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Cotton (Gossypium spp.) is the most important natural textile fiber crop in the world. The ideal plant architecture of cotton is suitable for mechanical harvesting and productivity in modern agricultural production. However, cotton genes regulating plant development and architecture have not been fully identified. We identified a basic helix-loop-helix (bHLH) transcription factor, GhPAS1 (PAGODA1 SUPPRESSOR 1) in G. hirsutum (Upland cotton). GhPAS1 was located in the nucleus and showed a strong transcription activation effect. Tissue-specific expression patterns showed that GhPAS1 was highly expressed in floral organs, followed by high expression in early stages of ovule development and rapid fiber elongation. GhPAS1 overexpression in Arabidopsis and BRZ (brassinazole, BR biosynthesis inhibitor) treatment indicated that GhPAS1 positively regulates and responds to the BR (brassinosteroid) signaling pathway and promotes cell elongation. GhPAS1 overexpression in Arabidopsis mediated plant development in addition to increasing plant biomass. Virus-induced gene silencing of GhPAS1 indicated that down-regulation of GhPAS1 inhibited cotton growth and development, as plant height, fruit branch length, and boll size of silenced plants were lower than in control plants. Fiber length and seed yield were also lower in silenced plants. We conclude that GhPAS1, a bHLH transcription factor, regulates plant development and architecture in cotton. These findings may help breeders and researchers develop cotton cultivars with desirable agronomic characteristics.

Long noncoding RNAs (lncRNAs) play roles in the development and progression of many cancers; however, the contributions of lncRNAs to human gallbladder cancer (GBC) remain largely unknown. In this study, we identify a group of differentially expressed lncRNAs in human GBC tissues, including prognosis‐associated gallbladder cancer lncRNA (lncRNA‐PAGBC), which we find to be an independent prognostic marker in GBC. Functional analysis indicates that lncRNA‐PAGBC promotes tumour growth and metastasis of GBC cells. More importantly, as a competitive endogenous RNA (ceRNA), lncRNA‐PAGBC competitively binds to the tumour suppressive microRNAs miR‐133b and miR‐511. This competitive role of lncRNA‐PAGBC is required for its ability to promote tumour growth and metastasis and to activate the AKT/mTOR pathway. Moreover, lncRNA‐PAGBC interacts with polyadenylate binding protein cytoplasmic 1 (PABPC1) and is stabilized by this interaction. This work provides novel insight on the molecular pathogenesis of GBC.

AimsTo identify the mutation spectrum and genotype–phenotype correlations offibrillin-1(FBN1) mutations in a Chinese cohort with congenital ectopia lentis (EL).MethodsPatients clinically suspected of congenital zonulopathy were screened using panel-based next-generation sequencing followed by multiplex ligation-dependent probe amplification. All the probands were subjected to thorough ocular examinations. Molecular and clinical data were integrated in pursuit of genotype–phenotype correlation.ResultsA total of 131 probands ofFBN1mutations from unrelated families were recruited. Around 65% of the probands were children younger than 9 years old. Overall, 110 distinctFBN1mutations were identified, including 39 novel ones. The most at-risk regions were exons 13, 2, 6, 15, 24 and 33 in descending order of mutation frequency. The most prevalent mutation was c.184C>T (seven, 5.34%) in the coding sequence and c.5788+5G>A (three, 2.29%) in introns. Missense mutations were the most frequent type (103, 78.63%); half of which were distributed in the N-terminal regions (53, 51.46%). The majority of missense mutations were detected in one of the calcium-binding epidermal growth factor-like domains (62, 60.19%), and 39 (62.90%) of them were substitutions of conserved cysteine residues. Microspherophakia (MSP) was found in 15 patients (11.45%). Mutations in the middle region (exons 22–42), especially exon 26, had higher risks of combined MSP (OR, 5.51 (95% CI 1.364 to 22.274), p=0.017).ConclusionsThis study extended the knowledge of theFBN1mutation spectrum and provided novel insights into its clinical correlation regarding EL and MSP in the Chinese population.

The study sought to compare the safety and effectiveness of drug-coated balloon (DCB) with bare nitinol stent in patients with complex femoropopliteal(FP) lesions in real-world practice.Patients with symptomatic (Rutherford stage 2 to 5) femoropopliteal lesions who underwent DCB or bare nitinol stent implantation at the Department of Cardiovascular Surgery of China-Japan Friendship Hospital from June 2016 to September 2017 were included. Demographics, angiographic and procedural variables were included. Freedom from target lesion revascularization (TLR), primary patency and major adverse events were obtained from follow-up results at 3,6 and12 months. Descriptive analysis was performed on all variables.A total of 90 eligible patients were enrolled, which included 51 DCB subjects (mean age, 63.1 ± 13.2 years; 76.5% male) with 55 lesions and 39 nitinol stent subjects (mean age, 66.5 ± 10.5 years; 61.5% male) with 42 lesions. Significant higher primary patency was observed in the DCB group compared with the stent group (74.5% vs. 52.4%; log-rank test P = 0.018; HR 0.335, 95%CI 0.124-0.903, P = 0.031). The rates of freedom from TLR (f-TLR) were 78.2% and 59.5% (log-rank test P = 0.032) for the DCB group and the stent group, respectively, at 12 months. CD-TLR rates were 18.2% vs. 38.1% with a P-value of 0.023. Female sex (HR 6.122, 95%CI 1.880-19.934, P = 0.003), lesion length over 20 cm (HR 5.514, 95%CI 2.312-13.148, P0.001) and renal insufficiency (HR 2.609, 95%CI 1.087-6.260, P = 0.032) were suggested as independent risk factors of reducing primary patency. There were no significant differences in major adverse events between the 2 groups.The result above demonstrates that DCB treatment has higher primary patency and lower TLR at 12 months than nitinol stent. These data confirm the safety and effectiveness of the DCB for patients with complex femoropopliteal lesions.

Hydrogen sulfide (H2S) is an important gaseous signal molecule which participates in various abiotic stress responses. However, the underlying mechanism of H2S associated salt tolerance remains elusive. In this study, sodium hydrosulfide (NaHS, donor of H2S) was used to investigate the protective role of H2S against salt stress at the biochemical and proteomic levels. Antioxidant activity and differentially expressed proteins (DEPs) of rice seedlings treated by NaCl or/and exogenous H2S were investigated by the methods of biochemical approaches and comparative proteomic analysis. The protein-protein interaction (PPI) analysis was used for understanding the interaction networks of stress responsive proteins. In addition, relative mRNA levels of eight selected identified DEPs were analyzed by quantitative real-time PCR. The result showed that H2S alleviated oxidative damage caused by salt stress in rice seedling. The activities of some antioxidant enzymes and glutathione metabolism were mediated by H2S under salt stress. Proteomics analyses demonstrated that NaHS regulated antioxidant related proteins abundances and affected related enzyme activities under salt stress. Proteins related to light reaction system (PsbQ domain protein, plastocyanin oxidoreductase iron-sulfur protein), Calvin cycle (phosphoglycerate kinase, sedoheptulose-1,7-bisphosphatase precursor, ribulose-1,5-bisphosphate carboxylase/oxygenase) and chlorophyll biosynthesis (glutamate-1-semialdehyde 2,1-aminomutase, coproporphyrinogen III oxidase) are important for NaHS against salt stress. ATP synthesis related proteins, malate dehydrogenase and 2, 3-bisphosphoglycerate-independent phosphoglycerate mutase were up-regulated by NaHS under salt stress. Protein metabolism related proteins and cell structure related proteins were recovered or up-regulated by NaHS under salt stress. The PPI analysis further unraveled a complicated regulation network among above biological processes to enhance the tolerance of rice seedling to salt stress under H2S treatment. Overall, our results demonstrated that H2S takes protective roles in salt tolerance by mitigating oxidative stress, recovering photosynthetic capacity, improving primary and energy metabolism, strengthening protein metabolism and consolidating cell structure in rice seedlings.

