bluuebunny/crossref_metadata_2025 huggingface dataset:
Compression Therapy Using Surgical Gloves Does Not Prevent Paclitaxel-induced Peripheral Neuropathy: Results From a Double-blind Phase 2 Trial 
Authors: Kotani Haruru , Terada Mitsuo , Mori Makiko , Horisawa Nanae , Sugino Kayoko , Kataoka Ayumi , Adachi Yayoi , Gondou Naomi , Yoshimura Akiyo , Hattori Masaya , Sawaki Masataka , Takahata Chihoko , Kobara Makiko , Iwata Hiroji
Published: October 2020

Background: Chemotherapy-induced peripheral neuropathy (CIPN) is a common adverse effect of paclitaxel (PTX). There is no known prophylactic measure, although there are some reports of prevention with compression therapy using surgical gloves. On account of its predominantly subjective symptoms, it is difficult to exclude bias when assessing for CIPN. In this study, we assessed the effectiveness of the same procedure for the prevention of paclitaxel-induced PN based on a double-blind study design.Methods: The patients with early and recurrent breast cancer (with no prior PTX exposure) initiating weekly chemotherapy with PTX 80 mg/m2 were enrolled. Each patient donned two gloves on each hand at every PTX infusion. Two one-size-smaller gloves were donned on one hand (study side) and two normal-size gloves were donned on the other hand (control side) during 90 minutes from 30 minutes before the infusion to 30 minutes after the end of the infusion. Study side are blind for both patients and assessing physicians according to determination of the study side by research nurses in the chemotherapy unit.The primary outcome was the difference in the frequency of CIPN (motor/sensory) determined by the physician using the common terminology criteria for adverse events (CTCAE v4.0), with an evaluation at each cycle of PTX infusion. McNemar test was used to assess the primary outcome.Results: Between July 2017 and November 2018, 56 patients were enrolled and 49 patients were evaluated. Overall, Grade ≥ 2 PN (sensory) was observed in 30.6% and 36.7% in the study and control sides, respectively (McNemar p = 0.25). PN (motor) was observed in 4.1% and 6.1% in the study and control sides, respectively (McNemar p = 1.0). Conclusion: Surgical glove compression therapy showed no statistically significant effect on the incidence of PTX-induced PN.Trial registrations: This study was registered with the University Hospital Medical Information Network (UMIN) Clinical Trials Registry managed by the National University Hospital Council of Japan (UMIN000027944).
The Efffect of Gender Differences to Fat Deposition In Yaks Based on an Integrated Transcriptomic and Metabonomics Analysis
Authors: Xiong Lin , Pei Jie , Yao Xixi , Wu Xiaoyun , Kalwar Qudratullah , Yan Ping , Guo Xian
Published: October 2020

Background: The study of fat deposition in yaks of different gender plays a positive role in improving the meat quality and breeding of yaks. In this work, the characteristic of fat deposition in male and female yaks, and the regulations of gender difference to fat deposition in yaks were explored. Result: Compared with male yaks, the female yaks possessed higher or more body fat rate (BFR) of visceral except liver, fat content in muscle and liver and subcutaneous fat (p < 0.05); the cholesterol (CH), triglyceride (TG), very low-density lipoprotein (VLDL), leptin (LEP) and cortisol (COR) in serum of female yaks were higher (p < 0.05 ); meanwhile, the fatty acid synthase (FAS), acetyl-CoA carboxylase (ACC), stearoyl-CoA desaturase (SCD) and diacylglycerol acyltransferase 1 (DGAT-1) in livers of female yaks were higher (p < 0.05). The metabonomics analysis showed 13(S)-HODE, linoleic acid and linolenic acid and myo-inositol in subcutaneous fat of female yaks increased (p < 0.05 ); meanwhile, the transcriptomic analysis the gene expressions of prenylcysteine oxidase 1 (PCYOX1), acyl-coenzyme a-cholesterol acyltransferase (ACAT), protein farnesyltransferase subunit beta (FNTB), apolipoprotein E (ApoE), DGAT2, very long chain fatty acids protein 6 (ELOVL6), NADP-dependent malic enzyme (ME1), SCD, acyl-CoA-binding protein (ACBP) and perilipin-5 (PLIN5), LEP, sterol regulatory element-binding protein 1 (SREBF1) upregulated in subcutaneous fat of female yaks (pFDR < 0.05), whereas the gene expressions of CPT1, acetyl-CoA acyltransferase 1(ACAA1) and adipose triglyceride lipase (ATGL) downregulated (pFDR < 0.01).Conclusion: The fat and cholesterol synthesis increased in liver of female yaks, and the fat transport in blood of female yaks increased too. In subcutaneous fat of female yaks, the high levels of myo-inositol activated the calcium signaling, following the increase of secretion in fat cell. Then, the high levels of LEP and 13(S)-HODE strengthened PPAR signal, and the fat synthesis, cholesterol synthesis, fatty acid biosynthesis of the linoleic and linolenic acid being the precursor increased, whereas lipolysis and fatty acid oxidation decreased by the regulation of downstream genes in PPAR signal. Meanwhile, SREBF1 also played an important part in the regulation of fat metabolism in yaks of different gender.
Allopolyploidization Enhances Genetic Recombination of the Ancestral Diploid Genome in the Evolution of Wheat
Authors: Wan Hongshen , Li Jun , Ma Shengwei , Yang Fan , Chai Liang , Xu Hongxing , Wang Qin , Liu Zehou , Pu Zongjun , Yang Wuyun
Published: October 2020

