The NERP-4-SNAT2 axis regulates pancreatic ß-cell maintenance and function.

Insulin secretion from pancreatic ß cells is regulated by multiple stimuli, including nutrients, hormones, neuronal inputs, and local signalling. Amino acids modulate insulin secretion via amino acid transporters expressed on ß cells. The granin protein VGF has dual roles in ß cells: regulating secretory granule formation and functioning as a multiple peptide precursor. A VGF-derived peptide, neuroendocrine regulatory peptide-4 (NERP-4), increases Ca2+ influx in the pancreata of transgenic mice expressing apoaequorin, a Ca2+-induced bioluminescent protein complex. NERP-4 enhances glucose-stimulated insulin secretion from isolated human and mouse islets and ß-cell-derived MIN6-K8 cells. NERP-4 administration reverses the impairment of ß-cell maintenance and function in db/db mice by enhancing mitochondrial function and reducing metabolic stress. NERP-4 acts on sodium-coupled neutral amino acid transporter 2 (SNAT2), thereby increasing glutamine, alanine, and proline uptake into ß cells and stimulating insulin secretion. SNAT2 deletion and inhibition abolish the protective effects of NERP-4 on ß-cell maintenance. These findings demonstrate a novel autocrine mechanism of ß-cell maintenance and function that is mediated by the peptide-amino acid transporter axis.

Impact of the lipase inhibitor orlistat on the human gut microbiota.

Orlistat, an anti-obesity agent, inhibits the metabolism and absorption of dietary fat by inactivating pancreatic lipase in the gut. The effect of orlistat on the gut microbiota of Japanese individuals with obesity is unknown. This study aimed to explore the effects of orlistat on the gut microbiota and fatty acid metabolism of Japanese individuals with obesity. Fourteen subjects with visceral fat obesity (waist circumference ≥85 cm) took orlistat orally at a dose of 60 mg, 3 times a day for 8 weeks. Body weight; waist circumference; visceral fat area; levels of short-chain fatty acids, gut microbiota, fatty acid metabolites in the feces, and gastrointestinal hormones; and adverse events were evaluated. Body weight, waist circumference, and blood leptin concentrations were significantly lower after orlistat treatment (mean ± standard deviation, 77.8 ± 9.1 kg; 91.9 ± 8.7 cm; and 4546 ± 3211 pg/mL, respectively) compared with before treatment (79.4 ± 9.0 kg; 94.4 ± 8.0 cm; and 5881 ± 3526 pg/mL, respectively). Significant increases in fecal levels of fatty acid metabolites (10-hydroxy-cis-12-octadecenoic acid, 10-oxo-cis-12-octadecenoic acid, and 10-oxo-trans-11-octadecenoic acid) were detected. Meanwhile, no significant changes were found in abdominal computed tomography parameters, blood marker levels, or short-chain fatty acid levels in the feces. Gut microbiota analysis revealed that some study subjects had decreased abundance of Firmicutes, increased abundance of Bacteroidetes, and increased α-diversity indices (Chao1 and ACE) after 8 weeks of treatment. The levels of Lactobacillus genus and Lactobacillus gasseri were significantly higher after 8 weeks of treatment. None of the subjects discontinued treatment or experienced severe adverse events. This study suggested that orlistat might alter gut microbiota composition and affect the body through fatty acid metabolites produced by the modified gut bacteria.

Iliopsoas muscle to visceral fat ratio on CT predicts Cushing's syndrome in elderly females with adrenal tumors.

