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Abstract Ultrasmall copper nanoclusters have recently emerged as promising photocatalysts for organic synthesis, owing to their exceptional light absorption ability and large surface areas for efficient interactions with substrates. Despite significant advances in cluster-based visible-light photocatalysis, the types of organic transformations that copper nanoclusters can catalyze remain limited to date. Herein, we report a structurally well-defined anionic Cu40 nanocluster that emits in the second near-infrared region (NIR-II, 1000−1700 nm) after photoexcitation and can conduct single-electron transfer with fluoroalkyl iodides without the need for external ligand activation. This photoredox-active copper nanocluster efficiently catalyzes the three-component radical couplings of alkenes, fluoroalkyl iodides, and trimethylsilyl cyanide under blue-LED irradiation at room temperature. A variety of fluorine-containing electrophiles and a cyanide nucleophile can be added onto an array of alkenes, including styrenes and aliphatic olefins. Our current work demonstrates the viability of using readily accessible metal nanoclusters to establish photocatalytic systems with a high degree of practicality and reaction complexity.

BackgroundYishen-Tongbi Decoction (YSTB), a traditional Chinese prescription, has been used to improve syndromes of rheumatoid arthritis (RA) for many years. Previous research has shown that YSTB has anti-inflammatory and analgesic properties. However, the underlying molecular mechanism of the anti-RA effects of YSTB remains unclear.Purpose and study designThe purpose of this research was to investigate how YSTB affected mice with collagen-induced arthritis (CIA) and RAW264.7 cells induced with lipopolysaccharide (LPS).ResultsThe findings show that YSTB could significantly improve the clinical arthritic symptoms of CIA mice (mitigate paw swelling, arthritis score, thymus and spleen indices, augment body weight), downregulated expression of pro-inflammatory cytokines like tumor necrosis factor-alpha (TNF-α), interleukin-1β (IL-1β), IL-6 and IL-17, while upregulated the level of anti-inflammatory like IL-10 and transforming growth factor-β (TGF-β). Meanwhile, YSTB inhibits bone erosion and reduces inflammatory cell infiltration, synovial proliferation, and joint destruction in CIA mice. In addition, we found that YSTB was able to suppress the LPS-induced inflammation of RAW264.7 cells, which was ascribed to the suppression of nitric oxide (NO) production and reactive oxygen species formation (ROS). YSTB also inhibited the production of inducible nitric oxide synthase and reduced the releases of pro-inflammatory cytokines TNF-α, IL-1β, and IL-6 in LPS-induced RAW264.7 cells. Furthermore, the phosphorylation expression of JAK2, JAK3, STAT3, p38, ERK and p65 protein could be suppressed by YSTB, while the expression of SOCS3 could be activated.ConclusionTaken together, YSTB possesses anti-inflammatory and prevention bone destruction effects in RA disease by regulating the JAK/STAT3/SOCS3 signaling pathway.

Abstract Despite promising preclinical and earlier clinical data, a recent phase III trial on the anti-β7 integrin antibody etrolizumab in Crohn’s disease (CD) did not reach its primary endpoint. The mechanisms leading to this outcome are not well understood. Here we characterize the β7+ T cell compartment from patients with CD in comparison to cells from individuals without inflammatory bowel disease. By flow cytometric, transcriptomic and functional profiling of circulating T cells, we find that triple-integrin-expressing (α4+β7+β1hi) T cells have the potential to home to the gut despite α4β7 blockade and have a specific cytotoxic signature. A subset of triple-integrin-expressing cells readily acquires αE expression and could be co-stimulated via E-Cadherin-αEβ7 interactions in vitro. Etrolizumab-s fails to block such αEβ7 signalling at high levels of T cell stimulation. Consistently, in CD patients treated with etrolizumab, T cell activation correlates with cytotoxic signatures. Collectively, our findings might add one important piece to the puzzle to explain phase III trial results with etrolizumab, while they also highlight that αEβ7 remains an interesting target for future therapeutic approaches in inflammatory bowel disease.

