Tea is supposed to have chemopreventive effect against various cancers. However, the protective role of tea in prostate cancer is still controversial. The aim of this study is to elucidate the association between tea consumption and prostate cancer risk by meta-analysis.
A total of 21 published articles were retrieved via both computerized searches and review of references. Estimates of OR/RR for highest versus non/lowest tea consumption levels were pooled on the basis of random effect model or fixed effect model as appropriate. Stratified analyses on tea type, population and study design were also conducted.
No statistical significance was detected between tea consumption and prostate cancer risk in meta-analysis of all included studies (odds ratio (OR) = 0.86, 95% CI (0.69-1.04)). Furthermore, stratified analyses on population (Asian, OR = 0.81, 95% CI (0.55-1.08); non-Asian, OR = 0.89, 95% CI (0.72-1.07)) and tea type (green tea, OR = 0.79, 95% CI (0.43-1.14); black tea, OR = 0.88, 95% CI (0.73-1.02)) also yielded non-significant association. Only the case–control study subgroup demonstrated a borderline protective effect for tea consumption against prostate cancer (OR = 0.77, 95% CI (0.55-0.98)).
Our analyses did not support the conclusion that tea consumption could reduce prostate cancer risk. Further epidemiology studies are needed.
Prostate cancer; Tea; Meta-analysis
Chronic stable angina pectoris (CSAP) is a common cardiovascular condition that endangers a patient’s life quality and longevity. As demonstrated in several clinical trials, acupuncture is attested to be effective for CSAP. Current trials are not adequate enough to provide high-quality evidence for clinical decision making, as a result of inadequate methodology design and small sample size. Notably, stark controversy toward acupoint specificity also exists in the clinical acupuncture trials for CSAP. Therefore, we designed the present study as a randomized controlled trial primarily to investigate the effectiveness of acupuncture in addition to routine care among patients with CSAP. Meanwhile, we examined whether acupoint on the disease-affected meridian (DAM) is superior to either acupoint on the non-affected meridian (NAM) or non-acupoint (NA), to further investigate the meridian-based characteristics of acupoint specificity.
This study was a multicenter, assessor and statistician blinded, randomized controlled trial in China. In this study, 404 participants in sum will be randomly assigned to four groups through central randomization in a 1:1:1:1 ratio. The whole study period is 20 weeks including a 4-week baseline period, a 4-week treatment period and a 12-week follow-up. Participants in the DAM group receive acupuncture stimulation at acupoints on the disease-affected meridian, and three different control groups will undergo acupuncture stimulation at the NAM, the non-acupoint and no intervention respectively, in addition to basic treatment. Participants in the acupuncture groups will receive 12 sessions of acupuncture treatment over 4 weeks, while the wait-listed (WL) group would receive free acupuncture treatment after the completion of the study. The outcome measures in this trial include the frequency of angina attack during 4 weeks as the primary outcome and eight other secondary outcomes.
This trial will provide new and relatively high-quality evidence in acupuncture treatment for CSAP. Moreover, this trial may further validate the meridian-based characteristics of acupoint specificity by comparing the strength of acupoints on the disease-affected meridian versus that of the non-affected meridian, to further inspire optimization of acupuncture therapy for CSAP.
Clinical Trials.gov NCT01686230
Chronic stable angina pectoris; Acupuncture; Acupoint specificity; Randomized controlled trial
To compare three continuous glucose monitoring (CGM) devices in subjects with type 1 diabetes under closed-loop blood glucose (BG) control.
RESEARCH DESIGN AND METHODS
Six subjects with type 1 diabetes (age 52 ± 14 years, diabetes duration 32 ± 14 years) each participated in two 51-h closed-loop BG control experiments in the hospital. Venous plasma glucose (PG) measurements (GlucoScout, International Biomedical) obtained every 15 min (2,360 values) were paired in time with corresponding CGM glucose (CGMG) measurements obtained from three CGM devices, the Navigator (Abbott Diabetes Care), the Seven Plus (DexCom), and the Guardian (Medtronic), worn simultaneously by each subject. Errors in paired PG–CGMG measurements and data reporting percentages were obtained for each CGM device.
