Search

Background & Aims We aimed to compare safety and effectiveness of vedolizumab to tumor necrosis factor (TNF)-antagonist therapy in ulcerative colitis in routine practice. Methods A multicenter, retrospective, observational cohort study (May 2014 to December 2017) of ulcerative colitis patients treated with vedolizumab or TNF-antagonist therapy. Propensity score weighted comparisons for development of serious adverse events and achievement of clinical remission, steroid-free clinical remission, and steroid-free deep remission. A priori determined subgroup comparisons in TNF-antagonist–naive and –exposed patients, and for vedolizumab against infliximab and subcutaneous TNF-antagonists separately. Results A total of 722 (454 vedolizumab, 268 TNF antagonist) patients were included. Vedolizumab-treated patients were more likely to achieve clinical remission (hazard ratio [HR], 1.651; 95% confidence interval [CI], 1.229-2.217), steroid-free clinical remission (HR, 1.828; 95% CI, 1.135-2.944), and steroid-free deep remission (HR, 2.819; 95% CI, 1.496-5.310) than those treated with TNF antagonists. Results were consistent across subgroup analyses in TNF-antagonist–naive and −exposed patients, and for vedolizumab vs infliximab and vs subcutaneous TNF-antagonist agents separately. Overall, there were no statistically significant differences in the risk of serious adverse events (HR, 0.899; 95% CI, 0.502-1.612) or serious infections (HR, 1.235; 95% CI, 0.608-2.511) between vedolizumab-treated and TNF-antagonist−treated patients. However, in TNF-antagonist−naive patients, vedolizumab was less likely to be associated with serious adverse events than TNF antagonists (HR, 0.192; 95% CI, 0.049-0.754). Conclusions Treatment of ulcerative colitis with vedolizumab is associated with higher rates of remission than treatment with TNF-antagonist therapy in routine practice, and lower rates of serious adverse events in TNF-antagonist−naive patients.

Background Resting-state functional magnetic resonance imaging has been widely used for the assessment of brain functional network, yet with inconsistent results. The present study aimed to investigate intranetwork and internetwork connectivity differences between patients with major depressive disorder (MDD) and healthy controls at the integrity, network and edge levels of 8 well-defined resting state networks. Methods Thirty patients with MDD and sixty-three healthy control subjects were recruited in this study. Results Compared with healthy controls, patients with MDD showed increased node degree in the right amygdala and putamen, increased connectivity strength in the deep gray matter network (DGN) and increased functional connectivity in intranetwork and internetwork. Meanwhile, MDD showed decreased connectivity strength in visual network-DGN pair. Limitations The sample size was small, and all patients in this study were of Asian ethnicity, especially Han individuals. Conclusions These findings demonstrate that MDD cases and healthy controls may have divergent intranetwork and internetwork connectivity at an early stage without confounding influence of medication. These differences may underlie cognitive and behavioral alterations in patients with MDD. And these differences may help with the discrimination of patients and healthy people at an early stage of MDD. More studies in the future are warranted to assist in the diagnosis of this burdensome disease.

Recent progress in immunotherapy provides hope of a complete cure to cancer patients. However, recent studies have reported that only a limited number of cancer patients with a specific immune status, known as “cold tumor”, can benefit from a single immune agent. Although the combination of immune agents with different mechanisms can partially increase the low response rate and improve efficacy, it can also result in more side effects. Therefore, discovering therapies that can improve tumors' response rate to immunotherapy without increasing toxicity for patients is urgently needed. Tumor interventional therapy is promising. It mainly includes transcatheter arterial chemoembolization, ablation, radioactive particle internal irradiation, and photodynamic interventional therapy based on a luminal stent. Interventional therapy can directly kill tumor cells by targeted drug delivery in situ, thus reducing drug dosage and systemic toxicity like cytokine release syndrome. More importantly, interventional therapy can regulate the immune system through numerous mechanisms, making it a suitable choice for immunotherapy to combine with. In this review, we provide a brief description of immunotherapies (and their side effects) on tumors of different immune types and preliminarily elaborate on interventional therapy mechanisms to improve immune efficacy. We also discuss the progress and challenges of the combination of interventional therapy and immunotherapy.

Our previous work has established a huntingtin knock-in (KI) pig model that displays striatal neuronal loss, allowing us to examine if somatic CAG expansion in striatum accounts for the preferential neurodegeneration in Huntington disease (HD). We found that HD KI pigs do not display somatic CAG expansion in striatum as HD KI mice and that the majority of polyQ repeats in exon 1 HTT in the striatum of HD KI mice are fairly stable. We also found that striatal MSH2 and MLH3, which are involved in DNA repair, are more abundant in mouse brains than pig brains. Consistently inhibiting MSH2 and MLH3 reduced the somatic CAG expansion in HD KI mouse striatum with no influence on neuropathology. Our findings suggest that somatic CAG expansion is species-dependent, occurs in a small fraction of the HD gene in mice, and does not critically contribute to HD neuropathology.

Objectives The authors sought to evaluate the association between mean mitral valve gradient (MVG) and clinical outcomes among patients who underwent MitraClip treatment for secondary mitral regurgitation (SMR) in the COAPT (Cardiovascular Outcomes Assessment of the MitraClip Percutaneous Therapy for Heart Failure Patients with Functional Mitral Regurgitation) trial. Background In the COAPT trial, patients with heart failure (HF) and severe SMR who remained symptomatic despite guideline-directed medical therapy had marked 2-year reductions in mortality and HF hospitalizations after treatment with MitraClip. Methods MitraClip-treated patients were divided into quartiles (Q) based on discharge echocardiographic MVG (n = 250). Endpoints including all-cause mortality, HF hospitalization, and health status measures at 2 years were compared between quartiles. Results Mean MVG after MitraClip was 2.1 ± 0.4 mm Hg, 3.0 ± 0.2 mm Hg, 4.2 ± 0.5 mm Hg, and 7.2 ± 2.0 mm Hg in Q1 (n = 63), Q2 (n = 61), Q3 (n = 62), and Q4 (n = 64), respectively. There was no difference across quartiles in the 2-year composite endpoint of all-cause mortality or HF hospitalization (43.2%, 49.2%, 40.6%, and 40.9%, respectively; p = 0.80), nor in improvements in New York Heart Association functional class, Kansas City Cardiomyopathy Questionnaire score, or 6-min walk time. Results were similar after adjustment for baseline clinical and echocardiographic characteristics, post-procedure MR grade, and number of clips (all-cause mortality or HF hospitalization Q4 [44.6%] vs. Q1 to Q3 [40.3%]; adjusted hazard ratio: 1.23, 95% confidence interval: 0.60 to 2.51; p = 0.57). Conclusions Among HF patients with severe SMR, higher MVGs on discharge did not adversely affect clinical outcomes following MitraClip. These findings suggest that in select patients with HF and SMR otherwise meeting the COAPT inclusion criteria, the benefits of MR reduction may outweigh the effects of mild-to-moderate mitral stenosis after MitraClip.

Background Few studies have evaluated if diastolic function could predict outcomes in patients with aortic stenosis. Objectives The authors aimed to assess the association between diastoli...

Acute intermittent porphyria (AIP) is a dominant inherited disorder with a low penetrance that is caused by mutations in the gene coding for hydroxymethylbilane synthase (HMBS). Information about the epidemiology and molecular genetic features of this rare disorder is crucial to clinical research, and particularly to the evaluation of new treatments. Variations in the prevalence and penetrance of AIP in various studies may due to the different inclusion criteria and methods of assessment. Here, the prevalence and penetrance of AIP are analyzed systematically, and the genetic traits of different populations and findings regarding the genotype-phenotype correlation are summarized. In addition, quite a few studies have indicated that AIP susceptibility was affected by other factors, such as modifying genes. Findings regarding possible modifying genes are documented here, helping to reveal the pathogenesis of and treatments for AIP. The status of research on AIP in China reveals the lack of epidemiological and genetic studies of the Chinese population, a situation that needs to be promptly remedied.

Porphyrias are a group of inherited metabolic diseases that include eight types, each of which is caused by a mutation that affects an enzyme of the heme biosynthetic pathway. When an enzyme defect has physiological significance, it leads to overproduction of pathway precursors prior to the defective step. The partial absence of the third enzyme in the heme biosynthetic pathway, porphobilinogen deaminase (PBGD) also known as hydroxymethylbilane synthase (HMBS), results in acute intermittent porphyria (AIP), which affects mainly women. Subjects who had AIP symptoms were deemed to have manifest AIP (MAIP). Clinical manifestations are usually diverse and non-specific. Acute AIP episodes may present with abdominal pain, nausea, and vomiting, and repeated episodes may result in a series of chronic injuries. Therefore, studying the mechanisms of acute and chronic manifestations of AIP is of great significance. This review aims to summarize the possible mechanisms of acute and chronic manifestations in patients with AIP.