The abnormal proliferation of vascular smooth muscle cells (VSMCs) is crucial in the atherosclerosis. Although long noncoding RNAs (lncRNAs) are implicated in a variety of diseases, their roles in activation of VSMCs proliferation and vascular disorder diseases are not well understood. In addition, heterogeneous nuclear ribonucleoprotein A2/B1 (hnRNPA2/B1) was reported to participate in lncRNAs-mediated function. Herein, we propose to investigate the role of lncRNA AC105942.1 and hnRNPA2/B1 in pathological VSMCs proliferation and the possible mechanisms in vitro. We have identified that lncRNA AC105942.1 was downregulated and hnRNPA2/B1 was upregulated in atherosclerotic plaques compared with normal artery tissues. Enhanced lncRNA AC105942.1 could noticeably inhibit Ang II-induced VSMCs proliferation. Further investigation suggested that lncRNA AC105942.1 could downregulate the expression of hnRNPA2/B1 and then regulate the level of CDK4 and p27. Taken together, our study indicated that lncRNA AC105942.1 downregulated hnRNPA2B1 to protect against the atherosclerosis by suppressing VSMCs proliferation. LncRNA AC105942.1 and hnRNPA2/B1 could represent potential therapeutic and diagnostic targets to atherosclerosis-related diseases.

Objective: To evaluate surgical outcomes of modified capsular tension ring (MCTR) and intraocular lens (IOL) implantation in eyes of Marfan syndrome (MFS). Methods: This retrospective case series included MFS patients receiving MCTR transscleral fixation and IOL in-the-bag implantation. The MCTR was sutured to the sclera through a sulcus by 9–0 polypropylene with the modified knotless Z-suture technique. Main outcomes were visual acuity and postoperative complications. Results: A total of 109 MFS patients (187 eyes) had the surgery. Patients were 15.47 ± 14.36 years old and followed up for 10.07 ± 8.99 months. MCTR and IOL implantations were performed in 174 eyes (93.05%). The postoperative BCVA (LogMAR) was 0.24 ± 0.24 (1 month), 0.26 ± 0.20 (3 months), 0.22 ± 0.20 (6 months), 0.20 ± 0.19 (12 months) and 0.25 ± 0.32 (over 12 months), which was significantly better than preoperatively (0.63 ± 0.35) ( p Conclusions: The visual improvement is significant in eyes of MFS undergoing MCTR transscleral fixation and IOL in-the-bag implantation. The long-term monitoring of complications is warranted, especially in the first-two years.

Objective The aim of this study was to investigate the effectiveness and safety of surgery combined with 125I seed brachytherapy for treatment of carcinoma ex pleomorphic adenoma (CXPA) of the parotid gland and to identify the factors associated with prognosis. Study Design We conducted a retrospective analysis of data of patients with CXPA of the parotid gland treated with surgery plus 125I seed brachytherapy at the Peking University School of Stomatology Hospital between December 2003 and July 2018. Results Fifty-five patients (median age, 51 years) were included in the study. Median follow-up was 50.5 months. The 3-, 5-, and 10-year overall survival rates were 91.1%, 91.1%, and 81.5%, respectively. The 3-, 5-, and 10-year local control rates were all 85.2%. Grades 1-3 adverse effects occurred in 22 patients; no grade 4 reactions occurred. T stage, N stage, tumor invasiveness, perineural invasion, and surgical margins significantly affected local control rates. Lymph node metastasis and perineural invasion were independent predictors of poor local control. Lymph node metastasis was an independent predictor of poor survival. Conclusions Surgery plus 125I seed brachytherapy appears to be an effective and safe treatment for CXPA of the parotid gland. T stage, N stage, tumor invasiveness, and perineural invasion are factors influencing prognosis.

Purpose: Immunotherapy is currently ineffective for nearly all pancreatic ductal adenocarcinomas (PDAC), largely due to its tumor microenvironment (TME) that lacks antigen-experienced T effector cells (Teff). Vaccine-based immunotherapies are known to activate antigen-specific Teffs in the peripheral blood. To evaluate the effect of vaccine therapy on the PDAC TME, we designed a neoadjuvant and adjuvant clinical trial of an irradiated, GM-CSF-secreting, allogeneic PDAC vaccine (GVAX). Patients and Methods: Eighty-seven eligible patients with resectable PDAC were randomly assigned (1:1:1) to receive GVAX alone or in combination with two forms of low-dose cyclophosphamide. Resected tumors following neoadjuvant immunotherapy were assessed for the formation of tertiary lymphoid aggregates (TLA) in response to treatment. The clinical endpoints are disease-free survival (DFS) and overall survival (OS). Results: The neoadjuvant treatment with GVAX either alone or with two forms of low-dose cyclophosphamide is safe and feasible without adversely increasing the surgical complication rate. Patients in Arm A who received neoadjuvant and adjuvant GVAX alone had a trend toward longer median OS (35.0 months) than that (24.8 months) in the historical controls who received adjuvant GVAX alone. However, Arm C, who received low-dose oral cyclophosphamide in addition to GVAX, had a significantly shorter DFS than Arm A. When comparing patients with OS > 24 months to those with OS < 15 months, longer OS was found to be associated with higher density of intratumoral TLA. Conclusions: It is safe and feasible to use a neoadjuvant immunotherapy approach for PDACs to evaluate early biologic responses. In-depth analysis of TLAs is warranted in future neoadjuvant immunotherapy clinical trials.

Due to the increased potential for application of natural biopolymers in the food industry, the goal of this study was to prospectively produce antimicrobial films using asparagus residue. In this study, cellulose was extracted from asparagus residue, and then 3 cellulose solutions of 0.008, 0.01 and 0.025 g/mL were applied to prepare films using a phase inversion process. Films were characterized by Fourier transform infrared spectroscopy (FTIR), X-ray diffraction (XRD), thermal gravimetric analysis (TGA) and scanning electron microscopy (SEM). The film produced by 0.01 g/mL asparagus cellulose solution exhibited a swelling ratio of 125.4% and excellent antimicrobial activity against Escherichia coli and Staphylococcus aureus using the disk agar diffusion method. This study presents a promising method for producing antimicrobial films with asparagus residue.

Enzymes have been proven to play considerable roles in disease diagnosis and biological functions. The feature extraction that truly reflects the intrinsic properties of protein is the most critical step for the automatic identification of enzymes. Although lots of feature extraction methods have been proposed, some challenges remain. In this study, we developed a predictor called IHEC_RAAC, which has the capability to identify whether a protein is a human enzyme and distinguish the function of the human enzyme. To improve the feature representation ability, protein sequences were encoded by a new feature-vector called ‘reduced amino acid cluster’. We calculated 673 amino acid reduction alphabets to determine the optimal feature representative scheme. The tenfold cross-validation test showed that the accuracy of IHEC_RAAC to identify human enzymes was 74.66% and further discriminate the human enzyme classes with an accuracy of 54.78%, which was 2.06% and 8.68% higher than the state-of-the-art predictors, respectively. Additionally, the results from the independent dataset indicated that IHEC_RAAC can effectively predict human enzymes and human enzyme classes to further provide guidance for protein research. A user-friendly web server, IHEC_RAAC, is freely accessible at http://bioinfor.imu.edu.cn/ihecraac .

Purpose To evaluate the efficacy of diagnosis systems based upon instance segmentation with convolutional neural networks (CNNs) for diagnosing acute promyelocytic leukemia (APL) in bone marrow smear images. Materials and methods A self-established dataset was used in this study that was exempted from review by the institution review board, which consisted of 13,504 bone marrow smear images. One subset of the dataset with 12,215 labeled images was split into training (80%) and validation (20%), another with 1289 labeled images was used to test, in which each test entry consists of about 130 images. An instance segmentation method named Mask R-CNN was used to detect and classify the nucleated cells. Here, we train a trained neural network from scratch; for comparison, we also use a network pre-trained on MS COCO (common objects in context, a data set provided by Microsoft which can be used for image recognition, the images in MS coco dataset are divided into training, validation and test sets) and fine-tuned with our dataset and both were trained with same data augmentation scheme. Diagnosis systems based on trained models and “FAB Classification” (French–American–British classification systems, a series of diagnostic criteria for acute leukemia, which was first proposed in 1976) were developed for diagnosing the test entry as APL or as not. Average precision (AP) and average recall (AR) were used to evaluate model performance. Results The best-performing model had an average precision of 62.5%, which was the augmented pre-trained Mask R-CNN with average recall 84.1%. The average precision of the pre-trained model was greater than that of the model trained from scratch (P Conclusion Deep learning technology such as instance segmentation with Mask R-CNN may accurately diagnose APL in bone marrow smear images with an average precision of 62.5% when 0.5 as IoU thresholds. A data augmentation and pre-trained approach further improved accuracy.

