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Abstract Background N4‐acetylcytidine (ac4C) represents a novel messenger RNA (mRNA) modification, and its associated acetyltransferase N‐acetyltransferase 10 (NAT10) plays a crucial role in the initiation and progression of tumors by regulating mRNA functionality. However, its role in hepatocellular carcinoma (HCC) development and prognosis is largely unknown. This study aimed to elucidate the role of NAT10‐mediated ac4C in HCC progression and provide a promising therapeutic approach. Methods The ac4C levels were evaluated by dot blot and ultra‐performance liquid chromatography‐tandem mass spectrometry with harvested HCC tissues. The expression of NAT10 was investigated using quantitative real‐time polymerase chain reaction, western blotting, and immunohistochemical staining across 91 cohorts of HCC patients. To explore the underlying mechanisms of NAT10‐ac4C in HCC, we employed a comprehensive approach integrating acetylated RNA immunoprecipitation and sequencing, RNA sequencing and ribosome profiling analyses, along with RNA immunoprecipitation, RNA pull‐down, mass spectrometry, and site‐specific mutation analyses. The drug affinity responsive targets stability, cellular thermal shift assay, and surface plasmon resonance assays were performed to assess the specific binding of NAT10 and Panobinostat. Furthermore, the efficacy of targeting NAT10‐ac4C for HCC treatment was elucidated through in vitro experiments using HCC cells and in vivo HCC mouse models. Results Our investigation revealed a significant increase in both the ac4C RNA level and NAT10 expression in HCC. Notably, elevated NAT10 expression was associated with poor outcomes in HCC patients. Functionally, silencing NAT10 suppressed HCC proliferation and metastasis in vitro and in vivo. Mechanistically, NAT10 stimulates the ac4C modification within the coding sequence (CDS) of high mobility group protein B2 (HMGB2), which subsequently enhances HMGB2 translation by facilitating eukaryotic elongation factor 2 (eEF2) binding to the ac4C sites on HMGB2 mRNA's CDS. Additionally, high‐throughput compound library screening revealed Panobinostat as a potent inhibitor of NAT10‐mediated ac4C modification. This inhibition significantly attenuated HCC growth and metastasis in both in vitro experiments using HCC cells and in vivo HCC mouse models. Conclusions Our study identified a novel oncogenic epi‐transcriptome axis involving NAT10‐ac4C/eEF2‐HMGB2, which plays a pivotal role in regulating HCC growth and metastasis. The drug Panobinostat validates the therapeutic potential of targeting this axis for HCC treatment.

BackgroundPCSK9 inhibitors are a novel class of lipid-lowering medications, and numerous clinical studies have confirmed their significant role in improving the progression of chronic kidney disease. However, recent case reports have indicated new evidence regarding their association with acute kidney injury (AKI), with some patients experiencing acute tubular injury after PCSK9 inhibitors use.ObjectivesTo clarify the relationship between PCSK9 inhibitors and AKI, we conducted a pharmacovigilance study.MethodsUsing the Food and Drug Administration Adverse Event Reporting System (FAERS) database from the third quarter of 2015 to the fourth quarter of 2022, a disproportionality analysis was employed to identify adverse events suggestive of AKI after PCSK9 inhibitors use. The drugs of interest included evolocumab and alirocumab.ResultsA total of 144,341 adverse event reports related to PCSK9 inhibitors were analyzed, among which 444 cases were suspected of AKI for evolocumab, and 172 cases for alirocumab. Evolocumab had a greater impact on AKI in males (ROR 1.4, 95% CI 1.54–1.69). The ROR and 95% CI for evolocumab and Alirocumab were 0.13 (0.12–0.14) and 0.26 (0.23–0.30) respectively. Further analysis of AKI associated with the concomitant use of PCSK9 inhibitors with cephalosporins, furosemide, torsemide, pantoprazole, omeprazole, and esomeprazole revealed ROR and 95% CI of 0.38 (0.23–0.62), 0.38 (0.31–0.48), 0.18 (0.08–0.38), 0.23 (0.17–0.29), 0.20 (0.16–0.26), and 0.14 (0.10–0.20) respectively.ConclusionThrough the FAERS database, we analyzed the clinical characteristics of AKI associated with PCSK9 inhibitors, exploring its risks. Our findings suggest that PCSK9 inhibitors might have a potential protective effect against AKI and exhibit similar effects when co-administered with other nephrotoxic drugs.

Pelvic masses frequently originate from the pelvic cavity and are often associated with uterine, ovarian, or intestinal disorders. This report describes the case of a patient with a pelvic mass diagnosed as a retroperitoneal dermoid cyst at our hospital. We analyzed this case and conducted a literature review, to mitigate the risk of misdiagnosis and enhance the treatment of retroperitoneal masses.

Abstract This study presents the first-ever synthesis of samarium-doped indium vanadate nanosheets (IVONSs:Sm) via microemulsion-mediated solvothermal method. The nanosheets were subsequently utilized as a nano-matrix in laser desorption/ionization mass spectrometry (LDI-MS). It was discovered that the as-synthesized IVONSs:Sm possessed the following advantages: improved mass spectrometry signal, minimal matrix-related background, and exceptional stability in negative-ion mode. These qualities overcame the limitations of conventional matrices and enabled the sensitive detection of small biomolecules such as fatty acids. The negative-ion LDI mechanism of IVONSs:Sm was examined through the implementation of density functional theory simulation. Using IVONSs:Sm-assisted LDI-MS, fingerprint recognitions based on morphology and chemical profiles of endogenous/exogenous compounds were also achieved. Notably, crucial characteristics such as the age of an individual’s fingerprints and their physical state could be assessed through the longitudinal monitoring of particular biomolecules (e.g., ascorbic acid, fatty acid) or the specific biomarker bilirubin glucuronide. Critical information pertinent to the identification of an individual would thus be facilitated by the analysis of the compounds underlying the fingerprint patterns. Graphical Abstract

As China shifts from urbanization to rural revitalization within its rural governance strategy, devising appropriate governance programs becomes crucial for the effective implementation of overarching strategies. This paper explores the policy pathway of the rural revitalization strategy via the lens of village relational governance. This paper builds a relational network of village governance using the Newtonian gravity model and proposes an effective relational governance policy by analyzing the impact of village cluster patterns under different policy rules. Empirical research was conducted in Guiyang County, Hunan Province, China. The findings of this paper are as follows. (1) Rural development in Guiyang County heavily relies on location advantages and natural resources, and there is an urgent need to reinvent the path of rural governance to foster potential rural clusters. (2) A comparative analysis of the relational networks shows that the assignment-based network has more high-clustering groups and fewer low-clustering clusters than the merit-based network, and it has more cluster types, resulting in a more balanced and diverse network structure. In contrast, the merit-based network has fewer cluster types and tends to have a centralized structure. (3) The assignment-type network has greater advantages in terms of agricultural productivity, preserving local culture, and protecting the environment. Simultaneously, its network path has the potential to boost the intrinsic vitality of rural areas and attract more groups to contribute to its development. This path is feasible due to the high level of organization within the Chinese villages. Consequently, this study recommends that the county government should actively decentralize power to villages and grant villages equal development rights to encourage villages to build network clusters with unique competitive advantages.