We sought to investigate the characteristics and prognostic impact of healed plaque (HP) detected by optical coherence tomography (OCT) in non-culprit segments in treated vessels.OCT analysis included HP having a different optical intensity with clear demarcation from underlying plaque, thin-cap fibroatheroma (TCFA), and minimal lumen area. Non-culprit lesion (NCL) was defined as a plaque with90° arc of disease (≥0.5 mm intimal thickness), length ≥2 mm, and location5 mm from the stent edges. Major adverse cardiac event (MACE) included cardiac death, myocardial infarction (MI), or ischemia-driven revascularization (IDR).We studied a total of 726 NCLs in 538 patients who underwent percutaneous coronary intervention with evaluable non-culprit segments by OCT. The prevalence of an HP was 17.8% (129/726) per lesion and 21.9% (118/538) per patient. At median follow-up of 2.2 years, there were 65 NCL-related MACE events, including 6 MIs and 65 IDRs of which 87.7% had a stable presentation. The presence of untreated HP was positively correlated with subsequent NCL-related MACE (hazard ratio [HR] 2.01, 95% confidence interval [CI], 1.20-3.37, p 0.01). There were 16 IDRs with stable angina occurring at a specific OCT-imaged NCL where an untreated HP was positively associated with subsequent NCL-related MACE (HR 3.72, 95% CI 1.35-10.30, p = 0.01) along with TCFA (HR 10.0, 95% CI 3.20-31.40, p 0.01) and minimal lumen area3.5 mmAn OCT-detected HP in an NCL is a marker for future (mostly) stable non-culprit-related MACE at both a patient- and lesion-level.

A very rare case of acute intermittent porphyria (AIP) co-existing Turner syndrome (TS) is reported for the first time. A 32-year-old woman was diagnosed with AIP due to recurrent acute abdominal pain, red urine and pathogenic mutation of Hydroxymethyl synthetase (HMBS) gene. At the same time, TS was confirmed by Karyotype analysis results of 46,X,i(X)(q10), which accompanied by primary amenorrhea, elevated serum concentrations of follicle-stimulating hormone (FSH). Since the first attack of AIP, the patient has been increasingly depressed, and Psychiatry identified major depression. Duloxetine was chosen after careful deliberation, and the patient's mood stabilized. AIP had not recurred after half a year. Since sex hormones are the exacerbating factor of acute attack of AIP, sex hormone replacement therapy for TS was not administered. In conclusion, the conditions of AIP co-existing TS are complicate, and the treatment still needs to be improved by multiple disciplines in the follow-up.

Objectives This study sought to evaluate the association between severity of left ventricular hypertrophy (LVH) before transcatheter aortic valve replacement (TAVR) and outcomes out to 5 years. Background Prior studies assessing the association between baseline LVH and outcomes after surgical or TAVR for aortic stenosis (AS) have yielded conflicting results. Methods Patients with severe symptomatic AS at intermediate or high risk in the PARTNER (Placement of Aortic Transcatheter Valve) 1, 2, and S3 trials and registries who received TAVR and had baseline measurements for left ventricular mass index (LVMi) were analyzed. The presence and severity of LVH was determined by LVMi using American Society of Echocardiography sex-specific cutoffs. Results Among 4,280 patients, those with no (n = 1,325), mild (n = 777), moderate (n = 628), and severe (n = 1,550) LVH had 5-year rates of death of 32.8%, 37.3%, 37.2%, and 44.8%, respectively (p Conclusions Severe baseline LVH is associated with higher 5-year death and rehospitalization rates after TAVR. These findings may have implications for the optimal timing of valve replacement and the potential role for medical therapy to slow or prevent LVH as AS progresses before valve replacement, but further studies are needed.

Background Greater early left ventricular mass index (LVMi) regression is associated with fewer hospitalizations 1 year after transcatheter aortic valve replacement (TAVR). The association between LVMi regression and longer-term post-TAVR outcomes is unclear. Objectives The purpose of this study was to determine the association between LVMi regression at 1-year post-TAVR and clinical outcomes between 1 and 5 years. Methods Among intermediate- and high-risk patients who received TAVR in the PARTNER (Placement of Aortic Transcatheter Valves) I, II, and S3 trials or registries and were alive at 1 year, we included patients with baseline moderate or severe left ventricular hypertrophy (LVH) and paired measurements of LVMi at baseline and 1 year. The associations between LVMi regression (percent change between baseline and 1 year) and death or rehospitalization from 1 to 5 years were examined. Results Among 1,434 patients, LVMi was 146 g/m2 (interquartile range [IQR]: 133 to 168 g/m2) at baseline and decreased 14.5% (IQR: 4.2% to 26.1%) to 126 g/m2 (IQR: 106 to 148 g/m2) at 1 year. After adjustment, greater LVMi regression at 1 year was associated with lower all-cause death (adjusted hazard ratio [aHR]: 0.95 per 10% decrease in LVMi; 95% confidence interval [CI]: 0.91 to 0.98; p = 0.004; aHR of the quartile with greatest vs. least LVMi regression: 0.61; 95% CI: 0.43 to 0.86; p = 0.005). Severe LVH at 1 year was observed in 39%, which was independently associated with increased all-cause death (aHR of severe LVH vs. no LVH: 1.71; 95% CI: 1.20 to 2.44; p = 0.003). Similar associations were found for rates of cardiovascular mortality and rehospitalization. Conclusions Among patients with moderate or severe LVH treated with TAVR who are alive at 1 year, greater LVMi regression at 1 year is associated with lower death and hospitalization rates to 5 years. These findings may have implications for the timing of valve replacement and the role of adjunctive medical therapy after TAVR.

Background Studies examining sex-related outcomes following percutaneous coronary intervention (PCI) have reported conflicting results. Objectives The purpose of this study was to examine the sex-related risk of 5-year cardiovascular outcomes after PCI. Methods The authors pooled patient-level data from 21 randomized PCI trials and assessed the association between sex and major adverse cardiac events (MACE) (cardiac death, myocardial infarction [MI], or ischemia-driven target lesion revascularization [ID-TLR]) as well as its individual components at 5 years. Results Among 32,877 patients, 9,141 (27.8%) were women. Women were older and had higher body mass index, more frequent hypertension and diabetes, and less frequent history of surgical or percutaneous revascularization compared with men. By angiographic core laboratory analysis, lesions in women had smaller reference vessel diameter and shorter lesion length. At 5 years, women had a higher unadjusted rate of MACE (18.9% vs. 17.7%; p = 0.003), all-cause death (10.4% vs. 8.7%; p = 0.0008), cardiac death (4.9% vs. 4.0%; p = 0.003) and ID-TLR (10.9% vs. 10.2%; p = 0.02) compared with men. By multivariable analysis, female sex was an independent predictor of MACE (hazard ratio [HR:]: 1.14; 95% confidence interval [CI:]: 1.01 to 1.30; p = 0.04) and ID-TLR (HR: 1.23; 95% CI: 1.05 to 1.44; p = 0.009) but not all-cause death (HR: 0.91; 95% CI: 0.75 to 1.09; p = 0.30) or cardiac death (HR: 0.97; 95% CI: 0.73 to 1.29; p = 0.85). Conclusions In the present large-scale, individual patient data pooled analysis of contemporary PCI trials, women had a higher risk of MACE and ID-TLR compared with men at 5 years following PCI.

BackgroundAtelectasis is a major cause of hypoxemia during general anesthesia and postoperative pulmonary complications (PPCs).Some previous reported that the combined use of lung recruitment procedures (LRMs) and positive end-expiratory pressure (PEEP) in mechanical ventilation mode contributes to the avoidance of PPCs in patients after general anesthesia, while others suggest that the use of LRMs makes patients more susceptible to hemodynamic disturbances and lung injury, and is of limited potential to decrease the incidence of PPCs. From this perspective, controversy exists as to whether LRMs should be routinely applied to surgical patients. More importantly, corresponding clinical studies are also lacking. Therefore, this trial was conducted with the aim of solving the above problem.MethodsIn current clinical trial, patients undergoing laparoscopic gynecologic surgery with healthy lungs were randomized to the recruitment maneuvers group (RM group; 6 cm H2O PEEP and RMs) and the control group (C group; 6 cm H2O PEEP and no RMs). Lung ultrasound was performed on patients at five separate time points. During mechanical ventilation, patients in the RM group received ultrasound-guided pulmonary resuscitation when atelectasis was detected, while the C group did not intervene. Lung ultrasound scores were used to evaluate the incidence and severity of atelectasis.ResultsAfter LRMs, the incidence of atelectasis was significantly lower in the RM group (40%) than in the C group (80%) 15 minutes after arrival in the post-anesthesia care unit (PACU), and this difference did not persist for 24 hours after surgery. Meanwhile, postoperative pulmonary complications showed no difference between the two groups.ConclusionsThe combination of LRMs and PEEP decreased the incidence of atelectasis 15 minutes after admission to the PACU, but did not improve PPCs in adults with healthy lungs. Hence, for lung-healthy patients undergoing gynecological laparoscopic surgery, we do not recommend routine recruitment maneuvers. Trial registration (prospectively registered)ChiCTR2000033529. Registered on June 4, 2020.

