Search

Cyclin D1, an oncogenic G1 cyclin which can be induced by environmental carcinogens and whose over-expression may cause dysplasia and carcinoma, has been shown to be a target for cancer chemoprevention and therapy. In this study, we investigated the effects and underlying mechanisms of action of a polyprenylated xanthone, gambogenic acid (GEA) on gefitinib-sensitive and -resistant lung cancer cells. We found that GEA inhibited proliferation, caused G1 arrest and repressed colony-forming activity of lung cancer cells. GEA induced degradation of cyclin D1 via the proteasome pathway, and triggered dephosphorylation of GSK3β which was required for cyclin D1 turnover, because GSK3β inactivation by its inhibitor or specific siRNA markedly attenuated GEA-caused cyclin D1 catabolism. GEA induced autophagy of lung cancer cells, possibly due to activation of GSK3β and inactivation of AKT/mTOR signal pathway. These results indicate that GEA is a cyclin D1 inhibitor and a GSK3β activator which may have chemopreventive and therapeutic potential for lung cancer. [ABSTRACT FROM AUTHOR]

Background: Chemotherapeutic agents including cisplatin, gemcitabine, and pemetrexed, significantly enhance the efficacy of immune checkpoint inhibitors (ICIs) in non-small cell lung cancer (NSCLC) by increasing PD-L1 expression and potentiating T cell cytotoxicity. However, the low response rate and adverse effects limit the application of chemotherapy/ICI combinations in patients., Methods: We screened for medicinal herbs that could perturb PD-L1 expression and enhance T cell cytotoxicity in the presence of anti-PD-L1 antibody, and investigated the underlying mechanisms., Results: We found that the aqueous extracts of Centipeda minima (CM) significantly enhanced the cancer cell-killing activity and granzyme B expression level of CD8 + T cells, in the presence of anti-PD-L1 antibody. Both CM and its active component 6-O-angeloylplenolin (6-OAP) upregulated PD-L1 expression by suppressing GSK-3β-β-TRCP-mediated ubiquitination and degradation. CM and 6-OAP significantly enhanced ICI-induced reduction of tumor burden and prolongation of overall survival of mice bearing NSCLC cells, accompanied by upregulation of PD-L1 and increase of CD8 + T cell infiltration. CM also exhibited anti-NSCLC activity in cells and in a patient-derived xenograft mouse model., Conclusions: These data demonstrated that the induced expression of PD-L1 and enhancement of CD8 + T cell cytotoxicity underlay the beneficial effects of 6-OAP-rich CM in NSCLCs, providing a clinically available and safe medicinal herb for combined use with ICIs to treat this deadly disease., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier GmbH. All rights reserved.)

Programmed cell death ligand 2 (PD-L2), a ligand for the receptor programmed cell death 1 (PD-1), has an identity of 34% with its twin ligand PD-L1 and exhibits higher binding affinity with PD-1 than PD-L1. However, the role of PD-L2 in non-small cell lung cancer (NSCLC) progression, especially tobacco-induced cancer progression, has not been fully understood. Here, we found that PD-L2 promoted tumor growth in murine models with recruitment of regulatory T cells (Tregs). In patients with NSCLC, PD-L2 expression level in tumor samples was higher than in counterpart normal controls and was positively associated with patients' response to anti-PD-1 treatment. Mechanismly, PD-L2 bound its receptor Repulsive guidance molecule B (RGMB) on cancer cells and activated extracellular signal-regulated kinase (Erk) and nuclear factor κB (NFκB), leading to increased production of chemokine CCL20, which recruited Tregs and contributed to NSCLC progression. Consistently, knockdown of RGMB or NFκB p65 inhibited PD-L2-induced CCL20 production, and silencing of PD-L2 repressed Treg recruitment by NSCLC cells. Furthermore, cigarette smoke and carcinogen benzo(a)pyrene (BaP) upregulated PD-L2 in lung epithelial cells via aryl hydrocarbon receptor (AhR)-mediated transcription activation, whose deficiency markedly suppressed BaP-induced PD-L2 upregulation. These results suggest that PD-L2 mediates tobacco-induced recruitment of Tregs via the RGMB/NFκB/CCL20 cascade, and targeting this pathway might have therapeutic potentials in NSCLC., (© 2024. The Author(s).)

Small cell lung cancer (SCLC) is a recalcitrant cancer characterized by high frequency loss-of-function mutations in tumor suppressors with a lack of targeted therapy due to absence of high frequency gain-of-function abnormalities in oncogenes. SMARCAL1 is a member of the ATP-dependent chromatin remodeling protein SNF2 family that plays critical roles in DNA damage repair and genome stability maintenance. Here, we showed that SMARCAL1 was overexpressed in SCLC patient samples and was inversely associated with overall survival of the patients. SMARCAL1 was required for SCLC cell proliferation and genome integrity. Mass spectrometry revealed that PAR6B was a downstream SMARCAL1 signal molecule which rescued inhibitory effects caused by silencing of SMARCAL1. By screening of 36 FDA-approved clinically available agents related to DNA damage repair, we found that an aza-anthracenedione, pixantrone, was a potent SMARCAL1 inhibitor which suppressed the expression of SMARCAL1 and PAR6B at protein level. Pixantrone caused DNA damage and exhibited inhibitory effects on SCLC cells in vitro and in a patient-derived xenograft mouse model. These results indicated that SMARCAL1 functions as an oncogene in SCLC, and pixantrone as a SMARCAL1 inhibitor bears therapeutic potentials in this deadly disease., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier B.V. All rights reserved.)

Background: The aorta-mitral annulus conjunction (AMC) is an uncommon site of origin of focal atrial tachycardias (ATs). Hence, the electrophysiological and ablation target characteristics are poorly described., Objective: The purpose of this study was to describe the characteristics of AMC ATs in detail., Methods: The study enrolled 650 patients with ATs, 21 (3.2%) of whom had ATs originating from the AMC. A comprehensive evaluation, including electrocardiography, electrophysiology study, computed tomography scan, and intracardiac echocardiography, was performed., Results: The majority (19, 90.5%) of ATs occurred spontaneously. The mean age of this group was 48.9 ± 21.6 years, with 12 being female (57.1%). Seventeen patients had a typical biphasic P wave with a prominent positive component. The earliest activation site in the right atrium was near the His bundle, with average activation -10.3 ± 6.0 ms preceding the P wave. The successful ablation targets were distributed as follows: 1 case at 9 o'clock, 6 cases at 10 o'clock, 7 cases at 11 o'clock, 6 cases at 12 o'clock, and 1 case in the left coronary cusp. The local AMC potential differed from the commonly perceived annular potential and was characterized by a prominent A wave and a smaller V wave (atrial-to-ventricular ratio > 1). The angle of encroachment on the left atrial anterior wall, compressed by the left coronary cusp, was significantly smaller in the AMC ATs group than in the control group consisted of 40 patients who underwent coronary artery CT scans because of the chest pain but without atrial arrhythmias were randomly selected, which may have contributed to the arrhythmia substrate (141.7° ± 11.5° vs 155.2° ± 13.9°; P = .026)., Conclusion: A new strategy for mapping AMC ATs has been introduced. The ablation target should have an atrial-to-ventricular ratio of >1., Competing Interests: Disclosures All authors report no disclosures., (Copyright © 2024. Published by Elsevier Inc.)

Tumor cells are usually considered defective in mitochondrial respiration, but human non-small cell lung cancer (NSCLC) tumor tissues are shown to have enhanced glucose oxidation relative to adjacent benign lung. Here, we reported that oncoprotein cancerous inhibitor of protein phosphatase 2A (CIP2A) inhibited glycolysis and promoted oxidative metabolism in NSCLC cells. CIP2A bound to pyruvate kinase M2 (PKM2) and induced the formation of PKM2 tetramer, with serine 287 as a novel phosphorylation site essential for PKM2 dimer-tetramer switching. CIP2A redirected PKM2 to mitochondrion, leading to upregulation of Bcl2 via phosphorylating Bcl2 at threonine 69. Clinically, CIP2A level in tumor tissues was positively correlated with the level of phosphorylated PKM2 S287. CIP2A-targeting compounds synergized with glycolysis inhibitor in suppressing cell proliferation in vitro and in vivo. These results indicated that CIP2A facilitates oxidative phosphorylation by promoting tetrameric PKM2 formation, and targeting CIP2A and glycolysis exhibits therapeutic potentials in NSCLC., (© 2023. The Author(s).)

