Pathogenic mutations in the appetite-regulating melanocortin-4 receptor (MC4R) represent the most common cause of monogenic obesity with limited treatment options. Glucagon-like peptide-1 receptor ...agonists (GLP-1 RAs) cause weight loss by reducing appetite. We assessed the effect of the GLP-1 RA liraglutide 3.0 mg for 16 weeks in 14 obese individuals with pathogenic MC4R mutations (BMI 37.5 ± 6.8) and 28 matched control participants without MC4R mutation (BMI 36.8 ± 4.8). Liraglutide decreased body weight by 6.8 kg ± 1.8 kg in individuals with pathogenic MC4R mutations and by 6.1 kg ± 1.2 kg in control participants. Total body fat, waist circumference, and fasting and postprandial glucose concentrations similarly decreased in both groups. Thus, liraglutide induced an equal, clinically significant weight loss of 6% in both groups, indicating that the appetite-reducing effect of liraglutide is preserved in MC4R causal obesity and that liraglutide acts independently of the MC4R pathway. Thus, liraglutide could be an effective treatment of the most common form of monogenic obesity.
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•Fully functional MC4Rs are not required for GLP-1 RA-mediated weight loss•Liraglutide caused a 6% weight loss in patients with MC4R mutations and controls•Fat mass, waist circumference, and glucose concentrations improved with treatment•Liraglutide is an effective treatment of the most common form of monogenic obesity
Iepsen et al. show that the diabetes and obesity drug liraglutide, which has appetite-suppressing effects, caused weight loss in obese patients with mutations in the appetite-regulating melanocortin-4 receptor (MC4R). These results show that the appetite effects of liraglutide are independent of the MC4R pathway and offer therapeutic opportunities for patients with MC4R causal obesity.
Abstract
Context
Hyperglucagonemia may develop in type 2 diabetes due to obesity-prone hepatic steatosis (glucagon resistance). Markers of glucagon resistance (including the glucagon-alanine index) ...improve following diet-induced weight loss, but the partial contribution of lowering hepatic steatosis vs body weight is unknown.
Objective
This work aimed to investigate the dependency of body weight loss following a reduction in hepatic steatosis on markers of glucagon resistance in type 2 diabetes.
Methods
A post hoc analysis was conducted from 2 previously published randomized controlled trials. We investigated the effect of weight maintenance (study 1: isocaloric feeding) or weight loss (study 2: hypocaloric feeding), both of which induced reductions in hepatic steatosis, on markers of glucagon sensitivity, including the glucagon-alanine index measured using a validated enzyme-linked immunosorbent assay and metabolomics in 94 individuals (n = 28 in study 1; n = 66 in study 2). Individuals with overweight or obesity with type 2 diabetes were randomly assigned to a 6-week conventional diabetes (CD) or carbohydrate-reduced high-protein (CRHP) diet within both isocaloric and hypocaloric feeding-interventions.
Results
By design, weight loss was greater after hypocaloric compared to isocaloric feeding, but both diets caused similar reductions in hepatic steatosis, allowing us to investigate the effect of reducing hepatic steatosis with or without a clinically relevant weight loss on markers of glucagon resistance. The glucagon-alanine index improved following hypocaloric, but not isocaloric, feeding, independently of macronutrient composition.
Conclusion
Improvements in glucagon resistance may depend on body weight loss in patients with type 2 diabetes.
Objective
To develop recommendations for prevention and treatment of glucocorticoid‐induced osteoporosis (GIOP).
Methods
We conducted a systematic review to synthesize the evidence for the benefits ...and harms of GIOP prevention and treatment options. The Grading of Recommendations Assessment, Development and Evaluation methodology was used to rate the quality of evidence. We used a group consensus process to determine the final recommendations and grade their strength. The guideline addresses initial assessment and reassessment in patients beginning or continuing long‐term (≥3 months) glucocorticoid (GC) treatment, as well as the relative benefits and harms of lifestyle modification and of calcium, vitamin D, bisphosphonate, raloxifene, teriparatide, and denosumab treatment in the general adult population receiving long‐term GC treatment, as well as in special populations of long‐term GC users.