Background: Genetic recombination produces different allelic combinations potentially, providing new variations to the selection pools for domestication. Allopolyploidization increases evolutionary potential of the hexaploid common wheat by taking its advantages of heterosis and gene redundancy. May there be any relationship between allopolyploidization and genetic recombination? To study the impact of allopolyploidization on genetic recombination in different ancestral genomes of wheat, we generated synthetic hexaploid wheat by crossed tetraploid Triticum turgidum with diploid Aegilops tauschii to simulate its evolutionary hexaploidization process. Results: Using Wheat Breeder’s Genotyping Array, the genotypes of F2 individuals were investigated in both tetraploid (A1A1B1B1 x A2A2B2B2) and their synthetic hexaploid wheat derived populations (A1A1B1B1DD x A2A2B2B2DD). And the genotypes of the diploid population (D1D1 x D2D2) and their synthetic hexaploid wheat derived population (AABBD1D1 x AABBD2D2) were obtained with DArT-Seq™ technology. Based on genotypes of F2 populations, the genetic recombination frequency of homologous chromosome were consequently calculated in ancestral tetraploid AABB (4x), diploid DD (2x) and their synthetic hexaploid AABBDD (6x) plants, respectively. The recombination frequency of the ancestral diploid genome DD from Aegilops tauschii was found enhanced significantly more than 2 folds after their hexaploidization, while no significant changes was found in their ancestral tetraploid genome AABB via hexaploidization.Conclusions: Allopolyploidization enhancing genetic recombination of the ancestral diploid genome is found to increase the evolutionary potential of wheat, which is beneficial for wheat to conquer their narrow origination of D genome, quickly spread and make it a major crop of the world.
Integrated Analysis of DNA Methylome and Transcriptome Reveals Epigenetic Regulation of CAM Photosynthesis in Pineapple
Authors: Wang Haifeng , Shi Yan , Zhang Xingtan , Chang Xiaojun , Yan Maokai , Zhao Heming , Qin Yuan
Published: October 2020

Background: Crassulacean acid metabolism (CAM) photosynthesis is an important carbon fixation pathway especially in arid environments because it leads to higher water-use efficiency compared to C3 and C4 plants. However, the role of DNA methylation in regulation CAM photosynthesis is not fully understood. Results: Here, we performed temporal DNA methylome and transcriptome analysis of non-photosynthetic (white base) and photosynthetic (green tip) tissues of pineapple leaf. The DNA methylation patterns and levels in these two tissues were generally similar for the CG and CHG cytosine sequence contexts. However, CHH methylation was reduced in white base leaf tissue compared with green tip tissue across diel time course in both gene and transposon regions. We identified thousands of local differentially methylated regions (DMRs) between green tip and white base at different diel periods. We also showed that thousands of genes that overlapped with DMRs were differentially expressed between white base and green tip leaf tissue across diel time course, including several important CAM pathway-related genes, such as beta-CA, PEPC, PPCK, and MDH. Conclusions: Together, these detailed DNA methylome and transcriptome maps provide insight into DNA methylation changes and enhance our understanding of the relationships between DNA methylation and CAM photosynthesis.
Dynamin-related protein 1 deficiency impairs mitophagy and accelerates lipopolysaccharide-induced inflammation in mice
Authors: Wang Lixiang , Li Xin , Hanada Yuki , Hasuzawa Nao , Nomura Masatoshi , Yamamoto Ken
Published: October 2020

Mitochondrial fusion and fission, which are strongly related to normal mitochondrial function, are referred to as mitochondrial dynamics. Mitochondrial fusion defects in the liver cause a non-alcoholic steatohepatitis-like phenotype and liver cancer. However, whether mitochondrial fission defect directly impair liver function and stimulate liver disease progression, too, is unclear. Dynamin-related protein 1 (DRP1) is a key factor controlling mitochondrial fission. We hypothesized that DRP1 defects are a causal factor directly involved in liver disease development and stimulate liver disease progression. We administered lipopolysaccharide (LPS) to liver-specific Drp1-knockout (Drp1LiKO) mice. We observed an enhanced inflammatory response accompanied by mitophagy impairment. Drp1 defects directly promoted hepatocyte apoptosis and subsequently induced infiltration of inflammatory macrophages enhanced inflammasome activation in the liver and increased pro-inflammatory cytokine expression in the liver and serum. Drp1 deletion increased the expression of numerous genes involved in the immune response and DNA damage in Drp1LiKO mouse primary hepatocytes. This is a novel mechanism of liver disease development in which Drp1 defect-induced mitochondrial dynamics dysfunction directly regulates the fate and function of hepatocytes and enhances LPS-induced acute liver injure in vivo.
Novel Micromotion-Balancing Drilling Technology to Increase Proximal Cortical Strain
Authors: Wang Yang , Duan Zhengwei , Lu Hua
Published: October 2020

