Kansas City VA Medical Center

BACKGROUND: Asymptomatic ventricular arrhythmias in patients with congestive heart failure are associated with increased rates of overall mortality and sudden death. Amiodarone is now used widely to prevent ventricular tachycardia and fibrillation. We conducted a trial to determine whether amiodarone can reduce overall mortality in patients with congestive heart failure and asymptomatic ventricular arrhythmias. METHODS: We used a double-blind, placebo-controlled protocol in which 674 patients with symptoms of congestive heart failure, cardiac enlargement, 10 or more premature ventricular contractions per hour, and a left ventricular ejection fraction of 40 percent or less were randomly assigned to receive amiodarone (336 patients) or placebo (338 patients). The primary end point was overall mortality, and the median follow-up was 45 months (range, 0 to 54). RESULTS: There was no significant difference in overall mortality between the two treatment groups (P = 0.6). The two-year actuarial survival rate was 69.4 percent (95 percent confidence interval, 64.2 to 74.6) for the patients in the amiodarone group and 70.8 percent (95 percent confidence interval, 65.7 to 75.9) for those in the placebo group. At two years, the rate of sudden death was 15 percent in the amiodarone group and 19 percent in the placebo group (P = 0.43). There was a trend toward a reduction in overall mortality among the patients with nonischemic cardiomyopathy who received amiodarone (P = 0.07). Amiodarone was significantly more effective in suppressing ventricular arrhythmias and increased the left ventricular ejection fraction by 42 percent at two years. CONCLUSIONS: Although amiodarone was effective in suppressing ventricular arrhythmias and improving ventricular function, it did not reduce the incidence of sudden death or prolong survival among patients with heart failure, except for a trend toward reduced mortality among those with nonischemic cardiomyopathy.

BACKGROUND AND PURPOSE: Rehabilitation care after stroke is highly variable and increasingly shorter in duration. The effect of therapeutic exercise on impairments and functional limitations after stroke is not clear. The objective of this study was to determine whether a structured, progressive, physiologically based exercise program for subacute stroke produces gains greater than those attributable to spontaneous recovery and usual care. METHODS: This randomized, controlled, single-blind clinical trial was conducted in a metropolitan area and 17 participating healthcare institutions. We included persons with stroke who were living in the community. One hundred patients (mean age, 70 years; mean Orpington score, 3.4) consented and were randomized from a screened sample of 582. Ninety-two subjects completed the trial. Intervention was a structured, progressive, physiologically based, therapist-supervised, in-home program of thirty-six 90-minute sessions over 12 weeks targeting flexibility, strength, balance, endurance, and upper-extremity function. Main outcome measures were postintervention strength (ankle and knee isometric peak torque, grip strength), upper- and lower-extremity motor control (Fugl Meyer), balance (Berg and functional reach), endurance (peak aerobic capacity and exercise duration), upper-extremity function (Wolf Motor Function Test), and mobility (timed 10-m walk and 6-minute walk distance). RESULTS: In the intention-to-treat multivariate analysis of variance testing the overall effect, the intervention produced greater gains than usual care (Wilk's lambda=0.64, P=0.0056). Both intervention and usual care groups improved in strength, balance, upper- and lower-extremity motor control, upper-extremity function, and gait velocity. Gains for the intervention group exceeded those in the usual care group in balance, endurance, peak aerobic capacity, and mobility. Upper-extremity gains exceeded those in the usual care group only in patients with higher baseline function. CONCLUSIONS: This structured, progressive program of therapeutic exercise in persons who had completed acute rehabilitation services produced gains in endurance, balance, and mobility beyond those attributable to spontaneous recovery and usual care.

Severe thunderstorm evolution is synthesized, using published and unpublished studies of radar, instrumented aircraft, visual and surface observations. These observations reveal the existence of a downdraft (originating at 7–10 km AGL) on the relative upwind side of the updraft. Air decelerates at the upwind stagnation point, is forced downward and mixes with air below which then reaches the surface through evaporative cooling and precipitation drag. The initially rotating updraft is then transformed into a new mesocyclone with a divided structure, in which the circulation center lies along the zone separating the rear blank downdraft from the updraft. This process appears to result, in part, from tilting of horizontal vorticity into the vertical. It is proposed that the zone of strong vertical velocity gradient across which the mesocyclone comes to be positioned is also characterized by a strong temperature gradient and is the genesis region of strong tornadoes. Although no direct observations are available yet, we further propose that the strong temperature contrast plays a potential modulating role in tornadogenesis by solenoidal generation of vorticity, in analogy with the extratropical cyclone, to which the transformed mesocyclone bears a striking resemblance.