There is no computed tomography (CT)-based numerical index for predicting Cushing's syndrome (CS) in patients with adrenal incidentalomas. We tested the hypothesis that the iliopsoas muscle (Ip-M) to visceral fat (V-fat) ratio (IVR) on CT may predict CS in elderly female patients with adrenal tumors. We examined the V-fat area, subcutaneous fat (S-fat) area, Ip-M area, V-fat/S-fat ratio, and IVR at the third lumbar vertebra (L3) level using abdominal CT in female patients aged ≥50 years with cortisol-producing adrenal tumor diagnosed with CS or non-functioning adrenal tumor (NFT) in the derivation cohort. We performed receiver operating characteristic (ROC) analysis to evaluate the diagnostic value of the V-fat/S-fat ratio and IVR for predicting CS. We assessed the usefulness of the IVR in a separate validation cohort. In the derivation cohort, the IVR was significantly lower in the 9 patients with CS than in the 15 patients with NFT (p < 0.001). In ROC analysis with a cut-off value of 0.067, the IVR showed a sensitivity of 100%, specificity of 80.0%, positive likelihood ratio (PLR) of 5.000, and negative likelihood ratio (NLR) of 0.000. The area under the curve was significantly higher for the IVR than for the V-fat/S-fat ratio (0.933 vs. 0.704, respectively, p = 0.036). In 23 patients in the validation cohort, the IVR demonstrated a PLR of 5.714 and an NLR of 0.327. The novel IVR index, based on single-slice CT at the L3 level, predicted CS in elderly female patients with adrenal tumors.

Association of Serum Levels of Cholesterol Absorption and Synthesis Markers with the Presence of Cardiovascular Disease: The CACHE Study CVD Analysis.

AIM: Serum levels of cholesterol absorption and synthesis markers have been associated with cardiovascular risk in the United States and European countries. In this study, we examined the relevance of these biomarkers and the presence of cardiovascular disease (CVD) in Japanese individuals. METHODS: The CACHE consortium, comprising of 13 research groups in Japan possessing data on campesterol, an absorption marker, and lathosterol, a synthesis marker measured by gas chromatography, compiled the clinical data using the REDCap system. RESULTS: Among the 2,944 individuals in the CACHE population, those with missing campesterol or lathosterol data were excluded. This cross-sectional study was able to analyze data from 2,895 individuals, including 339 coronary artery disease (CAD) patients, 108 cerebrovascular disease (CeVD) patients, and 88 peripheral artery disease (PAD) patients. The median age was 57 years, 43% were female, and the median low-density lipoprotein cholesterol and triglyceride levels were 118 mg/dL and 98 mg/dL, respectively. We assessed the associations of campesterol, lathosterol, and the ratio of campesterol to lathosterol (Campe/Latho ratio) with the odds of CVD using multivariable-adjusted nonlinear regression models. The prevalence of CVD, especially CAD, showed positive, inverse, and positive associations with campesterol, lathosterol, and the Campe/Latho ratio, respectively. These associations remained significant even after excluding individuals using statins and/or ezetimibe. The associations of the cholesterol biomarkers with PAD were determined weaker than those with CAD. Contrarily, no significant association was noted between cholesterol metabolism biomarkers and CeVD. CONCLUSION: This study showed that both high cholesterol absorption and low cholesterol synthesis biomarker levels were associated with high odds of CVD, especially CAD.

Liver-Expressed Antimicrobial Peptide 2 Is a Hepatokine That Predicts Weight Loss and Complete Remission of Type 2 Diabetes Mellitus after Vertical Sleeve Gastrectomy in Japanese Individuals.

INTRODUCTION: Vertical sleeve gastrectomy (VSG) is considered one of the most effective treatments for sustained weight loss and complete remission of type 2 diabetes mellitus (CR-T2DM). Liver-expressed antimicrobial peptide 2 (LEAP2), a ghrelin receptor antagonist peptide, is a metabolic hormone regulated by VSG. However, it is unknown whether LEAP2 can be used to predict the outcomes of VSG. This study aimed to evaluate LEAP2 as a predictive factor for weight loss and CR-T2DM after VSG. METHODS: This retrospective study included 39 Japanese participants with obesity who underwent VSG. Serum LEAP2, des-acyl ghrelin (DAG), and other metabolic and anthropometric parameters were studied before and at 12 months after VSG. Receiver operating characteristics (ROC) curve was generated to evaluate predictive score for weight loss with cut-off value of >50 percent excess weight loss. ROC curve was also generated to assess CR-T2DM. RESULTS: Serum LEAP2 levels were significantly higher in participants with body mass index (BMI) 32-50 kg/m2 than in those with normal weight. Participants with BMI >50 kg/m2 had lower serum LEAP2 concentrations than those with BMI 32-50 kg/m2. VSG caused a significant reduction in serum DAG concentrations, but it did not affect serum LEAP2 concentrations in either male or female participants. Preoperative serum LEAP2 concentration of 2.88 pmol/mL was the optimal cutoff value for predicting weight loss after VSG, with sensitivity of 80.0% and specificity of 75.9%. Preoperative serum LEAP2 level higher than 4.67 pmol/mL predicted CR-T2DM after VSG with sensitivity of 100% and specificity of 58.8%. CONCLUSION: Preoperative serum LEAP2 could predict weight loss and CR-T2DM as outcomes of VSG.