The Navigator had the best overall accuracy, with an aggregate mean absolute relative difference (MARD) of all paired points of 11.8 ± 11.1% and an average MARD across all 12 experiments of 11.8 ± 3.8%. The Seven Plus and Guardian produced aggregate MARDs of all paired points of 16.5 ± 17.8% and 20.3 ± 18.0%, respectively, and average MARDs across all 12 experiments of 16.5 ± 6.7% and 20.2 ± 6.8%, respectively. Data reporting percentages, a measure of reliability, were 76% for the Seven Plus and nearly 100% for the Navigator and Guardian.
A comprehensive head-to-head-to-head comparison of three CGM devices for BG values from 36 to 563 mg/dL revealed marked differences in performance characteristics that include accuracy, precision, and reliability. The Navigator outperformed the other two in these areas.
Persistent signaling by the oncogenic epidermal growth factor receptor (EGFR) is a major source of cancer resistance to EGFR targeting. We established that inactivation of two sterol biosynthesis pathway genes, SC4MOL (sterol C4-methyl oxidase-like) and its partner NSDHL (NADP-dependent steroid dehydrogenase-like), sensitized tumor cells to EGFR inhibitors. Bioinformatics modeling of interactions for the sterol pathway genes in eukaryotes allowed us to hypothesize, and then extensively validate an unexpected role for SC4MOL and NSDHL in controlling the signaling, vesicular trafficking and degradation of EGFR and its dimerization partners, ERBB2 and ERBB3. Metabolic block upstream of SC4MOL with ketoconazole or CYP51A1 siRNA rescued cancer cell viability and EGFR degradation. Inactivation of SC4MOL markedly sensitized A431 xenografts to cetuximab, a therapeutic anti-EGFR antibody. Analysis of Nsdhl-deficient Bpa1H/+ mice confirmed dramatic and selective loss of internalized PDGFR in fibroblasts, and reduced activation of EGFR and its effectors in regions of skin lacking NSDHL.
Acupuncture is a commonly used therapy for treating functional diarrhea (FD), although there is limited knowledge on the mechanism. The objectives of this study were to investigate the differences in brain activities elicited by acupuncture between FD patients and healthy controls (HC) so as to explore the possible mechanism. Eighteen FD patients and eighteen HC received 10 sessions of acupuncture treatment at ST25 acupoints. Functional magnetic resonance imaging (fMRI) scans were, respectively, performed before and after acupuncture. The defecation frequency, Bristol stool form scale (SBFS), and MOS 36-item Short Healthy Survey (SF-36) were employed to evaluate the clinical efficacy. After acupuncture, the FD patients showed a significant decrease in defecation frequency and BSFS score. The regional homogeneity (ReHo) map showed a decrease in the paracentral lobule and postcentral gyrus, and an increase in the angular gyrus, insula, anterior cingulate cortex (ACC), and precuneus in the FD group. Moreover, the changes in ReHo values in the ACC were correlated with the reduction in defecation frequency. Decreasing functional connectivity among the ACC, insula, thalamus, and orbital frontal cortex only existed in the FD group. Conclusively, acupuncture alleviated defecation frequency and improved stool formation in FD patients. The efficacy might result from the regulation of the homeostasis afferent processing network.
Processing of Aβ-precursor protein (APP) plays an important role in Alzheimer’s disease (AD) pathogenesis. The APP intracellular domain contains residues important in regulating APP function and processing, in particular the 682YENPTY687 motif. To dissect the functions of this sequence in vivo, we created an APP knock-in allele mutating Y682 to Gly (APPYG/YG mice). This mutation alters processing of APP and TrkA signaling, and leads to postnatal lethality and neuromuscular synapse defects when expressed on an APP-like protein 2 KO background. This evidence prompted us to characterize further the APPYG/YG mice. Here, we show that APPYG/YG mice develop aging-dependent decline in cognitive and neuromuscular functions, a progressive reduction in dendritic spines, cholinergic tone and TrkA levels in brain regions governing cognitive and motor functions. These data are consistent with our previous findings linking NGF and APP signaling and suggest a causal relationship between altered synaptic connectivity, cholinergic tone depression and TrkA signaling deficit, and cognitive and neuromuscular decline in APPYG/YG mice. The profound deficits caused by the Y682 mutation underscore the biological importance of APP and indicate that APPYG/YG are a valuable mouse model to study APP functions in physiological and pathological processes.