The selective removal of targeted pollutants from complex wastewater is challenging. Herein, a novel persulfate (PS)-based advanced oxidation system equipped with a series of two-dimensional (2D) bimetallic oxide nanosheets (NSs) catalysts is developed to selectively degrade bisphenol A (BPA) within mixed pollutants via initiating nonradical-induced polymerization. Results indicate that the Ni0.60Co0.40Ox NSs demonstrate the highest catalytic efficiency among all Ni-Co NSs catalysts. Specifically, BPA degradation rate is 47.34, 27.26, and 9.72 times higher than that of 4-chlorophenol, phenol, and 2,4-dichlorophenol in the mixed solution, respectively. The lower oxidative potential of BPA in relation to the other pollutants renders it the primary target for oxidation within the PDS activation system. PDS molecules combine on the surface of Ni0.60Co0.40Ox NSs to form the surface-activated complex, triggering the generation of BPA monomer radicals through H-abstraction or electron transfer. These radicals subsequently polymerize on the surface of the catalyst through coupling reactions. Importantly, this polymerization process can occur under typical aquatic environmental conditions and demonstrates resistance to background matrices like Cl− and humic acid due to its inherent nonradical attributes. This study offers valuable insights into the targeted conversion of organic pollutants in wastewater into value-added polymers, contributing to carbon recycle and circular economy.

Energy output and heating effects are essential for vapor-liquid fuel/air cloud detonation in the fuel-air explosive (FAE) applications or explosion accidents. The purpose of this study is to examine the dynamic large-size flame behavior, shock wave propagation law, and instantaneous thermal field generated by unconfined vapor-liquid propylene oxide (PO)/air cloud detonation. Based on computational fluid dynamics (CFD) and combustion theory, a numerical simulation is used to study the detonation process of a PO/air cloud produced by a double-event fuel-air explosive (DEFAE) of 2.16 kg. The large-scale flame behavior is characterized. The flame initially spreads radially and laterally in a wing shape. Subsequently, the developed flame increases with a larger aspect ratio. Moreover, the propagation laws of shock waves at different heights are discussed. The peak pressure of 1.3 m height level with a stepwise decline is obviously different from that of the ground with an amplitude of reversed 'N' shape. In the vast majority of the first 6.9 m, the destructive effect of the shock wave near the ground is greater than that of the shock wave at 1.3 m height. Furthermore, the dynamic instantaneous isothermal field is demonstrated. The scaling relationship of various isotherms in the instantaneous thermal field with the flame and initial cloud is summarized. The comprehensive numerical model used in this study can be applied to determine the overpressure and temperature distribution in the entire fuel/air cloud detonation field, providing guidance for assessing the extent of damage caused by DEFAE detonation.

Abstract The advances in determining the total structure of atomically precise metal nanoclusters have prompted extensive exploration into the origins of chirality in nanoscale systems. While chirality is generally transferrable from the surface layer to the metal–ligand interface and kernel, we present here an alternative type of gold nanoclusters (138 gold core atoms with 48 2,4-dimethylbenzenethiolate surface ligands) whose inner structures are not asymmetrically induced by chiral patterns of the outermost aromatic substituents. This phenomenon can be explained by the highly dynamic behaviors of aromatic rings in the thiolates assembled via π − π stacking and C − H···π interactions. In addition to being a thiolate-protected nanocluster with uncoordinated surface gold atoms, the reported Au138 motif expands the size range of gold nanoclusters having both molecular and metallic properties. Our current work introduces an important class of nanoclusters with intrinsic chirality from surface layers rather than inner structures and will aid in elucidating the transition of gold nanoclusters from their molecular to metallic states.

LKB1 mutations have been associated with primary resistance to immune checkpoint inhibitors in patients with lung cancer. Here the authors show that Lkb1-deficient lung tumors are characterized by defective trafficking and adhesion of T cells and that, by upregulating ICAM1 expression, CDK4/6 inhibitors sensitize LKB1 mutant lung cancer to anti-PD1 blockade.