Serum Values of Cholesterol Absorption and Synthesis Biomarkers in Japanese Healthy Subjects: The CACHE Study HEALTHY Analysis.

AIM: Blood cholesterol absorption and synthesis biomarkers predict cardiovascular risk. This study aimed to determine the values of serum non-cholesterol sterol markers [lathosterol (Latho), campesterol (Campe), and sitosterol (Sito)] in healthy individuals and factors affecting these markers. METHODS: The CACHE Consortium compiled clinical data, including serum Latho (cholesterol synthesis marker), and Campe and Sito (cholesterol absorption markers), by a gas chromatography method in 2944 individuals. Healthy subjects were selected by excluding those with prior cardiovascular disease, diabetes mellitus, hypertension, chronic kidney disease, familial hypercholesterolemia, sitosterolemia, current smokers, those with low (＜17 kg/m2) or high (≥ 30 kg/m2) body mass index (BMI), and those with treatment for dyslipidemia or hyperuricemia. Nonlinear regression stratified by sex was used to examine the associations of cholesterol metabolism markers with age, BMI, and serum lipid levels. RESULTS: Of 479 individuals selected, 59.4% were female; the median age was 48 years in females and 50 years in males. The three markers showed positively skewed distributions, and sex differences were present. Age was associated positively with Latho, inversely with Campe, but not significantly with Sito. BMI was associated positively with Latho, but not significantly with Campe or Sito. High-density lipoprotein cholesterol (HDL-C) was positively associated with Campe and Sito, but not significantly with Latho. Non-HDL-C was positively associated with the three markers. CONCLUSION: Our study results in the healthy subjects help to interpret the non-cholesterol sterol markers for cardiovascular risk assessment in patients with cardiovascular risk factors.

Association between Familial Hypercholesterolemia and Serum Levels of Cholesterol Synthesis and Absorption Markers: The CACHE Study FH Analysis.

AIM: Serum levels of cholesterol absorption and synthesis markers are known to be associated with cardiovascular risk. Familial hypercholesterolemia (FH) is a well-known inherited disorder presenting elevated low-density lipoprotein cholesterol (LDL-C) and total cholesterol (TC) levels and premature coronary disease. In this study, we aim to examine the differences in terms of serum markers of cholesterol metabolism between FH and non-FH individuals and to examine their associations with serum lipid levels. METHODS: In this study, we utilized data on serum markers of cholesterol metabolism, namely, lathosterol (Latho, synthesis marker), campesterol (Campe, absorption marker), and sitosterol (Sito, absorption marker) measured by gas chromatography of the CACHE consortium, which comprised of 13 research groups in Japan. Clinical data were compiled using REDCap system. Among the 2944 individuals in the CACHE population, we selected individuals without lipid-lowering medications and hemodialysis patients for this CACHE study FH analysis. Multivariable adjustment was performed to assess the associations. RESULTS: In this study, we analyzed data from 51 FH patients and 1924 non-FH individuals. After adjustment for possible confounders, the FH group was shown to have significantly higher Campe and Sito concentrations and insignificantly higher Latho concentrations than the non-FH group. These marker concentrations showed nonlinear associations with TC in the FH group. Campe/Latho and Sito/Latho ratios were significantly higher in the FH group than in the non-FH group. CONCLUSION: FH group had significantly elevated serum Campe and Sito concentrations and insignificantly elevated Latho concentrations; thus, intestinal cholesterol absorption relative to hepatic cholesterol synthesis was suggested to be elevated in patients with FH. Serum Latho, Campe, and Sito concentrations showed nonlinear associations with TC in the FH group.

