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Industrial flour served as a classical filler in wood industry for many years. However, its high-cost and competition for use as food stuff paved the way to a novel substitution tactic by using agriculture and forestry waste residues. Camellia oleifera shell and palm kernel meal are both by-products of oil-refining with advantages such as wide availability, great-reserve, renewability, and low-cost. Herein, a compound filler strategy was proposed by combining Camellia oleifera shell powder (Cosp) and palm kernel meal (PKM) to solve some drawbacks while Cosp as a single filler. The results showed that the bonding performance of plywood incorporating 20% single Cosp modified MUF was inferior with respect to MUF modified by same amount of industrial flour, due to the significantly increased viscosity, leading to a decrease in wet shear strength (1.63 MPa and 1.47 MPa for cold and hot-water soaking pretreatment, respectively). Encouraged, the overall status (including the viscosity, gel time, and solid content) of MUF modified by the compound filler displayed is regarded the best formulation for Coaps to PKM weight ratio of 5:5. Therefore, the wet shear strength for derived plywood samples with the adhesive incorporating 20% filler content, can reach 1.90 MPa and 1.88 MPa for cold and hot-water soaking pre-treatment, respectively. Interestingly, this bonding performance is similar to MUF resin modified by industrial flour. Thermogravimetric analysis (TGA), fourier transform infra-red spectroscopy (FT-IR), and scanning electron microscopy (SEM) were utilized to further confirm the potency of the compound filler modification strategy. Furthermore, the formaldehyde emission of MUF resin modified by the compound filler was effectively reduced by 8.24–14.12%, compared to industrial flour as filler. Cosp and PKM, as agricultural and forestry waste residue, exhibited the cost advantage for this approach based on calculation, which can save the cost of adhesive by over 40% for filler. The strategy for employing this compound filler provides a sustainable and environmentally friendly approach for green application of waste residues obtained from agriculture and forestry. • A fully bio-based compound filler consisted by Cosp and PKM was prepared. • The Cosp and PKM modified MUF maintained the outstanding bonding performance. • The formaldehyde release of MUF with Cosp and PKM filler was reduced by 8.24–14.12%. • The cost of filler utilized in MUF resin would go down by 40%. [ABSTRACT FROM AUTHOR]

Introduction: Muscle-invasive bladder cancer (BC) often occurs in patients with competing mortality risks, while also being associated with the highest rate of second primary nonurothelial cancers (SNUC) of all solid malignancies. We investigated the incidence, risk factors, and timing of SNUC as a competing mortality risk factor in patients with BC who were treated with curative intent radical cystectomy (RC).Methods: We performed a retrospective cohort study assessing patients who underwent RC for cT2-4 N0M0 BC from January 1, 2005 to December 31, 2018 at a single, high volume tertiary care referral center. The Fine-Gray multivariable regression model was used to evaluate predictive factors for SNUC. Cumulative incidence of mortality (CIM) was estimated with modified Kaplan-Meier analysis.Results: The median follow-up time for the 693 patients who underwent RC was 3.7 years (interquartile range [IQR] 1.9-5.9 years). SNUC developed in 85 (12.3%) patients at a median 3.0 years post-RC (IQR 1.2-5.5 years). On multivariable analysis, the only significant predictor for developing SNUC was freedom from BC recurrence or metastasis (HR 1.54, 95% CI 1.12-1.76, P = 0.019). The most common SNUCs were primary lung cancer (24, 3.2% of cohort) and colon cancer (9, 1.3% of cohort). BC surveillance imaging diagnosed SNUC in 35/52 (67.3%) patients with solid-organ visceral primaries. The overall mortality rate for any SNUC was 38.8%, with the 3 most lethal cancer types being pancreatic, lung, and colon (62.5%, 54.2%, and 44.4% mortality, respectively). The incidence of SNUC uniformly increased postoperatively, with a cumulative incidence of 22.1% (95% CI, 16.8-27.9%) at 12-years post-RC. 163 patients (23.5%) died from BC, 33 patients (4.8%) died from SNUC, and 94 patients (13.6%) died from other causes. While the CIM for BC plateaued around 5-years post-RC at 24%, the incidence of other-cause mortality uniformly rose throughout the postoperative period. By post-RC year 9 there was no significant difference in CIM between BC (CIM 27.2%, 95% CI, 23.5-31.1%) and other-causes (CIM 20.0%, 95% CI, 15.8-24.6%).Conclusions: The cumulative incidence of SNUC at 12-years post-RC was 22%, with the majority identified on BC surveillance imaging. While BC mortality plateaued around 5-years post-RC, mortality related to SNUC or other causes rose steadily in the postoperative period. These data have clinical significance with regards to patient counseling, survivorship and oncologic surveillance in the highly comorbid muscle-invasive BC population. [ABSTRACT FROM AUTHOR]