Abstract Background Culex pipiens pallens (Diptera: Culicidae) can survive at low temperature for long periods. Understanding the effects of low-temperature stress on the gut microflora and gene expression levels in Cx. pipiens pallens, as well as their correlation, will contribute to the study of the overwintering mechanism of Cx. pipiens pallens. Methods The gut bacteria were removed by antibiotic treatment, and the survival of Cx. pipiens pallens under low-temperature stress was observed and compared with the control group. Then, full-length 16S rRNA sequencing and the Illumina HiSeq X Ten sequencing platform were used to evaluate the gut microflora and gene expression levels in Cx. pipiens pallens under low-temperature stress. Results Under the low-temperature stress of 7 °C, the median survival time of Cx. pipiens pallens in the antibiotic treatment group was significantly shortened by approximately 70% compared to that in the control group. The species diversity index (Shannon, Simpson, Ace, Chao1) of Cx. pipiens pallens decreased under low-temperature stress (7 °C). Non-metric multidimensional scaling (NMDS) analysis divided all the gut samples into two groups: control group and treatment group. Pseudomonas was the dominant taxon identified in the control group, followed by Elizabethkingia and Dyadobacter; in the treatment group, Pseudomonas was the dominant taxon, followed by Aeromonas and Comamonas. Of the 2417 differentially expressed genes (DEGs), 1316 were upregulated, and 1101 were downregulated. Functional GO terms were enriched in 23 biological processes, 20 cellular components and 21 molecular functions. KEGG annotation results showed that most of these genes were related to energy metabolism-related pathways. The results of Pearson’s correlation analysis showed a significant correlation between the gut microcommunity at the genus level and several DEGs. Conclusions These results suggest that the mechanism of adaptation of Cx. pipiens pallens to low-temperature stress may be the result of interactions between the gut bacterial community and transcriptome. Graphical Abstract

Diabetic nephropathy (DN), the leading cause of end-stage renal disease, is the most significant microvascular complication of diabetes and poses a severe public health concern due to a lack of effective clinical treatments. Autophagy is a lysosomal process that degrades damaged proteins and organelles to preserve cellular homeostasis. Emerging studies have shown that disorder in autophagy results in the accumulation of damaged proteins and organelles in diabetic renal cells and promotes the development of DN. Autophagy is regulated by nutrient-sensing pathways including AMPK, mTOR, and Sirt1, and several intracellular stress signaling pathways such as oxidative stress and endoplasmic reticulum stress. An abnormal nutritional status and excess cellular stresses caused by diabetes-related metabolic disorders disturb the autophagic flux, leading to cellular dysfunction and DN. Here, we summarized the role of autophagy in DN focusing on signaling pathways to modulate autophagy and therapeutic interferences of autophagy in DN.

BackgroundThe increased risk of cardiovascular events in patients prescribed macrolides has been subject to debate for decades.MethodsMedline, EMBASE databases and ClinicalTrials.gov were searched from inception until August 31, 2022 for studies investigating the link between macrolides and cardiovascular risk. A meta-analysis was performed using a random-effects model.ResultsA total of 80 studies involving 39,374,874 patients were included. No association was found between macrolides and all-cause death. However, compared with the non-macrolide group, macrolides were associated with a significantly increased risk of ventricular arrhythmia or sudden cardiac death (VA or SCD) (azithromycin, relative ratio [RR]: 1.53; 95% confidence interval [CI]: 1.19 to 1.97; clarithromycin, RR: 1.52; 95% CI: 1.07 to 2.16). Besides, administration of macrolides was associated with a higher risk of cardiovascular disease (CVD) death (azithromycin, RR: 1.63; 95% CI: 1.17 to 2.27) and a slightly increased risk of myocardial infarction (MI) (azithromycin, RR: 1.08; 95% CI: 1.02 to 1.15). Interestingly, no association was observed between roxithromycin and adverse cardiac outcomes. Increased risk of VA or SCD was observed for recent or current use of macrolides, MI for former use, and CVD death for current use.ConclusionAdministration of macrolide antibiotics and timing of macrolide use are associated with increased risk for SCD or VTA and cardiovascular death, but not all-cause death.

