Myeloid cell-derived PROS1 inhibits tumor metastasis by regulating inflammatory and immune responses via IL-10.

Stimulation of TAM (TYRO3, AXL, and MERTK) receptor tyrosine kinases promotes tumor progression through numerous cellular mechanisms. TAM cognate ligands GAS6 and PROS1 (for TYRO3 and MERTK) are secreted by host immune cells, an interaction which may support tumor progression. Here, we revealed an unexpected antimetastatic role for myeloid-derived PROS1: suppressing metastatic potential in lung and breast tumor models. Pros1 deletion in myeloid cells led to increased lung metastasis, independent of primary tumor infiltration. PROS1-cKO bone marrow-derived macrophages (BMDMs) led to elevated TNF-α, IL-6, Nos2, and IL-10 via modulation of the Socs3/NF-κB pathway. Conditioned medium from cKO BMDMs enhanced EMT, ERK, AKT, and STAT3 activation within tumor cells and promoted IL-10-dependent invasion and survival. Macrophages isolated from metastatic lungs modulated T cell proliferation and function, as well as expression of costimulatory molecules on DCs in a PROS1-dependent manner. Inhibition of MERTK kinase activity blocked PROS1-mediated suppression of TNF-α and IL-6 but not IL-10. Overall, using lung and breast cancer models, we identified the PROS1/MERTK axis within BMDMs as a potent regulator of adaptive immune responses with a potential to suppress metastatic seeding and revealed IL-10 regulation by PROS1 to deviate from that of TNF-α and IL-6.

The volume of general surgery emergency cases in a government hospital during the COVID-19 pandemic and two other periods: a comparative, retrospective study.

BACKGROUND: During March and April 2020, reductions in non-COVID-19 hospital admissions were observed around the world. Elective surgeries, visits with general practitioners, and diagnoses of medical emergencies were consequently delayed. OBJECTIVE: To compare the characteristics of patients admitted to a northern Israeli hospital with common surgical complaints during three periods: the lockdown due to the COVID-19 outbreak, the Second Lebanon War in 2006, and a regular period. METHODS: Demographic, medical, laboratory, imaging, intraoperative, and pathological data were collected from electronic medical files of patients who received emergency treatment at the surgery department of a single hospital in northern Israel. We retrospectively compared the characteristics of patients who were admitted with various conditions during three periods. RESULTS: Patients' mean age and most of the clinical parameters assessed were similar between the periods. However, pain was reportedly higher during the COVID-19 than the control period (8.7 vs. 6.4 on a 10-point visual analog scale, P < 0.0001). During the COVID-19 outbreak, the Second Lebanon War, and the regular period, the mean numbers of patients admitted daily were 1.4, 4.4, and 3.0, respectively. The respective mean times from the onset of symptoms until admission were 3, 1, and 1.5 days, P < 0.001. The respective proportions of surgical interventions for appendiceal disease were 95%, 96%, and 69%; P = 0.03. CONCLUSIONS: Compared to a routine period, patients during the COVID-19 outbreak waited longer before turning to hospitalization, and reported more pain at arrival. Patients during both emergency periods were more often treated surgically than non-operatively.

Birth weight and autism spectrum disorder: A population-based nested case-control study.

