Adipose Signals Regulating Distal Organ Health and Disease.

Excessive adiposity in obesity is a significant risk factor for development of type 2 diabetes (T2D), nonalcoholic fatty liver disease, and other cardiometabolic diseases. An unhealthy expansion of adipose tissue (AT) results in reduced adipogenesis, increased adipocyte hypertrophy, adipocyte hypoxia, chronic low-grade inflammation, increased macrophage infiltration, and insulin resistance. This ultimately culminates in AT dysfunction characterized by decreased secretion of antidiabetic adipokines such as adiponectin and adipsin and increased secretion of proinflammatory prodiabetic adipokines including RBP4 and resistin. This imbalance in adipokine secretion alters the physiological state of AT communication with target organs including pancreatic ß-cells, heart, and liver. In the pancreatic ß-cells, adipokines are known to have a direct effect on insulin secretion, gene expression, cell death, and/or dedifferentiation. For instance, impaired secretion of adipsin, which promotes insulin secretion and ß-cell identity, results in ß-cell failure and T2D, thus presenting a potential druggable target to improve and/or preserve ß-cell function. The cardiac tissue is affected by both the classic white AT-secreted adipokines and the newly recognized brown AT (BAT)-secreted BATokines or lipokines that alter lipid deposition and ventricular function. In the liver, adipokines affect hepatic gluconeogenesis, lipid accumulation, and insulin sensitivity, underscoring the importance of adipose-liver communication in the pathogenesis of nonalcoholic fatty liver disease. In this perspective, we outline what is currently known about the effects of individual adipokines on pancreatic ß-cells, liver, and the heart.

A Rare Case of Abdominal Wall Skeletal Muscle Metastasis From Adenocarcinoma of the Pancreatic Head.

Pancreatic cancer can be aggressive and commonly metastasizes to various organs. Most commonly, pancreatic cancer metastasizes to the lung, liver, bones, and peritoneum, but very rarely does it spread to the abdominal wall or skeletal muscle. In this case, we discuss a patient who initially presented with weight loss and jaundice from a pancreatic head adenocarcinoma that later metastasized to the rectus abdominis muscle. A 63-year-old female presented with jaundice and weight loss. CT imaging revealed a 2.8 cm pancreatic head mass with pancreatic and biliary ductal dilation. Carbohydrate antigen 19-9 (CA 19-9) level was also found to be elevated to 1810 U/mL. An endoscopic ultrasound-guided biopsy was later performed and confirmed pancreatic adenocarcinoma. The patient underwent a Whipple pancreatoduodenectomy following initial treatment with neoadjuvant FOLFIRINOX chemotherapy. Following the Whipple procedure, she received adjuvant chemotherapy and subsequent imaging revealed no recurrence and decreased CA 19-9 level to 46 U/mL. Eight months afterward, the patient presented once again with lower abdominal pain. Repeat CA 19-9 level was found to have increased to 1503 U/mL. Repeat positron emission tomography scan imaging was performed and showed a 4.7 cm left rectus abdominis muscle mass. The mass was later biopsied, and pathology revealed recurrent, metastatic pancreatic adenocarcinoma. The patient was restarted on chemotherapy with paclitaxel and gemcitabine leading to a reduction in tumor size and CA 19-9 levels of 135 U/mL. However, surgical resection was later pursued due to increased tumor size only four months later. At this time, limited literature is available reporting the occurrence of pancreatic cancer metastasizing to the abdominal wall. Upon literature review, only five cases have been reported to date, and only two of the cases involved the skeletal muscle. Our rare case is the first-time documentation of rectus abdominis metastasis from pancreatic adenocarcinoma arising from the pancreatic head.

Esophageal Neuroendocrine Carcinoma Presenting After Definitive Chemoradiation of Squamous Cell Carcinoma in the Same Location.

Esophageal neuroendocrine carcinoma is very rare and highly aggressive. An 85-year-old man with a history of esophageal squamous cell carcinoma in remission presented 4 years after definitive chemoradiation with new-onset dysphagia. Endoscopy with biopsy revealed high-grade malignancy consistent with neuroendocrine carcinoma. Treatment options were limited to chemotherapy because of his metastatic disease, and he unfortunately died 14 months after diagnosis. The occurrence of esophageal neuroendocrine carcinoma in a site of prior squamous cell carcinoma is very uncommon, and this likely represents a case of radiation-induced malignancy. Therefore, when undergoing radiotherapy, patients and providers should discuss the possibility of this life-threatening complication.