Objectives: Receptor for advanced glycation end products (RAGE) expressed on adipocytes and immune cells can bind to ligand N(ε)-(carboxymethyl)-lysine (CML) and trigger dysregulation of adipokines and chronic inflammation. Soluble RAGE (sRAGE) mitigates the detrimental effect of RAGE. We examined the associations between circulating levels of CML-AGE and sRAGE and colorectal cancer (CRC).Methods: In a case-cohort study of the Women's Health Initiative Study, blood levels of CML-AGE and sRAGE were measured using ELISA. We used multivariable Cox regression model to estimate hazard ratios (HRs) and 95% confidence intervals (CIs) of incident CRC in relation to quartiles (Q) of biomarker levels.Results: Average follow-up was 7.8 years for 444 cases and 805 subcohort members. In the subcohort, CML-AGE and sRAGE were inversely correlated with BMI (P values<0.0001). Levels of CML-AGE and sRAGE were not associated with CRC. In BMI-specific analysis, the association between sRAGE and CRC was observed. Among women with BMI≥25kg/m(2), those with highest levels of sRAGE had significantly lower risk for CRC as compared to women with lowest levels of sRAGE (HRQ4versusQ1: 0.39; 95% CI: 0.17-0.91). This inverse association was not observed among women with BMI <25kg/m(2) (P value for interaction=0.01).Conclusions: Among postmenopausal women, the RAGE pathway may be involved in obesity-related CRC. [ABSTRACT FROM AUTHOR]

Background & Aims Statins have been reported to protect against esophageal adenocarcinoma (EAC) in patients with Barrett’s esophagus (BE). However, there are few data from adequately powered cohort studies of subjects with BE. Methods We conducted a nested case–control study of a cohort of BE patients identified from national Veteran Affairs (VA) outpatient files, diagnosed with BE from 2004 through 2009. New cases of EAC recorded after BE diagnosis were identified during a follow-up period that ended in 2011 and verified using electronic medical records. We selected patients with BE without EAC (controls) using incidence density sampling; 3 controls were matched to each case based on birth year and date of BE diagnosis. Our analysis included only male patients with at least 1 VA visit per year of follow up. We identified prescriptions for statins and non-statin lipid lowering medications filled after BE diagnosis and up to 90 days before EAC diagnosis for cases and controls (during the corresponding time period); we examined the association between statin use and EAC in conditional logistic regression models. Results We compared 311 EAC cases to 856 controls. Cases were less likely to use any statins than controls (40.2% vs 54.0%; P < .01). Significantly lower proportions of cases used statins for 6–18 months (10.0% cases vs 17.1% controls) and >18 months (19.3% vs 24.0%, respectively; P < .01). Simvastatin was the most commonly prescribed statin (accounting for 86.9% of statin use); the defined daily dose of simvastatin was lower in cases than in controls (21–40 mg/day, 9.3% vs 14.5%, respectively; and >40 mg/day, 8.4% vs 12.6%, respectively; P < .01). In multivariate analysis, statin use was inversely associated with development of EAC (adjusted odds ratio [OR], 0.65; 95% confidence interval [CI], 0.47–0.91). This protective association was strongest for patients with advanced-stage EAC: in a stratified analysis, comparison of 189 cases with stage 0–1 EAC to 520 controls produced an adjusted OR of 0.85 (95% CI, 0.54–1.33). Among patients with late-stage EAC (stages 2–4, n = 106) and 291 controls, the adjusted OR was 0.44 (95% CI, 0.25–0.79). We found no association between EAC and non-statin lipid-lowering medications. Conclusions In a case–control study of US veterans, statin use among those with BE appeared to decrease the risk of EAC. This protective effect was strongest against advanced-stage EAC, and increased with statin dose. [ABSTRACT FROM AUTHOR]

