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Chronic hepatitis B virus (HBV) infection remains a substantial public health burden worldwide. Alpha-interferon (IFNα) is one of the two currently approved therapies for chronic hepatitis B (CHB), to explore the mechanisms underlying IFNα treatment response, we investigated baseline and 24-week on-treatment intrahepatic gene expression profiles in 21 CHB patients by mRNA-seq. The data analyses demonstrated that PegIFNα treatment significantly induced antiviral responses. Responders who achieved HBV DNA loss and HBeAg or HBsAg seroconversion displayed higher fold change and larger number of up-regulated interferon-stimulated genes (ISGs). Interestingly, lower expression levels of certain ISGs were observed in responders in their baseline biopsy samples. In HBeAg+ patients, non-responders had relative higher baseline HBeAg levels than responders. More importantly, HBeAg- patients showed higher HBsAg loss rate than HBeAg+ patients. Although a greater fold change of ISGs was observed in HBeAg- patients than HBeAg+ patients, upregulation of ISGs in HBeAg+ responders exceeded HBeAg- responders. Notably, PegIFNα treatment increased monocyte and mast cell infiltration, but decreased CD8 T cell and M1 macrophage infiltration in both responders and non-responders, while B cell infiltration was increased only in responders. Moreover, co-expression analysis identified ribosomal proteins as critical players in antiviral response. The data also indicate that IFNα may influence the production of viral antigens associated with endoplasmic reticulum. Collectively, the intrahepatic transcriptome analyses in this study enriched our understanding of IFN-mediated antiviral effects in CHB patients and provided novel insights into the development of potential strategies to improve IFNα therapy.

A variant in signal transducer and activator of transcription 4 (STAT4) was reported to correlate with the response of interferon-α (IFN-α) in a retrospective study in hepatitis B e antigen (HBeAg)-positive chronic hepatitis B virus (CHB) patients. Here, we conducted a prospective study to analyze the effect of STAT4 genetic polymorphism on the response of pegylated interferon-α-2a (PegIFN-α-2a) in HBeAg-positive patients. A prospective, multicenter, open-label, parallel cohort study was performed. One hundred and fifty treatment-naïve and 156 nucleos(t)ide analog (NA)-experienced HBeAg-positive CHB patients were enrolled, respectively. All patients received PegIFN-α-2a treatment for 48 weeks and 24-week follow-up post PegIFN-α-2a treatment. Before treatment, STAT4 genetic polymorphism was determined by PCR and DNA sequencing. Serological markers, serum HBV DNA levels, and adverse events were collected at each visit. We observed a larger reduction of HBV DNA load and a significantly higher HBeAg seroconversion rate in the GT/TT group than in the GG group at week 72 (p = 0.002 and p = 0.023) in treatment-naïve patients. In NA-experienced patients, the HBeAg seroconversion rate in the GT/TT group was higher than that in the GG group at week 72 (p = 0.005). STAT4 rs7574865 gene polymorphism was the strongest independent predictor of HBeAg seroconversion in both paralleled cohorts. Also, patients in the GT/TT group had a higher hepatitis B surface antigen loss rate than in the GG group in the study. There was no significant difference in adverse events between GG and GT/TT groups. This prospective cohort study confirmed that STAT4 rs7574865 gene polymorphism is associated with HBeAg seroconversion and HBsAg loss irrespective of naïve and NA-experienced HBeAg-positive CHB patients treated with PegIFN-α-2a.

The long-term impact, incidence and risk factors of thyroid dysfunction in chronic hepatitis B (CHB) patients receiving pegylated interferon (IFN) alpha (PegIFN-alpha) therapy remain unclear. We aim to investigate the long-term safety of thyroid dysfunction in CHB patients receiving PegIFN-alpha. A retrospective observational study of 425 CHB patients with normal baseline thyroid function was carried out. Patients were followed up over 10 years to assess thyroid function after receiving IFN. At the end of the IFN therapy, 67 patients (15.8%) had developed thyroid dysfunction, 31 patients (46.3%) had hyperthyroidism and 64.4% presented with subclinical thyroid dysfunction. In follow-up of thyroid dysfunction patients, 37 patients (74.0%) spontaneously regained normal thyroid function. Pretreatment thyroid-stimulating hormone (TSH) level, thyroid peroxidase antibody (TPOAb) positivity and free thyroxine (FT4) were independent risk factors associated with thyroid dysfunction incidence. High TSH level (OR = 9.866, 95%CI, 3.245-29.998) was associated with a greater likelihood of hypothyroidism. High FT4 levels (OR = 0.464, 95%CI, 0.248-0.868) indicate a low likelihood of thyroid dysfunction. Thyroid dysfunction is a common but acceptable side effect of IFN therapy for CHB. Most thyroid dysfunction is reversible. Pretreatment TSH level and TPOAb positivity are risk factors for thyroid dysfunction development during IFN therapy. A high TSH level predicts an increased incidence of hypothyroidism. Moreover, FT4 may be a protective factor for thyroid dysfunction.

In the present study, a water-soluble neutral polysaccharide (CAPW-1) with an average molecular weight of 64 kDa was purified from the root of Cynanchum atratum Bunge (Apocynaceae). The monosaccharide residue analysis revealed that CAPW-1 was composed of arabinose and galactose with a relative molar ratio of 7: 3. The backbone of CAPW-1 was consisted of 1,3-Galp and 1,3,6-Galp, the branches were attached to the O-6 of 1,3-Galp, and the side chains contained 1,6-Galp, 1,3,6-Galp, 1,5-linked, 1,3-linked, 1,3,5-linked, and terminal-Araf, which was attached to the O-3 of side 1,6-Galp. The bioactivity study indicated CAPW-1 could stimulate the proliferation of RAW264.7 cells and promote the secretion of nitric oxide (NO), interleukin-6 (IL-6) and tumor necrosis factor-α (TNF-α) with no cytotoxicity. The results suggested a potential application of CAPW-1 as an immunostimulant for the treatment of diseases such as infection and tumor.

Primary immune thrombocytopenia (ITP) is an acquired autoimmune hemorrhagic disease. Loss of immune tolerance plays a crucial role in the pathogenesis of ITP. Monocytes and macrophages play an indispensable role in the pathophysiology of hematopoietic malignancies and have been implicated as key players in platelet destruction. Approximately 80% of adult patients with ITP exhibit corticosteroid treatment failure or become dependent, requiring novel therapy. Thrombopoietin (TPO) receptor agonists (TPO-RAs) have been used clinically to manage ITP effectively, however, little is known about the effect of TPO-RAs on monocyte and macrophage modulation in adult ITP. In this study, we investigated the phenotypic evolution and potential immunomodulatory roles of monocytes/macrophages in ITP patients receiving eltrombopag therapy. Results showed that the peripheral monocyte count positively correlated with IFN-γ/IL-4 ratio in ITP patients. Moreover, numerous phenotype-associated genes in ITP macrophages exhibited diverse responses, and ITP macrophages exhibited more M1-related characteristics. After eltrombopag therapy, the peripheral monocyte count and IFN-γ/IL-4 ratio significantly decreased in ITP patients. M1-related characteristics of ITP macrophages were partially reversed by eltrombopag. Therefore, this study revealed eltrombopag restored the monocyte dynamics and the associated Th1/Th2 imbalance, and partially reversed the M1-related characteristics of the ITP macrophages, which suggest the potential vital roles of TPO-RAs in regulating the monocyte/macrophage plasticity in ITP.