Amyloid Precursor Protein; YENTP domain; Alzheimer’s Disease; Dendritic spines; Cholinergic system; TrkA receptor; behavior
Alzheimer’s disease (AD), the most common cause of dementia in the elderly, has two pathological hallmarks: Aβ plaques and aggregation of hyperphosphorylated tau (p-tau). Aβ is a cleavage product of Amyloid Precursor Protein (APP). Presenilin 1 (PS1) and presenilin 2 (PS2) are the catalytic subunit of γ-secretase, which cleaves APP and mediates Aβ production. Genetic mutations in APP, PSEN1 or PSEN2 can lead to early onset of familial AD (FAD). Although mutations in the tau encoding gene MAPT leads to a subtype of frontotemporal dementia and these mutations have been used to model AD tauopathy, no MAPT mutations have been found to be associated with AD.
To model AD pathophysiology in mice without the gross overexpression of mutant transgenes, we created a humanized AD mouse model by crossing the APP and PSEN1 FAD knock-in mice with the htau mice which express wildtype human MAPT genomic DNA on mouse MAPT null background (APP/PS1/htau). The APP/PS1/htau mice displayed mild, age-dependent, Aβ plaques and tau hyperphosphorylation, thus successfully recapitulating the late-onset AD pathological hallmarks. Selected biochemical analyses, including p-tau western blot, γ-secretase activity assay, and Aβ ELISA, were performed to study the interaction between Aβ and p-tau. Subsequent behavioral studies revealed that the APP/PS1/htau mice showed reduced mobility in old ages and exaggerated fear response. Genetic analysis suggested that the fear phenotype is due to a synergic interaction between Aβ and p-tau, and it can be completely abolished by tau deletion.
The APP/PS1/htau model represents a valuable and disease-relevant late-onset pre-clinical AD animal model because it incorporates human AD genetics without mutant protein overexpression. Analysis of the mice revealed both cooperative and independent effects of Aβ and p-tau.
To complement the molecular pathways contributing to Parkinson's disease (PD) and identify potential biomarkers, gene expression profiles of two regions of the medulla were compared between PD patients and control. GSE19587 containing two groups of gene expression profiles [6 dorsal motor nucleus of the vagus (DMNV) samples from PD patients and 5 from controls, 6 inferior olivary nucleus (ION) samples from PD patients and 5 from controls] was downloaded from Gene Expression Omnibus. As a result, a total of 1569 and 1647 differentially expressed genes (DEGs) were, respectively, screened in DMNV and ION with limma package of R. The functional enrichment analysis by DAVID server (the Database for Annotation, Visualization and Integrated Discovery) indicated that the above DEGs may be involved in the following processes, such as regulation of cell proliferation, positive regulation of macromolecule metabolic process, and regulation of apoptosis. Further analysis showed that there were 365 common DEGs presented in both regions (DMNV and ION), which may be further regulated by eight clusters of microRNAs retrieved with WebGestalt. The genes in the common DEGs-miRNAs regulatory network were enriched in regulation of apoptosis process via DAVID analysis. These findings could not only advance the understandings about the pathogenesis of PD, but also suggest potential biomarkers for this disease.
