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Background: Brain metastases (BMs) are the most frequent intracranial tumours associated with poor clinical outcomes. Radiotherapy is essential in the treatment of these tumours, although the optimal radiation strategy remains controversial. The present study aimed to assess whether whole brain radiation therapy with a simultaneous integrated boost (WBRT + SIB) provides any therapeutic benefit over WBRT alone. Methods: We included and retrospectively analysed 82 patients who received WBRT + SIB and 83 who received WBRT alone between January 2012 and June 2021. Intracranial progression-free survival (PFS), local tumour control (LTC), overall survival (OS), and toxicity were compared between the groups. Results: Compared to WBRT alone, WBRT + SIB improved intracranial LTC and PFS, especially in the lung cancer subgroup. Patients with high graded prognostic assessment score or well-controlled extracranial disease receiving WBRT + SIB had improved intracranial PFS and LTC. Moreover, WBRT + SIB also improved the long-term intracranial tumour control of small cell lung cancer patients. When evaluating toxicity, we found that WBRT + SIB might slightly increase the risk of radiation-induced brain injury, and that the risk increased with increasing dosage. However, low-dose WBRT + SIB had a tolerable radiation-induced brain injury risk, which was lower than that in the high-dose group, while it was comparable to that in the WBRT group. Conclusions: WBRT + SIB can be an efficient therapeutic option for patients with BMs, and is associated with improved intracranial LTC and PFS. Furthermore, low-dose WBRT + SIB (biologically effective dose [BED] ≤ 56 Gy) was recommended, based on the acceptable risk of radiation-induced brain injury and satisfactory tumour control. Trial registration: Retrospectively registered. [ABSTRACT FROM AUTHOR]

Background: The plant hormone auxin is widely involved in plant growth, development, and morphogenesis, and the TIR1/AFB and AUX/IAA proteins are closely linked to rapid auxin response and signal transmission. However, their evolutionary history, historical patterns of expansion and contraction, and changes in interaction relationships are still unknown. Results: Here, we analyzed the gene duplications, interactions, and expression patterns of TIR1/AFBs and AUX/IAAs to understand their underlying mechanisms of evolution. The ratios of TIR1/AFBs to AUX/IAAs range from 4:2 in Physcomitrium patens to 6:29 in Arabidopsis thaliana and 3:16 in Fragaria vesca. Whole-genome duplication (WGD) and tandem duplication have contributed to the expansion of the AUX/IAA gene family, but numerous TIR1/AFB gene duplicates were lost after WGD. We further analyzed the expression profiles of TIR1/AFBs and AUX/IAAs in different tissue parts of Physcomitrium patens, Selaginella moellendorffii, Arabidopsis thaliana and Fragaria vesca, and found that TIR1/AFBs and AUX/IAAs were highly expressed in all tissues in P. patens, S. moellendorffii. In A. thaliana and F. vesca, TIR1/AFBs maintained the same expression pattern as the ancient plants with high expression in all tissue parts, while AUX/IAAs appeared tissue-specific expression. In F. vesca, 11 AUX/IAAs interacted with TIR1/AFBs with different interaction strengths, and the functional specificity of AUX/IAAs was related to their ability to bind TIR1/AFBs, thus promoting the development of specific higher plant organs. Verification of the interactions among TIR1/AFBs and AUX/IAAs in Marchantia polymorpha and F. vesca also showed that the regulation of AUX/IAA members by TIR1/AFBs became more refined over the course of plant evolution. Conclusions: Our results indicate that specific interactions and specific gene expression patterns both contributed to the functional diversification of TIR1/AFBs and AUX/IAAs. [ABSTRACT FROM AUTHOR]

Background: The outcome of patients with T4 esophageal squamous cell carcinoma (ESCC) is extremely poor. Two distinct therapeutic options are currently available for T4 esophageal cancers: neochemoradiotherapy followed by surgery (CRT-S) and definitive chemoradiotherapy (D-CRT). This study aimed to investigate the clinicopathologic characteristics of T4 ESCC in Chinese patients and compare the survival between the two therapeutic options.Methods: We retrospectively analyzed 125 patients with clinically unresectable T4 ESCC in Tianjin Medical University Cancer Institute and Hospital from January 2010 to December 2020. Overall survival (OS), progression-free survival (PFS) and associated factors were analyzed.Results: A total of 106 of 125 T4 ESCC patients were downstaged of the tumor by neoadjuvant CRT. Among 106 patients, 32 patients underwent CRT-S, and 74 patients underwent D-CRT. Patients in the CRT-S group had a higher OS (20.4 months vs. un-reached median OS, p = 0.037) and PFS (8.6 months vs. 21.0 months, p = 0.008) than those in the D-CRT group. In multivariate analysis, treatment was an independent predictor of PFS. After propensity score matching (PSM), 50 patients (CRT-S = 25; D-CRT = 25) were matched. Among these 50 patients, patients in the CRT-S group had a higher OS (15.6 months vs. un-reached median OS, p = 0.025) and PFS (7.2 months vs. 18.8 months, p = 0.026) than those in the D-CRT group. In multivariate analysis, treatment was an independent predictor for PFS.Conclusion: We demonstrated that CRT-S was superior to D-CRT for T4 ESCC patients who were downstaged by neo-CRT with respect to longer OS and PFS. Randomized controlled trials involving large population samples are needed to define the standard treatment for T4 ESCC. [ABSTRACT FROM AUTHOR]

Background: Non-alcoholic fatty liver disease (NAFLD) is characterized by ectopic accumulation of triglycerides in the liver. Emerging evidence has demonstrated that lipophagy regulates lipid mobilization and energy homeostasis in the liver. Sirtuin 3 (SIRT3), a mitochondrial NAD+-dependent deacetylase, modulates the activities of several substrates involving in autophagy and energy metabolism. Honokiol (HK) is a natural lignan from the plants of Magnolia genus that exhibits potent liver protective property. Methods: AML12 was challenged with 500 μM palmitic acid and 250 μM oleic acid mixture solution to induce lipotoxicity. C57BL/6J mice were fed with a choline-deficient high fat diet (CDHFD) to generate liver steatosis. The expression of autophagy-related and AMP-activated protein kinase (AMPK) pathway proteins was evaluated by Western blotting and immunofluorescence staining. Intracellular lipid accumulation was validated by Nile red staining. Molecular docking analysis was performed on AutoDock 4.2. Results: HK (5 and 10 μM) was found to attenuate lipid accumulation through promoting SIRT3-AMPK-mediated autophagy, mainly on lipid droplets. HK had hydrophobic interaction with amino acid residues (PHE294, GLU323 and VAL324) and NAD+. Moreover, HK improved mitochondrial function to enhance lipolysis, through decreasing the acetylated long-chain acyl-CoA dehydrogenase level. In CDHFD-fed mice, HK (2.5 and 10 mg/Kg) treatment obviously prevented lipid accumulation in the liver. And co-treatment of the AMPK inhibitor, Compound C, almost abolished the above changes. Conclusions: These results suggest that HK could ameliorate lipotoxicity in hepatocytes by activating SIRT3-AMPK-lipophagy axis, which might be a potential therapeutic agent against NAFLD. [ABSTRACT FROM AUTHOR]

Sonodynamic therapy (SDT), presenting spatial and temporal control of ROS generation triggered by ultrasound field, has attracted considerable attention in tumor treatment. However, its therapeutic efficacy is severely hindered by the intrinsic hypoxia of solid tumor and the lack of smart design in material band structure. Here in study, fine α-Fe2O3 nanoparticles armored with Pt nanocrystals (α-Fe2O3@Pt) was investigated as an alternative SDT agent with ingenious bandgap and structural design. The Schottky barrier, due to its unique heterostructure, suppresses the recombination of sono-induced electrons and holes, enabling superior ROS generation. More importantly, the composite nanoparticles may effectively trigger a reoxygenation phenomenon to supply sufficient content of oxygen, favoring the ROS induction under the hypoxic condition and its extra role played for ultrasound imaging. In consequence, α-Fe2O3@Pt appears to enable effective tumor inhibition with imaging guidance, both in vitro and in vivo. This study has therefore demonstrated a highly potential platform for ultrasound-driven tumor theranostic, which may spark a series of further explorations in therapeutic systems with more rational material design. [ABSTRACT FROM AUTHOR]