OBJECTIVE: To determine whether glatiramer acetate (GA) slows accumulation of disability in primary progressive multiple sclerosis. METHODS: A total of 943 patients with primary progressive multiple sclerosis were randomized to GA or placebo (PBO) in this 3-year, double-blind trial. The primary end point was an intention-to-treat analysis of time to 1- (entry expanded disability status scale, 3.0-5.0) or 0.5-point expanded disability status scale change (entry expanded disability status scale, 5.5-6.5) sustained for 3 months. The trial was stopped after an interim analysis by an independent data safety monitoring board indicated no discernible treatment effect on the primary outcome. Intention-to-treat analyses of disability and magnetic resonance imaging end points were performed. RESULTS: There was a nonsignificant delay in time to sustained accumulated disability in GA- versus PBO-treated patients (hazard ratio, 0.87 [95% confidence interval, 0.71-1.07]; p = 0.1753), with significant decreases in enhancing lesions in year 1 and smaller increases in T2 lesion volumes in years 2 and 3 versus PBO. Post hoc analysis showed that survival curves for GA-treated male patients diverged early from PBO-treated male subjects (hazard ratio, 0.71 [95% confidence interval, 0.53-0.95]; p = 0.0193). INTERPRETATION: The trial failed to demonstrate a treatment effect of GA on primary progressive multiple sclerosis. Both the unanticipated low event rate and premature discontinuation of study medication decreased the power to detect a treatment effect. Post hoc analysis suggests GA may have slowed clinical progression in male patients who showed more rapid progression when untreated.

BACKGROUND AND PURPOSE: The purpose of this study was to determine if compliance with poststroke rehabilitation guidelines was associated with better functional outcomes. METHODS: An inception cohort of 288 stroke patients in 11 Department of Veteran Affairs Medical Centers hospitalized between January 1998 and March 1999 were followed prospectively for 6 months. Data were abstracted from medical records and telephone interviews. The primary study outcome was the Functional Independence Motor Score (FIM). Secondary outcomes included Instrumental Activities of Daily Living (IADL), SF-36 physical functioning, and the Stroke Impact Scale (SIS). Acute and postacute rehabilitation guideline compliance scores (range 0 to 100) were derived from an algorithm. All outcomes were adjusted for case-mix. RESULTS: Average compliance scores in acute and postacute care settings were 68.2% (SD 14) and 69.5% (SD 14.4), respectively. After case-mix adjustment, level of compliance with postacute rehabilitation guidelines was significantly associated with FIM motor, IADL, and the SIS physical domain scores. SF-36 physical function was not associated with guideline compliance. Level of compliance with rehabilitation guidelines in acute settings was unrelated to any of the outcome measures. CONCLUSION: Greater levels of adherence to postacute stroke rehabilitation guidelines were associated with improved patient outcomes. Compliance with guidelines may be viewed as a quality-of-care indicator with which to evaluate new organizational and funding changes involving postacute stroke rehabilitation.

Circulating permeability factors may be important in idiopathic nephrotic syndrome (INS) including focal segmental glomerulosclerosis (FSGS) and in recurrence after renal transplantation. Evidence for plasma factors includes posttransplant recurrence of proteinuria and its response to plasmapheresis or immunoadsorption and induction of proteinuria in experimental animals by infusion of patient plasma or its fractions. The authors and other investigators have used proteomic techniques to seek pathogenic molecules. The authors have recently proposed cardiotrophin-like cytokine-1 (CLC-1) as an active factor in FSGS. Other potential permeability factors include hemopexin and vascular permeability factor in minimal change nephrotic syndrome (MCNS) and soluble urokinase receptor in FSGS. In the authors' studies, in vitro plasma permeability activity is blocked by diverse substances that may decrease levels of active molecules or block the effects of circulating permeability factors. It has been shown that the simple sugar galactose blocks the effect of FSGS serum on albumin permeability in vitro and decreases permeability activity when administered to patients. Because identities of permeability factors and their mechanisms of action are not well defined, therapy of INS/FSGS is empiric. Corticosteroids are the mainstay of initial therapy whereas calcineurin inhibitors such as cyclosporine A (CsA) and immunosuppressive medications provide adjunctive therapy. Nonspecific therapies such as blocking the renin-angiotensin system and controlling blood pressure and plasma lipids may also diminish proteinuria and slow progression. Identification of molecules that initiate proteinuria and application of findings from in vitro studies may lead to development of new treatments to arrest progression and prevent recurrence after transplantation.