Biased signaling has been reported with a series of G protein-coupled receptors (GPCRs), including β2-adrenergic receptor and μ-opioid receptor (OPRM1). The concept of biased signaling suggests that the agonists of one particular receptor may activate the downstream signaling pathways with different efficacies. Thus in an extreme case, agonists might activate different sets of signaling pathways, which provide a new route to develop drugs with increased efficacies and decreased side effects. Among the many factors, posttranslation modifications of receptor proteins have major roles in influencing the biased signaling. Take OPRM1, for example, the phosphorylation and palmitoylation of receptor can regulate the biased signaling induced by agonists. Thus, by modulating these posttranslation modifications, the biased signaling of GPCRs can be regulated. In addition, although it is not considered as posttranslation modification normally, the distribution of GPCRs on cell membrane, especially the distribution between lipid-raft and non-raft microdomains, also contributes to the biased signaling. Thus in this chapter, we described the methods used in our laboratory to study receptor phosphorylation, receptor palmitoylation, and membrane distribution of receptor by using OPRM1 as a model. A functional model was also provided on these posttranslational modifications at the last section of this chapter.
We investigated the correlation between obestatin and metabolic parameters and carotid intima-media thickness (IMT) in plasma of patients with type 2 diabetes mellitus (T2DM). We collected 103 patients aged from 60 to 83 years (69.26 ± 5.83 years) form January, 2007 to May, 2009. All patients were divided into normal glucose tolerance (NGT), impaired glucose tolerance (IGT), and T2DM according to the oral glucose tolerance test (OGTT). We found that higher levels of fasting insulin (Fins), fasting blood glucose, 2 h OGTT glucose, homeostasis model assessment of insulin resistance (HOMA-IR), low density lipoprotein cholesterol, glycated haemoglobin, and C-reactive protein (CRP), as well as lower obestatin level and higher intima-media thickness level (IMT), existed in T2DM group compared with NGT group and IGT group (P < 0.01). Also, obestatin level was independently associated with HOMA-IR and CRP, while IMT level was independently associated with HOMA-IR, triglyceride, Fins, and obestatin (P < 0.01), based on stepwise multiple regression analysis. Therefore, we deduced that the low level of plasma obestatin might be related to early arteriosclerosis in patients with T2DM via increasing IMT level, and elevated plasma obestatin levels might protect T2DM patients against carotid atherosclerosis to some extent.
Micro-RNAs typically function at the level of post-transcriptional gene silencing within the cytoplasm; however increasing evidence suggests that they may also function in nuclear, Argonaut containing complexes, to directly repress target gene transcription. We have investigated the role of micro-RNAs in mediating endoplasmic reticulum (ER) stress responses. ER stress triggers the activation of three signaling molecules: Ire-1α/β, PERK and ATF6 whose function is to facilitate adaption to the ensuing stress. We demonstrate that PERK induces miR-211, which in turn attenuates stress-dependent expression of the pro-apoptotic transcription factor chop/gadd153. MiR-211 directly targets the proximal chop/gadd153 promoter where it increases histone methylation and represses chop expression. Maximal chop accumulation ultimately correlates with miR-211 down regulation. Our data suggests a model where PERK-dependent miR-211 induction prevents premature chop accumulation and thereby provides a window of opportunity for the cell to re-establish homeostasis prior to apoptotic commitment.
miR-211; histone methylation; PERK; CHOP
Alzheimer’s Disease (AD) is often accompanied by changes in mood as well as increases in circulating cortisol levels, suggesting that regulation of the stress responsive Hypothalamic-Pituitary-Adrenal (HPA) axis is disturbed. Here, we show that APP is endogenously expressed in important limbic, hypothalamic, and midbrain nuclei that regulate HPA axis activity. Furthermore, in a knock-in mouse model of AD that expresses familial AD (FAD) mutations of both APP with humanized Aβ, and PS1, in their endogenous patterns (APP/hAβ/PS1 animals), Corticotropin Releasing Factor (CRF) levels are increased in key stress-related nuclei, resting corticosteroid levels are elevated and animals display increased anxiety-related behavior. Endocrine and behavioral phenotypes can be normalized by loss of one copy of Corticotropin Releasing Factor Receptor type-1 (Crfr1), consistent with a perturbation of central CRF signaling in APP/hAβ/PS1 animals. However, reductions in anxiety and corticosteroid levels conferred by hemizygosity of Crfr1 do not improve a deficit in working memory observed in APP/hAβ/PS1 mice, suggesting that perturbations of the CRF system are not the primary cause of decreased cognitive performance.