Background Acute myeloid leukemia (AML) is a heterogeneous cancer of the blood, though specific recurring cytogenetic abnormalities in AML are strongly associated with attaining complete response after induction chemotherapy, remission duration, and survival. Therefore recurring cytogenetic abnormalities have been used to segregate patients into favorable, intermediate, and adverse prognostic risk groups. However, it is unclear how expression of genes is associated with these prognostic risk groups. We postulate that expression of genes monotonically associated with these prognostic risk groups may yield important insights into leukemogenesis. Therefore, in this paper we propose penalized Bayesian ordinal response models to predict prognostic risk group using gene expression data. We consider a double exponential prior, a spike-and-slab normal prior, a spike-and-slab double exponential prior, and a regression-based approach with variable inclusion indicators for modeling our high-dimensional ordinal response, prognostic risk group, and identify genes through hypothesis tests using Bayes factor. Results Gene expression was ascertained using Affymetrix HG-U133Plus2.0 GeneChips for 97 favorable, 259 intermediate, and 97 adverse risk AML patients. When applying our penalized Bayesian ordinal response models, genes identified for model inclusion were consistent among the four different models. Additionally, the genes included in the models were biologically plausible, as most have been previously associated with either AML or other types of cancer. Conclusion These findings demonstrate that our proposed penalized Bayesian ordinal response models are useful for performing variable selection for high-dimensional genomic data and have the potential to identify genes relevantly associated with an ordinal phenotype.

Metabolite‐protein interactions (MPIs) play key roles in cancer metabolism. However, our current knowledge about MPIs in cancers remains limited due to the complexity of cancer cells. Herein, the authors construct an integrative MPI network and propose a MPI network based hepatocellular carcinoma (HCC) subtyping and mechanism exploration workflow. Based on the expressions of hub proteins on the MPI network, two prognosis‐distinctive HCC subtypes are identified. Meanwhile, multiple interdependent features of the poor prognostic subtype are observed, including hypoxia, DNA hypermethylation of metabolic pathways, fatty acid accumulation, immune pathway up‐regulation, and exhausted T‐cell infiltration. Notably, the immune pathway up‐regulation is probably induced by accumulated unsaturated fatty acids which are predicted to interact with multiple immune regulators like SRC and TGFB1. Moreover, based on tumor microenvironment compositions, the poor prognostic subtype is further divided into two sub‐populations showing remarkable differences in metabolism. The subtyping shows a strong consistency across multiple HCC cohorts including early‐stage HCC. Overall, the authors redefine robust HCC prognosis subtypes and identify potential MPIs linking metabolism to immune regulations, thus promoting understanding and clinical applications about HCC metabolism heterogeneity., The authors construct an integrative metabolite‐protein interaction (MPI) network and develop a MPI prediction model. The MPI network helps redefine robust hepatocellular carcinoma prognostic subtypes. The subtypes show remarkable differences in hypoxia, DNA methylation of metabolic enzymes, immune pathways, fatty acid accumulation as well as tumor microenvironment. Meanwhile, unsaturated fatty acids are potential links between the metabolism and immune regulations.

OBJECTIVES We sought to compare clinical outcomes after percutaneous coronary intervention (PCI) in patients on versus not on hemodialysis (HD) and examine whether high on-treatment platelet reactivity (HPR) further impacts outcomes among patients on HD. BACKGROUND Both chronic kidney disease (CKD) and HPR are predictors of major adverse cardiac events (MACE) after PCI. METHODS Two-year outcomes of patients from the prospective, multicenter ADAPT-DES study (N = 8,582) were analyzed according to HD status at enrollment. All patients underwent platelet function testing with the VerifyNow assay; HPR on clopidogrel was defined as P2Y12 reaction units (PRU) >208. RESULTS Compared with non-HD patients, patients on HD (n = 85) had significantly higher baseline PRU (median 254 vs. 188, p = .001) and more frequently had HPR (61.7% vs. 42.5%, p

The pharmaceutical effects of n-3 polyunsaturated fatty acids (n-3 PUFAs) as dietary nutrients on human health and diseases have gained much attention and are investigated for decades. Docosahexaenoic acid (DHA), eicosapentaenoic acid (EPA) and docosapentaenoic acid (DPA) are the three major n-3 PUFAs enriched in marine organisms, such as fish, shrimp, algae, and so on. It has been well known that n-3 PUFAs, especially DHA and EPA, are beneficial in reducing the risk of cardiovascular and cerebrovascular diseases. Accumulating evidence suggests that n-3 PUFAs might cure inflammatory diseases through several mechanisms, such as plasma membrane remodeling of lymphocytes, down-regulating pro-inflammatory cytokines, and alternating adhesion molecule expressions. Several molecular targets of n-3 PUFAs on immune-regulation have also been identified, such as GPR120 (FFA4), protein kinase C (PKC), and PPAR-γ. However, it remains inconclusive if dietary n-3 PUFAs function the same both in vitro and in vivo based on cohort studies. This review will focus on the molecular targets and mechanisms of anti-inflammatory and immunomodulatory effects of n-3 PUFAs on human health and diseases, such as obesity, tumor, diabetes, and autoimmune diseases.

Purpose/aim : Intervertebral disc degeneration (IDD) is the leading cause of lower back pain, and clinically useful drugs for IDD are unavailable. Mechanical stress overload-induced fibrosis plays a critical role in IDD. RhoA/MRTF-A signaling is known to regulate tissue fibrosis; however, the effect of RhoA/MRTF-A on the development of IDD is unclear. Materials and methods : The expression of aggrecan, collagen I, collagen II, MMP-12, CTGF, and MRTF-A in nucleus pulposus (NP) samples from IDD patients and controls was detected by immunohistochemical staining. Primary nucleus pulposus cells (NPCs) were isolated and cultured to establish an overload strain model treated with or without CCG-1423. The protein levels of RhoA, ROCK2, MRTF-A, CTGF, and MMP-12 as well as fibrosis-associated proteins were detected by western blotting and immunofluorescence. Results : Collagen I, MMP-12, and CTGF were significantly upregulated, and aggrecan and collagen II were significantly downregulated in the IDD samples. The cellular localization of MRTF-A was associated with intervertebral disc (IVD) degeneration. Overloaded strain enhanced the nuclear translocation of MRTF-A and changed the NPC morphology from spindle-shaped to long strips. Additional experiments showed that RhoA, ROCK2, MRTF-A, SRF, MMP-12, and CTGF were upregulated; however, aggrecan and collagen II were downregulated in NPCs under overload strain. CCG-1423, a RhoA/MRTF-A pathway inhibitor, reversed strain-induced fibrosis. Conclusion : Mechanical stress activates RhoA/MRTF-A signaling to promote extracellular matrix (ECM) degeneration in the NP, which is associated with the development of IDD. Our findings suggest that the RhoA/MRTF-A inhibitor CCG-1423 can alleviate NPC degeneration caused by overload stress and has potential as a therapeutic agent for IDD.

Background: Aortic valve replacement (AVR) is recommended for severe symptomatic aortic stenosis. However, the incidence of worsening tricuspid regurgitation (TR) following transcatheter compared with surgical AVR (TAVR, SAVR), and the impact of worsening TR on outcomes, is ill-defined. Accordingly, among patients randomized to TAVR or SAVR, we describe the differential incidence of worsening TR and its association with survival. Methods: From the PARTNER IIA trial (Placement of Aortic Transcatheter Valves IIA), 1334 patients were included with baseline and 30-day postprocedure core-lab echocardiograms. Worsening TR was defined as deterioration of ≥1 grade from baseline to 30 days. Outcomes included cardiovascular and all-cause death between 30 days and 2 years. Multivariable logistic regression was performed to identify associations with worsening TR; survival analyses were performed to assess associations with mortality. Results: Worsening TR occurred in 17.3% (125/721) of TAVR and 27.0% (165/611) of SAVR patients. On multivariable analysis, SAVR (odds ratio, 2.09 [95% CI, 1.40–3.11]), female sex (odds ratio, 2.22 [95% CI, 1.44–3.42]), atrial fibrillation (odds ratio, 1.61 [95% CI, 1.03–2.51]), and right ventricular enlargement (odds ratio, 2.25 [95% CI, 1.17–4.31]) were associated with worsening TR. Cardiovascular and all-cause death occurred in 9.0% (26/290) and 17.9% (52/290) of patients with worsening TR, compared with 4.8% (50/1042) and 10.9% (114/1042) without worsening TR, respectively. In patients with worsening TR, cardiovascular and all-cause death were similar in TAVR compared with SAVR, (hazard ratio, 1.09 [95% CI, 0.55–2.16]) and (hazard ratio, 1.07 [95% CI, 0.62–1.87]), respectively. After adjustment, worsening TR was independently associated with cardiovascular (hazard ratio, 3.62 [95% CI, 2.08–6.29]) and all-cause death (hazard ratio, 2.11 [95% CI, 1.37–3.27]). Conclusions: Worsening TR is associated with female sex, atrial fibrillation, right ventricular enlargement, and SAVR. Regardless of mode of AVR, worsening TR is similarly associated with a poor prognosis. Future studies should focus on whether preventing or treating worsening TR improves outcomes. Registration: URL: https://www.clinicaltrials.gov ; Unique identifier: NCT01314313.

