bluuebunny/crossref_metadata_2025_split huggingface dataset:
Mitophagy Promotes Sorafenib Resistance through Hypoxia-Inducible ATAD3A Dependent Axis
Authors: Wu Hong , Wang Tao , Liu Yiqiang , Li Xin , Xu Senlin , Wu Changtao , Zou Hongbo , Cao Mianfu , Jin Guoxiang , Lang Jinyi , Wang Bin , Liu Baohua , Luo Xiaolin , Xu Chuan 
Published: November 2020

Abstract
Background: The identification of novel targets for recovering sorafenib resistance is pivotal for Hepatocellular carcinoma (HCC) patients. Mitophagy is the programmed degradation of mitochondria, and is likely involved in drug resistance of cancer cells. Here, we identified hyperactivated mitophagy is essential for sorafenib resistance, and the mitophagy core regulator gene ATAD3A (ATPase family AAA domain containing 3A) was down regulated in hypoxia induced resistant HCC cells. Blocking mitophagy may restore the sorafenib sensitivity of these cells and provide a new treatment strategy for HCC patients. Methods: Hypoxia induced sorafenib resistant cancer cells were established by culturing under 1% O 2 with increasing drug treatment. RNA sequencing was conducted in transfecting LM3 cells with sh-ATAD3A lentivirus. Subsequent mechanistic studies were performed in HCC cell lines by manipulating ATAD3A expression isogenically where we evaluated drug sensitivity, molecular signaling events. In vivo study, we investigated the combined treatment effect of sorafenib and miR-210-5P antagomir. Results: We found a hyperactivated mitophagy regulating by ATAD3A-PINK/PARKIN axis in hypoxia induced sorafenib resistant HCC cells. Gain- and loss- of ATAD3A were related to hypoxia-induced mitophagy and sorafenib resistance. In addition, ATAD3A is a functional target of miR-210-5p and its oncogenic functions are likely mediated by increased miR-210-5P expression. miR-210-5P was upregulated under hypoxia and participated in regulating sorafenib resistance. In vivo xenograft assay showed that miR-210-5P antagomir combined with sorafenib abrogated the tumorigenic effect of ATAD3A down-regulation in mice. Conclusions: Loss of ATAD3A hyperactivates mitophagy which is a core event in hypoxia induced sorafenib resistance in HCC cells. Targeting miR-210-5P-ATAD3A axis is a novel therapeutic target for sorafenib-resistant HCC. Keywords: Mitophagy, ATAD3A, Hypoxia, Sorafenib resistance
Isolating the Energetic and Mechanical Consequences of Imposed Reductions in Ankle and Knee Flexion during Gait.
Authors: McCain Emily , Libera Theresa , Berno Matthew , Sawicki Gregory , Saul Katherine , Lewek Michael 
Published: November 2020

Abstract
Background: Weakness of ankle and knee musculature following injury or disorder results in reduced joint motion associated with metabolically expensive gait compensations to enable limb support and advancement. However, neuromechanical coupling between the ankle and knee make it difficult to discern independent roles of these restrictions in joint motion on compensatory mechanics and metabolic penalties.Methods: We sought to determine relative impacts of ankle and knee impairment on compensatory gait strategies and energetic outcomes using an unimpaired cohort (N=15) with imposed unilateral joint range of motion restrictions as a surrogate for reduced motion resulting from gait pathology. Participants walked on a dual-belt instrumented treadmill at 0.8 m s-1 using a 3D printed ankle stay and a knee brace to systematically limit ankle motion (restricted-ank), knee motion (restricted-knee), and ankle and knee motion (restricted-a+k) simultaneously. In addition, participants walked without any ankle or knee bracing (control) and with knee bracing worn but unrestricted (braced).Results: When ankle motion was restricted (restricted-ank, restricted-a+k) we observed decreased peak propulsion relative to the braced condition on the restricted limb. Reduced knee motion (restricted-knee, restricted-a+k) increased restricted limb circumduction relative to the restricted-ank condition through ipsilateral hip hiking. Interestingly, restricted limb average positive hip power increased in the restricted-ank condition but decreased in the restricted-a+k and restricted-knee conditions, suggesting that locking the knee impeded hip compensation. As expected, reduced ankle motion, either without (restricted-ank) or in addition to knee restriction (restricted-a+k) yielded significant increase in net metabolic rate when compared with the braced condition. Furthermore, the relative increase in metabolic cost was significantly larger with restricted-a+k when compared to restricted-knee condition.Conclusions: Our methods allowed for the reproduction of asymmetric gait characteristics including reduced propulsive symmetry and increased circumduction. The metabolic consequences bolster the potential energetic benefit of targeting ankle function during rehabilitation.
Laboratory and microcosm experiments reveal contrasted adaptive responses to ammonia and water mineralisation in aquatic stages of the sibling species Anopheles gambiae (sensu stricto) and Anopheles coluzzii&nbsp;
Authors: AKPODIETE NWAMAKA OLUCHUKWU , TRIPET FREDERIC 
Published: November 2020