Objective: To systematically review the clinical efficacy of total ankle arthroplasty (TAA) and ankle arthrodesis (AA) in the treatment of end-stage ankle arthritis., Methods: The PubMed, EMBASE and Cochrane Library databases were searched for articles published in the treatment of end-stage ankle arthritis with AA or TAA from the establishment of the database to June 2021. Bias risk tool was used to evaluate the quality of the literature. The American Orthopaedic Foot and Ankle Society Ankle-Hindfoot Scale(AOFAS), visual analog scale (VAS), ankle osteoarthritis scale(AOS), gait analysis (pace, frequency, stride), range of motion (ROM), satisfaction, complications and reoperation rate were analyzed by meta-analysis between AA and TAA groups by RevMan 5.3 software., Results: A total of 12 articles were included, including 1 050 patients in the AA group and 3 760 patients in the TAA group, totaling 4 810 patients. Meta-analysis showed that the total score of AOFAS[ MD =-3.12, 95%CI(-9.02, 2.96), P =0.31], pain score [ MD =1.60, 95% CI (-1.35, 4.54), P =0.29], alignmentl score[ MD =-0.04, 95% CI (-0.52, 0.44), P =0.88], VAS[ MD =0.10, 95% CI (-0.49, 0.68), P =0.74], and AOS total score [ MD =-4.01, 95% CI (-8.28, 0.25), P =0.06], the difference was not statistically significant ( P >0.05). The score of AOFAS functional in TAA group was significantly higher than that in TAA group[ MD =44.22, 95% CI (-8.01, -0.43), P =0.03]. There was no significant difference in gait analysis between the two groups ( P >0.05). Postoperative ROM [ MD =-4.93, 95% CI (-6.35, -3.52), P <0.000 01] and change in ROM from preoperative to follow-up[ MD =-5.74, 95% CI (-8.88, -2.61), P =0.0003] between two groups, the difference was statistically significant. There was no significant difference in satisfaction between the two groups [ OR =1.011, 95% CI (0.46, 2.23), P =0.98]. Complications [ OR =1.61, 95% CI (1.26, 2.06), P =0.0002] and non-revision reoperation [ OR =1.61, 95% CI (1.17, 2.21), P =0.003] were significantly lower in the TAA group than in the AA group. There was no significant difference in the rate of revision and reoperation( P >0.05) between the two groups [ OR =1.02, 95% CI (0.37, 2.78), P =0.97]., Conclusion: The clinical efficacy of AA is similar to that of TAA, but the non revision reoperation rate and main surgical complications of TAA are significantly reduced. Therefore, further high-quality methodological research and long-term follow-up are needed to confirm this conclusion.

Swanton et al. 1 find that PM 2.5 exposure is associated with EGFR/KRAS-driven lung cancer incidence. PM 2.5 increases EGFR pre-mutated alveolar type II cell progenitor function and tumorigenic activity through interstitial macrophage-secreted IL-1β, providing potential prevention approaches to inhibit cancer initiation., Competing Interests: Declaration of interests The authors declare no competing interests., (Copyright © 2023 The Author(s). Published by Elsevier Inc. All rights reserved.)

CD47 is an immunoglobulin that is overexpressed on the surface of a variety of cancer cells. CD47 forms a signaling complex with signal regulatory protein alpha (SIRPα), prompting the escape of cancer cells from macrophage-mediated phagocytosis. In recent years, CD47 has been shown to be highly expressed in many types of solid tumors and is associated with poor prognosis in patients. More and more studies have shown that inhibition of the CD47-SIRPα signaling pathway can promote adaptive immune responses and enhance the phagocytosis of tumor cells by macrophages. Humanized anti-CD47 IgG4 monoclonal antibody has been studied in clinical trials for the treatment of a variety of advanced solid tumors and lymphomas, demonstrating a sound safety profile and achieving partial remission in some patients. In this review we discuss the structure and function of CD47 and the mechanism of CD47 regulation in tumors, summarize the research progress in therapeutic antibody drugs targeting CD47 and a bottleneck in research that targeted drugs are more prone to result in serious adverse effects, and evaluated the potential of the applying CD47-SIRPα signaling pathway in anti-cancer therapy., (Copyright© by Editorial Board of Journal of Sichuan University (Medical Sciences).)

Background: Centipeda minima (L.) A. Braun & Asch (C. minima) has been used as a traditional Chinese herbal medicine to treat multiple diseases, including sinusitis, rhinitis, headache, and allergy. To date, the anticancer properties of C. minima have drawn considerable attention owing to the anticancer potential of C. minima extracts, the identification of active components, and the elucidation of underlying molecular mechanisms. However, the anticancer properties and significance of active components in C. minima have rarely been summarized., Purpose: This review presents a comprehensive summary of the anticancer properties exhibited by active components of C. minima., Methods: An extensive search for published articles on the anticancer activities and active components of C. minima was performed using Web of Science, PubMed, Science Direct, and Google Scholar., Results: C. minima extracts exhibited both anticancer and chemosensitizing effects. Phytochemical studies have identified the active anticancer components of C. minima extracts. Sesquiterpene lactones, such as 6-O-angeloylplenolin (6-OAP, or brevilin A) and arnicolide D, have similar structures and anticancer mechanisms. As the most abundant sesquiterpene lactone in C. minima, 6-OAP exhibits anticancer activities mainly by targeting Skp1-Cullin1-F-box protein (SCF) E3 ubiquitin ligase and signal transducers and activators of transcription 3 (STAT3). Clinical trials have assessed the potential of 6-OAP in patients with vertex balding and alopecia areata, given its effect on JAK-STATs signaling. Chlorogenic acid, a representative organic acid in C. minima, reportedly possesses anticancer potential and inhibits tumor growth by affecting tumor microenvironment and has been approved for phase II clinical trials in patients with glioma in China., Conclusion: In the present review, we highlight intriguing anticancer properties mediated by active compounds isolated from C. minima extracts, particularly sesquiterpene lactones, which might provide clues for developing novel anticancer drugs. Relevant clinical trials on chlorogenic acid and 6-OAP can promote anticancer clinical applications. Therefore, it is worth comprehensively elucidating underlying anticancer mechanisms and conducting clinical trials on C. minima and its active components., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2022. Published by Elsevier GmbH.)

Angiotensin-converting enzyme 2 (ACE2) is the receptor of COVID-19 pathogen SARS-CoV-2, but the transcription factors (TFs) that regulate the expression of the gene encoding ACE2 (ACE2) have not been systematically dissected. In this study we evaluated TFs that control ACE2 expression, and screened for small molecule compounds that could modulate ACE2 expression to block SARS-CoV-2 from entry into lung epithelial cells. By searching the online datasets we found that 24 TFs might be ACE2 regulators with signal transducer and activator of transcription 3 (Stat3) as the most significant one. In human normal lung tissues, the expression of ACE2 was positively correlated with phosphorylated Stat3 (p-Stat3). We demonstrated that Stat3 bound ACE2 promoter, and controlled its expression in 16HBE cells stimulated with interleukin 6 (IL-6). To screen for medicinal compounds that could modulate ACE2 expression, we conducted luciferase assay using HLF cells transfected with ACE2 promoter-luciferase constructs. Among the 64 compounds tested, 6-O-angeloylplenolin (6-OAP), a sesquiterpene lactone in Chinese medicinal herb Centipeda minima (CM), represented the most potent ACE2 repressor. 6-OAP (2.5 µM) inhibited the interaction between Stat3 protein and ACE2 promoter, thus suppressed ACE2 transcription. 6-OAP (1.25-5 µM) and its parental medicinal herb CM (0.125%-0.5%) dose-dependently downregulated ACE2 in 16HBE and Beas-2B cells; similar results were observed in the lung tissues of mice following administration of 6-OAP or CM for one month. In addition, 6-OAP/CM dose-dependently reduced IL-6 production and downregulated chemokines including CXCL13 and CX3CL1 in 16HBE cells. Moreover, we found that 6-OAP/CM inhibited the entry of SARS-CoV-2 S protein pseudovirus into target cells. These results suggest that 6-OAP/CM are ACE2 inhibitors that may potentially protect lung epithelial cells from SARS-CoV-2 infection., (© 2022. The Author(s), under exclusive licence to Shanghai Institute of Materia Medica, Chinese Academy of Sciences and Chinese Pharmacological Society.)

