Pregnancy induces a number of immunological, hormonal, and metabolic changes that are necessary for the mother to adapt her body to this new physiological situation. The microbiome of the mother, the placenta and the fetus influence the fetus growth and undoubtedly plays a major role in the adequate development of the newborn infant. Hence, the microbiome modulates the inflammatory mechanisms related to physiological and pathological processes that are involved in the perinatal progress through different mechanisms. The present review summarizes the actual knowledge related to physiological changes in the microbiota occurring in the mother, the fetus, and the child, both during neonatal period and beyond. In addition, we approach some specific pathological situations during the perinatal periods, as well as the influence of the type of delivery and feeding.
Background: Pembrolizumab is a standard of care as first line palliative therapy in PD-L1 overexpressing (≥50%) non-small cell lung cancer (NSCLC). This study aimed at the identification of KRAS and TP53defined mutational subgroups in the PD-L1 high population to distinguish long-term responders from those with limited benefit. Methods: In this retrospective, observational study, patients from 4 certified lung cancer centers in Berlin, Germany, having received pembrolizumab monotherapy as first line palliative treatment for lung adenocarcinoma (LuAD) from 2017 to 2018, with PD-L1 expression status and targeted NGS data available, were evaluated.Results: A total of 119 patients were included. Rates for KRAS, TP53 and combined mutations were 52.1%, 47.1% and 21.9%, respectively, with no association given between KRAS and TP53 mutations (P=0.24). By trend, PD-L1 expression was higher in KRAS-positive patients (75% vs. 65%, P=0.13).Objective response rate (ORR), median progression-free survival (PFS) and overall survival (OS) in the KRAS G12C group (n=32, 51.6%) were 63.3%, 19.8 months (mo.) and not estimable (NE), respectively. Results in KRAS other and wild type patients were similar and by far lower (42.7%, P=0.06; 6.2 mo., P<0.001; 23.4 mo., P=0.08). TP53 mutations alone had no impact on response and survival. However, KRAS G12C /TP53 co-mutations (n=12) defined a subset of long-term responders (ORR 100.0%, PFS 33.3 mo., OS NE). In contrast, patients with KRAS other /TP53 mutations showed a dismal prognosis (ORR 27.3%,
Low oxygen concentration (hypoxia) is part of normal embryonic development, yet the situation is complex. Oxygen (O2) is a janus gas with low levels signaling through hypoxia‐inducible transcription factor (HIF) that are required for development of fetal and placental vasculature and fetal red blood cells. This results in coupling of fetus and mother around midgestation as a functional feto‐placental unit (FPU) for O2 transport, which is required for continued growth and development of the fetus. Defects in these processes may leave the developing fetus vulnerable to O2 deprivation or other stressors during this critical midgestational transition when common septal and conotruncal heart defects (CHDs) are likely to arise. Recent human epidemiological and case–control studies support an association between placental dysfunction, manifest as early onset pre‐eclampsia (PE) and increased serum bio‐markers, and CHD. Animal studies support this association, in particular those using gene inactivation in the mouse. Sophisticated methods for gene inactivation, cell fate mapping, and a quantitative bio‐reporter of O2 concentration support the premise that hypoxic stress at critical stages of development leads to CHD. The secondary heart field contributing to the cardiac outlet is a key target, with activation of the un‐folded protein response and abrogation of FGF signaling or precocious activation of a cardiomyocyte transcriptional program for differentiation, suggested as mechanisms. These studies provide a strong foundation for further study of feto–placental coupling and hypoxic stress in the genesis of human CHD.
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