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Abstract The antiangiogenic agent apatinib has been shown to clinically improve responses to immune checkpoint inhibitors in several cancer types. Patients with N3 nasopharyngeal carcinoma have a high risk of distant metastasis, however, if the addition of immunotherapy to standard treatment could improve efficacy is unclear. In this phase II clinical trial (ChiCTR2000032317), 49 patients with stage TanyN3M0 nasopharyngeal carcinoma were enrolled and received the combination of three cycles of induction chemotherapy, camrelizumab and apatinib followed by chemoradiotherapy. Here we report on the primary outcome of distant metastasis-free survival and secondary end points of objective response rate, failure-free survival, locoregional recurrence-free survival, overall survival and toxicity profile. After induction therapy, all patients had objective response, including 13 patients (26.5%) with complete response. After a median follow-up of 28.7 months, the primary endpoint of 1-year distant metastasis-free survival was met for the cohort (1-year DMFS rate: 98%). Grade≥3 toxicity appeared in 32 (65.3%) patients, with the most common being mucositis (14[28.6%]) and nausea/vomiting (9[18.4%]). In this work, camrelizumab and apatinib in combination with induction chemotherapy show promising distant metastasis control with acceptable safety profile in patients with stage TanyN3M0 nasopharyngeal carcinoma.

Abstract Background Knee osteoarthritis (KOA) has a complex pathological mechanism and is difficult to cure. The traditional medicine Du Huo Ji Sheng Tang (DHJST) has been used for the treatment of KOA for more than one thousand years, but its mechanism for treating KOA has not been revealed. In our previous study, we confirmed that DHJST inhibited the activation of NLRP3 signaling in rats and humans. In the current study, we aimed to determine how DHJST inhibits NLRP3 to alleviate knee cartilage damage. Methods Mice were injected with NLRP3 shRNA or Notch1-overexpressing adenovirus into the tail vein to construct systemic NLRP3 low-expressing or Notch1 high-expressing mice. Mice were injected with papain into the knee joint to replicate the KOA model. DHJST was used to treat KOA model mice with different backgrounds. The thickness of the right paw was measured to evaluate toe swelling. The pathohistological changes and the levels of IL-1β, MMP2, NLRP3, Notch1, collagen 2, collagen 4, HES1, HEY1, and Caspase3 were detected by HE staining, ELISA, immunohistochemical staining, western blotting, or real-time qPCR. Results DHJST reduced tissue swelling and serum and knee cartilage IL-1β levels, inhibited cartilage MMP2 expression, increased collagen 2 and collagen 4 levels, decreased Notch1 and NLRP3 positive expression rates in cartilage, and decreased HES1 and HEY1 mRNA levels in KOA model mice. In addition, NLRP3 interference decreased cartilage MMP2 expression and increased collagen 2 and collagen 4 levels without affecting the expression levels of notch1, HES1 and HEY1 mRNA levels in the synovium of KOA mice. In KOA mice with NLRP interference, DHJST further reduced tissue swelling and knee cartilage damage in mice. Finally, Notch1-overexpressing mice not only showed more severe tissue swelling and knee cartilage degradation but also abolished the therapeutic effect of DHJST on KOA mice. Importantly, the inhibitory effects of DHJST on the mRNA expression of NLRP3, Caspase3 and IL-1β in the knee joint of KOA mice were completely limited after Notch1 overexpression. Conclusion DHJST significantly reduced inflammation and cartilage degradation in KOA mice by inhibiting Ntoch1 signaling and its subsequent NLRP3 activation in the knee joint.

Older individuals with macular diseases, such as age-related macular degeneration, experience central vision loss (CVL) due to degeneration of their photoreceptors and retinal cells. Patients with CVL may experience various vision impairments, including of visual acuity, fixation stability, contrast sensitivity, and stereoacuity. After CVL, most patients develop a preferred retinal locus outside the affected macular region, which serves as a new visual reference. In this review, we provide an overview of the visual function and impairment in individuals with CVL. In addition, the important role of biofeedback training on the visual function and activity of individuals with CVL is also reviewed. Accordingly, the location and development of the preferred retinal loci are discussed. Finally, this review discusses how to conduct biofeedback training to treat individuals with CVL.

AIM: To evaluate the application of optical coherence tomography angiography(OCTA)in diabetic patients without retinopathy(NDR)by Meta-analysis.METHODS: CNKI, WanFang Data, VIP, CBM, PubMed, and Embase databases were searched for relevant studies. The retrieval time was from the establishment of the database to October 2021. Two investigators independently screened the literature, extracted data and evaluated the quality of the included studies using the NOS scale. Meta-analysis and publication bias evaluation was performed using RevMan 5.3 and STATA, and sensitivity analysis was performed for results with large heterogeneity to ensure the accuracy of the results.RESULTS: A total of 44 studies, including 2 053 patients(2 600 eyes)with NDR and 1 775 healthy control patients(2 117 eyes), were included. The Meta-analysis was performed on 17 indexes including the area and perimeters of the foveal avascular zone(FAZ), the vascular density(VD)of FAZ-300um(FD300), acircularity index(AI), VD of macular area, ganglion cell complex(GCC)thickness and retinal nerve fiber layer(RNFL)thickness. Meta-analysis results showed that the area and perimeter of FAZ in superficial capillary plexus(SCP)and deep capillary plexus(DCP)in the NDR group were higher than those of healthy control patients, and FD300, VD of macular area and RNFL thickness were all lower than those in the control group(all P0.05).CONCLUSIONS: Compared to the healthy control group, NDR patients had increased FAZ area and perimetry, decreased VD of macular area and RNFL thickness and early retinal microvascular damage and neurodegenerative lesions. OCTA could be used as an auxiliary tool for early diagnosis of DR.

