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Background: Studies across racial/ethnic groups indicate that physical activity (PA) and alcohol consumption are positively associated, and that alcohol consumption is negatively associated with body mass index (BMI), but this relationship is less often evaluated in Hispanics. The purpose of this study was to assess the relationships between alcohol consumption, PA, and BMI in Hispanic adults. Methods: In this secondary data analysis of a Mexican-American cohort, we collected self-reported PA, alcohol consumption, and demographics, and measured height and weight. Linear regression assessed the association between PA and alcohol consumption with BMI, controlling for covariates. Total sample for analyses was n= 3897. Results: We found an inverse relationship between high PA and BMI in the full sample (adjusted estimate = − 0.03, 95% CI − 0.07, − 0.01) and in females, but not males. We also found an inverse relationship between current alcohol use and BMI in the full sample (adjusted estimate = − 0.05, 95% CI − 0.09, − 0.01) and both sexes. There was no significant interaction between PA and alcohol use on BMI. Conclusions: In this study of Mexican-origin adults, current alcohol use and high PA were associated with lower BMIs, but there was no interaction between PA and alcohol use. These results can be used to inform multiple behavior change interventions in Mexican-origin adults.

The primary aim of the study was to estimate the effect of sleep duration on prospective type 2 diabetes (T2D) risk across demographic characteristics and follow-up periods, and test body mass index (BMI) as a mediator and moderator.

Four new diterpenoid alkaloids, nagaconitines A-D (1–4), were isolated from the roots of Aconitum nagarumvar. heterotrichum, one tranditional Chinese medicinal plan.

Background: Depression and anxiety after stroke are common conditions that are likely to be neglected. Abnormal red blood cell (RBC) indices may be associated with neuropsychiatric disorders. However, the association of RBC indices with post-stroke depression (PSD) and poststroke anxiety (PSA) has not been sufficiently investigated. Methods: We aimed to investigate the trajectory of post-stroke depression and anxiety in our follow- up stroke clinic at 1, 3, and 6 months, and the association of RBC indices with these. One hundred and sixty-two patients with a new diagnosis of ischemic stroke were followed up at 1, 3, and 6 months, and underwent Patient Health Questionnaire-9 (PHQ-9) and the general anxiety disorder 7-item (GAD-7) questionnaire for evaluation of depression and anxiety, respectively. First, we used Kaplan-Meier analysis to investigate the accumulated incidences of post-stroke depression and post-stroke anxiety. Next, to explore the association of RBC indices with psychiatric disorders after an ischemic stroke attack, we adjusted for demographic and vascular risk factors using multivariate Cox regression analysis. Results: Of the 162 patients with new-onset of ischemic stroke, we found the accumulated incidence rates of PSD (1.2%, 17.9%, and 35.8%) and PSA (1.2%, 13.6%, and 15.4%) at 1, 3, and 6 months, respectively. The incident PSD and PSA increased 3 months after a stroke attack. Multivariate Cox regression analysis indicated independent positive associations between PSD risk and higher mean corpuscular volume (MCV) (OR=1.42, 95% CI=1.16-1.76), older age (OR=2.63, 95% CI=1.16-5.93), and a negative relationship between male sex (OR=0.95, 95% CI=0.91-0.99) and PSA. Conclusion: The risks of PSD and PSA increased substantially 3 months beyond stroke onset. Of the RBC indices, higher MCV, showed an independent positive association with PSD.

Background: Intracranial Atherosclerotic Stenosis (ICAS) is an important risk factor for cognitive impairment. However, it is unclear whether patients with ICAS are more likely to develop cognitive impairment after an acute, non-disabling ischemic stroke (minor stroke). Objective: We aimed to investigate the association between ICAS and post-stroke cognitive impairment. Methods: In this cross-sectional study, patients with acute, non-disabling ischemic stroke underwent two cognitive tests and imaging evaluation for ICAS, within two weeks after the stroke. To determine the association between ICAS and post-stroke cognitive impairment, we performed a multivariate logistic regression analysis adjusted for several demographic and vascular risk factors. Results: Of the 164 patients with minor stroke in this study, 98 (59.76%) were diagnosed with poststroke cognitive impairment (Montreal Cognitive Assessment score<26). After adjusting for potential confounders, we found that patients with ICAS were more likely to develop cognitive impairment after an acute, non-disabling ischemic stroke, compared to patients without ICAS (Odds Ratio: 2.13; 95% Confidence Interval: 1.07-4.26), and underperformed in the tests of visuospatial and executive function. Conclusion: In this cross-sectional study of a population that has experienced a minor stroke, our findings demonstrated a positive association between ICAS and post-stroke cognitive impairment.