Recent research on genomic profiling of pancreatic ductal adenocarcinoma (PDAC) has identified many potentially actionable alterations. However, the feasibility of using genomic profiling to guide routine clinical decision making for PDAC patients remains unclear. We retrospectively reviewed PDAC patients between October 2013 and December 2017, who underwent treatment at the Johns Hopkins Hospital and had clinical tumor next-generation sequencing (NGS) through commercial resources. Ninety-two patients with 93 tumors tested were included. Forty-eight (52%) patients had potentially curative surgeries. The median time from the tissue available to the NGS testing ordered was 229 days (interquartile range 62–415). A total of three (3%) patients had matched targeted therapies based on genomic profiling results. Genomic profiling guided personalized treatment for PDAC patients is feasible, but the percentage of patients who receive targeted therapy is low. The main challenges are ordering NGS testing early in the clinical course of the disease and the limited evidence of using a targeted approach in these patients. A real-time department level genomic testing ordering system in combination with an evidence-based flagging system for potentially actionable alterations could help address these shortcomings.

Objective We evaluated survival outcomes in patients with distal pancreatic ductal adenocarcinoma (D-PDAC) after distal pancreatectomy (DP) and adjuvant chemotherapy or chemoradiation. Methods A retrospective analysis of patients who underwent DP for D-PDAC from 2000 to 2015 at the Johns Hopkins Hospital was performed. Demographics, baseline risk factors, and type of adjuvant treatment were assessed for associations with overall survival (OS) and disease-free survival (DFS). Comparisons were made with log-rank tests and Cox proportional hazards regression models. Results A total of 294 patients underwent DP for D-PDAC. Of these, 105 patients were followed at the Johns Hopkins Hospital. Forty-five patients received chemotherapy only and 60 patients received chemoradiation. The median OS with chemoradiation was 33.6 months and 27.9 months (P = 0.54) with chemotherapy only. The median DFS was 15.3 months with chemoradiation and 19.8 months with chemotherapy only (P = 0.89). Elevated carbohydrate antigen 19-9, stage II to III disease, splenic vein involvement, and vascular invasion were significant risk factors in multivariate analyses. Conclusions In this retrospective analysis, there were no significant differences in OS or DFS with chemoradiation compared with chemotherapy alone after DP in patients with D-PDAC.

Sonodynamic therapy (SDT) represents a promising modality that provides the possibility of non-invasively eliminating solid tumors in a site-directed manner. In light of the complexity and heterogeneity of tumors, more and more studies are attempting to combine SDT with other therapeutic methods so as to achieve better tumor treatment effect, which sheds new light on the potential of SDT-based synergistic therapeutics. Herein, the representative studies of SDT-instructed multimodal synergistic cancer therapy are comprehensively presented, such as sono-chemotherapy, sono-radiotherapy, sono-immunotherapy, and sono-chemodynamic therapy, etc., and their incorporate mechanisms are discussed in detail. The current challenges and future prospects to promote the advanced development of SDT-based nanomedicines in this burgeoning research field are highlighted. It is believed that such an emerging synergistic therapeutic modality based on SDT will play a more significant role in the field of tumor precision treatment medicine.

Objective: Pancreatic ductal adenocarcinoma (PDAC) is a deadly malignancy, due in large part to its resistance to conventional therapies, including radiotherapy (RT). Despite RT exerting a modest antitumor response, it has also been shown to promote an immunosuppressive tumor microenvironment. Previous studies demonstrated that focal adhesion kinase inhibitors (FAKi) in clinical development inhibit the infiltration of suppressive myeloid cells and T regulatory (T regs) cells, and subsequently enhance effector T cell infiltration. FAK inhibitors in clinical development have not been investigated in combination with RT in preclinical murine models or clinical studies. Thus, we investigated the impact of FAK inhibition on RT, its potential as an RT sensitizer and immunomodulator in a murine model of PDAC. Methods: We used a syngeneic orthotopic murine model to study the effect of FAKi on hypofractionated RT. Results: In this study we showed that IN10018, a small molecular FAKi, enhanced antitumor response to RT. Antitumor activity of the combination of FAKi and RT is T cell dependent. FAKi in combination with RT enhanced CD8+ T cell infiltration significantly in comparison to the radiation or FAKi treatment alone (P < 0.05). FAKi in combination with radiation inhibited the infiltration of granulocytes but enhanced the infiltration of macrophages and T regs in comparison with the radiation or FAKi treatment alone (P < 0.01). Conclusions: These results support the clinical development of FAKi as a radiosensitizer for PDAC and combining FAKi with RT to prime the tumor microenvironment of PDAC for immunotherapy.

Non-small-cell lung cancer (NSCLC) remains the leading cause of cancer-related death worldwide. Accumulating research has highlighted the ability of exosome-encapsulated microRNAs (miRNAs or miRs) as potential circulating biomarkers for lung cancer. The current study aimed to evaluate the clinical significance of serum-derived exosomal miR-let-7e as a biomarker in the metastasis of NSCLC. Initially, the expression of miR-let-7e, SUV39H2, and CDH1 in human NSCLC tissues and exosomes isolated from the serum of NSCLC patients was determined by RT-qPCR, demonstrating that miR-let-7e was downregulated in NSCLC tissues and serum-derived exosomes, while SUV39H2 was upregulated in NSCLC tissues. Kaplan-Meier method revealed that both lower miR-let-7e expression and higher SUV39H2 expression were correlated with a lower survival rate of NSCLC patients. Next, SUV39H2 was predicted and validated to be a target of miR-let-7e using dual-luciferase reporter assay. NSCLC H1299 cells following ectopic expression and depletion experiments of miR-let-7e and SUV39H2 were treated with serum-derived exosomes, after which the viability, migration, and invasion of H1299 cells were detected using CCK-8 and Transwell assays. Further, in vivo experiments were conducted to elucidate the effect of exosomal miR-let-7e on tumorigenesis. Results revealed that miR-let-7e overexpression in serum-derived exosomes inhibited SUV39H2, resulting in impaired cell viability, migration, and invasion in vitro as well as delayed tumor growth in vivo. In conclusion, the key findings of the current study demonstrate that exosomal miR-let-7e from serum possesses anticarcinogenic properties against NSCLC via the SUV39H2/LSD1/CDH1 axis.

BACKGROUND To describe a technique in which the anterior jugular vein is preserved in the infrahyoid myocutaneous flap (IHMCF) to augment skin paddle venous drainage. METHODS From April 2018 to December 2019, 14 patients with primary oral cancer underwent radical resection and IHMCF reconstruction. Three-dimensional reconstruction of the anterior jugular vein was used to assess the venous drainage of the skin paddle preoperatively. The anterior jugular vein was preserved during dissection of the flap. Healing of the recipient and donor sites was observed. RESULTS Total flap necrosis occurred in one patient and marginal skin paddle necrosis occurred in one patient. No flap complications occurred in the other 12 patients. CONCLUSION This new approach to augment venous drainage of the IHMCF appears to be effective for decreasing risk of flap necrosis.

PurposeTo compare the foveal microvascular structure characteristics in children with a history of intravitreal injection of ranibizumab (IVR) versus laser photocoagulation (LP) for retinopathy of prematurity by optical coherence tomography angiography (OCTA).MethodsIn this cross-sectional study, a total of 17 children (28 eyes) underwent IVR and 20 children (37 eyes) underwent LP were recruited. The age of doing OCTA examination of the two groups are 5.4±1.1 years and 6.3±1.8 years, respectively (p=0.07). Spectral-domain OCTA was performed for all the eyes with a scan size of 3×3 mm. The data of the superficial retinal layer were analysed. The foveal avascular zone (FAZ) and vessel density (including vessel length density (VLD) and perfusion density (PD)) were measured using the software of OCTA (Cirrus AngioPlex 5000, Carl Zeiss, Meditec, Dubin, California, USA). The central foveal thicknesses (CFT) were measured by cross-sectional OCT.ResultsIn the central fovea, the retinal VLD and PD of patients with IVR were 13.82±2.99 mm/mm2 and 0.25±0.05 mm2/mm2, respectively, which were significantly lower than those of the LP group (15.64±2.71 mm/mm2 and 0.28±0.05 mm2/mm2, p=0.01 and p=0.006). The FAZ area of patients with IVR and LP were 0.13±0.09 mm2 and 0.09±0.07 mm2, respectively (p=0.048). The CFT of patients with IVR and LP were 200.7±16.7 µm and 220.9±22.7 µm, respectively (pConclusionThe IVR might contribute to microvascular changes in the macular zone, such as reducing the central foveal VLD and PD, while the LP might contribute to microstructural changes, such as smaller FAZ and thicker CFT.