Abstract The spatial and temporal characteristics of the factors influencing metro passenger flow are basic phenomena reflecting the environment‐land relationship. Existing studies tend to focus more on the characteristics of metro trips and the static built environment. One of the outstanding contributions of this paper is to expand the scope of the factors influencing the built environment of metro stations and explore the spatial differentiation and pattern characteristics of the static and dynamic environments. This paper provides additional empirical insights into spatiotemporal influencing factors of metro mobility patterns from the dynamic perspective. The results show spatial and temporal heterogeneity between four types of metro stations and their influencing factors. 21.59% of the stations are in in active areas, while the distribution of parking lots has a positive effect on metro passenger flow; 29.55% of the stations belong to integrated residential areas, and the number of residential areas is the dominant factor in such agglomerations; 38.64% of the areas belong to work areas, and such areas have the highest work‐related coefficients, but the work variable in the central city has a certain inhibiting effect; 10.23% of the stations are in commercial areas, which are mainly distributed within the central urban area.

Abstract Background Acute myeloid leukemia (AML) is a myeloid neoplasm makes up 7.6% of hematopoietic malignancies. Super-enhancers (SEs) represent a special group of enhancers, which have been reported in multiple cell types. In this study, we explored super-enhancer profiling through ChIP-Seq analysis of AML samples and AML cell lines, followed by functional analysis. Methods ChIP-seq analysis for H3K27ac was performed in 11 AML samples, 7 T-ALL samples, 8 B-ALL samples, and in NB4 cell line. Genes and pathways affected by GNE-987 treatment were identified by gene expression analysis using RNA-seq. One of the genes associated with super-enhancer and affected by GNE-987 treatment was LYL1 basic helix-loop-helix family member (LYL1). shRNA mediated gene interference was used to down-regulate the expression of LYL1 in AML cell lines, and knockdown efficiency was detected by RT-qPCR and western blotting. The effect of knockdown on the growth of AML cell lines was evaluated by CCK-8. Western blotting was used to detect PARP cleavage, and flow cytometry were used to determine the effect of knockdown on apoptosis of AML cells. Results We identified a total of 200 genes which were commonly associated with super-enhancers in ≧10 AML samples, and were found enriched in regulation of transcription. Using the BRD4 inhibitor GNE-987, we assessed the dependence of AML cells on transcriptional activation for growth and found GNE-987 treatment predominantly inhibits cell growth in AML cells. Moreover, 20 candidate genes were selected by super-enhancer profile and gene expression profile and among which LYL1 was observed to promote cell growth and survival in human AML cells. Conclusions In summary, we identified 200 common super-enhancer-associated genes in AML samples, and a series of those genes are cancer genes. We also found GNE-987 treatment downregulates the expression of super-enhancer-associated genes in AML cells, including the expression of LYL1. Further functional analysis indicated that LYL1 is required for AML cell growth and survival. These findings promote understanding of AML pathophysiology and elucidated an important role of LYL1 in AML progression.

AIM: To explore the changes of retinal optical coherence tomography angiography(OCTA)vessel density in Patients with Alzheimer's disease(AD)by Meta-analysis, and to explore the value of OCTA in early diagnosis of AD patients.METHODS: Embase, PubMed and Cochrane Library data were searched from January 2016 to September 2021 for relevant studies on vessel density in macular area of AD patients. Two researchers independently screened the literature, extracted the data, and evaluated the risk of inclusion bias using Newcastle-Ottawa Scale(NOS). Meta-analysis was performed using RevMan 5.3 software.RESULTS: A total of 740 cases(eyes)were included in 10 literatures, including 321 cases from the AD group and 419 cases from the control group(age-matched people with normal cognitive abilities). The results of the Meta-analysis showed that the superficial vessel density in macular area of AD patients was lower than that in control group(MD=-1.58, 95%CI -2.60- -0.55, P=0.003). The deep vessel density in macular area of AD patients was lower than that in control group(MD=-2.72, 95%CI -4.36- -1.07, P=0.001). The parafoveal vessel density in AD patients was lower than that in control group(MD=-1.44, 95%CI -1.94- -0.94, P

Abstract Background Neuroblastoma (NB) is a common extracranial malignancy with high mortality in children. Recently, super-enhancers (SEs) have been reported to play a critical role in the tumorigenesis and development of NB via regulating a wide range of oncogenes Thus, the synthesis and identification of chemical inhibitors specifically targeting SEs are of great urgency for the clinical therapy of NB. This study aimed to characterize the activity of the SEs inhibitor GNE987, which targets BRD4, in NB. Results In this study, we found that nanomolar concentrations of GNE987 markedly diminished NB cell proliferation and survival via degrading BRD4. Meanwhile, GNE987 significantly induced NB cell apoptosis and cell cycle arrest. Consistent with in vitro results, GNE987 administration (0.25 mg/kg) markedly decreased the tumor size in the xenograft model, with less toxicity, and induced similar BRD4 protein degradation to that observed in vitro. Mechanically, GNE987 led to significant downregulation of hallmark genes associated with MYC and the global disruption of the SEs landscape in NB cells. Moreover, a novel candidate oncogenic transcript, FAM163A, was identified through analysis of the RNA-seq and ChIP-seq data. FAM163A is abnormally transcribed by SEs, playing an important role in NB occurrence and development. Conclusion GNE987 destroyed the abnormal transcriptional regulation of oncogenes in NB by downregulating BRD4, which could be a potential therapeutic candidate for NB.