Identifying a metastasis-correlated immune cell composition within the tumor microenvironment (TME) of pancreatic ductal adenocarcinoma (PDAC) will help to develop promising and innovative therapeutic strategies. However, the dynamics of immune cell lineages in the TME of advanced PDAC remains elusive.

As a putative marker of cerebral small vessel disease, cerebral microbleeds (CMBs) have been associated with vascular cognitive impairment. Both iron accumulation and amyloid protein precursor (APP) dysregulation are recognized as pathological hallmarks underlying the progression of CMBs, but their cross-talk is not yet understood. In this study, we found a profound increase of amyloid formation with increasing FeCl3treatment, and a distinct change in APP metabolism and expression of iron homeostasis proteins (ferritin, Fpn1, iron regulatory protein) was observed at the 300 uM concentration of FeCl3. Further results revealed that extracellular iron accumulation might potentially induce binding of APP to BACE1 for amyloid formation and decrease the capability of APP/Fpn1 in mediating iron export. Our findings in this study, reflecting a probable relationship between iron dyshomeostasis and amyloid pathology, may help shed light on the underlying pathogenesis of CMBs in vascular cognitive impairment.

Mechanical thrombectomy (MT) is effective in managing patients with acute ischemic stroke (AIS) caused by large-vessel occlusions and allows for valuable histological analysis of thrombi. However, whether bridging therapy (pretreatment with intravenous thrombolysis before MT) provides additional benefits in patients with middle cerebral artery (MCA) occlusion remains unclear. Therefore, this study aimed to compare the effects of direct MT and bridging therapy, and to elucidate the correlation between thrombus composition and stroke subtypes. Seventy-three patients with acute ischemic stroke who received MT, were eligible for intravenous thrombolysis, and had MCA occlusion were included. We matched 21 direct MT patients with 21 bridging therapy patients using propensity score matching and compared their 3rd-month clinical outcomes. All MCA thrombi (n = 45) were histologically analyzed, and the red blood cell (RBC) and fibrin percentages were quantified. We compared the clot composition according to stroke etiology (large-artery atherosclerosis and cardioembolism) and intravenous thrombolysis application. The baseline characteristics showed no difference between groups except for a higher atrial fibrillation rate and NIHSS score on admission in the direct MT group. We performed a supportive analysis using propensity score matching but could not find any differences in the functional outcome, mortality, and intracerebral hemorrhage. In the histological clot analysis, the cardioembolic clots without intravenous thrombolysis pretreatment had higher RBC (P = 0.042) and lower fibrin (P = 0.042) percentages than the large-artery atherosclerosis thrombi. Similar findings were observed in the thrombi treated with recombinant tissue plasminogen activator (P = 0.012). In conclusion, there was no difference in the functional outcomes between the direct MT and bridging therapy groups. However, randomized trials are needed to elucidate the high ratio of cardioembolism subtype in our group of patients. The histological MCA thrombus composition differed between cardioembolism and large-artery atherosclerosis, and this finding provides valuable information on the underlying pathogenesis and thrombus origin.

Background: Cognitive impairment can occur after aneurysmal subarachnoid hemorrhage (aSAH) though it commonly tends to be neglected. Red blood cell (RBC) indices are associated with long-term functional outcomes, while it is unclear whether RBC indices could be a potential predictor of cognitive decline after aSAH. We aimed to investigate the association between RBC indices and post-aSAH cognitive impairment at 1 year. Methods: Patients with aSAH received neuropsychological test by the Montreal Cognitive Assessment (MoCA) and underwent serum and cerebrospinal fluid (CSF) samples test. To determine the association between RBC indices and cognitive impairment after acute aSAH, we adjusted for demographic and vascular risk factors using multivariate logistic regression analysis. Results: Of the 126 patients included in this study, 33% (42/126) of them were diagnosed with cognitive impairment (MoCA#156;26). After adjustment for potential confounders, increased mean corpuscular volume (MCV) (OR: 1.36, 95%CI: 1.19-1.55) and mean corpuscular hemoglobin (MCH) (OR: 1.61, 95%CI: 1.25-2.08), reflecting systemic iron status, are more likely to be associated with cognitive impairment after aSAH. Conclusion: In this aSAH population, our data shows the positive association between MCH and MCV and cognitive impairment at 1 year.