BACKGROUND: The presence of intestinal metaplasia (IM) in the columnar lined distal oesophagus defines Barrett's oesophagus with the risk of future malignant transformation. The distribution of both IM and dysplasia (low grade (LGD) and high grade (HGD)) within the columnar lined oesophagus is patchy and mosaic requiring random biopsies. Techniques that could help target areas of high yield within Barrett's mucosa would be helpful. AIM: To study the utility of high magnification chromoendoscopy (MCE) in the detection of IM, LGD, and HGD in patients with Barrett's oesophagus. METHODS: Consecutive patients detected with columnar mucosa in the distal oesophagus were studied using an Olympus magnification endoscope (GIF-Q16OZ, 115x). The distal oesophagus was sprayed with indigo carmine solution and the oesophageal columnar mucosa patterns were noted under high magnification and targeted for biopsy. All biopsies were read by pathologists blinded to the endoscopic findings. RESULTS: Eighty patients with suspected Barrett's oesophagus (that is, columnar lined distal oesophagus) were studied: mean age 62.7 years (range 35-81). Mean length of columnar mucosa was 3.7 cm (range 0.5-17). Three types of mucosal patterns were noted within the columnar mucosa after spraying indigo carmine and using MCE: ridged/villous pattern, circular pattern, and irregular/distorted pattern. The yield of IM on target biopsies according to the patterns was: ridged/villous 57/62 (97%) and circular 2/12 (17%). Six patients had an irregular/distorted pattern and all had HGD on biopsy (6/6 (100%)). Eighteen patients had LGD on target biopsies; all had the ridged/villous pattern. All patients with long segment Barrett's were identified using MCE whereas 23/28 patients (82%) with short segment Barrett's had the ridged/villous pattern. CONCLUSIONS: MCE helps visually identify areas with IM and HGD having specific patterns but not patients with LGD (appear similar to IM). MCE may be a useful clinical tool for the increased detection of patients with IM as well as for surveillance of patients for the detection of HGD. If these preliminary results are validated, MCE would help identify high yield areas, potentially eliminating the need for random biopsies.

BACKGROUND: Having sufficient healthcare access helps individuals proactively manage their health challenges, leading to positive long-term health outcomes. In the U.S., healthcare access is a public health issue as many Americans lack the physical or financial resources to receive the healthcare services they need. Mental healthcare is especially difficult due to lingering social stigmas and scarcity of services. Subsequently, those with mental health impairment tend to be complex patients, which may convolute delivery of services. OBJECTIVE: To quantify the prevalence of barriers to healthcare access among U.S. adults with and without mental health challenges (MHC) and evaluate the relationship between MHC and no usual source of care (NUSC). METHODS: A cross-sectional study was conducted with data from the 2017-2018 National Health Interview Survey. MHC was categorized into three levels: no (NPD), moderate (MPD) and severe (SPD) psychological distress. Eight barriers were quantified; one was used as the primary outcome: NUSC. Multivariable logistic regression was used to quantify associations between these characteristics. RESULTS: The sample included 50,103 adults. Most reported at least one barrier to healthcare access (95.6%) while 13.3% reported NUSC. For each barrier, rates were highest among those with SPD and lowest for those with NPD. However, in the multivariable model, SPD and MPD were not associated with NUSC (OR, 0.92; 95% CI, 0.83-1.01; 0.88; 0.73-1.07). Male sex (1.92; 1.78-2.06), Hispanic race/ethnicity (1.59; 1.42-1.77), and worry to afford emergent (1.38; 1.26-150) or normal (1.60; 1.46-1.76) healthcare were associated with NUSC. Having a current partner (0.88; 0.80-0.96), dependent(s) (0.77; 0.70-0.85) and paid sick leave (0.60; 0.56-0.65) were protective. CONCLUSIONS: The most prevalent barriers to healthcare access link to issues with affordability, and MHC exist more often when any barrier is reported. More work is needed to understand the acuity of burden as other social and environmental factors may hold effect.

