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Th cells integrate signals from their microenvironment to acquire distinct specialization programs for efficient clearance of diverse pathogens or for immunotolerance. Ionic signals have recently been demonstrated to affect T cell polarization and function. Sodium chloride (NaCl) was proposed to accumulate in peripheral tissues upon dietary intake and to promote autoimmunity via the Th17 cell axis. Here, we demonstrate that high-NaCl conditions induced a stable, pathogen-specific, antiinflammatory Th17 cell fate in human T cells in vitro. The p38/MAPK pathway, involving NFAT5 and SGK1, regulated FoxP3 and IL-17A expression in high-NaCl conditions. The NaCl-induced acquisition of an antiinflammatory Th17 cell fate was confirmed in vivo in an experimental autoimmune encephalomyelitis (EAE) mouse model, which demonstrated strongly reduced disease symptoms upon transfer of T cells polarized in high-NaCl conditions. However, NaCl was coopted to promote murine and human Th17 cell pathogenicity, if T cell stimulation occurred in a proinflammatory and TGF-β-low cytokine microenvironment. Taken together, our findings reveal a context-dependent, dichotomous role for NaCl in shaping Th17 cell pathogenicity. NaCl might therefore prove beneficial for the treatment of chronic inflammatory diseases in combination with cytokine-blocking drugs.

Background Behavioral weight loss interventions are frequently hampered by long-term inefficacy. As metabolic improvements and health-related quality of life (HRQoL) are diminished by weight regain, effective long-term strategies are highly desirable. We aimed to analyze whether an additional weight maintenance intervention could delay body weight regain and can induce a long-term improvement of metabolism and HRQoL for up to 48 months in humans. Given the short-term metabolic effects of natriuretic peptides (NP), we also investigated the role of the adipose atrial NP (ANP) system in this long-term context. Methods After a successful 12-week weight reduction program 143 subjects (age>18; BMI≥27 kg/m 2 ) were randomized (1:1) to a control group or a 12-month multimodal weight maintenance intervention focusing on nutritional counseling and physical exercises. Secondary trial outcomes including course of BMI, HOMA-IR, glucose response after oGTT (glucose AUC ), and HRQoL (SF-36) were analyzed yearly for 48 months. Adipose ANP receptor mRNA expression was analyzed during weight loss. Results Initial weight loss (− 4.7±1.5 kg/m 2 ) improved glucose AUC , HOMA-IR, and HRQoL. Although BMI was still reduced after 48 months (−1.98 [95% CI −2.61, −1.35] kg/m 2 ), benefits on HOMA-IR, glucose AUC , and mental health disappeared after 36 (−0.49 [−1.00, 0.02]), 18 (0.61 [−9.57, 10.79] mg dl −1 min −1 ), and 18 months (2.06 [−0.08, 4.20]), respectively, while improved physical health persisted up to months 48 (2.95 [0.49, 5.40]). Weight maintenance intervention inhibited weight regain and delayed impairment of HOMA-IR and glucose AUC (but not HRQoL) for up to 12 months. However, no metabolic long-term effect was seen beyond the intervention period. Lower adipose NPR-C and higher NPR-A mRNA expression after weight loss predicted smaller regain of weight ( r =0.398; p <0.05)/fat mass (FM) ( r =0.391; p <0.05) and longer improvement of HOMA-IR ( r =−0.422; p <0.05), respectively. Conclusions Additional benefits of a behavioral 12-month weight maintenance intervention after weight loss regarding body weight regain and metabolic improvement does not persist beyond the intervention period. However, weight loss-induced modulation of the adipose ANP system is probably involved in the long-term control of body weight regain and insulin sensitivity. Trial registration ClinicalTrials.gov NCT00850629 . Registered on February 25, 2009.