Abstract Recent studies uncovered the emerging roles of SAPCD2 (suppressor anaphase-promoting complex domain containing 2) in several types of human cancer. However, the functions and underlying mechanisms of SAPCD2 in the progression of neuroblastoma (NB) remain elusive. Herein, through integrative analysis of public datasets and regulatory network of GSK-J4, a small-molecule drug with anti-NB activity, we identified SAPCD2 as an appealing target with a high connection to poor prognosis in NB. SAPCD2 promoted NB progression in vitro and in vivo. Mechanistically, SAPCD2 could directly bind to cytoplasmic E2F7 but not E2F1, alter the subcellular distribution of E2F7 and regulate E2F activity. Among the E2F family members, the roles of E2F7 in NB are poorly understood. We found that an increasing level of nuclear E2F7 was induced by SAPCD2 knockdown, thereby affecting the expression of genes involved in the cell cycle and chromosome instability. In addition, Selinexor (KTP-330), a clinically available inhibitor of exportin 1 (XPO1), could induce nuclear accumulation of E2F7 and suppress the growth of NB. Overall, our studies suggested a previously unrecognized role of SAPCD2 in the E2F signaling pathway and a potential therapeutic approach for NB, as well as clues for understanding the differences in subcellular distribution of E2F1 and E2F7 during their nucleocytoplasmic shuttling.

Abstract Background Acute myeloid leukemia (AML) is a myeloid neoplasm accounts for 7.6% of hematopoietic malignancies. AML is a complex disease, and understanding its pathophysiology is contributing to the improvement in the treatment and prognosis of AML. In this study, we assessed the expression profile and molecular functions of CCAAT enhancer binding protein gamma (CEBPG), a gene implicated in myeloid differentiation and AML progression. Methods shRNA mediated gene interference was used to down-regulate the expression of CEBPG in AML cell lines, and knockdown efficiency was detected by RT-qPCR and western blotting. The effect of knockdown on the growth of AML cell lines was evaluated by CCK-8. Western blotting was used to detect PARP cleavage, and flow cytometry were used to determine the effect of knockdown on apoptosis of AML cells. Genes and pathways affected by knockdown of CEBPG were identified by gene expression analysis using RNA-seq. One of the genes affected by knockdown of CEBPG was Eukaryotic translation initiation factor 4E binding protein 1 (EIF4EBP1), a known repressor of translation. Knockdown of EIF4EBP1 was used to assess its potential role in AML progression downstream of CEBPG. Results We explored the ChIP-Seq data of AML cell lines and non-AML hematopoietic cells, and found CEBPG was activated through its distal enhancer in AML cell lines. Using the public transcriptomic dataset, the Cancer Cell Line Encyclopedia (CCLE) and western blotting, we also found CEBPG was overexpressed in AML. Moreover, we observed that CEBPG promotes AML cell proliferation by activating EIF4EBP1, thus contributing to the progression of AML. These findings indicate that CEBPG could act as a potential therapeutic target for AML patients. Conclusion In summary, we systematically explored the molecular characteristics of CEBPG in AML and identified CEBPG as a potential therapeutic target for AML patients. Our findings provide novel insights into the pathophysiology of AML and indicate a key role for CEBPG in promoting AML progression.

Soil microbial fuel cells (SMFCs) are an innovative device for soil-powered biosensors. However, the traditional SMFC sensors relied on anodic biosensing which might be unstable for long-term and continuous monitoring of toxic pollutants. Here, a carbon-felt-based cathodic SMFC biosensor was developed and applied for soil-powered long-term sensing of heavy metal ions. The SMFC-based biosensor generated output voltage about 400 mV with the external load of 1000 Ω. Upon the injection of metal ions, the voltage of the SMFC was increased sharply and quickly reached a stable output within 2~5 min. The metal ions of Cd2+, Zn2+, Pb2+, or Hg2+ ranging from 0.5 to 30 mg/L could be quantified by using this SMFC biosensor. As the anode was immersed in the deep soil, this SMFC-based biosensor was able to monitor efficiently for four months under repeated metal ions detection without significant decrease on the output voltage. This finding demonstrated the clear potential of the cathodic SMFC biosensor, which can be further implemented as a low-cost self-powered biosensor.

Neuroblastoma (NB) is the most common solid tumor of the neural crest cell origin in children and has a poor prognosis in high-risk patients. The oncogene MYCN was found to be amplified at extremely high levels in approximately 20% of neuroblastoma cases. In recent years, research on the targeted hydrolysis of BRD4 to indirectly inhibit the transcription of the MYCN created by proteolysis targeting chimaera (PROTAC) technology has become very popular. dBET57 (S0137, Selleck, TX, USA) is a novel and potent heterobifunctional small molecule degrader based on PROTAC technology. The purpose of this study was to investigate the therapeutic effect of dBET57 in NB and its potential mechanism. In this study, we found that dBET57 can target BRD4 ubiquitination and disrupt the proliferation ability of NB cells. At the same time, dBET57 can also induce apoptosis, cell cycle arrest, and decrease migration. Furthermore, dBET57 also has a strong antiproliferation function in xenograft tumor models in vivo. In terms of mechanism, dBET57 targets the BET protein family and the MYCN protein family by associating with CRBN and destroys the SE landscape of NB cells. Combined with RNA-seq and ChIP-seq public database analysis, we identified the superenhancer-related genes TBX3 and ZMYND8 in NB as potential downstream targets of dBET57 and experimentally verified that they play an important role in the occurrence and development of NB. In conclusion, these results suggest that dBET57 may be an effective new therapeutic drug for the treatment of NB.