Although the phytotoxicity of graphene-based materials has been investigated extensively, the effects of different graphene-based materials on nutrient uptake in plants remain unclear. Here, we analyzed the differences in phytotoxicity between single-layer graphene oxide (sGO) and multi-layer graphene oxide (mGO) by analyzing the growth status and nitrate (NO3–) accumulation in wheat plants at 0, 100, 200, 400, and 800 mg L−1 graphene oxide supply. Both sGO and mGO displayed concentration-dependent inhibitory effects on biomass, root length, number of lateral roots, and nitrogen (N) nutrient status. Treatment with 400 mg L−1 sGO caused 0.9-, 1.3-, and 1-fold higher reductions in NO3–-N, assimilated N, and total N concentrations in roots, respectively, than mGO treatment. Analysis of root oxidative stress and in situ NO3– uptake revealed that sGO caused more significant damage to the root tip and a lower NO3– net influx rate than mGO. In addition, the expression of NO3– transporter (NRT) genes in roots, including NRT1.5, NRT2.1, NRT2.2, NRT2.3, and NRT2.4, under sGO treatment were lower than those under mGO treatment. Overall, sGO treatment induced a more severe inhibitory effect on root growth and NO3– uptake and accumulation than mGO treatment, accompanied by significant suppression of the expression of NRTs in sGO-treated roots. This study provides a physiological and molecular basis for studying the phytotoxic effects of various sizes of graphene oxide.

AIM: To observe the early visual quality of the tri-focal and the mono-focal intraocular lens(IOLs)implantation in patients with age-related cataract, under comparison and analysis.METHODS: A retrospective research design. Totally 168 eyes of 119 age-related cataract patients who underwent cataract phacoemulsification combined with tri-focal and mono-focal IOLs implantation surgery in the cataract department from June 2018 to January 2021 were enrolled. In tri-focal and mono-focal group, 61 eyes of 44 cases and 107 eyes of 75 cases. One month after phacoemulsification combined with IOLs implantation, visual acuity, visual quality and contrast sensitivity were inspected. All data were under statistical analysis.RESULTS: On LogMAR uncorrected distance visual acuity(UDVA),uncorrected intermediate visual acuity(UIVA), uncorrected near visual acuity(UNVA), best corrected distance visual acuity(BDVA), distance corrected intermediate visual acuity(DIVA), distance corrected near visual acuity(DNVA), tri-focal group were extremely better than mono-focal group(all P0.05).CONCLUSION: Tri-focal IOLs can provide a full range of relatively better vision and visual quality in patients after age-related cataract phacoemulsification combined with IOLs implantation, and perform well under different conditions.

Objective: To study the clinic pathological characteristics, diagnosis and differential diagnosis of bronchiolar adenoma. Methods: Ten cases of bronchiolar adenoma in Lu′an people′s Hospital were collected from January to December 2020, and their clinical data, imaging results, histopathological features and immunohistochemical phenotype were analyzed with literature reviewed. Results: Of the patients, there were 4 males and 6 females, with age ranging from 49 to 79 years old. Most patients had no obvious clinical symptoms, and were found occasional pulmonary nodules by chest CT examination, with ground glass nodules on CT. All of the lesions were located in the periphery of the lung. Grossly, all of the tumors were well circumscribed, solid, and tan to brown on the cut surface. Six cases were the proximal type, and four case was the distal type. Microscopically, the tumor showed glandular, flat and papillary growth pattern, and a large amount of extracellular mucus could be seen. The lining cells of the cavity margin were mucous cells, ciliated cells, non-ciliated cuboidal cells and Clara cells. There was no atypia and mitosis. Continuous basal cell layer could be seen outside the cavity margin, and some tumors could be free of mucous cells and ciliated cells. Immunohistochemical staining of p40, p63 and CK5/6 showed the continuous basal cell layer. Conclusions: Bronchiolar adenoma is a kind of peripheral lung tumor composed of double-layer cells, the diagnosis requires the existence of a complete basal cell layer, and sometimes it is difficult to make a definite diagnosis. The existence of basal cell layer which is identified by immunological histochemistry (p40、p63 and CK5/6) is the key point for distinguish BA from lung adenocarcinoma.