ObjectiveTo analyze the clinical characteristics and correlation of Fournier’s gangrene induced by sodium-glucose cotransporter protein-2 (SGLT-2) inhibitors, providing references for safe clinical drug use.MethodsThe CNKI, WanFang, and PubMed databases were searched, and relevant documents were collected and statistically analyzed. The basic information of patients, drug use information, adverse reactions and outcomes were extracted and analyzed.ResultsA total of 12 patients (8 males and 4 females) were included, with an average age of 55.6 years (ranging from 34 to 72 years). SGLT-2 inhibitors associated with Fournier’s gangrene include empagliflozin (5 cases), dapagliflozin (5 cases), and canagliflozin (2 cases). Among them, 10 cases reported the time of first medication, ranging from 1 month to 6 years for the occurrence of adverse reactions. The most common concomitant drug was metformin (7 cases). Adverse reactions mainly manifested as redness, swelling and pain in the buttocks, perineum, perianal, scrotum and other positions, accompanied by an increased white blood cell count. Following surgery and antibiotic treatment, all patients showed improved.ConclusionFournier’s gangrene induced by SGLT-2 inhibitors is rare. If patients using SGLT-2 inhibitors are suspected of having Fournier’s gangrene, it is recommended to discontinue the drugs immediately and initiate active treatment to ensure clinical safety.

AbstractBackground T-cell large granular lymphocyte leukaemia (T-LGLL) generally has a favourable prognosis, but a small proportion of patients are facing a relatively short survival time. This study aimed to identify clinical factors associated with survival in patients with T-LGLL and develop a predictive model for guiding therapeutic decision-making.Materials and Methods We conducted a retrospective study on 120 patients with T-LGLL. Lasso regression was performed for feature selection followed by univariate and multivariate Cox regression analysis. A decision tree algorithm was employed to construct a model for predicting overall survival (OS) in T-LGLL.Results The median age of diagnosis for the entire cohort was 59 years, and 76.7% of patients reported disease-related symptoms. After a median follow-up of 75 months, the median OS was not reached. The 5-year OS rate was 82.2% and the 10-year OS rate was 63.8%. Multivariate analysis revealed that an Eastern Cooperative Oncology Group performance status over two and a platelet count below 100 × 109/L were independently associated with worse OS, leading to the development of a simplified decision tree model. The model’s performance was adequate when internally validated. The median OS of the high- and intermediate-risk- risk groups was 43 and 100 months respectively, whereas the median OS of the low-risk group was not reached. Furthermore, we found that immunosuppressive agent-based conventional treatment was unsatisfactory for our high-risk patients.Conclusions Our model is an easily applicable clinical scoring system for predicting OS in patients with T-LGLL. However, external validation is essential before implementing it widely.

ABSTRACTObjectives Primary mediastinal large B-cel l lymphoma (PMBCL) is a rare subtype of B-cell lymphoma that is not yet fully understood. This population-based study aimed to assess the latest survival and treatment strategies for patients with PMBCL.Methods The study used the dataset from the Surveillance, Epidemiology, and End Results Program registry to retrospectively analyze adult patients diagnosed with PMBCL between 2001 and 2018. The primary outcome measures included overall survival (OS) and disease-specific survival (DSS).Results Among the 814 identified cases, the study revealed a 5-year OS rate of 86.7% and a 5-year DSS rate of 88.2% after a median follow-up of 54 months. Cox regression analysis indicated that age over 60 years, pre-2010 diagnosis, non-White ethnicity, advanced stage, and absence of chemotherapy significantly reduced both OS and DSS. It also found that chemotherapy has remained the primary therapeutic protocol for PMBCL over the last 20 years, whereas the utilization of surgery and radiation declined significantly. Patients diagnosed with PMBCL between 2010 and 2018 had a significantly reduced mortality risk (∼50%) compared to those diagnosed between 2001 and 2009. Notably, in the era of rituximab’s widespread usage, recipients of radiotherapy exhibited a poorer OS rate than non-recipients.Conclusion Survival outcomes for patients with PMBCL have significantly improved in the current era, possibly due to the evolving treatment paradigm. The value of radiotherapy in PMBCL is still debated and requires further prospective evaluation.

The term “sea effect” generally refers to the process of air mass modification after cold air flows above a warm sea surface. Affected by the sea effect, small-scale and sudden fogs have occasionally been observed on the western coast of the Bohai Sea. A more in-depth study of this type of fog is crucial for ensuring the safety of maritime and aerial traffic routes in this region. This study investigated the formation mechanism of this specific type of fog on the morning of 17 October 2007, utilizing both meteorological stations and 255 m tower observations, combined with the results of the Weather Research and Forecasting model (WRF). It is demonstrated that Bohai Sea evaporation and the associated water vapor advection played crucial roles in the formation of fog along the west coast of the Bohai Sea. The cold return flow became more moist as it passed over the warm Bohai Sea, which was the primary contributor to triggering regional fog on the western coast. A moisture budget analysis revealed that water vapor from the Bohai Sea intruded into its western coast along an eastward trajectory, dominating the oscillations in the net moisture flux. The eastern water vapor flux significantly increased at 17:00 on the 16th (Local time, LST), reaching its peak at 21:00. Correspondingly, the fog water growth rate began to increase at 23:00 on the 16th, reaching its maximum at 03:00 on the 17th. A sensitivity experiment on evaporation further indicated that the Bohai sea effect played a decisive role in fog formation. With a tenfold reduction in evaporation from the Bohai Sea and subsequent significant weakening of water vapor advection, the simulated fog along the western coast of the Bohai Sea completely disappeared. Understanding the formation mechanism of this type of fog is beneficial for refining forecasting focal points, thereby enhancing forecast accuracy in a targeted manner.

Neoadjuvant chemoradiotherapy (nCRT) has become the standard treatment for patients with locally advanced rectal cancer (LARC). However, 20–40% of patients with LARC show little to no response to nCRT. Thus, comprehensively understanding the tumor microenvironment (TME), which might influence therapeutic efficacy, and identifying robust predictive biomarkers is urgently needed. Pre-treatment tumor biopsy specimens from patients with LARC were evaluated in detail through digital spatial profiling (DSP), public RNA sequencing datasets, and multiplex immunofluorescence (mIF). DSP analysis revealed distinct characteristics of the tumor stroma compared to the normal stroma and tumor compartments. We identified high levels of human leukocyte antigen-DR/major histocompatibility complex class II (HLA-DR/MHC-II) in the tumor compartment and B cells in the stroma as potential spatial predictors of nCRT efficacy in the Discovery cohort. Public datasets validated their predictive capacity for clinical outcomes. Using mIF in an independent nCRT cohort and/or the total cohort, we validated that a high density of HLA-DR/MHC-II+ cells in the tumor and CD20 + B cells in the stroma was associated with nCRT efficacy (all p ≤ 0.021). Spatial profiling successfully characterized the LARC TME and identified robust biomarkers with the potential to accurately predict nCRT response. These findings have important implications for individualized therapy.

Abstract The Mesozoic subduction history of the Paleo‐Pacific plate below the East Asian margin remains contentious, in part because the southern part is poorly understood. To address this, we conducted a sediment provenance study to constrain Mesozoic subduction history below West Sarawak, Borneo. A combination of detrital zircon U‐Pb geochronology, heavy minerals, trace element, and bulk rock Nd isotope data were used to identify the tectonic events. The overall maturity of mineral assemblages, dominantly felsic sources, abundant Precambrian‐aged zircons, and low εNd(0) values (average −13.07) seen in Late Triassic sedimentary rocks suggest a period of inactive subduction near Borneo. Slab shallowing subduction occurred between 200 and 170 Ma based on subdued magmatism and tectonic compression across West Sarawak. From c. 170 to 70 Ma there was widespread magmatism and we interpret the Paleo‐Pacific slab steepened. Collectively, we show the Paleo‐Pacific plate subduction had variable slab dip histories in Borneo.