The logistics and manufacturing industries are basic industries that support social development. First, this study classifies the carbon emissions from the logistics industry and pollution emissions from the manufacturing industry as undesirable outputs and evaluates the ecological efficiency of the logistics and manufacturing industries in the Yangtze River Delta from 2006 to 2016 by using the unexpected slacks-based measure (SBM) model. Second, the study analyzes the spatial differences in industrial correlation efficiency by using the exploratory spatial data analysis method. Third, the spatial econometric model is used to analyze the driving factors of the linkage ecological efficiency between logistics industry and manufacturing industry. Finally, the neural network model is used to predict the linkage ecological efficiency. The results show that the ecological efficiency of the manufacturing industry has steadily improved. The ecological efficiency of the logistics industry presents the rising trend in fluctuation. The level of the linkage development between the logistics and manufacturing industries is high. The results of the spatial heterogeneity analysis show that the spatial differentiation of high–high agglomeration and low–low agglomeration is obvious. The spatial agglomeration characteristics are relatively stable, and the spatial diffusion effect is strong. In space, the linkage ecological efficiency shows a trend of development from multiple agglomeration areas to one agglomeration area. The results of driving factor analysis show that foreign direct investment (FDI), government intervention (GI), and human capital (HP) have positive effects on linkage ecological efficiency, while industrial structure (IS), environmental regulation (ER), and energy intensity (EI) have negative effects on linkage ecological efficiency. The results of the linkage development trend analysis show that the linkage ecological efficiency of the two industries will tend to be stable in the future.

AIM: To preliminary evaluate retinal sensitivity and the fixation alterations in patients with diabetic macular edema(DME)under Xiaozhong decoction combined intravitreal conbercept therapy. METHODS: The 40 patients with DME were randomly divided into two groups. Treatment group: 20 patients(20 eyes), Xiaozhong decoction combined with conbercept group and treatment group; 20 patients(20 eyes), placebo combined with conbercept group in our hospital from January to October in 2017. The two groups were taken oral Chinese medicinals or placebo for 3mo respectively. BCVA(ETDRS visual acuity test)and CRT(OCT)of the two groups were observed, and the retinal sensitivity and fixation stability(P1, P2)were measured by MAIA microperimetry.RESULTS: After 3mo of treatment, BCVA of treatment group and control group increased by 4(-1, 11.5)and 0(-4, 0.75)letters compared with baseline(PPP>0.05). The sensitivity of retina in treatment group was the highest(20.11±4.98dB)at 2mo. P1 and P2 in the two groups increased significantly after treatment. The increase of P1 in the treatment group was significantly higher than that in the control group at 2mo(PP>0.05).CONCLUSION: Intravitreal conbercept could improve the fixation stability in DME patients, combined with Xiaozhong decoction was conducive to maintain fixation stability.

Abstract. Background. Human infections with zoonotic coronaviruses (CoVs), including severe acute respiratory syndrome (SARS)-CoV and Middle East respiratory syndrome (MERS)-CoV, have raised great public health concern globally. Here, we report a novel bat-origin CoV causing severe and fatal pneumonia in humans. Methods. We collected clinical data and bronchoalveolar lavage (BAL) specimens from five patients with severe pneumonia from Wuhan Jinyintan Hospital, Hubei province, China. Nucleic acids of the BAL were extracted and subjected to next-generation sequencing. Virus isolation was carried out, and maximum-likelihood phylogenetic trees were constructed. Results. Five patients hospitalized from December 18 to December 29, 2019 presented with fever, cough, and dyspnea accompanied by complications of acute respiratory distress syndrome. Chest radiography revealed diffuse opacities and consolidation. One of these patients died. Sequence results revealed the presence of a previously unknown β-CoV strain in all five patients, with 99.8% to 99.9% nucleotide identities among the isolates. These isolates showed 79.0% nucleotide identity with the sequence of SARS-CoV (GenBank NC_004718) and 51.8% identity with the sequence of MERS-CoV (GenBank NC_019843). The virus is phylogenetically closest to a bat SARS-like CoV (SL-ZC45, GenBank MG772933) with 87.6% to 87.7% nucleotide identity, but is in a separate clade. Moreover, these viruses have a single intact open reading frame gene 8, as a further indicator of bat-origin CoVs. However, the amino acid sequence of the tentative receptor-binding domain resembles that of SARS-CoV, indicating that these viruses might use the same receptor. Conclusion. A novel bat-borne CoV was identified that is associated with severe and fatal respiratory disease in humans.

For more than nine decades, transurethral resection of the prostate remains the gold standard for the surgical treatment of lower urinary tract symptoms due to benign prostatic obstruction. The occurrence of urethral strictures after transurethral resection of the prostate is one of the major late complications and has been reported as the leading cause of iatrogenic urethral strictures in patients older than 45 years who underwent urethroplasty. Although several postulations have been proposed to explain the urethral stricture after transurethral resection of the prostate, the exact etiology of urethral stricture after TURP is still controversial. Suggested etiological factors of urethral stricture formation after transurethral resection of the prostate include infection, mechanical trauma, prolonged indwelling catheter time, use of local anesthesia, and electrical injury by a stray current. One single treatment option is not appropriate for all stricture types. The management of urethral stricture following transurethral resection of the prostate includes minimally invasive endoscopic methods, including urethral dilation and direct visual incision, or open surgical procedures with varying urethroplasty techniques. Although scientific studies focusing on urethral strictures after transurethral resection of the prostate are relatively limited and sparse, we can apply the principles of urethral stricture management before making decisions on individual stricture treatment.