ObjectiveIn the tumour microenvironment, critical drivers of immune escape include the oncogenic activity of the tumour cell-intrinsic osteopontin (OPN), the expression of programmed death ligand 1 (PD-L1) and the expansion of tumour-associated macrophages (TAMs). We investigated the feasibility of targeting these pathways as a therapeutic option in hepatocellular carcinoma (HCC) mouse models.DesignWe analysed the number of tumour-infiltrating immune cells and the inflammatory immune profiles in chemically induced liver tumour isolated from wild-type and OPNknockout (KO) mice. In vitro cell cocultures were further conducted to investigate the crosstalk between TAMs and HCC cells mediated by OPN, colony stimulating factor-1 (CSF1) and CSF1 receptor (CSF1R). The in vivo efficacy of anti-PD-L1 and CSF1/CSF1R inhibition was evaluated in OPN overexpressing subcutaneous or orthotopic mouse model of HCC.ResultsThe numbers of TAMs, as well as the expression levels of M2 macrophage markers and PD-L1 were significantly decreased, but the levels of cytokines produced by T-helper 1 (Th1) cells were upregulated in tumour tissues from OPN KO mice compared with that from the controls. In addition, we observed a positive association between the OPN and PD-L1 expression, and OPN expression and TAM infiltration in tumour tissues from patients with HCC. We further demonstrated that OPN facilitates chemotactic migration, and alternative activation of macrophages, and promotes the PD-L1 expression in HCC via activation of the CSF1-CSF1R pathway in macrophages. Combining anti-PD-L1 and CSF1R inhibition elicited potent antitumour activity and prolonged survival of OPNhightumour-bearing mice. Histological, flow cytometric and ELISA revealed increased CD8+T cell infiltration, reduced TAMs and enhanced Th1/Th2 cytokine balance in multiple mouse models of HCC.ConclusionsOPN/CSF1/CSF1R axis plays a critical role in the immunosuppressive nature of the HCC microenvironment. Blocking CSF1/CSF1R prevents TAM trafficking and thereby enhances the efficacy of immune checkpoint inhibitors for the treatment of HCC.

Hepatopulmonary syndrome (HPS) increases the mortality of patients who suffered from liver cirrhosis, especially patients plagued by severe hypoxemia. Gene polymorphisms are reported to be related to the risk of HPS in cirrhotic patients. Thus, our study aims to elucidate the correlation between MMP‐2 and MMP‐9 gene polymorphisms and HPS in cirrhotic patients. A total of 152 cirrhotic patients suffering from HPS as well as another 152 cirrhotic patients without HPS were recruited. Polymerase chain reaction‐restriction fragment length polymorphism (PCR‐RFLP) was performed for MMP‐2 and MMP‐9 gene polymorphisms and logistic regression analysis for the relationship between clinicopathological features and HPS occurrence in cirrhotic patients. There were significant differences in genotype and allele frequency of MMP‐2 rs243865 and MMP‐9 rs3918242 polymorphisms between the HPS and control groups. CC/CT genotype and C allele of MMP‐2 rs243865 polymorphism as well as CC/TT genotype and T allele of MMP‐9 rs3918242 polymorphism increased the risk of HPS in cirrhotic patients. Genotypes of rs243865 and rs3918242 polymorphisms had remarkable correlations with spider nevi, clubbed fingers (toes), transaminase elevation, portal vein width, esophageal varices, Child‐Pugh classification and partial pressure of arterial oxygen (PaO2). Logistic regression analysis showed that rs243865 and rs3918242 polymorphisms, spider nevi, clubbed fingers (toes), esophageal varices, and Child‐Pugh classification were closely associated with the occurrence of HPS in cirrhotic patients. Our findings demonstrate that MMP‐2 rs243865 polymorphism and MMP‐9 rs3918242 polymorphism can increase the risk of HPS occurrence in cirrhotic patients, which provides a potential target for prevention of HPS in cirrhotic patients.

Hepatopulmonary syndrome (HPS) increases the mortality of patients who suffered from liver cirrhosis, especially patients plagued by severe hypoxemia. Gene polymorphisms are reported to be related to the risk of HPS in cirrhotic patients. Thus, our study aims to elucidate the correlation between MMP-2 and MMP-9 gene polymorphisms and HPS in cirrhotic patients. A total of 152 cirrhotic patients suffering from HPS as well as another 152 cirrhotic patients without HPS were recruited. Polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) was performed for MMP-2 and MMP-9 gene polymorphisms and logistic regression analysis for the relationship between clinicopathological features and HPS occurrence in cirrhotic patients. There were significant differences in genotype and allele frequency of MMP-2 rs243865 and MMP-9 rs3918242 polymorphisms between the HPS and control groups. CC/CT genotype and C allele of MMP-2 rs243865 polymorphism as well as CC/TT genotype and T allele of MMP-9 rs3918242 polymorphism increased the risk of HPS in cirrhotic patients. Genotypes of rs243865 and rs3918242 polymorphisms had remarkable correlations with spider nevi, clubbed fingers (toes), transaminase elevation, portal vein width, esophageal varices, Child-Pugh classification and partial pressure of arterial oxygen (PaO2). Logistic regression analysis showed that rs243865 and rs3918242 polymorphisms, spider nevi, clubbed fingers (toes), esophageal varices, and Child-Pugh classification were closely associated with the occurrence of HPS in cirrhotic patients. Our findings demonstrate that MMP-2 rs243865 polymorphism and MMP-9 rs3918242 polymorphism can increase the risk of HPS occurrence in cirrhotic patients, which provides a potential target for prevention of HPS in cirrhotic patients.