Active Consumption of Konjac and Konjac Products Improves Blood Glucose Control in Patients with Type 2 Diabetes Mellitus.

OBJECTIVE: Konjac is a food mainly consumed in Asian countries with high fiber and low energy. Although glucomannan, a component of konjac, have been used for several clinical studies, there is few reports using konjac itself. This study examined the effects of the active consumption of konjac in patients with type 2 diabetes mellitus (T2DM). METHODS: The study included 26 Japanese patients with T2DM. Participants were recommended to take konjac at least once a day using free konjac products (various noodles, rice, and desserts) and plate konjac for 12 weeks. RESULTS: HbA1c and fasting plasma glucose levels significantly decreased from 8.3 ± 0.9% to 8.0 ± 0.8% and from 173.2 ± 44.4 to 152.8 ± 36.7 mg/dL, respectively. No significant changes were observed in body weight and insulin resistance indices, but the index for insulin secretion significantly increased. Serum high molecular weight adiponectin levels significantly increased. Plasma ghrelin, leptin and glucagon-like peptide-1 levels tended to decrease (p = 0.084), decrease (p = 0.057) and increase (p = 0.071), respectively. Actual konjac intake positively correlated with age (r = 0.61, p = 0.001). Body weight and HbA1c significantly decreased in patients aged ≥50 years than in those aged <50 years, and the changes significantly inversely correlated with age. CONCLUSION: Active consumption of konjac and konjac products seems to be a useful dietary therapy with multifaceted action for T2DM. Further studies with greater sample size and long-term are needed to confirm these findings.

Relationship between Diabetes Mellitus and Serum Lathosterol and Campesterol Levels: The CACHE Study DM Analysis.

AIM: Risk of cardiovascular disease is increased in patients with diabetes mellitus (DM). Cholesterol metabolism (hepatic synthesis and intestinal absorption) is known to be associated with cardiovascular risk. Next, we examined the association of DM with cholesterol absorption/synthesis. METHODS: The CACHE Consortium, which is comprised of 13 research groups in Japan possessing data of lathosterol (Latho, synthesis marker) and campesterol (Campe, absorption marker) measured by gas chromatography, compiled the clinical data using the REDCap system. Among the 3597 records, data from 2944 individuals were used for several analyses including this study. RESULTS: This study analyzed data from eligible 2182 individuals including 830 patients with DM; 42.2% were female, median age was 59 years, and median HbA1c of patients with DM was 7.0%. There was no difference in Latho between DM and non-DM individuals. Campe and Campe/Latho ratio were significantly lower in DM individuals than in non-DM individuals. When the associations of glycemic control markers with these markers were analyzed with multivariable-adjusted regression model using restricted cubic splines, Campe and Campe/Latho ratio showed inverse associations with glucose levels and HbA1c. However, Latho showed an inverted U-shaped association with plasma glucose, whereas Latho showed a U-shaped association with HbA1c. These associations remained even after excluding statin and/or ezetimibe users. CONCLUSION: We demonstrated that DM and hyperglycemia were independent factors for lower cholesterol absorption marker levels regardless of statin/ezetimibe use.

Regulation of feeding and therapeutic application of bioactive peptides.