Corticotropin Releasing Factor; CRF; CRH; CRFR1; CRHR1; HPA axis; Alzheimer’s Disease; corticosteroids; APP; Presenilin; anxiety; depression
The instant-treatment effect of acupuncture for patients with migraines has been corroborated in numerous studies. However, most diseases are chronic and tend to recur, so the long-term effect of acupuncture can verify the existence of sustained efficacy or the placebo effect. Evaluating the efficacy of acupuncture in the prophylaxis of migraine without aura (MWoA) in China is also important because such studies are lacking.
This trial is a multicenter, prospective, pragmatic randomized controlled clinical trial. We will randomly allocate 249 participants to three groups of 83. Patients in the individualized acupoint group will be treated with individualized acupuncture point prescriptions. The non-acupoint control group will undergo insertion of acupuncture needles at four bilateral non-points in locations not corresponding to acupuncture points. The waiting-list control group will not undergo treatment but instead will receive 20 acupuncture treatments for free after a waiting period of 24 weeks. Participants in the individualized acupoint group and non-acupoint control group will receive 20 sessions over four weeks and then all participants will receive 20 weeks of follow-up.
The results of our trial will help to supply evidence for the long-term acupuncture effect for MWoA in a long follow-up period, and special attention will be paid to comparison with the placebo effect.
The trial was registered at ClinicalTrials.gov (NCT01687660) on 18 September 2012.
Study protocol; Pragmatic randomized controlled trial; Acupuncture; Migraine without aura
Pancreatic ductal adenocarcinoma represents 90% of pancreatic cancers and is an important cause of cancer death in the United States. Operative resection remains as the only treatment providing prolonged survival, but even after a curative resection, 5-year survival rates are low. Our aim was to identify the prognostic factors for long-term survival after resection of pancreatic ductal adenocarcinoma related to patients, treatments, and tumor biology.
Retrospective review identified 959 patients who underwent resection of their pancreatic adenocarcinoma between February 1985 and December 2010, of whom 499 were resected before November 2006 and represent the cohort we describe in this study. Patient, tumor, and treatment-related variables were assessed for their associations with 5- and 10-year overall survival.
Of the 499 patients, 49% were female and median age was 65 years. The majority of patients had stage IIb disease (60%). Actual 5-year survival after resection of pancreatic adenocarcinoma was 19% (95/499), and actual 10-year survival was 10% (33/329). Significant clinicopathologic factors predicting 5- and 10-year survival were negative margins and negative nodal status. Interestingly, 41% (39/95) of long-term survivors had positive nodes and 24% (23/95) had positive margins.
Pancreatic ductal adenocarcinoma demonstrates a very heterogeneous biology, but patients with negative resection margins and node negative cancers are more likely to survive 5 years after resection. However, our series demonstrates that the biology of the cancer rather than simple pathologic factors determine a patient’s prognosis.
Pancreatic fistula is a major source of morbidity after distal pancreatectomy (DP). We reviewed 462 consecutive patients undergoing DP to determine if the method of stump closure impacted fistula rates.
A retrospective review of clinicopatologic variables of patients who underwent DP between February 1994 and February 2008 was performed. The International Study Group classification for pancreatic fistula was utilized (Bassi et al., Surgery, 138(1):8–13, 2005).
The overall pancreatic fistula rate was 29% (133/462). DP with splenectomy was performed in 321 (69%) patients. Additional organs were resected in 116 (25%) patients. The pancreatic stump was closed with a fish-mouth suture closure in 227, of whom 67 (30%) developed a fistula. Pancreatic duct ligation did not decrease the fistula rate (29% vs. 30%). A free falciform patch was used in 108 patients, with a fistula rate of 28% (30/108). Stapled compared to stapled with staple line reinforcement had a fistula rate of 24% (10/41) vs. 33% (15/45). There is no significant difference in the rate of fistula formation between the different stump closures (p=0.73). On multivariate analysis, BMI>30 kg/m2, male gender, and an additional procedure were significant predictors of pancreatic fistula.