The function of interleukin-22 (IL-22) in intestinal barrier homeostasis remains controversial. Here, we map the transcriptional landscape regulated by IL-22 in human colonic epithelial organoids and evaluate the biological, functional and clinical significance of the IL-22 mediated pathways in ulcerative colitis (UC). We show that IL-22 regulated pro-inflammatory pathways are involved in microbial recognition, cancer and immune cell chemotaxis; most prominently those involving CXCR2+ neutrophils. IL-22-mediated transcriptional regulation of CXC-family neutrophil-active chemokine expression is highly conserved across species, is dependent on STAT3 signaling, and is functionally and pathologically important in the recruitment of CXCR2+ neutrophils into colonic tissue. In UC patients, the magnitude of enrichment of the IL-22 regulated transcripts in colonic biopsies correlates with colonic neutrophil infiltration and is enriched in non-responders to ustekinumab therapy. Our data provide further insights into the biology of IL-22 in human disease and highlight its function in the regulation of pathogenic immune pathways, including neutrophil chemotaxis. The transcriptional networks regulated by IL-22 are functionally and clinically important in UC, impacting patient trajectories and responsiveness to biological intervention.

Clear cell renal cell carcinoma (ccRCC) is a common malignant tumour of the urinary tract. The major causes of poor prognosis are the lack of early diagnosis and metastasis. Accumulating research reveals that circular RNAs (circRNAs) can play key roles in the development and the progression of cancer. However, the role of circRNAs in ccRCC is still uncertain.The circRNAs microarray (n = 4) was performed to investigate the circRNAs with differential expression in ccRCC tissues. The candidate circRNA was selected based on the cut-off criteria, such as circRNA expression abundance, circRNA size and the design of divergent primers. The circ-transportin-3 (TNPO3) levels in ccRCC tissues were tested by quantitative real-time (qRT)-PCR (n = 110). The characteristics and subcellular localization of circ-TNPO3 were identified via RNase R assay, qRT-PCR and fluorescence in situ hybridization (FISH). Then, we explored the biological roles of circ-TNPO3 in ccRCC via the function experiments in vitro and in vivo. RNA pull-down, RNA immunoprecipitation, bioinformatic analysis, RNA-FISH assays and rescue assays were applied to validate the interactions between circ-TNPO3, insulin-like growth factor 2 mRNA-binding protein 2 (IGF2BP2) and serpin family H member 1 (SERPINH1) to uncover the underlying molecular mechanisms of circ-TNPO3.We detected the obvious downregulation of circ-TNPO3 in ccRCC compared to matched adjacent normal tissues (n = 110). The lower circ-TNPO3 expression was found in ccRCC patients with distant metastasis, higher World Health Organization/International Society of Urologic Pathologists (WHO/ISUP) grade and more advanced tumour T stage. In vitro and in vivo, circ-TNPO3 significantly suppressed the proliferation and migration of ccRCC cells. Mechanistically, we elucidated that circ-TNPO3 directly bound to IGF2BP2 protein and then destabilized SERPINH1 mRNA. Moreover, IGF2BP2/SERPINH1 axis was responsible for circ-TNPO3's function of inhibiting ccRCC metastasis. Epithelial splicing regulatory protein 1 (ESRP1) was probably involved in the biogenesis of circ-TNPO3.Circ-TNPO3 can suppress ccRCC progression and metastasis via directly binding to IGF2BP2 protein and destabilizing SERPINH1 mRNA. Circ-TNPO3 may act as a potential target for ccRCC treatment.

Triple-negative breast cancer (TNBC) exhibits a high mortality rate and is the most aggressive subtype of breast cancer. As previous studies have shown that histone deacetylases (HDAC) may represent molecular targets for TNBC treatment, we screened a small library of synthetic molecules and identified a potent HDAC inhibitor (HDACi), YF438, which exerts effective anti-TNBC activity both in vitro and in vivo. Proteomic and biochemical studies revealed that YF438 significantly downregulated mouse double minute 2 homolog (MDM2) expression. In parallel, loss of MDM2 expression or blocking MDM2 E3 ligase activity rendered TNBC cells less sensitive to YF438 treatment, revealing an essential role of MDM2 E3 ligase activity in YF438-induced inhibition of TNBC. Mechanistically, YF438 disturbed the interaction between HDAC1 and MDM2, induced the dissociation of MDM2-MDMX, and subsequently increased MDM2 self-ubiquitination to accelerate its degradation, which ultimately inhibited growth and metastasis of TNBC cells. In addition, analysis of clinical tissue samples demonstrated high expression levels of MDM2 in TNBC, and MDM2 protein levels closely correlated with TNBC progression and metastasis. Collectively, these findings show that MDM2 plays an essential role in TNBC progression and targeting the HDAC1–MDM2–MDMX signaling axis with YF438 may provide a promising therapeutic option for TNBC. Furthermore, this novel underlying mechanism of a hydroxamate-based HDACi in altering MDM2 highlights the need for further development of HDACi for TNBC treatment. Significance: This study uncovers the essential role of MDM2 in TNBC progression and suggests that targeting the HDAC1–MDM2–MDMX axis with a hydroxamate-based HDACi could be a promising therapeutic strategy for TNBC.

Echocardiography is the first-line diagnostic technique for heart diseases. Although artificial intelligence techniques have made great improvements in the analysis of echocardiography, the major limitations remain to be the built neural networks are normally adapted to a few diseases and specific equipment. Here, we present an end-to-end deep learning framework named AIEchoDx that differentiates four common cardiovascular diseases (Atrial Septal Defect, Dilated Cardiomyopathy, Hypertrophic Cardiomyopathy, prior Myocardial Infarction) from normal subjects with performance comparable to that of consensus of three senior cardiologists in AUCs (99.50% vs 99.26%, 98.75% vs 92.75%, 99.57% vs 97.21%, 98.52% vs 84.20%, and 98.70% vs 89.41%), respectively. Meanwhile, AIEchoDx accurately recognizes critical lesion regions of interest along with each disease by visualizing the decision-making process. Furthermore, our analysis indicates that heterogeneous diseases, like dilated cardiomyopathy, could be classified into two phenogroups with distinct clinical characteristics. Finally, AIEchoDx performs efficiently as an anomaly detection tool when applying handheld device-produced videos. Together, AIEchoDx provides a potential diagnostic assistant tool in either cart-based echocardiography equipment or handheld echocardiography device for primary and point-of-care medical personnel with high diagnostic performance, and the application of lesion region identification and heterogeneous disease phenogrouping, which may broaden the application of artificial intelligence in echocardiography.

Objective To evaluate fatigue frequency and severity among patients with psoriatic arthritis (PsA) and assess the effect of fatigue severity on patient-reported outcome measures (PROMs) assessing quality of life, function, and work productivity. Methods Data were derived from the Adelphi Disease Specific Programme, a cross-sectional survey conducted in 2018 in the United States and Europe. Patients had physician-confirmed PsA. Fatigue was collected as a binary variable and through its severity (0-10 scale, using the 12-item Psoriatic Arthritis Impact of Disease fatigue question) from patients; physicians also reported patient fatigue (yes/no). Other PROMs included the 5-level EuroQol 5-dimension questionnaire (EQ-5D-5L) for health-related quality of life (HRQOL), Health Assessment Questionnaire–Disability Index, and Work Productivity and Activity Impairment Questionnaire. Multivariate linear regression was used to evaluate the association between fatigue severity and other PROMs. Results Among the 831 included patients (mean age 47.5 yrs, mean disease duration 5.3 yrs, 46.9% female, 48.1% receiving a biologic), fatigue was reported by 78.3% of patients. Patients with greater fatigue severity had greater disease duration, PsA severity, pain levels, body surface area affected by psoriasis, and swollen and tender joint counts (all P < 0.05). In multivariate analyses, patients with greater fatigue severity experienced worse physical functioning, HRQOL, and work productivity (all P < 0.001). Presence of fatigue was underreported by physicians (reported in only 32% of patients who self-reported fatigue). Conclusion Prevalence of patient-reported fatigue was high among patients with PsA and underrecognized by physicians. Fatigue severity was associated with altered physical functioning, work productivity, and HRQOL.