Results
Because of limited evidence regarding the benefits and harms of interventions in GC users, most recommendations in this guideline are conditional (uncertain balance between benefits and harms). Recommendations include treating only with calcium and vitamin D in adults at low fracture risk, treating with calcium and vitamin D plus an additional osteoporosis medication (oral bisphosphonate preferred) in adults at moderate‐to‐high fracture risk, continuing calcium plus vitamin D but switching from an oral bisphosphonate to another antifracture medication in adults in whom oral bisphosphonate treatment is not appropriate, and continuing oral bisphosphonate treatment or switching to another antifracture medication in adults who complete a planned oral bisphosphonate regimen but continue to receive GC treatment. Recommendations for special populations, including children, people with organ transplants, women of childbearing potential, and people receiving very high‐dose GC treatment, are also made.
Conclusion
This guideline provides direction for clinicians and patients making treatment decisions. Clinicians and patients should use a shared decision‐making process that accounts for patients’ values, preferences, and comorbidities. These recommendations should not be used to limit or deny access to therapies.
Objective
To develop recommendations for prevention and treatment of glucocorticoid‐induced osteoporosis (GIOP).
Methods
We conducted a systematic review to synthesize the evidence for the benefits ...and harms of GIOP prevention and treatment options. The Grading of Recommendations Assessment, Development and Evaluation methodology was used to rate the quality of evidence. We used a group consensus process to determine the final recommendations and grade their strength. The guideline addresses initial assessment and reassessment in patients beginning or continuing long‐term (≥3 months) glucocorticoid (GC) treatment, as well as the relative benefits and harms of lifestyle modification and of calcium, vitamin D, bisphosphonate, raloxifene, teriparatide, and denosumab treatment in the general adult population receiving long‐term GC treatment, as well as in special populations of long‐term GC users.
Results
Because of limited evidence regarding the benefits and harms of interventions in GC users, most recommendations in this guideline are conditional (uncertain balance between benefits and harms). Recommendations include treating only with calcium and vitamin D in adults at low fracture risk, treating with calcium and vitamin D plus an additional osteoporosis medication (oral bisphosphonate preferred) in adults at moderate‐to‐high fracture risk, continuing calcium plus vitamin D but switching from an oral bisphosphonate to another antifracture medication in adults in whom oral bisphosphonate treatment is not appropriate, and continuing oral bisphosphonate treatment or switching to another antifracture medication in adults who complete a planned oral bisphosphonate regimen but continue to receive GC treatment. Recommendations for special populations, including children, people with organ transplants, women of childbearing potential, and people receiving very high‐dose GC treatment, are also made.
Conclusion
This guideline provides direction for clinicians and patients making treatment decisions. Clinicians and patients should use a shared decision‐making process that accounts for patients' values, preferences, and comorbidities. These recommendations should not be used to limit or deny access to therapies.
Human cancer cells operate a variety of effective molecular and signaling mechanisms which allow them to escape host immune surveillance and thus progress the disease. We have recently reported that ...the immune receptor Tim-3 and its natural ligand galectin-9 are involved in the immune escape of human acute myeloid leukemia (AML) cells. These cells use the neuronal receptor latrophilin 1 (LPHN1) and its ligand fibronectin leucine rich transmembrane protein 3 (FLRT3, and possibly other ligands) to trigger the pathway. We hypothesized that the Tim-3-galectin-9 pathway may be involved in the immune escape of cancer cells of different origins. We found that studied breast tumors expressed significantly higher levels of both galectin-9 and Tim-3 compared to healthy breast tissues of the same patients and that these proteins were co-localized. Increased levels of LPHN2 and expressions of LPHN3 as well as FLRT3 were also detected in breast tumor cells. Activation of this pathway facilitated the translocation of galectin-9 onto the tumor cell surface, however no secretion of galectin-9 by tumor cells was observed. Surface-based galectin-9 was able to protect breast carcinoma cells against cytotoxic T cell-induced death. Furthermore, we found that cell lines from brain, colorectal, kidney, blood/mast cell, liver, prostate, lung, and skin cancers expressed detectable amounts of both Tim-3 and galectin-9 proteins. The majority of cell lines expressed one of the LPHN isoforms and FLRT3. We conclude that the Tim-3-galectin-9 pathway is operated by a wide range of human cancer cells and is possibly involved in prevention of anti-tumor immunity.