Background: We aimed to design a micromotion-balancing drilling system on the basis of the existing locking plate to maintain the balance of the micromotion of the cortex on both sides of a fracture region. We tested the system by subjecting it to a few biomechanical tests.Methods: According to the shape of screw holes on the cortex, the fixed fracture models were divided into a control group (standard screw hole group X126, 6 cases) and an experimental group (elliptical screw hole group N, 36 cases). The experimental group was further divided into 6 subgroups with 6 cases in each (N126, N136, N1256, N1356, N12356, N123456) on the basis of the number and distribution of the screws on the proximal fracture segment. The control, N126, and N136 groups were subjected to 500-N axial load, and other groups were subjected to 1000-N axial load. The displacements of the kinetic head, distal cortex, and proximal cortex were measured. The integral structural stiffness of the model and the proximal cortical strain were calculated. The data of each group were analyzed by paired t-tests.Results: When the distal cortical strains were 2%, 5%, and 10%, the proximal cortical strains in group N126 were 0.96%, 2.35% and 4.62%, respectively, which were significantly higher than those in the control group (X126) (p<0.05). When the distal cortical strains were 2%, 5% and 10%, the proximal cortical strain in group N126 was significantly higher than that in group N136 (p<0.05). However, there was no significant difference between the proximal cortical strains in the two groups with 4 screws (p>0.05). The proximal cortical strain in the 3-screw groups was significantly higher than that in the 4-screw groups (p<0.05), and there was no significant difference in the proximal cortical strain in the 4-, 5-, and 6-screw groups (p>0.05).Conclusions: The new drill and the matching sleeves enabled a conventional locking compression plate to be transformed into an internal fixation system and improved the balanced motion of the distal and proximal cortices. Thus, the strain on a fracture site can be controlled by adjusting the drill diameter and sleeve eccentricity.
Circulating mucosal associated invariant T cells identify patients responding to anti-PD1 therapy
Authors: De Biasi Sara , Gibellini Lara , Tartaro Domenico Lo , Mazza Emilia , Puccio Simone , Brummelman Jolanda , Williams Brandon , Kaihara Kelly , Forcato Mattia , Bicciato Silvio , Pinti Marcello , Depenni Roberta , Sabbatini Roberto , Dominici Massimo , Pellacani Giovanni , Lugli Enrico , Cossarizza Andrea
Published: October 2020

Immune checkpoint inhibitors that maintain anti-tumor T cell response are used for treating patients with metastatic melanoma. Since the response to treatment is extremely variable, biomarkers are urgently needed to identify patients who could benefit from such therapy. We combined single-cell RNA-sequencing and multiparameter flow cytometry to determine changes in circulating CD8+ T cells in patients with metastatic melanoma. A total of 28 patients starting anti-PD1 therapy were enrolled and followed for 6 months: 17 responded to therapy, whilst 11 did not. The proportion of activated and proliferating CD8+ T cells and of mucosal associated invariant T (MAIT) cells was significantly higher in responders before starting therapy and was maintained over time. MAIT cells expressed higher level of CXCR4 and produced more granzyme B; in silico analysis revealed that they are present in the tumor microenvironment. Finally, patients with higher levels of MAIT showed a better response to treatment.
Boosting Energy Storage Performance of Low-Temperature Sputtered CaBi2Nb2O9 Thin Film Capacitors Via Rapid Thermal Annealing
Authors: Yan Jing , Wang Yanling , Wang Chun-Ming , Ouyang Jun
Published: October 2020

CaBi 2 Nb 2 O 9 thin film capacitors were fabricated on SrRuO 3 -buffered Pt(111)/Ti/Si(100) substrates by adopting a two-step fabrication process. This process combines a low-temperature sputtering deposition with a rapid thermal annealing (RTA) to inhibit the grain growth, for the purposes of delaying the polarization saturation and reducing the ferroelectric hysteresis. By using this method, CaBi 2 Nb 2 O 9 thin films with uniformly distributed nanograins were obtained, which display a large recyclable energy density W rec ~69 J/cm 3 and a high energy efficiency η ~82.4%. A superior fatigue-resistance (negligible energy performance degradation after 10 9 charge-discharge cycles) and a good thermal stability (from -170 °C to 150 °C) have also been achieved. This two-step method can be used to prepare other bismuth layer-structured ferroelectric film capacitors with enhanced energy storage performances.
The Interval Between Insemination and Ovulation Predicts Outcome After Intrauterine Insemination With Donor Sperm (IUI-D)
Authors: MU XIN , Wang Hui , Liu Pei-jun , Shi Juan-zi
Published: October 2020

ObjectiveTo identify whether the time interval from insemination to ovulation (I-O interval) affects outcome after intrauterine insemination with donor sperm (IUI-D).DesignRetrospective study.SettingA single public medical center.Patient(s)1,165 couples, for 2,091 IUI-D cycles.Main Outcome MeasureLive birth rate (LBR) ResultsMultiple predictors were identified for LBR. The I-O interval was the predictor for LBR. An I-O interval ≥19 hours significantly decreased CPR (odds ratio [OR], 95% confidence interval [CI] =0.285, 0.171-0.475) and LBR (OR, 95%CI =0.322, 0.189-0.549). The presence of at least two follicles ≥18mm on ovulation day significantly increased the LBR (OR, 95%CI =1.274, 1.012-1.602). Women aged 35 years and older had a significant decreased LBR (OR, 95% CI =0.607, 0.377-0.976).Conclusion(s)The I-O interval, a new prognostic factor, combination with the women’s age and number of mature follicle, can predict the outcome after IUI-D. IUI-D is best performed within 19 hours of I-O interval for a higher probability of clinical pregnancy and live birth.
Gastric transcatheter chemoembolization can resolve advanced gastric cancer presenting with obstruction
Authors: Peng Dong , Qian Kun , Cheng Yuxi , Tao Wei , Zou Ying-Ying , Zhang Wei
Published: October 2020