Obesity and obesity-related diseases, such as diabetes mellitus and dyslipidemia, are worldwide pandemics; therefore, studies have been conducted energetically to elucidate the mechanism of obesity and develop anti-obesity drugs. Robust progress in the peptide chemistry and molecular biology has identified many peptides that regulate appetite and energy metabolism over the past dozen years. Several drugs, such as analogs or receptor agonists of anorectic peptides, have been developed. Overall, peptide-related drugs have powerful anti-obesity effects with fewer adverse effects than previous anti-obesity drugs. Liraglutide, a glucagon-like peptide-1 receptor agonist, was first used as an antidiabetic drug, and then high-dose liraglutide was used as an anti-obesity drug. Several candidates have been developed to explore their anti-obesity effects. Additionally, hybrid peptides consisting of two or more peptide sequences with strong anorectic effects have been designed. Here, we review peptides that are important for feeding regulation in terms of their mechanisms of action, interactions, and clinical application as anti-obesity drugs.

Identification of ENPP1 Haploinsufficiency in Patients With Diffuse Idiopathic Skeletal Hyperostosis and Early-Onset Osteoporosis.

Homozygous ENPP1 mutations are associated with autosomal recessive hypophosphatemic rickets type 2 (ARHR2), severe ossification of the spinal ligaments, and generalized arterial calcification of infancy type 1. There are a limited number of reports on phenotypes associated with heterozygous ENPP1 mutations. Here, we report a series of three probands and their families with heterozygous and compound heterozygous ENPP1 mutations. The first case (case 1) was a 47-year-old male, diagnosed with early-onset osteoporosis and low-normal serum phosphate levels, which invoked suspicion for hypophosphatemic rickets. The second and third cases were 77- and 54-year-old females who both presented with severe spinal ligament ossification and the presumptive diagnosis of diffuse idiopathic skeletal hyperostosis (DISH). Upon workup, fibroblast growth factor 23 (FGF23) was noted to be relatively high in case 2 and serum phosphorous was low-normal in case 3, and the diagnoses of X-linked hypophosphatemic rickets (XLH) and ARHR2 were considered. Genetic testing for genes related to congenital hypophosphatemic rickets was therefore performed, revealing heterozygous ENPP1 variants in cases 1 and 2 (case 1, c.536A>G, p.Asn179Ser; case 2, c.1352A>G, p.Tyr451Cys) and compound heterozygous ENPP1 variants in case 3 constituting the same variants present in cases 1 and 2 (c.536A>G, p.Asn179Ser and c.1352A>G, p.Tyr451Cys). Several in silico tools predicted the two variants to be pathogeneic, a finding confirmed by in vitro biochemical analysis demonstrating that the p.Asn179Ser and p.Tyr451Cys ENPP1 variants possessed a catalytic velocity of 45% and 30% compared with that of wild-type ENPP1, respectively. Both variants were therefore categorized as pathogenic loss-of-function mutations. Our findings suggest that ENPP1 mutational status should be evaluated in patients presenting with the diagnosis of idiopathic DISH, ossification of the posterior longitudinal ligament (OPLL), and early-onset osteoporosis. © 2022 American Society for Bone and Mineral Research (ASBMR).

Association of Kidney Function with Serum Levels of Cholesterol Absorption and Synthesis Markers: The CACHE Study CKD Analysis.

AIM: Serum levels of cholesterol absorption and synthesis markers are known to be associated with cardiovascular risk. Individuals with reduced kidney function or chronic kidney disease (CKD) are at an increased risk for cardiovascular disease. Hence, we examined the relationship between estimated glomerular filtration rate (eGFR) and serum markers of cholesterol absorption and synthesis. METHODS: The CACHE (Cholesterol Absorption and Cholesterol synthesis in High-risk patiEnts) Consortium, comprised of 13 research groups in Japan possessing data of lathosterol (Latho, synthesis marker) and campesterol (Campe, absorption marker) measured via gas chromatography, compiled the clinical data using the REDCap system. Among the 3597 records, data from 2944 individuals were utilized for five analyses including this CKD analysis. RESULTS: This study analyzed data from 2200 individuals including 522 hemodialysis patients; 42.3% were female, the median age was 58 years, and the median eGFR was 68.9 mL/min/1.73 m2. Latho, Campe, and Campe/Latho ratio were significantly different when compared across CKD stages. When the associations of eGFR with these markers were assessed with multivariable nonlinear regression models, Latho, Campe, and Campe/Latho ratio showed positive, inverse, and inverse associations with eGFR. These associations were significantly modified by sex, the presence/absence of diabetes mellitus, and the presence/absence of statin use. CONCLUSION: We showed that individuals with lower eGFR have lower cholesterol synthesis marker levels and higher cholesterol absorption marker levels in this large sample.