AIMS: There is a significant uncertainty regarding the effect of testosterone replacement therapy (TRT) on cardiovascular (CV) outcomes including myocardial infarction (MI) and stroke. The aim of this study was to examine the relationship between normalization of total testosterone (TT) after TRT and CV events as well as all-cause mortality in patients without previous history of MI and stroke. METHODS AND RESULTS: We retrospectively examined 83 010 male veterans with documented low TT levels. The subjects were categorized into (Gp1: TRT with resulting normalization of TT levels), (Gp2: TRT without normalization of TT levels) and (Gp3: Did not receive TRT). By utilizing propensity score-weighted Cox proportional hazard models, the association of TRT with all-cause mortality, MI, stroke, and a composite endpoint was compared between these groups. The all-cause mortality [hazard ratio (HR): 0.44, confidence interval (CI) 0.42-0.46], risk of MI (HR: 0.76, CI 0.63-0.93), and stroke (HR: 0.64, CI 0.43-0.96) were significantly lower in Gp1 (n = 43 931, median age = 66 years, mean follow-up = 6.2 years) vs. Gp3 (n = 13 378, median age = 66 years, mean follow-up = 4.7 years) in propensity-matched cohort. Similarly, the all-cause mortality (HR: 0.53, CI 0.50-0.55), risk of MI (HR: 0.82, CI 0.71-0.95), and stroke (HR: 0.70, CI 0.51-0.96) were significantly lower in Gp1 vs. Gp2 (n = 25 701, median age = 66 years, mean follow-up = 4.6 years). There was no difference in MI or stroke risk between Gp2 and Gp3. CONCLUSION: In this large observational cohort with extended follow-up, normalization of TT levels after TRT was associated with a significant reduction in all-cause mortality, MI, and stroke.

KETCHUM, LYNN D. . M.D.; COHEN, L KEIMAN M.D.; MASIFRS, FRANK W. M.D. Author Information

Estrogen has been shown to induce a rapid transient increase in c-myc mRNA in the rat uterus. However, no studies of the cell specificity of c-myc expression in the uterus have been reported, and nothing is known about the expression of c-myc in response to other steroids or during normal uterine preparation for implantation. To this end, the cell type-specific localization of c-myc protein was determined in the ovariectomized mouse uterus after progesterone (P4) and/or 17 beta-estradiol (E2) injection as well as during the periimplantation period. After E2 injection, a rapid accumulation of c-myc protein was detected exclusively in the uterine luminal and glandular epithelial nuclei in the ovariectomized mouse. Essentially all of these cells contained immunoreactive c-myc by 12 h postinjection. In contrast, after P4 injection, rapid accumulation of c-myc was noted exclusively in some of the stromal cell nuclei. Pretreatment of the ovariectomized mouse for 4 days with P4 (P4 priming) followed by E2 injection resulted in an increase in the number of c-myc-positive stromal cells, but few, if any, c-myc-positive cells were detected in the luminal and glandular epithelia. These uterine cell type-specific localizations of c-myc protein, induced by E2 or P4 injection, were followed within 18-24 h by DNA synthesis ([ 3H]thymidine incorporation) restricted to the epithelia or stroma, respectively. c-Myc was detected in the nuclei of luminal and glandular epithelia during proestrus and on days 1 and 2 of pregnancy, a period when the uterus is under the influence of estrogen. c-Myc-positive cells were detected in the stroma on day 3, and by day 4 a large number of stromal cell nuclei were c-myc positive. These changes are coincident with increasing P4 levels during early pregnancy. At the implantation chamber on day 5, many cells in the primary decidual zone as well as some of the deeper stromal cells were c-myc protein positive, whereas on day 6, c-myc protein was detected only in the secondary decidual zone. During this period of uterine preparation for embryo implantation and subsequent decidualization, there was a positive correlation between c-myc protein localized in specific populations of uterine cells and subsequent DNA synthesis in those cell types. Thus, both E2 and P4 induce cell type-specific accumulation of c-myc protein in the uterus of the ovariectomized mouse, with E2 induction of c-myc being restricted to epithelia, and P4 induction restricted to stroma.(ABSTRACT TRUNCATED AT 400 WORDS)