In DISCOVER-2, guselkumab, an interleukin-23 p19 subunit inhibitor, was efficacious in biologic-naïve psoriatic arthritis (PsA) patients. We report the effect of guselkumab on health-related quality of life (HRQoL) using the EuroQol 5-Dimension 5-Level (EQ-5D-5L) Index and Visual Analog Scale (EQ-VAS) through Week 52.Adults with active PsA were randomized to guselkumab 100 mg every 4 weeks (Q4W) or Weeks 0, 4, then every 8 weeks (Q8W), or placebo (crossover to guselkumab Q4W at Week 24). Least squares (LS) mean changes in EQ-5D-5L Index (0-1, US-based value set) and EQ-VAS (0-100) from baseline through Week 52 were assessed. Proportions of patients achieving minimally important differences (MIDs) were assessed through Week 52. Associations between patient clinical features and EQ-5D-5L Index and EQ-VAS scores were examined cross-sectionally with pooled data through Week 24.The analysis included 738 patients (Q4W n = 245; Q8W n = 248; placebo n = 245). At Week 24, LS mean changes from baseline in the Q4W, Q8W, and placebo groups were 0.12, 0.12, and 0.05, respectively, for EQ-5D-5L Index, and 18.2, 18.4, and 6.8, respectively, for EQ-VAS. At Week 52, improvement was maintained in the guselkumab groups and increased in the placebo crossover group. EQ-5D-5L Index MID was achieved by 56.0% in each guselkumab group at Week 24 and 66.2% in Q4W, 68.5% in Q8W, and 66.1% in placebo crossover group at Week 52. Higher C-reactive protein level, Psoriasis Area and Severity Index score, fatigue, and pain were correlated with worse EQ-5D-5L Index and EQ-VAS, based on pooled data through Week 24. Higher tender joint count was correlated with worse EQ-5D-5L, while higher swollen joint count was correlated with worse EQ-VAS.Guselkumab improved HRQoL through 52 weeks in patients with active PsA. Impairment in HRQoL was correlated with increased inflammation, fatigue, pain, and measures of skin and joint symptom severity.GOV: NCT03158285.

The phase 3 DISCOVER-2 trial evaluated the effect of guselkumab on impaired work productivity and nonwork activity in biologic-naïve patients with psoriatic arthritis (PsA).Adults with active PsA were randomized (1:1:1) to guselkumab 100 mg every 4 weeks (Q4W), guselkumab 100 mg at weeks 0 and 4 and then every 8 weeks (Q8W), or placebo (with crossover to guselkumab Q4W at week 24). Least squares mean change from baseline in Work Productivity and Activity Impairment Questionnaire for PsA (WPAI-PsA) domains and employment were assessed by treatment group. Multivariate analysis of data from weeks 0 through 24 assessed independent associations between PsA clinical features and WPAI-PsA domains.In total, 738 patients were evaluated (guselkumab Q4W n = 245; guselkumab Q8W n = 248; placebo n = 245). At week 24, improvements (reduced impairment) in presenteeism (Q4W -20.1%, Q8W -19.6%, placebo -10.5%), work productivity (Q4W -20.1%, Q8W -19.2%, placebo -10.6%), and nonwork activity (Q4W -20.5%, Q8W -21.2%, placebo -9.9%) were greater in guselkumab-treated versus placebo-treated patients. At week 52, following placebo crossover at week 24, improvements were similar among groups. Baseline absenteeism was minimal and did not change in any group. By week 52, 23.1-25.9% of guselkumab-treated patients who were unemployed at baseline were employed. All WPAI-PsA domains were positively associated with C-reactive protein level, fatigue, and pain. All domains except absenteeism were positively associated with enthesitis and Psoriasis Area and Severity Index score. Age was negatively associated with presenteeism and work productivity loss, female sex and tender joint count were positively associated with nonwork activity impairment, and dactylitis was positively associated with presenteeism.Both guselkumab regimens reduced work productivity loss and nonwork activity impairment in patients with active PsA. Association of work productivity loss and nonwork activity impairment with PsA joint and skin features suggests that improvement in both features is beneficial for optimizing improved work productivity loss and nonwork activity impairment.ClinicalTrials.gov identifier, NCT03158285.

Background Gastric cancer (GC) is one of the most common malignant tumors in China. Circular RNAs (circRNAs) are novel non-coding RNAs with important regulatory roles in cancer progression. IGF2BP3 has been found to play oncogenic roles in various cancers including GC, while the exact mechanism of IGF2BP3 is largely unknown. Methods The expression of IGF2BP3 in GC was evaluated by Western Blot and bioinformatics analysis. CircRNA expression profiles were screened via IGF2BP3 RIP-seq in GC. Sanger sequencing, RNase R digestion, nucleo-plasmic separation and RNA-FISH assays were used to detect the existence and expression of circARID1A. RNA ISH assay was employed to test the expression of circARID1A in paraffin-embedded GC tissues. Moreover, the function of circARID1A on cellular proliferation was assessed by CCK-8, plate colony formation, EdU assays and GC xenograft mouse model in vivo. Furthermore, the location or binding of circARID1A, IGF2BP3 protein and SLC7A5 in GC was evaluated by RNA-FISH/IF or RNA pull-down assays. Results We identified a novel circRNA, circARID1A, that can bind to IGF2BP3 protein. CircARID1A was significantly upregulated in GC tissues compared with noncancerous tissues and positively correlated with tumor length, tumor volume, and TNM stage. CircARID1A knockdown inhibited the proliferation of GC cells in vitro and in vivo and circARID1A played an important role in the oncogenic function of IGF2BP3. Mechanistically, circARID1A served as a scaffold to facilitate the interaction between IGF2BP3 and SLC7A5 mRNA, finally increasing SLC7A5 mRNA stability. Additionally, circARID1A was able to directly bind SLC7A5 mRNA through complementary base-pairing and then formed the circARID1A-IGF2BP3-SLC7A5 RNA–protein ternary complex and promoted the proliferation of GC via regulating AKT/mTOR pathway. Conclusions Altogether, our data suggest that circARID1A is involved in the function of IGF2BP3 and GC proliferation, and the circARID1A-IGF2BP3-SLC7A5 axis has the potential to serve as a novel therapeutic target for GC.

BACKGROUND & AIMS: Ustekinumab induces and maintains histologic improvement in patients with ulcerative colitis (UC). The clinical relevance of this endpoint alone, and in combination with endoscopic improvement, is unknown. METHODS: Histologic disease activity was evaluated in 2630 colonic biopsy samples from patients with UC treated in the UNIFI phase 3 UC clinical studies of ustekinumab. We evaluated associations between histologic improvement (defined as the composite of neutrophil infiltration in less than 5% of crypts and no crypt destruction, erosions, ulcerations, or granulation tissue) and clinical endpoints at the end of induction (week 8 and 16) and maintenance (week 44) periods. We assessed the validity of a combined histologic and endoscopic (Mayo endoscopy subscore, 0 or 1) improvement endpoint, which we called histo-endoscopic mucosal healing (or histo-endoscopic mucosal improvement). RESULTS: Histologic improvement was significantly (P < .0001) associated with clinical remission, lower mean disease activity scores, and greater improvement in disease activity at the end of induction and maintenance studies. Ustekinumab induced and maintained significantly higher rates of histologic improvement at induction week 8 and maintenance week 44 than placebo when more stringent definitions of histologic improvement were used. Histologic improvement and endoscopic improvement following induction were associated with 10% to 20% higher rates of histo-endoscopic mucosal healing, clinical remission, and corticosteroid-free remission at week 44 (all P < .05) in patients who received ustekinumab maintenance therapy. At week 44, 61% of patients (56/92) with histo-endoscopic mucosal healing after induction therapy achieved clinical remission, versus 39% of patients (9/23, P = .0983) and 34% of patients (24/71, P = .0009) with endoscopic or histologic improvement alone after induction, respectively. CONCLUSION: Data from the UNIFI program of ustekinumab in patients with UC treated with ustekinumab indicated the achievement of histo-endoscopic mucosal healing after induction therapy is associated with lower disease activity at the end of maintenance therapy than either histologic or endoscopic improvement alone. ClinicalTrials.gov number: NCT02407236. ispartof: GASTROENTEROLOGY vol:159 issue:6 ispartof: location:United States status: published

Aim: Histone deacetylases (HDACs) are one of the validated targets for cancer treatments. In our previous work, we designed a series of bis-substituted aromatic amide HDAC inhibitors (HDACis), among which compounds 7 and 8 showed promising anticancer effects. However, the low solubilities prevented their subsequent developments. We developed additional thiophene-based hydroxamate HDACis in order to improve their physicochemical properties. Materials & methods: In vitro biological evaluations of these analogs revealed potent antiproliferative and antimigrated activities. More importantly, compound 10h exhibited excellent in vivo antitumor activities in MDA-MB-231 xenograft model mice. Furthermore, 10h showed better anticancer activities and drug-like properties than 7. Results & conclusion: Our results proved that thiophene-based hydroxamate HDACis can serve as a promising framework for developing potential anticancer agents.