A beta cell subset with enhanced insulin secretion and glucose metabolism is reduced in type 2 diabetes.

The pancreatic islets are composed of discrete hormone-producing cells that orchestrate systemic glucose homeostasis. Here we identify subsets of beta cells using a single-cell transcriptomic approach. One subset of beta cells marked by high CD63 expression is enriched for the expression of mitochondrial metabolism genes and exhibits higher mitochondrial respiration compared with CD63lo beta cells. Human and murine pseudo-islets derived from CD63hi beta cells demonstrate enhanced glucose-stimulated insulin secretion compared with pseudo-islets from CD63lo beta cells. We show that CD63hi beta cells are diminished in mouse models of and in humans with type 2 diabetes. Finally, transplantation of pseudo-islets generated from CD63hi but not CD63lo beta cells into diabetic mice restores glucose homeostasis. These findings suggest that loss of a specific subset of beta cells may lead to diabetes. Strategies to reconstitute or maintain CD63hi beta cells may represent a potential anti-diabetic therapy.

Cross-species single-cell comparison of systemic and cardiac inflammatory responses after cardiac injury.

The immune system coordinates the response to cardiac injury and is known to control regenerative and fibrotic scar outcomes in the heart and subsequent chronic low-grade inflammation associated with heart failure. Here we profiled the inflammatory response to heart injury using single cell transcriptomics to compare and contrast two experimental models with disparate outcomes. We used adult mice, which like humans lack the ability to fully recover and zebrafish which spontaneously regenerate after heart injury. The extracardiac reaction to cardiomyocyte necrosis was also interrogated to assess the specific peripheral tissue and immune cell reaction to chronic stress. Cardiac macrophages are known to play a critical role in determining tissue homeostasis by healing versus scarring. We identified distinct transcriptional clusters of monocytes/macrophages in each species and found analogous pairs in zebrafish and mice. However, the reaction to myocardial injury was largely disparate between mice and zebrafish. The dichotomous response to heart damage between the mammalian and zebrafish monocytes/macrophages may underlie the impaired regenerative process in mice, representing a future therapeutic target.

Endoscopic Mucosal Resection of Pancreatic Rest Presenting as a Sub-epithelial Nodule in the Gastric Antrum.

Pancreatic rest/ectopic pancreas is a rare condition. An 82-year-old male presented with abdominal pain and was found to have an antral nodule on esophagogastroduodenoscopy (EGD). An endoscopic ultrasound (EUS) was done and the nodule was resected. Histology showed ectopic pancreatic tissue with pancreatic intraepithelial neoplasia, PanIN-1 (low-grade dysplasia). This case highlights the importance of considering pancreatic rest as a differential in patients who present with a gastric sub-epithelial lesion and the associated finding of PanIN-1 highlights the importance of resecting such heterogeneous appearing lesions given the potential risk of progressing to pancreatic ductal adenocarcinoma (PDA).

A Rare Case of Synchronous Intraductal Papillary Mucinous Neoplasm-Associated Pancreatic Adenocarcinoma and Signet Ring Cell Gastric Adenocarcinoma.

BACKGROUND Synchronous malignancies are primary cancers that are diagnosed in a single individual within a 2-month period. Synchronous malignancies are uncommon, involving only 2.4-8% of all cancer cases, with a very low number of cases of simultaneous gastric and pancreatic cancer. Although cases of synchronous malignancies do exist, synchronous pancreatic adenocarcinoma and signet ring cell (SRC) gastric adenocarcinoma have not been documented. CASE REPORT A 76-year-old woman with a previously diagnosed intraductal papillary mucinous neoplasm (IPMN) presented with left-sided abdominal pain. Initial workup, including computed tomography imaging and endoscopic ultrasound with biopsy, led to the diagnosis of pancreatic adenocarcinoma. Within 1 month of diagnosis, the patient underwent an extended Whipple procedure and was also found to have a primary SRC gastric adenocarcinoma on evaluation of the gastric tissue margins that were removed during the procedure. The patient was initiated on chemoradiation therapy with 5-fluorouracil. However, following a subsequent decline in performance status and multiple hospitalizations, she could not tolerate further cancer treatment and died soon afterwards. CONCLUSIONS Few cases of synchronous malignancies involving the stomach and pancreas have been reported. Because gastric cancer could easily be missed on screening endoscopy; physicians must have a high index of suspicion. In those patients with a prior history of cancer, biopsies should be performed to aid in early diagnosis. To our knowledge, only metachronous cases of SRC gastric and pancreatic adenocarcinoma have been documented. Therefore, this report represents the first case of synchronous SRC gastric adenocarcinoma and IPMN-associated pancreatic adenocarcinoma in the literature.