Trials describing 4- to 12-week courses of direct-acting antiviral drugs (DAAs) to treat hepatitis C virus (HCV) transmission from infected donors to uninfected kidney transplant recipients (D+/R- transplants) may be limited in "real-world" application by costs and delayed access to DAAs. We previously reported HCV transmission of 13% among D+/R- transplants with 2- to 4-day pangenotypic sofosbuvir/velpatasvir (SOF/VEL) perioperative prophylaxis, where one patient with HCV transmission was a nonresponder to first-line full-course DAA. Here, we report new data with a 7-day prophylaxis protocol (N = 50), as well as cumulative treatment and outcome data on all HCV D+/R- transplants (N = 102). Overall, nine patients (9/102; 9%; 95% CI: 5%-16%) developed HCV transmission, with a significant decline noted in the 7-day group (2/50; 4%; 95% CI: 0%-13%) compared with 2- to 4-day prophylaxis (7/52; 13%; 95% CI: 5%-25%). All patients with HCV transmission achieved sustained virologic response post full-course therapy (including one nonresponder from initial trial). A 1:1 matched analysis (N = 102) with contemporary HCV D-/R- transplants (controls) showed that although the pretransplant wait time was significantly shorter for D+/R- compared with D-/R- (mean: 1.8 vs. 4.4 years; p

Background: Most human diseases are systems diseases, and systems biomarkers will be powerful tools in facilitating the diagnosis, prognosis, and treatment effect monitoring of systems diseases. Circulating transthyretin (TTR) or prealbumin, one of the commonly ordered blood tests, has been indicated as a biomarker for cancers and non-cancer diseases. To test if TTR were a systems biomarker and the mechanisms of its regulation, TTR concentrations in 48 different types of human diseases and healthy controls were systematically analyzed in the current study. Methods: Serum TTR concentration was determined by the standard "Immune turbidimetric method" in the clinical laboratory of our hospital. TTR data from 137,305 independent tests of patients with 48 clinically defined diseases and 3,387 tests from healthy individuals who came to the hospital for physical examination during the past five years were retrieved. All data were statistically analyzed with SPSS v26, RStudio V.1.3.1073, and python libraries 3.8. Results: The mean and median values of serum TTR concentrations were significantly decreased (p 0.6) for 40 out of 48 diseases, and the highest AUCs were observed in sepsis (AUC 0.97), cirrhosis (AUC 0.97), and pancreatitis (AUC 0.94). Remarkably, the eight diseases with AUC < 0.6 were mainly kidney- and blood-related diseases with unconventional ROC curves and broad TTR concentration ranges. Furthermore, similar TTR concentration distributing patterns were present in the same category of diseases, such as different types of cancers, liver-related diseases, blood-related cancers and diseases, vascular diseases, autoimmune diseases, and kidney diseases. Conclusions: Significantly decreased TTR mean and median values were common in 47 out of 48 human diseases. The liver, kidney, blood, and pancreas were the major organs involved in regulating TTR concentrations. Systems swings between catabolic and anabolic phases explained the different dynamic TTR concentration ranges in different diseases. Overall facts plus ROC analysis indicated that TTR was a systems biomarker instead of a prognosis or malnutrition indicator used clinically during the past. Funding: This research was supported by the Natural Science Foundation of China (Grants 81672585 and 11804151), the Natural Science Foundation of Shandong province (ZR2020QH082), Youth fund of Affiliated Hospital of Qingdao University (Grant No. 3105), and “Clinic+X” project of Affiliated Hospital of Qingdao University (Grant No. 3442). Declaration of Interest: None to declare. Ethical Approval: The Ethics Review Committee of Qingdao University Hospital approved this study (QDFYWZLL26222)

Background Chemotherapy and gene therapy are used in clinical practice for the treatment of castration-resistant prostate cancer. However, the poor efficiency of drug delivery and serious systemic side effects remain an obstacle to wider application of these drugs. Herein, we report newly designed PEO-PCL micelles that were self-assembled and modified by spermine ligand, DCL ligand and TAT peptide to carry docetaxel and anti-nucleostemin siRNA. Results The particle size of the micelles was 42 nm, the zeta potential increased from − 12.8 to 15 mV after grafting with spermine, and the optimal N/P ratio was 25:1. Cellular MTT experiments suggested that introduction of the DCL ligand resulted in high toxicity toward PSMA-positive cells and that the TAT peptide enhanced the effect. The expression of nucleostemin was significantly suppressed in vitro and in vivo, and the tumour-inhibition experiment showed that the dual-drug delivery system suppressed CRPC tumour proliferation. Conclusions This targeted drug delivery system inhibited the G1/S and G2/M mitotic cycle via synergistic interaction of chemotherapeutics and gene drugs.

Background: Discharge patterns for patients following treatment of aortic stenosis with transcatheter (TAVR) or surgical aortic valve replacement (SAVR) are poorly defined and could impact long-term clinical outcomes. The objective is to define prevalence, predictors, and outcomes of patients discharged home versus other medical facility after either transcatheter or surgical aortic valve replacement. Methods: This is a retrospective analysis of the PARTNER 2 trial, which was a multicenter randomized trial of transcatheter versus surgical aortic valve replacement and associated registries. All patients that received either therapy and survived until discharge were included in the analysis. Two separate analyses were performed – one for those patients receiving TAVR and one for patients receiving SAVR. The primary outcome was two-year mortality in patients discharged home versus other medical facility. In addition, a prediction model was developed to predict discharge patterns following transcatheter or surgical aortic valve replacement. Results: 4,312 patients underwent TAVR and 22% (n= 958) were discharged to other medical facilities. 916 patients underwent SAVR and 52.4% (n = 480) were discharged to other medical facilities. Two-year mortality for patients undergoing aortic valve replacement and discharged to other medical facility versus home was 36.6% vs 18.0% in the TAVR group (p < 0.0001) and 19.7% vs 11.1% (p < 0.001) after SAVR. Patients discharged to other medical facility had worse quality of life and were more likely to be re-admitted after either procedure. Conclusion: After adjusting for risk factors that may be related to discharge location and death, discharge home versus discharge to other medical facility is associated with increased mortality and worse quality of life at 2 years following either TAVR or SAVR treatment of aortic stenosis.

The present study is aimed at investigating the association of NFE2L2 gene polymorphisms with risk and clinical characteristics of acute type A aortic dissection (AAAD) in a Han Chinese population. Six SNPs (rs1806649, rs13001694, rs2364723, rs35652124, rs6721961, and rs2706110) in NFE2L2 were genotyped using SNaPshot Multiplex Kit in 94 adult patients diagnosed with AAAD at our hospital, and 208 healthy Han Chinese subjects from the 1000 Genomes Project were served as the control group. The CC genotype of rs2364723 (CC versus (GC+GG), OR = 2.069 , 95% CI: 1.222-3.502, p = 0.006 ) and CC genotype of rs35652124 (CC versus (CT+TT), OR = 1.889 , 95% CI: 1.112-3.210, p = 0.018 ) were identified as risk factors for AAAD. Multivariable linear regression analysis revealed that the CC genotype of rs2364723 ( β = 5.031 , 95% CI: 1.878-8.183, p = 0.002 ) and CC genotype of rs35652124 ( β = 4.751 , 95% CI: 1.544-7.958, p = 0.004 ) were associated with increased maximum ascending aorta diameter of AAAD. Patients carrying rs2364723 CC genotype had a higher incidence of coronary artery involvement (31% vs. 12%, p = 0.027 ), while patients carrying rs35652124 CC genotype had a higher incidence of brain ischemia (9% vs. 0%, p = 0.045 ). In conclusion, NFE2L2 gene polymorphisms were correlated with risk and severity of AAAD in Han Chinese population.