Background & Aims Practice guidelines recommend a 1-time screening endoscopy for patients with gastroesophageal reflux disease (GERD) who are at high risk for Barrett’s esophagus or malignancy. However, little is known about the risk of cancer in patients with negative findings from screening endoscopies. Methods We conducted a retrospective cohort study using data from 121 Veterans Health Administration facilities nationwide to determine the incidence rate of esophageal adenocarcinoma (EA) separately, as well as any upper gastrointestinal cancers, in patients with an initial negative screening endoscopy (esophagogastroduodenoscopy [EGD]). We included veteran patients with GERD diagnosed between 2004 and 2009 who had a negative screening EGD within 1 year of diagnosis. We estimated the incidence rate of EA, and any upper gastrointestinal cancer, in patients with GERD who had a negative screening EGD. We examined differences in demographic, clinical, and facility factors among patients with and without cancer. Results We identified 68,610 patients with GERD and a negative screening EGD (mean age, 55.5 y; 90% men; 67.5% white). During a mean follow-up period of 3.2 years, 10 patients developed EA and 29 patients developed any upper gastrointestinal malignancies, including EA. The incidence of subsequent EA in this group was 4.6/100,000 patient-years of follow-up evaluation, whereas the incidence of any upper gastrointestinal cancers was 13.2/100,000 patient-years of follow-up evaluation. Patients with a subsequent cancer were significantly older and had higher comorbidity scores than patients without cancer. Other clinical and facility factors did not differ significantly between these 2 groups. Conclusions The risk of cancer is low, over a mean 3-year period, for patients with GERD who had a negative screening endoscopy. These findings justify recommendations for a 1-time screening endoscopy for patients with GERD. [ABSTRACT FROM AUTHOR]

Background: Practice guidelines recommend surveillance endoscopy every 2 to 3 years among patients with Barrett''s esophagus (BE) to detect early neoplastic lesions. Although surveys report that >95% of gastroenterologists recommend or practice BE surveillance, the extent and patterns of surveillance in clinical practice are unknown. Objective: To identify the extent and determinants of endoscopic surveillance among BE patients. Design: Retrospective cohort study. Setting: A total of 121 Veterans Affairs facilities nationwide. Patients: Veteran patients with BE diagnosed from 2003 to 2009, with follow-up through September 30, 2010. Intervention: Not an interventional study. Main Outcome Measurements: The proportions of patients with BE who received any EGD after the index BE EGD date. In the subgroup of patients with at least 6 years of follow-up, we also calculated proportions for regular (EGD during both 3-year intervals), irregular (EGD in only 1 interval), and no surveillance. We examined differences in demographics and clinical and facility factors among these groups in unadjusted and adjusted analyses. Results: We identified 29,504 patients with BE; 97% were men, 83% white, and their mean age was 61.8 years. During a 3.8-year median follow-up period, 45.4% of patients with BE received at least one EGD. Among the subgroup of 4499 patients with BE who had at least 6 years of follow-up, 23.0% had regular surveillance, and 26.7% had irregular surveillance. There was considerable facility-level variation in percentages with surveillance EGD across the 112 facilities and by geographic region of these facilities. Demographic and clinical factors did not explain these variations. Patients with at least one EGD were significantly more likely to be white; to be aged <65 years, with a low level of comorbidity; to have GERD, obesity, dysphagia, or esophageal strictures; to have more outpatient visits; and to be seen in smaller hospitals (<87 beds) than those without any EGD. Limitations: There might be misclassification of BE and surveillance EGD. Lack of pathology data on dysplasia, which dictates surveillance intervals. Conclusion: Endoscopic surveillance for BE is considerably less commonly practiced in Veterans Affairs facilities than is self-reported by physicians. Although several clinical factors are associated with variations in surveillance, facility-level factors play a large role. The comparative effectiveness of the different practice-based surveillance patterns needs to be examined. [Copyright &y& Elsevier]