Abstract Background Laparoscopic surgery, fast-track perioperative treatment and XELOX chemotherapy are effective strategies for shortening the duration of hospital stay for cancer patients. This trial aimed to clarify the safety and efficacy of the fast-track multidisciplinary treatment (FTMDT) model compared to conventional surgery combined with chemotherapy in Chinese colorectal cancer patients. Methods This trial was a prospective randomized controlled study with a 2 × 2 balanced factorial design and was conducted at six hospitals. Patients in group 1 (FTMDT) received fast-track perioperative treatment and XELOX adjuvant chemotherapy. Patients in group 2 (conventional treatment) received conventional perioperative treatment and mFOLFOX6 adjuvant chemotherapy. Subgroups 1a and 2a had laparoscopic surgery and subgroups 1b and 2b had open surgery. The primary endpoint was total length of hospital stay during treatment. Results A total of 374 patients were randomly assigned to the four subgroups, and 342 patients were finally analyzed, including 87 patients in subgroup 1a, 85 in subgroup 1b, 86 in subgroup 2a, and 84 in subgroup 2b. The total hospital stay of group 1 was shorter than that of group 2 [13 days, (IQR, 11–17 days) vs. 23.5 days (IQR, 15–42 days), P = 0.0001]. Compared to group 2, group 1 had lower surgical costs, fewer in-hospital complications and faster recovery (all P

Purpose: To summarize the imaging results of COVID-19 pneumonia and develop a computerized tomography (CT) screening procedure for patients at our institution with malignant tumors.Methods: Following epidemiological investigation, 1,429 patients preparing to undergo anti-tumor-treatment underwent CT scans between February 17 and April 16, 2020. When CT findings showed suspected COVID-19 pneumonia after the supervisor radiologist and the thoracic experience radiologist had double-read the initial CT images, radiologists would report the result to our hospital infection control staff. Further necessary examinations, including the RT-PCR test, in the assigned hospital was strongly recommended for patients with positive CT results. The CT examination room would perform sterilization for 30 min to 1 h. If the negative results of any suspected COVID-19 pneumonia CT findings were identified, the radiologists would upload the results to our Hospital Information Systems and inform clinicians within 2 h.Results: Fifty (0.35%, 50/1,429) suspected pneumonia cases, including 29 males and 21 females (median age: 59.5 years old; age range 27–79 years), were identified. A total of 34.0% (17/50) of the patients had a history of lung cancer and 54.0 (27/50) underwent chemotherapy or targeted therapy. Forty-six patients (92.0%) had prior CT scans, and 35 patients (76.1%) with suspected pneumonia were newly seen (median interval time: 62 days). Sub-pleura small patchy or strip-like lesions most likely due to fibrosis or hypostatic pneumonia and cluster of nodular lesions were the two main signs of suspected cases on CT images (34, 68.0%). Twenty-seven patients (54.0%) had, at least once, follow-up CT scan (median interval time: 18.0 days). Only one patient had an increase in size (interval time: 8 days), the immediately RT-PCR test result was negative.Conclusion: CT may be useful as a screening tool for COVID-19 based on imaging features. But the differential diagnosis between COVID-19 and other pulmonary infection and/or non-infectious disease is very difficult due to its overlapping imaging features.The confirmed diagnosis of the COVID-19 infection should be based on the etiologic eventually. The cancer patients at a low-incidence area would continue treatment by screening carefully before admission.

Objective: To identify whether the timing of surgery affects red blood cell (RBC) transfusion requirements in the elderly with intertrochanteric fractures. Methods: We retrospectively studied all patients undergoing surgical fixation of their intertrochanteric fractures in our hospital between January 2009 and December 2018 and analyzed the relationship between the timing of surgery and RBC transfusion. Results: A total of 679 patients were included in this study. The need for RBC transfusion was lower in the patients who underwent surgery within 12 h after admission (timing of surgery 12 h, >12 h group) (P = 0.046); lower in the the patients who underwent surgery within 24 h after admission (timing of surgery 24 h, >24 h group) (P = 0.008), and lower in the

BackgroundPancreatic ductal adenocarcinoma (PDAC) is the most aggressive form of pancreatic cancer. Its 5-year survival rate is only 3–5%. Perineural invasion (PNI) is a process of cancer cells invading the surrounding nerves and perineural spaces. It is considered to be associated with the poor prognosis of PDAC. About 90% of pancreatic cancer patients have PNI. The high incidence of PNI in pancreatic cancer limits radical resection and promotes local recurrence, which negatively affects life quality and survival time of the patients with pancreatic cancer.ObjectivesTo investigate the mechanism of PNI in pancreatic cancer, we analyzed the gene expression profiles of tumors and adjacent tissues from 50 PDAC patients which included 28 patients with perineural invasion and 22 patients without perineural invasion.MethodUsing Monte-Carlo feature selection and Incremental Feature Selection (IFS) method, we identified 26 key features within which 15 features were from tumor tissues and 11 features were from adjacent tissues.ResultsOur results suggested that not only the tumor tissue, but also the adjacent tissue, was informative for perineural invasion prediction. The SVM classifier based on these 26 key features can predict perineural invasion accurately, with a high accuracy of 0.94 evaluated with leave-one-out cross validation (LOOCV).ConclusionThe in-depth biological analysis of key feature genes, such as TNFRSF14, XPO1, and ATF3, shed light on the understanding of perineural invasion in pancreatic ductal adenocarcinoma.