The pancreatic fistula rate was 29%. Staplers with or without staple line reinforcement do not significantly reduce fistula rates after DP. Reduction of pancreatic fistulas after DP remains an unsolved challenge.
Distal pancreatectomy; Pancreatic fistula
An inducible activation approach is used to interrogate the positive feedback circuit underlying self-amplification of PI3K signals in fibroblasts. The results show that local positive feedback between PI3K and HRas drives asymmetric membrane extension and cell migration.
Self-amplification of phosphoinositide 3-kinase (PI3K) signaling is believed to regulate asymmetric membrane extension and cell migration, but the molecular organization of the underlying feedback circuit is elusive. Here we use an inducible approach to synthetically activate PI3K and interrogate the feedback circuitry governing self-enhancement of 3′-phosphoinositide (3-PI) signals in NIH3T3 fibroblasts. Synthetic activation of PI3K initially leads to uniform production of 3-PIs at the plasma membrane, followed by the appearance of asymmetric and highly amplified 3-PI signals. A detailed spatiotemporal analysis shows that local self-amplifying 3-PI signals drive rapid membrane extension with remarkable directional persistence and initiate a robust migratory response. This positive feedback loop is critically dependent on the small GTPase HRas. Silencing of HRas abrogates local amplification of 3-PI signals upon synthetic PI3K activation and results in short-lived protrusion events that do not support cell migration. Finally, our data indicate that this feedback circuit is likely to operate during platelet-derived growth factor–induced random cell migration. We conclude that positive feedback between PI3K and HRas is essential for fibroblasts to spontaneously self-organize and generate a productive migratory response in the absence of spatial cues.
Acute hepatitis C virus infection is associated with high rates of spontaneous clearance and variable rates of treatment-induced clearance. The benefit of early treatment versus awaiting spontaneous clearance is unknown, as is the optimal timing of treatment.
We performed a MEDLINE and EMBASE search for the time period 1950 to October 2008. All English language abstracts using the search terms acute hepatitis C, hepatitis C and acute and hepatitis C and acute disease or acute infection were reviewed. Bibliographies were reviewed.
Twenty-two studies including 1075 patients met inclusion criteria. The sustained virologic response (SVR) rate for treated patients was 78%, significantly higher than 55.1% in untreated patients (OR =3.08, 95% CI 1.8-4.8 p value<0.0001). Mean time from diagnosis to spontaneous clearance was 9.7 weeks (SD 6.5). SVR rates varied inversely with time from acute HCV diagnosis. SVR rates for treatment within 12 weeks was 82.5% (95% CI 75.6-89.3), significantly better than the clearance rates in untreated patients (p<0.001). Response rates fell to 66.9% for treatment between 12 and 24 weeks, and decreased further to 62.5% for treatment beyond 24 weeks.
Rates of viral clearance in treated patients with acute hepatitis C virus infection were significantly higher than that in untreated patients. Treatment rates were highest when treatment was initiated within 12 weeks of diagnosis. Based on these findings, we would advocate a 12 week period of observation for spontaneous clearance before treatment initiation. If no clearance has occurred by 12 weeks, treatment should be initiated.
acute hepatitis C; meta-analysis; spontaneous clearance; sustained virologic response
With only a third of Latinos achieving sustained virologic response (SVR), there is a need for enhanced HCV treatment. Amantadine has been proposed to improve response rates in addition to standard therapy with peginterferon a and ribavirin. Our objective is to evaluate whether triple therapy with amantadine improves SVR rates in this special population.
Treatment-naíe Latino subjects with HCV genotype 1 infection were randomized to receive peginterferon [alpha]-2a plus weight-based ribavirin for 48 weeks (double therapy) or the same regimen plus amantadine 200 mg daily (triple therapy). The primary endpoint was SVR. Predictors of liver fibrosis using APRI and Forns indices were also evaluated.