Background: This study aimed to probe and verify aberrantly methylated and expressed genes in hepatoblastoma and to analyze their interactions with tumor immune microenvironment.Methods: Aberrantly methylated and expressed genes were obtained by comprehensively analyzing gene expression and DNA methylation profiles from GSE81928, GSE75271 and GSE78732 datasets. Their biological functions were predicted by the STRING and Metascape databases. CIBERSORT was utilized for inferring the compositions of tumor-infiltrating immune cells (TIICs) in each sample. Correlation between hub genes and immune cells was then analyzed. Hub genes were validated in hepatoblastoma tissues via western blot or immunohistochemistry. After transfection with sh-NOTUM, migration and invasion of HuH-6 and HepG2 cells were investigated. The nude mouse tumorigenesis model was constructed.Results: Totally, 83 aberrantly methylated and expressed genes were determined in hepatoblastoma, which were mainly involved in metabolic and cancer-related pathways. Moreover, their expression was liver-specific. 13 hub genes were screened, which were closely related to immune cells in hepatoblastoma tissues. Among them, it was confirmed that AXIN2, LAMB1 and NOTUM were up-regulated and SERPINC1 was down-regulated in hepatoblastoma than normal tissues. NOTUM knockdown distinctly weakened migration and invasion of HuH-6 and HepG2 cells and tumor growth in vivo.Conclusions: This study identified aberrantly methylated and expressed signatures that were in relation to immune microenvironment in hepatoblastoma. Targeting NOTUM hub gene could suppress migration and invasion of hepatoblastoma cells. Thus, these aberrantly methylated and expressed genes might act as therapeutic agents in hepatoblastoma therapy. [ABSTRACT FROM AUTHOR]

Immunotherapies such as immune checkpoint blockade (ICB) and adoptive cell therapy (ACT) have revolutionized cancer treatment, especially in patients whose disease was otherwise considered incurable. However, primary and secondary resistance to single agent immunotherapy often results in treatment failure, and only a minority of patients experience long-term benefits. This review article will discuss the relationship between cancer immune response and mechanisms of resistance to immunotherapy. It will also provide a comprehensive review on the latest clinical status of combination therapies (e.g., immunotherapy with chemotherapy, radiation therapy and targeted therapy), and discuss combination therapies approved by the US Food and Drug Administration. It will provide an overview of therapies targeting cytokines and other soluble immunoregulatory factors, ACT, virotherapy, innate immune modifiers and cancer vaccines, as well as combination therapies that exploit alternative immune targets and other therapeutic modalities. Finally, this review will include the stimulating insights from the 2020 China Immuno-Oncology Workshop co-organized by the Chinese American Hematologist and Oncologist Network (CAHON), the China National Medical Product Administration (NMPA) and Tsinghua University School of Medicine. [ABSTRACT FROM AUTHOR]

Less than a year since the start of the COVID-19 pandemic, ten vaccines against SARS-CoV-2 have been approved for at least limited use, with over sixty others in clinical trials. This swift achievement has generated excitement and arrives at a time of great need, as the number of COVID-19 cases worldwide continues to rapidly increase. Two vaccines are currently approved for full use, both built on mRNA and lipid nanotechnology platforms, a success story of mRNA technology 20 years in the making. For patients with cancer, questions arise around the safety and efficacy of these vaccines in the setting of immune alterations engendered by their malignancy and/or therapies. We summarize the current data on leading COVID-19 vaccine candidates and vaccination of patients undergoing immunomodulatory cancer treatments. Most current cancer therapeutics should not prevent the generation of protective immunity. We call for more research in this area and recommend that the majority of patients with cancer receive COVID vaccinations when possible. [ABSTRACT FROM AUTHOR]

Background: The high incidence of gastric cancer (GC) and paradoxical high prevalence of advanced stage GC, amounting to around 2/3 at time of diagnosis, have urged doctors and researchers around the world not only to ameliorate the detection rate of GC at early stages but also to optimize the clinical management of GC at advanced stages. Content: We hereby recommend a more goal-oriented multimodality approach with objectives to increase survival rate and improve survival status. Based on precision and accurate clinical staging at diagnosis, we suggest that advanced stage GC (AGC) patients should be channeled into different treatment plans according to their disease status where they can be subjected to comprehensive measures involving chemo, radio, immunological, or target therapies depending on the pathophysiological behavior of their tumor. Patients assessed as potentially resectable cT4N + M0 can undergo neoadjuvant chemotherapy with intent of tumor downsizing and downgrading followed by surgery with intraoperative hyperthermic intraperitoneal chemotherapy (HIPEC) to decrease the incidence of peritoneal dissemination due to surgical trauma and adjuvant chemotherapy and radiation in cases of bulky nodal metastasis. In cases with distal metastasis, conversion therapy is recommended with the possibility of surgery of curative intent in case of favorable response. The options of alternate treatment options such as trans-catheter arterial chemoembolization (TACE) for limited liver lesions or neoadjuvant intraperitoneal plus systemic chemotherapy (NIPS) for peritoneal carcinomatosis have to be negotiated. With surgery as the cornerstone for cancer treatment, there is acknowledgment of the significance of perioperative comprehensive approaches but there has not been some consensus guiding clinical application. Henceforth, in this review, based on past literature, current guidelines and ongoing clinical trials, we have shared a proposal of the current treatment modalities in practice for the advanced stages of gastric cancer. Conclusion: Even though surgery is the golden standard of radical cancer treatment, clinical reality shows that without proper perioperative management, patients undergoing radical resections manifest high rates of recurrence and metastasis. Hence, in this review, we have outlined a clinical agenda to optimize the management of advanced stage GC with objective to improve survival outcome and quality of life of patients. [ABSTRACT FROM AUTHOR]

Background: Neuromyelitis optica spectrum disorder (NMOSD) is an inflammatory autoimmune disease of the central nervous system that involves B-cell receptor signaling as well as astrocyte–microglia interaction, which both contribute to evolution of NMOSD lesions. Main body: Through transcriptomic and flow cytometry analyses, we found that Bruton's tyrosine kinase (BTK), a crucial protein of B-cell receptor was upregulated both in the blood and cerebrospinal fluid of NMOSD patients. Blockade of BTK with zanubrutinib, a highly specific BTK inhibitor, mitigated the activation and maturation of B cells and reduced production of causal aquaporin-4 (AQP4) autoantibodies. In a mouse model of NMO, we found that both BTK and pBTK expression were significantly increased in microglia. Transmission electron microscope scan demonstrated that BTK inhibitor ameliorated demyelination, edema, and axonal injury in NMO mice. In the same mice colocalization of GFAP and Iba-1 immunofluorescence indicated a noticeable increase of astrocytes–microglia interaction, which was alleviated by zanubrutinib. The smart-seq analysis demonstrated that treatment with BTK inhibitor instigated microglial transcriptome changes including downregulation of chemokine-related genes and genes involved in the top 5 biological processes related to cell adhesion and migration, which are likely responsible for the reduced crosstalk of microglia and astrocytes. Conclusions: Our results show that BTK activity is enhanced both in B cells and microglia and BTK inhibition contributes to the amelioration of NMOSD pathology. These data collectively reveal the mechanism of action of BTK inhibition and corroborate BTK as a viable therapeutic target. [ABSTRACT FROM AUTHOR]