Abstract A man diagnosed as TAFRO syndrome was successfully responded to a novel immunosuppressive regimen containing methylprednisolone and mycophenolate mofetil. Blood cells firstly recovered, followed by the general situation and complete recover 1 month later, highlighting the danger of TAFRO syndrome and the importance of immunosuppressive agents in reversing pathological course.

Although classic Hodgkin lymphoma (cHL) is highly curable with current treatment paradigms, therapy fails in 10-25% of patients. This prospective multicenter phase II study attempted to investigate the efficacy and safety of the combination of tislelizumab with gemcitabine and oxaliplatin (T-GemOx) in relapsed or refractory cHL. Participants received six to eight courses of gemcitabine (1 g/m2 on day 1) and oxaliplatin (100 mg/m2 on day 1) combined with tislelizumab (200 mg on day 2) at 21-day intervals, followed by tislelizumab maintenance (every 2 months for 2 years). The main outcome measure was the best complete remission rate. As of August 2022, a total of 30 patients had been consecutively enrolled and given induction therapy. The best overall response rate and complete remission rate were 100% (95% confidence interval [CI]: 88.4-100%) and 96.7% (95% CI: 82.8-99.9%), respectively. The median duration of follow-up after initiation of T-GemOx was 15.8 months. The 12-month progression-free survival rate without autologous stem cell transplant was 96% (95% CI: 74.8-99.4%). There were 122 adverse events recorded, of which 93.4% were grade 1 or 2. Thrombocytopenia (10%) and anemia (6.7%) were the most common grade 3 or 4 adverse events. Overall, T-GemOx demonstrated promising antitumor activity with manageable toxicities as a salvage treatment for relapsed or refractory cHL. A longer follow-up duration is required to determine whether maintenance therapy with tislelizumab rather than transplantation can be curative following such a highly active regimen. This trial was registered with the Chinese Clinical Trials Registry (http://www.chictr.org.cn) on June 1, 2020, identifier ChiCTR2000033441.

Abstract The aim of this meta‐analysis was to review systematically and to identify the relationship between the severity and location of white matter hyperintensities (WMHs) and the degree of cognitive decline in patients with Parkinson’s disease (PD). We searched the PubMed, EMBASE, Web of Science, Ovid, and Cochrane Library databases for clinical trials of the severity and location of WMHs on the degree of cognitive impairment in PD through October 2020. We conducted the survey to compare the association of WMH burden in patients with PD with mild cognitive impairment (PD‐MCI) versus those with normal cognition (PD‐NC) and in patients with PD with dementia (PDD) versus those with PD without dementia (PD‐ND). Nine studies with PD‐MCI versus PD‐NC and 10 studies with PDD versus PD‐ND comparisons were included. The WMH burden in PD‐MCI patients was significantly different compared to that in PD‐NC patients (standard mean difference, SMD = 0.39, 95% CI: 0.12 to 0.66, p = 0.005), while there was no correlation shown in the age‐matched subgroup of the comparison. In addition, PDD patients had a significantly higher burden of WMHs (SMD = 0.8, 95% CI: 0.44 to 1.71, p

Summary: Background: Quantitative electroencephalography (QEEG) is a reliable and non-invasive diagnostic tool to quantify cortical synaptic injury or loss in the clinical assessment of neurodegenerative diseases, and may be able to differentiate various types of dementia. We investigated if QEEG indices can differentiate Parkinson's Disease (PD) with nondementia (PD-ND) from PD with dementia (PDD), and to determine if QEEG indices correlate with inflammation and lipid metabolism markers in PD. Methods: This clinical study collected data between July 1, 2018 and July 1, 2021 in Zhujiang Hospital of Southern Medical University in China and data was analysed. A total of 125 individuals comprising of 31 PDD, 47 patients with PD-ND and 47 healthy controls were included. We calculated the absolute spectral power (ASP) of frequency bands and the slow-to-fast frequency ratios of specific brain regions. Plasma levels of hypersensitive C-reactive protein (Hs-CRP), superoxide dismutase (SOD), and high-density lipoprotein cholesterol (HDL-C) were measured and correlations with QEEG indices were examined. Findings: A significantly higher ASP of delta frequency especially in the frontal region was observed in patients with PDD compared to PD-ND (P=0.004) and controls (P=0.000). Decreased HDL-C (OR=0.186, P=0.030), and increased Hs-CRP (OR =2.856, P=0.015) were associated with PDD. Frontal-delta ASP was negatively correlated with plasma HDL-C (r=−0.353, P=0.000) and SOD (r=−0.322, P=0.001), and positively correlated with Hs-CRP (r=0.342, P=0.000). Interpretation: We highlight novel correlations between QEEG indices and inflammation and lipid metabolism markers in PD-ND and PDD. QEEG indices, HDL-C and Hs-CRP are potentially useful for the evaluation of PDD. Our current findings suggest that peripheral inflammation might contribute to the pathogenesis of cognitive impairment and EEG slowing in PDD. The mechanism underlying frontal-delta ASP and its correlation with neuro-inflammatory and metabolic markers in PDD should be further investigated. Funding: The National Natural Science Foundation of China (NO: 81873777, 82071414); the Scientific Research Foundation of Guangzhou (NO: 202206010005); the Science and Technology Program of Guangdong of China (NO: 2020A0505100037); the High-level Hospital Construction Research Project of Maoming People's Hospital (NO: xz2020009); the Science and Technology Program of Maoming City (NO: 2021S0026). Dr EK Tan is supported by the National Medical Research Council, Singapore.

Abstract Following standard neoadjuvant chemoradiotherapy and total mesorectal excision, some patients with locally advanced rectal cancer achieve good response (pathological T0–2N0), while others show nonresponse (pathological T3–4N0 or node‐positive). To date, the clinicopathological predictors of good response and the necessity of adjuvant chemotherapy treatment (ACT) in good responders remain unclear. In this retrospective study, clinicopathological characteristics were surveyed to investigate the correlation with good response; furthermore, a propensity score matching (PSM) model was designed to balance the confounding factors between good responders treated with ACT or observation. A total of 2255 patients were enrolled, including 1069 good responders and 1186 nonresponders. The results of the survival analysis showed a good response predicted a better 3‐year prognosis (p 0.05). In conclusion, more cycles of nCT and a delay in surgery predicted a better response, and the delivery of ACT might be omitted in good responders.