Background & Aims: Little information is available about what factors determine serum levels of alpha fetoprotein (AFP) (eg, demographic, virologic, or clinical features) among individuals who do not develop hepatocellular carcinoma (HCC). This information might improve AFP-based algorithms for HCC detection. Methods: We examined data from patients in the national Veterans'' Affairs Hepatitis C Virus (HCV) Clinical Case Registry who received at least 1 AFP test (258,275 AFP tests in 76,357 patients; 1.9% developed HCC). We constructed hierarchical multivariate models of AFP levels. Potential predictors of AFP values included patients'' sex, race, cirrhosis status, Model for End-Stage Liver Disease (MELD) score, HCV genotype, level of alanine aminotransferase (ALT) within 30 days before the AFP test, time to diagnosis of HCC, and time elapsed from the HCV index date. Results: Significant determinants for increased levels of AFP included presence of cirrhosis, higher MELD scores, and increased levels of ALT. AFP levels were also affected by the interaction between ALT levels and the presence and time to development of HCC. Among patients who did not have HCC, the AFP level increased with the level of ALT; the AFP values in the presence of ALT 37–56 U/L, ALT 57–92 U/L, or ALT >92 U/L were 16%, 35%, and 68% higher, respectively, than AFP values at ALT 0–36 U/L. However, patients who developed HCC within 30 days of receiving the AFP test had a lower rate of increase in AFP with each higher category of ALT level, with increases of 31%, 39%, and 37% for the same respective ALT categories. Conclusions: In patients with chronic HCV infection, AFP and ALT values correlate; however, among patients with HCC, levels of AFP increase disproportionately to or unaccompanied by increases in levels of ALT. The prognostic and diagnostic value of AFP levels might be increased by adjusting for ALT values. [Copyright &y& Elsevier]

Background & Aims: Hepatocellular carcinoma (HCC) can result from hepatitis C virus (HCV)-related liver disease and is the fastest-growing cause of cancer-related death in the United States. α-fetoprotein (AFP) has been used as a prognostic factor for HCC, but the value of AFP as a prognostic factor for HCV-related HCC in the United States is unknown. We investigated whether higher levels of AFP at the time of diagnosis are associated with increased mortality of patients with HCV-related HCC. Methods: In a retrospective study, we collected data from a cohort of HCV-infected veterans, identifying incident HCC cases from October 1, 1998, to January 1, 2007 (n = 1480 patients). The mean serum levels of AFP, obtained within 60 days before to 30 days after HCC diagnosis, were determined for 1064 patients and categorized as less than 10 ng/mL (18%), 10 to less than 100 ng/mL (30%), 100 to less than 1000 ng/mL (22%), or 1000 ng/mL or more (29%). Cox proportional hazard models were used to associate serum levels of AFP with mortality, adjusting for demographic features, clinical factors, and treatment. Results: The median survival times were significantly lower among patients with higher levels of AFP: 709 days for patients with less than 10 ng/mL, 422 days for patients with 10 to less than 100 ng/mL, 208 days for patients with 100 to less than 1000 ng/mL, and 68 days for patients with 1000 ng/mL or more. In the multivariate analysis, increased levels of AFP (10 to <100, 100 to <1000, and ≥1000) were associated significantly with increased mortality, compared with a serum AFP level of less than 10; hazard ratios were 1.50, 2.23, and 4.35, respectively. Conclusions: Serum AFP level at the time of diagnosis with HCV-related HCC is an independent predictor of mortality. [Copyright &y& Elsevier]

