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Wen-Jie Cong,1,* Zhi-Peng Liu,2,* Yi-Xin Liang,2 Sheng-Lie Ye,2 Zhong-Ming Cai,2 Hao-Man Chen,2 Cheng-Wei Liao,2 Qun-Li Lin,3 Ren-Qian Feng,2 Xu-Dong Zhou,4 Yan-Zhi Wu,2 Le-Qiu Sun,5 Xue-Rong Huang,6 Man-Man Zhang,7 Gui-Qian Huang,8 Bei-Lei Zhu7 1Department of Acupuncture and Physiotherapy, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, Zhejiang, People’s Republic of China; 2The First Clinical School, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, Zhejiang, People’s Republic of China; 3Department of Neurology, Yongjia People’s Hospital, Wenzhou, Zhejiang, People’s Republic of China; 4Department of Neurology, Pingyang People’s Hospital, Wenzhou, Zhejiang, People’s Republic of China; 5Department of Neurology, Affiliated Yueqing Hospital of Wenzhou Medical University, Wenzhou, Zhejiang, People’s Republic of China; 6Department of Neurology, Ruian People’s Hospital, Wenzhou, Zhejiang, People’s Republic of China; 7Department of Neurology, The First Affiliated Hospital of Wenzhou Medical University Wenzhou Zhejiang People’s Republic of China; 8School of Mental Health, Wenzhou Medical University, Wenzhou, People’s Republic of China*These authors contributed equally to this workCorrespondence: Bei-Lei Zhu, Tel +86 13567896076, Email doczbl@163.comPurpose: To explore the predictive value of nutritional risk for all-cause death and functional outcomes among elderly acute stroke patients.Patients and Methods: A total of 479 elderly acute stroke patients were enrolled in this study. The nutritional risk of patients was screened by the GNRI and NRS-2002. The primary outcome was all-cause death, and the secondary outcome was poor prognosis defined as a modified Rankin Scale (mRS) score ≥ 3.Results: Based on the NRS-2002, patients with nutritional risk had a higher risk of all-cause death at 3 months (adjusted OR: 3.642, 95% CI 1.046~12.689) and at 3 years (adjusted OR: 2.266, 95% CI 1.259~4.076) and a higher risk of adverse functional outcomes at 3 months (adjusted OR: 2.748, 95% CI 1.518~4.972. Based on the GNRI, compared to those without nutritional risk, patients with mild malnutrition also had a higher risk of all-cause death at 3 months (adjusted OR: 7.186, 95% CI 1.550~33.315) and at 3 years (adjusted OR: 2.255, 95% CI 1.211~4.199) and a higher risk of adverse functional outcomes at 3 months (adjusted OR: 1.947, 95% CI 1.030~3.680), so patients with moderate and severe malnutrition had a higher risk of all-cause death at 3 months (adjusted OR: 6.535, 95% CI 1.380~30.945) and at 3 years (adjusted OR: 2.498, 95% CI 1.301~4.799) and a higher risk of adverse functional outcomes at 3 months (adjusted OR: 2.213, 95% CI 1.144~4.279).Conclusion: Nutritional risk increases the risk of poor short-term and long-term outcomes in elderly patients with acute stroke. For elderly stroke patients, we should pay attention to early nutritional risk screening, and effective intervention should be provided to improve the prognosis of such patients.Keywords: acute stroke, malnutrition, nutritional screening, all-cause death, GNRI, NRS-2002

Objective: To explore the effect of UV radiation resistance-associated gene (UVRAG) on ferroptosis induced by sorafenib in leukemia K562 cells., Methods: K562 cells were treated with 0, 0.625, 1.25, 2.5, 5, 10, and 20 μmol/L sorafenib for 24 or 48 hours, and the cell viability was detected by CCK-8 assay. Flow cytometry technology was used to detect the changes of reactive oxygen species (ROS) in K562 cells treated with 0, 5, and 10 μmol/L sorafenib for 24 hours. Western blot was used to detect the protein expression of GPX4 in K562 cells treated with 0, 5, and 10 μmol/L sorafenib and pretreatment with ferroptosis inhibitor. A recombinant lentiviral vector was used to construct UVRAG overexpression cell line in K562 cells. qPCR and Western blot were used to verify UVRAG gene overexpression, and Western blot detected the effect of UVRAG on the protein expression of GPX4 and HMGB1 after treatment with sorafenib., Results: Different concentrations of sorafenib could significantly inhibit the proliferation of K562 cells, and the cell viability gradually decreased with the increase of concentration ( r 24 h =-0.9841, r 48 h =-0.9970). The level of ROS was increased (When the concentration was 10 μmol/L, P <0.001), while the expression of GPX4 protein was decreased in the process of 0, 5, 10 μmol/L sorafenib-induced K562 cell death ( P <0.05), and the decrease in GPX4 protein could be partially reversed by pretreatment with ferroptosis inhibitor ( P <0.05). Compared with NC group and NC-Sorafenib group, the expression of GPX4 protein was significantly decreased (both P <0.05), while HMGB1 protein was significantly increased (both P <0.05)., Conclusion: Sorafenib can induce ferroptosis in K562 cells, and this process can be promoted by UVRAG .

Immunotherapy has emerged as a potent strategy in cancer treatment, with many approved drugs and modalities in the development stages. Despite its promise, immunotherapy is not without its limitations, including side effects and suboptimal efficacy. Using nanoparticles (NPs) as delivery vehicles to target immunotherapy to lymph nodes (LNs) can improve the efficacy of immunotherapy drugs and reduce side effects in patients. In this context, this paper reviews the development of LN-targeted immunotherapeutic NP strategies, the mechanisms of NP transport during LN targeting, and their related biosafety risks. NP targeting of LNs involves either passive targeting, influenced by NP physical properties, or active targeting, facilitated by affinity ligands on NP surfaces, while alternative methods, such as intranodal injection and high endothelial venule (HEV) targeting, have uncertain clinical applicability and require further research and validation. LN targeting of NPs for immunotherapy can reduce side effects and increase biocompatibility, but risks such as toxicity, organ accumulation, and oxidative stress remain, although strategies such as biodegradable biomacromolecules, polyethylene glycol (PEG) coating, and impurity addition can mitigate these risks. Additionally, this work concludes with a future-oriented discussion, offering critical insights into the field., (© 2024 Wiley‐VCH GmbH.)

Objective: To investigate the clinical efficacy and safety of ixazomib-containing regimens in the treatment of patients with multiple myeloma (MM)., Methods: A retrospective analysis was performed on the clinical efficacy and adverse reactions of 32 MM patients treated with a combined regimen containing ixazomib in the Hematology Department of the First People's Hospital of Lianyungang from January 2020 to February 2022. Among the 32 patients, 15 patients were relapsed and refractory multiple myeloma (R/RMM) (R/RMM group), 17 patients who responded to bortezomib induction therapy but converted to ixazomib-containing regimen due to adverse events (AE) or other reasons (conversion treatment group). The treatment included IPD regimen (ixazomib+pomalidomide+dexamethasone), IRD regimen (ixazomib+lenalidomide+dexamethasone), ICD regimen (ixazomib+cyclophosphamide+dexamethasone), ID regimen (ixazomib+dexamethasone)., Results: Of 15 R/RMM patients, overall response rate (ORR) was 53.3%(8/15), among them, 1 achieved complete response (CR), 2 achieved very good partial response (VGPR) and 5 achieved partial response (PR). The ORR of the IPD, IRD, ICD and ID regimen group were 100%（3/3）, 42.9%（3/7）, 33.3%（1/3）, 50%（1/2）， respectively， there was no statistically significant difference in ORR between four groups (χ 2 =3.375, P =0.452). The ORR of patients was 50% after first-line therapy, 42.9% after second line therapy, 60% after third line therapy or more, with no statistically significant difference among them (χ 2 =2.164, P =0.730). In conversion treatment group, ORR was 88.2%(15/17), among them, 6 patients achieved CR, 5 patients achieved VGPR and 4 patients achieved PR. There was no statistically significant difference in ORR between the IPD（100%， 3/3）, IRD（100%， 6/6）, ICD（100%， 3/3） and ID（60%， 3/5） regimen groups (χ 2 =3.737， P =0.184). The median progression-free survival (PFS) time of R/RMM patients was 9 months (95% CI : 6.6-11.4 months), the median overall survival (OS) time was 18 months (95% CI : 11.8-24.4 months). The median PFS time of conversion treatment group was 15 months (95% CI : 7.3-22.7 months), the median OS time not reached. A total of 10 patients suffered grade 3- 4 adverse event (AE). The common hematological toxicities were leukocytopenia, anemia, thrombocytopenia. The common non-hematological toxicities were gastrointestinal symptoms (diarrhea, nausea and vomit), peripheral neuropathy, fatigue and infections. Grade 1-2 peripheral neurotoxicity occurred in 7 patients., Conclusion: The ixazomib-based chemotherapy regimens are safe and effective in R/RMM therapy, particularly for conversion patients who are effective for bortezomib therapy. The AE was manageable and safe.