BackgroundThe clinical features of urticaria have not been fully illustrated.ObjectivesTo demonstrate clinical features of urticaria in different areas of southern and northern China.MethodsIn this hospital-based multicenter study, outpatients with urticaria filled in a questionnaire during the initial visit and follow-up (once per week, lasting for a month).ResultsOverall, 1,715 outpatients with urticaria with a mean age of 37.86 ± 16.08 years (range = 0.5–87 years) were recruited. The median disease duration was 1.94 ± 4.31 years (range = 0–58 years). More itching was observed in the northern areas higher than that in the southern areas (99.5 vs 94.1%, P < 0.001). The incidence of pain, arthralgia, and family history in southern areas was higher than that in northern areas (5.1 vs 1.1%, 9.6 vs 0, 10.6% vs 3.2%, P < 0.001). The leading subtypes of specified urticaria were chronic spontaneous urticaria (81.4%) and symptomatic dermographism (35.9%). The incidence of symptomatic dermographism and cold urticaria in the southern areas was lower than that in the northern areas (31.8 vs. 50.3%, 4 vs. 8.5%, P < 0.001). Allergic diseases were the most common concomitant disorders of urticaria. More than half of the patients had to avoid certain food, such as fish-prawn-crab (30.7%) and alcohol (20%). Ebastine (41.1%) was the most commonly prescribed drug. The disease duration negatively correlated with the severity of itching and number of wheals (>50/24H) (Spearman’s rank correlation test, p < 0.001).ConclusionThis study provides a profile of clinical characteristics of urticaria in China and filled the gap in the field of regional comparative studies on urticaria.

Background The prognostic value of early repolarization pattern (ERP) remains controversial. We aim to test the hypothesis that temporal changes in ERP are associated with increased risks for sudden cardiac death (SCD) and cardiovascular death. Methods and Results A total of 14 679 middle‐aged participants from the prospective, population‐based cohort were included in this analysis, with ERP status recorded at baseline and during 3 follow‐up visits in the ARIC (Atherosclerosis Risk in Communities) study. We related baseline ERP, time‐varying ERP, and temporal changes in ERP to cardiovascular outcomes. Cox models were used to estimate the hazard ratios (HRs) adjusted for possible confounding factors. With a median follow‐up of 22.5 years, there were 5033 deaths, 1239 cardiovascular deaths, and 571 SCDs. Time‐varying ERP was associated with increased risks of SCD (HR, 1.59 [95% CI, 1.25–2.02]), cardiovascular death (HR, 1.70 [95% CI, 1.44–2.00]), and death from any cause (HR, 1.16 [95% CI, 1.05–1.27]). Baseline ERP was also associated with 3 outcomes. Compared with those with consistently normal ECG findings, subjects with new‐onset ERP or consistent ERP experienced increased risks of developing SCD and cardiovascular death. The time‐varying ERP in women, White subjects, and anterior leads and J‐wave amplitudes ≥0.2 mV appeared to indicate poorer cardiovascular outcomes. Conclusions Our findings suggest that baseline ERP, time‐varying ERP, new‐onset ERP, and consistent ERP were independent predictors of SCD and cardiovascular death in the middle‐aged biracial population. Repeated measurements of the ERP might improve its use as a risk indicator for SCD.