BackgroundOne of the most common nasal external sites in extranodal Natural Killer/T-cell lymphoma (NKTCL) is in the gastrointestinal (GI) system. Despite this, reports on gastrointestinal-Natural Killer/T-cell lymphoma (GI-NKTCL) are very few. To obtain a better understanding of this manifestation of NKTCL, we conducted a retrospective study on GI-NKTCL to analyze its clinical features, genomic changes and immune infiltration.MethodsWe retrospectively collected patients diagnosed with GI-NKTCL in the Sixth Affiliated Hospital of Sun Yat-sen University from 2010 to 2020. From this cohort we obtained mutation data via whole exome sequencing.ResultsGenomic analysis from 15 patients with GI-NKTCL showed that the most common driving mutations were ARID1B(14%, 2/15), ERBB3(14%, 2/15), POT1(14%, 2/15), and TP53(14%, 2/15). In addition, we found the most common gene mutation in patients with GI-NKTCL to be RETSAT(29%, 4/15) and SNRNP70(21%, 3/15), and the most common hallmark pathway mutations to be G2M checkpoint pathway (10/15, 66.7%), E2F targets (8/15, 53.3%), estrogen response late (7/15, 46.7%), estrogen response early (7/15, 46.7%), apoptosis (7/15, 46.7%) and TNFA signaling via NFKB (7/15, 46.7%). In the ICIs-Miao cohort, SNRNP7-wild-type (WT) melanoma patients had significantly prolonged overall survival (OS) time compared with SNRNP7 mutant type (MT) melanoma patients. In the TCGA-UCEC cohort, the patients with RETSAT-MT or SNRNP7-MT had significantly increased expression of immune checkpoint molecules and upregulation of inflammatory immune cells.ConclusionsIn this study, we explored GI-NKTCL by means of genomic analysis, and identified the most common mutant genes (RETSAT and SNRNP70), pathway mutations (G2M checkpoint and E2F targets) in GI-NKTCL patients. Also, we explored the association between the common mutant genes and immune infiltration. Our aim is that our exploration of these genomic changes will aid in the discovery of new biomarkers and therapeutic targets for those with GI-NKTCL, and finally provide a theoretical basis for improving the treatment and prognosis of patients with GI-NKTCL.

Chimeric antigen receptor T cell (CAR-T) therapy has emerged as highly effective in relapsed/refractory (R/R) diffuse large B-cell lymphoma (DLBCL), but only about 40% patients have achieved sustained responses. Here, we conducted a phase II clinical trial testing efficacy and toxicities of CAR-T therapy in R/R non-Hodgkin’s lymphoma patients (NCT03196830). Among enrolled patients, 33 R/R DLBCL patients pretreated with DFC (decitabine, fludarabine plus cyclophosphamide) lymphodepletion chemotherapy and infused with tandem CD19-CD22 based CAR-T cells were drawn out for efficacy and toxicities of CAR-T therapy evaluation. With a median follow-up of 10.9(0.6-29.0) months, the best overall response and complete remission (CR) rates were 90.9% and 63.6%, respectively. The median progression-free survival (PFS) was 10.2 months and overall survival (OS) was undefined. The 2-year OS and PFS rates were 54.3% and 47.2%, respectively. No severe grade 4 cytokine release syndrome (CRS) was observed and grade 3 CRS was observed in only 7 patients; 3 patients developed mild immune effect or cell-associated neurotoxic syndrome. All toxicities were transient and reversible and no CAR-T-related mortality. Further subgroup analysis showed that achieving CR was an independent prognostic factor associated with favorable PFS and OS. The 2-year OS and PFS for patients who achieved CR within 3 months (undefined versus undefined P=0.021 and undefined versus undefined P=0.036) or during the follow-up period were significantly longer than those who did not (undefined versus 4.6 months P < 0.0001 and undefined versus 2.0months P

ObjectiveThis study aimed to develop an artificial intelligence model for predicting the pathological complete response (pCR) to neoadjuvant chemoradiotherapy (nCRT) of locally advanced rectal cancer (LARC) using digital pathological images.BackgroundnCRT followed by total mesorectal excision (TME) is a standard treatment strategy for patients with LARC. Predicting the PCR to nCRT of LARC remine difficulty.Methods842 LARC patients treated with standard nCRT from three medical centers were retrospectively recruited and subgrouped into the training, testing and external validation sets. Treatment response was classified as pCR and non-pCR based on the pathological diagnosis after surgery as the ground truth. The hematoxylin & eosin (H&E)-stained biopsy slides were manually annotated and used to develop a deep pathological complete response (DeepPCR) prediction model by deep learning.ResultsThe proposed DeepPCR model achieved an AUC-ROC of 0.710 (95% CI: 0.595, 0.808) in the testing cohort. Similarly, in the external validation cohort, the DeepPCR model achieved an AUC-ROC of 0.723 (95% CI: 0.591, 0.844). The sensitivity and specificity of the DeepPCR model were 72.6% and 46.9% in the testing set and 72.5% and 62.7% in the external validation cohort, respectively. Multivariate logistic regression analysis showed that the DeepPCR model was an independent predictive factor of nCRT (P=0.008 and P=0.004 for the testing set and external validation set, respectively).ConclusionsThe DeepPCR model showed high accuracy in predicting pCR and served as an independent predictive factor for pCR. The model can be used to assist in clinical treatment decision making before surgery.

BackgroundIn the era of immunotherapy, autologous stem cell transplantation (ASCT) in first-line therapy in patients with mantle cell lymphoma (MCL) has been a controversial topic. This report aimed to explore the association between ASCT and MCL survival through a systematic review with meta-analysis.MethodsWe performed a systematic search of original articles published from inception to September 2021 using PubMed, MEDLINE, Embase, and Cochrane Library databases.ResultsWe included studies that compared ASCT with non-ASCT consolidation in newly diagnosed transplant-eligible MCL. The endpoints were progression-free survival (PFS) and overall survival (OS). There were seven eligible studies (one randomized clinical trial, one prospective cohort study, and five observational studies) published between 2012 and 2021, in which the total number of participants was 3,271. In the non-intensive induction subgroup, patients with ASCT experienced a significant PFS but no OS benefit compared with those without ASCT. In the intensive induction subgroup, the PFS benefit from ASCT still existed but largely attenuated; no OS benefit was observed though only one study was suitable for evaluation. When compared to the rituximab maintenance arm, ASCT had a worse PFS and OS.ConclusionsIn the rituximab plus HiDAC era, the benefit of ASCT as a component of first-line treatment has been weakened. First-line maintenance strategy instead of ASCT seems worth exploring.

The strike-slip fault system in the southwestern margin of South China Sea (SCS) lies on the transition zone between the continental shelf and slope of SCS, which is an important ocean–continent boundary. By using submarine heat flow data, a seismic shear wave tomography model, and gravity potential field data, this paper investigates the distribution of submarine heat flow in the southwestern margin of SCS, the thermal–rheological structure of the crust and mantle, the temperature–viscosity characteristics of the upper mantle Vs low-velocity layer, the tangential stress field of the rheological boundary layer at the lithosphere base, and the convective velocity structure of the mantle asthenosphere. Our new results show that the deep geothermal activity in the southwestern margin of SCS is intense, and the high heat flow area of the mantle with Qm/Qs >70% is distributed along an NNE-trending strip. Moreover, both the east and west sides of the strike–slip fault zone correspond to two low-value areas with a viscosity coefficient of 1021–1022 Pa⋅s at Moho depth, and beneath the Nansha Block are strong and cold blocks with a viscosity coefficient of 1024–1025 Pa⋅s. The northward and eastward shear stress components τN and τE of the rheological boundary layer at the base of the lithosphere mantle decrease with depth. At 65-km depth, both τN and τE are greater than 5.5 × 108 N/m2. At 100-km depth, both τN and τE are less than 1 × 108 N/m2. The calculation results based on the seismic shear wave model of the upper mantle and the gravimetric geoid model indicate that the depth of 120–250 km is the low-velocity layer, and the average temperature of the mantle at 180-km depth can be up to 1,300°C. Moreover, the average effective viscosity coefficient is close to 1018 Pa⋅s, which satisfies the temperature and viscosity conditions for partial melting or convective migration of mantle material. The mantle convection calculation results show that the average flow rate is 8.5 cm/a at 200-km depth and 2.2 cm/a at 400-km depth.