Objective: To analyze the efficacy and safety of flumatinib, a second-generation tyrosine kinase inhibitor (TKI) independently developed in China, in patients with chronic myelogenous leukemia in chronic phase (CML-CP) who falied first-line and second-line treatment., Methods: The clinical data of 30 CML-CP patients treated with flumatinib in Lianyungang First People's Hospital from January 2020 to September 2022 were collected retrospectively. Among them, 15 patients who received imatinib first-line treatment but failed treatment were included in the second-line group, and the other 15 patients who failed second-line treatment with nilotinib or dasatinib were included in the third-line group. The hematological and molecular responses of the patients in the two groups at 3, 6 and 12 months of treatment, and the event-free survival (EFS) and adverse reactions of patients at the end of follow-up were statistical analyzed., Results: At 3, 6, and 12 months of treatment, 10, 11, and 12 patients in the second line group achieved major molecular response (MMR), which was higher than that of 3, 4, and 5 patients in the third line group ( P =0.010, P =0.011, P =0.010). At 3 months of treatment, 12 and 13 patients achieved complete hematological response (CHR) and early molecular response (EMR) in the second-line group, which was higher than that of 9 and 13 patients in the third-line group, but the difference between the two groups was not statistically significant ( P =0.232, P =1.000); At 6 and 12 months of treatment, 6 and 7 patients in the second-line group achieved MR4.5, which were higher than of 3 and 2 cases in the third-line group, but the difference was not statistically significant ( P =0.427, P =0.713). The hematological adverse reactions of patients in the second-line group during treatment the period were mainly grade 1-2 thrombocytopenia and anemia, and no grade 3-4 of adverse reactions occurred. In the third-line group, there were 2 cases of grade 1-2 thrombocytopenia, grade 1-2 anemia and white blood cell 3 cases were reduced each, 1 case of grade 3-4 anemia, 2 cases of grade 3-4 neutropenia. The non-hematological adverse reactions in the second-line group were rash (2 cases), headache (1 case), diarrhea (1 case), fatigue (1 case), limb pain (1 case). There were 1 cases of diarrhea, 1 cases of nausea, and 1 cases of edema in the third-line group. There was no statistical significance in hematological and non-hematological adverse reactions between the two groups of patients ( P >0.05). At the end of follow-up, the EFS rate of patients in the second-line group was higher than that in the third-line group (100% vs 93.3%), but the difference was not statistically significant ( P =0.317)., Conclusion: The second-generation TKI flumatinib independently developed in China, has good curative effect and safety for CML-CP patients who failed first-line and second-line treatment.

The deployment of imaging examinations has evolved into a robust approach for the diagnosis of lymph node metastasis (LNM). The advancement of technology, coupled with the introduction of innovative imaging drugs, has led to the incorporation of an increasingly diverse array of imaging techniques into clinical practice. Nonetheless, conventional methods of administering imaging agents persist in presenting certain drawbacks and side effects. The employment of controlled drug delivery systems (DDSs) as a conduit for transporting imaging agents offers a promising solution to ameliorate these limitations intrinsic to metastatic lymph node (LN) imaging, thereby augmenting diagnostic precision. Within the scope of this review, we elucidate the historical context of LN imaging and encapsulate the frequently employed DDSs in conjunction with a variety of imaging techniques, specifically for metastatic LN imaging. Moreover, we engage in a discourse on the conceptualization and practical application of fusing diagnosis and treatment by employing DDSs. Finally, we venture into prospective applications of DDSs in the realm of LNM imaging and share our perspective on the potential trajectory of DDS development., (© 2024. The Author(s).)

4-Hydroxyphenylpyruvate dioxygenase (HPPD, EC 1.13.11.27) is one of the most valuable herbicide targets due to its unique biological functions. In search of HPPD inhibitors with promising biological performance, we designed and synthesized a series of novel tetrazolamide-benzimidazol-2-ones using a structure-based drug design strategy. Among the synthesized compounds, 1-(2-chlorobenzyl)-3-methyl- N -(1-methyl-1 H -tetrazol-5-yl)-2-oxo-2,3-dihydro-1 H -benzo[ d ]imidazole-4-carboxamide, 25 , IC 50 = 10 nM, was identified to be the most outstanding HPPD inhibitor, which showed more than 36-fold increased Arabidopsis thaliana HPPD ( At HPPD) inhibition potency than mesotrione (IC 50 = 363 nM). Our At HPPD- 25 complex indicated that one nitrogen atom on the tetrazole ring and the oxygen atom on the amide group formed a classical bidentate chelation interaction with the metal ion, the benzimidazol-2-one ring created a tight π-π stacking interaction with Phe381 and Phe424, and some hydrophobic interactions were also found between the ortho -Cl-benzyl group and surrounding residues. Compound 32 showed more than 80% inhibition against all four tested weeds at 150 g ai/ha by the postemergence application. Our results indicated that the tetrazolamide-benzimidazol-2-one scaffold may be a new lead structure for herbicide discovery.

The sustainable development of mycorrhizal industry is the key to solve the problem of "mycorrhizal forestry contradiction". As a major province of edible mushroom production and forestry resources in China, Fujian Province is also an important origin of mycorrhizal technology research and development, so it is more typical and practical to establish an index system to evaluate the sustainability of mycorrhizal industry development in Fujian Province. Through research interviews and data collection, a sustainable capacity evaluation system of mycorrhizal industry was established with 21 indicators in six dimensions: economic, ecological, social, cultural, political, and technological. A combination of CRITIC empowerment method and cloud model was used to evaluate the sustainability of mycorrhizal industry development in Fujian Province. The results show that although the economic sustainability of the mycorrhizal industry in Fujian Province is average, the overall development trend is good and there are not too many problems. The sustainability of ecological, social and technological levels all have large differences in the development of indicators and the overall development status is average, but overall, the ecological, social and technological levels show a steady forward development from 2017 to 2020. The cultural and political dimensions of sustainability not only have large differences in the development of indicators and an average overall development status, but also have a small development span from 2017 to 2020 and a slow overall development., Competing Interests: The authors have declared that no competing interests exist., (Copyright: © 2023 Li et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.)

Lymph node metastasis (LNM) significantly impacts the prognosis of cancer patients. Despite significant advancements in diagnostic techniques and treatment modalities, clinical challenges continue to persist in the realm of LNM. These include difficulties in early diagnosis, limited treatment efficacy, and potential side effects and injuries associated with treatment. Nanotheranostics, a field within nanotechnology, seamlessly integrates diagnostic and therapeutic functionalities. Its primary goal is to provide precise and effective disease diagnosis and treatment simultaneously. The development of nanotheranostics for LNM offers a promising solution for the stratified management of patients with LNM and promotes the advancement of personalized medicine. This review introduces the mechanisms of LNM and challenges in its diagnosis and treatment. Furthermore, it demonstrates the advantages and development potential of nanotheranostics, focuses on the challenges nanotheranostics face in its application, and provides an outlook on future trends. We consider nanotheranostics a promising strategy to improve clinical effectiveness and efficiency as well as the prognosis of cancer patients with LNM., Competing Interests: Declaration of Competing Interest The authors declare no conflict of interes, (Copyright © 2023 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Background: Aberrant expression of miRNAs have been implicated in cancers, but the role of miRNAs in colorectal cancer (CRC) remains need to be elucidated. This study aimed to identify miRNAs that related to colorectal cancer (CRC) pathogenesis and determine the diagnostic value., Methods: Three GEO datasets (GSE128449, GSE35602 and GSE49246) with 131 samples were used to screen miRNAs that differential expression between tumor and control tissues. The expression of the identified miRNAs was validated in 50 clinical tissue samples and the GSE35834 dataset. The clinical significance of these miRNAs was analyzed in the TCGA dataset and clinical tissue samples. The expression of miRNAs in tissues and plasma samples were tested by RT-PCR assay in clinical samples, and their diagnostic value was determined., Results: The analysis of three GEO datasets revealed that miR-595 and miR-1237 were upregulated, while miR-126, miR-139, and miR-143 were downregulated in CRC tissues compared to control tissues. The differential expression of the five miRNAs in CRC tissues was confirmed using clinical tissue samples and GEO databases. There was no significant correlation between the TNM stage and tumor stage of CRC and any of the five miRNAs. Plasma expression of the miRNAs differed significantly between CRC and non-cancer patients, and each miRNA had moderate diagnostic value for CRC. Combining the five miRNAs provided better diagnostic potential for CRC than a single miRNA., Conclusions: This study demonstrated that five miRNAs were related to the pathogenesis of CRC, but independent of the stage of CRC; Plasma expression of these miRNAs have moderate diagnostic value, and combination of these miRNAs showed better diagnostic ability in CRC., (© 2023. The Author(s), under exclusive licence to Springer Nature B.V.)

