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Abstract Almost all non-small cell lung cancer (NSCLC) patients initially responding to EGFR tyrosine kinase inhibitors (TKIs) develop acquired resistance. Since KCa3.1 channels, expressed in mitochondria and plasma membrane, regulate similar behavioral traits of NSCLC cells as EGFR, we hypothesized that their blockade contributes to overcoming EGFR-TKI resistance. Meta-analysis of microarray data revealed that KCa3.1 channel expression in erlotinib-resistant NSCLC cells correlates with that of genes of integrin and apoptosis pathways. Using erlotinib-sensitive and –resistant NSCLC cells we monitored the role of mitochondrial KCa3.1 channels in integrin signaling by studying cell-matrix adhesion with single-cell force spectroscopy. Apoptosis was quantified with fluorescence-based assays. The function of mitochondrial KCa3.1 channels in these processes was assessed by measuring the mitochondrial membrane potential and by quantifying ROS production. Functional assays were supplemented by biochemical analyses. We show that KCa3.1 channel inhibition with senicapoc in erlotinib-resistant NSCLC cells increases cell adhesion by increasing β1-integrin expression, that in turn depends on mitochondrial ROS release. Increased adhesion impairs migration of NSCLC cells in a 3D matrix. At the same time, the senicapoc-dependent ROS production induces cytochrome C release and triggers apoptosis of erlotinib-resistant NSCLC cells. Thus, KCa3.1 channel blockade overcomes EGFR-TKI resistance by inhibiting NSCLC motility and inducing apoptosis.

Abstract Non-small cell lung cancer (NSCLC) has a poor prognosis with a 5 year survival rate of only ~ 10%. Important driver mutations underlying NSCLC affect the epidermal growth factor receptor (EGFR) causing the constitutive activation of its tyrosine kinase domain. There are efficient EGFR tyrosine kinase inhibitors (TKIs), but patients develop inevitably a resistance against these drugs. On the other hand, KCa3.1 channels contribute to NSCLC progression so that elevated KCa3.1 expression is a strong predictor of poor NSCLC patient prognosis. The present study tests whether blocking KCa3.1 channels increases the sensitivity of NSCLC cells towards the EGFR TKI erlotinib and overcomes drug resistance. mRNA expression of KCa3.1 channels in erlotinib-sensitive and -resistant NSCLC cells was analysed in datasets from Gene expression omnibus (GEO) and ArrayExpress. We assessed proliferation and migration of NSCLC cells. These (live cell-imaging) experiments were complemented by patch clamp experiments and Western blot analyses. We identified three out of four datasets comparing erlotinib-sensitive and -resistant NSCLC cells which revealed an altered expression of KCa3.1 mRNA in erlotinib-resistant NSCLC cells. Therefore, we evaluated the combined effect of erlotinib and the KCa3.1 channel inhibition with sencapoc. Erlotinib elicits a dose-dependent inhibition of migration and proliferation of NSCLC cells. The simultaneous application of the KCa3.1 channel blocker senicapoc increases the sensitivity towards a low dose of erlotinib (300 nmol/L) which by itself has no effect on migration and proliferation. Partial erlotinib resistance can be overcome by KCa3.1 channel blockade. The sensitivity towards erlotinib as well as the potentiating effect of KCa3.1 blockade is further increased by mimicking hypoxia. Our results suggest that KCa3.1 channel blockade may constitute a therapeutic concept for treating NSCLC and overcome EGFR TKI resistance. We propose that this is due to complementary mechanisms of action of both blockers.

The midbody is an organelle present at the bridge connecting two cells at the end of cell division. Here, the authors use mass spectrometry to define the midbody interactome and uncover a role for PP1 phosphatases in microtubule dynamics and regulation of cytokinesis.

(1) Background: Vaccination rates for severe acute respiratory syndrome-coronavirus-2 (SARS-CoV-2) are low in Austria. International obstetric societies recommend the SARS-CoV-2 mRNA vaccination for women in puerperium. (2) Methods: A prospective two-stage cohort study was conducted at the Medical University of Vienna between October 2022 and December 2022. Firstly, women in puerperium were assigned to the evaluation group (step 1), and secondly, another cohort of unvaccinated women were randomly assigned to study group A (written briefing) or B (written and oral briefing) (step 2). We evaluated the vaccination status among women in the evaluation group and the willingness to receive the vaccination in all three cohorts. (3) Results: We included 217 women in puerperium (evaluation: n = 69, A: n = 68; B: n = 80). In the evaluation group, 66.7% (n = 46/69) of the women were unvaccinated. A total of 45.7% (21/46) of the unvaccinated women categorically declined the SARS-CoV-2 vaccination. A total of 26.5% (n = 18/68) of women in study group A, and 43.8% (n = 35/80) of women in study group B expressed their willingness to receive the vaccination (p = 0.029). There were no differences in willingness to receive the vaccination between different age strata of women in study groups A and B. (D) Conclusion: Our qualitative data demonstrate a benefit from oral counseling in addition to written briefing in order to increase the willingness to receive the vaccination among women in puerperium.