Background Gastric transcatheter chemoembolization (GTC) is an interventional minimal invasive method, which has never been mentioned in the previous literature for advanced gastric cancer with obstruction. The purpose of this study was to evaluate its safety and efficacy in treating advanced gastric cancer with obstruction.MethodsAdvanced gastric cancer patients with obstruction who underwent GTC were retrospectively analysed from June 2017 to January 2020. Baseline information, peri-intervention data, and post-intervention follow-up information were collected. Clinical data obtained before and after the GTC were compared, and the survival of all patients was analysed.ResultForty-Two patients were included in this study. 42 (100%) patients achieved technical success, and 22 (52.4%) achieved clinical success. The median time of the GTC was 83 (30.0-180.0) minutes, and the median time of hospitalization after GTC was 3 (1-6) days. One patient experienced abdominal pain during and after GTC. Twenty (47.6%) of the 42 patients underwent gastrectomy after intervention. The pre-intervention gastric outlet obstruction scoring system(GOOSS) was 1 (0-1) and the post-intervention GOOSS was 2 (0-3) (p=0.000<0.05). The median follow-up time was 9.5 (3-35) months, and the overall survival time was 14 months. In the univariate survival analysis, a significant difference was observed between patients who did or did not undergo radical gastrectomy after GTC (p = 0.014<0.05).ConclusionsGTC is a safe and effective treatment, and furthermore, it could be an alternative method in treating advanced gastric cancer with obstruction.
Timing of surgery for benign periacetabular tumor: virtual finite element analysis and clinical verification on 39 cases
Authors: Yang Hongsheng , Zhang Wenli , Lang Yun , Fang Xiang , Hong Duan
Published: October 2020

BackgroundThe treatment of periacetabular tumor has always been met with great challenges, including the lack of a standard for the timing of surgery. The purposes of this study were to predict the risk for fracture by finite element analysis of benign periacetabular tumor; to guide the timing of operation; and to verify the practical application of this standard through clinical cases. MethodsBone defects in different areas of the acetabulum were constructed, and the fracture risk was predicted by finite element analysis. According to the results of finite element analysis and Enneking classification, the patients with benign periacetabular tumor were divided into the low fracture risk noninvasive lesion, low fracture risk invasive lesion, and high fracture risk groups. The grouping was used to guide the timing of operation. ResultsThis study included 39 patients who were followed-up for at least two years to verify the effectiveness of this program. The 12 patients in the low risk noninvasive lesion group that did not undergo operation showed no obvious pathological changes and no pathological fracture; there was no significant difference in the MSTS-93 score between the first and last visits (P > 0.05). The 7 patients in the low risk invasive lesion group were treated with adjuvant therapy before the operation; the MSTS-93 score was significantly lower on the first visit than on the last visit (P < 0.05). The 20 cases that had high risk for fracture underwent surgery after the diagnosis; of these, 13 patients achieved osseointegration of the graft bone and 7 patients had no prosthesis loosening, detachment, displacement or rupture after prosthesis replacement. The MSTS-93 score significantly improved from a preoperative value of 19.61 ± 7.32 to a final follow-up value of 26.28 ± 15.59 (P < 0.01). ConclusionsOur study confirmed that for benign periacetabular tumor, finite element analysis, combined with the nature of the tumor, can predict the risk for acetabular fracture and guide the appropriate timing and method of operation, thereby, enabling a safe therapeutic effect.
Inflammatory pseudotumor-like follicular dendritic cell sarcoma of the liver with hepatic lymphoma history: a case report and literature review
Authors: Zhang Erlei , Wang Wenqiang , Li Jian , Chen Dong , Huang Zhiyong
Published: October 2020

BackgroundInflammatory pseudotumor (IPT)-like follicular dendritic cell (FDC) sarcoma of the liver is very rare and mostly occurs in females. Up to now, 19 cases were reported in the English literature. Surgical resection remains the preferred method for the management of this kind of tumor. Case presentationWe reported a case of a 47-year-old male patient who had hepatitis B virus infection history and presented with up-abdominal discomfort. He underwent liver resection of segment VII for hepatic non-hodgkin lymphoma (B-cell lymphoma) 19 years ago. Serum alpha fetoprotein was normal. Imaging studies revealed a well-circumscribed, solid mass in the right hepatic lobe and was diagnosed as HCC or hepatic lymphoma. Right hemihepatectomy was performed and the patient was disease free after a follow-up of 20 months. Histological feature showed a mixture of chronic inﬂammatory cells and variable amounts of spindle cells. Immunohistochemical studies demonstrated that all the tumor cells showed strong nuclear in situ labeling for EBV-encoded small RNAs (EBER) and strongly positive staining with CD21 and CD35. A diagnosis of hepatic IPT-like FDC sarcoma was rendered. The coexistence of IPT-like sarcoma and non-Hodgkin’s lymphoma in same patient is extremely rare. He remains disease-free more than 40 months after surgical resection.ConclusionTo our knowledge, this is the first report to demonstrate hepatic IPT-like FDC sarcoma in a patient with primary hepatic non-hodgkin lymphoma history. Complete surgical resection should be pursued.
Mulching measures improve soil moisture in rain-fed jujube orchard in the loess hilly region of China
Authors: Tang Min , Li Hongchen , Zhang Chao , Zhao Xining , Gao Xiaodong , Wu Pute
Published: October 2020