Objective: To explore the effect of UVRAG on mitophagy in leukemia cells K562., Methods: K562 cells were induced with different concentrations of mitophagy inducer carbonylcyanide-m-chlorophenylhydrazone (CCCP) for 6, 12 and 24 hours, and the cell viability was detected by the CCK-8 assay. K562 cells were divided into NC, UVRAG -siRNA, UVRAG -siRNA+CCCP, and CCCP group, while Western blot was used to detect the expression of UVRAG protein. Flow cytometry was used to detect the changes in reactive oxygen species (ROS) and mitochondrial structural integrity. The expressions of autophagy related proteins P62 and LC3-Ⅱ/LC3-Ⅰ were detected by Western blot., Results: Compared with NC group, the expression of UVRAG protein in UVRAG -siRNA group significantly decreased ( P <0.01). Compared with CCCP group, in UVRAG -siRNA+CCCP group ROS, mitochondrial structure damage, and the expression of LC3-Ⅱ/LC3-Ⅰ decreased significantly ( P <0.05, P <0.05, P <0.01), while the expression of P62 protein increased ( P <0.05). Compared with NC group, the differences in the expressions of P62 and LC3-Ⅱ/LC3-Ⅰ protein, ROS, and mitochondrial structural integrity in UVRAG -siRNA group were not obvious ( P >0.05)., Conclusion: Under the treatment of CCCP, silencing UVRAG can inhibit mitophagy in K562 cells.

Objective: To investigate the clinical characteristics of RAS gene mutations in patients with acute myeloid leukemia (AML)., Methods: 43 myeloid gene mutations were detected using next-generation sequencing (NGS) in 180 patients with AML who were first diagnosed between May 2011 and February 2021. The molecular and clinical features of RAS gene mutations and their effects on efficacy and survival of patients were retrospectively analyzed., Results: Among 180 AML patients, the proportion of mutations in RAS pathway-related genes were NRAS (14.4%), KRAS (2.2%), FLT3-ITD (13.8%), PTPN11 (7.7%), KIT (5.0%), FLT3-TKD (3.8%) and CBL (2.7%). Seventy-three (40.6%) AML patients had gene mutations associated with the RAS pathway.The number of peripheral blood white blood cells and the proportion of bone marrow primitive juvenile cells in patients with NRAS/KRAS gene mutation were higher than those of patient with RAS wild-type, the difference was statistically significant (P<0.05). NRAS/KRAS gene mutations were significantly associated with the CBL gene mutation(r=0.287). In young AML patients (age <60 years), there were no significant differences in complete response rate (CR), progression-free survival (PFS), and overall survival (OS) between patients with RAS gene mutation and those with wild-type(P>0.05). In elderly AML patients (age≥60 years), PFS and OS in RAS mutants were significantly lower than those in wild-type patients(P<0.05)., Conclusion: In AML patients, RAS gene mutation is relatively common, and RAS gene mutation is associated with clinical characteristics and efficacy of patients, and may be a molecular marker of poor prognosis for elderly AML.

Nutritional Risk Screening index is a standard tool to assess nutritional risk, but epidemiological data are scarce on controlling nutritional status (CONUT) as a prognostic marker in acute haemorrhagic stroke (AHS). We aimed to explore whether the CONUT may predict a 3-month functional outcome in AHS. In total, 349 Chinese patients with incident AHS were consecutively recruited, and their malnutrition risks were determined using a high CONUT score of ≥ 2. The cohort patients were divided into high-CONUT (≥ 2) and low-CONUT (< 2) groups, and primary outcomes were a poor functional prognosis defined as the modified Rankin Scale (mRS) score of ≥ 3 at post-discharge for 3 months. Odds ratios (OR) with 95 % confidence intervals (CI) for the poor functional prognosis at post-discharge were estimated by using a logistic analysis with additional adjustments for unbalanced variables between the high-CONUT and low-CONUT groups. A total of 328 patients (60·38 ± 12·83 years; 66·77 % male) completed the mRS assessment at post-discharge for 3 months, with 172 patients at malnutrition risk at admission and 104 patients with a poor prognosis. The levels of total cholesterol and total lymphocyte counts were significantly lower in high-CONUT patients than low-CONUT patients ( P = 0·012 and < 0·001, respectively). At 3-month post discharge, there was a greater risk for the poor outcome in the high-CONUT compared with the low-CONUT patients at admission (OR: 2·32, 95 % CI: 1·28, 4·17). High-CONUT scores independently predict a 3-month poor prognosis in AHS, which helps to identify those who need additional nutritional managements.

Background: Stroke is a leading cause of death and functional impairment in older people. To assess the prospective association between fasting blood glucose-to-glycated hemoglobin ratio and all-cause mortality and poor prognosis in stroke patients., Methods: A total of 971 Chinese inpatients with acute stroke (mean age of 65.7) were consecutively enrolled in the prospective clinical study and followed up for 12 months after discharge. Stress hyperglycemia was measured using the ratio of fasting blood glucose (FBG, mmol/L)/glycated hemoglobin (HbA1c, %). The primary outcome was all-cause mortality, and secondary outcomes were poor prognosis defined as infectious complications, a National Institutes of Health Stroke Scale (NIHSS) score ≥ 6, a Barthel Index score ≤ 60, or a modified Rankin Scale (mRS) score of 3-6, presented as multivariate-adjusted odds ratios (ORs) with 95% confidence intervals (CIs) across the quartiles of the FBG/HbA1c ratio., Results: There were 35 (4.1%) all-cause deaths at 3 months and 85 (11.4%) at 12 months. The inpatients with the highest quartile of the FBG/HbA1c ratio had a higher risk of all-cause death at 3 months (adjusted OR: 5.16, 95% CI: 1.03-25.74) and at 12 months (adjusted OR: 2.59, 95% CI: 1.14-5.89)) and a higher risk of infectious complications (adjusted OR 2.37, 95% CI 1.27-4.43) and dysfunction (adjusted OR 1.79, 95% CI 1.06-3.01) during hospitalization than inpatients with the lowest quartile., Conclusions: Stress hyperglycemia, measured by the FBG/HbA1c ratio, was associated with an increased risk of adverse outcomes, including all-cause death, infectious complications, and dysfunction after stroke., (© 2022. The Author(s).)

Covering 1972 to 2021Malaria remains a significant public health problem in some regions of the world. The great efforts to control malaria have been severely compromised due to the widespread resistance of Plasmodium falciparum to nearly all frontline drugs. Pursuit of novel molecules from the sea will potentially result in new interventions against malaria, which are urgently needed to combat the increase of resistance. Focusing on the strategy of the "Blue Drug Bank", the molecules highlighted here can serve as an inspiration for future medicinal chemistry campaigns. This review covers the developments in the field of antimalarial marine lead compounds reported between 1972 and July 2021, and offers a comprehensive overview on their progresses and potentials. We selected 60 representative potential candidate molecules from 361 marine natural products, and highlighted their structure-activity relationships, molecular mechanisms of targets, and drug-like properties in order to assess their full potential to be developed. We summarized 107 clinically proven or potential antimalarial targets and their subcellular locations in the relevant target proteins, which linked the molecules to the target proteins at the subcellular level. Hence, it could be expected that natural products targeting different mechanisms may prove to be an effective strategy in antimalarial drug research and development in the future.

Objective: We aimed to investigate the effect and mechanisms of action of two drug pairs [Huangqi-Chuanxiong and Sanleng-Ezhu Herb (HCSE)] on the treatment of ischemic stroke. Materials and methods: We mined the current literature related to ischemic stroke and formulated a new formulation of Chinese herbs. Then, we identified the main candidate target genes of the new formulation by network pharmacology. Next, we performed enrichment analysis of the target genes to identify the potential mechanism of action of the new formulation in the treatment of ischemic stroke. Next, we experimentally validated the mechanism of action of the new formulation against ischemic stroke. Infarct volume and neurological deficits were evaluated by 2,3,5-triphenyltetrazolium (TTC) staining and Longa's score, respectively. The predicted pathways of signal-related proteins were detected by western blotting. Results: We mined the current literature and identified a new formulation of Chinese herbs for the treatment of ischemic stroke. The formulation included Huangqi, Chuanxiong, Sanleng and Ezhu. Next, we used network pharmacological analysis to identify 23 active compounds and 327 target genes for the new formulation. The key target genes were MAPK3 , MAPK1 , HSP90AA1 , STAT3 , PIK3R1 , PIK3CA and AKT1 . Kyoto Encyclopedia of Genes and Genomes (KEGG) enrichment analysis revealed significant enrichment of the PI3K/AKT and MAPK/ERK signaling pathways. By performing experiments, we found that the new formulation reduced the infarct volume of middle cerebral artery occlusion (MCAO) induced mice and activated the PI3K/AKT and MAPK/ERK signaling pathways. These findings confirmed that the new formulation has a significant protective effect against ischemic stroke injury by activating the PI3K/AKT and MAPK/ERK signaling pathways. Conclusion: We identified a new treatment formulation for ischemic stroke by data mining and network pharmacological target prediction. The beneficial effects of the new formulation act by regulating multiple target genes and pathways. The mechanism of action of the new formulation may be related to the AKT and ERK signaling pathways. Our findings provide a theoretical basis for the effects of the new formulation on ischemic stroke injury., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Zhao, Ding, Xia, Sheng, Shen, Cai and Yan.)