Small RNAs derived from tRNA fragmentation regulate the functional maturation of neonatal ß cells.

tRNA-derived fragments (tRFs) are an emerging class of small non-coding RNAs with distinct cellular functions. Here, we studied the contribution of tRFs to the regulation of postnatal ß cell maturation, a critical process that may lead to diabetes susceptibility in adulthood. We identified three tRFs abundant in neonatal rat islets originating from 5' halves (tiRNA-5s) of histidine and glutamate tRNAs. Their inhibition in these islets reduced ß cell proliferation and insulin secretion. Mitochondrial respiration was also perturbed, fitting with the mitochondrial enrichment of nuclear-encoded tiRNA-5HisGTG and tiRNA-5GluCTC. Notably, tiRNA-5 inhibition reduced Mpc1, a mitochondrial pyruvate carrier whose knock down largely phenocopied tiRNA-5 inhibition. tiRNA-5HisGTG interactome revealed binding to Musashi-1, which was essential for the mitochondrial enrichment of tiRNA-5HisGTG. Finally, tiRNA-5s were dysregulated in the islets of diabetic and diabetes-prone animals. Altogether, tiRNA-5s represent a class of regulators of ß cell maturation, and their deregulation in neonatal islets may lead to diabetes susceptibility in adulthood.

Scrt1, a transcriptional regulator of ß-cell proliferation identified by differential chromatin accessibility during islet maturation.

Glucose-induced insulin secretion, a hallmark of mature ß-cells, is achieved after birth and is preceded by a phase of intense proliferation. These events occurring in the neonatal period are decisive for establishing an appropriate functional ß-cell mass that provides the required insulin throughout life. However, key regulators of gene expression involved in functional maturation of ß-cells remain to be elucidated. Here, we addressed this issue by mapping open chromatin regions in newborn versus adult rat islets using the ATAC-seq assay. We obtained a genome-wide picture of chromatin accessible sites (~ 100,000) among which 20% were differentially accessible during maturation. An enrichment analysis of transcription factor binding sites identified a group of transcription factors that could explain these changes. Among them, Scrt1 was found to act as a transcriptional repressor and to control ß-cell proliferation. Interestingly, Scrt1 expression was controlled by the transcriptional repressor RE-1 silencing transcription factor (REST) and was increased in an in vitro reprogramming system of pancreatic exocrine cells to ß-like cells. Overall, this study led to the identification of several known and unforeseen key transcriptional events occurring during ß-cell maturation. These findings will help defining new strategies to induce the functional maturation of surrogate insulin-producing cells.

A circular RNA generated from an intron of the insulin gene controls insulin secretion.

Fine-tuning of insulin release from pancreatic ß-cells is essential to maintain blood glucose homeostasis. Here, we report that insulin secretion is regulated by a circular RNA containing the lariat sequence of the second intron of the insulin gene. Silencing of this intronic circular RNA in pancreatic islets leads to a decrease in the expression of key components of the secretory machinery of ß-cells, resulting in impaired glucose- or KCl-induced insulin release and calcium signaling. The effect of the circular RNA is exerted at the transcriptional level and involves an interaction with the RNA-binding protein TAR DNA-binding protein 43 kDa (TDP-43). The level of this circularized intron is reduced in the islets of rodent diabetes models and of type 2 diabetic patients, possibly explaining their impaired secretory capacity. The study of this and other circular RNAs helps understanding ß-cell dysfunction under diabetes conditions, and the etiology of this common metabolic disorder.

Ischemic Colitis in a Patient on Venovenous Extracorporeal Membrane Oxygenation (VV-ECMO) Treatment: An Emerging Complication?