Background Enrolment in a research study requires the participant’s informed consent. In the case of minors, informed consent of the respective legal guardian is obtained in conjunction with informed assent of the underage p articipant. Since comprehension of the information provided may be limited, effective interventions to improve understanding should be identified. Thus, it is the objective of this study to review quantitative studies that tested interventions to improve the understanding of information provided during assent processes in health research. The studied population consisted of minors that participated or were willing to participate in research. The primary outcome was the level of comprehension after intervention. Methods A systematic search was conducted in eleven databases including regional databases: PubMed, Web of Science, ERIC, PsycINFO, CINAHL, POPLINE, AIM, LILACS, WPRIM, IMSEAR, and IMEMR and included references from inception of the database until July 2018 except PubMed which spanned the period from May 2013 to July 2018. Search terms focused on Informed Consent/Assent, Minors, and Comprehension. To complement the search, reference lists of retrieved publications were additionally searched. We included all quantitative studies that were conducted in minors, tested an intervention, covered assent processes in health research, and assessed comprehension. One reviewer screened titles, abstracts, and full-texts to determine eligibility and collected data on study design, population, intervention, methods, outcome, and for critical appraisal. Interventions comprised enhanced paper forms, interspersed questions, multimedia format, and others. Results Out of 7089 studies initially identified, 19 studies comprising 2805 participants and conducted in seven countries were included in the review. Fourteen studies (74 %) tested an intervention against control and ten (53 %) were randomized controlled trials. Heterogeneous methodology as well as incomplete outcome and statistical reporting impaired the reliability of the collected data. Positive effects were suggested for use of enhanced paper forms, interspersed questions, use of pie charts, and organizational factors. Conclusions Improving assent in health research is an under-researched area with little reliable evidence. While some interventions are proposed to improve understanding in assent processes, further investigation is necessary to be able to give evidence-based recommendations. Trial registration PROSPERO ID: 106808 .

Background While short-term effects of weight loss on quality of life and metabolic aspects appear to be different in metabolically healthy (MHO) and metabolically unhealthy obese (MUO), respective long-term data is still missing. Given the high relevance of long-term changes, we aimed to address these in this post-hoc analysis of the MAINTAIN trial. Methods We analyzed 143 overweight/obese subjects (BMI ≥ 27 kg/m 2 , age ≥ 18 years) before and after a 3-month weight loss program (≥ 8% weight loss), after a 12-month period of a randomized weight maintenance intervention (n = 121), and after another 6 months without intervention (n = 112). Subjects were retrospectively grouped into MHO and MUO by the presence of metabolic syndrome and secondarily by estimates of insulin sensitivity (HOMA-IR and ISI Clamp ). Quality of life (QoL), blood pressure, lipids, HOMA-IR, and ISI Clamp were assessed and evaluated using mixed model analyses. Results Despite similar short- and long-term weight loss, weight loss-induced improvement of HOMA-IR was more pronounced in MUO than MHO after 3 months (MHO: 2.4[95%-CI: 1.9–2.9] vs. 1.6[1.1–2.1], p  = 0.004; MUO: 3.6[3.2–4.0] vs. 2.0[1.6–2.4], p  < 0.001; p  = 0.03 for inter-group comparison). After 21 months, the beneficial effect was no longer seen in MHO (2.0[1.5–2.6], p  = 1.0), while it remained partially preserved in MUO (2.9[2.4–3.3], p  = 0.002). QueryShort-term improvements of lipid parameters were similar in both groups. However, long-term improvements of HDL-cholesterol and triglycerides were only seen in MUO (44.4[41.5–47.4] vs. 49.3[46.2, 52.3] mg/dl, p  < 0.001; 176.8[158.9–194.8] vs. 138.8[119.4–158.3] mg/dl, p  < 0.001, respectively) but not in MHO. Weight loss-induced improvements in the QoL and particularly the physical health status were maintained in MUO until the end of the trial, while benefits disappeared over time in MHO. Group allocation by HOMA-IR and ISI Clamp revealed higher benefits for MUO mainly in parameters of the glucose metabolism and QoL. Conclusions Our data demonstrates stronger and longer-lasting improvements of metabolism and QoL in MUO after weight loss. Trial registration (ClinicalTrials.gov): NCT00850629. Registered 25 February 2009, https://clinicaltrials.gov/ct2/show/NCT00850629 .