BackgroundWater shortage is the main bottleneck restricting the healthy and sustainable development of rain-fed jujube orchards in the loess hilly region of China. Given the functions of mulching on soil moisture conservation, evaporation reduction, and water use efficiency improvement, maize straw mulching (SM) and pruned jujube branch mulching (BM) were applied to rain-fed jujube orchards in this study. Soil moisture dynamics, soil water storage, water consumption, and soil moisture attenuation after typical rainfall under SM, BM, and clean tillage (CT) were systematically studied. Results(1) The 0-60 cm soil layer was the seasonal fluctuation layer of soil moisture under SM, BM, and CT in both the normal precipitation year and the dry year. The 0-60, 60-160, and 160-280 cm soil layers under CT all obtained the lowest soil moisture content in the three experimental years. The soil moisture content of each soil layer under SM and BM was higher than that under CT, and SM showed the most obvious effect of increasing soil moisture. (2) SM and BM showed significant soil water storage effect in all the jujube growth stages in both the normal precipitation year and the dry year, and SM had a better water storage effect than BM. (3) SM and BM reduced the water consumption amount in each jujube growth stage. SM reduced water consumption amount by 94.3, 60.8, and 121.3 mm compared with CT in the whole growth period of jujube in 2014, 2015, and 2016, respectively. The water consumption amount of BM decreased by 34.8 mm and 31.0 mm respectively compared with that of CT in the whole growth period in 2014 and 2015. (4) CT had the maximum soil moisture loss rate under continuous drought after rainfall. The soil moisture loss rate of CT was above 37.3% on the eleventh day after the typical rainfall in 2014, 2015, and 2016. With the extension of drought, the soil moisture loss rate under SM increased slowly, while it increased rapidly under CT. ConclusionThis study suggests that straw mulching is the best mulching measure for rain-fed jujube orchards, and the pruned jujube branches can also be used for in-situ mulching, which can also obtain a certain moisture conservation effect.
Identification of Mechanisms of Resistance to ALK Inhibitors. Next-generation sequencing-based liquid biopsy profiling: A step towards personalized treatment.
Authors: Sánchez-Herrero Estela , Serna-Blasco Roberto , Ivanchuk Vadym , García-Campelo Rosario , Dómine Manuel , Sánchez José Miguel , Massuti Bartomeu , Reguart Noemi , Camps Carlos , Sanz-Moreno Sandra , Calabuig-Fariñas Silvia , Jantus-Lewintre Eloísa , Arnal Magdalena , Fernández-Orth Dietmar , González-Rumayor Víctor , Calvo Virginia , Provencio Mariano , Romero Atocha
Published: October 2020

Background: Despite impressive and durable responses, patients treated with ALK inhibitors (ALK-Is) ultimately progress. We investigated potential resistance mechanisms in a series of ALK-positive non-small cell lung cancer (NSCLC) patients progressing on different types of ALK-Is.Methods: 26 plasma and 2 cerebrospinal fluid samples collected upon disease progression to an ALK-I, from 24 advanced ALK-positive NSCLC patients, were analyzed by next-generation sequencing (NGS). A tool to retrieve variants at the ALK locus was developed. Results: 61 somatic mutations were detected in 14 genes: TP53, ALK, PIK3CA, SMAD4, MAP2K1 (MEK1) FGFR2, FGFR3, BRAF, EGFR, IDH2, MYC, MET, CCND3 and CCND1. Overall, We identified at least one mutation in ALK locus in 10 (38.5%) plasma samples, being the G1269A and G1202R mutations the most prevalent among patients progressing to first- and second-generation ALK-I treatment, respectively. An exon 19 deletion in EGFR was identified in a patient showing primary resistance to ALK-I. Likewise, the G466V mutation in BRAF and the F129L mutation in MAP2K1 (MEK1) were identified as the underlying mechanism of resistance in three patients who gained no or little benefit from second-line treatment with an ALK-I. Putative ALK-I resistance mutations were also found in PIK3CA and IDH2. Finally, a c-MYC gain, along with a loss of CCND1 and a FGFR3, were detected in a patient progressing on a first-line treatment with crizotinib. Conclusions: NGS analysis of liquid biopsies upon disease progression identified putative ALK-I resistance mutations in most cases, being a valuable approach to devise therapeutic strategies upon ALK-I failure.
S-nitrosylation of CYR61 protein reduces triple-negative breast cancer metastasis ability
Authors: Jia Lee , Lu Yusheng , He Sudan , Xie Huanzhang , Zhong Chunlian , Yang Xingtian , Yu Suhong , Lian Shu , Li Yumei , Lin Guoxing , Zhang Chen
Published: October 2020

BackgroundTriple-negative breast cancer (TNBC) is the most difficult cancer to be treated. TNBC expresses high level of matricellular cysteine-rich protein CYR61/CCN1 that plays a key role in producing cancer metastases and is an important target for metastasis chemoprevention. Nitric oxide (NO) can covalently bind to the thiol group of cysteines (termed S-nitrosylation) resulting in regulation of the targeted protein functions. MethodsProtein S-nitrosylation were detected by biotin-switch assay and western blotting assay. CYR61 protein S-nitrosylated sites and 3D structure were determined by mass spectrometry and MODELLER software. Adhesion assay, cell morphology assay, wound healing assay and transwell invasion assay were used to evaluate effects of CYR61 S-nitrosylation on the cell metastatic ability. In vivo metastasis activity of CYR61 S-nitrosylation were tested by intravenous injection and mammary xenograft implantation mouse metastatic models.ResultsS-nitrosylation by GSNO of CYR61 reached a plateau quickly and was confirmed by spectroscopic analysis and biotin-switch assay. Mass-spectrometry proteomic analysis revealed that S-nitrosylation predominantly occurred at Cys100, Cys117, Cys229 and Cys239, resulting in CYR61 structure relaxed and unstable evidenced by protein structure modeling. S-nitrosylation of MDA-MB-231 cells, their CYR61-overexpressed and CYR61–silenced counterparts significantly attenuated the metastatic ability of these cells, including their ability of adhesion, mobility, invasion, and interplay with platelets, and made the adhered cells unattached. The attenuation in metastatic ability proportionally increased with the degree of S-nitrosylation to CYR61 naturally-expressed or genetically-manipulated cells, and was demonstrated in mice, where, S-nitrosylation of these cell lines not only inhibited their acute seeding to lungs after an intravenous injection, but also inhibited the late development of these cells into the metastatic nodes after mammary xenograft implantation. Furthermore, orthotopically-implanted MDA-MB-231 developed mammary tumors and later lung metastasis; whereas, the same cells with S-nitrosylation developed no tumor and metastasis at all. Conclusionwe present the first evidence that S-nitrosylation of CYR61 can significantly inhibit metastatic aggressiveness of the TNBC MDA-MB-231 cells. This conceptual creative study opens a new avenue to prevent the most aggressive TNBC from metastases by S-nitrosylation to CYR61.
A Combinatorial Strategy for Tageting Papillary Thyroid Carcinoma with MEK Inhibitor and SHP2 Inhibitor
Authors: Zhi Jingtai , Yi Jiaoyu , Hou Xiukun , Wang Wei , Yang Weiwei , Hu Linfei , Huang Jianfeng , Guo Shicheng , Ruan Xianhui , Zheng Xiangqian , Gao Ming
Published: October 2020