Fifteen known amaryllidaceae alkaloids were isolated from the bulbs of Lycoris radiata. Some of the compounds and lycoricidine derivatives had been screened for the activities against tobacco mosaic virus (TMV) by the conventional half-leaf method. Lycoricidine derivatives were also carried out the assay of effect on systemic infection of TMV by western-blot and RT-PCR analysis. The tested compounds showed moderate inactivation effect, whereas the lycoricidine derivatives showed good protective effect. The protective inhibitory activity of compounds L1 (N-methyl-2,3,4-trimethoxylycoricidine) (60.8%) and L3 (N-methyl-2-methoxy-3,4-acetonidelycoricidine) (62.0%) was almost similar to the positive control, Ningnanmycin (66.4%). RT-PCR and Western-blot analysis displayed that compounds L1, L3, L5 (N-allyl-2,3,4-triallyloxylycoricidine) exhibited antiviral activity, which was evidenced by reducing TMV-CP gene replication and TMV-CP protein expression. Additionally, defensive enzyme activities confirmed that compound L1 could increase the activity of PAL, POD, SOD to improve disease resistance of tobacco.

The phytochemical study of Euphorbia resiniferaafforded 18 structurally diverse diterpenoids, including 14 new ingol-type diterpenoids, euphorblins A–N (1–14), a new rhamnofolane diterpenoid, euphorblin O (15), and three known analogues (16–18). The structures of these compounds were deduced using 2D NMR spectroscopy and NOE experiments. The structure of compound 1was confirmed by single-crystal X-ray crystallography. The abilities of the compounds to enhance lysosomal biosynthesis were evaluated through LysoTracker Red staining. Among the 10 active compounds, compounds 2, 4, and 18showed remarkable immunofluorescence strength, and their LysoTracker staining intensities were 155.9%, 143.5%, and 140.7%, respectively, greater than that of the control. A series of lysosomal genes were also found to be upregulated by these compounds, which further confirms their ability to induce lysosome biosynthesis and suggests that these diterpenoids have potential as lead compounds for the development of drugs for the treatment of lysosome-related diseases.