Introduction: Neuropilin 1 (NRP-1) is a novel co-receptor promoting SARS-CoV-2 infectivity. Animal data indicate a role in trans-endothelial lipid transport and storage. As human data are sparse, we aimed to assess the role of NRP-1 in 2 metabolic active tissues in human obesity and in the context of weight loss-induced short- and long-term metabolic changes. Methods: After a standardized 12-week weight reduction program, 143 subjects (age >18; body mass index ≥27 kg/m 2 , 78% female) were randomized to a 12-month lifestyle intervention or a control group using a stratified randomization scheme. This was followed by 6-month follow-up without any intervention. Phenotyping was performed before and after weight loss, after 12-month intervention and after subsequent 6 months of follow-up. Tissue-specific insulin sensitivity was estimated by HOMA-IR (whole body and mostly driven by liver), insulin sensitivity index (ISI) Clamp (predominantly skeletal muscle), and free fatty acid (FFA) suppression during hyperinsulinemic-euglycemic clamp (FFA Supp ) (predominantly adipose tissue). NRP-1 mRNA expression was measured in subcutaneous adipose tissue (NRP-1 AT ) and skeletal muscle (NRP-1 SM ) before and after weight loss. Results: NRP-1 was highly expressed in adipose tissue (7,893 [7,303–8,536] counts), but neither NRP-1 AT nor NRP-1 SM were related to estimates of obesity. Higher NRP-1 AT was associated with stronger FFA Supp (r = −0.343, p = 0.003) and a tendency to higher ISI Clamp (r = 0.202, p = 0.085). Weight loss induced a decline of NRP-1 AT but not NRP-1 SM . This was more pronounced in subjects with stronger reduction of adipose ACE-2 mRNA expression (r = 0.250; p = 0.032) but was not associated with short- and long-term improvement of FFA Supp and ISI Clamp . Conclusion: NRP-1 AT is related to adipose insulin sensitivity in obesity. Weight loss-induced decline of NRP-1 AT seems not to be involved in metabolic short- and long-term improvements after weight loss. However, weight loss-induced reduction of both NRP-1 AT and ACE-2 AT indicates a lower susceptibility of adipose tissue for SARS-CoV-2 after body weight reduction.

Background Anaplastic thyroid cancer (ATC) is a rare and aggressive neoplasm. We still lack effective treatment options, so survival rates remain very low. Here, we aimed to evaluate the activity of the combination of lenvatinib and pembrolizumab as systemic first-line therapy in ATC. Methods In a retrospective analysis, we investigated the activity and tolerability of combined lenvatinib (starting dose 14 to 24 mg daily) and pembrolizumab (200 mg every three weeks) as first-line therapy in an institutional cohort of ATC patients. Results Five patients with metastatic ATC received lenvatinib and pembrolizumab as systemic first-line therapy. The median progression-free survival was 4.7 (range 0.8–5.9) months, and the median overall survival was 6.3 (range 0.8-not reached) months. At the first follow-up, one patient had partial response, three patients had stable disease, and one patient was formally not evaluable due to interference of assessment by concomitant acute infectious thyroiditis. This patient was then stable for more than one year and was still on therapy at the data cutoff without disease progression. Further analyses revealed deficient DNA mismatch repair, high CD8 + lymphocyte infiltration, and low macrophage infiltration in this patient. Of the other patients, two had progressive disease after adverse drug reactions and therapy de-escalation, and two died after the first staging. For all patients, the PD-L1 combined positive score ranged from 12 to 100%. Conclusions The combination of lenvatinib and pembrolizumab was effective and moderately tolerated in treatment-naïve ATC patients with occasional long-lasting response. However, we could not confirm the exceptional responses for this combination therapy reported before in pretreated patients.

Background: Adrenocortical carcinoma (ACC) is a rare and aggressive malignancy. Complete tumor resection (R0) is critical for prognosis and may require multivisceral resection in locally advanced cases. However, data on outcomes after multivisceral resection for ACC remain limited. This study evaluates the perioperative and oncologic outcomes of patients undergoing multivisceral resection for suspected ACC. Methods: We retrospectively analyzed 21 patients who underwent multivisceral resection with curative intent for suspected ACC. Three were later diagnosed with other tumor entities (sarcoma, non-small cell lung carcinoma metastasis and ganglioneuroma). The remaining 18 patients with histologically confirmed ACC were compared with 19 patients who underwent isolated adrenalectomy during the same study period. Results: Patients undergoing multivisceral resection were significantly younger (p = 0.003), had larger (p < 0.001) and more advanced tumors according to ENSAT classification (p < 0.001). All but one had open surgery; laparoscopic or hybrid approaches were more common in the isolated adrenalectomy group. Multivisceral resections were associated with longer operative times (p = 0.002), all required an ICU admission (p < 0.001), and had longer hospital stays (p = 0.001). Lymphnode metastases were observed only in the multivisceral group (p = 0.002). No significant differences were found in complication rates (p = 0.081), resection status (p = 0.091), progression-free survival (p = 0.095), or overall survival (p = 0.71). Conclusions: Multivisceral resection is a safe and feasible approach in specialized centers and may achieve comparable oncologic outcomes to isolated adrenalectomy, even in patients with more advanced disease. It should be considered when R0 resection is required and technically achievable.