Indoleamine 2,3-dioxygenase 1 (IDO1), the enzyme that catabolizes tryptophan (Trp) metabolism to promote regulatory T cells (Tregs) and suppress CD8 + T cells, is regulated by several intrinsic signaling pathways. Here, we found that tobacco smoke, a major public health concern that kills 8 million people each year worldwide, induced IDO1 in normal and malignant lung epithelial cells in vitro and in vivo. The carcinogen nicotine-derived nitrosaminoketone (NNK) was the tobacco compound that upregulated IDO1 via activation of the transcription factor c-Jun, which has a binding site for the IDO1 promoter. The NNK receptor α7 nicotinic acetylcholine receptor (α7nAChR) was required for NNK-induced c-Jun activation and IDO1 upregulation. In A/J mice, NNK reduced CD8 + T cells and increased Tregs. Clinically, smoker patients with non-small-cell lung cancer (NSCLC) exhibited high IDO1 levels and low Trp/kynurenine (Kyn) ratios. In NSCLC patients, smokers with lower IDO1 responded better to anti-PD1 antibody treatment than those with higher IDO1. These data indicate that tobacco smoke induces IDO1 to catabolize Trp metabolism and immune suppression to promote carcinogenesis, and lower IDO1 might be a potential biomarker for anti-PD1 antibodies in smoker patients, whereas IDO1-high smoker patients might benefit from IDO1 inhibitors in combination with anti-PD1 antibodies., (© 2022. The Author(s).)

A 42-year-old male was hospitalized 13.5 hours after ingestion of 50 mg (approximately 0.7 mg/kg) colchicine in a suicide attempt. The patient developed gastrointestinal dysfunction, grade IV myelosuppression, and restrictive respiratory failure without occurrences of cardiovascular collapse or fatal dysrhythmias. Emergency treatment with integrated Chinese and Western medicine was started and the patient fully recovered without long-term complications. This report describes a massive overdose of colchicine successfully treated with integrated Chinese and Western medicine. Current treatment options are reviewed.

Background: Effective biomarkers for early diagnosis of lung cancer are needed. Previous studies have indicated positive associations between abnormal circulating cytokines and the etiology of lung cancer., Methods: Blood samples were obtained from 286 patients with pretreatment lung cancer and 80 healthy volunteers. Circulating cytokine levels were detected with a Luminex assay and enzyme-linked immunosorbent assay (ELISA). Urine samples were obtained from 284 patients and 122 healthy volunteers. CXC chemokine ligand 14 (CXCL14) expression in tumors and nontumor regions of lung tissues from 133 lung cancer cases was detected by immunohistochemical (IHC) staining and immunofluorescence (IF) staining of formalin fixed paraffin-embedded (FFPE) tissues., Results: Compared with healthy volunteers, a 65.7-fold increase was observed in the level of CXCL14 in the plasma of lung cancer patients, and a 1.7-fold increase was observed in the level of CXCL14 in the urine of lung cancer patients, achieving a 0.9464 AUC (area under the curve) value and a 0.6476 AUC value for differentiating between lung cancer patients and healthy volunteers, respectively. Stromal CXCL14 expression was significantly associated with advanced pathologic stage ( P <0.001), pathologic N stage ( P <0.001), and recurrence and metastasis ( P =0.014). Moreover, multivariate analysis suggested stromal CXCL14 expression as an independent predictor of DFS and OS., Conclusions: Our study demonstrates that CXCL14 might serve as a potential diagnostic and prognostic biomarker in patients with lung cancer., Impact: CXCL14 might serve as a potential diagnostic and prognostic biomarker in patients with lung cancer., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Tian, Ma, Yue, Liang, Li, Chen, Zhang, Sun, Huang, Zhang, Zhou, Wang, Zhang and Wang.)

The tumor suppressor p53 is usually inactivated by somatic mutations in malignant neoplasms, and its reactivation represents an attractive therapeutic strategy for cancers. Here, we reported that a new quinolone compound RYL-687 significantly inhibited non-small cell lung cancer (NSCLC) cells which express wild type (wt) p53, in contract to its much weaker cytotoxicity on cells with mutant p53. RYL-687 upregulated p53 in cells with wt but not mutant p53, and ectopic expression of wt p53 significantly enhanced the anti-NSCLC activity of this compound. RYL-687 induced production of reactive oxygen species (ROS) and upregulation of Nrf2, leading to an elevation of the NAD(P)H:quinoneoxidoreductase-1 (NQO1) that can protect p53 by inhibiting its degradation by 20S proteasome. RYL-687 bound NQO1, facilitating the physical interaction between NQO1 and p53. NQO1 was required for RYL-687-induced p53 accumulation, because silencing of NQO1 by specific siRNA or an NQO1 inhibitor uridine, drastically suppressed RYL-687-induced p53 upregulation. Moreover, a RYL-687-related prodrug significantly inhibited tumor growth in NOD-SCID mice inoculated with NSCLC cells and in a wt p53-NSCLC patient-derived xenograft mouse model. These data indicate that targeting NQO1 is a rational strategy to reactivate p53, and RYL-687 as a p53 stabilizer bears therapeutic potentials in NSCLCs with wt p53., (© 2021. The Author(s), under exclusive licence to CPS and SIMM.)

CACNA1E is a gene encoding the ion-conducting α1 subunit of R-type voltage-dependent calcium channels, whose roles in tumorigenesis remain to be determined. We previously showed that CACNA1E was significantly mutated in patients with non-small cell lung cancer (NSCLC) who were long-term exposed to household air pollution, with a mutation rate of 19% (15 of 79 cases). Here we showed that CACNA1E was also mutated in 207 (12.8%) of the 1616 patients with NSCLC in The Cancer Genome Atlas (TCGA) datasets. At mRNA and protein levels, CACNA1E was elevated in tumor tissues compared to counterpart non-tumoral lung tissues in NSCLCs of the public datasets and our settings, and its expression level was inversely associated with clinical outcome of the patients. Overexpression of wild type (WT) or A275S or R249G mutant CACNA1E transcripts promoted NSCLC cell proliferation with activation of epidermal growth factor receptor (EGFR) signaling pathway, whereas knockdown of this gene exerted inhibitory effects on NSCLC cells in vitro and in vivo. CACNA1E increased current density and Ca 2+ entrance, whereas calcium channel blockers inhibited NSCLC cell proliferation. These data indicate that CACNA1E is required for NSCLC cell proliferation, and blockade of this oncoprotein may have therapeutic potentials for this deadly disease., (Copyright © 2022 Elsevier Ltd. All rights reserved.)

Background: This study describes the electrophysiologic characteristics of the para-hisian accessory pathway (AP), the outcome of different ablation approaches, and ablation safety at different sites., Method: A total of 120 patients diagnosed as para-hisian AP were included in this study. The electrophysiologic characteristics and outcomes at different ablation sites were analyzed., Results: In total, 107 APs and 13 APs were diagnosed as right anteroseptal (RAS) and right midseptal (RMS), respectively. The significant ECG difference between RAS and RMS was lead III, which mainly manifested as positive and negative delta waves, respectively. Catheter trauma to AP was recorded in 21 of 120 (17.5%) patients. The recurrence rate of direct ablation at the "bumped" sites was higher than the conventional ablation method (37.5 vs. 14.1 %, p = 0.036). For RAS APs, there was no significant difference in the success rate between the inferior vena cava (IVC) and superior vena cava (SVC) approaches (76.6 vs. 73.3%, p = 0.63). The RAS was separated into three regions: (1) Site 1: superior part above the real "His" recorded site with far-field "His" potential; (2) Site 2 (true para-hisian): the site with near-field "His" potential; and (3) Site 3: inferior part below the biggest real "His" with far-field "His" potential. Mid-septal was defined as an area that is bounded anteriorly by His recording location and posteriorly by the roof of coronary sinus (CS) ostium. The incidence of atrioventricular (AV) conduction injury at different sites was as follows: 3 of 6 (50%) at Site 2, 4 of 13 (30.8%) at RMS, 7 of 34 (20.6%) at Site 3, and 3 of 46 (6.5%) at Site 1. Even if ablation was performed at the atrial side of the para-hisian region, the right bundle branch block (RBBB) was caused in 6 patients (5%)., Conclusion: Ablation via IVC or SVC was comparative for para-hisian APs, but not for the noncoronary cusp (NCC) approach. The AV conduction injury risk ranks as follows: Site 2 > RMS > Site 3 > Site 1. RBBB could be caused while ablating at the atrial side, which could further demonstrate the His bundle longitudinal dissociation theory., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Yang, Sun, Guo, Zhou, Liu, Wei, Xie and Ma.)