Background: As the pathogen of malaria, malaria parasite secretes a variety of proteins for its growth and reproduction. Objective: The identification of the secretory proteins of malaria parasite has crucial reference significance for the development of anti-malaria vaccines as well as medicine. Methods: In this study, a computational classification method was developed to identify the secreted proteins of Plasmodium. Amino acid composition, dipeptide composition, and tripeptide composition as well as reduced amino acids alphabets were proposed to illuminate protein sequences. We further used SVM to train and predict respectively and optimized the features. Results: 74 types of reduced amino acids alphabets were employed to predict secretory proteins. The results showed that the accuracy improved to 91.67% with 0.84 Mathew’s correlation coefficient (MCC) by dipeptide composition, and the highest prediction accuracy reached 92.26% after feature selection, which demonstrated that our method is prominent and reliable in the field of malaria parasite secreted proteins prediction. Conclusion: A intuitive web server iSP-RAAC (http://bioinfor.imu.edu.cn/isppseraac) was established for the convenience of most experimental scientists.

Circular DNA aptamers are powerful candidates for therapeutic applications given their dramatically enhanced biostability. Herein we report the first effort to evolve circular DNA aptamers that bind a human protein directly in serum, a complex biofluid. Targeting human thrombin, this strategy has led to the discovery of a circular aptamer, named CTBA4T-B1, that exhibits very high binding affinity (with a dissociation constant of 19 pM), excellent anticoagulation activity (with the half maximal inhibitory concentration of 90 pM) and high stability (with a half-life of 8 h) in human serum, highlighting the advantage of performing aptamer selection directly in the environment where the application is intended. CTBA4T-B1 is predicted to adopt a unique structural fold with a central two-tiered guanine quadruplex capped by two long stem–loops. This structural arrangement differs from all known thrombin binding linear DNA aptamers, demonstrating the added advantage of evolving aptamers from circular DNA libraries. The method described here permits the derivation of circular DNA aptamers directly in biological fluids and could potentially be adapted to generate other types of aptamers for therapeutic applications.

Purpose: This phase II study tested granulocyte-macrophage colony-stimulating factor (GM-CSF)-allogeneic pancreatic tumor cells (GVAX) and ipilimumab in metastatic pancreatic ductal adenocarcinoma (PDA) in the maintenance setting. Patients and Methods: Patients with PDA who were treated with front-line chemotherapy consisting of 5-fluorouracil, leucovorin, irinotecan, and oxaliplatin (FOLFIRINOX) in the metastatic setting and had ongoing response or stable disease after 8–12 doses were eligible. Patients were randomized 1:1 to treatment with GVAX and ipilimumab given every 3 weeks for four doses then every 8 weeks (Arm A) or to FOLFIRINOX continuation (Arm B). The primary objective was to compare overall survival (OS) between the two arms. Results: Eighty-two patients were included in the final analysis (Arm A: 40; Arm B: 42). The study was stopped for futility after interim analysis. Median OS was 9.38 months [95% confidence interval (CI), 5.0–12.2] for Arm A and 14.7 months (95% CI, 11.6–20.0) for Arm B (HR, 1.75; P = 0.019). Using immune-related response criteria, two partial responses (5.7%) were observed in Arm A and four (13.8%) in Arm B. GVAX + ipilimumab promoted T-cell differentiation into effector memory phenotypes both in the periphery and in the tumor microenvironment and increased M1 macrophages in the tumor. Conclusions: GVAX and ipilimumab maintenance therapy did not improve OS over continuation of chemotherapy and resulted in a numerically inferior survival in metastatic PDA. However, clinical responses and biological effects on immune cells were observed. Further study of novel combinations in the maintenance treatment of metastatic PDA is feasible.

OBJECTIVE To study the effect of total cranial reconstruction for sagittal synostosis (scaphocephaly) deformity in Chinese children. METHODS A retrospective analysis was performed involving 23 children with isolated non-syndromic sagittal synostosis who were treated by total calvarial vault remodeling after 1 year of age from May 2015 to June 2019 in the Department of Neurosurgery, Children's Hospital of Nanjing Medical University. The authors reconstruct patients' pre- and post-operative cranial thin-section CT scan images and those of the control group. The cephalic index (traditional, normative), intracranial volume, horizontal point of maximum width (H-PMW), vertical point of maximum width (V-PMW), frontal to head height ratio and occipital to head height ratio data were analyzed using a paired t test or Wilcoxon signed-rank test. RESULTS Twenty-three patients met the inclusion criteria, including 19 males and 4 females. The ratio of males to females was 4.7:1. All patients underwent total cranial reconstruction. The average age was 26.52 months (13-48 months), the average operation time was 214.13 minutes (150-265 minutes), and the average amount of suspended erythrocytes was 200 ml (100-400 ml). The cranial morphology of all patients improved significantly after the operation. The traditional cephalic index (pre-operative: 0.70 (0.04); post-operative: 0.78 (0.02)) and normative cephalic index (pre-operative: 0.68 (0.03); post-operative: 0.77 (0.02)) were significantly increased (P

Calcium is not only a nutrient necessary for plant growth but also a ubiquitous central element of different signaling pathways. Ca2+ deficiency in soil may cause embryo abortion, which can eventually lead to abnormal development of peanut pods during the harvest season. To further study the mechanisms by which Ca2+ affects the shells and kernels of peanuts, transcriptome sequencing was used to explore the genes differentially expressed in shells and kernels during the early stage of peanut pod development between Ca2+ sufficient and deficient treatments. In this study, 38,894 expressed genes were detected. RNA-seq based gene expression profiling showed a large number of genes at the transcriptional level that changed significantly in shells and kernels between the Ca2+ sufficient and deficient treatments, respectively. Genes encoding key proteins involved in Ca2+ signal transduction, hormones, development, ion transport, and nutrition absorption changed significantly. Meanwhile, in the early stage of pod development, calcium first promoted nutrient absorption and development of shells, which has less effect on the formation of seed kernels. These results provide useful information for understanding the relationship between Ca2+ absorption and pod development.

New versions of ENDF/B and JEFF data libraries have been released during the past two years with significant updates in the neutron reaction sublibrary and the thermal neutron scattering sublibrary. In order to get a more comprehensive impression of the criticality quality of these two latest neutron data libraries, and to provide reference for the selection of the evaluated nuclear data libraries for the science and engineering applications of the Reactor Monte Carlo code RMC, the criticality benchmarking of the two latest neutron data libraries has been performed. RMC was employed as the computational tools, whose processing capability for the continuous representation ENDF/B-Ⅷ.0 thermal neutron scattering laws was developed. The RMC criticality validation suite consisting of 116 benchmarks was established for the benchmarking work. The latest ACE format data libraries of the neutron reaction and the thermal neutron scattering laws for ENDF/B-Ⅷ.0, ENDF/B-Ⅶ.1, and JEFF-3.3 were downloaded from the corresponding official sites. The ENDF/B-Ⅶ.0 data library was also employed to provide code-to-code validation for RMC. All the calculations for the four different data libraries were performed by using a parallel version of RMC, and all the calculated standard deviations are lower than 30pcm. Comprehensive analyses including the C/E values with uncertainties, the δ k / σ values, and the metrics of χ 2 and | Δ | > , were conducted and presented. The calculated keff eigenvalues based on the four data libraries generally agree well with the benchmark evaluations for most cases. Among the 116 criticality benchmarks, the numbers of the calculated keff eigenvalues which agree with the benchmark evaluations within 3σ interval (with a confidence level of 99.6%) are 107, 109, 112, and 113 for ENDF/B-Ⅶ.0, ENDF/B-Ⅶ.1, ENDF/B-Ⅷ.0 and JEFF-3.3, respectively. The present results indicate that the ENDF/B-Ⅷ.0 neutron data library has a better performance on average.

