DP1 receptor signaling prevents the onset of intrinsic apoptosis in eosinophils and functions as a transcriptional modulator

Prostaglandin (PG) D2 is the ligand for the G‐protein coupled receptors DP1 (D‐type prostanoid receptor 1) and DP2 (also known as chemoattractant receptor homologous molecule, expressed on Th2 cells; CRTH2). Both, DP1 and DP2 are expressed on the cellular surface of eosinophils; although it has become quite clear that PGD2 induces eosinophil migration mainly via DP2 receptors, the role of DP1 in eosinophil responses has remained elusive. In this study, we addressed how DP1 receptor signaling complements the pro‐inflammatory effects of DP2. We found that PGD2 prolongs the survival of eosinophils via a DP1 receptor‐mediated mechanism that inhibits the onset of the intrinsic apoptotic cascade. The DP1 agonist BW245c prevented the activation of effector caspases in eosinophils and protected mitochondrial membranes from depolarization which—as a consequence—sustained viability of eosinophils. DP1 activation in eosinophils enhanced the expression of the anti‐apoptotic gene BCL‐XL, but also induced pro‐inflammatory genes, such as VLA‐4 and CCR3. In HEK293 cells that overexpress recombinant DP1 and/or DP2 receptors, activation of DP1, but not DP2, delayed cell death and stimulated proliferation, along with induction of serum response element (SRE), a regulator of anti‐apoptotic, early‐response genes. We conclude that DP1 receptors promote the survival via SRE induction and induction of pro‐inflammatory genes. Therefore, targeting DP1 receptors, along with DP2, may contribute to anti‐inflammatory therapy in eosinophilic diseases

Control of inflammation by stromal Hedgehog pathway activation restrains colitis

Inflammation disrupts tissue architecture and function, thereby contributing to the pathogenesis of diverse diseases; the signals that promote or restrict tissue inflammation thus represent potential targets for therapeutic intervention. Here, we report that genetic or pharmacologic Hedgehog pathway inhibition intensifies colon inflammation (colitis) in mice. Conversely, genetic augmentation of Hedgehog response and systemic small-molecule Hedgehog pathway activation potently ameliorate colitis and restrain initiation and progression of colitis-induced adenocarcinoma. Within the colon, the Hedgehog protein signal does not act directly on the epithelium itself, but on underlying stromal cells to induce expression of IL-10, an immune-modulatory cytokine long known to suppress inflammatory intestinal damage. IL-10 function is required for the full protective effect of small-molecule Hedgehog pathway activation in colitis; this pharmacologic augmentation of Hedgehog pathway activity and stromal IL-10 expression are associated with increased presence of CD4(+) Foxp3(+) regulatory T cells. We thus identify stromal cells as cellular coordinators of colon inflammation and suggest their pharmacologic manipulation as a potential means to treat colitis.11138Ysciescopu

Impact of the COVID-19 Pandemic on People Living With Rare Diseases and Their Families: Results of a National Survey

BACKGROUND: With more than 103 million cases and 1.1 million deaths, the COVID-19 pandemic has had devastating consequences for the health system and the well-being of the entire US population. The Rare Diseases Clinical Research Network funded by the National Institutes of Health was strategically positioned to study the impact of the pandemic on the large, vulnerable population of people living with rare diseases (RDs). OBJECTIVE: This study was designed to describe the characteristics of COVID-19 in the RD population, determine whether patient subgroups experienced increased occurrence or severity of infection and whether the pandemic changed RD symptoms and treatment, and understand the broader impact on respondents and their families. METHODS: US residents who had an RD and were 9 symptoms vs none: OR 82.5, 95% CI 29-234 and 5-9: OR 44.8, 95% CI 18.7-107). Median symptom duration was 16 (IQR 9-30) days. Hospitalization (7/71, 10%) and ventilator support (4/71, 6%) were uncommon. Respondents who acquired COVID-19 reported increased occurrence and severity of RD symptoms and use or dosage of select medications; those who did not acquire COVID-19 reported decreased occurrence and severity of RD symptoms and use of medications; those who did not know had an intermediate pattern. The pandemic made it difficult to access care, receive treatment, get hospitalized, and caused mood changes for respondents and their families. CONCLUSIONS: Self-reported COVID-19 was more frequent than expected and was associated with increased prevalence and severity of RD symptoms and greater use of medications. The pandemic negatively affected access to care and caused mood changes in the respondents and family members. Continued surveillance is necessary

Creating a multi-center rare disease consortium - the Consortium of Eosinophilic Gastrointestinal Disease Researchers (CEGIR).

 Eosinophilic gastrointestinal disorders (EGIDs) affect various segments of the gastrointestinal tract. Since these disorders are rare, collaboration is essential to enroll subjects in clinical studies and study the broader population. The Rare Diseases Clinical Research Network (RDCRN), a program of the National Center for Advancing Translational Sciences (NCATS), funded the Consortium of Eosinophilic Gastrointestinal Disease Researchers (CEGIR) in 2014 to advance the field of EGIDs. CEGIR facilitates collaboration among various centers, subspecialties, patients, professional organizations and patient-advocacy groups and includes 14 clinical sites. It has successfully initiated two large multi-center clinical studies looking to refine EGID diagnoses and management. Several pilot studies are underway that focus on various aspects of EGIDs including novel therapeutic interventions, diagnostic and monitoring methods, and the role of the microbiome in pathogenesis. CEGIR currently nurtures five physician-scholars through a career training development program and has published more than 40 manuscripts since its inception. This review focuses on CEGIR's operating model and progress and how it facilitates a framework for exchange of ideas and stimulates research and innovation. This consortium provides a model for progress on other potential clinical areas

KELT-25 b and KELT-26 b: A Hot Jupiter and a Substellar Companion Transiting Young A Stars Observed by TESS

We present the discoveries of KELT-25 b (TIC 65412605, TOI-626.01) and KELT-26 b (TIC 160708862, TOI-1337.01), two transiting companions orbiting relatively bright, early A stars. The transit signals were initially detected by the KELT survey and subsequently confirmed by Transiting Exoplanet Survey Satellite (TESS) photometry. KELT-25 b is on a 4.40 day orbit around the V = 9.66 star CD-24 5016 (Teff=8280-180+440 K, M ∗ = 2.18-0.11+0.12 M o˙), while KELT-26 b is on a 3.34 day orbit around the V = 9.95 star HD 134004 (Teff = 8640-240+500 K, M ∗ = 1.93-0.16+0.14 M o˙), which is likely an Am star. We have confirmed the substellar nature of both companions through detailed characterization of each system using ground-based and TESS photometry, radial velocity measurements, Doppler tomography, and high-resolution imaging. For KELT-25, we determine a companion radius of R P = 1.64-0.043+0.039 R J and a 3σ upper limit on the companion's mass of ∼64 M J. For KELT-26 b, we infer a planetary mass and radius of M P = 1.41-0.51+0.43MJ and R P = 1.94-0.058+0.060 R J. From Doppler tomographic observations, we find KELT-26 b to reside in a highly misaligned orbit. This conclusion is weakly corroborated by a subtle asymmetry in the transit light curve from the TESS data. KELT-25 b appears to be in a well-aligned, prograde orbit, and the system is likely a member of the cluster Theia 449