Background: The predictability and long-term outcome of the discrete pre-potential (DPP) of idiopathic ventricular arrhythmias (VAs) arising from the aortic sinuses of Valsalva (ASV) have not been fully identified. Methods: Of 687 consecutive patients undergoing ablation of outflow tract VAs, there were 105 (15.3%) patients with VAs originating from the ASV region who were included. Detailed mapping was performed within the ASV in all patients. Electrocardiographic, electrophysiological parameters, and long-term success rate were compared between patients with and without the DPPs. Results: A DPP was recorded in 67 of 105 (63.8%) patients, including 38 left sinus of Valsalva (LSV)-VAs (38/105, 36.2%) and 29 right sinus of Valsalva (RSV)-VAs (29/105, 27.6%). The patients with DPPs had wider QRS duration (152 ± 17 vs. 145 ± 14 ms, p < 0.001). The average of earliest activation time was significantly earlier in patients with DPPs (-38.6 ± 8.5 vs. -27.7 ± 5.7 ms, p < 0.001). Mean time from the first lesion to elimination of VAs was shorter in patients with DPPs (2.3 ± 2.1 s vs. 4.9 ± 1.0 s, p < 0.001). A stepwise logistic multivariable analysis identified only younger age as a significant predictor of DPP (age ≤ 35.5 years predicted DPP with 92.9% positive predictive value). During a follow-up duration of 42.5 ± 22.3 months, 63 (94.0%) patients with DPPs and 30 (78.9%) patients without DPPs remained free of recurrent VAs ( p = 0.027). Conclusion: Discrete pre-potentials were observed in 63.8% of patients with VAs arising from the ASV. Ablation in patients with DPPs was associated with higher long-term success. DPPs were seen more commonly in younger (age ≤ 35.5 years) patients., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2021 Wei, Guo, Zhou, Sun, Yang, Xie, Liang, Zhang, Wu and Ma.)

The development of cancer is a multistep and complex process involving interactions between tumor cells and the tumor microenvironment (TME). C-X-C chemokine ligand 13 (CXCL13) and its receptor, CXCR5, make crucial contributions to this process by triggering intracellular signaling cascades in malignant cells and modulating the sophisticated TME in an autocrine or paracrine fashion. The CXCL13/CXCR5 axis has a dominant role in B cell recruitment and tertiary lymphoid structure formation, which activate immune responses against some tumors. In most cancer types, the CXCL13/CXCR5 axis mediates pro-neoplastic immune reactions by recruiting suppressive immune cells into tumor tissues. Tobacco smoke and haze (smohaze) and the carcinogen benzo(a)pyrene induce the secretion of CXCL13 by lung epithelial cells, which contributes to environmental lung carcinogenesis. Interestingly, the knockout of CXCL13 inhibits benzo(a)pyrene-induced lung cancer and azoxymethane/dextran sodium sulfate-induced colorectal cancer in mice. Thus, a better understanding of the context-dependent functions of the CXCL13/CXCR5 axis in tumor tissue and the TME is required to design an efficient immune-based therapy. In this review, we summarize the molecular events and TME alterations caused by CXCL13/CXCR5 and briefly discuss the potentials of agents targeting this axis in different malignant tumors.

Thalidomide induces γ-globin expression in erythroid progenitor cells, but its efficacy on patients with transfusion-dependent β-thalassemia (TDT) remains unclear. In this phase 2, multi-center, randomized, double-blind clinical trial, we aimed to determine the safety and efficacy of thalidomide in TDT patients. A hundred patients of 14 years or older were randomly assigned to receive placebo or thalidomide for 12 weeks, followed by an extension phase of at least 36 weeks. The primary endpoint was the change of hemoglobin (Hb) level in the patients. The secondary endpoints included the red blood cell (RBC) units transfused and adverse effects. In the placebo-controlled period, Hb concentrations in patients treated with thalidomide achieved a median elevation of 14.0 (range, 2.5 to 37.5) g/L, whereas Hb in patients treated with placebo did not significantly change. Within the 12 weeks, the mean RBC transfusion volume for patients treated with thalidomide and placebo was 5.4 ± 5.0 U and 10.3 ± 6.4 U, respectively (P < 0.001). Adverse events of drowsiness, dizziness, fatigue, pyrexia, sore throat, and rash were more common with thalidomide than placebo. In the extension phase, treatment with thalidomide for 24 weeks resulted in a sustainable increase in Hb concentrations which reached 104.9 ± 19.0 g/L, without blood transfusion. Significant increase in Hb concentration and reduction in RBC transfusions were associated with non β0/β0 and HBS1L-MYB (rs9399137 C/T, C/C; rs4895441 A/G, G/G) genotypes. These results demonstrated that thalidomide is effective in patients with TDT., (© 2021. The Author(s).)

Butyrophilin 3A1 (BTN3A1), a major histocompatibility complex-associated gene that encodes a membrane protein with two extracellular immunoglobulin domains and an intracellular B30.2 domain, is critical in T-cell activation and adaptive immune response. Here, the expression of BTN3A1 in cancers was analyzed in eight databases comprising 86 733 patients of 33 cancers, and the findings were validated in patient samples and cell models. We showed that BTN3A1 was expressed in most cancers, and its expression level was strongly correlated with clinical outcome of 13 cancers. Mutations of BTN3A1 were detected, and the mutations were distributed throughout the entire gene. Gene set enrichment analysis showed that BTN3A1 co-expression genes and interacting proteins were enriched in immune regulation-related pathways. BTN3A1 was associated with tumor-infiltrating immune cells and was co-expressed with multiple immune checkpoints in patients with breast cancer (BRCA) and non-small cell lung cancer (NSCLC). We reported that BTN3A1 was downregulated in 46 of 65 (70.8%) NSCLCs, and its expression level was inversely associated with clinical outcome of the patients. BTN3A1 in tumor samples was lower than in counterpart normal tissues in 31 of 38 (81.6%) BRCAs. Bioinformatics analyses showed that BTN3A1 could be a target gene of transcription factor Spi-1 proto-oncogene (SPI1), and our 'wet' experiments showed that ectopic expression of SPI1 upregulated, whereas silencing of SPI1 downregulated, BTN3A1 expression in cells. These results suggest that BTN3A1 may function as a tumor suppressor and may serve as a potential prognostic biomarker in NSCLCs and BRCAs., (© 2021 The Authors. FEBS Open Bio published by John Wiley & Sons Ltd on behalf of Federation of European Biochemical Societies.)

Chemokines have emerged as important players in tumorigenic process. An extensive body of literature generated over the last two or three decades strongly implicate abnormally activated or functionally disrupted chemokine signaling in liaising most-if not all-hallmark processes of cancer. It is well-known that chemokine signaling networks within the tumor microenvironment are highly versatile and context-dependent: exert both pro-tumoral and antitumoral activities. The C-X-C motif chemokine ligand 13 (CXCL13), and its cognate receptor CXCR5, represents an emerging example of chemokine signaling axes, which express the ability to modulate tumor growth and progression in either way. Collateral evidence indicate that CXCL13-CXCR5 axis may directly modulate tumor growth by inducing proliferation of cancer cells, as well as promoting invasive phenotypes and preventing their apoptosis. In addition, CXCL13-CXCR5 axis may also indirectly modulate tumor growth by regulating noncancerous cells, particularly the immune cells, within the tumor microenvironment. Here, we review the role of CXCL13, together with CXCR5, in the human tumor microenvironment. We first elaborate their patterns of expression, regulation, and biological functions in normal physiology. We then consider how their aberrant activity, as a result of differential overexpression or co-expression, may directly or indirectly modulate the growth of tumors through effects on both cancerous and noncancerous cells., (© 2021. The Author(s), under exclusive license to Springer Nature Switzerland AG.)