Background: Pharmacologic targeting of components of MAPK/ERK pathway in thyroid carcinoma is often limited due to the development of adaptive resistance. However, the detailed mechanism for MEK inhibitor (MEKi) resistance is not fully understood in papillary thyroid carcinoma (PTC). Methods: RNA-seq was performed in MEKi-resistant PTC cell lines (K1, BCPAP, TPC-1 and KTC-1) to investigate the intrinsic mechanism of drug resistance. Colony formation assay, cell viability assay, cell cycle analysis and various murine models, including xenograft model, long-term MEKi-treated model, and transgenic model were conducted to evaluate the treatment effect of combination therapy (SHP099 and selumetinib). Results: Multiple receptor tyrosine kinases (RTKs) signaling pathways as well as Src-homology 2 domain-containing phosphatase 2 (SHP2) were activated in MEKi-resistant cells. Given the physiological role of SHP2 as the downstream of many RTKs, we first found that blockage of SHP2 abrogated MEKi resistance in thyroid cancer. Interestingly, we also found MEKi in combination with SHP2 inhibitor remarkably suppress rebound of MEK/ERK pathway compared to that of MEKi treatment alone, which significantly improved antitumor effects of MEKi. Various murine models confirmed the synergistic suppression on PTC in mice treated with both inhibitors. Conclusion: SHP2 blockade by SHP099 in combination with selumetinib is a promising therapeutic approach for advanced thyroid cancer.
Ferroptosis Involved in the Progression of Hepatocellular Carcinoma Through Circ0097009/miR-1261/SLC7A11 Axis
Authors: Lyu Ning , Zeng Yan , Kong Yanan , Chen Qifeng , Deng Haijing , Gao Guanfeng , Tang Hailin , Zhao Ming
Published: October 2020

Background: Circular RNAs (circRNAs) is a class of non-coding RNAs and have been demonstrated to play important roles in tumorigenesis. Nevertheless, how circRNAs regulate the progression of hepatocellular cancer (HCC) remains unclear.Methods: CircRNA microarrays was performed in HCC tissues to screen circRNAs that are extinct expressed. Quantitative real-time PCR (qRT-PCR) was conducted in HCC cell lines, and tissues and circ0097009 were found to be significantly up-regulated. Then, we explored the functions of circ0097009 in HCC by a series of experiments including cell proliferation, invasion and mouse xenograft assay. Additionally, luciferase assay and RNA immunoprecipitation (RIP) assay was used to explore the interactions of circ0097009, miRNA-1261 and SLC7A11 (a key regulator in cancer cell ferroptosis) in HCC.Results: Microarray analysis and qRT-PCR verified a circRNA circ0097009, which was significantly up-regulated in HCC tissues and cell lines. Knockdown of circ0097009 inhibited proliferation and invasion in HCC. Luciferase reporter assays showed that circ0097009 and SLC7A11 directly bind to miR-1261. Subsequent experiments showed that circ0097009 and SLC7A11 regulated the expression of each other by sponging miR-1261.Conclusions: Circ0097009 act as a competing endogenous RNA (ceRNA) to regulate SLC7A11 expression, a key regulator in cancer cell ferroptosis through sponging miR-1261 in HCC. Circ0097009 may be used as a diagnostic biomarker and potential target for HCC therapy.
Involvement and Targeted Intervention of Mortalin-Regulated Proteome Phosphorylated-Modification in Hepatocellular Carcinoma
Authors: Yang Ye , Jin Ming , Dai Yi , Shan Wenqi , Chen Shuai , Cai Rong , Yang Haojun , Tang Liming , Li Lei
Published: October 2020

BackgroundAngiogenesis and sorafenib resistance are the main obstacles to the treatment of advanced/recurrent hepatocellular carcinoma (HCC).MethodsThree HCC cell lines, HepG2 and Hep3B, and sorafenib-resistant HuH7, and xenografts in nude mice were used as experimental models. A cohort of 126 HCC patients and a cohort of 34 advanced recurrent HCC patients receiving sorafenib therapy were used to indicate the clinical significance.ResultsMortalin regulated the phosphorylated-modification of cancer associated proteome, causing the angiogenesis and sorafenib resistance in HCC cells. For one of the molecular mechanisms, via regulating the PI-3K/Akt, mortalin activated the VEGF/VEGFR2 and β-Catenin/Bcl-XL/anti-apoptosis signaling. Treatment the sorafenib resistant xenografts with sorafenib combining with mortalin knockdown facilitated the sorafenib-inhibited tumor growth and angiogenesis, and enhanced the apoptosis. Mortalin was a potential risk factor of HCC, predicting poor prognosis and sorafenib resistance. We finally revealed that, caffeic acid (CaA, C9H8O4) could bind to and induce the ubiquitination degradation of mortalin, leading to the inhibition of PI-3K/Akt, VEGF/VEGFR2, and β-Catenin/Bcl-XL/anti-apoptosis signal pathways.ConclusionsMortalin, which regulated the phosphorylated-modification of cancer associated proteome, caused angiogenesis and sorafenib resistance, and was a competitive risk factor of HCC. CaA could be recognized as a novel chemical inhibitor, targeting mortalin in HCC.
Combined Inhibition of AURKA and HSF1 Suppresses the Cell Proliferation and Promotes Cell Apoptosis of Hepatocellular Carcinoma by Activating Endoplasmic Reticulum Stress
Authors: Shen Zetian , Yin Li , Zhou Han , Ji Xiaoqin , Jiang Changchen , Zhu Xixu , He Xia
Published: October 2020