Liver-expressed antimicrobial peptide 2 functions independently of growth hormone secretagogue receptor in calorie-restricted mice.

Ghrelin is a gastric-derived peptide that stimulates feeding, blood glucose elevation, body temperature reduction, and growth hormone (GH) secretion. Liver-expressed antimicrobial peptide 2 (LEAP2) is an endogenous antagonist of the ghrelin receptor, also called growth hormone secretagogue receptor (GHSR). We studied the effects of LEAP2 administration on feeding, body weight, glycemia, body temperature, and inflammation-related genes in the liver in C57BL/6 J mice and Ghsr-knockout (Ghsr-KO) mice. We found that a single administration of LEAP2 did not abolish fasting-induced food intake in 24-h fasted C57BL/6 J mice or Ghsr-KO mice. Moreover, continuous LEAP2 administration to mice fed ad libitum for 6 days did not affect feeding, body temperature, plasma ghrelin, or blood glucose. By contrast, continuous LEAP2 administration to calorie-restricted C57BL/6 J mice and Ghsr-KO mice induced body weight loss, hypoglycemia, body temperature reduction, and upregulation of Il-6 and Il-1ß mRNAs in the liver. Our findings suggest that LEAP2 functions independently of GHSR, implying that LEAP2 affects physiology beyond the ghrelin-GHSR system.

Current status of diabetes treatment in Miyazaki Prefecture, Japan: Results of a questionnaire survey conducted in 2016 and 2020.

AIMS/INTRODUCTION: The Japanese diabetes treatment guidelines do not specify the first choice of hypoglycemic agents, unlike those of Western countries. Furthermore, the current situation in diabetes treatment is that the choice of hypoglycemic agents is determined by each physician. Therefore, we aimed to determine the current situation in Miyazaki Prefecture, Japan, in this context. For this, we carried out a questionnaire survey among physicians twice regarding the target value of glycated hemoglobin and the choice of hypoglycemic agents in various cases. MATERIALS AND METHODS: We administered an unsigned questionnaire to physicians in Miyazaki Prefecture, Japan, in July 2016 and March 2020. We divided responses into those of diabetologists and those of non-diabetologists, and analyzed each response. We then compared the results between both years. RESULTS: In total, 18 diabetologists and 142 non-diabetologists responded in 2016, and 21 diabetologists and 134 non-diabetologists responded in 2020. Many diabetologists chose biguanide as the first-line drug for obese type 2 diabetes patients. In addition, the rate of choice of sodium-glucose cotransporter 2 inhibitor (SGLT2i) among physicians almost increased in 2020. Some non-diabetologists, and even a few diabetologists, inappropriately chose SGLT2i and biguanide for patients with severe renal dysfunction. CONCLUSIONS: Because SGLT2i became available in 2016 and a few years have passed, both diabetologists and non-diabetologists seemed to refrain from prescribing SGLT2i. However, with the emergence of various lines of firm evidence regarding the use of SGLT2i, physicians started to prescribe it. However, some diabetologists and non-diabetologists chose hypoglycemic agents inadequately; therefore, there is a need for novel and precise information.

GHS-R1a deficiency mitigates lipopolysaccharide-induced lung injury in mice via the downregulation of macrophage activity.