We enrolled 124 patients with chronic hepatitis C genotype 1. Sixty-three received conventional therapy and 61 patients had triple therapy with amantadine. SVR at week 72 was achieved in 25 patients (39.7%) vs. 26 patients (42.6%) in the double and triple regimen, respectively (p = 0.561).After multivariate analysis, advanced fibrosis, obesity, and low pretreatment ALT levels were associated with non-response in both groups (p = 0.0234, p = 0.0012, p = 0.0249, respectively). APRI values delimited an area under the ROC curve (AUROC) of 0.724 and Forns index with AUROC of 0.733. There was no difference between both indices in predicting significant fibrosis (Knodell index: F3-F4).
Our study demonstrates that the addition of amantadine to standard treatment of chronic HCV does not improve SVR rates in Latino patients with genotype 1. Further research to improve response rates in this special population is needed.
Chronic hepatitis C; Amantadine; Latino; Peginterferon; Sustained virological response
Hepatitis B reactivation is a well-described complication in patients with inactive chronic hepatitis B receiving chemotherapy. Screening for HBV and preemptive therapy are recommended. However, the rates of HBV screening, prophylaxis and reactivation during rituximab-containing chemotherapy are unknown.
Patients and methods
We performed a retrospective study of patients with non-Hodgkin lymphoma (NHL) who received rituximab between August 1997 and September 2009. We evaluated patients for hepatitis B serologies, antiviral prophylaxis and hepatitis B reactivation during or up to 6 months after chemotherapy.
One thousand four hundred twenty nine patients underwent rituximab-containing chemotherapy for NHL. Hepatitis B serologies were documented in 524 (36.6%) patients. Of these, 20 (3.8 %) were HBsAg positive and 10 (50%) experienced HBV reactivation. Only half (5/10) had HBV serology documented prior to reactivation. Only 3/8 (37.5%) of patients with newly documented HBsAg positivity received antiviral prophylaxis. Virologic breakthrough occurred in 2 of the patients on chronic therapy, in one of three inactive carriers on prophylaxis and in 2 of 5 patients not receiving prophylaxis. Reactivation developed in another 5 patients not previously screened for hepatitis B. One patient developed ALF and died. Reactivation did not occur in 25 patients with isolated positive core antibody.
At tertiary care institutions hepatitis B serologies are infrequently assessed prior to rituximab-based chemotherapy and prophylaxis is uncommon. Greater adherence to recommendations for screening and prophylaxis is necessary. This suboptimal screening rate could be even lower in community hospitals and could result in significant harm to unscreened and unprophylaxed patients.
Chemotherapy; HBV Reactivation; Hepatitis B; HBV prophylaxis; Non-Hodgkin lymphoma; Rituximab
Neuroinflammation plays an important role in the pathogenesis of Parkinson’s disease (PD), inducing and accelerating dopaminergic (DA) neuron loss. Autophagy, a critical mechanism for clearing misfolded or aggregated proteins such as α-synuclein (α-SYN), may affect DA neuron survival in the midbrain. However, whether autophagy contributes to neuroinflammation-induced toxicity in DA neurons remains unknown.
Intraperitoneal injection of lipopolysaccharide (LPS, 5 mg/kg) into young (3-month-old) and aged (16-month-old) male C57BL/6J mice was observed to cause persistent neuroinflammation that was associated with a delayed and progressive loss of DA neurons and accumulation of α-SYN in the midbrain. The autophagic substrate-p62 (SQSTM1) persistently increased, whereas LC3-II and HDAC6 exhibited early increases followed by a decline. In vitro studies further demonstrated that TNF-α induced cell death in PC12 cells. Moreover, a sublethal dose of TNF-α (50 ng/ml) increased the expression of LC3-II, p62, and α-SYN, implying that TNF-α triggered autophagic impairment in cells.
Neuroinflammation may cause autophagic impairment, which could in turn result in DA neuron degeneration in midbrain.
MKC-1 is an orally available cell cycle inhibitor with downstream targets that include tubulin and the importin-β family. We conducted an open-label Phase II study with MKC-1 in patients with advanced pancreatic cancer.
Eligibility criteria included unresectable or metastatic pancreatic cancer, performance status of 1 or better, and failure of at least one prior regimen of chemotherapy. MKC-1 was administered orally, twice daily, initially at 100mg/m2 dosing for 14 consecutive days of a 28-day cycle. This schedule was modified during the trial to fixed and continuous dosing of 150mg per day.