Background & Aims Nonalcoholic fatty liver disease (NAFLD) is the leading cause of chronic liver disease in the United States. However, few data are available on recent trends in the incidence and prevalence of NAFLD in the U.S. Methods We analyzed the national Veterans Administration databases from 2003 to 2011 and calculated the age-adjusted prevalence and incidence of NAFLD for the overall sample of patients and by demographic subgroups. We used a previously validated algorithm to define NAFLD, which was based on persistent increases in levels of liver enzymes in the absence of positive results from tests for hepatitis C or hepatitis B or evidence of excessive alcohol use. Results Of the 9,784,541 patients with at least 1 visit to the Veterans Administration between 2003 and 2011, 1,330,600 patients (13.6%) had NAFLD. The annual incidence rates of NAFLD remained stable (from 2.2% to 3.2%) during the study duration. The prevalence of NAFLD increased from 6.3% in 2003 (95% confidence interval, 6.26%–6.3%) to 17.6% in 2011 (95% confidence interval, 17.58%–17.65%), a 2.8-fold increase. The incidence and prevalence increased at significantly greater rates in patients younger than 45 years vs older patients. Conclusions In a U.S. population, the annual incidence of NAFLD ranges from 2% to 3%. The prevalence of NAFLD more than doubled from 2003 through 2011; it is likely to continue to increase because of a steady overall incidence coupled with a rising incidence in younger individuals. [ABSTRACT FROM AUTHOR]

Background & Aims Hepatocellular carcinoma (HCC) can develop in individuals without cirrhosis. We investigated risk factors for development of HCC in the absence of cirrhosis in a U.S. population. Methods We identified a national cohort of 1500 patients with verified HCC during 2005 to 2010 in the U.S. Veterans Administration (VA) and reviewed their full VA medical records for evidence of cirrhosis and risk factors for HCC. Patients without cirrhosis were assigned to categories of level 1 evidence for no cirrhosis (very high probability) or level 2 evidence for no cirrhosis (high probability), which were based on findings from histologic analyses, laboratory test results, markers of fibrosis from noninvasive tests, and imaging features. Results A total of 43 of the 1500 patients with HCC (2.9%) had level 1 evidence for no cirrhosis, and 151 (10.1%) had level 2 evidence for no cirrhosis; the remaining 1203 patients (80.1%) had confirmed cirrhosis. Compared with patients with HCC in presence of cirrhosis, greater proportions of patients with HCC without evidence of cirrhosis had metabolic syndrome, nonalcoholic fatty liver disease (NAFLD), or no identifiable risk factors. Patients with HCC without evidence of cirrhosis were less likely to have abused alcohol or have hepatitis C virus infection than patients with cirrhosis. Patients with HCC and NAFLD (unadjusted odds ratio, 5.4; 95% confidence interval, 3.4–8.5) or metabolic syndrome (unadjusted odds ratio, 5.0; 95% confidence interval, 3.1–7.8) had more than 5-fold risk of having HCC in the absence of cirrhosis, compared with patients with HCV-related HCC. Conclusions Approximately 13% of patients with HCC in the VA system do not appear to have cirrhosis. NAFLD and metabolic syndrome are the main risk factors for HCC in the absence of cirrhosis. [ABSTRACT FROM AUTHOR]