Background: Long non-coding RNA (lncRNA) has been implicated in the pathogenesis of pulmonary tuberculosis (PTB). This study aims to investigate the involvement of lncRNA THRIL and HOTAIR gene single nucleotide polymorphisms (SNPs) and their expression levels in PTB susceptibility. Methods: A total of 456 PTB patients and 464 healthy controls participated in our study. we genotyped six SNPs of THRIL and HOTAIR genes using an improved multiple ligase detection reaction (iMLDR). Additionally, real-time reverse-transcriptase polymerase chain reaction was employed to detect the expression levels of THRIL and HOTAIR in peripheral blood mononuclear cells (PBMC) from 78 PTB patients and 84 healthy controls. Results: No significant differences in allele and genotype frequencies were observed for THRIL rs1055472, rs11058000, and HOTAIR rs12427129, rs1899663, rs4759314, and rs7958904 polymorphisms between PTB patients and healthy controls (all P > 0.05). Moreover, genotype frequencies of all SNPs did not show any association with PTB susceptibility in the dominant–recessive model. However, the frequencies of rs7958904 CC genotype and C allele in the HOTAIR gene were significantly correlated with leukopenia in PTB patients. Furthermore, the expression levels of the HOTAIR gene were significantly elevated in PTB patients compared to controls. Conclusions: Our study indicates that THRIL and HOTAIR gene SNPs might not contribute to PTB susceptibility, while the level of HOTAIR was increased in PTB patients. [ABSTRACT FROM AUTHOR]

Background: Adolescents with depression who engage in non-suicidal self harming behaviors are more likely to adopt negative coping strategies when faced with negative events. Therefore, these patients should be introduced to positive coping strategies. Evidences have showed that mindfulness-based interventions can positively impact the psychology of patients with mental disorders. This study was to explore the impact of a combination of mindfulness therapy and mentalization-based family therapy (MBFT) on suicidal ideation in adolescents with depressive disorder. Methods: Eighty adolescent patients with depression and suicidal ideation admitted to our hospital from September 2021 to February 2022 were selected as subjects. They were divided into a control group and a study group using the random number table method, with each group comprising 40 subjects. The control group received MBFT, whereas the study group received both mindfulness therapy and MBFT. The psychological status and suicidal ideations of the two groups were compared before and after the intervention. Results: The psychological health scores of both groups of patients were lower after the intervention, with the scores of the study group being lower than those of the control group (P < 0.05). The scores on the suicidal ideation scales for both groups were lower after intervention, and the study group scored lower than the control group (P < 0.05). The absolute values of the differences in psychological health scale scores and suicidal ideation scale scores before and after the intervention were higher in the study group than in the control group (P < 0.05). Conclusion: The combination of mindfulness therapy and MBFT can improve the psychological condition of adolescents with depression, reduce their suicidal ideations, and help them develop a healthy and positive outlook toward life, making this method worthy of clinical recommendation. [ABSTRACT FROM AUTHOR]

Background: Soil salinization has become a global problem restricting the seed yield and quality of crops, including wheat (Triticum aestivum L.). Salinity significantly alters plant morphology and severely disrupts physiological homeostasis. Salt tolerance of wheat has been widely studied whereas core ion transporters responsive to salt stress remain elusive. Results: In this study, the wheat seedlings were subjected to salinity toxicity for morpho-physiological and transcriptomic analysis of wheat salt tolerance. There was a inversely proportional relationship between salt concentrations and morpho-physiological parameters. Under the condition of 100 mM NaCl, the H2O2, O2−, MDA content and membrane permeability were significantly increased whereas the chlorophyll content was markedly decreased. Under salt stress, a larger proportion of Na+ was partitioned in the roots than in the shoots, which had a lower Na+/K+ ratio and proline content. Salt stress also obviously affected the homeostasis of other cations. Genome-wide transcriptomic analysis showed that a total of 2,807 and 5,570 differentially expressed genes (DEGs) were identified in the shoots and roots, respectively. Functionality analysis showed that these DEGs were mainly enriched in the KEGG pathways related to carbon metabolism, phenylalanine, and amino acid biosynthesis, and were primarily enriched in the GO terms involving proline metabolism and redox processes. The Na+ transporter genes were upregulated under salt stress, which repressed the gene expression of the K+ transporters. Salt stress also significantly elevated the expression of the genes involved in osmoregulation substances biosynthesis, and obviously affected the expression profiling of other cation transporters. Co-expression network analysis identified TaNHX6-D5/TaNHX4-B7 and TaP5CS2-B3 potentially as core members regulating wheat salt tolerance. Conclusions: These results might help us fully understand the morpho-physiological and molecular responses of wheat seedlings to salt stress, and provide elite genetic resources for the genetic modification of wheat salt tolerance. [ABSTRACT FROM AUTHOR]

Background: Osteoarthritis (OA) is widely recognized as the most common chronic joint disease accompanied by progressive cartilage and subchondral bone damage. Toddalolactone (TOD), a natural compound extracted from Toddalia asiatica (L.) Lam., has been widely used in the treatment of stroke, rheumatoid arthritis, and oedema. Nevertheless, what TOD acts as in the pathogenesis and progression of OA hasn't been reported. In this investigation, we have aimed to determine how TOD affects OA in vitro and in vivo. Methods: LPS (10 µg/ml) and IL-1β (10 ng/ml) were employed to induce chondrocyte inflammation or RANKL to induce osteoclast differentiation in bone marrow derived macrophages (BMMs). The effects of TOD on chondrocyte inflammation and osteoclast differentiation were evaluated. Anterior cruciate ligament transection (ACLT) was performed to develop an OA animal model and study the effects of TOD. Results: We found that TOD inhibited the expression of inflammatory and catabolic mediators (IL-6, IL-8, TNF-α, MMP2, MMP9, and MMP13) in inflammatory chondrocytes in vitro. Furthermore, TOD was proven to inhibit RANKL-induced-osteoclastogenesis and inhibit the expression of osteoclast marker genes. Our data also confirmed that TOD suppressed the destruction of articular cartilage and osteoclastogenesis via inhibiting the activation of NF-κB and MAPK signalling pathways. In the ACLT mouse model, we found that TOD attenuated cartilage erosion and inhibited bone resorption. Conclusions: These results showed that TOD can be adopted as a potential therapeutic agent for OA. [ABSTRACT FROM AUTHOR]

Background: Vertebral augmentation is the first-line treatment for the osteoporosis vertebral compression fractures. Bone cement leakage is the most common complication of this surgery. This study aims to assess the risk factors for different types of cement leakage and provides a nomogram for predicting the cement intradiscal leakage.Methods: We retrospectively reviewed 268 patients who underwent vertebral augmentation procedure between January 2015 and March 2019. The cement leakage risk factors were evaluated by univariate analysis. Different types of cement leakage risk factors were identified by the stepwise logistic analysis. We provided a nomogram for predicting the cement intradiscal leakage and used the concordance index to assess the prediction ability.Results: A total of 295 levels of vertebrae were included, with a leakage rate of 32.5%. Univariate analysis showed delayed surgery and lower vertebral compression ratio were the independent risk factors of cement leakage. The stepwise logistic analysis revealed percutaneous vertebroplasty was a risk factor in vein cement leakage; delayed surgery, preoperative compression ratio, and upper endplate disruption were in intradiscal cement leakage; age, preoperative fracture severity, and intravertebral vacuum cleft were in perivertebral soft tissue cement leakage; no factor was in spinal canal cement leakage. The nomogram for intradiscal cement leakage had a precise prediction ability with an original concordance index of 0.75.Conclusions: Delayed surgery and more vertebral compression increase the risk of cement leakage. Different types of cement leakage have different risk factors. We provided a nomogram for precise predicting the intradiscal cement leakage. [ABSTRACT FROM AUTHOR]