Air pollution caused by particulate matter has significantly improved in China in recent years since the implementation of a series of stringent clean-air regulations. However, surface ozone concentrations have increased, especially in developed city clusters, such as the Beijing–Tianjin–Hebei, Yangtze River Delta, Pearl River Delta, and Sichuan Basin regions. Due to the complexity and nonlinearity of the ozone formation, accurately locating major sources of ozone and its precursors is an important basis for the formulation of cost-effective pollution control strategies. In this paper, the authors systematically summarize the reported results and outcomes of the methods and main conclusions of ozone source apportionment (regions and categories) in China from the published literature, based on observation-based methods and emission-based methods, respectively. The authors aim to provide a comprehensive understanding of ozone pollution and reliable references for the formulation of air pollution prevention policies in China.

Abstract Background Hepatocellular carcinoma is the third top cause of cancer-related mortalities worldwide. The prognosis of HCC patients remains poor due to rapid progression and high incidence of tumor recurrence. Nicastrin (NCSTN), a core subunit of γ-Secretase, has been reported to play a vital role in tumor progression. However, no study till now has revealed its role in HCC. Methods The expression of NCSTN was evaluated by immunohistochemical staining, Western blot, and quantitative real-time PCR. Cell counting kit-8, colony formation and cell cycle assays were used for evaluating cell growth in vitro. Transwell and wound-healing assays were used for evaluating cell migration and invasion capacity. Immunofluorescence, subcellular protein fractionation and co-immunoprecipitation were used for location analysis of β-catenin. The in vivo functions of NCSTN were illustrated by xenograft tumor models. Results NCSTN was dramatically overexpressed in HCC compared to normal liver tissues. Elevated NCSTN expression level was significantly correlated to worse overall and recurrence-free survival of HCC patients. Enhanced NCSTN expression promoted HCC cell growth, migration and invasion in vitro and in vivo. Mechanistic investigations showed that NCSTN induced epithelial-mesenchymal transition (EMT) process via upregulation of Zeb1. Subsequently, we revealed that NCSTN facilitated nuclear translocation of β-catenin, a positive transcriptional regulator of Zeb1. Using Notch and AKT inhibitors, we revealed that NCSTN promoted β-catenin activation through Notch1 and AKT signaling pathway. NCSTN increased AKT and GSK-3β phosphorylation by cleavage of Notch1, which decreased GSK-3β/β-catenin complex. The inactivation of GSK-3β inhibited the β-catenin degradation and promoted nuclear translocation of β-catenin to initiate transcription of Zeb1, resulting in malignant phenotype. Conclusions Our results demonstrated that NCSTN promoted HCC cell growth and metastasis via β-catenin-mediated upregulation of Zeb1 in a Notch1/AKT dependent manner, suggesting that NCSTN might serve as a potential prognostic marker and therapeutic target for HCC.

BRAF is a serine/threonine kinase that harbors activating mutations in ∼7% of human malignancies and ∼60% of melanomas. Despite initial clinical responses to BRAF inhibitors, patients frequently develop drug resistance. To identify candidate therapeutic targets for BRAF inhibitor resistant melanoma, we conduct CRISPR screens in melanoma cells harboring an activating BRAF mutation that had also acquired resistance to BRAF inhibitors. To investigate the mechanisms and pathways enabling resistance to BRAF inhibitors in melanomas, we integrate expression, ATAC-seq, and CRISPR screen data. We identify the JUN family transcription factors and the ETS family transcription factor ETV5 as key regulators of CDK6, which together enable resistance to BRAF inhibitors in melanoma cells. Our findings reveal genes contributing to resistance to a selective BRAF inhibitor PLX4720, providing new insights into gene regulation in BRAF inhibitor resistant melanoma cells.

Objective: The purpose of this study was to evaluate the efficiency and safety of different treatment modalities for heterotopic pregnancy (HP) in vitro fertilization-embryo transfer (IVF-ET) cycles to avoid influence on intrauterine pregnancy (IUP). Materials and methods: Cases of HP (n = 90) were from the IVF/ICSI registry database at the Reproductive Hospital Affiliated to Shandong University. An additional 360 women were randomly selected as controls. The primary outcome to examine the risk factors, diagnostic modalities and the impact of different treatment modalities for HP. Results: Our results showed that surgical treatment had a certain effect on improving the live-birth rate, although the effect was not statistically significant (87.9% vs. 70.8%, P = 0.055). The risk factors for HP included previous tubal surgery and hydrosalpinx. Fourteen days after embryo transfer, the serum levels of β-human chorionic gonadotropin (β-hCG) and estradiol (E2) were lower in the HP group than in the IUP group (P

Objective: The objective of the study was to evaluate the effects of recurrent hydrosalpinx after proximal tubal ligation and distal salpingostomy on the outcomes of in vitro fertilization (IVF) or intracytoplasmic sperm injection (ICSI) treatment. Materials and Methods: Seven hundred and twenty-six patients with hydrosalpinx undergoing laparoscopic surgery before IVF were enrolled in the study. Five hundred and sixty-two patients treated with proximal tubal ligation and distal salpingostomy were included in Group A. One hundred and sixty-four cases managed with salpingectomy were grouped into Group B. Group A were further divided into two subgroups. One hundred and forty-six patients in Group A1 had a recurrence of hydrosalpinx. Four hundred and sixteen patients in Group A2 had no repetition of hydrosalpinx. We compared the pregnancy outcomes of their subsequent fresh embryo transfer cycles among the three groups. Results: There were no significant differences among the three groups in terms of age, body mass index (23.56 ± 3.27 vs. 23.13 ± 3.42 vs. 23.63 ± 3.73, P = 0.195), basal hormone level (7.03 ± 1.75 vs. 7.08 ± 2.26 vs. 7.44 ± 2.93, P = 0.195), antral follicle count (12.25 ± 5.92 vs. 12.63 ± 5.71 vs. 11.70 ± 4.98, P = 0.188), duration of gonadotropin (Gn) (11.19 ± 2.1 vs. 10.93 ± 1.84 vs. 10.79 ± 2.03, P = 0.182), consumption of Gn (2136.73 ± 855.65 vs. 1997.15 ± 724.72 vs. 2069.05±765.12 , P = 0.14), endometrial thickness (1.1 ± 0.27 vs. 1.1 ± 0.24 vs. 1.1 ± 0.17, P = 0.352), base follicle-stimulating hormone (6.21 ± 3.43 vs. 6.52 ± 3.20 vs. 5.89 ± 3.10, P = 0.1), number of embryos transferred (1.87 ± 0.36 vs. 1.83 ± 0.42 vs. 1.88 ± 0.37, P = 0.224), and number of high-grade embryos (3.77 ± 2.42 vs. 4.01 ± 2.72 vs. 4.17 ± 2.74, P = 0.41). No differences were detected in clinical pregnancy rate (50% vs. 54.8% vs. 50%, P = 0.439), the live birth rate (86.3% vs. 82.0% vs. 87.8%, P = 0.398), fertilization rate (64.1% vs. 64.4% vs. 64.7%, P = 0.928), and biochemical pregnancy rate (4% vs. 4.5% vs. 7%, P = 0.332) among the three groups. Conclusion: The recurrence of hydrosalpinx after tubal ligation does not affect the outcomes of IVF/ICSI. It is not necessary to worry about the effect of recurrent hydrosalpinx on pregnancy outcomes of IVF/ICSI that may due to the spread of inflammation through lymphatic circulation or blood circulation.