Although islet transplantation plays an effective and powerful role in the treatment of diabetes, a large amount of islet grafts are lost at an early stage due to instant blood-mediated inflammatory reactions, immune rejection, and β-cell toxicity resulting from immunosuppressive agents. Timely intervention based on the viability and function of the transplanted islets at an early stage is crucial. Various islet transplantation imaging techniques are available for monitoring the conditions of post-transplanted islets. Due to the development of various imaging modalities and the continuous study of contrast agents, non-invasive islet transplantation imaging in vivo has made great progress. The tracing and functional evaluation of transplanted islets in vivo have thus become possible. However, most studies on contrast agent and imaging modalities are limited to animal experiments, and long-term toxicity and stability need further evaluation. Accordingly, the clinical application of the current achievements still requires a large amount of effort. In this review, we discuss the contrast agents for MRI, SPECT/PET, BLI/FI, US, MPI, PAI, and multimodal imaging. We further summarize the advantages and limitations of various molecular imaging methods.

Microsurgical reconstruction for anterior maxillary defects presents a surgical challenge. The objective of this study was to ascertain the feasibility of a new series of intraoral surgical approach using deep circumflex iliac artery (DCIA) flap to achieve functional reconstruction for anterior maxillary defects. Two male patients with anterior maxillary defects (Brown Class IC) were treated in this study. Both patients underwent computer-assisted maxillary reconstruction with a DCIA flap (with pedicle positioning laterally to the bony flap) using intraoral anastomosis techniques. The overall DCIA flap survival rate was 100% and mucosa was all healed uneventfully. One patient received dental implantation and loaded with prosthetic superstructures. Both patients were satisfied with their postoperative oral function and appearance. This study illustrated a new and feasible series of surgical design for anterior maxillary bone defect reconstruction with DCIA flaps and intraoral anastomosis assisted by digital techniques.

Background Pancreatic cancer is a highly malignant tumor of the digestive system. Early pancreatic cancer is often difficult to diagnosis due to its atypical clinical symptoms. Patients with pancreatic cancer have a very poor prognosis because they have lost the opportunity for radical surgical tumor resection and they are less sensitive to the clinically used radiotherapy and chemotherapy. Methods In this study, a peptide targeting pancreatic cancer cells was screened by phage display technology, and its targeting property was evaluated in vitro using PANC1 cells by fluorescence imaging and flow cytometry. Furthermore, the targeting peptide was conjugated to the pro-apoptotic KLAKLAKKLAKLAK (KLA), the fusion peptide and its targeting ability that allowing KLA to specifically enter pancreatic tumor cells in vitro and in vivo was confirmed by fluorescence imaging and in vivo imaging system (IVIS). Its mechanism was determined using flow cytometry, mitochondrial membrane potential evaluation and Western blot. The inhibitory effect on pancreatic tumor growth and toxic effects were evaluated by animal experiment. Results Due to the internalization facilitated by the targeting mechanism of the targeting peptide, KLA specifically entered pancreatic cancer cells, destroyed mitochondria and induced apoptosis. The fusion peptide and its targeting ability that allowing KLA to specifically enter pancreatic tumor cells and exert a significant inhibitory effect on pancreatic tumor growth with reduced toxic effects. Conclusion This approach possesses potential advantages in the clinical diagnosis and treatment of pancreatic cancer.

MiR-183 is a tumor onco-miR and has been shown by our previous studies to be overexpressed in esophageal squamous cell carcinomas (ESCCs). In this study, we sought to determine the possible mechanisms of miR-183 in ESCC. In our study, cell migration and invasion, real-time PCR, Western blot, and chromatin immunoprecipitation (ChIP) assays were used to explore the mechanism of miR-183 in three ESCC cell lines. We found several potential transcription factors, including c-Jun, by bioinformatics methods. Using a ChIP assay, we identified that c-Jun binds to the promoter region of pre-miR-183 and that upregulated c-Jun expression is related to increased expression of miR-183. We found that downregulation of miR-183 significantly reduced the cell invasiveness and migration of ESCC cells, whereas upregulation of miR-183 via a mimic increased the cell migration and invasion of ESCC cells. We further discovered one direct miR-183 target gene, Smad4, which has been implicated in invasion and metastasis. Furthermore, miR-183 promoted epithelial-mesenchymal transition (EMT), which is involved in the invasion and migration of ESCC cells. Dysregulation of miR-183 has an important role in tumor growth and invasion because miR-183 targets Smad4. Therefore, suppression of miR-183 may provide a potential approach for treatment.

Cell senescence is a fundamental mechanism of aging and appears to play vital roles in the onset and prognosis of cardiovascular disease, fibrotic pulmonary disease, liver disease and tumor. Moreover, an increasing body of evidence shows that cell senescence plays an indispensable role in the formation and development of atherosclerosis. Multiple senescent cell types are associated with atherosclerosis, senescent human vascular endothelial cells participated in atherosclerosis via regulating the level of endothelin-1 (ET-1), nitric oxide (NO), angiotensin II and monocyte chemoattractant protein-1 (MCP-1), senescent human vascular smooth muscle cells-mediated plaque instability and vascular calcification via regulating the expression level of BMP-2, OPN, Runx-2 and inflammatory molecules, and senescent macrophages impaired cholesterol efflux and promoted the development of senescent-related cardiovascular diseases. This review summarizes the characteristics of cell senescence and updates the molecular mechanisms underlying cell senescence. Moreover, we also discuss the recent advances on the molecular mechanisms that can potentially regulate the development and progression of atherosclerosis.

Epigenetic regulation of gene expression in cancer cells has been extensively studied in recent decades, resulting in the FDA approval of multiple epigenetic agents for treating different cancer types. Recent studies have revealed novel roles of epigenetic dysregulation in altering the phenotypes of immune cells and tumor-associated stromal cells, including fibroblasts and endothelial cells. As a result, epigenetic dysregulation of these cells reshapes the tumor microenvironment (TME), changing it from an antitumor environment to an immunosuppressive environment. Here, we review recent studies demonstrating how specific epigenetic mechanisms drive aspects of stromal and immune cell differentiation with implications for the development of solid tumor therapeutics, focusing on the pancreatic ductal adenocarcinoma (PDA) TME as a representative of solid tumors. Due to their unique ability to reprogram the TME into a more immunopermissive environment, epigenetic agents have great potential for sensitizing cancer immunotherapy to augment the antitumor response, as an immunopermissive TME is a prerequisite for the success of cancer immunotherapy but is often not developed with solid tumors. The idea of combining epigenetic agents with cancer immunotherapy has been tested both in preclinical settings and in multiple clinical trials. In this review, we highlight the basic biological mechanisms underlying the synergy between epigenetic therapy and immunotherapy and discuss current efforts to translate this knowledge into clinical benefits for patients.

Atherosclerosis is an immune inflammatory disease and a major cause of mortality and morbidity worldwide. It is generally considered that a number of potent proinflammatory cytokines have a great influence on its pathogenesis, including IL-1β, IL-6, TNF-α, and NF-κB. A growing amount of empirical evidence indicates that the mechanism of cardiac dysfunction caused by lipopolysaccharide (LPS) is the activation of inflammation, but the exact mechanism in atherosclerosis is still unclear. Previous studies have shown that interferon-induced protein with tetratricopeptide repeats 1 (IFIT1) participates in inflammation, but the effects and possible mechanism of action of IFIT1 on proinflammatory response remain largely unexplained. We found that LPS induced upregulation of IFIT1 expression in a time- and concentration-dependent manner in human umbilical vein endothelial cells (HUVECs). Overexpression of IFIT1 significantly upregulated LPS-induced expression of IL-1β, IL-6, TNF-α, and NF-κB in HUVECs. IFIT1-siRNA treatment dramatically decreased LPS-induced expression of IL-1β, IL-6, TNF-α, and NF-κB in HUVECs. The above results show that LPS induces expression of IL-1β, IL-6, TNF-α, and NF-κB through upregulating IFIT1 expression in HUVECs, and suggested that IFIT1 could act as potential therapeutic target to ameliorate atherosclerosis-related diseases.