Abstract
Background: The sibling species of the malaria mosquito, Anopheles gambiae (sensu stricto) and Anopheles coluzzii co-exist in many parts of West Africa and are thought to have recently diverged through a process of ecological speciation with gene flow. Divergent larval ecological adaptations, resulting in Genotype × Environment (G × E) interactions have been proposed as important drivers of speciation in these species. In West Africa, An. coluzzii tends to be associated with permanent man-made larval habitats such as irrigated rice fields which are typically more eutrophic and mineral and ammonia-rich than the temporary rain pools exploited by An. gambiae (s.s.) Methods: To highlight G × E interactions at the larval stage and their possible role in ecological speciation of these species, we first investigated the effect of exposure to ammonium hydroxide and water mineralisation on larval developmental success. Mosquito larvae were exposed to two water sources and increasing ammonia concentrations in small containers until adult emergence. In a second experiment, larval developmental success was compared across 2 contrasted microcosms to highlight G × E interactions under conditions like those found in the natural environment. Results: The first experiment revealed significant G × E interactions in developmental success and phenotypic quality for both species in response to increasing ammonia concentrations and water mineralisation. The An. coluzzii strain outperformed the An. gambiae (s.s.) strain under limited conditions that were closer to more eutrophic habitats. The second experiment revealed divergent crisscrossing reaction norms in the developmental success of the sibling species in the two contrasted larval environments. As expected, An. coluzzii had higher emergence rates in the rice paddy environment with emerging adults of superior phenotypic quality compared to An. gambiae (s.s.), and vice versa in the rain puddle environment.Conclusions: Evidence for such G × E interactions lends support to the hypothesis that divergent larval adaptations to the environmental conditions found in man-made habitats such as rice-fields in An. coluzzii may have been an important driver of its ecological speciation.
Roquin1 inhibits the proliferation of breast cancer cells by inducing G1/S cell cycle arrest via selectively destabilizing the mRNAs of cell cycle–promoting genes
Authors: Lu Wenbao , Zhou Meicen , Wang Bing , Liu Xueting , Li Bingwei 
Published: November 2020

Abstract
Background: Dysregulation of cell cycle progression is one of the common features of human cancer cells, however, its mechanism remains unclear. This study aims to clarify the role and the underlying mechanisms of Roquin1 in cell cycle arrest induction in breast cancer. Methods: Public cancer databases were analyzed to identify the expression pattern of Roquin1 in human breast cancers and the significant association with patient survival. Quantitative real-time PCR and western blots were performed to detect the expression of Roquin1 in breast cancer samples and cell lines. Cell counting, MTT assay, flow cytometry, and in vivo study were conducted to investigate the effects of Roquin1 on cell proliferation, cell cycle progression and tumor progression. RNA-sequencing was applied to identify the differential genes and pathways regulated by Roquin1. RNA immunoprecipitation assay, luciferase reporter assay, mRNA half-life detection, RNA affinity binding assay, and RIP-ChIP were used to explore the molecular mechanisms of Roquin1. Results: We showed that Roquin1 expression in breast cancer tissues and cell lines was inhibited, and the reduction in Roquin1 expression was associated with poor overall survival and relapse free survival of patients with breast cancer. Roquin1 overexpression inhibited breast cancer cell proliferation and induced G1/S cell cycle arrest without causing significant apoptosis. In contrast, knockdown of Roquin1 promoted breast cancer cell growth and cycle progression. Moreover, in vivo induction of Roquin1 by adenovirus significantly suppressed breast tumor growth and metastasis. Mechanistically, Roquin1 selectively destabilizing cell cycle–promoting genes, including Cyclin D1, Cyclin E1, cyclin dependent kinase 6 (CDK6) and minichromosome maintenance 2 (MCM2) through targeting the stem–loop structure in the 3’untranslated region (3’UTR) of mRNAs via its ROQ domain, leading to the downregulation of cell cycle–promoting mRNAs. Conclusions: Our findings demonstrated that Roquin1 was a novel breast tumor suppressor and could induce G1/S cell cycle arrest by selectively downregulating the expression of cell cycle–promoting genes, which might as a potential molecular target for breast cancer treatment.
Patterns of flea infestation in rodents and insectivores from intensified agro-ecosystems, NW Spain
Authors: Herrero-Cófreces Silvia , Flechoso Manuel Fabio , Rodríguez-Pastor Ruth , Luque-Larena Juan José , Mougeot Francois 
Published: November 2020