Background: Ropivacaine, a local anesthetic, exhibits anti-tumor effects in various cancer types. However, its specific functions and the molecular mechanisms involved in breast cancer cell stemness remain elusive. Methods: The effects of ropivacaine on breast cancer stemness were investigated by in vitro and in vivo assays (i.e., FACs, MTT assay, mammosphere formation assay, transwell assays, western blot, and xenograft model). RNA-seq, bioinformatics analysis, Western blot, Luciferase reporter assay, and CHIP assay were used to explore the mechanistic roles of ropivacaine subsequently. Results: Our study showed that ropivacaine remarkably suppressed stem cells-like properties of breast cancer cells both in vitro and in vivo. RNA-seq analysis identified GGT1 as the downstream target gene responding to ropivacaine. High GGT1 levels are positively associated with a poor prognosis in breast cancer. Ropivacaine inhibited GGT1 expression by interacting with the catalytic domain of AKT1 directly to impair its kinase activity with resultant inactivation of NF-κB. Interestingly, NF-κB can bind to the promoter region of GGT1. KEGG and GSEA analysis indicated silence of GGT1 inhibited activation of NF-κB signaling pathway. Depletion of GGT1 diminished stem phenotypes of breast cancer cells, indicating the formation of NF-κB /AKT1/GGT1/NF-κB positive feedback loop in the regulation of ropivacaine-repressed stemness in breast cancer cells. Conclusion: Our finding revealed that local anesthetic ropivacaine attenuated breast cancer stemness through AKT1/GGT1/NF-κB signaling pathway, suggesting the potential clinical value of ropivacaine in breast cancer treatment. [ABSTRACT FROM AUTHOR]

Background: The neural cells in the brains of patients with Parkinson’s disease (PWP) display aberrant synchronized oscillatory activity within the beta frequency range. Additionally, enhanced gamma oscillations may serve as a compensatory mechanism for motor inhibition mediated by beta activity and also reinstate plasticity in the primary motor cortex affected by Parkinson’s disease. Transcranial alternating current stimulation (tACS) can synchronize endogenous oscillations with exogenous rhythms, thereby modulating cortical activity. The objective of this study is to investigate whether the addition of tACS to multidisciplinary intensive rehabilitation treatment (MIRT) can improve symptoms of PWP so as to enhance the quality of life in individuals with Parkinson’s disease based on the central-peripheral-central theory. Methods: The present study was a randomized, double-blind trial that enrolled 60 individuals with Parkinson’s disease aged between 45 and 70 years, who had Hoehn-Yahr scale scores ranging from 1 to 3. Participants were randomly assigned in a 1:1 ratio to either the tACS + MIRT group or the sham-tACS + MIRT group. The trial consisted of a two-week double-blind treatment period followed by a 24-week follow-up period, resulting in a total duration of twenty-six weeks. The primary outcome measured the change in PDQ-39 scores from baseline (T0) to 4 weeks (T2), 12 weeks (T3), and 24 weeks (T4) after completion of the intervention. The secondary outcome assessed changes in MDS-UPDRS III scores at T0, the end of intervention (T1), T2, T3, and T4. Additional clinical assessments and mechanistic studies were conducted as tertiary outcomes. Discussion: The objective of this study is to demonstrate that tACS can enhance overall functionality and improve quality of life in PWP, based on the framework of MIRT. Additionally, it seeks to establish a potential correlation between these therapeutic effects and neuroplasticity alterations in relevant brain regions. The efficacy of tACS will be assessed during the follow-up period in order to optimize neuroplasticity and enhance its potential impact on rehabilitation efficiency for PWP. Trial registration: Chinese Clinical Trial Registry ChiCTR2300071969. Registered on 30 May 2023. [ABSTRACT FROM AUTHOR]

Background: Adipose-derived stem cells (ADSCs) promote tissue regeneration and repair. Cryoprotective agents (CPAs) protect cells from cryodamage during cryopreservation. Safe and efficient cryopreservation of ADSCs is critical for cell-based therapy in clinical applications. However, most CPAs are used at toxic concentrations, limiting their clinical application. Objective: The aim of this study is to develop a non-toxic xeno-free novel CPA aiming at achieving high-efficiency and low-risk ADSC cryopreservation. Methods: We explored different concentrations of trehalose (0.3 M, 0.6 M, 1.0 M, and 1.25 M) and glycerol (10%, 20%, and 30% v/v) for optimization and evaluated and compared the outcomes of ADSCs cryopreservation between a combination of trehalose and glycerol and the commonly used CPA DMSO (10%) + FBS (90%). All samples were slowly frozen and stored in liquid nitrogen for 30 days. The effectiveness was evaluated by the viability, proliferation, migration, and multi-potential differentiation of the ADSCs after thawing. Results: Compared with the groups treated with individual reagents, the 1.0 M trehalose (Tre) + 20% glycerol (Gly) group showed significantly higher efficiency in preserving ADSC activities after thawing, with better outcomes in both cell viability and proliferation capacity. Compared with the 10% DMSO + 90% FBS treatment, the ADSCs preserved in 1.0 M Tre + 20% Gly showed similar cell viability, surface markers, and multi-potential differentiation but a significantly higher migration capability. The results indicated that cell function preservation can be improved by 1.0 M Tre + 20% Gly. Conclusions: The 1.0 M Tre + 20% Gly treatment preserved ADSCs with a higher migration capability than 10% DMSO + 90% FBS and with viability higher than that with trehalose or glycerol alone but similar to that with 10% DMSO + 90% FBS and fresh cells. Moreover, the new CPA achieves stemness and multi-potential differentiation similar to those in fresh cells. Our results demonstrate that 1.0 M Tre + 20% Gly can more efficiently cryopreserve ADSCs and is a non-toxic CPA that may be suitable for clinical applications. [ABSTRACT FROM AUTHOR]

Background: Cultivated peanut (Arachis hypogaea, AABB genome), an allotetraploid from a cross between A. duranensis (AA genome) and A. ipaensis (BB genome), is an important oil and protein crop with released genome and RNA-seq sequence datasets. These datasets provide the molecular foundation for studying gene expression and evolutionary patterns. However, there are no reports on the proteomic data of A. hypogaea cv. Tifrunner, which limits understanding of its gene function and protein level evolution. Results: This study sequenced the A. hypogaea cv. Tifrunner leaf and root proteome using the tandem mass tag technology. A total of 4803 abundant proteins were identified. The 364 differentially abundant proteins were estimated by comparing protein abundances between leaf and root proteomes. The differentially abundant proteins enriched the photosystem process. The number of biased abundant homeologs between the two sub-genomes A (87 homeologs in leaf and root) and B (69 and 68 homeologs in leaf and root, respectively) was not significantly different. However, homeologous proteins with biased abundances in different sub-genomes enriched different biological processes. In the leaf, homeologs biased to sub-genome A enriched biosynthetic and metabolic process, while homeologs biased to sub-genome B enriched iron ion homeostasis process. In the root, homeologs with biased abundance in sub-genome A enriched inorganic biosynthesis and metabolism process, while homeologs with biased abundance in sub-genome B enriched organic biosynthesis and metabolism process. Purifying selection mainly acted on paralogs and homeologs. The selective pressure values were negatively correlated with paralogous protein abundance. About 77.42% (24/31) homeologous and 80% (48/60) paralogous protein pairs had asymmetric abundance, and several protein pairs had conserved abundances in the leaf and root tissues. Conclusions: This study sequenced the proteome of A. hypogaea cv. Tifrunner using the leaf and root tissues. Differentially abundant proteins were identified, and revealed functions. Paralog abundance divergence and homeolog bias abundance was elucidated. These results indicate that divergent abundance caused retention of homologs in A. hypogaea cv. Tifrunner. [ABSTRACT FROM AUTHOR]