BACKGROUND: Artificial intelligence (AI) tools increase detection of precancerous polyps during colonoscopy and might contribute to long-term colorectal cancer prevention. The aim of the study was to investigate the incremental effect of the implementation of AI detection tools in screening colonoscopy on colorectal cancer incidence and mortality, and the cost-effectiveness of such tools. METHODS: We conducted Markov model microsimulation of using colonoscopy with and without AI for colorectal cancer screening for individuals at average risk (no personal or family history of colorectal cancer, adenomas, inflammatory bowel disease, or hereditary colorectal cancer syndrome). We ran the microsimulation in a hypothetical cohort of 100 000 individuals in the USA aged 50-100 years. The primary analysis investigated screening colonoscopy with versus without AI every 10 years starting at age 50 years and finishing at age 80 years, with follow-up until age 100 years, assuming 60% screening population uptake. In secondary analyses, we modelled once-in-life screening colonoscopy at age 65 years in adults aged 50-79 years at average risk for colorectal cancer. Post-polypectomy surveillance followed the simplified current guideline. Costs of AI tools and cost for downstream treatment of screening detected disease were estimated with 3% annual discount rates. The main outcome measures included the incremental effect of AI-assisted colonoscopy versus standard (no-AI) colonoscopy on colorectal cancer incidence and mortality, and cost-effectiveness of screening projected for the average risk screening US population. FINDINGS: In the primary analyses, compared with no screening, the relative reduction of colorectal cancer incidence with screening colonoscopy without AI tools was 44·2% and with screening colonoscopy with AI tools was 48·9% (4·8% incremental gain). Compared with no screening, the relative reduction in colorectal cancer mortality with screening colonoscopy with no AI was 48·7% and with screening colonoscopy with AI was 52·3% (3·6% incremental gain). AI detection tools decreased the discounted costs per screened individual from $3400 to $3343 (a saving of $57 per individual). Results were similar in the secondary analyses modelling once-in-life colonoscopy. At the US population level, the implementation of AI detection during screening colonoscopy resulted in yearly additional prevention of 7194 colorectal cancer cases and 2089 related deaths, and a yearly saving of US$290 million. INTERPRETATION: Our findings suggest that implementation of AI detection tools in screening colonoscopy is a cost-saving strategy to further prevent colorectal cancer incidence and mortality. FUNDING: European Commission and Japan Society of Promotion of Science.

Chronic kidney disease (CKD) affects >10% of the adult population. Each year, approximately 120,000 Americans develop end-stage kidney disease and initiate dialysis, which is costly and associated with functional impairments, worse health-related quality of life, and high early-mortality rates, exceeding 20% in the first year. Recent declarations by the World Kidney Day and the U.S. Government Executive Order seek to implement strategies that reduce the burden of kidney failure by slowing CKD progression and controlling uremia without dialysis. Pragmatic dietary interventions may have a role in improving CKD outcomes and preventing or delaying dialysis initiation. Evidence suggests that a patient-centered plant-dominant low-protein diet (PLADO) of 0.6–0.8 g/kg/day composed of >50% plant-based sources, administered by dietitians trained in non-dialysis CKD care, is promising and consistent with the precision nutrition. The scientific premise of the PLADO stems from the observations that high protein diets with high meat intake not only result in higher cardiovascular disease risk but also higher CKD incidence and faster CKD progression due to increased intraglomerular pressure and glomerular hyperfiltration. Meat intake increases production of nitrogenous end-products, worsens uremia, and may increase the risk of constipation with resulting hyperkalemia from the typical low fiber intake. A plant-dominant, fiber-rich, low-protein diet may lead to favorable alterations in the gut microbiome, which can modulate uremic toxin generation and slow CKD progression, along with reducing cardiovascular risk. PLADO is a heart-healthy, safe, flexible, and feasible diet that could be the centerpiece of a conservative and preservative CKD-management strategy that challenges the prevailing dialysis-centered paradigm.