AIM: To respectively evaluate macular morphological features and functional parameters by using spectral-domain optical coherence tomography (SD-OCT) and macular integrity assessment (MAIA) in patients with diabetic macular edema (DME). METHODS: This prospective, non-controlled, open study included 61 eyes of 38 consecutive patients with DME. All patients underwent best-corrected visual acuity (BCVA) measurement, MAIA microperimetry, and SD-OCT. DME morphology, including central retinal thickness (CRT) and central retinal volume (CRV); integrity of the external limiting membrane (ELM) and photoreceptor inner segment/outer segment (IS/OS) junction; and the deposition of hard macular exudates were assessed within a 1000-μm central subfield area. MAIA microperimetry parameters evaluated were average threshold (AT)-retinal sensitivity, macular integrity index (MI), fixation points within a circle of radius 1° (P1) and 2° (P2), and bivariate contour ellipse area considering 63% and 95% of the fixation points (A63 and A95, respectively). RESULTS: MI was significantly higher in eyes with disrupted ELM or IS/OS, compared with eyes with intact ELM and IS/OS. Values of BCVA (logMAR), total AT, AT within 1000-μm diameter, P2, A63, A95, and CRT were significantly worse in eyes with disrupted IS/OS, compared with eyes with intact IS/OS. The values of BCVA (logMAR), AT within 1000-μm diameter, and CRT were significantly worse in eyes with disrupted ELM, compared with eyes with intact ELM. These parameters were not significantly different between eyes with or without hard macular exudate deposition. CRV was not significantly different in the presence or absence of the integrity of ELM, IS/OS, or deposition of hard macular exudates. At the center, nasal and temporal sectors of the fovea, significant negative correlations were observed between retinal thickness and AT of the corresponding area. At the inferior and superior sectors of the fovea, no correlations were observed between retinal thickness and AT of the corresponding area. In the intact IS/OS group, significant negative correlations were observed between CRT and central AT. There was no correlation between retinal sensitivity and thickness when the IS/OS layer was disrupted. Multiple linear regression analyses revealed that IS/OS integrity was an independent factor affecting MI. CONCLUSION: Functional (BCVA and visual field) and morphological parameters (retinal thickness) were significantly associated with an intact IS/OS. Local photoreceptor integrity was a strong predictor of local visual function throughout the retina. MI revealed the functional status in DME, reflecting the IS/OS juction status in the macula.

Introduction Evidence suggests that smoking by family members and friends is a strong predictor of smoking uptake in adolescents, yet the influence on electronic cigarette (e-cigarette) use has not been systematically reviewed and quantified. Methods Relevant studies were identified by searches of the PubMed and ScienceDirect databases up to December 2016. The summary odds ratios (ORs) with 95% confidence intervals (CIs) were calculated using a random-effects model. Results A total of 21 studies were included in this meta-analysis. A positive association was observed between adolescent e-cigarette use and smoking by family members (OR=1.47, 95% CI=1.30-1.66) and friends (OR=2.72, 95% CI=1.87-3.95), even after adjusting for the individual smoking status. Stratified by family members, the association with smoking in siblings (OR=1.87, 95% CI=1.35-2.60) was more prominent than that in parents (OR=1.41, 95% CI=1.19- 1.68) and other family members (OR=1.39, 95% CI=1.12-1.72). Conclusions The present meta-analysis suggests that smoking by family members and friends is significantly associated with increased probability of e-cigarette use in adolescents.

Understanding the host–guest chemistry of α-/β-/γ- cyclodextrins (CDs) and a wide range of organic species are fundamentally attractive, and are finding broad contemporary applications toward developing efficient drug delivery systems. With the widely used β-CD as the host, we herein demonstrate that its inclusion behaviors toward an array of six simple and bio-conjugatable adamantane derivatives, namely, 1-adamantanol (adm-1-OH), 2-adamantanol (adm-2-OH), adamantan-1-amine (adm-1-NH2), 1-adamantanecarboxylic acid (adm-1-COOH), 1,3-adamantanedicarboxylic acid (adm-1,3-diCOOH), and 2-[3-(carboxymethyl)-1-adamantyl]acetic acid (adm-1,3-diCH2COOH), offer inclusion adducts with diverse adamantane-to-CD ratios and spatial guest locations. In all six cases, β-CD crystallizes as a pair supported by face-to-face hydrogen bonding between hydroxyl groups on C2 and C3 and their adjacent equivalents, giving rise to a truncated-cone-shaped cavity to accommodate one, two, or three adamantane derivatives. These inclusion complexes can be terminated as (adm-1-OH)2⊂CD2 (1, 2:2), (adm-2-OH)3⊂CD2 (2, 3:2), (adm-1-NH2)3⊂CD2 (3, 3:2), (adm-1-COOH)2⊂CD2 (4, 2:2), (adm-1,3-diCOOH)⊂CD2 (5, 1:2), and (adm-1,3-diCH2COOH)⊂CD2 (6, 1:2). This work may shed light on the design of nanomedicine with hierarchical structures, mediated by delicate cyclodextrin-based hosts and adamantane-appended drugs as the guests.