Low birth weight (<2,500 g) and preterm birth (<37 weeks) were found to be associated with increased risk of autism spectrum disorder (ASD), however, the data regarding the entire birth weight (BW) and gestational age (GA) range are inconclusive. In this population nested case-control study, based on the Israeli National Insurance Institute records, we aimed to estimate the associations in the Israeli population. The study population included all children born between 2000 and 2012 and diagnosed with ASD (N = 12,635 cases), and a random 20% sample of children born in the same period who were not diagnosed with ASD (N = 369,548 controls). We used multiple logistic regression models to calculate the risk of ASD for each BW and GA category, adjusted for covariates (child sex, maternal age, paternal age, population group, maternal wage, paternal wage, having a sibling with ASD, multiple gestation and socioeconomic status). BW < 3,000 g and GA < 39 weeks were associated with higher risk of ASD, including BW of 2,500-3,000 g (adjusted odds ratio [AOR], 1.18; 95% CI, 1.12-1.24, in comparison to the 3,000-3,500 g category) and GA of 37 & 38 weeks (AOR, 1.35; 95% CI, 1.25-1.45 and AOR, 1.13; 95% CI 1.06-1.20, respectively; in comparison to GA of 40 weeks). To account for the high correlation between GA and BW, we modeled BW percentiles for gestational age and found that the BW < 20th percentile was associated with an increased risk of ASD (AOR, 1.10; 95% CI, 1.01-1.19). These results demonstrate that associations of ASD with BW and GA are not limited to commonly used clinical cutoffs. Autism Res 2020, 13: 655-665. © 2020 International Society for Autism Research, Wiley Periodicals, Inc. LAY SUMMARY: Autism spectrum disorder (ASD) has been associated with low birth weight (<2,500 g) in prior research. Our study aims to describe the relationship between birth weight (BW) and ASD in the Israeli population. We found that BW <3,000 g was associated with a higher risk of ASD. These results demonstrate that an increased risk of ASD is not confined to clinically defined cutoffs such as BW < 2,500 g.

Protein S Negatively Regulates Neural Stem Cell Self-Renewal through Bmi-1 Signaling.

Revealing the molecular mechanisms underlying neural stem cell self-renewal is a major goal toward understanding adult brain homeostasis. The self-renewing potential of neural stem and progenitor cells (NSPCs) must be tightly regulated to maintain brain homeostasis. We recently reported the expression of Protein S (PROS1) in adult hippocampal NSPCs, and revealed its role in regulation of NSPC quiescence and neuronal differentiation. Here, we investigate the effect of PROS1 on NSPC self-renewal and show that genetic ablation of Pros1 in neural progenitors increased NSPC self-renewal by 50%. Mechanistically, we identified the upregulation of the polycomb complex protein Bmi-1 and repression of its downstream effectors p16Ink4a and p19Arf to promote NSPC self-renewal in Pros1-ablated cells. Rescuing Pros1 expression restores normal levels of Bmi-1 signaling, and reverts the proliferation and enhanced self-renewal phenotypes observed in Pros1-deleted cells. Our study identifies PROS1 as a novel negative regulator of NSPC self-renewal. We conclude PROS1 is instructive for NSPC differentiation by negatively regulating Bmi-1 signaling in adult and embryonic neural stem cells.

Protein S Regulates Neural Stem Cell Quiescence and Neurogenesis.

Neurons are continuously produced in brains of adult mammalian organisms throughout life-a process tightly regulated to ensure a balanced homeostasis. In the adult brain, quiescent Neural Stem Cells (NSCs) residing in distinct niches engage in proliferation, to self-renew and to give rise to differentiated neurons and astrocytes. The mechanisms governing the intricate regulation of NSC quiescence and neuronal differentiation are not completely understood. Here, we report the expression of Protein S (PROS1) in adult NSCs, and show that genetic ablation of Pros1 in neural progenitors increased hippocampal NSC proliferation by 47%. We show that PROS1 regulates the balance of NSC quiescence and proliferation, also affecting daughter cell fate. We identified the PROS1-dependent downregulation of Notch1 signaling to correlate with NSC exit from quiescence. Notch1 and Hes5 mRNA levels were rescued by reintroducing Pros1 into NCS or by supplementation with purified PROS1, suggesting the regulation of Notch pathway by PROS1. Although Pros1-ablated NSCs show multilineage differentiation, we observed a 36% decrease in neurogenesis, coupled with a similar increase in astrogenesis, suggesting PROS1 is instructive for neurogenesis, and plays a role in fate determination, also seen in aged mice. Rescue experiments indicate PROS1 is secreted by NSCs and functions by a NSC-endogenous mechanism. Our study identifies a duple role for PROS1 in stem-cell quiescence and as a pro-neurogenic factor, and highlights a unique segregation of increased stem cell proliferation from enhanced neuronal differentiation, providing important insight into the regulation and control of NSC quiescence and differentiation. Stem Cells 2017;35:679-693.