Gastroparesis is commonly attributed to idiopathic or diabetic causes.
We aimed to describe atypical causes of gastroparesis and examine the clinical features and severity of delayed gastric emptying ...compared with idiopathic and diabetic causes.
Between 2018 and 2021, gastroparesis patients being evaluated at our tertiary care center completed a 4-hour gastric emptying scintigraphy and questionnaires assessing for gastrointestinal disorders, including patient assessment of upper gastrointestinal symptoms. Patients were divided into groups relating to gastroparesis cause: diabetic, postsurgical (PSGp), connective tissue (CTGp), neurological and idiopathic.
Two hundred fifty-six patients with delayed emptying on gastric emptying scintigraphy completed the questionnaires. Gastroparesis causes included 149 (58.2%) idiopathic, 60 (23.4%) diabetic, 29 (11.3%) postsurgical, 13 (5.1%) connective tissue, and 5 (2.0%) neurological. In each group, most patients were female and White. Gastric retention at 4 hours was significantly greater in patients with diabetic (39.3±25.7% P<0.001), postsurgical (41.3±24.0% P=0.002), and connective tissue gastroparesis (37.8±20.0% P=0.049) compared with patients with idiopathic gastroparesis (25.5±17.6%). In PSGp, diabetic and idiopathic causes, the main symptoms were early satiety and postprandial fullness, whereas in CTGp, bloating and abdominal distension were the predominant symptoms. Vomiting severity was significantly greater in patients with diabetes compared with idiopathic gastroparesis (2.9±1.9 vs. 2.1±1.8 P=0.006).
Atypical causes contributed to gastroparesis in 47 of 256 (18.4%) patients with delayed gastric emptying. Gastric emptying was significantly more delayed in PSGp and CTGp patients. PSGp patients mainly experienced stomach fullness and early satiety, whereas CTGp patients had predominantly bloating and distension.
Sodalis glossinidius is an intra- and extracellular symbiont of the tsetse fly (Glossina sp.), which feeds exclusively on vertebrate blood. S. glossinidius resides in a wide variety of tsetse tissues ...and may encounter environments that differ dramatically in iron content. The Sodalis chromosome encodes a putative TonB-dependent outer membrane heme transporter (HemR) and a putative periplasmic/inner membrane ABC heme permease system (HemTUV). Because these gene products mediate iron acquisition processes by other enteric bacteria, we characterized their regulation and physiological role in the Sodalis/tsetse system. Our results show that the hemR and tonB genes are expressed by S. glossinidius in the tsetse fly. Furthermore, transcription of hemR in Sodalis is repressed in a high-iron environment by the iron-responsive transcriptional regulator Fur. Expression of the S. glossinidius hemR and hemTUV genes in an Escherichia coli strain unable to use heme as an iron source stimulated growth in the presence of heme or hemoglobin as the sole iron source. This stimulation was dependent on the presence of either the E. coli or Sodalis tonB gene. Sodalis tonB and hemR mutant strains were defective in their ability to colonize the gut of tsetse flies that lacked endogenous symbionts, while wild-type S. glossinidius proliferated in this same environment. Finally, we show that the Sodalis HemR protein is localized to the bacterial membrane and appears to bind hemin. Collectively, this study provides strong evidence that TonB-dependent, HemR-mediated iron acquisition is important for the maintenance of symbiont homeostasis in the tsetse fly, and it provides evidence for the expression of bacterial high-affinity iron acquisition genes in insect symbionts.
Abstract
Background: Retention of a normally functioning bladder would likely improve patient quality of life in the treatment of muscle-invasive bladder cancer (MIBC). Detection of residual cancer ...in bladder-sparing approaches relies on TURBT/bladder biopsy and clinical assessment. Historically, there is a 15-50% salvage cystectomy or metastasis rate with bladder sparing after chemotherapy alone or chemoradiotherapy. We hypothesized that clinical recurrence in bladder-sparing approaches was due to undetected subclinical disease at the time of (false) cT0 bladder assessment. We designed a next-generation sequencing (NGS) test to determine if residual mutations detected in the urine might be a surrogate for residual disease in MIBC patients undergoing RC.
Methods: Patient samples were collected on IRB-approved protocols. DNA was isolated from whole urine (n=4 precystectomy samples), urine supernatant (n=17 prechemotherapy specimens, 15 precystectomy specimens, n=18 patients total), and germline (n=22) and sequenced using a targeted NGS panel of commonly mutated bladder cancer genes with sample indices and unique molecular barcodes. Twenty-one patients had neoadjuvant chemotherapy. TURBT tissue collected prior to neoadjuvant chemotherapy also underwent whole-exome sequencing (WES; n=17) as a benchmark. Single-nucleotide variants in urine (SNVU) and in TURBT tissue (SNVT) were compared. Persistence or clearance of SNVU was correlated to residual disease status at the time of radical cystectomy.