1,8-Cineole (also known as eucalyptol) is mostly extracted from the essential oils of plants, which showed extensively pharmacological properties including anti-inflammatory and antioxidant mainly via the regulation on NF-κB and Nrf2, and was used for the treatment of respiratory diseases and cardiovascular, etc . Although various administration routes have been used in the application of 1.8-cineole, few formulations have been developed to improve its stability and bioavailability. This review retrospects the researches on the source, biological activities, mechanisms, and application of 1,8-cineole since 2000, which provides a view for the further studies on the application and formulations of 1,8-cineole.

The vascular endothelium, which plays an essential role in maintaining the normal shape and function of blood vessels, is a natural barrier between the circulating blood and the vascular wall tissue. The endothelial damage can cause vascular lesions, such as atherosclerosis and restenosis. After the vascular intima injury, the body starts the endothelial repair (re-endothelialization) to inhibit the neointimal hyperplasia. Endothelial progenitor cell is the precursor of endothelial cells and plays an important role in the vascular re-endothelialization. However, re-endothelialization is inevitably affected in vivo and in vitro by factors, which can be divided into two types, namely, promotion and inhibition, and act on different links of the vascular re-endothelialization. This article reviews these factors and related mechanisms.

Purpose: Our study aimed to establish and validate prognostic nomograms based on gross tumor volume (GTV) and cervical nodal volume (CNV) for nasopharyngeal carcinoma (NPC) patients treated with two cycles of concurrent chemoradiotherapy (CCRT)., Methods: From 2012 to 2015, 620 eligible patients who received radical treatment at the Cancer Hospital of Shantou University Medical College were recruited for a nomogram study. Variables were determined in a training set of 463 patients from 2012 to 2014 by X-tile analysis, univariate and multivariate Cox proportional hazard analyses, and the least absolute shrinkage and selection operator (LASSO). Another cohort of 157 patients in 2015 was validated with bootstrap resampling. The concordance index (C-index) and calibration curves were applied to assess its predictive discriminative and accuracy ability, while decision curve analysis (DCA), X-tile analysis and Kaplan-Meier curve for clinical application., Results: Independent prognostic variables for overall survival (OS) were age, GTV, CNV, cranial nerve, positive cervical lymph node laterality below the caudal border of cricoid cartilage (LNBC), and were selected for the nomogram. Optimal prognostic factors including Karnofsky performance status (KPS), age, GTV, CNV, LNBC were incorporated in the nomogram for progression-free survival (PFS). In the training set, the C-index of our nomograms for OS and PFS were 0.755 (95% CI, 0.704 to 0.807) and 0.698 (95% CI, 0.652 to 0.744). The calibration curve showed good agreement between nomogram-predicted and actual survival. DCA indicated that our nomograms were of clinical benefit., Conclusion: Our nomograms are capable of effective prognostic prediction for patients with NPC., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2021 Zhang, Li, Hong, Cai, Huang, Lin and Yang.)

Urothelial carcinoma (UC) is the predominant form of bladder cancer. Significant molecular heterogeneity caused by diverse molecular alterations brings about large variations in the response to treatment in UC. An improved understanding of the genetic mechanisms underlying the development and progression of UC is essential. Through deep analysis of next-generation sequencing data of 99 UC patients, we found that 18% of cases had recurrent somatic mutations in zinc finger protein gene zinc finger protein 83 (ZNF83). ZNF83 mutations were correlated with poor prognosis of UC. We also found a hotspot mutation, p.E293V, in the evolutionarily well-conserved region of ZNF83. ZNF83-E293V increased tumor growth and reduced the apoptosis of UC cells compared to wild-type ZNF83 both in vitro and in mice xenografted tumors. ZNF83-E293V activated nuclear factor κB (NF-κB) more potently than did the wild-type protein owing to its decreased transcriptional repression for S100A8. The NF-κB inhibitors could pharmacologically block the tumor growth in mice engrafted with ZNF83-E293V-transfected UC cells. These findings provide a mechanistic insight and a potential therapeutic strategy for UC, which established a foundation for using the ZNF83-E293V mutation as a predictive biomarker of therapeutic response from NF-κB inhibitors., (Copyright © 2020 The Author(s). Published by Elsevier Inc. All rights reserved.)

The interaction of sperm with the oocyte is pivotal during the process of mammalian fertilization. The limited numbers of sperm that reach the fallopian tube as well as anatomic restrictions indicate that human sperm-oocyte encounter is not a matter of chance but a directed process. Chemotaxis is the proposed mechanism for re-orientating sperm toward the source of a chemoattractant and hence to the oocyte. Chemokines represent a superfamily of small (8-11 kDa), cytokine-like proteins that have been shown to mediate chemotaxis and tissue-specific homing of leukocytes through binding to specific chemokine receptors such as CCRs. Here we show that CCR6 is abundantly expressed on human sperms and in human testes. Furthermore, radioligand-binding experiments showed that CCL20 bound human sperm in a specific manner. Conversely, granulosa cells of the oocyte-surrounding cumulus complex as well as human oocytes represent an abundant source of the CCR6-specific ligand CCL20. In human ovaries, CCL20 shows a cycle-dependent expression pattern with peak expression in the preovulatory phase and CCL20 protein induces chemotactic responses of human sperm. Neutralization of CCL20 in ovarian follicular fluid significantly impairs sperm migratory responses. Conversely, analyses in infertile men with inflammatory conditions of the reproductive organs demonstrate a significant increase of CCL20/CCR6 expression in testis and ejaculate. Taken together, findings of the present study suggest that CCR6-CCL20 interaction may represent an important factor in directing sperm-oocyte interaction., (© The Author(s) 2020. Published by Oxford University Press on behalf of Society for the Study of Reproduction. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Background: Malnutrition is confirmed to be associated with poor outcomes in stroke patients. The present study aimed to confirm that being at risk of malnutrition assessed by Nutritional Risk Screening Tool 2002 (NRS-2002) and the Controlling Nutritional Status (CONUT) score predicts poor outcomes at 3 months in acute ischemic stroke (AIS) patients., Methods: In total, 682 patients with AIS were recruited within 7 days of stroke onset consecutively and 110 were dropped out. They were screened for risk of malnutrition using NRS-2002 and the CONUT score. The primary outcome is the follow-up modified Rankin Scale (mRS) score. Poor outcomes were defined as an (mRS) score ≥ 3 at 3 months post discharge., Results: There was a significant difference in the mRS score at 3 months between patients at risk of malnutrition compared to those not at risk assessed by NRS-2002(P < 0.001) and CONUT (P = 0.011). The logistic regression model showed that the risk of malnourishment (according to NRS-2002), low risk of malnourishment (according to CONUT), and the moderate-to-severe risk of malnourishment (according to CONUT) were associated with higher risk of poor outcomes at 3 months (P < 0.001, P = 0.033, and P = 0.007). The multivariate logistic regression model (adjusted for confounding factors) demonstrated that the risk of malnourishment, according to the NRS-2002, was associated with the increasing risk of poor outcomes at 3 months (odds ratio = 2.31; 95% CI: 1.24-4.30; P = 0.008)., Conclusions: The risk of malnutrition assessed by NRS-2002 and CONUT can predict poor outcomes at 3 months in AIS patients. NRS-2002 is superior to CONUT in predicting poor outcomes at 3 months.

Background: The association between natural killer (NK) cells and survival in colorectal cancer (CRC) patients remains controversial. This study aimed to clarify the prognostic value of peripheral blood NK cells in CRC patients., Methods: A total of 447 CRC patients who underwent radical surgery and chemotherapy were retrospectively analyzed. Cox regression analyses were used to identify independent prognostic indicators. Correlation between NK cell percentage and other clinicopathological features (gender, age, histological grade, tumor stage, immune cells, and inflammatory indicators) was analyzed. The prognostic values of the combinations of NK cell percentage and other clinicopathological features were also determined., Results: Multivariate Cox regression analysis revealed that NK cell percentage in the peripheral blood was an independent prognostic indicator in CRC patients. A higher percentage of NK cells indicated a longer survival time than a lower percentage. NK cell percentage was positively correlated to the T and B lymphocyte counts and negatively correlated to the patients' age and albumin levels. With an area of 0.741 under a receiver operating characteristic curve, NK cells have a moderate predictive value for 3rd-year survival in CRC. This area increased to 0.851 by combining NK cell percentage with the B lymphocyte count. Elderly patients and those at an advanced clinical stage presented a lower percentage of NK cells than younger patients and those at an early clinical stage., Conclusions: This study demonstrated that NK cells in the blood were an independent predictor of survival in CRC patients, and the combined count of NK cells and B lymphocytes could increase the prognostic value.