Abstract
Background: Fleas frequently infest small mammals and play important vectoring roles in the epidemiology of (re)emerging zoonotic disease. Rodent outbreaks in intensified agro-ecosystems of NW Spain have been recently linked to periodic zoonotic disease spillover to local human populations. Obtaining qualitative and quantitative information about the composition and structure of the whole flea and small mammal host coexisting communities is paramount to understand disease transmission cycles and to dilucidate the disease-vectoring role of flea species. The aims of this research were to: i) characterise and quantify the flea community parasiting a small mammal guild in intensive farmlands in NW Spain, and ii) determine and evaluate patterns of co-infection and the variables that may influence parasitological parameters.Methods: We conducted a large scale survey stratified by season and habitat of fleas parasitizing the small mammal host guild. We report on the prevalence, mean intensity, and mean abundance of flea species parasitizing Microtus arvalis, Apodemus sylvaticus, Mus spretus and Crocidura russula. We also report on aggregation patterns (variance-to-mean ratio and Discrepancy index), co-infection of hosts by different flea species (Fager Index), and used Generalized Linear Mixed Models to study flea parameter variation according to season, habitat and host sex. Results: Three flea species dominated the system: Ctenophthalmus apertus gilcolladoi, Leptopsylla taschenbergi and Nosopsyllus fasciatus. Results showed a high aggregation pattern of fleas in all hosts. All host species in the guild shared C. a. gilcolladoi and N. fasciatus, but L. taschenbergi mainly parasitized mice (M. spretus and A. sylvaticus). We found significant male-biased infestation patterns in mice, seasonal variations in flea abundances for all rodent hosts (M. arvalis, M. spretus and A. sylvaticus), and relatively lower infestation values for voles inhabiting alfalfas. Simultaneous co-infections occurred in a third of all hosts, and N. fasciatus was the commonest flea co-infecting small mammal hosts. Conclusions: The generalist N. fasciatus and C. a. gilcolladoi dominated the flea community, and a high percentage of co-infections with both species occurred within the small mammal guild. Nosopsyllus fasciatus may show higher competence of inter-specific transmission, and future research should unravel its role in the circulation of rodent-borne zoonoses.
Value of AFP and PIVKA-II in diagnosis of HBV-related hepatocellular carcinoma and prediction of vascular invasion and tumor differentiation
Authors: Si Yuan-quan , Wang Xiu-Qin , Fan Gang , Wang Chang-Yin , Zheng Yuan-Wen , Song Xie , Pan Cui-Cui , Chu Fu-Lu , Liu Zhan-Feng , Lu Bing-Ru , Lu Zhi-Ming 
Published: November 2020