Objective. To develop an artificial intelligence method predicting lymph node metastasis (LNM) for patients with colorectal cancer (CRC). Impact Statement. A novel interpretable multimodal AI-based method to predict LNM for CRC patients by integrating information of pathological images and serum tumor-specific biomarkers. Introduction. Preoperative diagnosis of LNM is essential in treatment planning for CRC patients. Existing radiology imaging and genomic tests approaches are either unreliable or too costly. Methods. A total of 1338 patients were recruited, where 1128 patients from one centre were included as the discovery cohort and 210 patients from other two centres were involved as the external validation cohort. We developed a Multimodal Multiple Instance Learning (MMIL) model to learn latent features from pathological images and then jointly integrated the clinical biomarker features for predicting LNM status. The heatmaps of the obtained MMIL model were generated for model interpretation. Results. The MMIL model outperformed preoperative radiology-imaging diagnosis and yielded high area under the curve (AUCs) of 0.926, 0.878, 0.809, and 0.857 for patients with stage T1, T2, T3, and T4 CRC, on the discovery cohort. On the external cohort, it obtained AUCs of 0.855, 0.832, 0.691, and 0.792, respectively (T1-T4), which indicates its prediction accuracy and potential adaptability among multiple centres. Conclusion. The MMIL model showed the potential in the early diagnosis of LNM by referring to pathological images and tumor-specific biomarkers, which is easily accessed in different institutes. We revealed the histomorphologic features determining the LNM prediction indicating the model ability to learn informative latent features.

Abstract Background N6-methyladenosine (m6A) modification, the most abundant internal methylation of eukaryotic RNA transcripts, is critically implicated in RNA processing. As the largest known component in the m6A methyltransferase complex, KIAA1429 plays a vital role in m6A methylation. However, its function and mechanism in hepatocellular carcinoma (HCC) remain poorly defined. Methods Quantitative PCR, western blot and immunohistochemistry were used to measure the expression of KIAA1429 in HCC. The effects of KIAA1429 on the malignant phenotypes of hepatoma cells were examined in vitro and in vivo. MeRIP-seq, RIP-seq and RNA-seq were performed to identify the target genes of KIAA1429. Results KIAA1429 was considerably upregulated in HCC tissues. High expression of KIAA1429 was associated with poor prognosis among HCC patients. Silencing KIAA1429 suppressed cell proliferation and metastasis in vitro and in vivo. GATA3 was identified as the direct downstream target of KIAA1429-mediated m6A modification. KIAA1429 induced m6A methylation on the 3′ UTR of GATA3 pre-mRNA, leading to the separation of the RNA-binding protein HuR and the degradation of GATA3 pre-mRNA. Strikingly, a long noncoding RNA (lncRNA) GATA3-AS, transcribed from the antisense strand of the GATA3 gene, functioned as a cis-acting element for the preferential interaction of KIAA1429 with GATA3 pre-mRNA. Accordingly, we found that the tumor growth and metastasis driven by KIAA1429 or GATA3-AS were mediated by GATA3. Conclusion Our study proposed a complex KIAA1429-GATA3 regulatory model based on m6A modification and provided insights into the epi-transcriptomic dysregulation in hepatocarcinogenesis and metastasis.

Impaired decision-making has been observed in suicide attempters during the Iowa Gambling Task (IGT). Decision-making performance is influenced by somatic markers and explicit knowledge, but it is still unclear of the influencing role on decision-making performance in suicidal individuals. We aimed to investigate whether there is a decision-making deficit in suicide attempters, suicide ideators, as well as the distinct roles of somatic markers and explicit knowledge wherein. Thirteen suicide attempters, 23 suicide ideators, and 19 healthy controls performed the IGT. Both somatic markers (by the skin conductance responses, SCRs) and explicit knowledge (by the subjective experience rating and a list of questions) were recorded. No significant differences were found among the three groups on IGT performance, explicit knowledge, and anticipatory SCRs. IGT Performance of suicide attempters was positively correlated with explicit knowledge index while behavior performance was positively associated with the SCRs in healthy controls. These results indicate that the suicide attempters seem to apply a compensatory strategy by mostly utilizing explicit knowledge to perform normally as healthy controls in the IGT.

Background and AimsHepatic and coagulation function are routine laboratory tests prior to curative hepatectomy. The prognostic value of gamma-glutamyl transpeptidase (GGT) to platelet ratio (GPR) and international normalized ratio (INR) in surgically treated patients with intrahepatic cholangiocarcinoma (ICC) remains unclear.MethodsICC patients received curative hepatectomy in two west China centers were included. Time-dependent ROC curves were conducted to compare established indexes with prognostic value for ICC. GPR-INR score was introduced and evaluated using the Time-dependent AUC curve and Kaplan-Meier survival analysis. A novel nomogram based on the GPR-INR score was proposed; Harrell’s C-index, calibration curve and decision curve analysis were used to assess this nomogram.ResultsA total of 653 patients were included. The areas under ROC curves of GPR and INR in OS and RFS were superior to other indexes. Patients with a high GPR-INR score (1,2) presented significantly decreased overall survival (OS) and recurrence-free survival (RFS); GPR-INR sore, along with several clinicopathological indexes were selected into the nomogram, the calibration curve for OS probability showed good coincidence between the nomogram and the actual surveillance. The C-index of the nomogram was 0.708 (derivation set) and 0.746 (validation set), which was more representative than the C-indexes of the GPR-INR score (0.597, 0.678). In decision curve analysis, the net benefits of the nomogram in derivation and validation set were higher than Barcelona Clinic Liver Cancer staging (BCLC) classification and American Joint Committee on Cancer (AJCC) TNM 8th staging system.ConclusionsThe proposed nomogram generated superior discriminative ability to established staging systems; it is profitable to applicate this nomogram in clinical practice.

BackgroundPatients with lateral lymph nodes (LLNs) metastasis are not effectively treated with neoadjuvant chemoradiotherapy. This study aimed to compare the efficacy of three neoadjuvant therapeutic regimens, namely, chemotherapy, chemoradiotherapy, and chemoradiotherapy with a dose boost of LLNs, and to identify the optimal approach for treating LLNs metastasis of locally advanced rectal cancer.MethodsA total of 202 patients with baseline LLNs metastasis (short axis ≥5 mm) and treated with neoadjuvant treatment, followed by radical surgery from 2011 to 2019, were enrolled. The short axis of the LLNs on baseline and restaging MRI were recorded. Survival outcomes were compared.ResultsIn the booster subgroup, shrinkage of LLNs was significantly greater than in the neoadjuvant chemotherapy and chemoradiotherapy subgroups (P

The existence of intratumoral tertiary lymphoid structure (iTLS) has been reported to correlative with favorable clinical outcomes for patients with hepatocellular carcinoma (HCC). However, little is known about the role of peritumoral TLS (pTLS). This study aimed to investigate the prognostic role of pTLS either alone or jointly with iTLS and the potential association with local immune response in HCC. The formation and cellular composition of TLS was evaluated by hematoxylin & eosin and immunohistochemistry. Evaluation of tumor-infiltrating immune cells and formation of germinal center (GC) inside TLS was performed by immunohistochemistry. The gene expression profiles were analyzed by real-time PCR. In a total of 360 patients from two independent cohorts, the pTLS was identified in most, whereas iTLS could be observed in only approximately 30% of HCC specimens. Patients with high pTLS densities were associated with improved outcomes, those present with characteristic morphology of GC, particularly, showing an even better prognosis. The combination of pTLS and iTLS allowed the identification of patients with best prognosis. Tumors with high pTLS density showed significantly increased expression of Th1-, Th17- and immune suppression-related genes, as well as significantly higher infiltration of CD3+, CD8+ and CD20+ cells and lower infiltration of FOXP3+, CD68+ and PD1+ cells. Conclusively, we provide evidence that pTLS is associated with intratumoral immune infiltration, highlighting the dynamic interplay between pTLS and immune cells recruitment. High pTLS density links to a tumor microenvironment with an active immune reaction and improved patient survival and represents a promising prognostic biomarker for HCC.