Background & Aims Nonalcoholic fatty liver disease (NAFLD) is a risk factor for hepatocellular carcinoma (HCC). However, no systemic studies from the United States have examined temporal trends, HCC surveillance practices, and outcomes of NAFLD-related HCC. Methods We identified a national cohort of 1500 patients who developed HCC from 2005 through 2010 from Veterans Administration (VA) hospitals. We reviewed patients’ full VA medical records; NAFLD was diagnosed based on histologic evidence for, or the presence of, the metabolic syndrome in the absence of hepatitis C virus (HCV) infection, hepatitis B, or alcoholic liver disease. We compared annual prevalence values for the main risk factors (NAFLD, alcohol abuse, and HCV), as well a HCC surveillance and outcomes, among HCC patients. Results NAFLD was the underlying risk factor for HCC in 120 patients (8.0%); the annual proportion of NAFLD-related HCC remained relatively stable (7.5%–12.0%). In contrast, the proportion of HCC cases associated with HCV increased from 61.0% in 2005 (95% confidence interval, 53.1%–68.9%) to 74.9% in 2010 (95% confidence interval, 69.0%–80.7%). The proportion of HCC cases associated with only alcohol abuse decreased from 21.9% in 2005 to 15.7% in 2010, and the annual proportion of HCC cases associated with hepatitis B remained relatively stable (1.4%–3.5%). A significantly lower proportion of patients with NAFLD-related HCC had cirrhosis (58.3%) compared with patients with alcohol- or HCV-related HCC (72.4% and 85.6%, respectively; P < .05). A significantly higher percentage of patients with NAFLD-related HCC did not receive HCC surveillance in the 3 years before their HCC diagnosis, compared with patients with alcohol- or HCV-associated HCC. A lower proportion of patients with NAFLD-related HCC received HCC-specific treatment (61.5%) than patients with HCV-related HCC (77.5%; P < .01). However, the 1-year survival rate did not differ among patients with HCC related to different risk factors. Conclusions NAFLD is the third most common risk factor for HCC in the VA population. The proportion of NAFLD-related HCC was relatively stable from 2005 through 2010. Although patients with NAFLD-related HCC received less HCC surveillance and treatment, a similar proportion survive for 1 year, compared with patients with alcohol-related or HCV-related HCC. [ABSTRACT FROM AUTHOR]

Background: For patients with Stage II breast cancer with one to three positive lymph nodes, controversy exists about whether radiation as a component of treatment provides a survival benefit. Methods and Materials: We analyzed data from patients with Stage II breast cancer with one to three positive lymph nodes diagnosed from 1988–2002 in the Surveillance, Epidemiology, and End Results registry and compared the outcome of 12,693 patients treated with breast-conservation therapy with radiation (BCT + XRT) with the 18,902 patients treated with mastectomy without radiation (MRM w/o XRT). Results: Patients treated with BCT + XRT were younger, were more likely to be treated in recent years of the study period, more commonly had T1 primary tumors, and had fewer involved nodes compared with those treated with MRM w/o XRT (p < 0.001 for all differences). The 15-year breast cancer–specific survival rate for the BCT + XRT group was 80% vs. 72% for the MRM w/o XRT group (p < 0.001). Cox regression analysis showed that MRM w/o XRT was associated with a hazard ratio for breast cancer death of 1.19 (p < 0.001) and for overall death of 1.25 (p < 0.001). The survival benefit in the BCT + XRT group was not limited to subgroups with high-risk disease features. Conclusions: Radiation use was independently associated with improved survival for patients with Stage II breast cancer with one to three positive lymph nodes. Because multivariate analyses of retrospective data cannot account for all potential biases, these data require confirmation in randomized clinical trials. [Copyright &y& Elsevier]