OBJECTIVE: Since the publication of the Asia-Pacific consensus on gastro-oesophageal reflux disease in 2008, there has been further scientific advancement in this field. This updated consensus focuses on proton pump inhibitor-refractory reflux disease and Barrett's oesophagus. METHODS: A steering committee identified three areas to address: (1) burden of disease and diagnosis of reflux disease; (2) proton pump inhibitor-refractory reflux disease; (3) Barrett's oesophagus. Three working groups formulated draft statements with supporting evidence. Discussions were done via email before a final face-to-face discussion. We used a Delphi consensus process, with a 70% agreement threshold, using Grading of Recommendations Assessment, Development and Evaluation (GRADE) criteria to categorise the quality of evidence and strength of recommendations. RESULTS: A total of 32 statements were proposed and 31 were accepted by consensus. A rise in the prevalence rates of gastro-oesophageal reflux disease in Asia was noted, with the majority being non-erosive reflux disease. Overweight and obesity contributed to the rise. Proton pump inhibitor-refractory reflux disease was recognised to be common. A distinction was made between refractory symptoms and refractory reflux disease, with clarification of the roles of endoscopy and functional testing summarised in two algorithms. The definition of Barrett's oesophagus was revised such that a minimum length of 1 cm was required and the presence of intestinal metaplasia no longer necessary. We recommended the use of standardised endoscopic reporting and advocated endoscopic therapy for confirmed dysplasia and early cancer. CONCLUSIONS: These guidelines standardise the management of patients with refractory gastro-oesophageal reflux disease and Barrett's oesophagus in the Asia-Pacific region.

Recent application of immunotherapy in clinical oncology revolutionized our management of advanced human cancers. Check point inhibitors targeting CTLA4 and PD-1/PD-L1 axis are immunotherapeutic agents currently available to treat a variety of cancers. However, a novel therapeutic approach is needed to further improve patient outcome with these agents. Indoleamine 2,3-dioxygenase 1 (IDO1) is a rate-limiting enzyme in the metabolism of essential amino acid tryptophan in the peripheral tissue. IDO1 is overexpressed in human cancer cells and suppresses effector T cell function and promotes regulatory T cells (Tregs). Overexpression of IDO1 is associated with poor patient survival in several types of human cancer. These findings indicate that IDO1 is a promising target that can improve the treatment outcome in the field of Immuno-oncology. Several orally available IDO1 inhibitors including Epacadostat have entered human clinical trials over the last few years without a major safety concern. Although there is no objective response in single-agent trials, combination regimens with PD-1 inhibitors appear to exceed the activity of PD-1 inhibitors alone. Recent phase III ECHO 301 trial testing the combination of Epacadostat with Pembrolizumab in melanoma did not show superior outcome compared to Pembrolizumab alone. This lead to halting of other phase III trials using IDO1 inhibitors. In this minireview, we will discuss the recent clinical development of Epacadostat and other IDO1 inhibitors.

// Dhruv Kumar 1 , Dwijendra Gupta 2 , Sharmila Shankar 3 , Rakesh K. Srivastava 1 1 Department of Pharmacology, Toxicology and Therapeutics, and Medicine, The University of Kansas Medical Center, 3901 Rainbow Boulevard, Kansas City, KS, 66160, USA 2 Center of Bioinformatics and Department of Biochemistry, University of Allahabad, Allahabad, India 3 Kansas City VA Medical Center, 4801 Linwood Boulevard, Kansas City, MO 64128, USA Correspondence to: Dr. Rakesh K. Srivastava, email: rsrivastava.lab@gmail.com Dr. Sharmila Shankar, email: sharmila.shankar@va.gov Keywords: CSCs, Rotenone, CD9, CD63, CD81, Alix, Atg7, LC3. Abbreviations: Atg , Autophagy related gene; CSC , Cancer Stem Cell; DAPI , 4',6-diamidino-2-phenylindole; FBS , Fetal bovine serum; LC3 , Microtubule-associated protein 1 light chain 3; miRNA , micro RNA Received: July 03, 2014      Accepted: September 06, 2014      Published: September 17, 2014 ABSTRACT Cancer recognized as one of the leading irrepressible health issues is contributing to increasing mortality-rate day-by-day. The tumor microenvironment is an important field of cancer to understand the detection, treatment and prevention of cancer. Recently, cancer stem cell (CSC) research has shown promising results aiming towards cancer diagnostics and treatment. Here, we found that prostate and breast cancer stem cells secreted vesicles of endosomal origin, called exosomes showed strong connection between autophagy and exosomes released from CSCs. Exosomes may serve as vesicles to communicate with neoplastic cells (autocrine and paracrine manner) and normal cells (paracrine and endocrine manner) and thereby suppress immune systems and regulate neoplastic growth, and metastasis. They can also be used as biomarkers for various cancers. We detected tetraspanin proteins (CD9, CD63, CD81), Alix and tumor susceptibility gene-101 (TSG101) of exosomal markers from rotenone treated CSCs. We have also detected the induction of autophagy genes, Atg7 and conversion of autophagy marker (LC3-I to LC3-II), and tetraspanin proteins (CD9, CD63, CD81) in rotenone treated CSCs by western blotting. The mRNA expression of CD9, CD63, CD81 and TSG101 analyzed by qRT-PCR showed that the rotenone induced the expression of CD9, CD63, CD81 and TSG101 in CSCs. Electron microscopy of rotenone treated CSCs showed the mitochondrial damage of CSCs as confirmed by the release of exosomes from CSCs. The constituents of exosomes may be useful to understand the mechanism of exosomes formation, release and function, and also serve as a useful biomarker and provide novel therapeutic strategies for the treatment and prevention of cancer.