The Chinese medicine compound, Jisuikang, can promote recovery of neurological function by inhibiting lipid peroxidation, scavenging oxygen free radicals, and effectively improving the local microenvironment after spinal cord injury. However, the mechanism remains unclear. Thus, we established a rat model of acute spinal cord injury using a modified version of Allen's method. Jisuikang (50, 25, and 12.5 g/kg/d) and prednisolone were administered 30 minutes after anesthesia. Basso, Beattie, and Bresnahan locomotor scale scores and the oblique board test showed improved motor function recovery in the prednisone group and moderate-dose Jisuikang group compared with the other groups at 3–7 days post-injury. The rats in the moderate-dose Jisuikang group recovered best at 14 days post-injury. Hematoxylin-eosin staining and transmission electron microscopy showed that the survival rate of neurons in treatment groups increased after 3–7 days of administration. Further, the structure of neurons and glial cells was more distinct, especially in prednisolone and moderate-dose Jisuikang groups. Western blot assay and immunohistochemistry showed that expression of brain-derived neurotrophic factor (BDNF) in injured segments was maintained at a high level after 7–14 days of treatment. In contrast, expression of nerve growth factor (NGF) was down-regulated at 7 days after spinal cord injury. Real-time fluorescence quantitative polymerase chain reaction showed that expression of BDNF and NGF mRNA was induced in injured segments by prednisolone and Jisuikang. At 3–7 days after injury, the effect of prednisolone was greater, while 14 days after injury, the effect of moderate-dose Jisuikang was greater. These results confirm that Jisuikang can upregulate BDNF and NGF expression for a prolonged period after spinal cord injury and promote repair of acute spinal cord injury, with its effect being similar to prednisolone.

Puerarin (PUE) is a Chinese traditional medicine known to enhance glucose uptake into the insulin cells to downregulate the blood glucose levels in the treatment of type II diabetes. Nevertheless, the bioavailability of pristine PUE is limited due to its poor solubility and low intestinal permeability. In this work, we demonstrate that the solubility of PUE can be significantly enhanced via its co-crystallization with L-Proline (PRO). Two crystalline phases, namely, the solvate-free form [PUE][PRO] (I) and the solvated form [PUE]2[PRO]∙EtOH∙(H2O)2 (II) are isolated. These two phases are characterized by single-crystal X-ray diffraction (SCXRD), powder X-ray diffraction (PXRD), Fourier-transformed infrared (FT-IR) spectra, nuclear magnetic resonance (NMR), and thermogravimetric analysis in association with differential scanning calorimetry (TGA-DSC). The solubility and dissolution rate of both I and II in water, gastrointestinal tract at pH 1.2, and phosphate buffer at pH 6.8 indicates a nearly doubled increase as compared to the pristine PUE. 3-(4,5-Dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay of pristine PUE, I and II against murine colon cancer cell lines CT-26 and human kidney cell lines HEK-293 indicated that neither compound exhibits obvious cytotoxicity after 24 h. This work showcases that the readily available and biocompatible PRO can be a promising adjuvant to enhance the physicochemical properties of PUE toward orally administered drug formulation with improved pharmacokinetics.

Tenofovir alafenamide (TAF) is a prodrug of tenofovir as a potent nucleotide reverse transcriptase inhibitor. It serves as the key component of Genvoya® for the first-line treatment of human immunodeficiency virus infection (HIV) and is the active component of Vemlidy® for the treatment of chronic hepatitis B. Vemlidy® is also a monotherapeutic regimen formulated as TAF hemifumarate (1; TAF:fumarate = 2:1). In this work, we report for the first time the single-crystal structure of TAF fumarate hemihydrate (2, TAF:fumarate:H2O = 2:2:1). Compound 2 is initially documented as a salt in which one proton of the fumaric acid migrates to the amine group of the adenine moiety in TAF. It was recently proposed that ca. 20–30% proton is transferred to the N atom on the aromatic adenine backbone. We herein provide definitive single-crystal X-ray diffraction results to confirm that 2, though phase pure, is formed as a mixture of co-crystal (75%) and salt (25%). It features two pairs of TAF fumarates, wherein one of the four H atoms on the fumaric acid is transferred to the N atom of the adjacent adenine moiety while the other three carboxylates remain in their intrinsic acid form. Compound 2 is a metastable phase during the preparation of 1 and can be isolated by halting the reaction during the refluxing of TAF and fumaric acid in acetonitrile (MeCN). Our report complements the previous characterizations of TAF monofumarate, and its elusive structural patterns are finally deciphered.

Using ab initio calculations, we investigate the interactions among neutral excess oxygen atoms and amorphous silica (a-SiO2), along with hole trapping on neutral excess-oxygen defects. The calculations demonstrate that the interaction of excess oxygen with the a-SiO2 network results in two distinct defect structures referred to as the oxygen bridge-bonded (OBB) and peroxy linkage configurations. The OBB configuration may relax to a lower-energy structure after trapping a hole, representing a potential relaxation channel to the peroxy radical (POR) defect. The calculated hyperfine parameters are in excellent agreement with POR defect experiments and show that the oxygen atoms trapping the unpaired spin are bound to only one silicon atom. This implies that the OBB configuration is the major precursor of POR defects.

The mechanism involved in neural regeneration after spinal cord injury is unclear. The myelin-derived protein Nogo-A, which is specific to the central nervous system, has been identified to negatively affect the cytoskeleton and growth program of axotomized neurons. Studies have shown that Nogo-A exerts immediate and chronic inhibitory effects on neurite outgrowth. In vivo, inhibitors of Nogo-A have been shown to lead to a marked enhancement of regenerative axon extension. We established a spinal cord injury model in rats using a free-falling weight drop device to subsequently investigate Nogo-A expression. Nogo-A mRNA and protein expression and immunoreactivity were detected in spinal cord tissue using real-time quantitative PCR, immunohistochemistry and western blot analysis. At 24 hours after spinal cord injury, Nogo-A protein and mRNA expression was low in the injured group compared with control and sham-operated groups. The levels then continued to drop further and were at their lowest at 3 days, rapidly rose to a peak after 7 days, and then gradually declined again after 14 days. These changes were observed at both the mRNA and protein level. The transient decrease observed early after injury followed by high levels for a few days indicates Nogo-A expression is time dependent. This may contribute to the lack of regeneration in the central nervous system after spinal cord injury. The dynamic variation of Nogo-A should be taken into account in the treatment of spinal cord injury.