Using a longitudinal sample of young Chinese students (fall and spring in grades 1 and 2: times 1–4, respectively) and growth curve analysis, this study examined whether the initial status and growth rates of compounding awareness from time 1 to time 4 uniquely contribute to reading comprehension at time 4 and whether word‐reading efficiency at time 4 mediates the association between initial status and growth in compounding awareness and reading comprehension at time 4. The results indicated that initial status and growth rates of compounding awareness made a significant direct contribution to reading comprehension at the end of second grade after controlling for IQ, phonological awareness, and vocabulary knowledge. The relationship between initial status and growth rates of compounding awareness and reading comprehension were fully mediated by word‐reading efficiency. The findings underscore the importance of growth in compounding awareness for reading comprehension and add to the literature about the nature of the morphological awareness and reading comprehension relationship in Chinese. 本研究从中国小学生抽取一个纵向样本(研究数据的收集分别在秋季和春季进行:一、二年级各有1至4个数据收集时间点),并以增长曲线分析的方法,考查学生的词素复合意识的初始状态和从时间点1至4期间的增长速度,对时间点4的阅读理解是否有独特的贡献,并考查时间点4的单字阅读效率,对词素复合意识的初始状态和增长与时间点4的阅读理解之间的关联是否会有介导作用的影响。研究结果显示,词素复合意识的初始状态和增长速度,在控制了智商、语音意识、词汇知识后,对二年级期末的阅读理解有显著直接贡献;词素复合意识的初始状态和增长速度与阅读理解之间的关系,均完全受到单字阅读效率的介导作用影响。这些研究结果显示出词素复合意识的增长对阅读理解的重要性,并增添了研究中文词素意识与中文阅读理解关系性质的文献。 Usando una muestra longitudinal de estudiantes jóvenes chinos (otoño y primavera en los grados 1 y 2: de una a cuatro veces respectivamente) y un análisis de curva de crecimiento, este estudio examinó si el estado inicial y los índices del aumento en la conciencia de palabras compuestas desde la primera hasta la cuarte vez contribuyen excepcionalmente a la comprensión lectora en la cuarta vez, y si la eficacia en la lectura de palabras en la cuarta vez media la asociación entre el estado inicial y el aumento en la conciencia de palabras compuestas y la comprensión lectora la cuarta vez. Los resultados indicaron que el estado inicial y los índices de aumento de la conciencia de palabras compuestas contribuyeron de forma directa y significante a la comprensión lectora al finalizar el segundo grado después de controlar por el CI, la conciencia fonológica, y el conocimiento de vocabulario. La relación entre el estado inicial y el aumento de la conciencia de palabras compuestas y la comprensión lectora fueron totalmente mediadas por la eficacia en la lectura de palabras. Las conclusiones subrayan la importancia del aumento de la conciencia de palabras compuestas para la comprensión lectora y añaden a la literatura sobre la naturaleza de la relación entre la conciencia morfológica y la comprensión lectora en chino. باستخدام عينة طولية الأمد من الطلاب الصينيين (فصلي الخريف والربيع للصف 1 و 2: 1‐4 مرات، على التوالي)، وبتحليل منحنى النمو، تناولت هذه الدراسة ما إذا كان الوضع الأساسي ومعدلات النمو للوعي المركب يتضاعف من المرة 1 إلى المرة 4 تساهم إفرادياً في فهم القراءة في المرة (4) وبالإضافة تناولت هذه الدراسة اذا ما كانت كفاءة قراءة الكلمة في المرة 4 لها علاقة وصل بين الوضع الأساسي والنمو في تراكم الوعي والفهم في المرة 4. وأشارت النتائج إلى أن الوضع الأساسي ومعدلات النمو لتراكم الوعي قدمت مساهمة مباشرة وهامة لفهم القراءة في نهاية الصف الثاني بعد السيطرة على معدل الذكاء، والوعي اللفظي، ومعرفة المفردات. الوضع الأساسي ومعدلات النمو لتراكم الوعي والفهم لها علاقة وصل كاملة عن طريق كفاءة قراءة الكلمة. تؤكد هذه النتائج على أهمية النمو في تراكم الوعي للقراءة والفهم وأضف الى ذلك المقالات حول طبيعة علاقة الوعي الصرفي والفهم باللغة الصينية. Ha ocнoвe paзвepнyтoгo иccлeдoвaния млaдшиx шкoльникoв, пpoвeдeннoм в Китae (oceнью и вecнoй в 1 и 2 клaccax, в oбщeй cлoжнocти 4 paзa), и aнaлизa кpивoй pocтa, aвтopы paзбиpaлиcь, тoлькo ли изнaчaльнoe пoнимaниe зaкoнoв cлoвooбpaзoвaния и тeмпы eгo pocтa c пepвoгo дo чeтвepтoгo cpeзa cпocoбcтвyют пoнимaнию пpoчитaннoгo, a тaкжe являeтcя ли кaчecтвo чтeния oтдeльныx cлoв cвязyющим звeнoм мeждy нaвыкaми cлoвooбpaзoвaния и пoнимaниeм пpoчитaннoгo к кoнцy 2 клacca. Peзyльтaты пoкaзaли, чтo нaчaльный cтaтyc и тeмпы pocтa нaвыкoв cлoвooбpaзoвaния внocят нeпocpeдcтвeнный и cyщecтвeнный вклaд в пoнимaниe пpoчитaннoгo к кoнцy 2 клacca – c yчeтoм IQ, фoнoлoгичecкoгo пoнимaния и cлoвapнoгo зaпaca. A кaчecтвo чтeния oтдeльныx cлoв вceцeлo oпpeдeляeт oтнoшeния мeждy нaчaльным cтaтycoм и тeмпaми pocтa нaвыкoв cлoвooбpaзoвaния и пoнимaния пpoчитaннoгo. Пoдчepкивaeтcя вaжнocть paзвития нaвыкoв cлoвooбpaзoвaния для пoнимaния пpoчитaннoгo. Cтaтья зaймeт дocтoйнoe мecтo в cпиcкe литepaтypы o пpиpoдe мopфoлoгичecкoгo пoнимaния и чтeния тeкcтoв нa китaйcкoм языкe. En utilisant un échantillon longitudinal de jeunes élèves chinois (premier et dernier trimestre de 1eet 2eannée, vus 1 à 4 fois respectivement) et une analyse des courbes de développement, cette recherche se demande si le statut initial et les taux de progression de la conscience composite du temps 1 au temps 4 sont seuls à contribuer à la compréhension de la lecture au temps 4 ou si l'efficacité de la lecture de mots au temps 4 joue un rôle dans l'association entre le statut initial et les progrès de la conscience composite et de la compréhension au temps 4. Les résultats montrent que le statut initial et les taux de développement apportent une contribution directe et significative à la compréhension de la lecture en fin de 2eannée après contrôle du QI, de la conscience morphologique et de la connaissance du vocabulaire. Les relations entre le statut initial et les taux de développement de la conscience composite avec la compréhension de la lecture passent totalement par l'efficacité de la lecture des mots. Ces résultats minimisent l'importance du développement de la conscience composite dans la compréhension de la lecture et apportent une contribution à la littérature sur la nature des relations entre la conscience morphologique et la compréhension de la lecture en chinois.