Traumatic injury and hemorrhagic shock result in endothelial cell activation and vascular dysfunction that, if not corrected, can propagate multiorgan failure. Angiopoietin-1 and angiopoietin-2 are important regulators of endothelial cell function, and the ratio of plasma angiopoietin-2-to-1 is a useful indicator of overall vascular health. We therefore characterized plasma angiopoietin-2/-1 ratios over time after trauma in adults in an effort to gain insight into the pathophysiology that may drive post-traumatic vasculopathy and organ injury. We performed a single-center prospective observational study to measure plasma angiopoietin-1 and -2 levels and determine angiopoietin-2/-1 ratios in adult trauma patients upon hospital arrival and after 12, 24, and 48 h. Compared with levels in healthy adults, angiopoietin-1 levels were significantly elevated at hospital arrival, and angiopoietin-2 levels were significantly elevated at 12, 24, and 48 h. These kinetics translated in angiopoietin-2/-1 ratios that were significantly greater than controls at 24 and 48 h. After regression analysis, elevated angiopoietin-2 levels were independently associated with blunt injuries at admission, with coagulopathy at admission and 12 h, and with hemorrhagic shock at 24 and 48 h. Significant correlations were observed between both angiopoietins and 24-h transfusion requirements. Angiopoietin-2/-1 ratios correlated with mechanical ventilation duration and intensive care unit and hospital lengths of stay. In this study, we demonstrate novel temporal associations between angiopoietin dysregulation and blunt injuries, acute coagulopathy, and hemorrhagic shock. Moreover, our findings highlight the presence of endothelial activation following traumatic insults in adults that may contribute to worse clinical outcomes.

Human preimplantation development is a complex process involving dramatic changes in transcriptional architecture. For a better understanding of their time-spatial development, it is indispensable to identify key genes. Although the single-cell RNA sequencing (RNA-seq) techniques could provide detailed clustering signatures, the identification of decisive factors remains difficult. Additionally, it requires high experimental cost and a long experimental period. Thus, it is highly desired to develop computational methods for identifying effective genes of development signature. In this study, we first developed a predictor called EmPredictor to identify developmental stages of human preimplantation embryogenesis. First, we compared the F-score of feature selection algorithms with differential gene expression (DGE) analysis to find specific signatures of the development stage. In addition, by training the support vector machine (SVM), four types of signature subsets were comprehensively discussed. The prediction results showed that a feature subset with 1,881 genes from the F-score algorithm obtained the best predictive performance, which achieved the highest accuracy of 93.3% on the cross-validation set. Further function enrichment demonstrated that the gene set selected by the feature selection method was involved in more development-related pathways and cell fate determination biomarkers. This indicates that the F-score algorithm should be preferentially proposed for detecting key genes of multi-period data in mammalian early development.

Metastatic pancreatic ductal adenocarcinoma (PDAC) is one of the most lethal solid tumours despite the use of multi-agent conventional chemotherapy regimens. Such poor outcomes have fuelled ongoing efforts to exploit the tumour microenvironment (TME) for therapy, but strategies aimed at deconstructing the surrounding desmoplastic stroma and targeting the immunosuppressive pathways have largely failed. In fact, evidence has now shown that the stroma is multi-faceted, which illustrates the complexity of exploring features of the TME as isolated targets. In this Review, we describe ways in which the PDAC microenvironment has been targeted and note the current understanding of the clinical outcomes that have unexpectedly contradicted preclinical observations. We also consider the more sophisticated therapeutic strategies under active investigation - multi-modal treatment approaches and exploitation of biologically integrated targets - which aim to remodel the TME against PDAC.

Purpose Metformin combined with the mTOR inhibitor rapamycin showed potential synergistic anti-tumor activity in preclinical studies in pancreatic ductal adenocarcinoma (PDA). This phase 1b study (NCT02048384) was conducted to evaluate the feasibility and activity of metformin +/- rapamycin in the maintenance setting for unselected patients with metastatic PDA (mPDA) treated with chemotherapy. Materials and methods Eligible patients with stable or responding mPDA after ≥ 6 months on chemotherapy were randomized 1:1 to metformin alone (Arm A) or with rapamycin (Arm B), stratified by prior treatment with FOLFIRINOX. Fluorodeoxyglucose (FDG) PET scans and peripheral blood mononuclear cells were obtained for exploratory analyses. Results 22 subjects (11 per arm) received treatment per protocol. Median PFS/OS were 3.5 and 13.2 months respectively, with 2 year OS rate of 37%; there were no differences between arms. No responses were observed by RECIST; however, decreases in FDG avidity and/or CA19-9 were observed in several long-term survivors. Treatment related adverse events of Grade ≥ 3 occurred in 0% vs 27% of patients in Arm A vs B and were asymptomatic hematologic or electrolyte abnormalities that were not clinically significant. Improved survival was associated with low baseline neutrophil: lymphocyte ratio, baseline lack of assessable disease by PET, and greater expansion of dendritic cells following treatment. Conclusions Metformin +/- rapamycin maintenance for mPDA was well-tolerated and several patients achieved stable disease associated with exceptionally long survival. Further prospective studies are needed to clarify the role of these agents in the maintenance setting and to enhance patient selection for such approaches.

Atopic dermatitis (AD) seriously affects the quality of life of children and their families. This meta-analysis aimed to comprehensively analyze health education on the treatment of children with AD and the quality of life of the patient's family. A comprehensive search of reference lists in PubMed, Embase, Cochrane Library, Wanfang, CNKI, and VIP databases from inception until April 2018 was performed. The weighted mean difference (WMD) with 95% confidence interval (CI) was calculated. A total of eight randomized controlled trials studies were included in the analysis. The heterogeneity among enrolled studies was statistically significant, and the random effects model was used. The meta-analysis showed that the health education group had significantly lower SCORing Atopic Dermatitis (SCORAD) (WMD = 7.57 [95% CI 2.77, 12.36], P = 0.002 at 3 months; WMD = 6.88 [95% CI 2.68, 11.08], P = 0.001 at 6 months; WMD = 8.67 [95% CI 3.67, 13.67], P = 0.0007 at 12 months), objective SCORAD (WMD = 7.60 [95% CI 1.37, 13.83], P = 0.02 at 6 months; WMD = 5.15 [95% CI 1.89, 8.41], P = 0.002 at 12 months), and Infants' Dermatology Quality of Life Index (WMD = 0.96 [95% CI 0.06, 1.86], P = 0.04 at 3 months, and WMD = 1.50 [95% CI 0.33, 2.67] at 6 months, P = 0.01) scores compared with the non-health education group. Health education could improve the treatment of children with AD and promote disease control.

Cancer immunotherapy has reached a critical point, now that immune checkpoint inhibitors and two CAR-T products have received market approval in treating 16 types of cancers and 1 tissue-agnostic cancer indication. Accompanying these advances, the 2018 Nobel Prize was awarded for the discovery of immune checkpoint pathways, which has led to the revolution of anti-cancer treatments. However, expanding the indications of immuno-oncology agents and overcoming treatment resistance face mounting challenges. Although combination immunotherapy is an obvious strategy to pursue, the fact that there have been more failures than successes in this effort has served as a wake-up call, placing emphasis on the importance of building a solid scientific foundation for the development of next-generation immuno-oncology (IO) agents. The 2019 China Cancer Immunotherapy Workshop was held to discuss the current challenges and opportunities in IO. At this conference, emerging concepts and strategies for IO development were proposed, focusing squarely on correcting the immunological defects in the tumor microenvironment. New targets such as Siglec-15 and new directions including neoantigens, cancer vaccines, oncolytic viruses, and cytokines were reviewed. Emerging immunotherapies were discussed in the areas of overcoming primary and secondary resistance to existing immune checkpoint inhibitors, activating effector cells, and targeting immunosuppressive mechanisms in the tumor microenvironment. In this article, we highlight old and new waves of IO therapy development, and provide perspectives on the latest momentum shifts in cancer immunotherapy.