Orai3 calcium (Ca2+) channels are implicated in multiple breast cancer processes, such as proliferation and survival as well as resistance to chemotherapy. However, their involvement in the breast cancer cell migration processes remains vague. In the present study, we exploited MDA-MB-231 and MDA-MB-231 BrM2 basal-like estrogen receptor-negative (ER−) cell lines to assess the direct role of Orai3 in cell migration. We showed that Orai3 regulates MDA-MB-231 and MDA-MB-231 BrM2 cell migration in two distinct ways. First, we showed that Orai3 remodels cell adhesive capacities by modulating the intracellular Ca2+ concentration. Orai3 silencing (siOrai3) decreased calpain activity, cell adhesion and migration in a Ca2+-dependent manner. In addition, Orai3 interacts with focal adhesion kinase (FAK) and regulates the actin cytoskeleton, in a Ca2+-independent way. Thus, siOrai3 modulates cell morphology by altering F-actin polymerization via a loss of interaction between Orai3 and FAK. To summarize, we demonstrated that Orai3 regulates cell migration through a Ca2+-dependent modulation of calpain activity and, in a Ca2+-independent manner, the actin cytoskeleton architecture via FAK.

The prevalence of obesity is growing worldwide, and strategies to overcome this epidemic need to be developed urgently. Bariatric surgery is a very effective treatment option to reduce excess weight and often performed in women of reproductive age. Weight loss influences fertility positively and can resolve hormonal imbalance. So far, guidelines suggest conceiving after losing maximum weight and thus recommend conception at least 12–24 months after surgery. As limited data of these suggestions exist, further evidence is urgently needed as well for weight gain in pregnancy. Oral glucose tolerance tests for the diagnosis of gestational diabetes mellitus (GDM) should not be performed after bariatric procedures due to potential hypoglycaemic adverse events and high variability of glucose levels after glucose load. This challenges the utility of the usual diagnostic criteria for GDM in accurate prediction of complications. Furthermore, recommendations on essential nutrient supplementation in pregnancy and lactation in women after bariatric surgery are scarce. In addition, nutritional deficiencies or daily intake recommendations in pregnant women after bariatric surgery are not well investigated. This review summarizes current evidence, proposes clinical recommendations in pregnant women after bariatric surgery, and highlights areas of lack of evidence and the resulting urgent need for more clinical investigations.

Genetic variation in human maternal DNA contributes to the susceptibility for development of gestational diabetes mellitus (GDM).We assessed 77 maternal single nucleotide gene polymorphisms (SNPs) for associations with GDM or plasma glucose levels at OGTT in pregnancy.960 pregnant women (after dropouts 820: case/control: m99'WHO: 303/517, IADPSG: 287/533) were enrolled in two countries into this case-control study. After genomic DNA isolation the 820 samples were collected in a GDM biobank and assessed using KASP (LGC Genomics) genotyping assay. Logistic regression risk models were used to calculate ORs according to IADPSG/m'99WHO criteria based on standard OGTT values.The most important risk alleles associated with GDM were rs10830963/G of MTNR1B (OR = 1.84/1.64 [IADPSG/m'99WHO], p = 0.0007/0.006), rs7754840/C (OR = 1.51/NS, p = 0.016) of CDKAL1 and rs1799884/T (OR = 1.4/1.56, p = 0.04/0.006) of GCK. The rs13266634/T (SLC30A8, OR = 0.74/0.71, p = 0.05/0.02) and rs7578326/G (LOC646736/IRS1, OR = 0.62/0.60, p = 0.001/0.006) variants were associated with lower risk to develop GDM. Carrying a minor allele of rs10830963 (MTNR1B); rs7903146 (TCF7L2); rs1799884 (GCK) SNPs were associated with increased plasma glucose levels at routine OGTT.We confirmed the robust association of MTNR1B rs10830963/G variant with GDM binary and glycemic traits in this Caucasian case-control study. As novel associations we report the minor, G allele of the rs7578326 SNP in the LOC646736/IRS1 region as a significant and the rs13266634/T SNP (SLC30A8) as a suggestive protective variant against GDM development. Genetic susceptibility appears to be more preponderant in individuals who meet both the modified 99'WHO and the IADPSG GDM diagnostic criteria.