Previous studies have reported that the Ras homolog family member A (RhoA)/myocardin‑related transcription factor A (MRTF‑A) nuclear translocation axis positively regulates fibrogenesis induced by mechanical forces in various organ systems. The aim of the present study was to determine whether this signaling pathway was involved in the pathogenesis of nucleus pulposus (NP) fibrosis induced by mechanical overload during the progression of intervertebral disc degeneration (IVDD) and to confirm the alleviating effect of an MRTF‑A inhibitor in the treatment of IVDD. NP cells (NPCs) were cultured on substrates of different stiffness (2.9 and 41.7 KPa), which mimicked normal and overloaded microenvironments, and were treated with an inhibitor of MRTF‑A nuclear import, CCG‑1423. In addition, bipedal rats were established by clipping the forelimbs of rats at 1 month and gradually elevating the feeding trough, and in order to establish a long‑term overload‑induced model of IVDD, and their intervertebral discs were injected with CCG‑1423 in situ. Cell viability was determined by Cell Counting Kit‑8 assay, and protein expression was determined by western blotting, immunofluorescence and immunohistochemical staining. The results demonstrated that the viability of NPCs was not affected by the application of force or the inhibitor. In NPCs cultured on stiff matrices, MRTF‑A was mostly localized in the nucleus, and the expression levels of fibrotic proteins, including type I collagen, connective tissue growth factor and α‑smooth muscle cell actin, were upregulated compared with those in NPCs cultured on soft matrices. The levels of these proteins were reduced by CCG‑1423 treatment. In rats, 6 months of upright posture activated MRTF‑A nuclear‑cytoplasmic trafficking and fibrogenesis in the NP and induced IVDD; these effects were alleviated by CCG‑1423 treatment. In conclusion, the results of the present study demonstrated that the RhoA/MRTF‑A translocation pathway may promote mechanical overload‑induced fibrogenic activity in NP tissue and partially elucidated the molecular mechanisms underlying the occurrence of IVDD.

Antiangiogenic tyrosine kinase inhibitors (AA‐TKIs) have become a promising therapeutic strategy for colorectal cancer (CRC). In clinical practice, a significant proportion of cancer patients temporarily discontinue AA‐TKI treatment due to recurrent toxicities, economic burden or acquired resistance. However, AA‐TKI therapy withdrawal‐induced tumour revascularization frequently occurs, hampering the clinical application of AA‐TKIs. Here, this study demonstrates that tumour perivascular cells mediate tumour revascularization after withdrawal of AA‐TKI therapy. Pharmacological inhibition and genetic ablation of perivascular cells largely attenuate the rebound effect of CRC vascularization in the AA‐TKI cessation experimental settings. Mechanistically, tumour perivascular cell‐derived extracellular vehicles (TPC‐EVs) contain Gas6 that instigates the recruitment of endothelial progenitor cells (EPCs) for tumour revascularization via activating the Axl pathway. Gas6 silence and an Axl inhibitor markedly inhibit tumour revascularization by impairing EPC recruitment. Consequently, combination therapy of regorafenib with the Axl inhibitor improves overall survival in mice metastatic CRC model by inhibiting tumour growth. Together, these data shed new mechanistic insights into perivascular cells in off‐AA‐TKI‐induced tumour revascularization and indicate that blocking the Axl signalling may provide an attractive anticancer approach for sustaining long‐lasting angiostatic effects to improve the therapeutic outcomes of antiangiogenic drugs in CRC.

Acute intermittent porphyria (AIP) is an autosomal dominant disease caused by mutations in porphobilinogen deaminase (PBGD), the third enzyme of the heme synthesis pathway. Symptoms of AIP usually manifest as intermittent acute attacks with occasional neuropsychiatric crises. The management of AIP includes treatment of acute attacks, prevention of attacks, long-term monitoring and treatment of chronic complications. Intravenous injection of heme is the most effective method of treating acute attacks. Carbohydrate loading is used when heme is unavailable or in the event of mild attacks. Symptomatic treatment is also needed during attacks. Prevention of attacks includes eliminating precipitating factors, heme prophylaxis and liver transplantation. New treatment options include givosiran (siRNA) to down-regulate ALA synthase-1 (ALAS1) and the messenger RNA of PBGD (PBGD mRNA) delivered to the liver cells of patients with AIP. Long-term monitoring of chronic complications includes regular liver-kidney function and hepatocellular carcinoma (HCC) screening.

Drug-eluting stent (DES) is a promising strategy for esophageal cancer. However, full-covered drug-loaded stents cause damage to non-tumor tissue in the esophagus, and the development controlled-release system to prevent non-tumor tissue injure is currently a major challenge. Here, in situ mineralized manganese dioxide coating on Ce6 embedded electrospun fibers covered stent was developed for effective tumor therapy via intraluminal photodynamic therapy (PDT), which could reduce phototoxicity to normal esophageal tissue. Oxidation of manganese ions, which was previously swelled between fibers, was used to accomplish mineralization. After implantation, the manganese dioxide coating in situ reacts with tumor endogenous H+ and H2O2, which, on the one hand, could effectively alleviate the hypoxic microenvironment which leads to resistance to PDT, and on the other hand, could expose the Ce6-fibers below the coating for intraluminal PDT. In addition, due to the slow degradation of the coating, this stent could own sustained photodynamic performance for up to one month. Notably, the PDT efficiency of the stent was investigated on orthotopic rabbit esophageal cancer models. Overall, this work suggests that in situ mineralized manganese dioxide coated electrospun fibers covered stent may provide a new strategy for advanced esophageal cancer patients as a functional drug delivery platform.

Acute intermittent porphyria (AIP) is a rare inherited metabolic disease associated with heme metabolism. Primary Sjogren's syndrome (PSS) is a common autoimmune disease. The combined presence of AIP and PSS complicates treatment. A rare case of concomitant AIP and PSS is reported in this paper. A 30-year-old woman with AIP had recurrent acute abdominal pain, nausea and vomiting, constipation, persistent chest, back, and waist pain, red urine, positivity for porphobilinogen (PBG) in urine and a pathogenic mutation of the HMBS gene. Two and a half years after she was diagnosed with AIP, she was diagnosed with PSS based on dryness of the eyes and mouth, the elevation of immunoglobulins (IgG and IgA) and positive results on an anti-SS-A antibody test, an anti-SS-B antibody test, Schirmer's test and a labial gland biopsy. A mutation in the HMBS gene was detected in the patient and her cousin, but the patient had more severe AIP and more severe symptoms (such as epilepsy and a limp), which may be related to the co-morbidity of PSS. According to her PSS activity score, the patient had an ESSDAI score of 9 and required systemic treatment. However, potential medications were limited by AIP, so mycophenolate mofetil was eventually added to delay the progression of the primary disease.

Background: Although aortic valve replacement is associated with a major benefit in high-gradient (HG) severe aortic stenosis (AS), the results in low-gradient (LG, mean gradient 2 ) and LG; and normal-flow (left ventricular ejection fraction ≥50% and stroke volume index ≥35 mL/m 2 ) and LG. The primary objective is to determine in the PARTNER 2 trial (The Placement of Aortic Transcatheter Valves) and registry the outcomes after aortic valve replacement of the 4 flow-gradient groups. Methods: A total of 3511 patients from the PARTNER 2 Cohort A randomized trial (n=1910) and SAPIEN 3 registry (n=1601) were included. The flow-gradient pattern was determined at baseline transthoracic echocardiography and classified as follows: (1) HG; (2) CLF-LG; (3) paradoxical low-flow-LG; and (4) normal-flow-LG. The primary end point for this analysis was the composite of (1) death; (2) rehospitalization for heart failure symptoms and valve prosthesis complication; or (3) stroke. Results: The distribution was HG, 2229 patients (63.5%); CLF-LG, 689 patients (19.6%); paradoxical low-flow-LG, 247 patients (7.0%); and normal-flow-LG, 346 patients (9.9%). The 2-year rate of primary end point was higher in CLF-LG (38.8%) versus HG: 31.8% ( P =0.002) and normal-flow-LG: 32.1% ( P =0.05) but was not statistically different from paradoxical low-flow-LG: 33.6% ( P =0.18). There was no significant difference in the 2-year rates of clinical events between transcatheter aortic valve replacement versus surgical aortic valve replacement in the whole cohort and within each flow-gradient group. Conclusions: The LG AS pattern was highly prevalent (36.5%) in the PARTNER 2 trial and registry. CLF-LG was the most common pattern of LG AS and was associated with higher rates of death, rehospitalization, or stroke at 2 years compared with the HG group. Clinical outcomes were as good in the LG AS groups with preserved left ventricular ejection fraction compared with the HG group.

