Differential Effects of Pancreatic Cancer-Derived Extracellular Vesicles Driving a Suppressive Environment

Pancreatic ductal adenocarcinoma (PDAC) cells display extensive crosstalk with their surrounding environment to regulate tumor growth, immune evasion, and metastasis. Recent advances have attributed many of these interactions to intercellular communication mediated by small extracellular vesicles (sEVs), involving cancer-associated fibroblasts (CAF). To explore the impact of sEVs on monocyte lineage transition as well as the expression of checkpoint receptors and activation markers, peripheral blood monocytes from healthy subjects were exposed to PDAC-derived sEVs. Additionally, to analyze the role of sEV-associated HA in immune regulation and tissue-resident fibroblasts, monocytes and pancreatic stellate cells were cultured in the presence of PDAC sEVs with or depleted of HA. Exposure of monocytes to sEVs resulted in unique phenotypic changes in HLA-DR, PD-L1, CD86 and CD64 expression, and cytokine secretion that was HA-independent except for IL-1β and MIP1β. In contrast, monocyte suppression of autologous T cell proliferation was reduced following exposure to HA-low sEVs. In addition, exposure of stellate cells to sEVs upregulated the secretion of various cytokines, including MMP-9, while removal of HA from PDAC-derived sEVs attenuated the secretion of MMP-9, demonstrating the role of sEV-associated HA in regulating expression of this pro-tumorigenic cytokine from stellate cells. This observation lends credence to the findings from the TCGA database that PDAC patients with high levels of enzymes in the HA synthesis pathway had worse survival rates compared with patients having low expression of these enzymes. PDAC-derived sEVs have an immune modulatory role affecting the activation state of monocyte subtypes. However, sEV-associated HA does not affect monocyte phenotype but alters cytokine secretion and suppression of autologous T cell proliferation and induces secretion of pro-tumorigenic factors by pancreatic stellate cells (PSC), as has been seen following the conversion of PSCs to cancer-associated fibroblasts (CAFs). Interruption of the hexosamine biosynthetic pathway, activated in PDAC producing the key substrate (UDP-GlcNAc) for HA synthesis, thus, represents a potential clinical interception strategy for PDAC patients. Findings warrant further investigations of underlying mechanisms involving larger sample cohorts

The Habitable Exoplanet Observatory (HabEx) Mission Concept Study Final Report

The Habitable Exoplanet Observatory, or HabEx, has been designed to be the Great Observatory of the 2030s. For the first time in human history, technologies have matured sufficiently to enable an affordable space-based telescope mission capable of discovering and characterizing Earthlike planets orbiting nearby bright sunlike stars in order to search for signs of habitability and biosignatures. Such a mission can also be equipped with instrumentation that will enable broad and exciting general astrophysics and planetary science not possible from current or planned facilities. HabEx is a space telescope with unique imaging and multi-object spectroscopic capabilities at wavelengths ranging from ultraviolet (UV) to near-IR. These capabilities allow for a broad suite of compelling science that cuts across the entire NASA astrophysics portfolio. HabEx has three primary science goals: (1) Seek out nearby worlds and explore their habitability; (2) Map out nearby planetary systems and understand the diversity of the worlds they contain; (3) Enable new explorations of astrophysical systems from our own solar system to external galaxies by extending our reach in the UV through near-IR. This Great Observatory science will be selected through a competed GO program, and will account for about 50% of the HabEx primary mission. The preferred HabEx architecture is a 4m, monolithic, off-axis telescope that is diffraction-limited at 0.4 microns and is in an L2 orbit. HabEx employs two starlight suppression systems: a coronagraph and a starshade, each with their own dedicated instrument

The Habitable Exoplanet Observatory (HabEx) Mission Concept Study Final Report

The Habitable Exoplanet Observatory, or HabEx, has been designed to be the Great Observatory of the 2030s. For the first time in human history, technologies have matured sufficiently to enable an affordable space-based telescope mission capable of discovering and characterizing Earthlike planets orbiting nearby bright sunlike stars in order to search for signs of habitability and biosignatures. Such a mission can also be equipped with instrumentation that will enable broad and exciting general astrophysics and planetary science not possible from current or planned facilities. HabEx is a space telescope with unique imaging and multi-object spectroscopic capabilities at wavelengths ranging from ultraviolet (UV) to near-IR. These capabilities allow for a broad suite of compelling science that cuts across the entire NASA astrophysics portfolio. HabEx has three primary science goals: (1) Seek out nearby worlds and explore their habitability; (2) Map out nearby planetary systems and understand the diversity of the worlds they contain; (3) Enable new explorations of astrophysical systems from our own solar system to external galaxies by extending our reach in the UV through near-IR. This Great Observatory science will be selected through a competed GO program, and will account for about 50% of the HabEx primary mission. The preferred HabEx architecture is a 4m, monolithic, off-axis telescope that is diffraction-limited at 0.4 microns and is in an L2 orbit. HabEx employs two starlight suppression systems: a coronagraph and a starshade, each with their own dedicated instrument.Comment: Full report: 498 pages. Executive Summary: 14 pages. More information about HabEx can be found here: https://www.jpl.nasa.gov/habex