How the NPs effect the growth and physiological response like the release of organic acids along the root exudates is largely unknown yet. In this study, the effects of titanium dioxide (TiO2) and silicon dioxide (SiO2) nanoparticles (NPs) treatments (1000 mg/L) on maize seedlings for 6 days were examined. Plant biomass, pigment, malondialdehyde (MDA), reactive oxygen species (ROS) production, and contents of organic acids in root exudates were analyzed. SiO2 NPs significantly reduced (p 0.05) in chlorophyll a content compared to the CK, while chlorophyll b increased by 28.9% (p

Background Circulating tumor cells (CTCs) has been demonstrated as a promising liquid biopsy marker for breast cancer (BC). However, the intra-patient heterogeneity of CTCs remains a challenge to clinical application. We aim at profiling aggressive CTCs subpopulation in BC utilizing the distinctive metabolic reprogramming which is a hallmark of metastatic tumor cells. Methods Oncomine, TCGA and Kaplan–Meier plotter databases were utilized to analyze expression and survival relevance of the previously screened metastasis-promoting metabolic markers (PGK1/G6PD) in BC patients. CTCs detection and metabolic classification were performed through micro-filtration and multiple RNA in situ hybridization using CD45 and PGK1/G6PD probes. Blood samples were collected from 64 BC patients before treatment for CTCs analysis. Patient characteristics were recorded to evaluate clinical applications of CTCs metabolic subtypes, as well as morphological EMT subtypes classified by epithelial (EpCAM/CKs) and mesenchymal (Vimentin/Twist) markers. Results PGK1 and G6PD expressions were up-regulated in invasive BC tissues compared with normal mammary tissues. Increased tissue expressions of PGK1 or G6PD indicated shortened overall and relapse-free survival of BC patients (P +CTCs (DAPI+CD45−PGK1/G6PD+) was detectable (range 0–54 cells/5 mL) in 61.8% of tCTCs > 0 patients. Increased GM+CTCs number and positive rate were correlated with tumor metastasis and progression (P +CTCs ≥ 2/5 mL level presented superior AUC of ROC at 0.854 (95% CI 0.741–0.968) in the diagnosis of BC metastasis (sensitivity/specificity: 66.7%/91.3%), compared with that of tCTCs (0.779) and CTCs-EMT subtypes (E-CTCs 0.645, H-CTCs 0.727 and M-CTCs 0.697). Moreover, GM+CTCs+ group had inferior survival with decreased 2 years-PFS proportion (18.5%) than GM+CTCs− group (87.9%; P = 0.001). Conclusions This work establishes a PGK1/G6PD-based method for CTCs metabolic classification to identify the aggressive CTCs subpopulation. Metabolically active GM+CTCs subtype is suggested a favorable biomarker of distant metastasis and prognosis in BC patients.

Background Drug resistance is a major obstacle to treating cancers because it desensitizes cancer cells to chemotherapy. Recently, attention has been focused on changes in the tumor immune landscape after the acquisition of drug resistance. Programmed death-ligand-1 (PD-L1) is an immune suppressor that inhibits T cell-based immunity. Evidence has shown that acquired chemoresistance is associated with increased PD-L1 expression in cancer cells. However, the underlying mechanism is still largely unknown. Methods PD-L1 expression in three drug-resistant A549/CDDP, MCF7/ADR and HepG2/ADR cell lines was detected by qRT-PCR, western blotting and flow cytometry, and a T cell proliferation assay was performed to test its functional significance. Then, the potential roles of JNK/c-Jun, histone H3 acetylation, histone deacetylase 3 (HDAC3) and the E3 ligase COP1 in the PD-L1 increase were explored through ChIP assays and gain- and loss-of-function gene studies. Furthermore, murine xenograft tumor models were used to verify the role of JNK/c-Jun and HDAC3 in PD-L1 expression in A549/CDDP cells in vivo. Finally, the correlations of PD-L1, c-Jun and HDAC3 expression in clinical cisplatin-sensitive and cisplatin-resistant non-small cell lung cancer (NSCLC) tissues were analyzed by immunohistochemistry and Pearson’s correlation coefficient. Results PD-L1 expression was significantly increased in A549/CDDP, MCF7/ADR and HepG2/ADR cells and was attributed mainly to enhanced JNK/c-Jun signaling activation. Mechanistically, decreased COP1 increased c-Jun accumulation, which subsequently inhibited HDAC3 expression and thereby enhanced histone H3 acetylation of the PD-L1 promoter. Furthermore, PD-L1 expression could be inhibited by JNK/c-Jun inhibition or HDAC3 overexpression in vivo, which could largely reverse inhibited CD3+ T cell proliferation in vitro. PD-L1 expression was significantly increased in the cisplatin-resistant clinical NSCLC samples and positively correlated with c-Jun expression but negatively correlated with HDAC3 expression. Conclusions Enhanced histone H3 acetylation of the PD-L1 promoter via the COP1/c-Jun/HDAC3 axis was crucial for the PD-L1 increase in drug-resistant cancer cells. Our study reveals a novel regulatory network for the PD-L1 increase in drug-resistant cancer cells and that combined PD-L1-targeting strategies could improve T cell-based immunity in drug-resistant cancers.

Although bariatric surgery can achieve sustained weight loss, there are major differences in the magnitude of weight change post-operatively. Reduced resting energy expenditure (REE) plays an important role in unsatisfactory weight loss effect by contributing to positive energy balance. To identify pre- and post-surgical predictors related to satisfactory percent of total weight loss (%TWL) in Chinese individuals with obesity after laparoscopic sleeve gastrectomy (LSG). A retrospective cohort study was conducted in 97 ethnic Chinese with mean body mass index (BMI) of 37.2 kg/m2, focusing on body composition, anthropometric and metabolic energy expenditure parameters, and %TWL before and 6 months after LSG. Patients were divided post-operatively into those with or without satisfactory %TWL (%TWL ≥ 20%). Multiple stepwise logistic regression analysis was used to identify predictors. Satisfactory %TWL was achieved in 53 (54.6%) patients 6 months after surgery. The univariate analysis of post-operative variables showed that patients with satisfactory %TWL had significantly higher resting energy expenditure/body weight (REE/BW) and lower respiratory quotient (RQ) than those who did not (P

The present study sought to investigate the effect of non-mitogenic acidic fibroblast growth factor (NM-aFGF) loaded PEGylated nanoliposomes (NM-aFGF-PEG-lips) combined with the ultrasound-targeted microbubble destruction (UTMD) technique on modulating diabetic cardiomyopathy (DCM)and the mechanism involved. Animal studies showed that the diabetes mellitus (DM) group exhibited typical myocardial structural and functional changes of DCM. The indexes from the transthoracic echocardiography showed that the left ventricular function in the NM-aFGF-PEG-lips + UTMD group was significantly improved compared with the DM group. Histopathological observation further confirmed that the cardiomyocyte structural abnormalities and mitochondria ultrastructural changes were also significantly improved in the NM-aFGF-PEG-lips + UTMD group compared with DM group. The cardiac volume fraction (CVF) and apoptosis index in the NM-aFGF-PEG-lips + UTMD group decreased to 10.31 ± 0.76% and 2.16 ± 0.34, respectively, compared with those in the DM group (CVF = 21.4 ± 2.32, apoptosis index = 11.51 ± 1.24%). Moreover, we also found significantly increased superoxide dismutase (SOD) activity and glutathione peroxidase (GSH-Px) activity as well as clearly decreased lipid hydroperoxide levels and malondialdehyde (MDA) activity in the NM-aFGF-PEG-lips + UTMD group compared with those in the DM group (p

The main diagnostic indicators of ovarian cancer (OC), including carbohydrate antigen 125 (CA125) and human epididymis protein 4 (HE4), show good sensitivity and poor specificity or vice versa. This study investigated changes in CA125 and HE4 expression and their correlation in serum-derived exosomes of 55 patients with OC (OC group), 33 patients with malignant tumors (non-OC group), and 55 normal controls (NC group). We compared serum and exosomal CA125 and HE4 levels to determine whether their contents in exosomes were elevated. We also compared the diagnostic efficacy of serum HE4, serum CA125, exosomal CA125, and serum HE4+exosomal CA125 in OC using the receiver operating characteristic (ROC) curve. CA125 levels in serum-derived exosomes in all groups significantly increased (P < 0.0001) compared with serum CA125 levels. HE4 was undetected in exosomes. The ROC curve showed the following values: serum CA125: 0.9093 (area), 87.27% (sensitivity), and 90.91% (specificity); serum HE4: 0.9302, 83.64%, and 94.55%; exosomal CA125: 0.9755, 94.55%, and 92.73%; and serum HE4+exosomal CA125: 0.9861, 96.36%, and 92.73%. In conclusion, CA125 can be detected at higher levels in exosomes than in serum, significantly improving OC diagnosis sensitivity. The serum HE4+exosomal CA125 combination significantly improves OC diagnostic efficiency.