20 of an original target of 33 patients were accrued, with a median age of 61 (range 44 to 81). No objective responses were observed, with one patient demonstrating stable disease. Overall survival was 101 days from the start of MKC-1 administration, and median time to progression was 42 days. The most common adverse events listed as related or possibly related to MKC-1 administration were hematologic toxicities and fatigue. One patient developed grade 5 (fatal) pancytopenia. Grade 3 and 4 events included cytopenias (lymphopenia, anemia), hyperbilirubinemia, pneumonia, mucositis, fatigue, infusion reaction, anorexia, and hypoalbuminemia.
MKC-1 administration was associated with substantial toxicity and did not demonstrate sufficient activity in patients with advanced pancreatic cancer to justify further exploration in this patient population.
Pancreatic cancer; Phase II; MKC-1; importin; tubulin
Whether acupuncture is efficacious for patients with functional dyspepsia is still controversial. So we designed a randomised controlled trial to settle the problem.
Methods and analysis
We designed a multicentre, two-arm, sham-controlled clinical trial. 200 participants with functional dyspepsia will be randomly assigned to the true acupuncture (TA) group and sham acupuncture (SA) group in a 1:1 ratio. Participants in the TA group will receive acupuncture at points selected according to syndrome differentiation. Participants in the sham acupuncture group will receive penetrations at sham points. Participants in both groups will receive 20 sessions of electroacupuncture in 4 weeks, five times continuously with a 2 day rest in a week. The primary outcome is the proportion of patients reporting the absence of dyspeptic symptoms at 16 weeks after inclusion. The secondary outcome includes a Short-Form Leeds Dyspepsia Questionnaire, the Chinese version of the 36-Item Short Form Survey, the Chinese version of the Nepean dyspepsia index, etc.
Ethics and dissemination
The study protocol has been approved by the institutional review boards and ethics committees of the first affiliated hospital of Chengdu University of TCM, the first affiliated hospital of Hunan University of TCM and Chongqing Medical University, respectively (from April to August 2012). The results of this trial will be disseminated in a peer-reviewed journal and presented at international congresses.
Complementary Medicine; Epidemiology; Gastroenterology
Vectors based on adeno-associated virus (AAV) are effective in gene delivery in vivo. Tissue-specific gene expression is often needed to minimize ectopic expression in unintended cells and undesirable consequences. Here we investigated if incorporation of target sequences of tissue-specific microRNA (miRNA) into AAV vectors could inhibit ectopic expression in tissues such as the liver and hematopoietic cells. First we inserted liver-specific miR-122 target sequences (miR-122T) into the 3′ untranslated region (UTR) of a number of AAV vectors. After intravenous delivery in mice, we found that 5 copies of the 20mer miR-122T reduced liver expression of luciferase by 50-fold and β-galactosidase (LacZ) by 70-fold. Five copies of miR-122T also reduced mRNA levels of a secretable protein (myostatin propeptide) from the AAV vector plasmid by 23–fold in the liver. However, gene expression in other tissues including the heart was not inhibited. Similarly, we inserted 4 copies of miR-142-3pT or miR-142-5pT, both hematopoietic lineage-specific, into the 3′ UTR of the AAV-luciferase vector. We wished to see if they could prolong transgene expression by inhibiting expression in antigen-presenting cells. However, in vivo luciferase gene expression in major tissues declined with time regardless of the miR-142 target sequences used. Quantitative analysis of the vector DNA in various tissues revealed that the decline of transgene expression in vivo was mainly due to promoter shut-off other than loss of AAV-transduced cells by immune destruction. Moreover, transgene expression was not detected in circulating mononuclear cells after delivering AAV9 vector with or without miR142T. These results demonstrate that live-specific miR-122 target sequence in AAV vectors was highly efficient in reducing liver expression, whereas hematopoietic miR-142 target sequences were ineffective in preventing decline of AAV vector gene expression in non-hematopoietic tissues resulted from promoter shut-off.