Long-lived bone marrow plasma cells (BMPCs) are a persistent and essential source of protective antibodies
. Individuals who have recovered from COVID-19 have a substantially lower risk of ...reinfection with SARS-CoV-2
. Nonetheless, it has been reported that levels of anti-SARS-CoV-2 serum antibodies decrease rapidly in the first few months after infection, raising concerns that long-lived BMPCs may not be generated and humoral immunity against SARS-CoV-2 may be short-lived
. Here we show that in convalescent individuals who had experienced mild SARS-CoV-2 infections (n = 77), levels of serum anti-SARS-CoV-2 spike protein (S) antibodies declined rapidly in the first 4 months after infection and then more gradually over the following 7 months, remaining detectable at least 11 months after infection. Anti-S antibody titres correlated with the frequency of S-specific plasma cells in bone marrow aspirates from 18 individuals who had recovered from COVID-19 at 7 to 8 months after infection. S-specific BMPCs were not detected in aspirates from 11 healthy individuals with no history of SARS-CoV-2 infection. We show that S-binding BMPCs are quiescent, which suggests that they are part of a stable compartment. Consistently, circulating resting memory B cells directed against SARS-CoV-2 S were detected in the convalescent individuals. Overall, our results indicate that mild infection with SARS-CoV-2 induces robust antigen-specific, long-lived humoral immune memory in humans.
The benefit of surgery in high‐grade gastroenteropancreatic neuroendocrine neoplasms (GEP NEN) and mixed neuroendocrine‐non‐neuroendocrine neoplasms (MiNEN) is uncertain. The present study aimed to ...investigate outcomes after tumour surgery in patients with high‐grade (Ki‐67 > 20%) GEP NEN or MiNEN stage I‐III or stage IV. We analysed data from patients treated in the period 2007‐2015 at eight Nordic university hospitals. Overall survival (OS) and progression‐free survival (PFS)/disease‐free survival (DFS) were analysed by Kaplan‐Meier estimates. Prognostic factors were evaluated using Cox regression. We included 201 surgically resected patients, 143 stage I‐III and 58 stage IV, with 68% having neuroendocrine carcinoma, 23% MiNEN, 5% neuroendocrine tumour G3 and 4% uncertain NEN G3. Primary tumours were located in colon/rectum (52%), oesophagus/cardia (19%), pancreas (10%), stomach (7%), jejunum/ileum (5%), duodenum (4%), gallbladder (2%) and anal canal (1%). For patients with stage I‐III, median DFS was 12 months (95% confidence interval CI = 5.5‐18.5) and median OS was 32 months (95% CI = 24.0‐40.0). For patients with stage I‐III and an R0 resection, median DFS was 21 months (95% CI = 4.9‐37.1) and median OS was 39 months (95% CI = 25.0‐53.0). For patients with stage IV, median PFS/DFS was 4 months (95% CI = 1.9‐6.1) and median OS was 11 months (95% CI = 4.8‐17.2). For patients with stage IV and an R0 resection, median DFS was 6 months (95% CI = 0‐16.4) and median OS was 32 months (95% CI = 25.5‐38.5). Performance status > 1 and colorectal primary were associated with poor prognosis. There was no difference in survival between patients with high‐grade GEP NEN and MiNEN. Surgery of the primary tumour in patients with loco‐regional high‐grade GEP NEN or MiNEN led to good long‐term results and should be considered if an R0 resection is considered achievable. Highly selected patients with stage IV disease may also benefit from surgery.
We present the largest study reported to date in patients undergoing surgical resection for high‐grade gastroenteropancreatic neuroendocrine neoplasms or mixed neuroendocrine‐non‐neuroendocrine neoplasms. We conclude that surgery is beneficial if an R0 resection margin can be obtained. These results may impact future clinical guidelines.
High mobility group box 1 (HMGB1) is a non-histone protein which is predominantly localised in the cell nucleus. However, stressed, dying, injured or dead cells can release this protein into the ...extracellular matrix passively. In addition, HMGB1 release was observed in cancer and immune cells where this process can be triggered by various endogenous as well as exogenous stimuli. Importantly, released HMGB1 acts as a so-called “danger signal” and could impact on the ability of cancer cells to escape host immune surveillance. However, the molecular mechanisms underlying the functional role of HMGB1 in determining the capability of human cancer cells to evade immune attack remain unclear. Here we report that the involvement of HMGB1 in anti-cancer immune evasion is determined by Toll-like receptor (TLR) 4, which recognises HMGB1 as a ligand. We found that HGMB1 induces TLR4-mediated production of transforming growth factor beta type 1 (TGF-β), displaying autocrine/paracrine activities. TGF-β induces production of the immunosuppressive protein galectin-9 in cancer cells. In TLR4-positive cancer cells, HMGB1 triggers the formation of an autocrine loop which induces galectin-9 expression. In malignant cells lacking TLR4, the same effect could be triggered by HMGB1 indirectly through TLR4-expressing myeloid cells present in the tumour microenvironment (e. g. tumour-associated macrophages).
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