Background: Oilseed rape (B. napus L.) has great potential for phytoremediation of cadmium (Cd)-polluted soils due to its large plant biomass production and strong metal accumulation. Soil properties and the presence of other soluble compounds or ions, cause a heterogeneous distribution of Cd. Results: The aim of our study was to reveal the differential responses of B. napus to different Cd abundances. Herein, we found that high Cd (50 μM) severely inhibited the growth of B. napus, which was not repressed by low Cd (0.50 μM) under hydroponic culture system. ICP-MS assays showed that the Cd2+ concentrations in both shoots and roots under 50 μM Cd were over 10 times higher than those under 0.50 μM Cd. Under low Cd, the concentrations of only shoot Ca2+/Mn2+ and root Mn2+ were obviously changed (both reduced); under high Cd, the concentrations of most cations assayed were significantly altered in both shoots and roots except root Ca2+ and Mg2+. High-throughput transcriptomic profiling revealed a total of 18,021 and 1408 differentially expressed genes under high Cd and low Cd conditions, respectively. The biological categories related to the biosynthesis of plant cell wall components and response to external stimulus were over-accumulated under low Cd, whereas the terms involving photosynthesis, nitrogen transport and response, and cellular metal ion homeostasis were highly enriched under high Cd. Differential expression of the transporters responsible for Cd uptake (NRAMPs), transport (IRTs and ZIPs), sequestration (HMAs, ABCs, and CAXs), and detoxification (MTPs, PCR, MTs, and PCSs), and some other essential nutrient transporters were investigated, and gene co-expression network analysis revealed the core members of these Cd transporters. Some Cd transporter genes, especially NRAMPs and IRTs, showed opposite responsive patterns between high Cd and low Cd conditions. Conclusions: Our findings would enrich our understanding of the interaction between essential nutrients and Cd, and might also provide suitable gene resources and important implications for the genetic improvement of plant Cd accumulation and resistance through molecular engineering of these core genes under varying Cd abundances in soils. [ABSTRACT FROM AUTHOR]

Significant scientific advances in immunotherapy and targeted therapy approaches have improved clinical outcomes and increased treatment options for patients with genitourinary (GU) malignancies. We highlight the clinical trial developments released at the ASCO 2023 annual meeting, including PARP inhibitors for prostate cancer, antibody drug conjugates and fibroblast growth factor receptor inhibitors for urothelial cancer, and HIF2a inhibitors for renal cell carcinoma. Novel agents such as bispecific antibodies, chimeric antigen receptor T-cells, and radiopharmaceuticals are currently in early phase development and also have high potential impact for the GU cancer landscape. With more treatment options, the field will need to define best treatment sequencing to optimize outcomes for each patient. [ABSTRACT FROM AUTHOR]

Background: Intramuscular fat (IMF) is associated with meat quality and insulin resistance in animals. Research on genetic mechanism of IMF decomposition has positive meaning to pork quality and diseases such as obesity and type 2 diabetes treatment. In this study, an IMF trait segregation population was used to perform RNA sequencing and to analyze the joint or independent effects of genes and long intergenic non-coding RNAs (lincRNAs) on IMF. Results: A total of 26 genes including six lincRNA genes show significantly different expression between high- and low-IMF pigs. Interesting, one lincRNA gene, named IMF related lincRNA (IRLnc) not only has a 292-bp conserved region in 100 vertebrates but also has conserved up and down stream genes (< 10 kb) in pig and humans. Real-time quantitative polymerase chain reaction (RT-qPCR) validation study indicated that nuclear receptor subfamily 4 group A member 3 (NR4A3) which located at the downstream of IRLnc has similar expression pattern with IRLnc. RNAi-mediated loss of function screens identified that IRLnc silencing could inhibit both of the RNA and protein expression of NR4A3. And the in-situ hybridization co-expression experiment indicates that IRLnc may directly binding to NR4A3. As the NR4A3 could regulate the catecholamine catabolism, which could affect insulin sensitivity, we inferred that IRLnc influence IMF decomposition by regulating the expression of NR4A3. Conclusions: In conclusion, a novel functional noncoding variation named IRLnc has been found contribute to IMF by regulating the expression of NR4A3. These findings suggest novel mechanistic approach for treatment of insulin resistance in human beings and meat quality improvement in animal. [ABSTRACT FROM AUTHOR]

Background: Autism is a complex neurodevelopmental disorder with high heritability. Zinc finger protein 804A (ZNF804A) was suggested to play important roles in neurodevelopment. Previous studies indicated that single-nucleotide polymorphism (SNP) rs1344706 in ZNF804A was strongly associated with schizophrenia and might influence social interaction. Only one study explored the significance of ZNF804A polymorphisms in autism, which discovered that rs7603001 was nominally associated with autism. Moreover, no previous study investigated the association between ZNF804A and autism in a Han Chinese population. Here, we investigated whether these two SNPs (rs1344706 and rs7603001) in ZNF804A contribute to the risk of autism in a Han Chinese population. Methods: We performed a family-based association study in 640 Han Chinese autism trios. Sanger sequencing was used for sample genotyping. Then, single marker association analyses were conducted using the family-based association test (FBAT) program. Results: No significant association was found between the two SNPs (rs1344706 and rs7603001) in ZNF804A and autism (P > 0.05). Conclusions: Our findings suggested that rs1344706 and rs7603001 in ZNF804A might not be associated with autism in a Han Chinese population. [ABSTRACT FROM AUTHOR]

Background: Populus (poplar) tree species including hybrid varieties are considered as promising biomass feedstock for biofuels and biochemicals production due to their fast growing, short vegetative cycle, and widely distribution. In this work, poplar was pretreated with acetic acid (AC) to produce xylooligosaccharides (XOS), and hydrogen peroxide–acetic acid (HPAC) was used to remove residual lignin in AC-pretreated poplar for enzymatic hydrolysis. The aim of this work is to produce XOS and monosaccharides from poplar by a two-step pretreatment method. Results: The optimal conditions for the AC pretreatment were 170 °C, 5% AC, and 30 min, giving a XOS yield of 55.8%. The optimal HPAC pretreatment conditions were 60 °C, 2 h, and 80% HPAC, resulting in 92.7% delignification and 87.8% cellulose retention in the AC-pretreated poplar. The two step-treated poplar presented 86.6% glucose yield and 89.0% xylose yield by enzymatic hydrolysis with a cellulases loading of 7.2 m/g dry mass. Very high glucose (93.8%) and xylose (94.6%) yields were obtained with 14.3 mg cellulases/g dry mass. Both Tween 80 and β-glucosidase enhanced glucose yield of HPAC-pretreated poplar by alleviating the accumulation of cellobiose. Under the optimal conditions, 6.9 g XOS, 40.3 g glucose, and 8.9 g xylose were produced from 100 g poplar. Conclusions: The AC and HPAC pretreatment of poplar represented an efficient strategy to produce XOS and fermentable sugars with high yields. This two-step pretreatment was a recyclable benign and advantageous scheme for biorefinery of the poplar into XOS and monosaccharides. [ABSTRACT FROM AUTHOR]

Background: Three main enzymes including cathepsin B, cathepsin D and acid phosphatase are involved in vitellin degradation, which is a major biochemical event of the embryonic development and can provide nutrients and metabolites for tick embryos. In the present study, the mRNA expression profiles and enzymatic activity of cathepsin B, cathepsin D and acid phosphatase were investigated during embryonic development in the tick Haemaphysalis longicornis. Results: The results revealed that all three enzymes were expressed throughout embryonic development. Both cathepsin B and acid phosphatase transcripts were accumulated during the first four days. Cathepsin B reached its highest expression on day 5, whereas the peak expression of acid phosphatase and cathepsin D occurred on day 11. The highest activity of cathepsin B was observed on the first day of egg development, whereas cathepsin D reached its highest activity on day 13. Acid phosphatase activity increased gradually during the first five days and then remained stable until the end of egg development. Conclusions: Three enzymes were expressed and activated in eggs, and also presented different dynamic changes with the development of embryos. The profiles of both mRNA expression and enzymatic activity of these enzymes indicate that they are controlled orderly and play multiple roles during embryonic development in ticks. [ABSTRACT FROM AUTHOR]