The One Strain Many Compounds (OSMAC) method was applied to explore the chemical diversities of secondary metabolites produced by Neosartorya fischeri NRRL 181. Four pyripyropenes 1⁻4, eight steroids 5⁻11, and four prenylated indole alkaloids 12⁻15, were obtained from the fungus cultured in petri dishes containing potato dextrose agar (PDA). 1,7,11-trideacetylpyripyropene A (1) and 1,11-dideacetyl pyripyropene A (2) were obtained and spectroscopically characterized (1D, 2D NMR, and HR-ESI-MS) from a natural source for the first time. It offered a sustainable source of these two compounds, which were usually used as starting materials in preparing pyripyropene derivatives. In addition, as compared with all the other naturally occurring pyripyropenes, 1 and 2 possessed unique acetylation patterns that did not follow the established late-step biosynthetic rules of pyripyropenes. The natural occurrence of 1 and 2 in the fungus implied that the timing and order of hydroxylation and acetylation in the late-step biosynthetic pathway of pyripyropenes remained to be revealed. The isolation and identification of 1⁻15 indicated that the OSMAC method could remarkably alter the metabolic profile and enrich the chemical diversities of fungal metabolites. Compounds 1⁻4 exhibited no obvious cytotoxicity against the triple-negative breast cancer cell line MDA-MB-231 as compared with taxol.

Vitreoushumour(VH)is a transparent, highly hydrated gel, which occupies the vitreous cavity. The protein composition of the VH would change in pathological conditions of the retina, which has been testified in many studies. In the last decade, proteomics analyses have been performed to study the proteome of the human VH and hope to find some specific proteins in the aetiology of diabeticretinopathy(DR). Recent proteomic studies on the VH from animal models of autoimmune uveitis have identified some specific proteins in related entophthalmia.

To assess the impact of oxaliplatin-containing adjuvant chemotherapy on the survival of patients with locally-advanced rectal cancer.Data on patients with pathologically-confirmed T3/4 or N1/2 rectal cancer who accepted radical surgery at our center from January 2002 to June 2009 were reviewed retrospectively. The patients' 5-year overall survival (OS), disease-specific survival (DSS), and recurrence-free survival (RFS) were analyzed by comparing those who accepted radical surgery only (Group S) with those who accepted radical surgery and oxaliplatin-containing adjuvant chemotherapy (Group SO).A total of 236 patients were analyzed (Group S 135; Group SO 101). Group S patients were older and had a higher proportion with stage II disease and more perioperative complications than those in Group SO (P

BACKGROUND: This study aimed to evaluate the feasibility of intraarterial (IA) delivery and in vivo MR imaging of superparamagnetic iron oxide (SPIO)-labeled mesenchymal stem cells (MSCs) in a canine stroke model. METHODOLOGY: MSCs harvested from beagles' bone marrow were labeled with home-synthesized SPIO. Adult beagle dogs (n = 12) were subjected to left proximal middle cerebral artery (MCA) occlusion by autologous thrombus, followed by two-hour left internal carotid artery (ICA) occlusion with 5 French vertebral catheter. One week later, dogs were classified as three groups before transplantation: group A: complete MCA recanalization, group B: incomplete MCA recanalization, group C: no MCA recanalization. 3×10(6) labeled-MSCs were delivered through left ICA. Series in vivo MRI images were obtained before cell grafting, one and 24 hours after transplantation and weekly thereafter until four weeks. MRI findings were compared with histological studies at the time point of 24 hours and four weeks. PRINCIPAL FINDINGS: Home-synthesized SPIO was useful to label MSCs without cell viability compromise. MSCs scattered widely in the left cerebral hemisphere in group A, while fewer grafted cells were observed in group B and no cell was detected in group C at one hour after transplantation. A larger infarction on the day of cell transplantation was associated with more grafted cells in the brain. Grafted MSCs could be tracked effectively by MRI within four weeks and were found in peri-infarction area by Prussian blue staining. CONCLUSION: It is feasible of IA MSCs transplantation in a canine stroke model. Both the ipsilateral MCA condition and infarction volume before transplantation may affect the amount of grafted cells in target brain. In vivo MR imaging is useful for tracking IA delivered MSCs after SPIO labeling.

There is a strong need to assess early tumor response to chemotherapy in order to avoid adverse effects from unnecessary chemotherapy and allow early transition to second-line therapy. This study was to quantify tumor perfusion changes with dynamic contrast-enhanced ultrasound (CEUS) in the evaluation of early tumor response to cytotoxic chemotherapy. Sixty nude mice bearing with MCF-7 breast cancer were administrated with either adriamycin or sterile saline. CEUS was performed on days 0, 2, 4 and 6 of the treatment, in which time-signal intensity (SI) curves were obtained from the intratumoral and depth-matched liver parenchyma. Four perfusion parameters including peak enhancement (PE), area under the curve of wash-in (WiAUC), wash-in rate (WiR) and wash-in perfusion index (WiPI) were calculated from perfusion curves and normalized with respect to perfusion of adjacent liver parenchyma. Histopathological analysis was conducted to evaluate tumor perfusion, tumor cell density, microvascular density (MVD) and proliferating cell density. Significant decreases of tumor normalized perfusion parameters (i.e., nPE, nWiAUC, nWiR and nWiPI) were noticed between adriamycin-treated and control groups (P0.05). Significant decreases of tumor perfusion, tumor cell density, MVD and proliferating cell density were seen in adrianycin-treated group 2 days after therapy when compared to control group (P