Acute respiratory distress syndrome (ARDS) is a critical illness syndrome characterized by dysregulated pulmonary inflammation. Currently, effective pharmacological treatments for ARDS are unavailable. Ghrelin, an endogenous ligand for the growth hormone secretagogue receptor type 1a (GHS-R1a), has a pivotal role in regulating energy metabolism and immunomodulation. The role of endogenous ghrelin in ARDS remains unresolved. Herein, we investigated the role of endogenous ghrelin signaling by using GHS-R1a-null (ghsr-/-) mice and lipopolysaccharide (LPS)-induced ARDS model. Ghsr-/- mice survived longer than controls after LPS-induced lung injury. Ghsr-/- mice showed lower levels of pro-inflammatory cytokines and higher oxygenation levels after lung injury. The peritoneal macrophages isolated from ghsr-/- mice exhibited lower levels of cytokines production and oxygen consumption rate after LPS stimulation. Our results indicated that endogenous ghrelin plays a pivotal role in initiation and continuation in acute inflammatory response in LPS-induced ARDS model by modulating macrophage activity, and highlighted endogenous GHS-R1a signaling in macrophage as a potential therapeutic target in this relentless disease.

Combined detection of lymphocyte clonality and MALT1 translocations in bronchoalveolar lavage fluid for diagnosing pulmonary lymphomas.

Diagnosis of pulmonary lymphoma using small tissue samples is difficult and often requires surgical procedures; thus, a less invasive sampling method is desirable. We previously showed that pulmonary mucosa-associated lymphoid tissue (MALT) lymphoma can be diagnosed by detecting MALT lymphoma translocation gene 1 (MALT1) translocations in bronchoalveolar lavage fluid (BALF) cells. Analysis of B-cell clonality based on immunoglobulin heavy chain (IGH) gene rearrangements was also reportedly useful for diagnosing pulmonary lymphoma. The aim of this prospective multicenter study was to evaluate the yet unknown diagnostic potential of combined detection of MALT1 translocations and clonality using BALF. We analyzed B- and T-cell clonality based on IGH and T-cell receptor (TCR) rearrangements together with MALT1 translocations using BALF of patients with clinically suspected pulmonary lymphomas. In total, 39 patients were evaluated and categorized into three groups: B-cell lymphoma, lymphoproliferative disorders, and other diseases. IGH rearrangement detection for B-cell lymphoma diagnosis exhibited sensitivity and specificity of 88.9% and 90.0%, respectively. TCR rearrangements were not observed in patients with B-cell lymphomas. The presence of IGH rearrangements together with the absence of TCR rearrangements indicated 96.0% specificity for the diagnosis of B-cell lymphoma. The sensitivity and specificity of MALT1 translocations for diagnosing MALT lymphoma were 28.6% and 100%, respectively. The combined detection of lymphocyte clonality and MALT1 translocations using BALF is suitable for screening and diagnosis of B-cell lymphomas. Analysis of specific genes such as MALT1 should improve the precision of B-cell lymphoma diagnosis.

ERAD components Derlin-1 and Derlin-2 are essential for postnatal brain development and motor function.

Derlin family members (Derlins) are primarily known as components of the endoplasmic reticulum-associated degradation pathway that eliminates misfolded proteins. Here we report a function of Derlins in the brain development. Deletion of Derlin-1 or Derlin-2 in the central nervous system of mice impaired postnatal brain development, particularly of the cerebellum and striatum, and induced motor control deficits. Derlin-1 or Derlin-2 deficiency reduced neurite outgrowth in vitro and in vivo and surprisingly also inhibited sterol regulatory element binding protein 2 (SREBP-2)-mediated brain cholesterol biosynthesis. In addition, reduced neurite outgrowth due to Derlin-1 deficiency was rescued by SREBP-2 pathway activation. Overall, our findings demonstrate that Derlins sustain brain cholesterol biosynthesis, which is essential for appropriate postnatal brain development and function.

Transition From Distinct Types of KRAS Mutation-Harboring Multifocal Lung Adenocarcinoma to Rhabdoid Tumor: A Longitudinal Follow-Up.