Abstract Background Hepatic cavernous hemangioma is the most common type of benign liver tumor. Although ruptures and hemorrhages of hepatic hemangioma are rare complications, they are associated with high mortality. Most practitioners only pay more attention to abdominal hemorrhages caused by the rupture of hepatic hemangiomas. However, spontaneous intracapsular hemorrhages can often be neglected and poorly understood. Case presentation A 65-year-old man was referred to our institution with right upper quadrant pain, which had occurred suddenly and without a history of recent trauma. The blood test results were normal. Magnetic resonance imaging (MRI) of the abdomen showed a cystic mass in the right liver lobe. Considering the possibility of hepatic cystadenoma with hemorrhage, the patient underwent a right hepatic lobectomy. The pathological findings unexpectedly revealed intratumoral hemorrhage of hepatic hemangioma. The patient recovered well and was discharged eight days after surgery. Conclusions Intracapsular hemorrhage of hepatic cavernous hemangioma is challenging to diagnose and has a high potential risk of rupture. MRI is beneficial for diagnosing subacute internal hemorrhage cases, and it is recommended to undergo surgery for patients with a definitive diagnosis.

Objective To investigate and analyse the medication and blood pressure control of patients with hypertension in Yuetan community. Methods During June 1, 2018 to January 31, 2019, totally 504 patients with hypertension from the community were investigated, by questionnaire to survey the medication, The blood pressure of patientswere checked by clinic measurement and their history and records were reviewed. Results Systolic blood pressure(SBP)＜140 mmHg and diastolic blood pressure(DBP)＜90 mmHg, were defined as standard blood pressures in this investigation. The survey showed that the clinic blood pressure compliance rate was 62.3%, the rate of regular medication was 96%, and the proportion of taking one kind of antihypertensive medicine and combining two kinds of antihypertensive medicine was the highest(40.3% and 39.1%, respectively). Among the patients taking three types of antihypertensive medicine, angiotensin-converting enzyme inhibitor(ACEI)/ angiotensin receptor blocker(ARB)(A)+beta blocker(B)+ calcium antagonist(CCB)(C), accounted for the highest proportion (54.8%). The second was the combination of A+C+diuretic(D)(29.0%). Among the two antihypertensive medicine combinations, A+C took the largest proportion(46.2%), followed by B+C(31.5%), while the combination of A+D was lower(9.6%). CCB accounted for the largest proportion (63.5%) in single medicine treatment, followed by ACEI/ARB(26.6%), and diuretic was the lowest (1.0%). Conclusions The proportion of diuretics prescription in hypertension medication in Yuetan community is relatively low, especially in the mono-therapy treatment and in group of patients with two antihypertensive medicines. It is suggested that clinicians should pay more attention to diuretics and its rational use, especially for hypertension patients with high salt intake. In such a situation, low to medium doses thiazide diuretics should be given with priority.

In this work, we have investigated the process Ds+→K+K−π+, taking into account the contributions from the S-wave pseudoscalar-pseudoscalar interaction within the chiral unitary approach, and also the intermediate ϕ resonance. By analyzing the BESIII and BABAR measurements, we conclude that the f0(980) state, dynamically generated from the S-wave pseudoscalar-pseudoscalar interaction, gives the dominant contribution close to the K+K− threshold in the K+K− invariant mass distribution of the decay Ds+→K+K−π+ in S-wave. On the other hand, our results imply that the lineshape adopted by BESIII and BABAR for the resonances a0(980) and f0(980) is not advisable in the fit to the data close to the K+K− threshold.