Objective: This study aims to investigate the anti-tumor effect of combined inhibition of aurora kinase A (AURKA) and heat shock transcription factor 1 (HSF1) for hepatocellular carcinoma (HCC) and the underlying mechanism.Methods: The expression of AURKA and HSF1 in HCC tissues and cell lines were detected by Immunohistochemistry (IHC), qRT-PCR and Western blot. Then, AURKA was downregulated in HepG2 cells by lentivirus-induced RNA interfere. Cell viability, invasion, migration and apoptosis were examined by CCK8, clone formation, transwell assays and flow cytometry analysis. The expression of proteins related to cell cycle, apoptosis and endoplasmic reticulum stress (ERS) were detected by Western blot. The tumor in vivo growth was measured on nude mice model. Histopathological examination was performed with HE staining.Results: AURKA and HSF1 were highly expressed in HCC tissues and cells, as well as negative related with prognosis. Knockdown of AURKA significantly inhibited the colony formation and migration of HCC cells. Besides, AURKA inhibitor (Danusertib) significantly reduced the proliferation and migration of HCC cells, and promoted cell apoptosis. Combined inhibition of AURKA and HSF1 induced cell apoptosis of HCC cells and increased the expression of ERS-associated proteins including p-eIF2α, ATF4 and CHOP in vitro. Additionally, combined inhibition of AURKA and HSF1 displayed an excellent antitumor activity on HCC model with relative low cytotoxicity.Conclusion: Combined inhibition of AURKA and HSF1 display excellent anti-tumor effect on HCC by activating endoplasmic reticulum stress, suggesting that AURKA and HSF1 can served as potential targets for HCC treatment.
Piecewise Sparse Approximation via Threshold P_OMP with Application to Surface Reconstruction
Authors: Zhong Yijun , Li Chongjun
Published: October 2020

Sparse signal representations have gained extensive study in recent years. In applications, there are large amounts of signals that are structured. Motivated by signal decomposition and scattered data reconstruction applications, we consider a particular type of structured signals which can be represented by a union of several sparse vectors. We define this type of signal as piecewise sparse signals. To find a piecewise sparse representation of a signal, we propose a thresholding version of piecewise orthogonal matching pursuit(TP OMP), which aims to overcome the disadvantages of P_OMP. We also establish the connection of piecewise sparsity and sampling over a union of subspaces. We evaluate the performance of the proposed greedy programs through simulations on surface reconstruction.
“They’re Not Doing Enough.”: Women’s Experiences with Opioids and Naloxone in Toronto
Authors: MacLeod Emilie , Tajbakhsh Iren , Hamilton-Wright Sarah , Laliberte Nancy , Wiese Jessica , Matheson Flora I
Published: October 2020

BACKGROUND: Amid increasing opioid overdose deaths in Canada, there is currently a need for up-to-date research on Canadian women’s experiences with opioids and their recently down-scheduled antidote, naloxone. Studies on Canadian take-home naloxone programs are promising, but research on perspectives outside these programs is limited. As the first qualitative study since the inception of the 2010’s opioid crisis to focus on Canadian women’s experiences and perspectives, our objective was to address these knowledge gaps and to identify resulting flaws in current policies, responses, and practices.METHODS: We conducted semi-structured, qualitative interviews from January to April 2018 with 10 women with experience of opioid use. They were recruited through the study’s community health partner in Toronto. They provided demographic information, experiences with opioids and naloxone, and their views on the Canadian government’s responses to the opioid crisis. Interviews were transcribed verbatim and inductive thematic analysis was conducted to determine major themes within the data.RESULTS: Participants who had used illicit opioids since the Canadian government’s down-scheduling of naloxone in 2016 were much more knowledgeable about naloxone than participants who had only used opioids prior. The portability, dosage form, and effects of naloxone are important considerations for women who use opioids. Social alienation, violence, and isolation affect the wellbeing of women who use opioids. The Canadian government’s response to the opioid crisis was perceived as neglectful and inadequate. Participants demonstrated differing needs and views on ideal harm reduction approaches, despite facing similar structural issues surrounding stigma, addiction management, and housing.CONCLUSIONS: Participants experienced with naloxone use found it to be useful in preventing fatal overdose, however many of their needs with regards to physical, mental, and social health, housing, harm reduction, and access to opioid treatment remained unmet.
Spatio-temporal Analysis of Cardiovascular Emergency Medical Requests: To Inform Policy and Practice
Authors: Azimi Ali , Bagheri Nasser , Mostafavi Mostafa , Furst MaryAnne , Hashtarkhani Soheil , Amin Fateme Hashemi , Eslami Saeid , Kiani Fatemeh , VafaeiNezhad Reza , Akbari Toktam , Golabpour Amin , Kiani Behzad
Published: October 2020