The aim of the present study was to identify natural compounds that bear significant anti‑tumor activity. Thus, the effects of 63 small molecules that were isolated from traditional Chinese medicinal herbs on A549 human non‑small cell lung cancer (NSCLC) and MCF‑7 breast cancer cells were examined. It was found that ursolic acid (UA), a natural pentacyclic triterpenoid, exerted significant inhibitory effect on these cells. Further experiments revealed that UA inhibited the proliferation of various lung cancer cells, including the NSCLC cells, H460, H1975, A549, H1299 and H520, the human small cell lung cancer (SCLC) cells, H82 and H446, and murine Lewis lung carcinoma (LLC) cells. UA induced the apoptosis and autophagy of NSCLC cells. The inhibition of the mammalian target of rapamycin (mTOR) signaling pathway, but not the activation of the extracellular signal‑regulated kinase 1/2 (ERK1/2) signaling pathway contributed to the UA‑induced autophagy of NSCLC cells. Moreover, the inhibition of autophagy by chloroquine (CQ) or siRNA for autophagy‑related gene 5 (ATG5) enhanced the UA‑induced inhibition of cell proliferation and promotion of apoptosis, indicating that UA‑induced autophagy is a pro‑survival mechanism in NSCLC cells. On the whole, these findings suggest that combination treatment with autophagy inhibitors may be a novel strategy with which enhance the antitumor activity of UA in lung cancer.

Background: Acupuncture at Zusanli (ST36), Quchi (LI11), and Tianshu (ST25) is commonly used in septic patients by traditional Chinese physicians. The protective effect of acupuncture at ST36 on the intestinal barrier is associated with Cholinergic Anti-Inflammatory Pathway (CAIP). However, its detailed mechanism and whether acupuncture at LI11 and ST25 have similar effects to ST36 remain unclear., Aim: To explore the effects of electroacupuncture (EA) at ST36, LI11, and ST25 on septic rats and investigate the role of the spleen in the treatment of EA at ST36., Methods: A septic rat model caused by cecal ligation and puncture (CLP) and a postsplenectomy (SPX) CLP rat model were established. Rats were divided into nine groups depending on different treatments. Serum levels of TNF- α , IL-10, D-lactic acidosis (D-LA), double amine oxidase (DAO), and T-lymphocyte subgroup level in intestinal lymph nodes were compared., Results: EA could not improve the 2-day survival of CLP rats. For CLP rats, EA at ST36 and LI11 significantly decreased the levels of TNF- α , IL-10, DAO, and D-LA in serum and normalized intestinal T-cell immunity. For SPX CLP rats, EA at ST36 failed to reduce serum concentrations of TNF- α , IL-10, and D-LA but increased the values of CD3 + CD4 + /CD3 + CD8 + cells and Treg/Th17 cells., Conclusions: EA at ST36 and LI11, respectively, could alleviate inflammation reaction, protect the intestinal barrier, and maintain intestinal T-cell function in septic rats. Spleen participated in the protective effect of EA at ST36 in sepsis., Competing Interests: The authors declare that they have no conflicts of interest., (Copyright © 2020 Dong-ping Xie et al.)

Improvac has been tentatively used to immune-castrate roosters. The aim of this study was to investigate whether Improvac affected skeletal muscle development in chickens. The muscle fiber type and size and the expression levels of genes related to muscle development in pectoral and thigh muscles were examined at 5, 9, and 14 wk of age in the control, early, late, and early + late Improvac-treated groups. Immunocastration with Improvac affected the development of thigh muscles and the expression of MYH1B, MSTN, and SM. The cross-sectional area in the early group was significantly larger than in the control group at the 14th week (P < 0.01). At the fifth week, the expression levels of MYH1B, MYOD, and MSTN in the early group were significantly higher than those in the control group (P < 0.05), and at the ninth week, the expression level of SM1 in the control group was significantly lower than that in early and late groups (P < 0.05). Immunocastration did not affect pectoral muscle development or the expression of genes related to muscle development., (Copyright © 2020. Published by Elsevier Inc.)

RNA‑binding protein Musashi‑2 (MSI2) serves as a regulator of numerous pivotal biological processes associated with cancer initiation, development and resistance to treatment, and may represent a promising drug target. However, whether MSI2 inhibition is of value in antitumor treatment remains to be determined. The present study demonstrated that MSI2 was upregulated in non‑small cell lung cancer (NSCLC) and was inversely associated with the clinical outcome of the patients. Molecular docking analysis demonstrated that the small compound largazole binds to and may be a potential inhibitor of MSI2. Largazole markedly decreased the protein and mRNA levels of MSI2 and suppressed its downstream mammalian target of rapamycin signaling pathway. Largazole also inhibited the proliferation and induced apoptosis of NSCLC and chronic myeloid leukemia (CML) cells (including bone marrow mononuclear cells harvested from CML patients). These results indicate that MSI2 is an emerging therapeutic target for NSCLC and CML, and the MSI2 inhibitor largazole may hold promise as a treatment for these malignancies.

Background: How the oncoprotein epidermal growth factor receptor (EGFR) evades proteolytic degradation and accumulates in non-small cell lung cancer (NSCLC) remains unclear, and ubiquitin pathway genes (UPGs) that are critical to NSCLC needs to be systematically identified., Methods: A total of 696 UPGs (including E1, E2, E3, and deubiquitinases) were silenced by small interfering RNA (siRNA) library in NSCLC cells, the candidates were verified, and their significance was evaluated in patients with NSCLC. The effects of a candidate gene on EGFR were investigated in vitro and in vivo., Findings: We report 31 candidates that are required for cell proliferation, with the E2 ubiquitin conjugase CDC34 as the most significant one. CDC34 is elevated in tumor tissues in 76 of 114 (66.7%) NSCLCs and inversely associated with prognosis, is higher in smoker patients than nonsmoker patients, and is induced by tobacco carcinogens in normal human lung epithelial cells. Forced expression of CDC34 promotes, whereas knockdown of CDC34 inhibits, NSCLC cell proliferation in vitro and in vivo. CDC34 competes with c-Cbl to bind Y1045 to inhibit polyubiquitination and degradation of EGFR. In EGFR-L858R and EGFR-T790M/Del (exon 19)-driven lung tumor growth in mouse models, knockdown of CDC34 significantly inhibits tumor formation., Interpretation: These results demonstrate that an E2 enzyme is capable of competing with E3 ligase to stabilize substrates, and CDC34 represents an attractive therapeutic target for NSCLCs., Funding: National Key Research and Development Program of China, National Natural Science Foundation of China, and the CAMS Innovation Fund for Medical Sciences., Competing Interests: Declaration of Competing Interest No potential conflicts of interest were disclosed., (Copyright © 2020 The Author(s). Published by Elsevier B.V. All rights reserved.)

Background: Many studies have documented the abnormal concentrations of major/trace elements in serum or malignant tissues of patients, but very few works systematically tested the concentrations of elements in tumor tissues in comparison with paired adjacent normal tissues from the same patients., Methods: Tumor and adjacent normal lung tissues were obtained from 93 patients with previously untreated NSCLC, and 43 patients whose tumor and paired normal lung tissues reached 200 mg or more were selected for measurement of the elements' concentrations using an inductively coupled plasma-atomic emission spectrometer., Results: We found that the concentrations of the 52 elements varied from 0.4 ng/g tissue (Lu, Pd, and Tm) to 1 658 000 ng/g (Na), 1 951 000 ng/g (P), and 2 495 000 ng/g (K). Thirty eight of the 52 (73.1%) elements showed approximately equal concentrations in tumor and adjacent normal lung tissues of the patients. The concentrations of nine elements (K, P, Mg, Zn, Rb, Cu, Se, Cs, and Tl) in tumor samples were significantly higher than their paired normal lung tissues, and five elements (Na, Fe, Cr, Cd, and Ge) exhibited decreased concentrations in cancer samples compared to counterpart normal lung tissues. Low Fe in tumor samples was associated with smoking history, whereas low Cr was associated with histology (squamous cell carcinoma) of the patients., Conclusions: Our results demonstrate that measurement of elements' concentrations in both cancer and paired normal tissues is important to get insights into the roles of these elements in carcinogenesis, and therapeutic approaches to normalize the elements are warranted to treat NSCLCs., (© 2019 The Authors. Cancer Medicine published by John Wiley & Sons Ltd.)