Objective: To analyze the related factors affecting the nosopoiesis of childhood acute leukemia from the perspective of indoor environmental exposure, behavior and lifestyle., Methods: The clinical data of 64 children with acute leukemia were retrospectively analyzed, and 50 healthy children were selected as the control group during the same period. The basic data of children, indoor environment, behavior and lifestyle of parents in 2 groups were recorded. Univariate and multivariate logistic regression analysis were used to analyze the related factors affecting the incidence of childhood acute leukemia, and the OR (95%CI) value was calculated., Results: The unvariate analysis showed that the daily wine-drinking rate of father and pesticide use rate in acute leukemia group were significantly higher than those in control group (P<0.05). Multivariate Logistic regression analysis showed that indoor ventilation during summer sleep of children (OR=0.35, 95%CI: 0.14-0.88) and contact with other children before 3 years old (OR=0.34, 95%CI: 0.18-0.65) were protective factors for provention of childhood acute leukemia (P<0.05). Mothers had a history of exposure to chemical substances (OR=3.68, 95%CI: 1.64-8.27), and children had a history of exposure to chemical substances (OR=3.84, 95%CI: 1.64-9.01), family had internal decoration history after child birth (OR = 1.38, 95%CI: 1.05-1.81) and family uses of pesticides (OR=2.17, 95%CI: 1.08-4.36), all these factors were independent risk factors for acute leukemia (P<0.05)., Conclusion: Indoor environmental exposure, behavior and lifestyle of children and parents may be closely related with the nosopoiesis of childhood acute leukemia.

Summary Although subcutaneous immunotherapy （SCIT） and sublingual immunotherapy （SLIT） have a positive effect, there are drawbacks such as long treatment time period, frequent treatment times, and risk of adverse reactions. Peripheral superficial lymph node injection of allergen immunotherapy （ILIT） as an emerging specific immunotherapy method has the advantages of high safety, less adverse reactions, short treatment time, less treatment times, less patient pain, and exact curative effect. In recent years, more and more scholars have conducted extensive research on intra-lymphatic injection of immunotherapy for allergic diseases. This paper systematically summarizes the theoretical basis, method, safety, effectiveness and possible immune mechanism of ILIT., Competing Interests: The authors of this article and the planning committee members and staff have no relevant financial relationships with commercial interests to disclose., (Copyright© by the Editorial Department of Journal of Clinical Otorhinolaryngology Head and Neck Surgery.)

Background: This study was performed to examine the factors affecting attitudes regarding prenatal diagnosis and clinical treatment by analyzing the clinical data of women with positive noninvasive prenatal testing (NIPT) results., Methods: We collected clinical data for women with positive NIPT results. The women received prenatal genetic consultation. The women with true positive results received prenatal genetic counseling again, and decided whether to continue or terminate their pregnancy., Results: A total of 228 women received positive NIPT results. The prenatal diagnosis was accepted in 174 cases (76.3%), and 124 women were confirmed to have true positive NIPT results. The positive predictive values (PPV) of T21/T18/T13 and fetal sex chromosome aneuploidy were 88.4% and 42.9%, respectively. All (99/99, 100%) of the women with T21/T18/T13 terminated their pregnancies, while 25.0% (6/24) of women with fetal SCA continued their pregnancies. An NIPT result of Chr(9) microduplication was obtained in one woman, which was confirmed by chromosomal microarray analysis (CMA)., Conclusions: NIPT exhibited good detection accuracy for T21/T18/T13, and also contributed to identifying fetal SCA and substructural chromosomal abnormalities. With a positive NIPT result, the attitudes of pregnant women regarding prenatal diagnosis and clinical treatment are related to the severity of disease, cognitive ability, and the level of prenatal genetic counseling., Competing Interests: Conflicts of Interest: The authors have no conflicts of interest to declare.

Background: Colorectal cancer (CRC) originating from the right-sided or left-sided colon is distinct clinicopathological entity. The KRAS status and its prognostic value in CRC remain controversial. This study aimed to investigate the association of KRAS status with clinicopathological features and prognostic value in CRC., Methods: 178 colon cancer and 145 rectal cancer patients were enrolled. KRAS mutation test was performed on paraffin-embedded tumor samples using PCR methods. The colon cancer was divided into right-sided colon cancer (RCC) and left-sided colon cancer (LCC). Studies that reported the association of KRAS mutation with CRC clinical features and prognosis in databases were searched prior to 2018. The data of the present study was combined with the data of published studies using meta-analysis methods., Results: No significant difference between colon cancer and rectal cancer regarding the KRAS status. The KRAS mutation was much frequent in RCC than in LCC (p = 0.010). 17 studies with 11,385 colon cancer patients were selected, the pooled results of our data and previous published data showed that KRAS mutation was more frequent in RCC compared with in LCC (p < 0.01); KRAS mutation was not associated with the prognosis in RCC patient; however, KRAS mutation indicated a poor prognosis in LCC patients compared with KRAS wild type (p < 0.01)., Conclusion: KRAS status has no difference between colon cancer and rectal cancer. KRAS mutation was more frequent in RCC than in LCC, and associated with a poor prognosis in LCC patients, but not in RCC patients.

Poyang Lake region is the largest freshwater lake impacted area in China. Quantitative analysis of trade-off and synergy in ecosystem service is of great significance for realizing regional sustainable development. Based on multi-source data of remote sensing, soil, meteorology and DEM, we quantitatively measured food supply service, soil conservation service and water yield service in Poyang Lake region from 2005 to 2015, and analyzed their spatiotemporal patterns and evolution characteristics. The spatial and temporal characteristics of trade-off and synergy between services on the scale of 1 km×1 km were analyzed by using correlation analysis, hot spot analysis and spatial mapping method. The differences of ecosystem services and their relationships in the perspective of land use were studied. The results showed that food supply service increased, soil conservation service decreased, and water yield service increased first and then decreased during the study period. In terms of spatial distribution, food supply service presented "low-high-low-high" in the northwest-southeast direction, soil conservation service was concentrated in high and low values, and water yield service was high in south and low in north. There were trade-off relationships between food supply and soil conservation, and between food supply and water yield. There was synergistic relationship between soil conservation and water yield. Moreover, the relationship between food supply and soil conservation showed a spatial pattern of synergy in northern but trade-off in southern region. There was a clear spatial trade-off between food supply and water yield, and from north to south the relationship between soil conservation and water yield existed synergy-tradeoff-synergy differentiation, like a "sandwich". Among different land use types, there was a significant synergy between cultivated land and food supply, garden land and soil conservation, water area and water yield, but trade-off relationships between construction land and three services. The relationship between food supply and soil conservation and water yield was mainly trade-off in different land use types. The relationship between soil conservation and water yield was synergy in cultivated land, garden land, grassland and construction land, but was trade-off in water and unused land. The hot spots of multiple ecosystem services in the Poyang Lake region were mainly in the eastern and sou-thern plain areas, with a decreasing trend.

Objective: To discuss the detectability of NIPT for pregnant women at advanced maternal age (AMA), and mainly focused on how many fetal abnormalities will be missed by NIPT., Methods: A total of 4194 women at AMA who accepted cytogenetic prenatal diagnosis were recruited in this study. All the AMA women received amniocentesis at 18-23 weeks. Combined with our detection level of NIPT and literature reports, we evaluated the detectability of NIPT., Results: After cell karyotype analysis, a total of 233 (5.56%) fetuses were confirmed to have chromosomal abnormalities, including 91.0% were abnormal chromosome number and 9.0% were abnormal chromosome structure. According to the detectability of NIPT we calculated, 87.6% abnormal results could also be detected by NIPT. However, NIPT would miss 12.4% abnormal results which could be originally found by the karyotype analysis of amniotic fluid cells. The major types of missed fetal abnormalities include structural rearrangement, mosaic and triploidy. Meanwhile, there were no relationship between the detectability of NIPT and the age of AMA pregnant women., Conclusions: About 12.4% of fetal chromosomal abnormalities will be missed if NIPT completely replaces invasive prenatal diagnosis in AMA women. Fortunately, these types of fetal abnormalities missed by NIPT did not increase with the age elevating of pregnant women., (Copyright © 2018 Elsevier B.V. All rights reserved.)

Accumulating evidence has shown that transforming acidic coiled-coil 3 (TACC3) is deregulated in a broad spectrum of cancers. In the present study, we reported that TACC3 was markedly elevated in bladder cancer, especially in muscle-invasive bladder cancers (MIBCs). The upregulation of TACC3 was positively associated with tumor invasiveness, grade, T stage, and progression in patients with bladder cancer. Furthermore, a Kaplan-Meier survival analysis showed that patients with bladder cancer whose tumors had high TACC3 expression experienced a dismal prognosis compared with patients whose tumors had low TACC3 expression. Functional studies have found that TACC3 is a prerequisite for the development of malignant characteristics of bladder cancer cells, including cell proliferation and invasion. Moreover, TACC3 promoted G1/S transition, which was mediated via activation of the transcription of E2F1, eventually enhancing cell proliferation. Notably, the overexpression of TACC3 or E2F1 indicates a high sensitivity to cisplatin. Taken together, these findings define a tumor-supportive role for TACC3, which may also serve as a prognostic and therapeutic indicator in bladder cancers.