Protein lysine crotonylation was recently identified as a vital posttranslational modification in cellular processes, particularly through the modification of histones. We show that lysine crotonylation is an important modification of the cytoplastic and mitochondria proteins. Enzymes in glycolysis, the tricarboxylic acid (TCA) cycle, fatty acid metabolism, glutamine metabolism, glutathione metabolism, the urea cycle, one-carbon metabolism and mitochondrial fusion/fission dynamics are found to be extensively crotonylated in pancreatic cancer cells. This modulation is mainly controlled by a pair of crotonylation writers and erasers including CBP/p300, HDAC1, and HDAC3. The dynamic crotonylation of metabolic enzymes is involved in metabolism regulation which is linked with tumor progression. Interestingly, the activation of MTHFD1 by decrotonylation at Lys354 and Lys553 promotes the development of pancreatic cancer by increasing resistance to ferroptosis. Our study suggests that crotonylation represents a metabolic regulatory mechanism in the pancreatic cancer progression.

Aberrant activation of receptor tyrosine kinases (RTKs) and the subsequent metabolic reprogramming play critical roles in cancer progression. Our previous study has shown that Golgi membrane protein 1 (GOLM1) promotes hepatocellular carcinoma (HCC) metastasis by enhancing the recycling of RTKs. However, how this RTK recycling process is regulated and coupled with RTK degradation remains poorly defined. Here, we demonstrate that cholesterol suppresses the autophagic degradation of RTKs in a GOLM1-dependent manner. Further mechanistic studies reveal that GOLM1 mediates the selective autophagy of RTKs by interacting with LC3 through an LC3-interacting region (LIR), which is regulated by a cholesterol-mTORC1 axis. Lowering cholesterol by statins improves the efficacy of multiple tyrosine kinase inhibitors (TKIs) in vivo. Our findings indicate that cholesterol serves as a signal to switch GOLM1-RTK degradation to GOLM1-RTK recycling and suggest that lowering cholesterol by statin may be a promising combination strategy to improve the TKI efficiency in HCC.

.Membrane bioreactor (MBR) is considered to be a promising technology for combine biological with filtration and many advantages over conventional activated sludge (CAS) processes. In this study, the submerged membrane bioreactor which was explored by our research group and JDL Environmental Protection Ltd. at condition of aerobic-MBR and SBR-MBR were investigated. Hydraulic characteristics of MBR by the tracer experiments showed the total dead space (Vd, %) in the MBR was 3.2%. Compared with aerobic-MBR situation, the SBR-MBR exhibited better performance of average NH4+-N, total nitrogen, and phosphorus removal efficiency 90%, 86%, 57% respectively. The content of protein was correlated to sludge activity and organic matter. The initial membrane fouling was caused by layer pollution and subsequently the extra-cellular polymeric substances (EPS) contributed.

Tissue factor (TF) expression on islets has been shown to trigger instant blood-mediated inflammatory reaction (IBMIR), leading to rapid islet loss in portal vein islet transplantation. This study investigated whether antisense RNA-mediated TF gene knockdown in islets could suppress IBMIR as a strategy to overcome IBMIR. Neonatal porcine islet cell clusters (NICCs) were transfected with or without TF-specific antisense RNA or a nonspecific RNA by a lipid-based method. Expression of both TF gene and protein in NICCs was analyzed after transfection by real-time PCR, Western blot, and FACS, respectively. The impact of antisense RNA transfection on NICC viability and in vitro function was examined by FACS and insulin release test, respectively. The effect of TF knockdown in NICCs on IBMIR was assessed with an in vitro tubing loop assay using human blood. A significant reduction in TF gene and protein expression was achieved in TF antisense RNA but not control RNA transfected NICCs, which did not affect NICCs' viability or their insulin secreting capacity. Incubation of TF antisense RNA transfected with human blood resulted in a considerable reduction in blood clot formation, platelet consumption, and complement and coagulation activation compared to that observed in the loops containing human blood and untreated or control RNA transfected NICCs. Consistent with these findings, infiltrating neutrophils in the blood clots with entrapped TF antisense RNA transfected NICCs was also reduced substantially compared to that seen in the clots containing untreated or control RNA transfected NICCs. This study presents a nontoxic TF antisense RNA-mediated TF knockdown in porcine islets that leads to an effective suppression of IBMIR, suggesting a potentially new strategy to improve islet transplantation outcomes.