Objectives The aim of this study was to examine the independent association of short-term complications of transcatheter aortic valve replacement (TAVR) with survival and quality of life at 1 year. Background Prior studies have examined the mortality and cost implications of various complications of TAVR. However, many of these complications may primarily affect patients’ quality of life after TAVR, which has not been previously studied. Methods Among patients at intermediate or high surgical risk who underwent TAVR as part of the PARTNER (Placement of Aortic Transcatheter Valve) 2 studies and survived 30 days, the association between complications within the 30 days after TAVR and mortality and quality of life at 1 year was examined. Quality of life was assessed using the Kansas City Cardiomyopathy Questionnaire and the Short-Form 12. Complications assessed included major and minor stroke, life-threatening and major bleeding, vascular injury, stage 3 acute kidney injury, new pacemaker implantation, and mild and moderate or severe paravalvular leak (PVL). Multivariable models that included all complications as well as baseline clinical factors were used to examine the independent association of each complication with outcomes. Results Among 3,763 TAVR patients, major stroke and stage 3 acute kidney injury were associated with markedly increased risk for 1-year mortality, with adjusted hazard ratios of 5.4 (95% confidence interval [CI]: 3.1 to 9.5) and 4.9 (95% CI: 2.7 to 8.8), respectively, as well as poorer quality of life among survivors (reductions in 1-year Kansas City Cardiomyopathy Questionnaire overall summary score of 15.1 points [95% CI: 24.8 to 5.3 points] and 14.7 points [95% CI: 25.6 to 3.8 points], respectively). Moderate or severe PVL, life-threatening bleeding, and major bleeding were each associated with a more modest increase in mortality and decrement in quality of life, whereas mild PVL was associated with a small decrease in quality of life. After adjusting for baseline characteristics and other complications, need for a new pacemaker, minor stroke, and vascular injury were not independently associated with poor outcomes. Conclusions Among patients undergoing TAVR, similar events are associated with increased mortality and impaired quality of life at 1 year. These results suggest that despite considerable progress, efforts to further reduce stroke, acute kidney injury, bleeding, and moderate or severe PVL are likely to yield important clinical benefits and remain key targets for device iteration and procedural improvement.

BackgroundAcute ischemic stroke can be caused by in situ stenotic vessel occlusion. In the present study, we compared the extent of arterial wall damage and miRNA expression following stent retriever use under normal and stenotic conditions.MethodsThe stent retriever procedure was simulated in three dogs by the creation of four stenoses on each side of the common carotid artery (CCA) to allow five stent passages. Device safety was also assessed in normal control models by five passages through both CCAs. Device manipulation-related damage to the arterial walls was evaluated and compared between groups by angiography and pathological analysis. Real-time PCR was used to evaluate the differences in the expression of miRNAs between the two groups.ResultsTwenty-four stenoses were created in three model dogs, and the mean stenosis rate was 65.58%±18.95%. Angiography revealed greater vasospasm in the stenotic group than in the non-stenotic group (1.17±0.17 vs 0.5±0.23; P=0.04). Pathological examination revealed that SR passage through the stenotic lumen caused higher injury scores (1.63±0.19 vs 0.25±0.09 for the non-stenotic lumen; PConclusionIn our model dogs, SR thrombectomy resulted in more severe tissue damage to the arterial wall under stenotic conditions than under non-stenotic conditions. The damage may have resulted from upregulation of miR21-3p, miR29-3p, and miR26a expression.

Background Whether high on-aspirin platelet reactivity (HAPR) confers an increased risk of adverse outcomes after percutaneous coronary intervention (PCI) remains unclear. We sought to examine the specific relationship between HAPR and clinical outcomes in ADAPT-DES. Methods A total of 8,526 “all-comer” patients in the ADAPT-DES registry who underwent placement of drug-eluting stents (DES) and were treated with aspirin and clopidogrel were assessed to measure platelet reactivity. HAPR was characterized as ≥550 aspirin reaction units and high on-clopidogrel platelet reactivity as >208 P2Y12 reaction units. Univariable and propensity-adjusted multivariable analyses were used to assess the relationship between HAPR and clinical outcomes. Results HAPR was present in 478 (5.6%) patients. Patients with HAPR were older and had more comorbid illnesses and more complex coronary anatomy. During 2-year follow-up, HAPR was not associated with increased rates of major adverse cardiac events (MACE), stent thrombosis, myocardial infarction, or all-cause mortality. In propensity-adjusted multivariable analyses, HAPR was not an independent predictor of MACE after successful PCI (multivariable adjusted hazard ratio: 1.04; 95% CI 0.64-1.69, P = .87). Nor was HAPR associated with reduced bleeding. Even among patients with concomitant high on-clopidogrel platelet reactivity, HAPR was not associated with worse ischemic outcomes (adjusted hazard ratio for 2-year MACE: 1.06; 95% CI 0.55-2.00, P = .87). Conclusions HAPR was infrequently present in a large registry of patients undergoing PCI. There was no clear relationship between HAPR and 2-year clinical outcomes. Investigations of antiplatelet regimens without aspirin after DES implantation are ongoing and should inform future management of patients undergoing PCI.

BACKGROUND The aims of this study were to investigate the incidence and risk factors for the development of bone metastases and prognosis in women with cancer of the uterine cervix using database analysis. MATERIAL AND METHODS The National Cancer Institute (NCI) Surveillance, Epidemiology, and End Results (SEER) database was analyzed for the incidence and survival rates of women diagnosed with uterine cervical cancer in the United States between 2010-2015. Multivariate logistic regression analysis identified risk factors for bone metastases. Kaplan-Meier analysis estimated the overall survival. Proportional hazard regression analysis estimated prognostic factors associated with bone metastases. RESULTS There were 19,363 women with uterine cervical cancer, and 469 women were diagnosed with bone metastases on initial diagnosis (2.42%). Increased T-stage, N-stage, non-squamous and non-adenocarcinoma histology, high-grade tumors, and the presence of lung, liver, and brain metastases were all significantly associated with early bone metastases. There were 364 patients with cervical cancer and bone metastases on initial diagnosis who were followed-up for at least one year. Multivariate Cox regression analysis showed that unmarried status and lung, liver, and brain metastases were significantly associated with reduced overall survival. No other significant risk or prognostic associations were found. CONCLUSIONS SEER data analysis showed that women with uterine cervical cancer had some standard risk factors associated with bone metastases, and with prognosis, but a heterogeneous group of risk factors was also present. The findings of this study may have clinical application in screening for bone metastases in women with cervical cancer.

Lentinan is a polysaccharide extracted from Shiitake mushrooms that have been used to improve general health for thousands of years in Asia. Lentinan injection is a clinically approved drug in several countries in Asia. The purpose of this study is to review the structure, preclinical and clinical studies, and molecular mechanisms of lentinan. Most importantly, the clinical effectiveness of lentinan as an adjuvant therapeutic drug in treating patients with lung cancer in China during the past 12 years is analyzed statistically. We carried out literature search of randomized controlled trials (RCTs) published from 2004 to 2016 based on CNKI (China National Knowledge Infrastructure), VIP (Chongqing VIP Chinese Scientific Journals Database) and Wanfang database, and 38 eligible RCTs of lentinan-associated lung cancer treatment were identified, containing 3,117 patients. The structure and function relationship and underlying molecular mechanism of lentinan as an immunostimulant has been summarized. The mean value of overall response rate in treating lung cancer was increased from 43.3% of chemotherapy alone to 56.9% of lentinan plus chemotherapy [p

Aortic aneurysm and dissection (AAD) are a set of life-threatening diseases. This study aimed to investigate the genetic mechanisms of AAD by integrating transcriptome-wide association study (TWAS) and mRNA expression profile.The genome-wide association study (GWAS) summary data of AAD was obtained from the UK Biobank, which contains 452,264 White British individuals, including 1470 AAD patients. The TWAS analysis was performed by integrating expression quantitative trait loci (eQTL) data of aorta and the GWAS dataset of AAD using the FUSION software. The TWAS significant genes and differentially expressed genes (DEGs) identified by mRNA expression profile of aortic dissection were integrated to find common genes and biological process. For TWAS significant genes, protein-protein interaction (PPI) network analysis was further conducted based on STRING database.TWAS identified 423 genes with P 0.05. After comparing the results of TWAS and mRNA expression profile, 11 overlapping genes (PDE8B, IKBKE, HMGA1, PKM, CHST1, DUS3L, S100A16, PTGS1, RAB38, PDLIM5, NOL6) and 15 common gene ontology (GO) terms (including extracellular matrix organization, external encapsulating structure organization, cell-substrate adhesion, actin filament-based process, focal adhesion, protein kinase activity) were identified. 9 hub genes of the TWAS results were identified via PPI network analysis, including RPS9, RPS18, RSRC1, DNAJC3, HBS1L, PRKCA, NCAM1, ITGB3, FTSJ3.Multiple candidate genes and biological processes associated with AAD were identified by the present integrative study of TWAS and mRNA expression profile. Further studies are needed to elucidate the genetic mechanisms of AAD.