Background and aims Many clinical trials have demonstrated that statins convey protective effects against atherosclerosis independent of cholesterol-lowering capacities. Other evidence indicates that pyroptosis, a type of programmed cell death, is likely involved in atherosclerosis, but the effects and mechanisms of statins on pyroptosis must be further revealed. Methods Here, we explored the effects and mechanisms of atorvastatin on pyroptosis in human vascular endothelial cells by quantitative real-time polymerase chain reaction and Western blot analyses. Results Atorvastatin upregulated long non-coding RNA (lncRNA) NEXN-AS1 and the expression of NEXN at both the mRNA and protein levels in a concentration- and time-dependent manner. Atorvastatin inhibited pyroptosis by decreasing the expression levels of the canonical inflammasome pathway biomarkers NLRP3, caspase-1, GSDMD, IL-1β, and IL-18 at both the mRNA and protein levels. The promotion effects of atorvastatin on NEXN-AS1 and NEXN expression could be significantly abolished by knockdown of lncRNA NEXN-AS1 or NEXN, and its inhibitory effects on pyroptosis were also markedly offset by knock-down of lncRNA NEXN-AS1 or interference of NEXN. Conclusions These results demonstrated that atorvastatin regulated pyroptosis via the lncRNA NEXN-AS1-NEXN pathway, which provides a new insight into the mechanism of how atorvastatin promotes non-lipid-lower effects against the development of atherosclerosis and gives new directions on how to reverse atherosclerosis.

Background The Hedgehog (Hh) signalling pathway is overexpressed in pancreatic ductal adenocarcinoma (PDA). Preclinical studies have shown that Hh inhibitors reduce pancreatic cancer stem cells (pCSC), stroma and Hh signalling. Methods Patients with previously untreated metastatic PDA were treated with gemcitabine and nab-paclitaxel. Vismodegib was added starting on the second cycle. The primary endpoint was progression-free survival (PFS) as compared with historical controls. Tumour biopsies to assess pCSC, stroma and Hh signalling were obtained before treatment and after cycle 1 (gemcitabine and nab-paclitaxel) or after cycle 2 (gemcitabine and nab-paclitaxel plus vismodegib). Results Seventy-one patients were enrolled. Median PFS and overall survival (OS) were 5.42 months (95% confidence interval [CI]: 4.37–6.97) and 9.79 months (95% CI: 7.85–10.97), respectively. Of the 67 patients evaluable for response, 27 (40%) had a response: 26 (38.8%) partial responses and 1 complete response. In the tumour samples, there were no significant changes in ALDH + pCSC following treatment. Conclusions Adding vismodegib to chemotherapy did not improve efficacy as compared with historical rates observed with chemotherapy alone in patients with newly diagnosed metastatic pancreatic cancer. This study does not support the further evaluation of Hh inhibitors in this patient population. Trial registration ClinicalTrials.gov Identifier: NCT01088815.

To investigate whether quantitative radiomics features extracted from computed tomography (CT) can predict microsatellite instability (MSI) status in an Asian cohort of patients with stage Ⅱ colorectal cancer (CRC).This retrospective study was approved by our institutional review board, and the informed consent requirement was waived. From March 2016 to March 2018, 119 Chinese patients with pathologically confirmed stage Ⅱ CRC, available MSI status, and preoperative contrast-enhanced CT images were included in this study. Clinical and pathological information was obtained from the institutional database. The radiomics features were extracted from portal venous-phase CT images of segmented volumes of each entire primary tumor by using Matrix Laboratory (MATLAB), and radiomics signatures were generated using the least absolute shrinkage and selection operator logistic regression model. The minority group was balanced via synthetic minority over-sampling technique method. The association between the clinicopathologic characteristics and MSI status was assessed using Student's t test, Chi-square, or Fisher's exact test. The predictive efficacy of MSI status using radiomics features, clinical factors (including age, gender, CT-reported tumor location, differentiation degree of tumor, smoking history, hypertension history, family history of cancer, diabetes history, level of the Ki-67 expression, and laboratory analysis) and the combined models were evaluated, respectively. Predictive performance was evaluated by the area under receiver operating characteristic curve, accuracy, sensitivity, and specificity.MSI status was significantly associated with tumor location (p = 0.043); differentiation degree of tumor (p0.0001), hypertension history (p = 0.012), and the level of the Ki-67 expression (p = 0.015). Six radiomics features and 11 clinical characteristics were selected for predicting MSI status. The model that used the combination of clinical factors and radiomics features achieved the overall best performance than using either of the two features alone, yielding the area under the curve, sensitivity, and specificity of 0.752, 0.663, 0.841 for the combined model, 0.598, 0.371, 0.825 for clinical factors alone, and 0.688, 0.517, 0.858 for radiomics features alone, respectively.CT-based radiomic features of stage Ⅱ CRC are associated with MSI status. Combining analysis of clinical features and CT features could improve predictive efficacy and could potentially select the patients for individualized therapy noninvasively.

This study aimed to evaluate intraoral anastomosis of a deep circumflex iliac artery (DCIA) flap in combination with computer-assisted techniques for mandibular reconstruction. Between December 2015 and March 2018, 4 patients with mandibular discontinuity defects caused by ablative tumor surgery were included in the study. Mandibular reconstruction was performed with a DCIA flap using computer-assisted and intraoral anastomosis techniques. A computer-aided design-computer-aided manufacturing cutting guide, a reconstruction stereomodel, and a prebent reconstruction plate were used for mandibular reconstruction in each patient. Anastomosis was performed on the facial artery and vein using the deep circumflex iliac vessels through an intraoral approach. The resulting error-grade color map was used to evaluate repeatability between the preoperative design and postoperative results. Mandibular reconstruction with a DCIA flap using computer-assisted and intraoral anastomosis techniques was successful in all 4 patients. All flaps survived with no severe complications. Satisfactory cosmetic outcomes and occlusion with sufficient bone height for implants were achieved postoperatively. Repeatability between the virtual plan and postoperative result was 81.1% ± 8.2% within 1 mm, 85.8% ± 8.1% within 2 mm, and 89.6% ± 6.7% within 3 mm. The use of intraoral anastomosis and computer-assisted techniques with DCIA flaps for mandibular reconstruction without additional facial scarring is feasible and advantageous. However, the findings should be interpreted cautiously owing to the relatively short follow-up time and limited number of patients involved in this study.

KRAS is the most common oncogene to be mutated in lung cancer, and therapeutics directly targeting KRAS have proven to be challenging. The mutations of KRAS are associated with poor prognosis, and resistance to both adjuvant therapy and targeted EGFR TKI. EGFR TKIs provide significant clinical benefit for patients whose tumors bear EGFR mutations. However, tumors with KRAS mutations rarely respond to the EGFR TKI therapy. Thus, combination therapy is essential for the treatment of lung cancers with KRAS mutations. EGFR TKI combined with inhibitors of MAPKs, PI3K/mTOR, HDAC, Wee1, PARP, CDK and Hsp90, even miRNAs and immunotherapy, were reviewed. Although the effects of the combination vary, the combined therapeutics are one of the best options at present to treat KRAS mutant lung cancer.

Objective To perform molecular diagnosis and genetic counseling in a young Chinese couple with congenital hearing loss. Methods Variant screening analysis was performed by PCR and direct Sanger sequencing or targeted next-generation sequencing of all known hearing loss genes. Novel variants were evaluated by PolyPhen2 and PROVEAN software tools to evaluate possible effects on protein function. Results We identified causative variants in the young couple: c.235delC (rs80338943)/c.299-300delAT (rs111033204) compound heterozygous variants of GJB2 in the husband and c.1828G>A (p.Glu610Lys, rs535637788)/c.2825-2827delAGA compound heterozygous variants of LOXHD1 in the wife. The LOXHD1 c.1828G>A variant has only previously been reported in a Mexican-American individual in the 1000 Genomes Project database. Using PolyPhen2 and PROVEAN, we speculated that the LOXHD1 variant c.1828G>A is potentially pathogenic. Conclusion We carried out molecular diagnosis in a young couple with congenital hearing loss, and identified different disease-causing genes in the two individuals. The LOXHD1 variant c.1828G>A present in the wife had not previously been reported in individuals with congenital hearing loss. We determined this to be a potential pathogenic variant, and a novel variant associated with hearing loss in a Chinese individual.