Detection of lung cancer by sputum cytology has low sensitivity but is noninvasive and, if improved, could be a powerful tool for early lung cancer detection. To evaluate whether the accuracy of diagnosing lung cancer by evaluating sputa for cytologic atypia and genetic abnormalities is greater than that of conventional cytology alone, automated scoring of genetic abnormalities for 3p22.1 and 10q22.3 (SP-A) by fluorescence in situhybridization (FISH) and conventional cytology was done on sputa from 35 subjects with lung cancer, 25 high-risk smokers, and 6 healthy control subjects. Multivariate analysis was performed to select variables that most accurately predicted lung cancer. A model of probability for the presence of lung cancer was derived for each subject. Cells exfoliated from patients with lung cancer contained genetic aberrations and cytologic atypias at significantly higher levels than in those from control subjects. When combined with cytologic atypia, a model of risk for lung cancer was derived that had 74% sensitivity and 82% specificity to predict the presence of lung cancer, whereas conventional cytology achieved only 37% sensitivity and 87% specificity. For diagnosing lung cancer in sputum, a combination of molecular and cytologic variables was superior to using conventional cytology alone.

Based on in vitro studies, Rho guanine nucleotide exchange factors (RhoGEFs) are key regulators of mitogenic and transforming pathways. At least 1 family member, PDZ‐RhoGEF, also integrates signaling between monomeric Rho G proteins and heterotrimeric G proteins through a so‐called regulator of G‐protein signaling (RGS) domain. Recently, the authors reported that 3 single‐nucleotide polymorphisms (SNPs) in 2 members of the RGS family were associated with significant reductions in the risk of cancer.For the current report, the authors studied the risk of lung cancer associated with a nonsynonymous SNP (rs868188; Ser1416Gly) in PDZ‐RhoGEF in a large lung cancer case‐control study of 2260 Caucasians and 369 Mexican Americans.Compared with individuals who had the wild‐type genotype (AA), Mexican Americans with the variant genotypes (AG and GG) had a significantly reduced risk for lung cancer (odds ratio [OR], 0.57; 95% confidence interval [95%CI], 0.34‐0.94). The protective effect appeared to be more evident in younger individuals (OR, 0.42; 95%CI, 0.20‐0.91), men (OR, 0.36; 95%CI, 0.18‐0.71), and ever smokers (OR, 0.50; 95%CI, 0.29‐0.88). A joint effect was observed between Ser1416Gly and polymorphisms in 2 cell‐cycle control genes: p53 (intron 3) and cyclin D1 (CCND1). Tallying the variant alleles of the 4 RGS gene SNPs, a gene‐dosage effect was apparent. Compared with individuals who had <3 variant alleles, patients with ≥3 variant alleles had a 51% reduction in lung cancer risk (OR, 0.49; 95%CI, 0.28‐0.88).To the authors' knowledge, this is the first epidemiological study to link PDZ‐RhoGEF polymorphisms with cancer risk. The results suggest that there are interactions between RGS2, RGS6, and PDZ‐RhoGEF and validate this family of proteins as key regulators of tumorigenesis. Cancer 2006. © 2006 American Cancer Society.

Glutathione S‐transferase (GST) π (GSTP1) is a detoxification enzyme with substrate specificity for both exogenous carcinogens and chemotherapy agents. Genetic polymorphisms of GSTP1 exon 5 (Ile105Val) and exon 6 (Ala114Val) appear to reduce this enzyme's activity. Previously, the authors reported that the exon 6 variant was associated with an increased risk of lung carcinoma, particularly among men, younger patients, and ever smokers. In this study, the authors hypothesized that variant GSTP1 genotype would result in reduced inactivation of chemotherapy agents and improved survival in patients with advanced‐stage nonsmall cell lung carcinoma (NSCLC), a population that is likely to receive platinum‐based chemotherapy.Patients with Stage III and IV NSCLC who were enrolled in a molecular epidemiology study were identified, and a polymerase chain reaction‐restriction fragment length polymorphism assay was used to genotype GSTP1 exons 5 and 6 in 424 patients and 425 patients, respectively.Patients who had the exon 6 variant genotype (Ala/Val or Val/Val) had significantly better survival compared with patients who had the wild type genotype (Ala/Ala; P = 0.037), with median survival of 16.1 months and 11.4 months, respectively. Multivariate analysis revealed a reduced adjusted hazard ratio (HR) of death associated with the exon 6 variant genotype of 0.75 (95% confidence interval [95% CI], 0.54–1.05). This protective association was observed in younger patients (younger than age 62 yrs; HR, 0.59; 95% CI, 0.57–0.97) and in males (HR, 0.64; 95% CI, 0.41–0.99). GSTP1 exon 5 genotype was not associated with survival.GSTP1 exon 6 variant genotypes may be associated with improved survival among patients with Stage III and IV NSCLC. Cancer 2006. © 2005 American Cancer Society.