Results: In benchmark samples from 15 patients, 46/76 SNVT identified by WES were also identified as SNVU in prechemotherapy urine samples. In precystectomy urine samples, absence of SNVU occurred in 5/6 patients achieving pT0 cystectomy specimens. In comparison, SNVU were detected in the precystectomy urine in 12/13 patients with residual disease. Absence/presence of SNVU was associated with residual disease status (p=0.0029, Fisher). In addition, TERT promoter hotspot mutations that are not detectable using WES-based approaches were detected in 9 of 22 patients in at least one urine specimen, and additional SNVU were detected that were not detected in tumor tissue.
Conclusion: Presence/absence of SNVU strongly associates with residual disease status. Additional samples from urothelial cancer patients are currently being analyzed to determine the optimal urine compartment (cell-free vs. pellet vs. whole urine). Validation studies may encourage the use of urine biomarkers to improve residual disease detection in cystectomy avoidance algorithms.
Citation Format: Phillip H. Abbosh, Uttam Satyal, David Liu, Ilsiya Ibragimova, Lauren Szeto, Benjamin Miron, James Ford, Daniel Parker, Aeen Asgar, Daniel M. Geynisman, R. Katherine Alpaugh, Paul Cairns, Costas D. Lallas, Edouard J. Trabulsi, Jean Hoffman-Censits, Eliezer M. Van Allen, Alexander Kutikov, Elizabeth R. Plimack. Use of deep sequencing of urinary DNA as a biomarker of residual disease status at the time of radical cystectomy abstract. In: Proceedings of the AACR Special Conference on Bladder Cancer: Transforming the Field; 2019 May 18-21; Denver, CO. Philadelphia (PA): AACR; Clin Cancer Res 2020;26(15_Suppl):Abstract nr B29.
Like many organs, the kidney stiffens after injury, a process that is increasingly recognized as an important driver of fibrogenesis. Yes-associated protein (YAP) and transcriptional coactivator with ...PDZ-binding motif (TAZ) are related mechanosensory proteins that bind to Smad transcription factors, the canonical mediators of profibrotic TGF-
responses. Here, we investigated the role of YAP/TAZ in the matrix stiffness dependence of fibroblast responses to TGF-
In contrast to growth on a stiff surface, fibroblast growth on a soft matrix led to YAP/TAZ sequestration in the cytosol and impaired TGF-
-induced Smad2/3 nuclear accumulation and transcriptional activity. YAP knockdown or treatment with verteporfin, a drug that was recently identified as a potent YAP inhibitor, elicited similar changes. Furthermore, verteporfin reduced YAP/TAZ levels and decreased the total cellular levels of Smad2/3 after TGF-
stimulation. Verteporfin treatment of mice subjected to unilateral ureteral obstruction similarly reduced YAP/TAZ levels and nuclear Smad accumulation in the kidney, and attenuated renal fibrosis. Our data suggest that organ stiffening cooperates with TGF-
to induce fibrosis in a YAP/TAZ- and Smad2/3-dependent manner. Interference with this YAP/TAZ and TGF-
/Smad crosstalk likely underlies the antifibrotic activity of verteporfin. Finally, through repurposing of a clinically used drug, we illustrate the therapeutic potential of a novel mechanointerference strategy that blocks TGF-
signaling and renal fibrogenesis.
3 The gyroscopic device has also been shown to be the patient-preferred device in a head-to-head trial with large grip, weighted cutlery, and swivel spoon for a cohort of PD and essential tremor ...patients who self-reported difficulty with eating tasks. The authors obtained ethics approval for this study before commencement through the University of Sydney Human Research Ethics Committee. Paradoxically, less rice was transferred with the device switched on compared with switched off for the sixty-second-timed-transfer-task (P = 0.0138, 95% confidence interval: −22.81 to −3.39).
Long COVID or post-acute sequelae of SARS-CoV-2 (PASC) is a clinical syndrome featuring diverse symptoms that can persist for months following acute SARS-CoV-2 infection. The aetiologies may include ...persistent inflammation, unresolved tissue damage or delayed clearance of viral protein or RNA, but the biological differences they represent are not fully understood. Here we evaluate the serum proteome in samples, longitudinally collected from 55 PASC individuals with symptoms lasting ≥60 days after onset of acute infection, in comparison to samples from symptomatically recovered SARS-CoV-2 infected and uninfected individuals. Our analysis indicates heterogeneity in PASC and identified subsets with distinct signatures of persistent inflammation. Type II interferon signaling and canonical NF-κB signaling (particularly associated with TNF), appear to be the most differentially enriched signaling pathways, distinguishing a group of patients characterized also by a persistent neutrophil activation signature. These findings help to clarify biological diversity within PASC, identify participants with molecular evidence of persistent inflammation, and highlight dominant pathways that may have diagnostic or therapeutic relevance, including a protein panel that we propose as having diagnostic utility for differentiating inflammatory and non-inflammatory PASC.
PDF