Hepatocellular carcinoma (HCC) is the third leading cause of cancer death globally, with hepatitis B virus (HBV) infection accounting for over half of all cases. HBV leads to the development of HCC according to a body of literature. Our previous research and other studies also suggest that HBV causes chemotherapeutic treatment resistance, however, the mechanism is uncertain. The WNT family, which encodes secreted signaling molecules, has been linked to carcinogenesis in a variety of malignancies, including HCC. However, little is known regarding WNT7B, a WNT ligand, in the development of HCC and HBV-induced chemoresistance. In this study, the bioinformatics analysis and immunohistochemistry (IHC) staining of clinical samples revealed that WNT7B was overexpressed in HBV-associated HCC tissues versus nontumor liver tissues, which was related to HCC patient survival. Further study in vitro showed that WNT7B and its receptor frizzled-4 (FZD4) were upregulated in response to large hepatitis B surface antigens (L-HBs). L-HBs increased canonical WNT signaling in HCC cells through WNT7B/FZD4. According to functional experiments, WNT7B enhanced the cell proliferation and metastasis in HCC. In vivo and in vitro studies investigated whether L-HBs induced sorafenib resistance by WNT7B in HCC. Interestingly, L-HBs suppressed sorafenib-induced mitophagy by increasing WNT7B/CTNNB1 signaling, resulting in chemoresistance. The findings revealed that WNT7B could be a promising molecular therapeutic target as well as a predictor of sorafenib resistance in HBV-related HCC. The suppression of HBV structural proteins such as L-HBs may play a crucial role in systemic chemotherapy resistance in HBV-associated HCC.

In the present study, we surveyed the ascomycetes from bamboo of Phyllostachys across Sichuan Province, China. A biphasic approach based on morphological characteristics and multigene phylogeny confirmed seven species, including one new genus, two new species, and five new host record species. A novel genus Paralloneottiosporina is introduced to accommodate Pa. sichuanensis that was collected from leaves of Phyllostachys violascens. Moreover, the newly introduced species Bifusisporella sichuanensis was isolated from leaves of P. edulis, and five species were newly recorded on bamboos, four species belonging to Apiospora, viz. Ap. yunnana, Ap. neosubglobosa, Ap. jiangxiensis, and Ap. hydei, and the last species, Seriascoma yunnanense, isolated from dead culms of P. heterocycla. Morphologically similar and phylogenetically related taxa were compared. Comprehensive descriptions, color photo plates of micromorphology are provided.

Deficiency of the DNA damage repair (DDR) signaling pathways is potentially responsible for genetic instability and oncogenesis in tumors, including colorectal cancer. However, the correlations of mutated DDR signaling pathways to the prognosis of colorectal cancer liver metastasis (CRLM) after resection and other clinical applications have not been fully investigated. Here, to test the potential correlation of mutated DDR pathways with survival and pre-operative chemotherapy responses, tumor tissues from 146 patients with CRLM were collected for next-generation sequencing with a 620-gene panel, including 68 genes in 7 DDR pathways, and clinical data were collected accordingly. The analyses revealed that 137 of 146 (93.8%) patients had at least one mutation in the DDR pathways. Mutations in BER, FA, HRR and MMR pathways were significantly correlated with worse overall survival than the wild-types (P < 0.05), and co-mutated DDR pathways showed even more significant correlations (P < 0.01). The number of mutated DDR pathways was also proved an independent stratifying factor of overall survival by Cox multivariable analysis with other clinical factors and biomarkers (hazard ratio = 9.14; 95% confidence interval, 1.21–68.9; P = 0.032). Additionally, mutated FA and MMR pathways were positively and negatively correlated with the response of oxaliplatin-based pre-operative chemotherapy (P = 0.0095 and 0.048, respectively). Mutated DDR signaling pathways can predict pre-operative chemotherapy response and post-operative survival in CRLM patients.

In epithelial cells Zeb1 is involved in the epithelial to mesenchymal transition. In this study, the authors show in a mouse model of breast cancer, that Zeb1 expression in stromal cells is required for tumour formation and metastasis.