Abstract
Background: To explore the value of alpha fetoprotein (AFP) and protein induced by vitamin K absence or antagonist-II (PIVKA-II) in diagnosis of HBV-related hepatocellular carcinoma (HCC) and their relationship with vascular invasion, tumor differentiation and size. Methods: A total of 433 participants were enrolled in this study including 266 cases with HBV-related HCC, 87 cases with HBV DNA positive benign liver disease and 80 healthy individuals. Then we explored the correlation between AFP, PIVKA-II serum level and several pathological features such as vascular invasion, tumor differentiation and size. The value of these two markers used singly or jointly in diagnosing HBV-related HCC was evaluated by receiver operating characteristic (ROC) curve. The ROC curve was also plotted to identify AFP, PIVKA-II serum cut-off values that would best distinguish HBV-related HCC patients with and without vascular invasion.Results: The level of AFP and PIVKA-II in HBV-related HCC group was significantly higher (Z was 7.428, 11.243 respectively, all P<0.01). When AFP and PIVKA-II were used as the individual tumor marker, the areas under the ROC curve (AUC) of HBV-related HCC diagnosis were 0.765 (95% CI, 0.713～0.8170) for AFP, 0.901 (95% CI, 0.868～0.935) for PIVKA-II, and 0.917 (95% CI, 0.886～0.948) for AFP and PIVKA-II simultaneously. The serum levels of AFP and PIVKA-II were positively correlated with tumor differentiation and size. High AFP and PIVKA-II expression was signiﬁcantly associated with the presence of vascular invasion (P was 0.007 and 0.014 respectively). The AFP level >64.4ng/ml or PIVKA-II level >957.61mAU/ml was the best critical value to predict the presence of vascular invasion. Conclusion: Our results validate that AFP and PIVKA-II play a significant role in the diagnosis of HBV-related HCC. The diagnostic value of AFP and PIVKA-II combined detection or single assay of PIVKA-II is higher than that of separate assay of AFP. Moreover, their concentration has important clinical value in judging tumor size, tumor cell differentiation and vascular invasion.
Clinicopathologic Characteristics and Surgical Outcome of Synthetic Fiber Conjunctival Granuloma
Authors: Chen Zhang , Wang Tianyang , Pan Qintuo , Zhang Zhaoliang , Zhang Zongduan 
Published: November 2020

Abstract
Background: Until recently, synthetic fiber conjunctival granuloma (SFCG) is rarely reported and has been poorly understood. Our study was to explore the clinical features, histopathologic characteristics, surgical outcomes, and prognosis of SFCG after surgical excision. Methods: Retrospective review of clinical findings, histopathological and immunohistochemical studies identified 18 cases of SFCG. Specimens were routinely processed and stained with H&E. Immunohistochemical stains for GMS, PAS, CD68 and CK-pan were also performed.Results: Eighteen patients with an average age of 9.3±6.6 years had a tender white to red mass on the conjunctiva. All the lesions were completely removed, and none of the patients relapsed. Histologically, all of the specimens revealed inflammatory granulation tissues with a large number of inflammatory cells infiltration and the presence of synthetic fibers. Immunohistochemical stains were positive for CD68, CK, GMS and PAS. Conclusions: Synthetic fiber conjunctival granuloma is an uncommon lesion with foreign body sensation caused by inoculation of synthetic exogenous materials. These lesions are mostly unilateral and occur in the inferior conjunctival fornix. SFCGs are characterized by a large number of inflammatory cells infiltration and the presence of synthetic fibers. Surgical excision followed by topical corticosteroids has been clinically proven to be effective.
FLT-PET for the assessment of systemic sarcoidosis including cardiac and CNS involvement: A prospective study with comparison to FDG-PET
Authors: Martineau Patrick , Pelletier-Galarneau Matthieu , Juneau Daniel , Leung Eugene , Nery Pablo , deKemp Rob , Beanlands Rob , Birnie David 
Published: November 2020