Objetivo: Evaluar los efectos sistémicos y terapéuticos del tratamiento con testosterona tópica del liquen escleroso vulvar. Métodos: Este estudio clínico prospectivo incluyó 10 mujeres post-menopáusicas con liquen escleroso vulvar. Se administró propionato de testosterona (0.04 g al día) en forma tópica por 4 semanas. Se determinaron las concentraciones séricas de andrógenos (testosterona, androstendiona y dehidroepiandrosterona) antes y después de 4 semanas de tratamiento, y la vulvodinia se evaluó por una escala visual análoga horizontal. Resultados: Las concentraciones séricas de testosterona total aumentaron en todas las pacientes (p

Obesity is associated with lower breastfeeding rates. The underlying pathophysiological mechanisms are not well-understood, but there is increasing evidence on an association between parameters of maternal glucose metabolism and prolactin concentrations. In this cross-sectional observational study we investigate the relationship between breastfeeding, maternal obesity, and maternal glucose metabolism postpartum with beta cell function as a primary outcome measure. We investigated 106 women (44% obese) prospectively recruited during the pregnancy, who underwent a 75 g – 2 h oral glucose tolerance test (OGTT) between the 3rd and 5th months postpartum. At this time point, we tested the relationship between breastfeeding status, maternal prolactin concentrations, maternal obesity, and fasting and dynamic indices of glucose metabolism using multivariate logistic regression in a post hoc analysis of prospective observational data. During the study visit at a mean of 122 (SE 9.3) days after delivery, 47% of obese women and 68% of non-obese women were breastfeeding (p < 0.05). Lactation and higher prolactin concentrations were associated with lower prepregnancy weight and lower postpartum insulin concentrations. Prehepatic beta-cell function was decreased in both obese (mean (SD); 0.16 (0.04) vs. 0.19 (0.05), p < 0.05) and non-obese (0.12 (0.05) vs. 0.16 (0.06), p < 0.01), lactating women. Obese lactating women have significantly lower first (1135.1 (306.7) pmol/L vs. 1517.3 (475.8) pmol/L, p < 0.01) and second phase insulin secretion (mean (SD), 300.2 (70.7) pmol/L vs. 393.1 (115.5) pmol/L, p < 0.01) as shown by Stumvoll indices when comparing to obese non-lactating women. Prehepatic beta-cell function and Stumvoll 1st phase insulin secretion index, but not BMI, were independently and negatively associated with breastfeeding and circulating prolactin concentrations. Beta-cell function during lactation relates to breastfeeding and circulating prolactin concentrations independently of obesity. The well-known positive effects of lactation on maternal and offspring outcomes might reflect a causative relationship of higher breastfeeding rates in metabolically healthier women. • We found significantly decreased beta-cell function in both obese and non-obese mothers who breastfeed, when compared to non-breastfeeding mothers. • Beta-cell function is independently and negatively associated with breastfeeding and circulating prolactin concentrations. • The well-known positive effects of lactation on maternal and offspring outcomes might reflect a causative relationship of higher breastfeeding rates in metabolically healthier women. [ABSTRACT FROM AUTHOR]

OBJECTIVE: Adiponectin is an adipocyte-specific protein that has been found to be associated with insulin sensitivity and obesity. Because gestational diabetes mellitus is associated with obesity and decreased insulin sensitivity, we have analyzed plasma adiponectin levels in women with gestational diabetes mellitus. STUDY DESIGN: Twenty women with gestational diabetes mellitus and 21 unaffected women were included in the study. Plasma adiponectin levels were analyzed with the use of enzyme-linked immunosorbent assay. RESULTS: Women with gestational diabetes mellitus were significantly older (34.3 years vs 29.4 years; P < .001) than unaffected women. Adiponectin plasma levels were significantly lower in women with gestational diabetes mellitus when compared with women without gestational diabetes mellitus (5827 +/- 1988 ng/mL vs 8085 +/- 3816 ng/mL; P = .02). Adiponectin plasma levels were correlated negatively with plasma glucose concentrations of the oral glucose tolerance test ( r > -0.38; P < .04) and correlated positively with gestational age ( r = 0.36; P = .03). CONCLUSION: Our data show that decreased plasma adiponectin levels were found in women with gestational diabetes Copyright © 2004 by Elsevier Science (USA). [ABSTRACT FROM AUTHOR]