Purpose: We aimed to investigate the characteristics of focal atrial tachycardias (ATs) arising from the pulmonary veins (PVs), as well as the safety and long-term efficacy of cryoballoon (CB) versus radiofrequency (RF) ablation in this population., Methods: Eighty-three patients with ATs arising from PVs from a consecutive series of 487 patients who underwent CB and RF ablation were retrospectively reviewed. Patients who had a prior history of atrial fibrillation (AF) were excluded. The AT origin was confirmed during the conventional electrophysiological study and activation mapping. The ablation approach was at the discretion of the operators., Results: Thirty-five patients were managed with focal ablation, 25 were ablated with unilateral PV isolation (PVI), and the remaining 23 were performed with CB ablation. All procedures were successfully ablated. There was no significant difference in procedure time between CB group and RF focal group (43.7 ± 11.8 min vs. 45.8 ± 11.2 min, P = 0.121), whereas the fluoroscopy time in CB group was longer than in RF PVI group (10.1 ± 2.5 min vs. 8.4 ± 2.8 min, P < 0.001). There was 1 recurrence in CB group, 4 recurrences of AT in RF focal group, and 2 recurrence in RF PVI group (P = 0.643). Repeat ablation was performed in 6 of 7 patients. Seventy-eight patients were available for long-term follow-up. At a mean of 5.4 ± 4.6-year follow-up, 77 of 78 patients were free from AT without antiarrhythmic medication after 1.1 ± 0.3 procedures. No patient had procedural complications and developed AF during the follow-up period., Conclusions: CB ablation is an effective and safe tool to treat ATs originating from the PVs. The ATs originating from the PVs represent an isolated clinical process and are not likely to be the forerunner of a more diffuse process leading to the development of PV AF.

Immunocastration (vaccination against Gonadotropin-releasing hormone (GnRH)) has been regarded as a friendly substitution to physical castration in animals. To date, a few studies have reported the use of Improvac for immunocastration in boar and one study in broiler chickens; however, there is an apparent dearth of scientific evidence regarding the application of Improvac for immunocastration in birds. In the present study, we evaluated the effects of Improvac-based immunocastration on testosterone levels and spermatogenesis in broiler chickens and the effects of Improvac on the expression of genes related to testosterone biosynthesis and metabolism as well as spermatogenesis. The birds were randomly divided into 4 groups (n = 30 each): Control group (non-immunized), Early group (immunized with Improvac at week 3), Late group (immunized with Improvac at week 6), and Early + Late group (immunized with Improvac at weeks 3 and 6). Immunization with Improvac significantly improved the average daily gain compared to the Control group. Of note, following Improvac vaccination, the reproductive efficiency was significantly decreased in male broiler chickens. Furthermore, parameters such as the serum testosterone concentration, spermatogenesis, and the expression levels of genes related to testosterone metabolism (Cyp17A1, Cyp19, HSD3B1, and HSD17B3) and spermatogenesis (Cyclin A1 and Cyclin A2) were significantly reduced in the immunized groups compared to the Control group. Taken together, these findings reveal that immunization against GnRH can be achieved, at least partially, in male broiler chickens. The results of our study also support the hypothesis of using Improvac as an alternative solution to caponization, with considerably improved animal welfare., (© 2019 Poultry Science Association Inc.)

Post-thawed sperm quality parameters vary across different species after cryopreservation. To date, the molecular mechanism of sperm cryoinjury, freeze-tolerance and other influential factors are largely unknown. In this study, significantly dysregulated microRNAs (miRNAs) and mRNAs in boar and giant panda sperm with different cryo-resistance capacity were evaluated. From the result of miRNA profile of fresh and frozen-thawed giant panda sperm, a total of 899 mature, novel miRNAs were identified, and 284 miRNAs were found to be significantly dysregulated (195 up-regulated and 89 down-regulated). Combined analysis of miRNA profiling of giant panda sperm and our previously published data on boar sperm, 46, 21 and 4 differentially expressed (DE) mRNAs in boar sperm were believed to be related to apoptosis, glycolysis and oxidative phosphorylation, respectively. Meanwhile, 87, 17 and 7 DE mRNAs in giant panda were associated with apoptosis, glycolysis and oxidative phosphorylation, respectively. Gene ontology (GO) analysis of the targets of DE miRNAs showed that they were mainly distributed on membrane related pathway in giant panda sperm, while cell components and cell processes were tied to the targets of DE miRNAs in boar sperm. Finally, Kyoto Encyclopedia of Genes and Genomes (KEGG) analysis of DE mRNAs indicated that most of these DE mRNAs were distributed in membrane signal transduction-related pathways in giant panda sperm, while those in boar sperm were mainly distributed in the cytokine-cytokine receptor interaction pathway and inflammatory related pathways. In conclusion, although the different freezing extenders and programs were used, the DE miRNAs and mRNAs involved in apoptosis, energy metabolism, olfactory transduction pathway, inflammatory response and cytokine-cytokine interactions, could be the possible molecular mechanism of sperm cryoinjury and freeze tolerance., Competing Interests: The authors declare no conflict of interest.

Background: Dextrocardia with situs inversus is a rare cardiac positional anomaly. Catheter ablation procedures performed in this set of patients have not been sufficiently reported., Methods: A total of 10 patients with dextrocardia and situs inversus who received catheter ablation for supraventricular tachycardia (SVT) were included from a cohort of over 20 000 cases of catheter ablation for SVT in three centers from 2005 to 2016. All patients underwent electrophysiologic study and catheter ablation of SVT. Ablation targets were selected based on different tachycardia mechanisms with the primary endpoint of noninduction of tachycardia., Results: The average age was 32.4 ± 5.6 years. Congenitally corrected transposition of great arteries (TGA) with situs inversus and D-looping of the ventricles and aorta (congenitally corrected TGA {I,D,D}) was found in four patients, while the other six patients exhibited mirror-image dextrocardia {I,L,L}. The mechanisms of SVT were atrioventricular nodal reentrant tachycardia in four patients, atrioventricular reentrant tachycardia in three, typical atrial flutter in one, intra-atrial reentrant tachycardia in one, and focal atrial tachycardia in one. Immediate procedural success was achieved in 9 out of 10 patients with no procedural complications. During a follow-up period of 6.3 ± 3.5 years on average, all patients remained free from recurrent tachycardia., Conclusions: For patients with dextrocardia and situs inversus, catheter ablation of SVT is safe and feasible. Differences in catheter maneuver and fluroscopy projection, along with difficulties in distorted anatomy are major obstacles for successful ablation., (© 2019 Wiley Periodicals, Inc.)

Background: While the left sinus of Valsalva (LSV) is a frequent origin of ventricular arrhythmias (VAs). Uncommonly, VAs with right bundle branch block (RBBB) morphology may be successfully terminated from the LSV., Objective: We aimed to investigate the electrocardiographic and electrophysiologic characteristics of VAs with RBBB which were successfully eliminated from the LSV., Methods: We identified patients with VAs successfully ablated from the LSV from January 2014 to December 2017 and compared electrophysiologic characteristics and ablation sites of those VAs with RBBB versus a control group of patients with left bundle branch block morphology., Results: We identified 18 patients with RBBB and predominant "R" waves in the precordial leads. In 12 (66.7%) patients, a small "s" wave in lead V2 and positive "R" in the remaining pericardial leads could be seen. Overall, a single "V" potential was seen in 72.2% of patients in the study group, while discrete potentials were recorded in 80% of the patients in the control group. The majority (88.9%) of the VAs could only be terminated at the nadir of the LSV in the study group. After mean follow-up of 33 ± 14 months, 93.8% and 92% were free of VAs after initial ablation in study and control group, respectively (P = 0.99)., Conclusion: Some VAs with predominant monophasic "R" wave in precordial leads could be terminated from LSV, especially a small "s" wave in lead V2 was recorded. The nadir of LSV is highly successful for RBBB VAs and single electrogram was recorded at the target for most of the cases., (© 2019 Wiley Periodicals, Inc.)