Blocking the migration of regulatory T cells (Tregs) to the tumor microenvironment is a promising strategy for tumor immunotherapy. Treg accumulation in the leukemic hematopoietic microenvironment (LHME) has adverse impacts on patient outcomes. The mechanism and effective methods of disrupting Treg accumulation in the LHME have not been well established. Here, we studied the distribution and characteristics of Tregs in the LHME, investigated the effects of Treg ablation on leukemia progression, explored the mechanisms leading to Treg accumulation, and studied whether blocking Treg migration to the LHME delayed leukemia progression in MLL-AF9-induced mouse acute myeloid leukemia (AML) models using wildtype (WT) and Foxp3DTR/GFP mice. Increased accumulation of more activated Tregs was detected in the LHME. Inducible Treg ablation prolonged the survival of AML mice by promoting the antileukemic effects of CD8+ T cells. Furthermore, both local expansion and migration accounted for Treg accumulation in the LHME. Moreover, blocking the CCL3-CCR1/CCR5 and CXCL12-CXCR4 axes inhibited Treg accumulation in the LHME and delayed leukemia progression. Our findings provide laboratory evidence for a potential leukemia immunotherapy by blocking the migration of Tregs.

BackgroundWe aimed to understand how glycaemic levels among COVID-19 patients impact their disease progression and clinical complications.MethodsWe enrolled 2,366 COVID-19 patients from Huoshenshan hospital in Wuhan. We stratified the COVID-19 patients into four subgroups by current fasting blood glucose (FBG) levels and their awareness of prior diabetic status, including patients with FBGResultsCOVID-19 patients with higher FBG and unknown diabetes in the past (group 3) are more likely to progress to the severe or critical stage than patients in other groups (severe: 38.46% vs 23.46%-30.70%; critical 7.69% vs 0.61%-3.96%). These patients also have the highest abnormal level of inflammatory parameters, complications, and clinical adversities among all four groups (all pConclusionOur study shows that COVID-19 patients with current high FBG levels but unaware of pre-existing diabetes, or possibly new onset diabetes as a result of COVID-19 infection, have a higher risk of more severe adverse outcomes than those aware of prior diagnosis of diabetes and those with low current FBG levels.

Objective To examine the clinical characteristics of patients with asymptomatic novel coronavirus disease 2019 (COVID-19) and compare them with those of patients with mild disease. Design A retrospective cohort study. Setting Multiple medical centers in Wuhan, Hubei, China. Participants A total of 3,263 patients with laboratory-confirmed severe acute respiratory syndrome coronavirus 2 (SARS-Cov-2) infection between February 4, 2020, and April 15, 2020. Main outcome measures Patient demographic characteristics, medical history, vital signs, and laboratory and chest computed tomography (CT) findings. Results A total of 3,173 and 90 patients with mild and moderate, and asymptomatic COVID-19, respectively, were included. A total of 575 (18.2%) symptomatic patients and 4 (4.4%) asymptomatic patients developed the severe illness. All asymptomatic patients recovered; no deaths were observed in this group. The median duration of viral shedding in asymptomatic patients was 17 (interquartile range, 9.25–25) days. Patients with higher levels of ultrasensitive C-reactive protein (odds ratio [OR] = 1.025, 95% confidence interval [CI], 1.01–1.04), lower red blood cell volume distribution width (OR = 0.68, 95% CI 0.51–0.88), lower creatine kinase Isoenzyme(0.94, 0.89–0.98) levels, or lower lesion ratio (OR = 0.01, 95% CI 0.00–0.33) at admission were more likely than their counterparts to have asymptomatic disease. Conclusions Patients with younger ages and fewer comorbidities are more likely to be asymptomatic. Asymptomatic patients had similar laboratory characteristics and longer virus shedding time than symptomatic patients; screen and isolation during their infection were helpful to reduce the risk of SARS-CoV-2 transmission.

Myelodysplastic syndrome (MDS) is a heterogeneous group of clonal hematopoietic neoplasms. The progression of malignancy is closely associated with immune regulation. Macrophages are indispensable tissue components and have been proposed to play a role in the pathophysiology of hematopoietic malignancies. However, the specific role of macrophages in the development of MDS remains unclear. Here, we investigated the characteristics and phenotypic evolution of macrophages from patients with MDS. Macrophages from patients with MDS expressed CD68, CD86 and CD163. Furthermore, MDS macrophages exhibited more M2-related characteristics. Moreover, a number of phenotype-associated genes in MDS macrophages exhibited diverse responses to iron overload or iron chelation upon stimulation by ferric chloride or deferoxamine (DFO, an iron chelator). Ferric chloride polarized MDS macrophages to exhibit more M1-related characteristics, a phenomenon that could be partially reversed by DFO. Therefore, this study reveals the characteristics and phenotypic evolution of MDS macrophages and broadens the knowledge of macrophage plasticity in hematopoietic malignancies.

Aims Small-for-gestational-age (SGA) fetus is an important public health issue because of its high mortality and long-term effects on health. Maternal hyperuricemia is associated with diverse adverse pregnant outcomes and neonatal disturbance. We aimed to evaluate whether maternal hyper-uric acid (HUA) is associated with the risk of SGA fetus and to explore whether it can modify the association between maternal hyper-blood pressure (HBP) and SGA fetus. Materials and methods We performed a population-based cross-section retrospective study, a total of 6715 pregnant females were recruited. Multiple logistic regression analysis was performed to identify risk factors significantly correlated with SGA fetus, and then studied the effect of maternal HUA on the association between maternal HBP and SGA fetus. Key findings We collected 537 SGA fetuses among 6715 pregnant females. Maternal HUA was an independent risk factor for SGA delivery (odds ratio (OR), 2.737; 95% confidence interval (CI), 2.110–3.551). A dose–response association between maternal uric acid and SGA delivery was found among normotensive and hypertensive group. Compared with those whose uric acid was lower than 270 μmo/L with normal–blood pressure (NBP), the risk for SGA delivery in those whose uric acid was higher than 370 μmo/L with stage 2 or 3 hypertension increased 12.695–fold. Significance Our results suggest that maternal HUA could increase the risk of neonatal SGA, and maternal HUA could be superimposed upon pre-existing maternal HBP and increase the risk for SGA fetus.

Histone deacetylases (HDACs) has proved to be promising target for the development of antitumor drugs. In this study, we reported the design and synthesis of a class of novel hydroxamate-based bis-substituted aromatic amide HDAC inhibitors with 1,2,4-oxadiazole core. Most newly synthesized compounds displayed excellent HDAC1 inhibitory effects and significant anti-proliferative activities. Among them, compounds 11a and 11c increased acetylation of histone H3 and H4 in dose-dependent manner. Furthermore, 11a and 11c remarkably induced apoptosis in HepG2 cancer cells. Finally, the high potency of compound 11a was rationalized by molecular docking studies.

