services during the pandemic. Lessons learnt should be used to avert the ongoing reproductive health crisis while India plans to manage a third wave of the pandemic. Funding The MaatHRI platform and this study are funded by a Medical Research Council Career Development Award to MN (Ref:MR/P022030/1). The funder has no role in the study design, data collection, analysis, or writing the pape

Reproductive Health Crisis During Waves One and Two of the COVID-19 Pandemic in India: Incidence and Deaths From Severe Maternal Complications in More than 202000 Hospital Births

BACKGROUND: The SARS-CoV-2 pandemic in India has adversely affected many aspects of population health. We need detailed evidence of the impact on reproductive health in India so that lessons can be learnt. METHODS: Hospital-based repeated monthly survey of nine severe maternal complications and death in 15 hospitals across five states in India covering a total of 202,986 hospital births, December-2018 through to May-2021. We calculated incidence rates (with 95% confidence intervals (CIs)) per 1000 hospital births, case-fatality and rate ratios (RR) with 95% CIs. Linear regression was used to examine the association between the Government Response Stringency Index (GRSI) for India and changes in hospital births, incidence and case-fatality. FINDINGS: There was a significant decrease in hospital births per month during the pandemic period with a 4.8% decrease per 10% increase in the GRSI scores (p < 0.001). The overall incidence of severe complications in the pandemic period was not significantly different from the pre-pandemic period, but hospital admissions from septic abortion was 56% higher (RR=1.56; 95% CI=1.22-1.99; p < 0.001). The overall case-fatality of complications increased by 23% (RR=1.23; 95% CI=1.03-1.46; p = 0.022) and remained high across the different phases of the pandemic with a notable significant increase in deaths from heart failure in pregnancy. INTERPRETATION: Our study supports the legitimacy of the calls made to maintain sexual and reproductive health services as essential services during the pandemic. Lessons learnt should be used to avert the ongoing reproductive health crisis while India plans to manage a third wave of the pandemic. FUNDING: The MaatHRI platform and this study are funded by a Medical Research Council Career Development Award to MN (Ref:MR/P022030/1). The funder has no role in the study design, data collection, analysis, or writing the paper

Relationship between anaemia, coagulation parameters during pregnancy and postpartum haemorrhage at childbirth: a prospective cohort study

Objectives To investigate the association between coagulation parameters and severity of anaemia (moderate anaemia: haemoglobin (Hb) 7–9.9 g/dL and severe anaemia: Hb Design A prospective cohort study of pregnant women recruited in the third trimester and followed-up after childbirth. Setting Ten hospitals across four states in India. Participants 1342 pregnant women. Intervention Not applicable. Methods Hb and coagulation parameters: fibrinogen, D-dimer, D-dimer/fibrinogen ratio, platelets and international normalised ratio (INR) were measured at baseline. Participants were followed-up to measure blood loss within 2 hours after childbirth and PPH was defined based on blood loss and clinical assessment. Associations between coagulation parameters, Hb, anaemia and PPH were examined using multivariable logistic regression models. Outcomes measures Adjusted OR with 95% CI. Results In women with severe anaemia during the third trimester, the D-dimer was 27% higher, mean fibrinogen 117 mg/dL lower, D-dimer/fibrinogen ratio 69% higher and INR 12% higher compared with women with no/mild anaemia. Mean platelets in severe anaemia was 37.8×109/L lower compared with women with moderate anaemia. Similar relationships with smaller effect sizes were identified for women with moderate anaemia compared with women with no/mild anaemia. Low Hb and high INR at third trimester of pregnancy independently increased the odds of PPH at childbirth, but the other coagulation parameters were not found to be significantly associated with PPH. Conclusion Altered blood coagulation profile in pregnant women with severe anaemia could be a risk factor for PPH and requires further evaluation.</p