Developing polymer composites that can work in harsh environment are important for advancing materials industry. However, the composites generally based-on epoxy or phenolics resins that can endure both extremely high and low temperature are still rather limited. In this work, melamine-hexamethylenediamine (MH) thermoset which is structurally different from conventional matrices was used as matrix resin for woven glass fiber reinforced MH (GFRMH) laminated composite. Owing to the excellent thermostability (T d ≈ 460 °C) and interfacial compatibility of the MH matrix, the fabricated composites exhibited exceptional resistance to extreme temperature and mechanical performances, which are superior to that of the representative commercial epoxy-based composites. Particularly, the heat deflection temperature (HDT) of GFRMH was above 300 °C which is much higher than that of the representative high-performance commercial composites (220–270 °C). Moreover, GFRMH composite exhibited excellent retainability even at 425 °C while severe carbonization and delamination occurred to all the selected commercial products. Further, the GFRMH laminate exhibited flexural strength of 541 MPa at room temperature, higher than that of the commercial products by 80–160 MPa. Remarkably, the flexural strength increased to 852 MPa at 77 K without declining of toughness, suggesting the excellent resistance to cryogenic temperature. In summary, the results of the study disclosed the suitability of MH resin as a new matrix of glass fiber reinforced engineering materials. [ABSTRACT FROM AUTHOR]

Annual cervical cancer screening with Papanicolaou (Pap) and human papillomavirus (HPV) testing after stem cell transplant (SCT) is recommended, but the uptake is unknown. We aimed to determine the prevalence and predictors of cervical cancer screening in patients with hematologic malignancies. We searched MarketScan Commercial Claims database for women who underwent allogeneic or autologous SCT. The primary outcome was cervical cancer screening, defined as procedures or abnormal results for HPV and/or Pap testing according administrative codes within 2 years after SCT. A multivariable logistic regression model was fitted with cancer type, SCT year, age, geographic area, insurance plan, comorbidity, and presence of graft-versus-host disease (GVHD).The study included 1484 patients; 1048 patients (70.6%) had autologous and 436 (29.4%) allogeneic SCT. Mean age was 52.5 years. Overall, 660 patients (44.5%) had screening within 2 years after SCT, 214 (49.1%) with allogeneic SCT and 446 (42.6%) with autologous SCT ( P  = .02). In the allogeneic SCT group, patients with GVHD had a lower rate of screening than patients without GVHD (42.5% versus 55.4%, P  < .01), and GVHD was associated with lower odds of screening (odds ratio, .50; 95% confidence interval, .32 to .79). In the autologous SCT group, patients with comorbid medical conditions had a lower rate of screening than patients without comorbidity (36.0% versus 45.7%, P  < .01). In both allogeneic and autologous SCT groups older patients had lower odds of screening. Cervical cancer screening rates after SCT are low, particularly in patients with GVHD, who are at significant risk of second malignancies. Future work is needed to develop strategies to increase uptake. [ABSTRACT FROM AUTHOR]

Pancreatic islet β-cell dysfunction is a signature feature of Type 2 diabetes pathogenesis. Consequently, knowledge of signals that regulate β-cell function is of immense clinical relevance. Transforming growth factor (TGF)-β signaling plays a critical role in pancreatic development although the role of this pathway in the adult pancreas is obscure. Here, we define an important role of the TGF-β pathway in regulation of insulin gene transcription and β-cell function. We identify insulin as a TGF-β target gene and show that the TGF-β signaling effector Smad3 occupies the insulin gene promoter and represses insulin gene transcription. In contrast, Smad3 small interfering RNAs relieve insulin transcriptional repression and enhance insulin levels. Transduction of adenoviral Smad3 into primary human and non-human primate islets suppresses insulin content, whereas, dominant-negative Smad3 enhances insulin levels. Consistent with this, Smad3-deficient mice exhibit moderate hyperinsulinemia and mild hypoglycemia. Moreover, Smad3 deficiency results in improved glucose tolerance and enhanced glucose-stimulated insulin secretion in vivo. In ex vivo perifusion assays, Smad3-deficient islets exhibit improved glucose-stimulated insulin release. Interestingly, Smad3-deficient islets harbor an activated insulin-receptor signaling pathway and TGF-β signaling regulates expression of genes involved in β-cell function. Together, these studies emphasize TGF-β/Smad3 signaling as an important regulator of insulin gene transcription and β-cell function and suggest that components of the TGF-β signaling pathway may be dysregulated in diabetes. [ABSTRACT FROM AUTHOR]