Interactions between the epithelium and the immune system are critical in the pathogenesis of inflammatory bowel disease (IBD). In this study, we mapped the transcriptional landscape of human colonic epithelial organoids in response to different cytokines responsible for mediating canonical mucosal immune responses. By profiling the transcriptome of human colonic organoids treated with the canonical cytokines interferon gamma, interleukin-13, -17A, and tumor necrosis factor alpha with next-generation sequencing, we unveil shared and distinct regulation patterns of epithelial function by different cytokines. An integrative analysis of cytokine responses in diseased tissue from patients with IBD (n = 1,009) reveals a molecular classification of mucosal inflammation defined by gradients of cytokine-responsive transcriptional signatures. Our systems biology approach detected signaling bottlenecks in cytokine-responsive networks and highlighted their translational potential as theragnostic targets in intestinal inflammation.

PURPOSE: Gestational diabetes mellitus (GDM) is a growing public health problem worldwide and its etiology remains unclear. The pathophysiology of GDM is similar to that of type 2 diabetes (T2DM) and insulin resistance (IR) is the main reason for the development of GDM. Carnitine palmitoyltransferase 1A (CPT1A) is a candidate gene for metabolic disorders; however, the association of the CPT1A gene and GDM has not yet been studied. We aimed to explore whether single-nucleotide polymorphisms (SNPs) of the CPT1A gene could influence the risk of GDM. METHODS: We examined 18 single-nucleotide polymorphisms (SNPs) in the CPT1A gene and the risk of GDM in a nested case-control study of 334 GDM patients and 334 controls. The controls who had no GDM were randomly selected through matching to cases by age and residence. RESULTS: After adjusting the family history of diabetes, pre-pregnancy body mass index, and multiple comparison correction, the CPT1A rs2846194 and rs2602814 were associated with reduced GDM risk while rs59506005 was associated with elevated GDM risk. Moreover, the GGAC haplotype in the CPT1A gene (rs17399246 rs1016873 rs11228450 rs10896396) was associated with a reduced risk of GDM. CONCLUSION: Our study provides evidence for an association between genetic polymorphisms in the CPT1A and the risk of GDM.

AIM The aim is to examine the association between seven candidate single nucleotide polymorphisms in AMPKα1 and gestational diabetes in Chinese people. METHOD We used a matched nested case-control study design, individuals including 334 participants with gestational diabetes and 334 healthy pregnant women. Confirmed 334 gestational diabetes cases and maternal age and district of residence matched controls (1:1) were enrolled. We examined seven candidate single nucleotide polymorphisms in AMPKα1 gene and the risk of gestational diabetes. The associations were estimated in Co-dominant, Dominant, Recessive, and Alleles models. The odds ratios (ORs) and their 95% confidence intervals (95% CI) were estimated by unconditional logistical regression as a measure of the associations between genotypes and gestational diabetes adjusting for maternal age, prepregnancy body mass index (BMI), fetal sex and parity. RESULT At the gene level, we found that AMPKα1 was associated with gestational diabetes (p = 0.008). After adjusting the covariates and multiple comparison correction, AMPKα1 (rsc1002424, rs10053664, rs13361707) polymorphisms were associated with the risk of gestational diabetes. In addition, gestational diabetes was related to the AAGGA haplotype comprising rs1002424, rs2570091, rs10053664, rs13361707 and rs3805486 in the haplotype models (p = 0.011). CONCLUSIONS This study provides evidence that the AMPKα1 genotypes (rs1002424 G/A, rs10053664 A/G, rs13361707 A/G) and the haplotype (AAGGA) are relevant genetic factors in a Chinese population with gestational diabetes.

Exposure to air pollutants may be associated with preterm birth (PB) through oxidative stress, metabolic detoxification, and immune system processes. However, no study has investigated the interactive effects of maternal air pollution and genetic polymorphisms in these pathways on risk of PB. The study included 126 PB and 310 term births. A total of 177 single nucleotide polymorphisms (SNPs) in oxidative stress, immune function, and metabolic detoxification-related genes were examined and analyzed. The China air quality index (AQI) was used as an overall estimation of ambient air pollutants. Among 177 SNPs, four SNPs (GPX4-rs376102, GLRX-rs889224, VEGFA-rs3025039, and IL1A-rs3783550) were found to have significant interactions with AQI on the risk of PB (Pinteraction were 0.001, 0.003, 0.03, and 0.04, respectively). After being stratified by the maternal genotypes in these four SNPs, 1.38 to 1.76 times of the risk of PB were observed as per interquartile range increase in maternal AQI among women who carried the GPX4-rs376102 AC/CC genotypes, the GLRX-rs889224 TT genotype, the VEGFA-rs3025039 CC genotype, or the IL1A-rs3783550 GT/TT genotypes. After adjustment for multiple comparisons, only GPX4-rs376102 and AQI interaction remained statistically significant (false discovery rate (FDR)=0.17). After additional stratification by preeclampsia (PE) status, a strongest association was observed in women who carried the GPX4-rs376102 AC/CC genotypes (OR, 2.26; 95% CI, 1.41–3.65, Pinteraction=0.0002, FDR=0.035) in the PE group. Our study provided the first evidence that association between maternal air pollution and PB risk may be modified by the genetic polymorphisms in oxidative stress and immune function genes. Future large studies are necessary to replicate and confirm the observed associations.

MicroRNA-885 (miR-885) has been shown to act as vital regulator of tumorigenesis and its tumor-suppressive role has been investigated in several human cancers. However, the role of miR-885 in regulation of epithelial mesenchymal transition of liver cancer cells yet unknown. This study was undertaken to investigate the tumor-suppressive role of miR-885 and investigate its effects on epithelial mesenchymal transition of human liver cancer cells. The results revealed that miR-885 to be significantly (P 0.05) repressed in liver cancer and tissues and cell lines. Overexpression of miR-885 resulted in significant (P 0.05) decline in the proliferation of liver cancer cells. Additionally, migration and invasion of the liver cancer cells was also suppressed upon miR-182 overexpression which was associated with alteration of the proteins associated with epithelial mesenchymal transition. TMOD1 was identified as the target of miR-885 and the regulatory role of miR-885 was elucidated to be exerted via post-transcriptional silencing of TMOD1. The silencing of TMOD1 by miR-885 inhibited the expression of mesenchymal markers but enhanced the expression levels of epithelial markers. The results of present study revealed miR-885 proved the tumor-suppressive role of miR-885 in liver cancer and points towards its therapeutic implications in liver cancer management.

ObjectiveThe functional role of interleukin-22 (IL22) in chronic inflammation is controversial, and mechanistic insights into how it regulates target tissue are lacking. In this study, we evaluated the functional role of IL22 in chronic colitis and probed mechanisms of IL22-mediated regulation of colonic epithelial cells.DesignTo investigate the functional role of IL22 in chronic colitis and how it regulates colonic epithelial cells, we employed a three-dimentional mini-gut epithelial organoid system, in vivo disease models and transcriptomic datasets in human IBD.ResultsAs well as inducing transcriptional modules implicated in antimicrobial responses, IL22 also coordinated an endoplasmic reticulum (ER) stress response transcriptional programme in colonic epithelial cells. In the colon of patients with active colonic Crohn’s disease (CD), there was enrichment of IL22-responsive transcriptional modules and ER stress response modules. Strikingly, in an IL22-dependent model of chronic colitis, targeting IL22 alleviated colonic epithelial ER stress and attenuated colitis. Pharmacological modulation of the ER stress response similarly impacted the severity of colitis. In patients with colonic CD, antibody blockade of IL12p40, which simultaneously blocks IL12 and IL23, the key upstream regulator of IL22 production, alleviated the colonic epithelial ER stress response.ConclusionsOur data challenge perceptions of IL22 as a predominantly beneficial cytokine in IBD and provide novel insights into the molecular mechanisms of IL22-mediated pathogenicity in chronic colitis. Targeting IL22-regulated pathways and alleviating colonic epithelial ER stress may represent promising therapeutic strategies in patients with colitis.Trial registration numberNCT02749630.