Introduction: Endoscopic ultrasound (EUS) may play a role in evaluating treatment response after definitive chemoradiation therapy (dCRT) for esophageal squamous cell carcinoma (ESCC). This study explored the prognostic markers of EUS with biopsies and developed two nomograms for survival prediction. Methods: A total of 821 patients newly diagnosed with ESCC between January 2015 and December 2019 were reviewed. We investigated the prognostic value of the changes in tumor imaging characteristics and histopathological markers by an interim response evaluation, including presence of stenosis, ulceration, tumor length, tumor thickness, lumen involvement, and tumor remission. Independent prognostic factors of progression-free survival (PFS) and overall survival (OS) were determined using Cox regression analysis and further selected to build two nomogram models for survival prediction. The receiver operating characteristic (ROC) curve, calibration curve, and decision curve analysis (DCA) were used to respectively assess its discriminatory capacity, predictive accuracy, and clinical usefulness. Results: A total of 155 patients were enrolled in this study and divided into the training (109 cases) and testing (46 cases) cohorts. Tumor length, residual tumor thickness, reduction in tumor thickness, lumen involvement, and excellent remission (ER) of spatial luminal involvement in ESCC (ER/SLI) differed significantly between responders and non-responders. For patients undergoing dCRT, tumor stage (P = 0.001, 0.002), tumor length (P = 0.013, 0.008), > 0.36 reduction in tumor thickness (P = 0.004, 0.004) and ER/SLI (P = 0.041, 0.031) were independent prognostic markers for both PFS and OS. Time-dependent ROC curves, calibration curves, and DCA indicated that the predicted survival rates of our two established nomogram models were highly accurate. Conclusion: Our nomogram showed high accuracy in predicting PFS and OS for ESCC after dCRT. External validation and complementation of other biomarkers are needed in further studies. [ABSTRACT FROM AUTHOR]

Introduction: Endoscopic ultrasound (EUS) may play a role in evaluating treatment response after definitive chemoradiation therapy (dCRT) for esophageal squamous cell carcinoma (ESCC). This study explored the prognostic markers of EUS with biopsies and developed two nomograms for survival prediction. Methods: A total of 821 patients newly diagnosed with ESCC between January 2015 and December 2019 were reviewed. We investigated the prognostic value of the changes in tumor imaging characteristics and histopathological markers by an interim response evaluation, including presence of stenosis, ulceration, tumor length, tumor thickness, lumen involvement, and tumor remission. Independent prognostic factors of progression-free survival (PFS) and overall survival (OS) were determined using Cox regression analysis and further selected to build two nomogram models for survival prediction. The receiver operating characteristic (ROC) curve, calibration curve, and decision curve analysis (DCA) were used to respectively assess its discriminatory capacity, predictive accuracy, and clinical usefulness. Results: A total of 155 patients were enrolled in this study and divided into the training (109 cases) and testing (46 cases) cohorts. Tumor length, residual tumor thickness, reduction in tumor thickness, lumen involvement, and excellent remission (ER) of spatial luminal involvement in ESCC (ER/SLI) differed significantly between responders and non-responders. For patients undergoing dCRT, tumor stage (P = 0.001, 0.002), tumor length (P = 0.013, 0.008), > 0.36 reduction in tumor thickness (P = 0.004, 0.004) and ER/SLI (P = 0.041, 0.031) were independent prognostic markers for both PFS and OS. Time-dependent ROC curves, calibration curves, and DCA indicated that the predicted survival rates of our two established nomogram models were highly accurate. Conclusion: Our nomogram showed high accuracy in predicting PFS and OS for ESCC after dCRT. External validation and complementation of other biomarkers are needed in further studies. [ABSTRACT FROM AUTHOR]

Background: Ropivacaine, a local anesthetic, exhibits anti-tumor effects in various cancer types. However, its specific functions and the molecular mechanisms involved in breast cancer cell stemness remain elusive. Methods: The effects of ropivacaine on breast cancer stemness were investigated by in vitro and in vivo assays (i.e., FACs, MTT assay, mammosphere formation assay, transwell assays, western blot, and xenograft model). RNA-seq, bioinformatics analysis, Western blot, Luciferase reporter assay, and CHIP assay were used to explore the mechanistic roles of ropivacaine subsequently. Results: Our study showed that ropivacaine remarkably suppressed stem cells-like properties of breast cancer cells both in vitro and in vivo. RNA-seq analysis identified GGT1 as the downstream target gene responding to ropivacaine. High GGT1 levels are positively associated with a poor prognosis in breast cancer. Ropivacaine inhibited GGT1 expression by interacting with the catalytic domain of AKT1 directly to impair its kinase activity with resultant inactivation of NF-κB. Interestingly, NF-κB can bind to the promoter region of GGT1. KEGG and GSEA analysis indicated silence of GGT1 inhibited activation of NF-κB signaling pathway. Depletion of GGT1 diminished stem phenotypes of breast cancer cells, indicating the formation of NF-κB /AKT1/GGT1/NF-κB positive feedback loop in the regulation of ropivacaine-repressed stemness in breast cancer cells. Conclusion: Our finding revealed that local anesthetic ropivacaine attenuated breast cancer stemness through AKT1/GGT1/NF-κB signaling pathway, suggesting the potential clinical value of ropivacaine in breast cancer treatment. [ABSTRACT FROM AUTHOR]

Background: Calcineurin B-like proteins (CBLs) are ubiquitous Ca2+ sensors that mediate plant responses to various stress and developmental processes by interacting with CBL-interacting protein kinases (CIPKs). CBLs and CIPKs play essential roles in acclimatization of crop plants. However, evolution of these two gene families in the genus Medicago is poorly understood. Results: A total of 68 CBL and 135 CIPK genes have been identified in five genomes from Medicago. Among these genomes, the gene number of CBLs and CIPKs shows no significant difference at the haploid genome level. Phylogenetic and comprehensive characteristic analyses reveal that CBLs and CIPKs are classified into four clades respectively, which is validated by distribution of conserved motifs. The synteny analysis indicates that the whole genome duplication events (WGDs) have contributed to the expansion of both families. Expression analysis demonstrates that two MsCBLs and three MsCIPKs are specifically expressed in roots, mature leaves, developing flowers and nitrogen fixing nodules of Medicago sativa spp. sativa, the widely grown tetraploid species. In particular, the expression of these five genes was highly up-regulated in roots when exposed to salt and drought stress, indicating crucial roles in stress responses. Conclusions: Our study leads to a comprehensive understanding of evolution of CBL and CIPK gene families in Medicago, but also provides a rich resource to further address the functions of CBL-CIPK complexes in cultivated species and their closely related wild relatives. [ABSTRACT FROM AUTHOR]

Background: Diabetic retinopathy (DR) has become a leading cause of global blindness as a microvascular complication of diabetes. Regular screening of diabetic retinopathy is strongly recommended for people with diabetes so that timely treatment can be provided to reduce the incidence of visual impairment. However, DR screening is not well carried out due to lack of eye care facilities, especially in the rural areas of China. Artificial intelligence (AI) based DR screening has emerged as a novel strategy and show promising diagnostic performance in sensitivity and specificity, relieving the pressure of the shortage of facilities and ophthalmologists because of its quick and accurate diagnosis. In this study, we estimated the cost-effectiveness of AI screening for DR in rural China based on Markov model, providing evidence for extending use of AI screening for DR. Methods: We estimated the cost-effectiveness of AI screening and compared it with ophthalmologist screening in which fundus images are evaluated by ophthalmologists. We developed a Markov model-based hybrid decision tree to analyze the costs, effectiveness and incremental cost-effectiveness ratio (ICER) of AI screening strategies relative to no screening strategies and ophthalmologist screening strategies (dominated) over 35 years (mean life expectancy of diabetes patients in rural China). The analysis was conducted from the health system perspective (included direct medical costs) and societal perspective (included medical and nonmedical costs). Effectiveness was analyzed with quality-adjusted life years (QALYs). The robustness of results was estimated by performing one-way sensitivity analysis and probabilistic analysis. Results: From the health system perspective, AI screening and ophthalmologist screening had incremental costs of $180.19 and $215.05 but more quality-adjusted life years (QALYs) compared with no screening. AI screening had an ICER of $1,107.63. From the societal perspective which considers all direct and indirect costs, AI screening had an ICER of $10,347.12 compared with no screening, below the cost-effective threshold (1–3 times per capita GDP of Chinese in 2019). Conclusions: Our analysis demonstrates that AI-based screening is more cost-effective compared with conventional ophthalmologist screening and holds great promise to be an alternative approach for DR screening in the rural area of China. [ABSTRACT FROM AUTHOR]