BACKGROUND There have been few reports of colonic ischemia in patients receiving venovenous extracorporeal membrane oxygenation (VV-ECMO) treatment, and all patients died during the same hospitalization. CASE REPORT A 48-year-old man was admitted with acute respiratory failure secondary to multifocal pneumonia and required VV-ECMO treatment. He developed abdominal distention and colon dilatation and was subsequently found to have ischemic colitis. He was able to recover from critical illness and ischemic colitis with supportive treatment including colonic decompression. CONCLUSIONS Ischemic colitis is associated with mortality in patients receiving ECMO treatment. The understanding of the pathophysiology is still evolving and requires further research to improve patient outcomes.

Speech treatment improves dysarthria in multisystemic ataxia: a rater-blinded, controlled pilot-study in ARSACS.

We aimed to provide proof-of-principle evidence that intensive home-based speech treatment can improve dysarthria in complex multisystemic degenerative ataxias, exemplified by autosomal recessive spastic ataxia Charlevoix-Saguenay (ARSACS). Feasibility and piloting efficacy of speech training specifically tailored to cerebellar dysarthria was examined through a 4-week program in seven patients with rater-blinded assessment of intelligibility (primary outcome) and naturalness and acoustic measures of speech (secondary outcomes) performed 4 weeks before, immediately prior to, and directly after training (intraindividual control design). Speech intelligibility and naturalness improved post treatment. This provides piloting evidence that ataxia-tailored speech treatment might be effective in degenerative cerebellar disease.

Coordination and timing deficits in speech and swallowing in autosomal recessive spastic ataxia of Charlevoix-Saguenay (ARSACS).

BACKGROUND: Autosomal recessive spastic ataxia of Charlevoix-Saguenay (ARSACS) is a rare early onset neurodegenerative disease that typically results in ataxia, upper motor neuron dysfunction and sensorimotor peripheral neuropathy. Dysarthria and dysphagia are anecdotally described as key features of ARSACS but the nature, severity and impact of these deficits in ARSACS are not known. A comprehensive quantitative and qualitative characterization of speech and swallowing function will support diagnostics, provide insights into the underlying pathology, and guide day-to-day clinical management. METHODS: 11 consecutive non-Quebec ARSACS patients were recruited, and compared to healthy participants from several published and unpublished cohorts. A comprehensive behavioural assessment including objective acoustic analysis and expert perceptual ratings of motor speech, the Clinical Assessment of Dysphagia in Neurodegeneration (CADN), videofluoroscopy and standardized tests of dysarthria and swallowing related quality of life was conducted. RESULTS: Speech in this ARSACS cohort is characterized by pitch breaks, prosodic deficits including reduced rate and prolonged intervals, and articulatory deficits. The swallowing profile was characterized by delayed initiation of the swallowing reflex and late epiglottic closure. Four out of ten patients were observed aspirating thin liquids on videofluoroscopy. Patients report that they regularly cough or choke on thin liquids and solids during mealtimes. Swallowing and speech-related quality of life was worse than healthy controls on all domains except sleep. CONCLUSIONS: The dysphagia and dysarthria profile of this ARSACS cohort reflects impaired coordination and timing. Dysphagia contributes to a significant impairment in functional quality of life in ARSACS, and appears to manifest distinctly from other ARSACS dysfunctions such as ataxia or spasticity.

Circular RNAs as novel regulators of ß-cell functions in normal and disease conditions.

OBJECTIVE: There is strong evidence for an involvement of different classes of non-coding RNAs, including microRNAs and long non-coding RNAs, in the regulation of ß-cell activities and in diabetes development. Circular RNAs were recently discovered to constitute a substantial fraction of the mammalian transcriptome but the contribution of these non-coding RNAs in physiological and disease processes remains largely unknown. The goal of this study was to identify the circular RNAs expressed in pancreatic islets and to elucidate their possible role in the control of ß-cells functions. METHODS: We used a microarray approach to identify circular RNAs expressed in human islets and searched their orthologues in RNA sequencing data from mouse islets. We then measured the level of four selected circular RNAs in the islets of different Type 1 and Type 2 diabetes models and analyzed the role of these circular transcripts in the regulation of insulin secretion, ß-cell proliferation, and apoptosis. RESULTS: We identified thousands of circular RNAs expressed in human pancreatic islets, 497 of which were conserved in mouse islets. The level of two of these circular transcripts, circHIPK3 and ciRS-7/CDR1as, was found to be reduced in the islets of diabetic db/db mice. Mimicking this decrease in the islets of wild type animals resulted in impaired insulin secretion, reduced ß-cell proliferation, and survival. ciRS-7/CDR1as has been previously proposed to function by blocking miR-7. Transcriptomic analysis revealed that circHIPK3 acts by sequestering a group of microRNAs, including miR-124-3p and miR-338-3p, and by regulating the expression of key ß-cell genes, such as Slc2a2, Akt1, and Mtpn. CONCLUSIONS: Our findings point to circular RNAs as novel regulators of ß-cell activities and suggest an involvement of this novel class of non-coding RNAs in ß-cell dysfunction under diabetic conditions.