Histone deacetylases (HDACs) have been proved to be promising targets for the treatment of cancer, and five histone deacetylase inhibitors (HDACis) have been approved on the market for the treatment of different lymphomas. In our previous work, we designed a series of novel coumarin-containing hydroxamate HDACis, among which compounds 6 and 7 displayed promising activities against tumor growth. Based on a molecular docking study, we further developed 26 additional analogues with the aim to improve activity of designed compounds. Several of these new derivatives not only showed excellent HDAC1 inhibitory effects, but also displayed significant growth inhibitory activities against four human cancer cell lines. Representative compounds, 13a and 13c, showed potent anti-proliferative activities against solid tumor cell lines with IC50 values of 0.36&ndash, 2.91 M and low cytotoxicity against Beas-2B and L-02 normal cells. Immunoblot analysis revealed that 13a and 13c dose-dependently increased the acetylation of histone H3 and H4. Importantly, the two compounds displayed much better anti-metastatic effects than SAHA against the MDA-MB-231 cell line. Moreover, 13a and 13c arrested MDA-MB-231 cells at G2/M phase and induced MDA-MB-231 cell apoptosis. Finally, the molecular docking study rationalized the high potency of compound 13c.

Most ovarian cancer patients respond well to initial platinum-based chemotherapy. However, within a year, many patients experience disease recurrence with a platinum resistant phenotype that responds poorly to second line chemotherapies. As a result, new strategies to address platinum resistant ovarian cancer (PROC) are needed. Herein, we report that NP co-delivery of cisplatin (CP) and wortmannin (Wtmn), a DNA repair inhibitor, synergistically enhances chemoradiotherapy (CRT) and reverses CP resistance in PROC. We encapsulated this regimen in FDA approved poly(lactic-co-glycolic acid)-poly(ethylene glycol) (PLGA-PEG) NPs to reduce systemic side effects, enhance cellular CP uptake, improve Wtmn stability, and increase therapeutic efficacy. Treatment of platinum-sensitive ovarian cancer (PSOC) and PROC murine models with these dual-drug loaded NPs (DNPs) significantly reduced tumor burden versus treatment with combinations of free drugs or single-drug loaded NPs (SNPs). These results support further investigation of this NP-based, synergistic drug regimen as a means to combat PROC in the clinic.

Histone deacetylase inhibitors (HDACi) are small molecules targeting epigenetic enzymes approved for hematologic neoplasms, which have also demonstrated clinical activities in solid tumors. In our present study, we screened our internal compound library and discovered a novel HDACi, WW437, with potent anti-breast cancer ability in vitro and in vivo. WW437 significantly inhibited phosphorylated EphA2 and EphA2 expression. Further study demonstrated WW437 blocked HDACs-EphA2 signaling axis in breast cancer. In parallel, we found that EphA2 expression positively correlates with breast cancer progression; and combined use of WW437 and an EphA2 inhibitor (ALW-II-41-27) exerted more remarkable effect on breast cancer growth than either drug alone. Our findings suggested inhibition of HDACs-EphA2 signaling axis with WW437 alone or in combination with other agents may be a promising therapeutic strategy for advanced breast cancer., Highlights • WW437 is a novel HDACi, which displays potent anticancer activity in breast cancer. • HDACs-EphA2 signaling axis represents a novel target in breast cancer. • WW437 is a promising therapeutic agent for advanced breast cancer, alone or in combination with EphA2 inhibitor. Histone deacetylase inhibitors (HDACi) are small molecules targeting epigenetic enzymes approved for cutaneous T-cell lymphoma (CTCL), peripheral T-cell lymphoma (PTCL) and multiple myeloma (MM) treatment, which have also demonstrated clinical activities in solid tumors, including lung cancer and breast cancer. Herein we report a novel HDACi WW437, which displays potent anticancer activity in both cultured cancer cells and xenograft models. Importantly, our work reveals WW437 significantly blocked the HDACs-EphA2 signaling axis in breast cancer. WW437 exhibited significant inhibitory effects on tumor growth and metastases with little toxicity, and tumors from treated mice showed decreased EphA2 expression, suggesting that EphA2 may be a useful biomarker of response to WW437. We also found that EphA2 expression positively correlates with tumor progression in aggressive breast cancer.

The ubiquitin–proteasome system (UPS) participates in both physiological and pathological processes through the posttranslational regulation of intracellular signal transduction pathways. F-box and WD-40 domain protein 11 (Fbxw11) is a component of the SCF (Skp1–Cul1–F-box) E3 ubiquitin ligase complex. Fbxw11 regulates various signal transduction pathways, and it may have pathological roles in tumorigenesis. However, the role of Fbxw11 in the development of leukemia and the underlying mechanisms remain largely unknown. In this study, Fbxw11 expression was aberrantly upregulated in patients with lymphocytic leukemia. Its expression was dramatically decreased in patients who achieved complete remission (CR) after chemotherapy. The high level of Fbxw11 expression in L1210 lymphocytic leukemia cells stimulated cell proliferation in vitro and tumor formation in vivo. The effects were mediated by the stimulation of cell cycle progression rather than the induction of apoptosis. Furthermore, a bioinformatics analysis suggested concomitant activation of the NF-κB and β-catenin/TCF signaling pathways, which were confirmed by reporter gene assays. Moreover, blocking experiments suggested the involvement of both pathways in the growth-promoting effects of Fbxw11. Our results reveal the role of Fbxw11 in lymphocytic leukemia cells and imply that Fbxw11 may serve as a potential molecular target for the treatment of lymphocytic leukemia.

Background & aims To avoid liver biopsy, many noninvasive models comprised of serum markers for liver fibrosis assessment have been developed. Given that most of them were developed in hepatitis C cohorts and few of them have been validated in Chinese hepatitis B patients, we aim to conduct this validation and compare their diagnostic accuracies in such a population. Methods A total of 937 HBV-infected patients who underwent liver biopsy were included in this single-centre retrospective study. The diagnostic accuracies of the 17 noninvasive models were assessed by areas under the receiver-operating characteristic curves (AUROCs), using histologically evaluated fibrotic stages of the biopsy specimens as standards. To compare efficiencies of the models, a grading system based on AUROC levels was developed. Results For discriminating significant fibrosis in all patients, the best three noninvasive models were King's score (AUROC = 0.756), Virahep-C model (AUROC = 0.756) and GPR (AUROC = 0.744); and for diagnosing cirrhosis, Lok index (AUROC = 0.832), FI (AUROC = 0.820) and FIB-4 (AUROC = 0.818) got the first three places. AUROCs in HBeAg-positive group were generally higher than those in HBeAg-negative group. In addition, based on the grading system, Virahep-C and GPR outstood others in evaluating liver fibrosis in all patients. Conclusions In Chinese HBV-infected patients, Virahep-C models and GPR had high accuracies in diagnosing liver fibrosis and cirrhosis, while the most discussed models like APRI and FIB-4 did not outstand. Assessment should take into account the HBeAg sero-status, since these noninvasive models were more appropriate for HBeAg-positive patients than HBeAg-negative ones.

The cGAS-STING pathway plays essential roles in detecting cytosolic dsDNA and initiating antiviral and antibacterial responses in vertebrates. However, knowledge about its function in antiviral response of invertebrates is very limited. In the present study, a gene encoding a Mab21-containing protein, a cGAS homologue, was identified from a decapod crustacean Litopenaeus vannamei and designated as LvMab21cp. LvMab21cp was mainly distributed in intestine and hepatopancreas, showing similar expression profile with other genes in the cGAS-STING pathway, such as LvSTING and LvIRF. The expression levels of LvMab21cp, LvSTING and LvIRF were up-regulated in intestine and hepatopancreas of shrimp after white spot syndrome virus (WSSV) infection. Knockdown of LvMab21cp by dsRNA-mediated RNA interference could decrease the expression levels of its putative downstream genes, including LvSTING, LvIRF, LvVago4 and LvVago5, and enhance the in vivo propagation of WSSV in shrimp. Overexpression of LvMab21cp and LvSTING in HEK 293T cells activated the expression of mammalian IFNs upon simulation with interferon stimulatory DNA (ISD). These data suggest that LvMab21cp was a cGAS homologue, a member of the shrimp cGAS-STING pathway, and play an important role during WSSV infection. To our knowledge, this is the first report to show the role of the cGAS-STING pathway in the antiviral response of invertebrates, which will provide new insights into the innate immunity of invertebrates.