Abstract Background The transforming growth factor β (TGFβ) and bone morphogenetic protein (BMP) signaling pathways are both constitutively activated in triple-negative breast cancer (TNBC). We are interested in isolating the naturally-derived small-molecule inhibitor that could simultaneously targeting TGFβ/BMP pathways and further studying its anti-proliferative/−metastatic effects as well as the underlying mechanisms in multiple tumor models. Methods Multiple in vitro cell-based assays are used to examine the compound’s inhibitory efficacy on TNBC cell growth, stemness, epithelial-mesenchymal transition (EMT), invasion and migration by targeting TGFβ/BMP signaling pathways. Transgenic breast cancer mouse model (MMTV-PyMT), subcutaneous xenograft and bone metastasis models are used to examine ZL170’s effects on TNBC growth and metastasis potentials in vivo. Results ZL170 dose-dependently inhibits cell proliferation, EMT, stemness, invasion and migration in vitro via specifically targeting canonical TGFβ/BMP-SMADs pathways in TNBC cells. The compound significantly hinders osteolytic bone metastasis and xenograft tumor growth without inflicting toxicity on vital organs of tumor-bearing nude mice. ZL170 strongly inhibits primary tumor growth and lung metastases in MMTV-PyMT transgenic mice. ZL170-treated tumors exhibit impaired TGFβ/BMP signaling pathways in both epithelial and stromal compartments, thereby creating a suppressive tumor microenvironment characterized by reduced extracellular matrix deposition and decreased infiltration of stromal cells. Conclusions ZL170 inhibits tumor EMT, stemness and metastasis and could be further developed as a potent anti-metastatic agent used in combination with cytotoxic drugs for treatment of TNBC and other advanced metastatic cancers.

Neostagonosporella sichuanensis sp. nov. was found on Phyllostachys heteroclada collected from Sichuan Province in China and is introduced in a new genus Neostagonosporella gen. nov. in this paper. Evidence for the placement of the new taxon in the family Phaeosphaeriaceae is supported by morphology and phylogenetic analysis of a combined LSU, SSU, ITS and TEF 1-α DNA sequence dataset. Maximum-likelihood, maximum-parsimony and Bayesian inference phylogenetic analyses support Neostagonosporella as a distinct genus within this family. The new genus is compared with related genera of Phaeosphaeriaceae and full descriptions and illustrations are provided. Neostagonosporella is characterised by its unique suite of characters, such as multiloculate ascostromata and cylindrical to fusiform, transversely multiseptate, straight or curved ascospores, which are widest at the central cells. Conidiostromata are multiloculate, fusiform to long fusiform or rhomboid, with two types conidia; macroconidia vermiform or subcylindrical to cylindrical, transversely multiseptate, sometimes curved, almost equidistant between septa and microconidia oval, ellipsoidal or long ellipsoidal, aseptate, rounded at both ends. An updated phylogeny of the Phaeosphaeriaceae based on multigene analysis is provided.

Background/Aims: Early repolarization syndrome (ERS) has been recently recognized as early repolarization pattern with idiopathic ventricular fibrillation. However, the genetic background of ERS has not been fully understood. Methods: A Chinese family with sudden cardiac death associated with ERS was investigated. Direct sequencing of ERS susceptibility genes was performed on the proband and family members. Whole-cell patch-clamp methods were used to characterize the mutant channel expressed in HEK 293 cells. Results: One missense mutation (p. K801T) was found in the hERG (KCNH2 gene) by the direct sequencing of candidate genes. Whole cell voltage clamp studies of the K801T mutation in HEK 293 cells demonstrated a 1.5-fold increase in maximum steady state current (37.2±7.3 vs 20.3±4.4 pA/pF) that occurred at a 20 mV more positive potential compared to the wild type channels. The voltage dependence of inactivation was significantly shifted in the positive voltage direction (WT -59.5±1.4 vs K801T -44.3±1.2 mV). Kinetic analysis revealed slower inactivation rates of K801T, but faster rates of activation and deactivation. The hERG channel blockers tested inhibited K801T-hERG channel in concentration response, and the potencies of these drugs can be rank-ordered as follows: quinidine> disopyramide> sotalol> flecainide. Conclusion: Our study indicated that the K801T mutation caused the gain of function of hERG channels that may account for the clinical phenotype of ERS. Quinidine and disopyramide could improve the function of K801T-hERG mutant channel, and may be therapeutic options for patients with the K801T hERG mutation.