Regulation of Human Cystic Fibrosis Transmembrane Conductance Regulator (Cftr) by Serum- and Glucocorticoid-Inducible Kinase (Sgk1)

Background: Serum- and glucocorticoid-inducible kinase-1 (SGK1) increases CFTR Cl currents in Xenopus oocytes by an unknown mechanism. Because SGK increases the plasma membrane expression of other ion channels, the goal of this paper was to test the hypothesis that SGK1 stimulates CFTR Cl currents by increasing the number of CFTR Cl channels in the plasma membrane. Methods: CFTR Cl currents were measured in Xenopus oocytes by the two-electrode voltage clamp technique, and CFTR in the plasma membrane was determined by laser scanning confocal microscopy. Results: wt-SGK1 stimulated CFTR Cl currents by 42% and increased the amount of CFTR in the plasma membrane by 35%. A kinase-dead SGK mutant (K127N) had a dominant-negative effect on CFTR, reducing CFTR Cl currents by 38%. In addition, deletion of the C-terminal PDZ-interacting motif (SGK1-ΔSFL) increased CFTR Cl currents by 108%. Thus, SGK1-ΔSFL was more effective than wt-SGK1 in stimulating CFTR Cl currents. Neither wt-SGK nor the K127N mutant had any effect on Cl currents in oocytes when expressed alone in the absence of CFTR. Conclusion: SGK1 stimulates CFTR Cl currents in Xenopus oocytes by increasing the number of channels in the plasma membrane. Moreover, the effect of SGK may be mediated by protein-protein interactions involving the PDZ interacting motif

Shared heritability and functional enrichment across six solid cancers

Correction: Nature Communications 10 (2019): art. 4386 DOI: 10.1038/s41467-019-12095-8Quantifying the genetic correlation between cancers can provide important insights into the mechanisms driving cancer etiology. Using genome-wide association study summary statistics across six cancer types based on a total of 296,215 cases and 301,319 controls of European ancestry, here we estimate the pair-wise genetic correlations between breast, colorectal, head/neck, lung, ovary and prostate cancer, and between cancers and 38 other diseases. We observed statistically significant genetic correlations between lung and head/neck cancer (r(g) = 0.57, p = 4.6 x 10(-8)), breast and ovarian cancer (r(g) = 0.24, p = 7 x 10(-5)), breast and lung cancer (r(g) = 0.18, p = 1.5 x 10(-6)) and breast and colorectal cancer (r(g) = 0.15, p = 1.1 x 10(-4)). We also found that multiple cancers are genetically correlated with non-cancer traits including smoking, psychiatric diseases and metabolic characteristics. Functional enrichment analysis revealed a significant excess contribution of conserved and regulatory regions to cancer heritability. Our comprehensive analysis of cross-cancer heritability suggests that solid tumors arising across tissues share in part a common germline genetic basis.Peer reviewe

Vaginal Hysterectomy for Treatment of Cervical Ectopic Pregnancy

BACKGROUND: Cervical ectopic pregnancy can lead to catastrophic hemorrhage, and may be managed conservatively with intra-amniotic methotrexate (MTX), systemic MTX, or both; surgical evacuation with or without balloon tamponade; and uterine artery embolization. However, some patients require hysterectomy, which has traditionally been performed abdominally. CASE: A 39-year-old parous woman was diagnosed with cervical ectopic pregnancy at an estimated 7 1/7 weeks of gestation. Her β-hCG level remained at 29,433 milli-international units/mL, and the gestational sac persisted on ultrasonography after first intra-amniotic then multidose systemic MTX treatment. After a review of other fertility-sparing procedures, she chose definitive treatment with hysterectomy because she did not desire future childbearing. She underwent a successful vaginal hysterectomy, a novel approach for this condition. CONCLUSION: Vaginal hysterectomy can be performed successfully for treatment of cervical ectopic pregnancy in patients who have completed childbearing and for whom conservative treatment has failed

Seawater carbonate chemistry and shell dissolution in dead gastropod larvae and adult Limacina helicina pteropods

Ocean acidification (OA) increases aragonite shell dissolution in calcifying marine organisms. It has been proposed that bacteria associated with molluscan shell surfaces in situ could damage the periostracum and reduce its protective function against shell dissolution. However, the influence of bacteria on shell dissolution under OA conditions is unknown. In this study, dissolution in dead shells from gastropod larvae and adult pteropods (Limacina helicina) was examined following a 5-day incubation under a range of aragonite saturation states (Ωarag; values ranging from 0.5 to 1.8) both with and without antibiotics. Gastropod and pteropod specimens were collected from Puget Sound, Washington (48°33′19″N, 122°59′49″W and 47°41′11″N, 122°25′23″W, respectively), preserved, stored, and then treated in August 2015. Environmental scanning electron microscopy (ESEM) was used to determine the severity and extent of dissolution, which was scored as mild, severe, or summed (mild + severe) dissolution. Shell dissolution increased with decreasing Ωarag. In gastropod larvae, there was a significant interaction between the effects of antibiotics and Ωarag on severe dissolution, indicating that microbes could mediate certain types of dissolution among shells under low Ωarag. In L. helicina, there were no significant interactions between the effects of antibiotics and Ωarag on dissolution. These findings suggest that bacteria may differentially influence the response of some groups of shelled planktonic gastropods to OA conditions. This is the first assessment of the microbial–chemical coupling of dissolution in shells of either gastropod larvae or adult L. helicina under OA

Diagnostic Biopsy Does Not Commonly Induce Intratumoral CD8 T Cell Infiltration in Merkel Cell Carcinoma

<div><h3>Background</h3><p>Merkel cell carcinoma is a polyomavirus-associated cancer that is strongly linked with T lymphocyte immune suppression in epidemiologic studies. CD8+ T cell infiltration into MCC tumors (intratumoral) has recently been shown to be strongly predictive of improved survival. In contrast, the presence of CD8+ T cells at the border of the tumor (peritumoral) had no independent prognostic value. Spontaneous regression has been reported for MCC approximately one thousand times more often than would be expected given the frequency of this cancer. Many of these events began shortly after biopsy, and in some cases lymphocytic infiltration was described.</p> <h3>Methodology/Principal Findings</h3><p>To determine whether CD8+ lymphocyte infiltration in MCC tumors is commonly altered by biopsy.33 MCC patients who had microscopic confirmation of MCC on both an initial biopsy and a re-excision specimen were included in this study. Intratumoral and peritumoral CD8 lymphocyte infiltration was quantitated using immunohistochemistry and compared using the paired t-test in biopsy versus re-excision samples. There was a trend toward increased CD8 infiltration after biopsy in a peritumoral (‘stalled’) pattern (p = 0.08), however, biopsy was not associated with a significant increase in CD8 T cells in the clinically more important intratumoral location (p = 0.58).</p> <h3>Conclusions/Significance</h3><p>The initial diagnostic biopsy for MCC does not commonly alter intratumoral CD8+ T cell infiltration, suggesting it does not directly induce immunologic recognition of this cancer. Because CD8 infiltration is typically stable after biopsy, this parameter may be useful to assess the efficacy of future immune therapies for this virus-associated, immunogenic, often-lethal cancer.</p> </div