Whether tobacco carcinogens enable exposed cells immune escape resulting in carcinogenesis, and why patients who smoke respond better to immunotherapies than non-smokers, remains poorly understood. Here we report that cigarette smoke and the carcinogen benzo(a)pyrene (BaP) induce PD-L1 expression on lung epithelial cells in vitro and in vivo, which is mediated by aryl hydrocarbon receptor (AhR). Anti-PD-L1 antibody or deficiency in AhR significantly suppresses BaP-induced lung cancer. In 37 patients treated with anti-PD-1 antibody pembrolizumab, 13/16 (81.3%) patients who achieve partial response or stable disease express high levels of AhR, whereas 12/16 (75%) patients with progression disease exhibit low levels of AhR in tumor tissues. AhR inhibitors exert significant antitumor activity and synergize with anti-PD-L1 antibody in lung cancer mouse models. These results demonstrate that tobacco smoke enables lung epithelial cells to escape from adaptive immunity to promote tumorigenesis, and AhR predicts the response to immunotherapy and represents an attractive therapeutic target.

Due to lower farrowing rate and reduced litter size with frozen-thawed semen, over 90% of artificial insemination (AI) is conducted using liquid stored boar semen. Although substantial progress has been made towards optimizing the cryopreservation protocols for boar sperm, the influencing factors and underlying mechanisms related to cryoinjury and freeze tolerance of boar sperm remain largely unknown. In this study, we report the differential expression of mRNAs and miRNAs between fresh and frozen-thawed boar sperm using high-throughput RNA sequencing. Our results showed that 567 mRNAs and 135 miRNAs were differentially expressed (DE) in fresh and frozen-thawed boar sperm. Gene ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) enrichment analyses revealed that the majority of DE mRNAs were enriched in environmental information processing such as cytokine-cytokine receptor interactions, PI3K-Akt signaling, cell adhesion, MAPK, and calcium signaling pathways. Moreover, the targets of DE miRNAs were enriched in significant GO terms such as cell process, protein binding, and response to stimuli. In conclusion, we speculate that DE mRNAs and miRNAs are heavily involved in boar sperm response to environment stimuli, apoptosis, and metabolic activities. The differences in expression also reflect the various structural and functional changes in sperm during cryopreservation.

Introduction: The procedural findings and clinical outcome of second-generation cryoballoon (CB2) ablation in patients with variant pulmonary vein (PV) anatomy have not been fully investigated., Methods: A total of 424 consecutive patients who underwent PV isolation with CB2 were included. Computed tomographic (CT) scan was performed in all patients before the procedure. The study population was divided into common PV, accessory PV, and nonvariant PV groups according to the CT scan. Procedural findings and clinical outcome between the three groups were compared., Results: Variant PV anatomy was observed in 118 of 424 (27.8%) patients. PV isolation was successfully achieved in all patients in three groups with low rates of need for touch-up ablation (P = 0.974). Total procedure time was longer in the accessory PV group compared with nonvariant PV group (53.7 ± 12.9 vs 49.5 ± 8.8 minutes; P < 0.001). More number of applications per patient were required in accessory PV group compared with the nonvariant PV and common PV groups (7.5 ± 2.1 vs 6.5 ± 1.6, P < 0.001; 7.5 ± 2.1 vs 6.8 ± 1.4, P = 0.027, respectively). No significant difference in phrenic nerve (PN) injury was observed between the three groups (P = 0.693). During mean follow-up duration of 16.1 ± 3.3 months, there was no significant difference in rates of atrial fibrillation (AF) recurrences in the three groups (13 of 43 common PV group, 21 of 75 accessory PV group, and 80 of 306 nonvariant PV group, P = 0.178)., Conclusion: Variant PV patterns are common in patients undergoing ablation for drug-resistant AF. CB2 ablation appears to be a reasonable strategy in the setting of the variant PV anatomy with a small increase in procedure time and the number of cryoapplications., (© 2018 Wiley Periodicals, Inc.)

Red wine consists of a large amount of compounds such as resveratrol, which exhibits chemopreventive and therapeutic effects against several types of cancers by targeting cancer driver molecules. In this study, we tested the anti-lung cancer activity of 11 red wine components and reported that a natural polyphenol compound ellagic acid (EA) inhibited lung cancer cell proliferation at an efficacy approximately equal to that of resveratrol. EA markedly increased the expression of the autophagosomal marker LC3-II as well as inactivation of the mechanistic target of rapamycin signalling pathway. EA elevated autophagy-associated cell death by down-regulating the expression of cancerous inhibitor of protein phosphatase 2A (CIP2A), and CIP2A overexpression attenuated EA-induced autophagy of lung cancer cells. Treating tumour-bearing mice with EA resulted in significant inhibition of tumour growth with suppression of CIP2A levels and increased autophagy. In addition, EA potentiated the inhibitory effects of the natural compound celastrol on lung cancer cells in vitro and in vivo by enhancing autophagy and down-regulating CIP2A. These findings indicate that EA may be a promising chemotherapeutic agent for lung cancer, and that the combination of EA and celastrol may have applicability for the treatment of this disease., (© 2018 The Authors. Journal of Cellular and Molecular Medicine published by John Wiley & Sons Ltd and Foundation for Cellular and Molecular Medicine.)

Selenium (Se) is an essential micronutrient that has several important functions in animal and human health. The biological functions of Se are carried out by selenoproteins (encoded by twenty-five genes in human and twenty-four in mice), which are reportedly present in all three domains of life. As a component of selenoproteins, Se has structural and enzymatic functions; in the latter context it is best recognized for its catalytic and antioxidant activities. In this review, we highlight the biological functions of Se and selenoproteins followed by an elaborated review of the relationship between Se and female reproductive function. Data pertaining to Se status and female fertility and reproduction are sparse, with most such studies focusing on the role of Se in pregnancy. Only recently has some light been shed on its potential role in ovarian physiology. The exact underlying molecular and biochemical mechanisms through which Se or selenoproteins modulate female reproduction are largely unknown; their role in human pregnancy and related complications is not yet sufficiently understood. Properly powered, randomized, controlled trials (intervention vs. control) in populations of relatively low Se status will be essential to clarify their role. In the meantime, studies elucidating the potential effect of Se supplementation and selenoproteins (i.e., GPX1, SELENOP, and SELENOS) in ovarian function and overall female reproductive efficiency would be of great value.

Background: Catheter ablation of ventricular arrhythmias (VAs) originating from the para-Hisian region could be challenging because of a potential damage to atrioventricular conduction system., Objective: The purpose of this study was to evaluate the safety and efficacy of catheter ablation of VAs originating from the para-Hisian region via a systematic direct approach from aortic sinus cusps (ASCs)., Methods: Twenty-one consecutive patients with VAs with para-Hisian origin were included. Electrophysiological mapping of the entire right ventricle was initially performed, and then retrograde ASC mapping was performed when the earliest ventricular activation was recorded in the His bundle region. Ablation was preferentially performed within ASCs in all patients., Results: Radiofrequency energy delivery resulted in the elimination of VAs in 17 of 21 patients (81%). In the remaining 4 patients, radiofrequency application was initiated at the target site of the right ventricular septum around the His bundle region and clinical VAs were finally successfully eliminated without junctional rhythm in 2 of 4 patients. During a mean follow-up of 34.8 ± 11.3 months, 1 of the 19 acute successful patients had VA recurrence. No procedure-related complications occurred during ablation or follow-up., Conclusion: Catheter ablation of VAs originating from the para-Hisian region via a direct approach from ASCs may be safe and effective in most unselected patients., (Copyright © 2018 Heart Rhythm Society. Published by Elsevier Inc. All rights reserved.)

Background: Capacitation, a prerequisite for oocyte fertilization, is a complex process involving series of structural and functional changes in sperms such as membrane modifications, modulation of enzyme activities, and protein phosphorylation. In order to penetrate and fertilize an oocyte, mammalian sperms must undergo capacitation. Nevertheless, the process of sperm capacitation remains poorly understood and requires further elucidation. In the current study, via high throughput sequencing, we identified and explored the differentially expressed microRNAs (miRNAs) and mRNAs involved in boar sperm capacitation., Results: We identified a total of 5342 mRNAs and 204 miRNAs that were differentially expressed in fresh and capacitated boar sperms. From these, 12 miRNAs (8 known and 4 newly identified miRNAs) and their differentially expressed target mRNAs were found to be involved in sperm capacitation-related PI3K-Akt, MAPK, cAMP-PKA and Ca 2+ signaling pathways., Conclusions: Our study is first to provide the complete miRNA and transcriptome profiles of boar sperm. Our findings provide important insights for the understanding of the RNA profile in boar sperm and future elucidation of the underlying molecular mechanism relevant to mammalian sperm capacitation.