Objective: To evaluate the clinical value of combined detection of BCL-2 and PD-L1 in predicting the prognosis of newly diagnosed patients with acute leukemia (AL)., Methods: A total of 100 cases of AL in our hospital from Jan. 2013 to Sep. 2016 were enrolled in the study. The mRNA expression of BCL-2 and PD-L1 in peripheral blood of patients was detected by RT-PCR, and the prognosis of the patients was followed up. According to the follow-up results, these patients were divided into complete remission group and no remission group, the statistical analysis of different indexes predicting the prognosis was performed., Results: Compared with the healthy control group, the positive rates of BCL-2 and PD-L1 in the bone marrow specimens of AL patients significantly increased (P<0.01). The BCL-2 predicting the prognosis of patients showed that the area under the curve (AUC) was 0.725(P=0.006), the diagnostic threshold was 1.550, the sensitivity(Sen) and specificity(Spe) were 72% and 84%, respectively. The single PD-L1 detection for predicting the prognosis of patients showed that AUC was 0.740 (P=0.004), diagnostic threshold was 12.500, Sen and Spe were 66.7% and 73.1%, respectively. The diagnostic index of combined detection was 77.90, which were higher than that of series detection 54.75, and higher than that of the independent diagnostic index., Conclusion: Detection of BCL-2 combined with PD-L1 can be used to evaluate the prognosis of patients with newly diagnosed acute leukemia, which can improve the specificity and sensitivity of the detection, and has higher clinical diagnostic value than single actection.

Decreased sperm quality was caused by oxidative stress in semen from patients with leucocytospermia. Curcumin is a traditional Chinese herbal monomer extracted from Zingiberaceae turmeric and zedoary turmeric and has antioxidative and anti-inflammatory effects. This study aimed to investigate the effects and specific molecular mechanisms of curcumin on sperm quality in patients diagnosed with leucocytospermia. Forty cases of semen samples were collected from patients with leucocytospermia and 35 cases from normal fertile male. Computer-assisted semen analysis (CASA) was used to detect sperm motility after curcumin incubation. ELISA was used to measure the changes in H 2 O 2 , sperm mitochondrial DNA (mtDNA), cytochrome B (Cyt B) and NADH dehydrogenase 5 (NADH5) contents before and after curcumin treatment. The results indicate that curcumin can significantly improve sperm motility from the patients with leucocytospermia. After curcumin treatment, the level of the H 2 O 2 was significantly decreased in the supernatant of curcumin-incubated spermatozoa from leucocytospermic patients. The content of mtDNA was significantly decreased, while the content of Cyt B and NADH5 in spermatozoa was significantly increased. In conclusion, curcumin can significantly improve sperm motility of leucocytospermic patients, against the oxidative damage induced by H 2 O 2 . Therefore, curcumin may play a role in mitigating the H 2 O 2 -induced injury to sperm., (© 2017 Blackwell Verlag GmbH.)

Objective: Obstructive sleep apnea (OSA) is associated with increased carotid intima-media thickness (IMT), an early marker of atherosclerosis. Continuous positive airway pressure (CPAP) is the first-line treatment for OSA. A meta-analysis was performed to determine whether CPAP therapy could decrease carotid IMT., Methods: The PubMed, Embase, Web of Science, and Cochrane library were searched before March, 2017. Weighted mean difference (WMD) was calculated to estimate the treatment effects of pre and post-CPAP therapy. Seven studies were examined and the meta-analysis was performed using STATA 12.0., Results: There was no change of carotid IMT before and after CPAP treatment in OSA patients (WMD = 0.052, 95% confidence interval (CI) = -0.002 to 0.105, z = 1.90, p = 0.057). Meanwhile, meta-analysis of the two RCTs showed that carotid IMT was not changed in CPAP group when compared with control group (WMD = 0.002 95% CI = -0.125 to 0.129, z = 0.03, p = 0.976). Subgroup analyses indicated that carotid IMT was significantly decreased after CPAP use in more severe OSA patients (AHI≥50) (WMD = 0.073, 95% CI = 0.022 to 0.124, z = 2.80, p = 0.005) and patients with therapeutic duration ≥6 months (WMD = 0.121, 95% CI = 0.019 to 0.223, z = 2.32, p = 0.021)., Conclusions: CPAP had no impact on carotid IMT in OSA patients. However, carotid IMT was significantly decreased after CPAP treatment in more severe OSA patients and patients with longer CPAP usage.

Epigallocatechin-3-gallate (EGCG), the bioactive polyphenol in green tea, has been demonstrated to have various biological activities. Our study aims to investigate the antiproliferation and antimigration effects of EGCG against bladder cancer SW780 cells both in vitro and in vivo. Our results showed that treatment of EGCG resulted in significant inhibition of cell proliferation by induction of apoptosis, without obvious toxicity to normal bladder epithelium SV-HUC-1 cells. EGCG also inhibited SW780 cell migration and invasion at 25-100 μM. Western blot confirmed that EGCG induced apoptosis in SW780 cells by activation of caspases-8, -9 and -3, Bax, Bcl-2 and PARP. Besides, animal study demonstrated that EGCG [100 mg/kg, intraperitoneal (i.p.) injection daily for 3 weeks] decreased the tumor volume significantly in mice bearing SW780 tumors, as well as the tumor weight (decreased by 68.4%). In addition, EGCG down-regulated the expression of nuclear factor-kappa B (NF-κB) and matrix metalloproteinase (MMP)-9 in both protein and mRNA level in tumor and SW780 cells. When NF-κB was inhibited, EGCG showed no obvious effect in cell proliferation and migration. In conclusion, our study demonstrated that EGCG was effective in inhibition SW780 cell proliferation and migration, and presented first evidence that EGCG inhibited SW780 tumor growth by down-regulation of NF-κB and MMP-9., (Copyright © 2016 Elsevier Inc. All rights reserved.)

Objective: Sleep-disordered breathing (SDB) has been suggested to be associated with chronic kidney disease (CKD). Positive airway pressure (PAP) is an effective treatment for SDB, but the impact of PAP therapy on glomerular filtration rate (GFR) in patients with SDB remains unclear. The present meta-analysis was performed to determine whether PAP therapy could increase GFR., Design: A systematic search of PubMed, Embase, Web of Science, and Cochrane library was performed for literature published up to January 2016. Standardized mean difference (SMD) was calculated to estimate the treatment effects of pre- and post-PAP therapy., Results: A total of eight studies with 240 patients were pooled into a meta-analysis. The meta-analysis showed that there was no change of GFR before and after PAP treatment in SDB patients (SMD = 0.010, 95 % confidence interval (CI) = -0.331 to 0.350, z = 0.06, p = 0.956), Subgroup analyses indicated that GFR was significantly increased after PAP treatment in elder patients (≥55 years) (SMD = -0.283, 95 % CI = -0.518 to -0.047, z = 2.35, p = 0.019) and patients with therapeutic duration ≥ 3 months (SMD = -0.276, 95 % CI = -0.522 to -0.031, z = 2.20, p = 0.027)., Conclusion: The present meta-analysis suggested that PAP treatment had no impact on GFR in SDB patients. However, longer PAP usage for SDB patients significantly improved GFR. In elder SDB subjects, PAP was also associated with a statistically significant increase in GFR.

The majority of bladder cancer-associated mortalities are due to transitional cell carcinoma (TCC), which is the most prevalent and chemoresistant malignancy of the bladder. Sperm acrosome associated 5 (SPACA5)/Spaca5 is a sperm acrosome-associated, c-type lysozyme-like protein that has been recently identified, and has been designated as an attractive candidate antigen for cancer testis. In the present study, the expression profile of SPACA5 / Spaca5 was analyzed in spermatogenesis and TCC of the bladder using diverse molecular and cellular biology methods. Using reverse transcription-polymerase chain reaction (RT-PCR) to analyze the multi-tissue distribution and temporal expression of SPACA5 / Spaca5 , the SPACA5 / Spaca5 gene was determined to be generally not expressed in normal tissue, with the exception of the testis, and it could be detected at a low level on day 20 after birth in mouse testes and at a higher level on day 28. Immunohistochemistry staining revealed that the SPACA5/Spaca5 protein was exclusively observed in the elongated spermatid of the normal testes, and was ectopically expressed in the cytoplasm of TCC, while it was not expressed in normal bladder tissues. The frequency of SPACA5 messenger RNA was detected in 45% of TCC (9/20) by RT-quantitative PCR. Furthermore, SPACA5 protein was more frequently detected in high-grade than in low-grade tumors (61.54 vs. 30.00%, P=0.035). Accordingly, high SPACA5 staining scores were observed to be significantly associated with high-grade tumors (n=65, R=0.279, P=0.027). Collectively, our findings indicated that SPACA5 / Spaca5 may be important in male spermatogenesis and may be used as a potential target for specific immunotherapy in patients suffering from TCC.