Validation and Psychometric Properties of the German Version of the SWAL-QOL.

The SWAL-QOL questionnaire is a common tool for evaluating patients' dysphagia-specific quality of life. A validated German version is not available. This study aimed to establish a German version of the SWAL-QOL (G-SWAL-QOL) using a standardized translation procedure and to systematically evaluate its psychometric properties. The original SWAL-QOL was translated into German following international translation guidelines. A pilot study (45 subjects) confirmed comprehensibility of the G-SWAL-QOL. A consecutive series of 158 subjects (103 patients with dysphagia; 55 healthy controls) was then recruited to assess validity and reliability of the G-SWAL-QOL. Construct validity was analyzed through a correlation analysis with both (i) the Anderson Dysphagia Inventory (ADI-D) and (ii) the Short Form 36 (SF-36). Internal consistency and test-retest reliability were evaluated to determine reliability. All questions of the G-SWAL-QOL were comprehensible, except one which was subsequently revised. Construct validity of the G-SWAL-QOL was demonstrated by moderate to high correlations with the ADI-D (Spearman's rho 0.36 - 0.88). The G-SWAL-QOL was able to differentiate between patients with dysphagia and healthy controls (p < 0.001) and was sensitive to disease severity measured by different food textures. Reliability of the G-SWAL-QOL was good to excellent for both internal consistency (Cronbach's α > 0.7 for all domains, except eating desire [α = 0.69]) and test-retest reliability (Spearman's rho ≥ 0.68 for all domains; ICC > 0.8 for all domains). The G-SWAL-QOL is a valid and reliable measuring tool for dysphagia-specific quality of life in German-speaking persons.

Therapeutic potential of miRNAs in diabetes mellitus.

miRNAs are major regulators of gene expression that are emerging as central players in the development of many human diseases, including diabetes mellitus. In fact, the manifestation of diabetes is associated with alterations in the miRNA profile in insulin-secreting cells, insulin target tissues and, in case of long-term diabetes complications, in many additional organs. Diabetes also results in changes in the profile of miRNAs detectable in blood and other body fluids. This has boosted an ever increasing interest in the use of circulating miRNAs as potential biomarkers to predict the development of diabetes and its devastating complications. Moreover, promising approaches to correct the level of selected miRNAs are emerging, permitting to envisage new therapeutic strategies to treat diabetes and its complications.

Solid pseudopapillary neoplasm, pancreas type, presenting as a primary ovarian neoplasm.

Solid pseudopapillary neoplasm has historically been associated with the pancreas, categorized as a tumor of low malignancy. Recently, solid pseudopapillary neoplasm was reported to arise as a primary ovarian tumor in 3 women. We report a fourth case identified in a 48 year-old woman with an 8-cm left ovarian mass. A left salpingo-oophorectomy was performed. Microscopic examination demonstrated a predominately cystic neoplasm comprised of solid nests of cells with an epithelioid to plasmacytoid appearance, associated with blood vessels, hemorrhage, and degenerative changes, that is, pseudopapillary structures. The tumor cells stained focally for pancytokeratin, progesterone receptor, and CD57 with diffuse nuclear expression of ß-catenin. Ki-67 was 5% to 10%. Synaptophysin, inhibin, and E-cadherin stains were negative. Clinical and radiologic follow-up of our patient demonstrated no pancreatic lesions. This is a rare report of a primary ovarian solid pseudopapillary neoplasm. Prolonged follow-up is needed to determine how this case will fare clinically.