To systematically unveil transcription factors (TFs) that are critical to lung carcinogenesis, here we conducted a genome-wide lethality screening in non-small cell lung cancer (NSCLC) cells and reported that among the 1530 TFs tested, 21 genes were required for NSCLC cell proliferation and were negatively or positively associated with overall survival (OS) of patients with NSCLC. These included 11 potential tumor suppressing genes (AFF3, AhR, AR, CBFA2T3, CHD4, KANK2, NR3C2, PTEN, PRDM16, RB1, and STK11) and 10 potential oncogenic TFs (BARX1, DLX6, ELF3, EN1, ETV1, FOXE1, HOXB7, IRX4, IRX5, and SALL1). The expression levels of IRX5 were positively associated with OS of smoker and inversely associated with OS of non-smoker patients with lung adenocarcinoma. We showed that tobacco carcinogen benzo(a)pyrene (BaP) induced upregulation of IRX5 in lung epithelial cells, and Cyclin D1 was a downstream target of IRX5. Furthermore, silencing of IRX5 by lentivirus mediated transfection of short hairpin RNA significantly inhibited tumor growth in nude mice. These results indicate that tobacco smoke can modulate TFs to facilitate lung carcinogenesis, and inhibition of IRX5 may have therapeutic potentials in NSCLCs., (Copyright © 2018 Elsevier B.V. All rights reserved.)

Sperm cryopreservation and artificial insemination are important methods for giant panda breeding and preservation of extant genetic diversity. Lower conception rates limit the use of artificial insemination with frozen-thawed giant panda sperm, due to the lack of understanding of the cryodamaging or cryoinjuring mechanisms in cryopreservation. Long non-coding RNAs (lncRNAs) are involved in regulating spermatogenesis. However, their roles during cryopreservation remain largely unexplored. Therefore, this study aimed to identify differentially expressed lncRNAs and mRNAs associated with cryodamage or freeze tolerance in frozen-thawed sperm through high throughput sequencing. A total of 61.05 Gb clean reads and 22,774 lncRNA transcripts were obtained. From the sequencing results, 1477 significantly up-regulated and 1,396 significantly down-regulated lncRNA transcripts from fresh and frozen-thawed sperm of giant panda were identified. GO and KEGG showed that the significantly dysregulated lncRNAs and mRNAs were mainly involved in regulating responses to cold stress and apoptosis, such as the integral component of membrane, calcium transport, and various signaling pathways including PI3K-Akt, p53 and cAMP. Our work is the first systematic profiling of lncRNA and mRNA in fresh and frozen-thawed giant panda sperm, and provides valuableinsights into the potential mechanism of cryodamage in sperm.

Aims: We aimed to examine the electrocardiographic and electrophysiologic characteristics of anterograde-conducting decremental accessory pathways (DAP) and to identify surrogate criteria to distinguish short atrioventricular (SAV) DAP from atriofascicular (AF) AP and long atrioventricular (LAV) DAP., Methods and Results: We identified all patients with DAPs and analysed electrocardiographic and electrophysiologic characteristics. Distal insertion sites were examined using existing criteria, including V-H interval, ventricular activation at the right ventricular apex, and around tricuspid annulus during antidromic atrioventricular re-entrant tachycardia (A-AVRT) or complete pre-excitation and evaluated the AV node-like properties according to the response to adenosine and radiofrequency ablation. Out of 45 patients with DAPs, 28 (62.2%) had SAV-DAP (13 with definite AF-AP, 2 with definite LAV-DAP, 2 indeterminate). In all, 50% of SAV-DAPs and 53.3% of AF-AP/LAV-DAPs had 'rS' pattern in lead III. Longer QRS duration (159.9 ± 17.4 ms vs. 139.2 ± 14.3 ms, P < 0.0001) during full pre-excitation or A-AVRT differentiated SAV-DAP from AF-AP. The QRS-V(His) interval was longer for those with SAV-DAP compared vs. AF-AP/LAV-DAP (45.3 ± 2.4 ms vs. 22.9 ± 2.5 ms, P < 0.0001) and a cut-off value of 33.0 ms differentiated the two (sensitivity 81.3%, specificity 87.5%)., Conclusion: The majority of the SAV-DAPs are located at the TA free wall. An 'rS' pattern in lead III is frequently seen in SAV-DAP as well as AF-AP/LAV-DAPs. Measuring the QRS-V(His) interval would be helpful to distinguish SAV-DAP from AF-AP/LAV-DAP.

Background: Right atrial (RA) dual-loop reentrant tachycardia has been described in patients who have undergone open heart surgery. However, the prevalence, electrophysiological (EP) substrate, and ablation outcomes have been poorly characterized., Objective: The purpose of this study was to investigate the prevalence, EP substrate, and ablation outcomes for RA dual-loop reentrant tachycardia after cardiac surgery., Methods: We identified all patients with atrial tachycardia (AT) after cardiac surgery. We compared EP findings and outcomes of those with RA dual-loop reentrant tachycardia to a control group of patients with RA macroreentrant arrhythmias in the setting of linear RA free-wall (FW) scar., Results: Of the 127 patients with 152 postsurgical ATs, 28 of the ATs (18.4%) had RA dual-loop reentry and 24 of 28 (85.7%) had tricuspid annular reentry combined with FW incisional reentry. An incision length >51.5 mm along the FW predicted the substrate for a second loop. In 22 of 23 patients (95.7%) with initial ablation in the cavotricuspid isthmus, a change in the interval between Halo d to CS p could be recorded, and 15 of 23 patients (65.2%) had coronary sinus activation pattern change. Complete success was achieved in 25 of 28 patients (89.3%) in the dual-loop reentry group and in 64 of 69 patients (92.8%) in the control group. After mean follow-up of 33.9 ± 24.2 months, 24 of 28 patients (85.7%) and 60 of 69 patients (86.95%) were free of arrhythmias after the initial procedure in the 2 groups, respectively., Conclusion: The prevalence of RA dual-loop reentry is 18.4% of ATs with prior atriotomy scar. A long incision should alert physicians to the possibility of a second loop at the FW. Halo and coronary sinus activation patterns provide important clues to circuit transformation., (Copyright © 2018 Heart Rhythm Society. Published by Elsevier Inc. All rights reserved.)

Introduction: To assess the predictors of hemoptysis using second-generation cryoballoon (CB)., Methods: Thirty patients with hemoptysis after second-generation CB ablation and 60 age-, gender-, and body mass index-matched controls were recruited. Anatomic parameters were obtained from preprocedural cardiac computed tomography (CT). Pulmonary vein isolation was performed with 28-mm balloon using single 3-minute freeze technique., Results: Clinical and procedural characteristics were similar between the groups. A shorter distance between left superior PV (LSPV) and left main bronchus (LMB) was associated with hemoptysis (7.8 ± 4.3 mm vs. 12.5 ± 3.5 mm, P < 0.001), whereas no significant difference in the distance between right superior PV (RSPV) and right main bronchus (RMB) was found between groups (11.9 ± 3.5 mm vs. 12.9 ± 4.6 mm, P = 0.089). Additionally, the mean thickness of the connective tissue interposed between RSPV and RMB was significantly thicker than that between LSPV and LMB in both groups (both P < 0.001). A stepwise logistic multivariate analysis identified only the LMB-LSPV distance as an independent predictor of hemoptysis (odd ratio [OR] 2.676; 95% CI 1.121-4.843, P < 0.001). A cutoff value ≤ 9.5 mm predicted hemoptysis after CB ablation with 93.8% sensitivity and 75.0% specificity., Conclusion: Hemoptysis is a relatively rare event following second-generation CB ablation. The bronchi location obtained from CT aids in identifying high-risk population for the complication., (© 2018 Wiley Periodicals, Inc.)