BACKGROUND: Biopsy specimens obtained from the gastro-oesophageal junction can reveal intestinal metaplasia in patients presenting for routine upper endoscopy. The site of biopsy may play a critical role in determining the dysplasia risk of a patient. AIMS: To evaluate prospectively the dysplasia risk in patients with intestinal metaplasia of the distal oesophagus or within the gastric cardia. METHODS: Patients with short segment Barrett's oesophagus (SSBO) and cardia intestinal metaplasia (CIM) were followed prospectively. RESULTS: 177 patients with SSBO were identified (mean age 62 years, range 38-82; 91% whites). Twenty prevalence cases of dysplasia in SSBO were detected: 17 low grade dysplasia (LGD), three high grade dysplasia (HGD). Seventy six patients with CIM were identified (mean age 67 years, range 37-81; 81% whites). A single prevalence case of LGD in CIM was detected. During follow up of 78 SSBO and 34 CIM patients, dysplasia developed in nine (seven LGD, two HGD) with SSBO and in one (LGD) with CIM. There were significant differences between the two groups with respect to age, ethnicity, dysplasia prevalence, and incidence. Time to dysplasia progression was significantly longer in CIM compared with SSBO patients. Of the five patients with SSBO and HGD, one developed adenocarcinoma of the oesophagus on follow up. No HGD or cancers have been detected over this time period in CIM patients. CONCLUSIONS: The dysplasia risk is significantly greater in SSBO than in CIM patients, indicating two potentially different clinical processes. Future studies should separate SSBO from CIM in order to enhance the understanding of the pathophysiology and malignant potential of each entity.

BACKGROUND: Artificial intelligence computer-aided detection (CADe) of colorectal neoplasia during colonoscopy may increase adenoma detection rates (ADRs) and reduce adenoma miss rates, but it may increase overdiagnosis and overtreatment of nonneoplastic polyps. PURPOSE: To quantify the benefits and harms of CADe in randomized trials. DESIGN: Systematic review and meta-analysis. (PROSPERO: CRD42022293181). DATA SOURCES: Medline, Embase, and Scopus databases through February 2023. STUDY SELECTION: Randomized trials comparing CADe-assisted with standard colonoscopy for polyp and cancer detection. DATA EXTRACTION: Adenoma detection rate (proportion of patients with ≥1 adenoma), number of adenomas detected per colonoscopy, advanced adenoma (≥10 mm with high-grade dysplasia and villous histology), number of serrated lesions per colonoscopy, and adenoma miss rate were extracted as benefit outcomes. Number of polypectomies for nonneoplastic lesions and withdrawal time were extracted as harm outcomes. For each outcome, studies were pooled using a random-effects model. Certainty of evidence was assessed using the GRADE (Grading of Recommendations Assessment, Development and Evaluation) framework. DATA SYNTHESIS: Twenty-one randomized trials on 18 232 patients were included. The ADR was higher in the CADe group than in the standard colonoscopy group (44.0% vs. 35.9%; relative risk, 1.24 [95% CI, 1.16 to 1.33]; low-certainty evidence), corresponding to a 55% (risk ratio, 0.45 [CI, 0.35 to 0.58]) relative reduction in miss rate (moderate-certainty evidence). More nonneoplastic polyps were removed in the CADe than the standard group (0.52 vs. 0.34 per colonoscopy; mean difference [MD], 0.18 polypectomy [CI, 0.11 to 0.26 polypectomy]; low-certainty evidence). Mean inspection time increased only marginally with CADe (MD, 0.47 minute [CI, 0.23 to 0.72 minute]; moderate-certainty evidence). LIMITATIONS: This review focused on surrogates of patient-important outcomes. Most patients, however, may consider cancer incidence and cancer-related mortality important outcomes. The effect of CADe on such patient-important outcomes remains unclear. CONCLUSION: The use of CADe for polyp detection during colonoscopy results in increased detection of adenomas but not advanced adenomas and in higher rates of unnecessary removal of nonneoplastic polyps. PRIMARY FUNDING SOURCE: European Commission Horizon 2020 Marie Skłodowska-Curie Individual Fellowship.