IntroductionPrimary breast marginal zone lymphoma (PBMZL) is a rare occurrence and less is known about its characteristics, treatments, and outcomes.MethodsWe retrospectively reviewed 370 cases of early-stage PBMZL from the Surveillance, Epidemiology, and End Results database. Statistical analyses were performed to describe clinical features, determine prognostic factors, and compare different therapeutic strategies.ResultsAt a median follow-up of 68.5 months, the 5-year overall survival (OS) and disease-specific survival (DSS) rate were 81.2 and 95.4%, respectively. We divided the cohort into four treatment groups and compared their characteristics and survival: radiotherapy (RT) ± surgery (Sx) (n = 142, 38.4%), Sx alone (n = 71, 19.2%), any chemotherapy (CT) (n = 63, 17.0%), and none of the above (n = 94, 25.4%). Age of onset and laterality of lesions tended to relate to the choice of different treatments. Multivariate Cox analysis showed that advanced age (>60 years), concomitant tumor, and any CT (vs RT ± Sx) predicted poorer OS, while for DSS, there was no meaningful indicator (P > 0.05). Patients aged >60 years or treated with any CT seemed to have shorter DSS, but the difference only approached statistical significance. Then we applied a propensity score-matched analysis to demonstrate that neither RT- nor Sx-containing therapy could bring a better OS or DSS. The competing risk model suggested that CT was the only contributor to higher PBMZL-specific mortality.ConclusionOur results show an indolent behavior of early-stage PBMZL with long-term survival. Conventional oncological treatments fail to bring survival benefits; especially CT is detrimental to survival, suggesting that observation may be advisable in the management of early-stage PBMZL, and further research on novel targeted agents is warranted for patients in need.

Abstract Introduction Thallium poisoning is a rare occurrence. Therefore, thallium poisoning is easily misdiagnosed and is often accompanied by a series of serious sequelae and can even result in death in severe cases. Here, we report long‐term follow‐up of a case of a patient who was poisoned with thallium on two separate occasions. Methods A 43‐year‐old man was initially misdiagnosed as gastroenteritis, diabetic peripheral neuropathy, and Guillain–Barré Syndrome (GBS) within 21 months. The correct diagnosis was confirmed by blood and urine thallium assays. After Prussian blue treatment, thallium was undetectable in the blood by day 60. Following this investigation, a criminal suspect confessed to two instances of adulterating thallium sulfate in the patient's beverage. A 6‐year follow‐up was performed after discharge, and a comprehensive literature was review. Results We found that the original gastrointestinal symptoms, skin lesions, and hair loss were reversed and had recovered, except for residual neurologic damage, even with long‐term rehabilitation. Discussion Thallium intoxication may have been initially identified if neurologic symptoms had occurred concurrently with gastrointestinal and cutaneous symptoms. Neurologic damage represented the main sequelae of thallium poisoning in our present case report.

Background: Liver function is a routine laboratory test prior to curative liver resection. It remains unclear whether the albumin–bilirubin (ALBI) grade and albumin-to-alkaline phosphatase ratio (AAPR) can predict long-term outcomes of surgically treated patients with intrahepatic cholangiocarcinoma (ICC).Methods: This study investigated the correlation between ALBI grade and AAPR with overall survival (OS) after liver resection and then compared their accuracy to the Child–Pugh score. Harrell's concordance index (C-index) and Akaike information criterion (AIC) were used to compare accuracy of models.Results: A total of 620 ICC patients were included, 477 in derivation cohort and 143 for validation. 0.348 was identified as the cutoff value for AAPR after calculating the Youden index. In the derivation cohort, elevated ALBI grade was associated with worse prognosis [hazard ratio (HR): 1.751, 95% confidence interval (CI): 1.329 to 2.306], and a decreased AAPR value was correlated with shorter OS (HR: 1.969, 95% CI: 1.552 to 2.497). Multivariate analysis suggested that the ALBI grade, AAPR, CA19-9, tumor number, and microvascular invasion were independent prognostic predictors for OS. ALBI grade and AAPR showed more accuracy in evaluating OS for surgically treated ICC patients than the Child–Pugh score (C-index: 0.559, 0.600 vs. 0.528; AIC: 3023.84, 3007.73 vs. 3034.66). Our findings were validated in an independent cohort from another clinical center.Conclusions: Importantly, the ALBI grade and AAPR showed greater discriminatory power than the Child–Pugh score in assessing long-term outcomes following hepatectomy for ICC. The AAPR was more accurate than the ALBI grade. It was beneficial to consider the ALBI grade and AAPR as useful surrogate markers to identify patients at risk of poor postoperative outcomes.

Abstract Background The increase in the levels of reactive oxygen species (ROS) in acute myeloid leukemia (AML) patients has been previously described; thus, it is important to regulate ROS levels in AML. Methods Flow cytometry were used to assess the in vitro effect of compound kushen injection (CKI). Quantitative proteomics were used to analyse the mechanism. The AML patient-derived xenograft (PDX) model were used to evaluate the in vivo effect of CKI. Results We found that intracellular ROS levels in AML cells were decreased, the antioxidant capacity were increased when treated with CKI. CKI inhibited the proliferation of AML cells and enhanced the cytotoxicity of AML cells, which has few toxic effects on haematopoietic stem cells (HSCs) and T cells. At the single-cell level, individual AML cells died gradually by CKI treatment on optofluidic chips. CKI promoted apoptosis and arrested cell cycle at G1/G0 phase in U937 cells. Furthermore, higher peroxiredoxin-3 (Prdx3) expression levels were identified in CKI-treated U937 cells through quantitative proteomics detection. Mechanically, the expression of Prdx3 and peroxiredoxin-2 (Prdx2) was up-regulated in CKI-treated AML cells, while thioredoxin 1 (Trx1) was reduced. Laser confocal microscopy showed that the proteins Prdx2 could be Interacted with Trx1 by CKI treatment. In vivo, the survival was longer and the disease was partially alleviated by decreased CD45+ immunophenotyping in peripheral blood in the CKI-treated group in the AML PDX model. Conclusions Antioxidant CKI possess better clinical application against AML through the Prdxs/ROS/Trx1 signalling pathway.