BACKGROUND Rhabdoid tumor (RT) of the lung is a rare and aggressive malignancy. The origin of and the mutation responsible for RT are entirely unknown. The distinction between RT associated with subtypes of lung cancer and SMARCA4-deficient thoracic sarcomas is also unknown. CASE REPORT Three pulmonary subsolid nodules in the right S6, left S6, and left S8 were identified in a 78-year-old Japanese woman. At 3 and 9 months later, a chest CT showed unchanged sizes, but at 15 months the development of a 37-mm mass in the right S6 was observed. The patient's systemic condition deteriorated rapidly, and she died 1 month later. An autopsy revealed that the mass consisted of 90% RT and 10% lung adenocarcinoma. There were another 2 adenocarcinoma lesions in the left lung. KRAS mutation analyses revealed the same KRAS mutation (G12D) in the adenocarcinoma and RT components in the identical mass and metastatic RT, indicating that all of these components had the same clonality. A different KRAS mutation in each of the 3 adenocarcinoma lesions was detected (right S6: G12D, left S6: A59G, left S8: G12C), indicating that the multiple adenocarcinoma lesions were truly multifocal lung adenocarcinoma. The adenocarcinoma and RT components retained SMARCA4 expression. CONCLUSIONS This is the first evidence of RT originating from multifocal lung adenocarcinoma. KRAS mutation is thought to be responsible for the RT's emergence via the epithelial-mesenchymal transition. Patients with multiple subsolid nodules should be followed closely; aggressive surgical intervention should be considered given concerns about the evolution of this aggressive malignancy.

[A case of hemichorea due to insular and parietal cortical infarctions].

A 70-year-old man visited our hospital with a chief complaint of involuntary movements, diagnosed as chorea, involving the right upper and lower limbs. Brain MRI showed acute cerebral infarctions involving the left insular and parietal cortices. Chorea is usually due to dysfunction of components of the basal ganglia pathways, such as the caudate nucleus or subthalamic nucleus, and is rarely caused by lesions of the insular or parietal cortex. Here, we describe a case of cerebral infarctions in the left insular and parietal cortices and chorea of the right limbs, and discuss the relationship between the mechanism of chorea and insular and parietal cortical lesions.

Neuromedin U uses Gαi2 and Gαo to suppress glucose-stimulated Ca2+ signaling and insulin secretion in pancreatic ß cells.

Neuromedin U (NMU), a highly conserved peptide in mammals, is involved in a wide variety of physiological processes, including impairment of pancreatic ß-cell function via induction of mitochondrial dysfunction and endoplasmic reticulum (ER) stress, ultimately suppressing insulin secretion. NMU has two receptors, NMU receptor 1 (NMUR1) and NMUR2, both of which are G-protein-coupled receptors (GPCRs). Only NMUR1 is expressed in mouse islets and ß cell-derived MIN6-K8 cells. The molecular mechanisms underlying the insulinostatic action mediated by NMUR1 in ß cells have yet to be elucidated. In this study, we explored the molecular mechanism driving impairment of insulin secretion in ß cells by the NMU-NMUR1 axis. Pretreatment with the Gαi/o inhibitor Bordetella pertussis toxin (PTX), but not the Gαq inhibitor YM254890, abolished NMU-induced suppression of glucose-stimulated insulin secretion and calcium response in ß cells. Knockdown of Gαi2 and Gαo in ß cells counteracted NMU-induced suppression of insulin secretion and gene alterations related to mitochondrial fusion (Mfn1, Mfn2), fission (Fis1, Drp1), mitophagy (Pink1, Park2), mitochondrial dynamics (Pgc-1α, Nrf1, and Tfam), ER stress (Chop, Atp2a3, Ryr2, and Itpr2), intracellular ATP level, and mitochondrial membrane potential. NMU decreased forskolin-stimulated intracellular cAMP in both mouse and human islets. We concluded that NMUR1 coupled to PTX-sensitive Gαi2 and Gαo proteins in ß cells reduced intracellular Ca2+ influx and cAMP level, thereby causing ß-cell dysfunction and impairment. These results highlight a novel signaling mechanism of NMU and provide valuable insights into the further investigation of NMU functions in ß-cell biology.