Background: Epithelial-mesenchymal transition (EMT) is one of the mechanisms of airway remodeling in chronic asthma. Interleukin (IL)-24 has been implicated in the promotion of tissue fibrosis, and increased IL-24 levels have been observed in the nasal secretions and sputum of asthmatic patients. However, the role of IL-24 in asthmatic airway remodeling, especially in EMT, remains largely unknown. We aimed to explore the effect and mechanism of IL-24 on EMT and to verify whether IL-37 could alleviate IL-24-induced EMT in chronic asthma.Methods: BEAS-2B cells were exposed to IL-24, and cell migration was assessed by wound healing and Transwell assays. The expression of EMT-related biomarkers (E-cadherin, vimentin, and α-SMA) was evaluated after the cells were stimulated with IL-24 with or without IL-37. A murine asthma model was established by intranasal administration of house dust mite (HDM) extracts for 5 weeks, and the effects of IL-24 and IL-37 on EMT and airway remodeling were investigated by intranasal administration of si-IL-24 and rhIL-37.Results: We observed that IL-24 significantly enhanced the migration of BEAS-2B cells in vitro. IL-24 promoted the expression of the EMT biomarkers vimentin and α-SMA via the STAT3 and ERK1/2 pathways. In addition, we found that IL-37 partially reversed IL-24-induced EMT in BEAS-2B cells by blocking the ERK1/2 and STAT3 pathways. Similarly, the in vivo results showed that IL-24 was overexpressed in the airway epithelium of an HDM-induced chronic asthma model, and IL-24 silencing or IL-37 treatment could reverse EMT biomarker expression.Conclusions: Overall, these findings indicated that IL-37 mitigated HDM-induced airway remodeling by inhibiting IL-24-mediated EMT via the ERK1/2 and STAT3 pathways, thereby providing experimental evidence for IL-24 as a novel therapeutic target and IL-37 as a promising agent for treating severe asthma. [ABSTRACT FROM AUTHOR]

Background: Diabetic retinopathy (DR) has become a leading cause of global blindness as a microvascular complication of diabetes. Regular screening of diabetic retinopathy is strongly recommended for people with diabetes so that timely treatment can be provided to reduce the incidence of visual impairment. However, DR screening is not well carried out due to lack of eye care facilities, especially in the rural areas of China. Artificial intelligence (AI) based DR screening has emerged as a novel strategy and show promising diagnostic performance in sensitivity and specificity, relieving the pressure of the shortage of facilities and ophthalmologists because of its quick and accurate diagnosis. In this study, we estimated the cost-effectiveness of AI screening for DR in rural China based on Markov model, providing evidence for extending use of AI screening for DR.Methods: We estimated the cost-effectiveness of AI screening and compared it with ophthalmologist screening in which fundus images are evaluated by ophthalmologists. We developed a Markov model-based hybrid decision tree to analyze the costs, effectiveness and incremental cost-effectiveness ratio (ICER) of AI screening strategies relative to no screening strategies and ophthalmologist screening strategies (dominated) over 35 years (mean life expectancy of diabetes patients in rural China). The analysis was conducted from the health system perspective (included direct medical costs) and societal perspective (included medical and nonmedical costs). Effectiveness was analyzed with quality-adjusted life years (QALYs). The robustness of results was estimated by performing one-way sensitivity analysis and probabilistic analysis.Results: From the health system perspective, AI screening and ophthalmologist screening had incremental costs of $180.19 and $215.05 but more quality-adjusted life years (QALYs) compared with no screening. AI screening had an ICER of $1,107.63. From the societal perspective which considers all direct and indirect costs, AI screening had an ICER of $10,347.12 compared with no screening, below the cost-effective threshold (1-3 times per capita GDP of Chinese in 2019).Conclusions: Our analysis demonstrates that AI-based screening is more cost-effective compared with conventional ophthalmologist screening and holds great promise to be an alternative approach for DR screening in the rural area of China. [ABSTRACT FROM AUTHOR]

Background: Formin, a highly conserved multi-domain protein, interacts with microfilaments and microtubules. Although specifically expressed formin genes in anthers are potentially significant in research on male sterility and hybrid wheat breeding, similar reports in wheat, especially in thermo-sensitive genic male sterile (TGMS) wheat, remain elusive. Results: Herein, we systematically characterized the formin genes in TGMS wheat line BS366 named TaFormins (TaFHs) and predicted their functions in inducing stress response. In total, 25 TaFH genes were uncovered, majorly localized in 2A, 2B, and 2D chromosomes. According to the neighbor-joining (NJ) method, all TaFH proteins from wheat and other plants clustered in 6 sub-groups (A-F). The modeled 3D structures of TaFH1-A/B, TaFH2-A/B, TaFH3-A/B and TaFH3-B/D were validated. And different numbers of stress and hormone-responsive regulatory elements in their 1500 base pair promoter regions were contained in the TaFH genes copies. TaFHs had specific temporal and spatial expression characteristics, whereby TaFH1, TaFH4, and TaFH5 were expressed highly in the stamen of BS366. Besides, the accumulation of TaFHs was remarkably lower in a low-temperature sterile condition (Nanyang) than fertile condition (Beijing), particularly at the early stamen development stage. The pollen cytoskeleton of BS366 was abnormal in the three stages under sterile and fertile environments. Furthermore, under different stress levels, TaFHs expression could be induced by drought, salt, abscisic acid (ABA), salicylic acid (SA), methyl jasmonate (MeJA), indole-3-acetic acid (IAA), polyethylene glycol (PEG), and low temperature. Some miRNAs, including miR167, miR1120, and miR172, interacts with TaFH genes; thus, we constructed an interaction network between microRNAs, TaFHs, phytohormone responses, and distribution of cytoskeleton to reveal the regulatory association between upstream genes of TaFH family members and sterile. Conclusions: Collectively, this comprehensive analysis provides novel insights into TaFHs and miRNA resources for wheat breeding. These findings are, therefore, valuable in understanding the mechanism of TGMS fertility conversion in wheat. [ABSTRACT FROM AUTHOR]

Background: Chronic neuropathic pain is a frequent sequel to peripheral nerve injury and maladaptive nervous system function. Divanillyl sulfone (DS), a novel structural derivative of 4,4'-dihydroxydibenzyl sulfoxide from a traditional Chinese medicine Gastrodia elata with anti-nociceptive effects, significantly alleviated neuropathic pain following intrathecal injection. Here, we aimed to investigate the underlying mechanisms of DS against neuropathic pain.Methods: A chronic constrictive injury (CCI) mouse model of neuropathic pain induced by sciatic nerve ligation was performed to evaluate the effect of DS by measuring the limb withdrawal using Von Frey filament test. Immunofluorescence staining was used to assess the cell localizations and expressions of Iba-1, ASC, NLRP3, and ROS, the formation of autolysosome. The levels of NLRP3-related proteins (caspase-1, NLRP3, and IL-1β), mitophagy-related proteins (LC3, Beclin-1, and p62), and apoptosis-related proteins (Bcl-XL and Bax) were detected by Western blotting. The apoptosis of BV-2 cell and caspase activity were evaluated by flow cytometry.Results: DS significantly alleviated the neuropathic pain by increasing the mechanical withdrawal threshold and inhibiting the activation of NLRP3 in CCI-induced model mice. Our findings indicated that DS promoted the mitophagy by increasing the LC3II and Beclin 1 and decreasing the levels of p62 protein in BV-2 cell. This is accompanied by the inhibition of NLRP3 activation, which was shown as inhibited the expression of NLRP3 in lysates as well as the secretion of mature caspase-1 p10 and IL-1β p17 in supernatants in cultured BV-2 microglia. In addition, DS could promote mitophagy-induced improvement of dysfunctional mitochondria by clearing intracellular ROS and restoring mitochondrial membrane potential.Conclusion: Together, our findings demonstrated that DS ameliorate chronic neuropathic pain in mice by suppressing NLRP3 inflammasome activation induced by mitophagy in microglia. DS may be a promising therapeutic agent for chronic neuropathic pain. [ABSTRACT FROM AUTHOR]