Abstract Background Several epidemiological researches have indicated that microvessel density (MVD), reflecting angiogenesis, was a negatively prognostic factor of cervical cancer. However, the results were inconsistent. Therefore, we performed a meta-analysis to evaluate the association between microvessel density and the survival probability of patients with cervical cancer. Method There was a comprehensive search of the PubMed, EMBASE and Cochrane databases up to August 31, 2017. Based on a fixed-effects or random-effects model, the hazard ratio (HR) and 95% confidence intervals (CIs) were calculated from researches on overall survival (OS) and disease-free survival (DFS). Result Totally, we included 13 observational researches, involving 1097 patients with cervical cancer. The results showed that high level of microvessel density was negatively correlated with OS (HR = 1.79, 95% CIs 1.31–2.44, I 2 = 60.7%, P = 0.003) and DFS (HR = 1.47, 95% CIs 1.13–1.80, I 2 = 0%, P = 0.423) of cervical cancer patients. In subgroup analysis, high counts of MVD were significantly associated with a poor survival (including OS and DFS) of the patients detected by anti-factor VIII antibodies or in European origin. Conclusion The present meta-analysis indicated that survival with high level of MVD was significant poorer than with low MVD in cervical cancer patient. Standardization of MVD assessment is needed.

An improved and efficient method for the synthesis of thioamides is presented. For this transformation, dimethylamine as the key intermediate is generated in situ from dimethylformamide (DMF). All the tested substrates produced the desired products with excellent isolated yields.

Fibrosing diseases are a leading cause of morbidity and mortality worldwide and, therefore, there is a need for safe and effective antifibrotic therapies. Adenosine, generated extracellularly by the dephosphorylation of adenine nucleotides, ligates specific receptors which play a critical role in development of hepatic and dermal fibrosis. Results of recent clinical trials indicate that tenofovir, a widely used antiviral agent, reverses hepatic fibrosis/cirrhosis in patients with chronic hepatitis B infection. Belonging to the class of acyclic nucleoside phosphonates, tenofovir is an analogue of AMP. We tested the hypothesis that tenofovir has direct antifibrotic effects in vivo by interfering with adenosine pathways of fibrosis using two distinct models of adenosine and A2AR-mediated fibrosis.Thioacetamide (100mg/kg IP)-treated mice were treated with vehicle, or tenofovir (75mg/kg, SubQ) (n = 5-10). Bleomycin (0.25U, SubQ)-treated mice were treated with vehicle or tenofovir (75mg/kg, IP) (n = 5-10). Adenosine levels were determined by HPLC, and ATP release was quantitated as luciferase-dependent bioluminescence. Skin breaking strength was analysed and H&E and picrosirus red-stained slides were imaged. Pannexin-1expression was knocked down following retroviral-mediated expression of of Pannexin-1-specific or scrambled siRNA.Treatment of mice with tenofovir diminished adenosine release from the skin of bleomycin-treated mice and the liver of thioacetamide-treated mice, models of diffuse skin fibrosis and hepatic cirrhosis, respectively. More importantly, tenofovir treatment diminished skin and liver fibrosis in these models. Tenofovir diminished extracellular adenosine concentrations by inhibiting, in a dose-dependent fashion, cellular ATP release but not in cells lacking Pannexin-1.These studies suggest that tenofovir, a widely used antiviral agent, could be useful in the treatment of fibrosing diseases.

Due to the scarcity of resources of Ziziphi spinosae semen (ZSS), many inferior goods and even adulterants are generally found in medicine markets. To strengthen the quality control, HPLC fingerprint common pattern established in this paper showed three main bioactive compounds in one chromatogram simultaneously. Principal component analysis based on DAD signals could discriminate adulterants and inferiorities. Principal component analysis indicated that all samples could be mainly regrouped into two main clusters according to the first principal component (PC1, redefined as Vicenin II) and the second principal component (PC2, redefined as zizyphusine). PC1 and PC2 could explain 91.42% of the variance. Content of zizyphusine fluctuated more greatly than that of spinosin, and this result was also confirmed by the HPTLC result. Samples with low content of jujubosides and two common adulterants could not be used equivalently with authenticated ones in clinic, while one reference standard extract could substitute the crude drug in pharmaceutical production. Giving special consideration to the well-known bioactive saponins but with low response by end absorption, a fast and cheap HPTLC method for quality control of ZSS was developed and the result obtained was commensurate well with that of HPLC analysis. Samples having similar fingerprints to HPTLC common pattern targeting at saponins could be regarded as authenticated ones. This work provided a faster and cheaper way for quality control of ZSS and laid foundation for establishing a more effective quality control method for ZSS. Keywords: Adulterant, Common pattern, Principal component analysis, Quality control, Ziziphi spinosae semen

One new pentacyclic triterpenoid, 3β-carboxylicfilic-4(23)-ene (1), and three known pentacyclic triterpenoids, adian-5-en-3α-ol (2), fernenol (3), and fern-7-en-3β-ol (4) were isolated from the petroleum ether phase of the ethanolic extract of Ainsliaea yunnanensis Franch. Their structures were established by spectroscopic methods including 1-D and 2-D NMR, and MS experiments. Compounds 1, 2, 3, and 4 showed significant selective cytotoxicity against human acute monocytic leukemia cell line (THP-1) with IC50 values of 5.12 μM, 1.78 μM, 1.74 μM, and 1.75 μΜ, respectively. Compound 1 also showed an anti-inflammatory effect through the inhibition of the activity of NF-κB by blocking the nuclear translocation of p65.

Various seismic attributes of gas hydrate bearing sediments were analyzed in the accretionary prism offshore of southwestern Taiwan utilizing seismic imaging, velocity analysis, AVO analysis, and AVO inversion of large offset seismic data. A bottom-simulating reflector (BSR) is clearly observed on the seismic section with a reversed polarity compared to that of the seabed reflection. Instantaneous amplitude sectioning clearly shows lateral variations of the BSR. The zero-phase waveform of the BSR is distinct and the weak reflectors above the BSR can be observed on the instantaneous phase section. AVO analysis shows the absolute value of the negative BSR amplitude increasing with offset. A low P-wave interval velocity layer was found below the strong BSR by detailed velocity analysis. Both the P (normal incident P-wave reflection coefficient) and G (AVO gradient) values are highly negative for the strong BSR on the P and G sections, and they lie in the third quadrant of the P and G cross-plot section. The P+G (reflectivity of Poisson¡¦s ratio) value is also negative on the P+G section and the P-G (normal incident S-wave reflection coefficient) value is approximately zero on the P-G section along the same strong BSR. All the seismic characters described above suggest that a gas hydrate layer exists together with a free gas layer below it along strong BSRs in the area offshore southwestern Taiwan.

The area around the Dongsha Island in the northeastern South China Sea was generally known for the occurrence of gas hydrate related features, like BSR, cold seep carbonates and chemoautotrophic bacteria. To precisely evaluate the potential of gas hydrate occurrence in the NE South China Sea, marine geology of the large Dongsha slope region is studied based on more geophysical and geological data including multiple-channel seismic and high resolution sub-bottom topographic images. The east Dongsha slope area represents the largest slumping zone in the northern slope of the South China Sea, and might exhibit the highest potential of gas hydrate occurrences. The central Dongsha slope area, with very thin Cenozoic sediments, was tectonically disturbed by the latest Cenozoic uplifting and magmatism events, therefore is unfavorable for gas hydrate occurrence. The west Dongsha slope area with the deepest Cenozoic depression and moderate to minor slumping bodies might be favorable for gas hydrate occurrence.