Objectives Lung ultrasound detection of B-lines has become a simple, semiquantitative, noninvasive tool for evaluating pulmonary congestion in heart failure (HF) patients. This study compared the correlation of B-lines with E/eʹ, NT-proBNP, and ejection fraction (EF) in acute decompensated heart failure (ADHF). Methods Eighty-two consecutive patients who were diagnosed with acute decompensated HF were divided into two groups: preserved ejection fraction heart failure (HFpEF, EF≥50%, n=32) and reduced ejection fraction heart failure (HFrEF, EF

Twenty-five novel pregnenolone/2-cyanoacryloyl conjugates (6-30) were designed and prepared, with the aim of developing novel anticancer drugs with dual NF-κB inhibitory and anti-proliferative activities. Compounds 22 and 27-30 showed inhibition against TNF-α-induced NF-κB activation in luciferase assay, which was confirmed by Western blotting. Among them, compound 30 showed potent NF-κB inhibitory activity (IC50=2.5μM) and anti-proliferative against MCF-7, A549, H157, and HL-60 cell lines (IC50=6.5-36.2μM). The present study indicated that pregnenolone/2-cyanoacryloyl conjugate I can server asa novel scaffold for developing NF-κB inhibitors and anti-proliferative agents in cancer chemotherapy.

Tumor angiogenesis is characterized by abnormal vessel morphology, endowing tumor with highly hypoxia and unresponsive toward treatment. To date, mounting angiogenic factors have been discovered as therapeutic targets in antiangiogenic drug development. Among them, vascular endothelial growth factor receptor 2 (VEGFR2) inhibitors exerts potent antiangiogenic activity in tumor therapy. Therefore, it may provide a valid strategy for cancer treatment through targeting the tumor angiogenesis via VEGFR2 pathway. In this study, we established a high-profile compounds library and certificated a novel compound named N-(N-pyrrolidylacetyl)-9-(4-bromobenzyl)-1,3,4,9-tetrahydro-β-carboline (YF-452), which remarkably inhibited the migration, invasion and tube-like structure formation of human umbilical vein endothelial cells (HUVECs) with little toxicity invitro. Rat thoracic aorta ring assay indicated that YF-452 significantly blocked the formation of microvascular exvivo. In addition, YF-452 inhibited angiogenesis in chick chorioallantoic membrane (CAM) and mouse corneal micropocket assays. Moreover, YF-452 remarkably suppressed tumor growth in xenografts mice model. Furthermore, investigation of molecular mechanism revealed that YF-452 inhibited VEGF-induced phosphorylation of VEGFR2 kinase and the downstream protein kinases including extracellular signal regulated kinase (ERK), focal adhesion kinase (FAK) and Src. These results indicate that YF-452 inhibits angiogenesis and may be a potential antiangiogenic drug candidate for cancer therapy.

Histone deacetylases (HDACs) belong to a group of epigenetic regulatory enzymes that participate in modulating the acetylation level of histone lysine residues as well as non-histone proteins, and they play a key role in the regulation of gene expression. HDACs are potential anticancer drug targets highly expressed in various kinds of cancer cells. So far, five small molecules targeting HDACs have been approved for the therapy of cancer, and over 20 inhibitors of HDACs are under different phases of clinical trials. Among them, hydroxamate-based HDAC inhibitors (HDACis) represent a well-investigated series of chemical entities. The current review covers the recent progress in the discovery process, form SAHA to hydroxamate HDAC inhibitors with branched CAP region and linear linker. At the same time, the pharmacological and structure-activity relationship (SAR) studies of the specific derivatives from SAHA and the HDACis with branched CAP region and linear linker are also introduced.

Objective To evaluate the instant effects and five-year clinical outcomes of coronary artery disease patients complicated with diabetes mellitus after StentBoost-optimized percutaneous coronary intervention (PCI). Methods From March 2009 to July 2010, 184 patients undergoing PCI at our hospital were found stent underexpansion or malapposition by StentBoost after stents implantation and were divided into the diabetic (n=73, 39.67%) and the non-diabetic group (n=111, 60.33%). All patients received StentBoost-guided post-dilatation after stent implantation. The instant procedural results were measured and clinical outcome after five-year follow-up was analyzed in each group. Between-group comparisons were performed using Chi-square test or Student's t test. Multivariate logistic regression analysis was carried out to reveal the independent predictors for long-term clinical outcomes of StentBoost-optimized PCI . Results After StentBoost-guided post-dilatation, the minimum diameter (MinLD), maximum diameter (MaxLD) and average diameter in both groups increased significantly than before (P

The effects of microplastics on aquatic organisms are drawing growing attention, but little has been focused on their effects on the toxicity of other chemicals. In this study, we examined the acute and chronic toxicity of micro-polystyrene (5.8 μm dia.), and its effects on the toxicity of three antimicrobial agents (triclosan, triclocarban and methyl-triclosan) to Daphnia magna. Results indicated that polystyrene had a low acute toxicity with an EC50 of 36.5 mg/L. The presence of polystyrene (1 mg/L) did not produce significant effect on the acute toxicity of three chemicals, because the 95% confidence intervals of their EC50 values had a large overlap of 11.3%–48.3%. For the 21 day chronic toxicity, polystyrene alone had significant toxicity with concentrations of at least 2 mg/L, which prolonged the time of the first brood, limited the number of broods, and reduced the total number of neonates. Compared with the chemicals alone, the addition of polystyrene enhanced their reproduction toxicity. Based on the various reproduction indicators, an intrinsic rate of natural increase (rm) was calculated to assess the rate of population growth. Results suggested that the rm values of three chemicals decreased in the presence of PS, and further decreased with increasing PS concentrations. Among the three chemicals, methyl-triclosan was the most affected. These results suggested that the presence of microplastics would exacerbate the detrimental influence of pollutants on Daphnia magna.

A series of new cinnamic acid-pregenolone hybrids (5a-5o) was designed, synthesized and evaluated for their in vitro antiproliferative activity. Some of them showed potential antiproliferative activity and selectivity towards a panel of cancer cell lines, including A549, H157, HepG2, MCF-7, and HL-60. Among these analogs, compound 5f showed the most promising activity with IC50 values ranging from 3.2 to 6.8 μM, and it was taken as a model compound in the following antiproliferative mechanism study. In Hoechst 33258 staining assay, 5f-treated A549 cells displayed significant apoptosis characteristics. Flow cytometry analysis revealed that 5f showed the antiproliferative activity against A549 via G1 cell cycle arrest and inducing apoptosis. Western blotting analysis demonstrated that 5f enhanced apoptosis of A549 cells by down-regulating Bcl-2 and up-regulating Bax protein expression. The present study highlighted this series of cinnamic acid-pregenolone hybrids as a new antiproliferative lead prototype.

A series of novel coumarin-based hydroxamate derivatives were designed and synthesized as histone deacetylase inhibitors (HDACis). Selective compounds showed a potent HDAC inhibition with nM IC50 values, with the best compound (10e) being nearly 90 times more active than vorinostat (SAHA) against HDAC1. Compounds 10e and 11d also increased the levels of acetylated histone H3 and H4, which is consistent with their strong HDAC inhibition. In addition, 10e and 11d displayed a higher potency toward human A549 and Hela cancer cell lines compared with SAHA. Moreover, 10e and 11d significantly arrested A549 cells at the G2/M phase and enhanced apoptosis. Molecular docking studies revealed the possible mode of interaction of compounds 10e and 12a with HDAC1. Our findings suggest that these novel coumarin-based HDAC inhibitors provide a promising scaffold for the development of new potential cancer chemotherapies.