Objective: To investigate the effect of 50 mg alteplase to intermediate-risk acute pulmonary embolism (APE) with right ventricular dysfunction. Methods: From May 2011 to May 2015, a total of 73 patients with intermediate-risk APE, furthermore, right ventricular systolic pressure (RVSP)>40 mmHg and B-type natriuretic peptide (BNP)>100 ng/L, were allocated to receive 50 mg alteplase plus anti-coagulation (thrombolysis group, TG, n =35) or anticoagulation alone (control group CG, n =38) according to their will.Tricuspid annular plane systolic excursion (TAPSE), Right ventricular fractional area change (RVFAC), RVSP, BNP, CT obstruction index (CTOI) were detected at prior treatment, 1 st day, 14 th day, 3 rd month, 6 th month. The adverse events consisting of hemodynamic decompensation (within 14 days), mortality, bleeding, recurrent pulmonary embolism (PE), RVSP>40 mmHg (at 6 th month) were recorded. Results: At prior treatment, TAPSE, RVFAC, RVSP, BNP and CTOI between TG and CG were (10.9±1.4) vs (11.4±1.2) mm, (27.8±3.9)% vs (28.1±4.1)%, (55.6±7.9) vs (54.6±8.4) mmHg, (491±76) vs (482±71) ng/L and (23.4±4.2)% vs (23.7±4.5)%. There was not statistical difference between two groups (all P >0.05). From 1 st to 14 th day, these indexes had better and faster improvement in TG than CG. At 6 th month, TAPSE, RVFAC, RVSP and CTOI between two groups were (17.5±1.3) vs (15.4±1.1) mm, (49.4±3.9)% vs (46.0±2.8)%, (15.8±2.2) vs (17.8±4.2) mmHg, and (1.7±1.6)% vs (4.0±3.0)% (all P <0.05), BNP was (66±13) vs (71±15) ng/L ( P >0.05). From prior treatment to 6 th month, the tendency of variation of these index in TG was better than CG ( P <0.05). From prior treatment to 14 th day, 3 cases of hemodynamic decompensation occurred in CG, 0 case in TG.During treatment, there were not cases of death and major bleeding. At 6 th month, there were 4 cases of RVSP>40 mmHg in CG, while 0 case in TG ( P =0.048). Conclusion: 50 mg alteplase can reduce the thrombus in pulmonary artery, improve right ventricular function quickly, and decrease the risk of elevated RVSP in the long term, for the patients with intermediate-risk APE.

Objective: To investigate the effects of interferon-α2b combined with thalidomid(THD) on the proliferation and apoptosis of HEL cells, and expression of JAK2V617F-mutated gene., Methods: The cell survival rates were assayed by CCK-8 after HEL cells were treated by interferon-α2b, thalidomid and thalidomid combined with interferon-α2b for 24, 48 and 72 hours, while the apoptosis and expression of JAK2V617F mutation gene were detected by flow cytometry and fluorescence quantitative PCR respectively after treatmemt for 48 hours., Results: IFN-α2b combined with THD could more obviously inhibit the proliferation of HEL cells than IFN-α2b or THD alone for 24 and 48 and 72 hours, and the differences between groups were statistically significant(P<0.05). In addition, the apoptosis-inducing effect of IFN-α2b combined with THD on HEL cells was more obvious than that of IFN-α2b used alone, the differences was statistically significant(P<0.05). Although IFN-α2b combined with THD can decrease the JAK2V617F mutation gene expression more obviously than IFN-α2b alone,but the difference was no statistically significant (P>0.05). And the remaining groups showed statistically significance(P<0.05)., Conclusion: IFN-α2b combined with THD can obviously inhibit the proliferation and induce apoptosis of HEL cells more than that of IFN-α2b alone, but the effect of reducing JAK2V617F mutation gene expression is not different.

The persistence infection of low-risk type (type 6 or type 11) of human papillomavirus (HPV) is the main cause of genital warts. Given the high rate of recurrence after treatment, the use of a new molecular agent is certain to be of value. The aim of this study was to achieve targeted inactivation of viral E 7 gene in keratinocytes using the reprogrammed clustered regularly interspaced short palindromic repeats (CRISPR)/CRISPR-associated (Cas) 9 system. To accomplish this, a universal CRISPR-Cas9 system for targeting both HPV6/11 E 7 genes was constructed by using a dual guide RNA vector. After transfection of the vector into E 7-transformed keratinocytes, the expression level of E 7 protein was measured using western-blot analysis and the sequence of the E 7 gene was determined using Sanger sequencing. Cell proliferation was analyzed by CCK-8 assay, and cell apoptosis was evaluated by Hoechst 33258 staining, flow cytometry analysis and ELISA assay. The results indicated that both HPV6/11 E 7 genes can be inactivated by the single CRISPR-Cas9 system. Furthermore, silencing of E 7 led to inhibition of cell proliferation and induction of apoptosis in E 7-transformed keratinocytes but not in normal keratinocytes. Our data suggested that the reprogrammed CRISPR-Cas9 system has the potential for the development of an adjuvant therapy for genital warts.

Objective: To investigate the clinicopathological features of testicular malignant Leydig cell tumor (TMLCT) and improve the non-invasive diagnosis of the disease., Methods: We retrospectively analyzed the clinicopathological data on a case of TMLCT, detected the circulating tumor cells (CTC) in the peripheral venous blood, and reviewed the related literature., Results: The patient, a 47-year-old male, underwent radical orchidoepididymectomy under general anesthesia. Postoperative pathology confirmed the lesion to be TMLCT, which was mainly composed of Leydig cells and suspected with vessel carcinoma embolus. Immunohistochemistry showed the tumor cells to be positive for α-inhibin, Ki67, CD30, vimentin, EMA, and PLAP, but negative for CK, CK7, S100, CD10, SMA, Des, AFP, hCG, CEA, CK19, CD117, Oct-4, LCA, CD20, Pax-5, CD3, and CD43. Two CTCs were detected in the peripheral venous blood. The patient received 3 courses of chemotherapy for retroperitoneal multiple lymph nodes metastasis post-operatively. Subsequent CT imaging manifested no obvious reduction of the retroperitoneal lymph nodes and consequently the patient again underwent retroperitoneal lymphadenectomy and cryoablation. At 8 months after treatment, CT examination revealed notably enlarged retroperitoneal lymph nodes with the right adrenal gland evidently invaded., Conclusion: TMLCT is an extremely rare sex-gonad stromal tumor with high malignancy and poor prognosis, and CTCs may be used for its early diagnosis and prognostic prediction.

Traditional Chinese medicine is increasingly used to treat cancer. Our clinical experiences identify Hedyotis diffusa plus Scutellaria barbata as the most common herb-pair (couplet medicinal) used for the core treatment of bladder cancer. This study aims to investigate the antitumor effect of the herb-pair in bladder cancer cells. The results show that Hedyotis diffusa plus Scutellaria barbata inhibited bladder cancer cell growth and clone formation in a dose-dependent and time-dependent manner. It also induced cell apoptosis through decreasing Akt activation and reducing the expression of antiapoptotic proteins Bcl-2 and Mcl-1. Further experiments showed that miR-155 was reduced by the herb-pair and miRNA-155 inhibitor induced cell apoptosis and suppressed Akt activation. Overexpression of miR-155 reversed herb-pair induced cell apoptosis through activating Akt pathway in both bladder cancer cell lines. The findings reveal that Hedyotis diffusa plus Scutellaria barbata reduce Akt activation through reducing miR-155 expression, resulting in cell apoptosis. It demonstrated the potential mechanism of Hedyotis diffusa plus Scutellaria barbata for the core treatment of bladder cancer.

Objective: To evaluate the incidence rate of IDH1 in acute myeloid leukemia and analyze its effect on clinical characteristics and prognosis., Methods: Mononuclear cells in bone marrow samples were collected from 192 adult patients with newly diagnosed AML. Polymerase chain reaction (PCR) and direct sequencing were used to amplify exon 4 of IDH1 gene, the gene sequencing was used to analyze the gene mutations, at same time, the detection of NPM1, FLT3-TKD, FLT3-ITD, C-KIT, CEPBA, TET2 and JAK2V617F and MLL mutations were carried out, the follow-up was used to determine its therapeutic efficacy and outcomes of patients. The clinical and laboratory data of these cases were collected, and their clinical characteristics and prognosis were then analyzed., Results: Among the 192 AML patients, 13 cases were detected with IDH1 gene mutation, the mutation rate was 6.77% [95% CI (5.70%-13.38%)]. The sequencing chart of IDH1 gene showed double peaks, the mutations were heterozygous, out of them c.G395A (p.R132H) was found in 8 cases, c.C394T was found in 4 cases (p.R132C), c.C394A (p.R132S) was found in 1 cases, R132H and R132C are common, 13 cases showed missense mutation. The median age in mutation group was 52 years old, the median age in unnutration group was 40 years, there was significant difference between them (P = 0.010). Mutation rate of IDH1 gene in M1 and M2 was significantly higher than that in other FAB subtypes. There were no significant difference in sex, newly diagnosed peripheral white blood cell count, hemoglobin, platelet count, peripheral blood and bone marrow original cell proportion of primitive cells between them. Mutation of IDH1 gene had certain correlation with NPM1 gene mutation, but no correlation with FLT3-TKD, FLT3-ITD, C-KIT, TET2 and JAK2V617F and MLL natations was found. In addition, the IDH1 mutation easily occurred in patients with normal karyotype or in patients with middle prognostic risk karyotype, IDH1 mutation occurred in 11 cases with normal karyotype, the mutation rate was 10.28%, IDH1 mutation were observed in 2 cases with abnormal karyotype, the mutation rate was 3.50%, there was significant difference. In AML patients with middle prognostic risk karyotype. The complete remission (CR) and the 3 year survival (OS) rate of IDH1 mut patients were less than that in IDH1 wt, there was significant difference (P < 0.05)., Conclusions: The IDH1 mutation more easily occurr in older AML patients and mutations effect of IDH1 on clinical characteristics may represent a molecular marker for poor prognosis in AML.