Abstract
BACKGROUND:FDG’s biodistribution limits the evaluation of cardiac sarcoidosis (CS) and neurosarcoidosis (NS). While protocols for cardiac suppression exist, they can be inconvenient for patients and lead to incomplete cardiac suppression in many cases. Furthermore, FDG PET is limited in the detection of neurosarcoidosis due to an inability to suppress high level of physiological uptake within the brain. FLT has been shown to accumulate in sarcoidosis lesions and this tracer lacks significant physiological myocardial and brain uptake, suggesting that this tracer may be useful for the assessment of sarcoidosis, including CS and NS, without the need for patient preparation. This prospective pilot study examined the performance of FLT vs FDG PET for systemic sarcoidosis, including cardiac and neural involvement.MATERIALS AND METHODS:14 subjects with sarcoidosis were prospectively recruited and imaged with FDG- and FLT-PET. Two blinded, experienced readers independently reviewed the FLT-PET and FDG-PET images. Lesion distribution was compared between FLT and FDG. Agreement between FLT- and FDG-PET was determined using Cohen’s kappa and the intra-class correlation coefficient. Inter-observer variability of FLT and FDG-PET was assessed.RESULTS:12 subjects had CS as per Heart Rhythm Society criteria and 1 had NS. FLT-PET was positive in 12 (86%), and FDG-PET in 11 (79%), with cardiac uptake present in 6 (50%) and 7 (58%) of subjects with CS, respectively. The subject with NS demonstrated uptake on both FLT and FDG-PET, with more lesions on FLT. There were no significant differences in the anatomical distribution of lesions between FLT and FDG. SUVs were significantly (p<0.001) higher for FDG than FLT (5.8 ± 3.0 vs 2.3 ± 1.1, respectively), but not (p=0.90) after adjusting for blood pool activity (2.8 ± 1.4 vs 2.8 ± 1.1, respectively). Agreement between FLT- and FDG-PET was good to excellent for the diagnosis of sarcoidosis, lung involvement, CS, and NS (κ = 0.76, 0.69, 0.86, and 1.0, respectively). Inter-observer agreement for FLT was excellent for diagnosing sarcoidosis, CS and NS (κ = 0.81, 0.85, and 1.0, respectively) and comparable to that of FDG.CONCLUSIONS:FLT-PET may be useful for the assessment of systemic sarcoidosis, as well as cardiac and neural involvement.
Effectiveness of chiropractic manipulation versus sham manipulation for recurrent headaches in children aged 7-14 years. A randomised clinical trial
Authors: Lynge Susanne , Dissing Kristina Boe , Vach Werner , Christensen Henrik Wulf , Hestbaek Lise 
Published: November 2020

Abstract
Background To investigate the effectiveness of chiropractic spinal manipulation versus sham manipulation in children aged 7-14 with recurrent headaches.Methods Design: A two-arm, single-blind, superiority randomised controlled trial.Setting: One chiropractic clinic and one paediatric specialty practice in Denmark Participants: 199 children aged 7 to 14 years, who experienced at least one episode of headache per week for the previous 6 months and with at least one musculoskeletal dysfunction identified. Interventions: All participants and parents received standard oral and written advice to reduce headaches. In addition, children in the active treatment group received chiropractic spinal manipulation and children in the control group received sham manipulation for a period of 4 months. Number and frequency of treatments were based on the chiropractor’s individual evaluation in the active treatment group, and the children in the control group received approximately eight visits during the treatment period.Primary outcome measures: ‘Number of days with headache’, ‘pain intensity’ and ‘medication’ were reported weekly by text messages, and global perceived effect by text message after 4 months. A planned fixed sequence strategy based on an initial outcome data analysis was used to prioritize outcomes. ‘Number of days with headache’ and ‘pain intensity’ were chosen as equally important outcomes of highest priority, followed by global perceived effect and medication. The significance level for the first two outcomes was fixed to 0.025 to take multiplicity into account.Results Chiropractic spinal manipulation resulted in significantly fewer days with headaches (reduction of 0.81 vs. 0.41, p=0.019, NNT=7 for 20% improvement) and better global perceived effect (dichotomized into improved/not improved, OR=2.8 (95% CI: 1.5-5.3), NNT=5) compared with a sham manipulation procedure. There was no difference between groups for pain intensity during headache episodes. Due to methodological shortcomings, no conclusions could be drawn about medication use.Conclusions Chiropractic spinal manipulation resulted in fewer headaches and higher global perceived effect, with only minor side effects. It did not lower the intensity of the headaches.Since the treatment is easily applicable, of low cost and minor side effects, chiropractic spinal manipulation might be considered as a valuable treatment option for children with recurrent headaches.Trial registration ClinicalTrials.gov, identifier NCT02684916, registered 02/18/2016 – retrospectively registered. https://clinicaltrials.gov/ct2/show/NCT02684916