// Xin Chen 1, * , Yufei Fu 2, * , Hongfei Xu 1, * , Peng Teng 1 , Qiong Xie 1 , Yiran Zhang 1 , Caochong Yan 1 , Yiqiao Xu 4 , Chunqi Li 4 , Jianying Zhou 3 , Yiming Ni 1 and Weidong Li 1 1 Department of Thoracic and Cardiovascular Surgery, The First Affiliated Hospital of Zhejiang University, Hangzhou, PR China 2 Zhejiang Key Laboratory of Gastro-Intestinal Pathophysiology, Zhejiang Hospital of Traditional Chinese Medicine, First Affiliated Hospital of Zhejiang Chinese Medical University, Hangzhou, PR China 3 Department of Respiratory Disease, The First Affiliated Hospital, Zhejiang University, Hangzhou, PR China 4 Hunter Biotechnology, Inc., Hangzhou, PR China * These authors contributed equally to this work Correspondence to: Weidong Li, email: dr_liweidong@163.com Yiming Ni, email: Ni_yiming@hotmail.com Jianying Zhou, email: drzjy@163.com Keywords: SOX5; EMT; lung adenocarcinoma; prognosis Received: January 31, 2017 Accepted: October 11, 2017 Published: November 06, 2017 ABSTRACT Lung cancer is the leading cause of cancer-related death worldwide. Epithelial-mesenchymal transition (EMT) promotes lung cancer progression and metastasis, especially in lung adenocarcinoma. Sex determining region Y-box protein 5 (SOX5) is known to stimulate the progression of various cancers. Here, we used immunohistochemical analysis to reveal that SOX5 levels were increased in 90 lung adenocarcinoma patients. The high SOX5 expression in lung adenocarcinoma and non-tumor counterparts correlated with the patients’ poor prognosis. Inhibiting SOX5 expression attenuated metastasis and progression in lung cancer cells, while over-expressing SOX5 accelerated lung adenocarcinoma progression and metastasis via EMT. An in vivo zebrafish xenograft cancer model also showed SOX5 knockdown was followed by reduced lung cancer cell proliferation and metastasis. Our results indicate SOX5 promotes lung adenocarcinoma tumorigenicity and can be a novel diagnosis and prognosis marker of the disease.

Background Individual randomized controlled trials (RCTs) of periprocedural anticoagulation with bivalirudin versus heparin during percutaneous coronary intervention (PCI) have reported conflicting results. Study-level meta-analyses lack granularity to adjust for confounders, explore heterogeneity, or identify subgroups that may particularly benefit or be harmed. Objective To overcome these limitations, we sought to develop an individual patient-data pooled database of RCTs comparing bivalirudin versus heparin. Methods We conducted a systematic review to identify RCTs in which ≥1,000 patients with acute myocardial infarction (AMI) undergoing PCI were randomized to bivalirudin versus heparin. Results From 738 identified studies, 8 RCTs met the prespecified criteria. The principal investigators of each study agreed to provide patient-level data. The data were pooled and checked for accuracy against trial publications, with discrepancies addressed by consulting with the trialists. Consensus-based definitions were created to resolve differing antithrombotic, procedural, and outcome definitions. The project required 3.5 years to complete, and the final database includes 27,409 patients (13,346 randomized to bivalirudin and 14,063 randomized to heparin). Conclusion We have created a large individual patient database of bivalirudin versus heparin RCTs in patients with AMI undergoing PCI. This endeavor may help identify the optimal periprocedural anticoagulation regimen for patient groups with different relative risks of adverse ischemic versus bleeding events, including those with ST-segment and non-ST-segment elevation MI, radial versus femoral access, use of a prolonged bivalirudin infusion or glycoprotein inhibitors, and others. Adherence to standardized techniques and rigorous validation processes should increase confidence in the accuracy and robustness of the results.

Background The present study aimed to evaluate the value of admission serum uric acid (UA) level in predicting in-hospital risk of death in patients with acute type A aortic dissection (AAAD). Methods From January 2016 to June 2019, 186 consecutive patients with AAAD who underwent thoracic aortic surgery were retrospectively studied. Serum UA levels were measured on admission. Forward conditional logistic regression was performed to identify independent risk factors for in-hospital death. Receiver operating characteristic (ROC) analysis was performed to assess the most clinical useful level of serum UA for predicting postoperative in-hospital mortality. Results Increased level of serum UA was found in non-survivors compared with those survived (446 ± 123 vs 371 ± 111 umol/L, p p = 0.009), UA (OR = 1.006, 95% CI 1.002–1.010, p = 0.002), D-dimer (OR = 1.025, 95% CI 1.005–1.013, p = 0.012), operation time (OR = 1.009, 95% CI 1.005–1.013, p p = 0.005) were identified as independent risk factors of in-hospital mortality in AAAD patients. The best cut-off value of admission serum UA in predicting in-hospital mortality was determined to be 415 umol/L. Subgroup analysis showed that in the subgroup of total arch replacement, UA was significantly associated with in-hospital death (OR = 1.010, 95% CI 1.005–1.015, p p = 0.611). Conclusions Elevated serum UA level on admission is an independent predictor of in-hospital mortality in patients with AAAD.

We report two patients with aorta-pulmonary vein fistulas and discuss the surgical management of these congenital lesions.

Objectives There are limited data on bivalirudin monotherapy in patients with non-ST-segment elevation acute coronary syndromes (NSTE-ACS) with positive biomarkers of myocardial necrosis (troponin and/or creatine kinase-myocardial band isoenzyme). We sought to evaluate the safety and efficacy of bivalirudin monotherapy in patients with positive biomarkers from the Acute Catheterization and Urgent Intervention Triage Strategy (ACUITY) trial. Patients and methods We compared the net adverse clinical events [composite ischemia - (death, myocardial infarction, or unplanned ischemic revascularization) - or noncoronary artery bypass graft surgery (CABG)-related major bleeding] among patients with biomarker-positive NSTE-ACS in the ACUITY trial overall and by antithrombotic strategy. Results Among 13 819 patients with NSTE-ACS enrolled in ACUITY, 4728 patients presented with positive biomarkers and underwent an early invasive strategy. Of those, 1547 were randomized to heparin plus a glycoprotein IIb/IIIa inhibitor (GPI), 1555 to bivalirudin plus GPI, and 1626 to bivalirudin monotherapy. Compared with biomarker-negative patients, biomarker-positive patients had higher 30-day rates of net adverse clinical events (14.0 vs. 12.4%; P = 0.04), all-cause death (1.3 vs. 0.5%; P = 0.001), cardiac death (1.1 vs. 0.5%; P = 0.005), and non-CABG-related major bleeding (6.5 vs. 5.2%, P = 0.03). At 30 days, bivalirudin monotherapy was associated with significantly less non-CABG-related major bleeding (bivalirudin monotherapy 4.1% vs. bivalirudin plus GPI 8.4% vs. heparin plus GPI 7.1%) with comparable rates of composite ischemia (bivalirudin monotherapy 9.2% vs. bivalirudin plus GPI 9.9% vs. heparin plus GPI 8.4%). In a multivariable model, bivalirudin monotherapy was associated with a significant reduction in non-CABG-related major bleeding but was not associated with an increased risk of death, myocardial infarction, unplanned revascularization or stent thrombosis. Conclusion Compared with heparin plus GPI or bivalirudin plus GPI, bivalirudin monotherapy provides similar protection from ischemic events with less major bleeding at 30 days among patients with NSTE-ACS and positive biomarkers.

Background: Calcific aortic valve disease (CAVD) is the most common type of valvular heart disease in the elderly. This study is aimed to explore molecular mechanism of CAVD via bioinformatics analysis. Methods: The gene expression profiles of GSE51472 (including 5 normal aortic valve and 5 calcified aortic valve) and GSE83453 (including 8 normal aortic valve and 19 calcified aortic valve) were downloaded from the Gene Expression Omnibus (GEO) database. Differentially expressed genes (DEGs) were screened using the MetaDE package in R software. Functional and pathway enrichment analysis were performed based on Gene ontology (GO) and KEGG pathway database. Then, STRING database, Cytoscape and MCODE were applied to construct the protein-protein interaction (PPI) network and screen hub genes. Pathway enrichment analysis was further performed for hub genes and gene clusters identified via module analysis. Results: A total of 107 DEGs were identified in CAVD (53 up-regulated genes, and 54 down-regulated genes), and they were mainly enriched in the terms of immune response, extracellular matrix organization, leukocyte transendothelial migration, cell adhesion molecules (CAMs), and fatty acid metabolism. Five hub genes including VCAM1, MMP9, ITGB2, RAC2, and vWF were identified via PPI network, which were mainly enriched in terms of leukocyte transendothelial migration and cell adhesion. An independently down-regulated protein cluster containing ALDH2, HIBCH, ACADVL, ECHDC2, VAT1L, and MAOA was also identified via PPI network. Conclusions: The present study identified VCAM1, MMP9, ITGB2, RAC2, vWF and ALDH2 as key genes in the progression of CAVD. Immune cells infiltration might play a key role in the progression of CAVD, while ALDH2-mediated detoxification effect might play a protective role in CAVD. Further studies are needed to elucidate the pathogenesis of CAVD.