The authors set out to assess the correlation between smoking‐related second primary tumor (SPT) development and cigarette smoking habits after diagnosis and definitive treatment in patients with early‐stage head and neck squamous cell carcinoma who were enrolled in a placebo‐controlled randomized chemoprevention trial of 13‐cis‐retinoic acid.Longitudinal data collected for 10 years after the index diagnosis are presented for 1190 patients. Cox proportional hazards regression models were used to examine the effects of changes in smoking behavior on smoking‐related SPT development.One‐third of all patients who quit smoking within 12 months before randomization experienced recurrence, compared with 6.9% and 10.4% of all never‐smokers and former smokers, respectively. Approximately 16% of all current smokers stopped smoking, and nearly 22% of current smokers developed SPTs, compared with 14.5%, 13.2%, and 8.8% of all recent smokers, former smokers, and never‐smokers, respectively. The probability of developing a smoking‐related SPT was highest among patients who were current smokers at randomization. These patients, regardless of whether they ceased smoking during follow‐up, were nearly three times more likely than patients who had never smoked to develop a smoking‐related SPT. In contrast, former smokers and recent quitters who continued to abstain from smoking during follow‐up were approximately 1.5 times more likely to develop an SPT compared with patients who had never smoked.Patients who continue to smoke after the successful treatment of their index head and neck malignancies have a substantially higher risk of developing smoking‐related SPTs. Cancer 2004. © 2004 American Cancer Society.

The XRCC3 protein participates in DNA double-strand breaks and recombinational repair. A single C-to-T nucleotide change at codon 241 (Thr241Met) has been identified in the XRCC3 gene. Using a hospital-based case–control approach, the authors studied the XRCC3 polymorphism as a possible genetic risk factor for lung carcinoma in African Americans and Mexican Americans. A total of 112 patients with lung carcinoma were frequency matched with 190 control participants on the basis of age, gender, and ethnicity. Polymerase chain reaction-restriction fragment length polymorphism molecular analysis was used successfully to identify the XRCC3 polymorphism in peripheral blood lymphocytes. No significant association between the XRCC3 variant allele polymorphism (odds ratio [OR], 1.25; 95% confidence interval [95% CI], 0.72–2.15) and lung carcinoma risk was noted. However, a significantly increased risk for lung carcinoma (OR, 5.20; 95% CI, 1.59–17.03) was evident in heavy smokers with the variant T-allele genotypes. Furthermore, a joint effect of the T-allele and heavy smoking was observed (OR, 37.31; 95% CI, 11.43–121.72). The XRCC3 polymorphism appeared to be associated with increased risk of lung carcinoma in certain subgroups. It is plausible that the association is very heavily dependent on the degree of smoking. Further studies with larger sample sizes will be necessary to confirm these findings. Cancer 2003. © 2003 American Cancer Society. DOI 10.1002/cncr.11692

Objective: This study evaluated the joint effects of tobacco smoking and alcohol consumption on the risk of second primary tumors (SPT) in patients with early-stage head and neck squamous cell carcinoma (HNSCC). Methods: Data are presented for 1181 patients enrolled in a placebo-controlled chemoprevention trial of 13-cis-retinoic acid. Nearly 17% of patients presented with a SPT. The log rank test and Cox proportional hazards model were used to examine risk factors for SPT development. Results: After adjusting for the time from the index diagnosis to randomization, age at diagnosis, stage, and site of the primary cancer, the factors that emerged as simultaneous predictors of SPT development were continued smoking and alcohol intake after the index diagnosis. Increased SPT risk was associated with older age (RR = 2.1; 95% CI 1.5–2.8); stage II diagnosis (RR = 1.5; 95% CI 1.1–2.1); index diagnosis of pharyngeal cancer (RR = 1.6; 95% CI 1.1–2.5); current smoking at registration (RR = 2.1; 95% CI 1.3–3.6) and continued alcohol consumption post-diagnosis (RR = 1.3; 95% CI 1.0–1.7). Conclusion: Important associations exist between SPT development and continued smoking and alcohol consumption after treatment for HNSCC.

Correction to: Mod Pathol 2008; 21: 950–960; doi:10.1038/modpathol.2008.71; published online 23 May 2008 In this article, the author has made the following corrections: Page 952, Table 1 has been corrected (see revised table below). Page 953, right column, third paragraph (Comparison of Patient Characteristics, Genetic Changes in Sputum and Cancer Status), beginning from third line, after '(Table 1).

Correction to: Modern Pathology advance online publication 23 May 2008; doi:10.1038/modpathol.2008.71; Modern Pathology (2008) 21, 950–960; doi:10.1038/modpathol.2008.71 In this article, two authors' names were listed incorrectly. The correct author names are Xiaoying Gao and Feng Jiang.