A cross-national exploration of societal-level factors associated with child physical abuse and neglect

Children around the world experience violence at the hands of their caregivers at alarming rates. A recent review estimates that a minimum of 50% of children in Asia, Africa, and North America experienced severe physical violence by caregivers in the past year, with large variations between countries. Identifying modifiable country-level factors driving these geographic variations has great potential for achieving population-level reductions in rates of child maltreatment. This study builds on previous research by focusing on caregiver-reported physical abuse and neglect victimisation, examining 22 societal factors representing 11 different constructs among 42 countries from 5 continents at different stages of development. Our findings suggest that gender inequity may be important for both child physical abuse and neglect. Indicators of literacy and development may also be important for child neglect. Given the limitations of the correlational findings and measurement issues, it is critical to continue to investigate societal-level factors of child maltreatment so that interventions and prevention efforts can incorporate strategies that have the greatest potential for population-level impact

Elevated Risk for Antimicrobial Drug–Resistant Shigella Infection among Men Who Have Sex with Men, United States, 2011–2015

Shigella spp. cause ≈500,000 illnesses in the United States annually, and resistance to ciprofloxacin, ceftriaxone, and azithromycin is emerging. We investigated associations between transmission route and antimicrobial resistance among US shigellosis clusters reported during 2011–2015. Of 32 clusters, 9 were caused by shigellae resistant to ciprofloxacin (3 clusters), ceftriaxone (2 clusters), or azithromycin (7 clusters); 3 clusters were resistant to >1 of these drugs. We observed resistance to any of these drugs in all 7 clusters among men who have sex with men (MSM) but in only 2 of the other 25 clusters (p<0.001). Azithromycin resistance was more common among MSM-associated clusters than other clusters (86% vs. 4% of clusters; p<0.001). For adults with suspected shigellosis, clinicians should culture feces; obtain sex histories; discuss shigellosis prevention; and choose treatment, when needed, according to antimicrobial drug susceptibility. Public health interviews for enteric illnesses should encompass sex practices; health messaging for MSM must include shigellosis prevention

Evaluation of the impact of shigellosis exclusion policies in childcare settings upon detection of a shigellosis outbreak

Abstract Background In the event of a shigellosis outbreak in a childcare setting, exclusion policies are typically applied to afflicted children to limit shigellosis transmission. However, there is scarce evidence of their impact. Methods We evaluated five exclusion policies: Children return to childcare after: i) two consecutive laboratory tests (either PCR or culture) do not detect Shigella, ii) a single negative laboratory test (PCR or culture) does not detect Shigella, iii) seven days after beginning antimicrobial treatment, iv) after being symptom-free for 24 h, or v) 14 days after symptom onset. We also included four treatments to assess the policy options: i) immediate, effective treatment; ii) effective treatment after laboratory diagnosis; iii) no treatment; iv) ineffective treatment. Relying on published data, we calculated the likelihood that a child reentering childcare would be infectious, and the number of childcare-days lost per policy. Results Requiring two consecutive negative PCR tests yielded a probability of onward transmission of < 1%, with up to 17 childcare-days lost for children receiving effective treatment, and 53 days lost for those receiving ineffective treatment. Conclusions Of the policies analyzed, requiring negative PCR testing before returning to childcare was the most effective to reduce the risk of shigellosis transmission, with one PCR test being the most effective for the least childcare-days lost

Cannabis Use and the Developing Brain: Highs and Lows

Although cannabis is a naturally occurring plant with a long history of use by humans, the chemicals it contains, called cannabinoids, can act on the human body in many ways. Use of cannabis during important periods of development, such as during pregnancy and adolescence, can have a long-lasting impact on the way the brain forms and develops its systems to control emotions and other functions. This article gives an overview of some of the effects of cannabinoids on the developing brain, before birth and as teenagers, and provides information about how young people can prevent or minimize the negative effects of cannabis on their brains