Background:Response time to cardiovascular emergency medical requests is an important indicator in reducing cardiovascular disease (CVD) related mortality. This study aims to develop an index of response time and investigate potential clusters in the pattern of CVD-related calls over time and space.Methods:This cross-sectional study was conducted in Mashhad, north-eastern Iran, between August 2017 and December 2019. An emergency medical service (EMS) response time matrix to CVD-related calls was computed using spatial and classical statistical analyses. The Anselin Local Moran's I was performed to identify potential clusters in the patterns of CVD-related calls, response time, call-to-hospital arrival time, and scene-to-hospital arrival time at small area level (neighborhood level) in Mashhad, Iran.Results:There were 84,239 CVD-related emergency request calls, of which 60.21 percent were transported to clinical centers by EMS, and 2.62 percent (a total of 2203 persons) died before EMS arrival. The number of CVD-related emergency calls increased by almost 15% in 2018 and 20% in 2019. The peak in the number of calls occurred between 9 p.m. and 1 a.m., and the lowest number of calls were recorded between 3 a.m. and 9 a.m. Saturday was the busiest day of week in terms of call volume. There were statistically significant clusters in the pattern of CVD-related calls in the south-eastern region of Mashhad. Further, we found a large spatial variation in scene-to-hospital arrival time and call-to-hospital arrival time in the area under study.Conclusion:The use of geographical information systems and spatial analyses in modelling and quantifying EMS response time provides a new vein of knowledge for decision makers in emergency services management. This also enables policy makers to design tailored interventions to improve response time and reduce CVD-related mortality.
Accuracy for mortality prediction with additive biomarkers including interleukin-6 in critically ill patients: a multicenter prospective observational study
Authors: Yamamoto Ryo , Sasaki Junichi , Shibusawa Takayuki , Nakada Taka-aki , Mayumi Toshihiko , Takasu Osamu , Matsuda Kenichi , Shimazui Takashi , Otsubo Hiroki , Teshima Yuto , Nabeta Masakazu , Moriguchi Takeshi , Oda Shigeto
Published: October 2020

Background: Several inflammation markers have been reported to be associated with unfavorable clinical outcomes in critically ill patients. We aimed to elucidate whether serum IL-6 concentration considered with sequential organ failure assessment (SOFA) score can better predict mortality in critically ill patients.Methods: A prospective observational study was conducted at five university hospitals in 2016–2018. Critically ill adult patients who met ≥2 systemic inflammatory response syndrome criteria on admission were included, and those who died or discharged within 48 hours were excluded. Inflammatory biomarkers including interleukin (IL) -6, -8, and -10, tumor necrosis factor-α, and procalcitonin were blindly measured daily for 3 days. Area under the receiver operating characteristic curve (AUROC) for SOFA score at Day 2 according to 28-day mortality was calculated as a baseline. Combination models of SOFA score and additional biomarkers were developed using logistic regression, and AUROC calculated in each model was compared with the baseline.Results: Among 161 patients included in the study, 18 (11.2%) did not survive at Day 28. Univariate analysis for each biomarker identified that the IL-6 (Days 1–3), IL-8 (Days 0–3), and IL-10 (Days 1–3) were higher in non-survivors versus survivors. Analyses of 28-day mortality prediction by a single biomarker showed IL-6, -8, and -10 at Days 1–3 had a significant discrimination power, and the IL-6 at Day 3 had the highest AUROC (0.766 [0.656–0.876]). Baseline AUROC for SOFA score predicting 28-day mortality was 0.776 (0.672–0.880). The combination model using additional IL-6 concentration at Day 3 had higher AUROC than baseline (AUROC = 0.844, AUROC improvement = 0.068 [0.002–0.133]), whereas other biomarkers did not improve accuracy in predicting 28-day mortality.Conclusions: Accuracy for 28-day mortality prediction was improved by adding serum IL-6 concentration to SOFA score.Trial registration: N/A (This study did not include any health-related interventions)
A subgroup of Ugandan elite and viremic controllers naturally control HIV-1 infection by blocking R5-tropic viral entry.
Authors: Kayongo Alex , Semugenze Derrick , Nantongo Mary , Semitala Fred , Niwaha Anxious Jackson , Kalyesubula Robert , Kirenga Bruce , Bagaya Bernard Sentalo , Joloba Moses Lutaakome
Published: October 2020

Background: World over, there are antiretroviral therapy naïve individuals infected with HIV who maintain their CD4+T cell count above 500 cells/µl over 7-10 years and viral loads well controlled below undetectable levels (termed elite controllers, ECs) or at least 2,000 copies/mL (termed viremic controllers, VCs) for at least 12 months. Mechanisms responsible for HIV control in these individuals have not been fully elucidated. We hypothesized that CD4+T cells from elite and viremic controllers are naturally resistant to HIV-1 infection by blocking R5-tropic viral entry. We conducted a case-controlled study in which archived peripheral blood from 31 ECs/VCs and 15 progressors were investigated using in vitro HIV-1 infectivity assays. Results: Briefly, we purified CD4+T cells from peripheral blood using EasySep CD4+ positive selection kit followed by CD4+T cell activation using IL-2, anti-CD28 and anti-CD3. Three days post-activation, CD4+T cells were spinoculated and co-cultured with vesicular stomatitis virus G (VSV-G)-pseudotyped HIV, R5 (ADA-enveloped)- and X4 (NL4.3-enveloped v)-tropic HIV-1. Three days post infection, we quantified and compared the percentage infection of CD4+T cells in cases and controls. We demonstrate that a subgroup of Ugandan elite and viremic controllers possess CD4+T cells that are specifically resistant to R5-tropic virus, remaining fully susceptible to X4-tropic virus. Conclusion: Our study suggests that a subgroup of Ugandan elite and viremic controllers naturally control HIV-1 infection by blocking R5-tropic viral entry. Further research is needed to explore mechanisms of HIV control in the African population.