Background Age-related sarcopenia is a serious global health issue in elderly individuals and for the community as it induces disability and significant economic burden. The purpose of the study is to understand the factors associated with sarcopenia and the role of growth hormone (GH) and insulin-like growth factor (IGF-1) in the occurrence of sarcopenia. Methods Elderly patients (n = 3276) were included in this cross-sectional study. Survey and measurement of body composition (bioelectrical impedance), grip strength, and step speed were performed according to the Asian Working Group on Sarcopenia (AWGS) diagnostic criteria. Hematological and hormonal indicators were compared between patients with and without sarcopenia in order to identify the associated factors. Results There were significant differences in the demographic parameters between the sarcopenia and non-sarcopenia groups (all P P P P Conclusions GH and IGF-1 are associated with sarcopenia in the elderly. IGF-1 and MGF are independently associated with the reduction of skeletal muscle mass, along with BMI and gender.

We conducted an adaptive design single-center pilot trial between October 2017 and November 2018 to determine the safety and efficacy of ultra-short-term perioperative pangenotypic direct acting antiviral (DAA) prophylaxis for deceased hepatitis C virus (HCV)-nucleic acid test (NAT) positive donors to HCV negative kidney recipients (D+/R-). In Group 1, 10 patients received one dose of SOF/VEL (sofusbuvir/velpatasvir) pretransplant and one dose on posttransplant Day 1. In Group 2A (N = 15) and the posttrial validation (Group 2B; N = 25) phase, patients received two additional SOF/VEL doses (total 4) on Days 2 and 3 posttransplant. Development of posttransplant HCV transmission triggered 12-week DAA therapy. For available donor samples (N = 27), median donor viral load was 1.37E + 06 IU/mL (genotype [GT]1a: 70%; GT2: 7%; GT3: 23%). Overall viral transmission rate was 12% (6/50; Group 1:30% [3/10]; Group 2A:13% [2/15]; Group 2B:4% [1/25]). For the 6 viremic patients, 5 (83%) achieved sustained virologic response (3 with first-line DAA therapy; and two after retreatment with second-line DAA). At a median follow-up of 8 months posttransplant, overall patient and allograft survivals were 98%, respectively. The 4-day strategy reduced viral transmission to 7.5% (3/40; 95% confidence interval [CI]: 1.8%-20.5%) and could result in avoidance of prolonged posttransplant DAA therapy for most D+/R - transplants.

Aneurysmal subarachnoid hemorrhage (SAH) causes high rates of mortality and morbidity. A covered stent is an effective endovascular treatment for complicated aneurysms intractable to endovascular coiling and surgical clipping. However, in-stent restenosis and delayed endothelialization are the main challenges contributing to its safety. In this study, we designed a biofunctional stent covered with dual drug-loaded electrospun fibers to achieve programmed vascular endothelial growth factor (VEGF) and paclitaxel (PTX) release for the early promotion of stent endothelialization and long-term inhibition of stenosis caused by smooth muscle hyperplasia. By encapsulating PTX-loaded mesoporous silica nanoparticles (MSNs) within electrospun polylactic acid (PLA) fibers, the release period of PTX was effectively extended. Furthermore, VEGF was conjugated onto the surface of the membrane by reacting with polydopamine (PDA) for quick release. The in vitro drug release profile revealed the sustained release of PTX, which persisted for 63 days without early burst release, while up to 87.05% of VEGF was rapidly released within 3 days. After 6 days of incubation, cell experiments demonstrated that the dual drug-loaded scaffold effectively prompted endothelial cell proliferation (488% vs. 386% in the control group, P = 0.001) and inhibited the proliferation of smooth muscle cells (SMCs) using the 21-day extracts (155% vs. 303% in the control group, P = 0.039). Animal studies showed that compared to bare stents, the drug-loaded covered stents improved the immediate- and mid-term complete aneurysm occlusion rates (P 0.05). The drug-loaded covered stents also showed earlier endothelialization promotion and better lumen restenosis than normal covered stents (0% vs. 25%, P = 0.29) for 12 weeks. Overall, a programmed dual drug-loaded scaffold that effectively occluded the aneurysm sac was developed in this study, and the discrete release of VEGF and PTX promoted endothelialization and prevented in-stent stenosis. This study provided a new method to improve the biosafety of implanted covered stents for the treatment of intracranial aneurysms. STATEMENT OF SIGNIFICANCE: Aneurysmal subarachnoid hemorrhage (SAH) is one of the most common hemorrhage stroke resulted in a nearly 40% mortality and 33% morbidity due to sudden rupture of an intracranial aneurysm. Endovascular coil embolism is a popular treatment for aneurysm but this technique run high risk of bleeding, mass effect, low complete occlusion rate and higher recanalization rate due to its operation conducted within aneurysm sac. A bio-functional membrane knitted by dual-drug loaded electrospun fibers covered on a stent was designed to realize programed vascular endothelial growth factor and paclitaxel release for the early promotion of vascular endothelium and long-term inhibition of stenosis caused by smooth muscle hyperplasia. This study provides new method to improve the biosafety of covered stent insertion for the treatment of intracranial aneurysms.

Purpose To compare the extent of arterial wall damage when SR and CA were used for treatment of AIS models to evaluate their efficacy and safety. Methods A thrombin-induced thrombus was pre-injected into the right distal external carotid-maxillary artery (ECMA) in 12 dogs to create an acute thrombus occlusion model and were randomly divided into the SR group (n = 6; received SR treatment) and CA group (n = 6; received CA treatment). Device safety was also assessed by five passages through the normal left ECMA using each device. Device manipulation-related damage to arterial walls, final flow restoration, recanalization time and complications were recorded. Results Sixteen retriever and 10 aspiration attempts were performed in the SR and CA groups. Reperfusion time was significantly reduced in the CA group (17.83 ± 1.96 vs. 28.33 ± 3.26 in the SR group; P = 0.02). Stent retriever thrombectomy resulted in an increased risk of endothelium denudation (1.17 ± 0.24 in SR group vs. 0.42 ± 0.15 in CA group; P = 0.01) and reduced frequency of vessel vasospasm (0.67 ± 0.14 in SR group vs. 0.25 ± 0.13 in CA group; P = 0.04). Injury score and thrombus deposition were similar between the two groups (P > 0.05). TICI 2b/3 flow restoration values of the right ECMA were 100 % in both groups. Device-related complications, including dissection (P = 0.21), side branch influence (P = 0.24), and distal thromboembolism (P = 1.00), did not differ between the two groups. Conclusion Both devices had similar efficacy and caused minimal arterial wall damage in our dog models. SR was more likely to cause endothelium denudation, while CA had a greater risk of vasospasm.

TPS5100 Background: NEPC is an aggressive cancer with poor prognosis. No standard treatment approach for NEPC exists and it remains an unmet need. NEPC is usually treatment-emergent, characterized by histological transformation from adenocarcinoma to a high-grade neuroendocrine tumor (NET), and may develop in 15%–20% of patients (pts) treated with standard prostate adenocarcinoma therapies, including novel hormonal therapies. The inhibitory Notch ligand, Delta-like ligand 3 (DLL3), is highly expressed on the surface of cancer cells, including NEPC cells, making it an attractive and a promising therapeutic target. AMG 757 is an HLE BiTE immuno-oncology therapy designed to redirect cytotoxic T cells to tumor cells by binding DLL3 on cancer cells and CD3 on T cells, resulting in T cell activation and expansion and T cell-dependent killing of tumor cells. AMG 757 showed in vitro activity in DLL3-expressing NETs, including NEPC. Preliminary results of an on-going first-in-human study suggest AMG 757 is safe and effective in pts with small cell lung cancer (NCT03319940), which prompted its study in NEPC. Methods: NCT04702737 is an open-label, phase 1b study evaluating AMG 757 infusion in pts with metastatic de novo or treatment-emergent NEPC, consisting of dose exploration and then dose expansion. Key eligibility criteria include adults (≥18 y) with NEPC whose disease progressed/recurred after ≥1 treatment course including a platinum-based regimen for de novo NEPC or an androgen signaling inhibitor, measurable disease per modified RECIST 1.1 per Prostate Cancer Working Group 3 modifications, ECOG performance status ≤2, life expectancy > 3 mo, adequate organ function, and no untreated/symptomatic brain metastases. Primary objectives are to evaluate safety and tolerability and determine the maximum tolerated dose or recommended phase 2 dose of AMG 757. Secondary objectives are to evaluate antitumor activity (ie, objective response, duration of response, progression-free survival, overall response) and characterize pharmacokinetics. The starting dose for dose exploration will be based on the dose deemed safe and tolerable in the ongoing trial of AMG 757 in SCLC. The study is open to enrollment. Clinical trial information: NCT04702737.