The mutant promoter of human telomerase reverse transcriptase (hTERT) shows high transcriptional activity in bladder cancer cells. Some up-regulated microRNAs (miRNAs) are reported as oncogenic factors in bladder cancer. Previous studies report that miRNAs can be inhibited by base-pairing interactions. The purpose of this study is to construct a synthetic device driven by mutant hTERT promoter to suppress four up-regulated miRNAs and to verify its effects on phenotypes of bladder cancer cells and human normal cells. Tandem bulged miRNA binding sites targeting oncogenic miRNAs were inserted into the 3' untranslated region (3' UTR) of mutant hTERT promoter-driven Renilla luciferase gene to construct a synthetic tumor-specific device, miRNA sponges. A negative control was generated by using tandem repeated sequences without targeting any known miRNA. Bladder cancer cells (T24, 5637, UM-UC-3) and human fiber cells (HFC) were transfected with devices. Various functional assays were used to detect the effects of this device. The activity of the mutant hTERT promoter detected by luciferase assay was about three times as large as the wild-type hTERT promoter in bladder cancer cells, while it could not be measured in HFC. Other assays indicated that the synthetic device can significantly inhibit cell growth, decrease motility, and induce apoptosis in bladder cancer cells but not in HFC. A synthetic biology platform is employed to construct tumor-specific miRNA sponges that can be used to target oncogenic miRNAs to inhibit the progression of bladder cancer cells without affecting normal cells.

Testicular germ cell tumor (TGCT) is a most common testicular malignancy with an increasing incidence, and its pathogenesis and mechanisms are not yet clear. The next generation sequencing has become the main tool to uncover the underlying mechanisms of TGCT. The differential gene expressions, gene mutation, predisposing gene-dominated signaling pathways, and changes of the relevant genes in the sex chromosome are largely involved in the occurrence and development of TGCT. Studies on the genomics of TGCT contribute a lot to identifying the pivotal pathogenic genes and paving a theoretical ground for the early screening and targeted therapy of TGCT. This paper summarizes the advances in the studies of the genomics of TGCT so as to reveal thetmechanisms of the disease at the genetic level.

The aim of this study was to determine how the function of human stromal antigen 2 (STAG2) plays an important role in proper chromosome separation. STAG2 mRNA in normal bladder cells and bladder tumor cells was evaluated by RT-PCR. The protein levels of STAG2 in normal bladder cells and bladder tumor cells were determined by western blot. A cell proliferation assay was used to measure the growth of tumor cells and STAG2-inhibited normal cells, and STAG2- inhibited normal cells were subjected to karyotype analysis. Both STAG-2 mRNA and protein expression levels were lower in bladder cancer cells compared to the controls. Knockdown of STAG2 caused aneuploidy in normal bladder cells, leading to a decreased expression of the cohesin complex components SMC1, SMC3 and RAD21, but there was no obvious effect of STAG2 knockdown on cell proliferation. Our study indicated that abnormal expression of STAG2 could cause aneuploidy in normal bladder cells.

Background: Previous studies suggested that the H63D and C282Y polymorphisms in the HFE genes were susceptible to many cancer types, nevertheless, the present results were inconclusive. Thus, the present study was aimed to evaluate the association between the HFE polymorphisms (H63D and C282Y) and cancer risk via meta-analysis., Materials and Methods: We retrieved PubMed, Google Scholar, Embase and Web of Science databases for all eligible studies up to April 1, 2015. All the statistical analysis was conducted by STATA 12.0., Results: Finally, a total of 20 publications including 24 case-control studies, comprising 6,524 cases and 31,080 controls for HFE-C282Y polymorphism and 19 publications including 21 case control studies, comprising 5,648 cases and 14,257 controls for HFE-H63D polymorphism were enrolled in our analysis. An increased risk for overall cancer risk was identified in HFE-H63D polymorphism under allele contrast (D vs H: OR=1.153; 95%CI=1.031- 1.289, Pheterogeneity=0.002), homozygotes vs wide type (DD vs HH: OR=1.449; 95%CI=1.182-1.777, Pheterogeneity=0.391), dominant model (DD+HD vs HH: OR=1.145; 95%CI=1.007-1.301, Pheterogeneity=0.002) and recessive model (DD vs HD+HH: OR=1.416 ; 95%CI=1.156-1.735, Pheterogeneity=0.549), as well as HFE- C282Y under homozygotes vs wide type (YY vs CC: OR=1.428, 95%CI=1.017-2.006, Pheterogeneity=0.220). In addition, in the stratified analysis by cancer type, an increased risk was identified in hepatocellular carcinoma and breast cancer in C282Y polymorphism, as well as pancreatic cancer in H63D polymorphism, whereas a decreased risk of colorectal cancer was identified in C282Y polymorphism., Conclusions: Present study suggested that H63D and C282Y polymorphisms associated with an increased risk of overall cancer. Nevertheless, well- designed study with large sample size will be continued on this issue of interest.

Common genetic variation Q192R in the paraoxonase 1 (PON1) gene has been considered to be implicated in the development of many cancers. Nevertheless, results from the related studies were inconsistent. To elucidate the association, we performed a meta-analysis for 8,112 cases and 10,037 controls from 32 published case-control studies. Odds ratios (ORs) with 95% confidence intervals (CIs) were used to assess the strength of the association by STATA 12.0 software. Overall, we revealed that the PON1-192R allele was associated with a reduced risk of the overall cancers. Moreover, in the stratified analysis by cancer types (breast cancer, prostate cancer, brain cancer etc.), the results showed that PON1-192R allele was associated with a decreased risk in breast cancer (R vs Q: OR=0.605, 95% CI=0.378-0.967, Pheterogeneity=0.000; RR vs QQ: OR=0.494, 95% CI=0.275-0.888, Pheterogeneity=0.002; RQ vs QQ: OR=0.465, 95% CI=0.259-0.835, Pheterogeneity=0.000; and RR+RQ vs QQ: OR=0.485, 95% CI=0.274-0.857, Pheterogeneity=0.000), and associated with prostate cancer in homozygote (RR vs QQ: OR=0.475, 95% CI=0.251- 0.897, Pheterogeneity=0.001) and recessive models (RR vs RQ+QQ: OR=0.379, 95% CI=0.169-0.853, Pheterogeneity=0.000), while an increased risk was identified in lymphoma (R vs Q: OR=1.537, 95% CI=1.246-1.896, Pheterogeneity=0.944; RR vs QQ: OR=2.987, 95% CI=1.861-4.795, Pheterogeneity=0.350; RR+RQ vs QQ: OR=1.354, 95% CI=1.021-1.796, Pheterogeneity=0.824; and RR vs RQ+QQ: OR=2.934, 95% CI=1.869-4.605, Pheterogeneity=0.433), and an increased risk in prostate cancer under heterozygote comparison (RQ vs QQ: OR=1.782, 95% CI=1.077-2.950, Pheterogeneity=0.000) and dominant models (RR+RQ vs QQ: OR=1.281, 95% CI=1.044-1.573, Pheterogeneity=0.056). When subgroup analysis that performed by the control source (hospital based or population based), a decreased risk of the overall cancers was revealed by homozygote (RR vs QQ: OR=0.601, 95% CI=0.366-0.987, Pheterogeneity=0.000) and dominant models (RR vs RQ+QQ: OR=0.611, 95% CI=0.384-0.973, Pheterogeneity=0.000) in hospital based group. Stratifying by ethnicity, a significantly reduced risk of the overall cancers under allele contrast model (R vs Q: OR=0.788, 95% CI=0.626-0.993, Pheterogeneity=0.000) was uncovered in Caucasian. In summary, these findings suggested that PON1 Q192R polymorphism was associated with a reduced risk of the overall cancers, nevertheless, it might increase cancer susceptibility of prostate and lymphoma risk. Large well-designed epidemiological studies will be continued on this issue of interest.