Objective This study evaluated serum ferritin (SF) levels and investigated their relationships with various clinical markers in patients with multiple myeloma (MM). Furthermore, the effects and molecular mechanism of deferoxamine (DFO) in myeloma cells were studied. Methods Clinical data from 84 patients with MM were collected to evaluate SF content and its relationship with several important clinical parameters. MM1S and MM1R myeloma cells were chosen to investigate the effects of iron and DFO on cell survival and apoptosis. Results Increased SF levels were detected in newly diagnosed patients, especially those with stage III disease or the κ isotype. SF content was positively correlated with β2-microglobulin, interleukin-6, and lactate dehydrogenase expression. Furthermore, patients with progressive or relapsed disease had higher SF levels. Importantly, iron chelation with DFO efficiently inhibited myeloma cell survival and accelerated apoptosis by regulating apoptosis-related genes. Conclusions The importance of SF for MM was highlighted. Additionally, it is suggested that DFO may be a good therapeutic option for MM.

Atherosclerosis is the major cause of myocardial infarction and stroke, which is a leading cause of morbidity and mortality in developed countries. During the pathological process of atherosclerosis, inflammation participates in all stages of atherosclerosis. Tumor necrosis factor-α (TNF-α), one of the most important inflammatory factor, induces apoptosis of endothelial cells, which play a central role in endothelial dysfunction. However, the underlying mechanism involved in long noncoding RNA (lncRNA) remains unclear. In the present study, we demonstrated the role of lncRNA highly upregulated in liver cancer (HULC) in TNF-α-induced apoptosis. HULC expression was decreased with TNF-α treatment. Restoring HULC expression rescued the apoptosis induced by TNF-α. HULC regulated TNF-α-induced apoptosis through regulation of miR-9 expression. Furthermore, RNA immunoprecipitation and RNA pull-down assays showed that HULC modulated miR-9 expression through association with DNA methyltransferases and suppression of miR-9 expression. HULC-miR-9 pathway may be a potential target for treating atherosclerosis.

Performance incentives for preventive care may encourage inappropriate testing, such as cancer screening for patients with short life expectancies. Defining screening colonoscopies for patients with a >50% 4-year mortality risk as inappropriate, the authors performed a pre-post analysis assessing the effect of introducing a cancer screening incentive on the proportion of screening colonoscopy orders that were inappropriate. Among 2078 orders placed by 23 attending physicians in 4 academic general internal medicine practices, only 0.6% (n = 6/1057) of screening colonoscopy orders in the preintervention period and 0.6% (n = 6/1021) of screening colonoscopy orders in the postintervention period were deemed “inappropriate.” This study found no evidence that the incentive led to an increase in inappropriate screening colonoscopy orders.

A series of novel histone deacetylase (HDAC) inhibitors were designed, synthesized and evaluated based on the strategies of a hybrid of the classic pharmacophore of HDAC inhibitors with the thiazolidinone scaffold. Some of the compounds 12i showed potent HDAC1 inhibition with nM IC50 values, more importantly, compound displayed much better anti-metastatic effects than vorinostat (SAHA) against migration of the A549 cell line. Further mechanism exploration implied that compound 12i may inhibit tumor metastasis via modulating the epithelial-mesenchymal transition (EMT) and upregulating the acetylation of α-tubulin.

The anionic form-dependent binding interaction of halo-phenolic substances with human transthyretin (hTTR) has been observed previously. This indicates that ionizable compounds should be the primary focus in screening potential hTTR disruptors. Here, the potential binding potency of halo-benzoic acids, halo-benzenesulfonic acids/sulfates and halo-phenylboronic acids with hTTR was determined and analyzed by competitive fluorescence displacement assay integrated with computational methods. The laboratorial results indicated that the three test groups of model compounds exhibited a distinct binding affinity to hTTR. All the tested halo-phenylboronic acids, some of the tested halo-benzoic acids and halo-benzenesulfonic acids/sulfates were shown to be inactive with hTTR. Other halo-benzoic acids and halo-benzenesulfonic acids/sulfates were moderate and/or weak hTTR binders. The binding affinity of halo-benzoic acids and halo-benzenesulfonic acids/sulfates with hTTR was similar. The low distribution ability of the model compounds from water to hTTR may be the reason why they exhibited the binding potency observed with hTTR. By introducing other highly hydrophobic compounds, we observed that the binding affinity between compounds and hTTR increased with increasing molecular hydrophobicity. Those results indicated that the highly hydrophobic halo-benzoic acids and halo-benzenesulfonic acids/sulfates may be high-priority hTTR disruptors. Finally, a binary classification model was constructed employing three predictive variables. The sensitivity (Sn), specificity (Sp), predictive accuracy (Q) values of the training set and validation set were >0.83, indicating that the model had good classification performance. Thus, the binary classification model developed here could be used to distinguish whether a given ionizable compound is a potential hTTR binder or not.

Hepatotoxicity is a key concern in the clinical translation of nanotherapeutics because preclinical studies have consistently shown that nanotherapeutics accumulate extensively in the liver. However, clinical stage nanotherapeutics have not shown increased hepatotoxicity. Factors that can contribute to the hepatotoxicity of nanotherapeutics beyond the intrinsic hepatotoxicity of nanoparticles (NPs) are poorly understood. Because of this knowledge gap, clinical translation efforts have avoided hepatotoxic molecules. Herein, by examining the hepatotoxicity of nanoformulations of known hepatotoxic compounds, we demonstrated that nanotherapeutics are associated with lower hepatotoxicity than their small molecule counterparts. We then found that the reduced hepatotoxicity is related to the uptake of nanotherapeutics by macrophages in the liver. These findings can facilitate further development and clinical translation of nanotherapeutics.

Rationale: Left atrial myxoma is a common primary cardiac tumor, however, due to poor image quality or atypical myxoma images, it is often misdiagnosed by echocardiograph. A case of left atrial myxoma being misdiagnosed as a thrombus, which successively caused acute myocardial infarction (AMI) and stroke, is very rare. Contrast-enhanced echocardiography can play an important role in definitive diagnosis. Patient concerns: A 44-year-old woman was diagnosed AMI because of chest pain with no significant stenosis in the coronary arteries. One month later, the patient was suddenly found unconscious, magnetic resonance imaging (MRI) showed acute multiple cerebral infarctions in the left cerebral hemisphere. Diagnoses: Left atrial myxoma, acute myocardial infarction, and stroke. Interventions: The patient was given a cardiac surgery for tumor resection, the mass was surgically removed and histopathologic findings showed myxoma. Outcomes: After several weeks of rehabilitation, the patient was able to resume daily activities without chest discomfort or dyspnea. One year later, echocardiography showed no recurrence of left atrial myxoma. The patient generally was in good condition. Lessons: Although myxoma is mostly benign, this patient occurred AMI and stroke because of misdiagnosis. Comprehensive assessments should be performed with multiple imaging methods for cardiac masses. If necessary, contrast-enhanced echocardiography should be used to clarify, so as not to delay the timing of surgery and bring potential risk of death to patients.

Breast cancer is one of the most lethal cancers in women when it reaches the metastatic stage. Here, we screen a library of small molecules for inhibitors of breast cancer cell invasion, and use structure/activity relationship studies to develop a series of small molecules with improved activity. We find WJ460 as one of the lead compounds exerting anti-metastatic activity in the nanomolar range in breast cancer cells. Proteomic and biochemical studies identify myoferlin (MYOF) as the direct target of WJ460. In parallel, loss of MYOF or pharmacological inhibition of MYOF by WJ460 reduces breast cancer extravasation into the lung parenchyma in an experimental metastasis mouse model, which reveals an essential role of MYOF in breast cancer progression. Our findings suggest that MYOF can be explored as a molecular target in breast cancer metastasis and that targeting MYOF by WJ460 may be a promising therapeutic strategy in MYOF-driven cancers.