Clinical interpretation of complex biomarkers for precision oncology currently requires manual investigations of previous studies and databases. Conversational large language models (LLMs) might be beneficial as automated tools for assisting clinical decision-making. To assess performance and define their role using 4 recent LLMs as support tools for precision oncology. This diagnostic study examined 10 fictional cases of patients with advanced cancer with genetic alterations. Each case was submitted to 4 different LLMs (ChatGPT, Galactica, Perplexity, and BioMedLM) and 1 expert physician to identify personalized treatment options in 2023. Treatment options were masked and presented to a molecular tumor board (MTB), whose members rated the likelihood of a treatment option coming from an LLM on a scale from 0 to 10 (0, extremely unlikely; 10, extremely likely) and decided whether the treatment option was clinically useful. Number of treatment options, precision, recall, F1 score of LLMs compared with human experts, recognizability, and usefulness of recommendations. For 10 fictional cancer patients (4 with lung cancer, 6 with other; median [IQR] 3.5 [3.0-4.8] molecular alterations per patient), a median (IQR) number of 4.0 (4.0-4.0) compared with 3.0 (3.0-5.0), 7.5 (4.3-9.8), 11.5 (7.8-13.0), and 13.0 (11.3-21.5) treatment options each was identified by the human expert and 4 LLMs, respectively. When considering the expert as a criterion standard, LLM-proposed treatment options reached F1 scores of 0.04, 0.17, 0.14, and 0.19 across all patients combined. Combining treatment options from different LLMs allowed a precision of 0.29 and a recall of 0.29 for an F1 score of 0.29. LLM-generated treatment options were recognized as AI-generated with a median (IQR) 7.5 (5.3-9.0) points in contrast to 2.0 (1.0-3.0) points for manually annotated cases. A crucial reason for identifying AI-generated treatment options was insufficient accompanying evidence. For each patient, at least 1 LLM generated a treatment option that was considered helpful by MTB members. Two unique useful treatment options (including 1 unique treatment strategy) were identified only by LLM. In this diagnostic study, treatment options of LLMs in precision oncology did not reach the quality and credibility of human experts; however, they generated helpful ideas that might have complemented established procedures. Considering technological progress, LLMs could play an increasingly important role in assisting with screening and selecting relevant biomedical literature to support evidence-based, personalized treatment decisions.

The efficacy of antitumor immunity is associated with the metabolic state of cytotoxic T cells, which is sensitive to the tumor microenvironment. Whether ionic signals affect adaptive antitumor immune responses is unclear. In the present study, we show that there is an enrichment of sodium in solid tumors from patients with breast cancer. Sodium chloride (NaCl) enhances the activation state and effector functions of human CD8 + T cells, which is associated with enhanced metabolic fitness. These NaCl-induced effects translate into increased tumor cell killing in vitro and in vivo. Mechanistically, NaCl-induced changes in CD8 + T cells are linked to sodium-induced upregulation of Na + /K + -ATPase activity, followed by membrane hyperpolarization, which magnifies the electromotive force for T cell receptor (TCR)-induced calcium influx and downstream TCR signaling. We therefore propose that NaCl is a positive regulator of acute antitumor immunity that might be modulated for ex vivo conditioning of therapeutic T cells, such as CAR T cells. In this paper and the related paper from Lugli and colleagues the authors show that high levels of NaCl inside the tumor have a beneficial effect on CD8 + T cells and their ability to control tumor growth as a result of enhanced T cell receptor activity.

Metastatic involvement of the pituitary gland is a rare but clinically significant phenomenon, that often poses diagnostic and therapeutic challenges. The aim of this study was to provide a comprehensive analysis of the origin of pituitary metastases using data from the German Pituitary Tumor Registry, one of the globally largest collections of pituitary pathology specimens. Here, we report data from a retrospective analysis of patients with metastases to the pituitary registered between 1990 and 2022. Out of 17,896 pituitary cases in the registry during this period, a total of 96 metastases to the pituitary gland were identified, accounting for 0.5% of all pituitary tumors in the registry. The mean age of the patients was 64 years. Breast cancer was identified as the primary tumor in 25% of total cases (n = 24/96) and in 50% of female patients. The second most prevalent primary tumor was lung cancer (18.75%, n = 18/96), followed by renal cell carcinoma (14.58%, n = 14/96). In comparison to current meta-analyses, this cohort shows a higher prevalence of metastases originating from the kidney. Furthermore, in contrast to the existing literature, no case of primary thyroid tumor was identified. Our study highlights the importance of pituitary metastases as a differential diagnosis in patients presenting with pituitary tumors.