Adherence of Candida albicans to host tissues is a necessary step for maintenance of its commensal status and is likely a necessary step in the pathogenesis of candidiasis. The extracellular matrix (ECM) proteins are some of the host tissue and plasma proteins to which C. albicans adheres through adhesins located on the fungal cell surface. To isolate genes encoding ECM adhesins, an assay was developed based on the ability of yeast cells to adhere to magnetic beads coated with the ECM protein fibronectin, type IV collagen, or laminin. A C. albicans genomic library was constructed by cloning XbaI-partially-digested and size-selected fragments into pAUR112, an Escherichia coli-yeast low-copy-number shuttle vector. The C. albicans library was transformed into Saccharomyces cerevisiae YPH 499, and clones capable of adherence were selected by using ECM protein-coated magnetic beads. A plasmid containing an approximately 8-kb insert was isolated from 29 adherent clones. These clones exhibited adherence to all ECM protein-coated magnetic beads and to human buccal epithelial cells. The ALA1 gene (for agglutinin-like adhesin) was localized by subcloning it into a 5-kb XbaI fragment which retained the adherence phenotype in both orientations. The complete DNA sequence of the 5-kb insert was determined, and an open reading frame (ORF) encoding 1,419 amino acid residues was identified. Deletions from the 5' and 3' ends extending into the DNA sequence encoding the 1,419-amino-acid ORF product inactivated the adherence phenotype, suggesting that it is the coding region of the ALA1 gene. A database search identified ALA1 to be similar to the C. albicans ALS1 (for agglutinin-like sequence 1) protein and the S. cerevisiae agglutinin protein (AG alpha1), although the homology at the primary amino acid sequence level is limited to the first half of each of these proteins. ALA1 contains a central domain of six tandem repeats of 36 amino acids. We discuss the significance of various predicted ALA1 structural motifs and their relationships to function in the adherence process.

MDS is characterized by ineffective hematopoiesis that leads to peripheral cytopenias. Development of effective treatments has been impeded by limited insight into pathogenic pathways governing dysplastic growth of hematopoietic progenitors. We demonstrate that smad2, a downstream mediator of transforming growth factor-beta (TGF-beta) receptor I kinase (TBRI) activation, is constitutively activated in MDS bone marrow (BM) precursors and is overexpressed in gene expression profiles of MDS CD34(+) cells, providing direct evidence of overactivation of TGF-beta pathway in this disease. Suppression of the TGF-beta signaling by lentiviral shRNA-mediated down-regulation of TBRI leads to in vitro enhancement of hematopoiesis in MDS progenitors. Pharmacologic inhibition of TBRI (alk5) kinase by a small molecule inhibitor, SD-208, inhibits smad2 activation in hematopoietic progenitors, suppresses TGF-beta-mediated gene activation in BM stromal cells, and reverses TGF-beta-mediated cell-cycle arrest in BM CD34(+) cells. Furthermore, SD-208 treatment alleviates anemia and stimulates hematopoiesis in vivo in a novel murine model of bone marrow failure generated by constitutive hepatic expression of TGF-beta1. Moreover, in vitro pharmacologic inhibition of TBRI kinase leads to enhancement of hematopoiesis in varied morphologic MDS subtypes. These data directly implicate TGF-beta signaling in the pathobiology of ineffective hematopoiesis and identify TBRI as a potential therapeutic target in low-risk MDS.