Background: The clinical staging systems for adenocarcinoma of the esophagogastric junction (AEG) are controversial. We aimed to propose a prognostic nomogram based on real-world data for predicting survival of Siewert type II/III AEG patients after surgery.Methods: A total of 396 patients with Siewert type II/III AEG diagnosed and treated at the Center for Gastrointestinal Surgery, the First Affiliated Hospital, Sun Yat-sen University, from June 2009 to June 2017 were enrolled. The original data of 29 variables were exported from the electronic medical records system. The nomogram was established based on multivariate Cox regression coefficients, and its performance was measured using Harrell's concordance index (C-index), receiver operating characteristic (ROC) curve analysis and calibration curve.Results: A nomogram was constructed based on nine variables. The C-index for overall survival (OS) prediction was 0.76 (95% CI, 0.72 to 0.80) in the training cohort, in the validation-1 cohort was 0.79 (95% CI, 0.72 to 0.86), and 0.73 (95% CI, 0.67 to 0.80) in the validation-2 cohort. Time-dependent ROC curves and calibration curves in all three cohorts showed good prognostic predictive accuracy. We further proved the superiority of the nomogram in predictive accuracy for OS to pathological TNM (pTNM) staging system and other independent prognostic factors. Kaplan-Meier survival curves demonstrated the pTNM stage, grade of differentiation, positive lymph node, log odds of positive lymph node and organ invasion were prognostic factors with good discriminative ability.Conclusion: The established nomogram demonstrated a more precise prognostic prediction for patients with Siewert type II/III AEG. [ABSTRACT FROM AUTHOR]

Background:  Patients with lymphoproliferative disorders following hematopoietic stem cell transplant (HSCT) most commonly present with fever and lymphadenopathy within the first 5 months of transplant. Pulmonary post-transplant lymphoproliferative disorder (PTLD) is a particularly aggressive and rapidly progressive disease, with high morbidity and mortality. There are a very limited number of reported pulmonary PTLD cases following HSCT in patients with acute myeloid leukemia (AML). Early diagnosis and detection of pulmonary PTLD is critical given its high lethality. However, variable clinical presentations and nonspecific radiographic findings make pulmonary PTLD difficult to distinguish from other more common causes of pulmonary disease in AML patients.Case Presentation: Here, we describe a 68-year-old Caucasian man who presented for salvage induction therapy following relapse of his AML after a haploidentical allogeneic HSCT 10 months earlier. He developed recurrent fevers, dry cough, and hypoxemia, with chest computed tomography (CT) showing bibasilar consolidations and increased nodularity without increased lymphadenopathy. His symptoms initially improved with antibiotic and antifungal therapy, but his follow-up chest CT showed progression of disease despite symptomatic improvement. Epstein-Barr virus (EBV) was detected in his blood by polymerase chain reaction (PCR), and a lung biopsy revealed monomorphic PTLD with B cells positive for EBV. Unfortunately, the patient's condition rapidly deteriorated, and he passed away prior to treatment initiation.Conclusions:  To our knowledge, this is the first reported case of an AML patient developing pulmonary PTLD relatively late in his post-transplant course in the setting of relapsed disease and salvage therapy. Pulmonary PTLD, a rare but highly lethal disorder, can imitate the symptoms and radiographic findings of pneumonia, a common diagnosis in immunocompromised AML patients. This case illustrates the importance of considering pulmonary PTLD in the differential diagnosis for pulmonary disease in AML patients with a history of HSCT, especially in the setting of progressive radiographic findings despite broad antibacterial and antifungal therapy. Further, our case demonstrates the importance of biopsy and uninterrupted EBV DNA monitoring in the definitive diagnosis of PTLD, given nonspecific symptomatology and radiographic findings. [ABSTRACT FROM AUTHOR]

Background: Chinese wheat mosaic virus (CWMV) is a severe threat to winter wheat and is transmitted by Polymyxa graminis. The mechanisms of interactions between CWMV and plants are poorly understood. In this study, a comparative proteomics analysis based on nanoliquid chromatography mass spectrometry (MS)/MS was conducted to characterize proteomic changes in plants responding to CWMV infection. Results: In total, 2751 host proteins were identified, 1496 of which were quantified and 146 up-regulated and 244 down-regulated proteins were identified as differentially expressed proteins (DEPs). Kyoto Encyclopedia of Genes and Genomes (KEGG) enrichment analysis showed that DEPs were most strongly associated with photosynthesis antenna proteins, MAPK signaling plant and glyoxylate and dicarboxylate metabolism pathways. Subcellular localization analysis predicted that more than half of the DEPs were localized in the chloroplast, an organelle indispensable for abscisic acid (ABA) synthesis. Our results suggest that CWMV infection interrupts normal chloroplast functions and decreases ABA concentrations in Nicotiana benthamiana. Further analysis showed that the ABA pathway was suppressed during CWMV infection and that ABA treatment induced plant hosts defenses against CWMV. Conclusions: We identified several candidate proteins expressed during CWMV infection, and the ABA pathway was strongly associated with responses to CWMV infection in N. benthamiana. [ABSTRACT FROM AUTHOR]

Background: Although cultural factors play a crucial role in experience of stigma, there is scant review on the impact and importance of culture on stigma of mental illness across Pacific Rim Region. This study aims to investigate: 1) the cultural factors related to stigmatizing beliefs about mental illness in Pacific Rim region, and 2) culture-specific measures and interventions on stigma of mental illness. Methods: A systematic search of papers was conducted in the MEDLINE, Embase, CINAHL, Web of Science, PsycINFO, Scopus, Cochrane Library and Google scholar through January 2003 to April 2019. Results: Forty-one studies in Pacific Rim region which met the inclusion criteria were included in the study. The rate of stigma of mental illness (e.g., public stigma: from 25.4 to 85.2%) was relatively high in Pacific Rim region. Culture factors (e.g., Collectivism, Confucianism, face concern and familism, religion and supernatural beliefs) contributed to people's stigmatizing behaviors and attitudes toward persons with mental illness, their relatives and mental health professionals. Certain measurements were developed and employed to assess different type of cultural factors related to stigma of mental illness. Conclusions: Cultural factors play an important role in influencing the rate and performance of stigma of mental illness. Further research on stigma of mental illness and culture-specific interventions to reduce the stigma should be conducted in the Pacific Rim region. [ABSTRACT FROM AUTHOR]

Background: Sigesbeckia glabrescens Makino (SG) has been traditionally used for rheumatism and joint protection. However, the anti-arthritic effects and underling mechanisms of SG have not been demonstrated. In this study, we investigated the anti-arthritic effects and mechanisms of SG extract (SGE) on collagen-induced arthritic rats and interleukin (IL)-1β-stimulated human synovial SW982 cells. Methods: Rats were induced to arthritis by collagen for 15 days and then received SGE treatment for 35 days. The body weight and arthritis severity score of the rats were monitored weekly. At the end of the experiment, the radiographic and histological changes of rats' hind paw were obtained; the serum C-reactive protein was detected by enzyme-linked immunosorbent assay (ELISA); the expression levels of interleukin (IL)- 1β, IL6 and IL-10 in the joint muscles were determined by ELISA and immunohistochemical staining; and the level of regulatory T cells (Tregs) in the spleen was detected using flow cytometry. In addition, 3-(4,5-Dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay and scratch wound healing assay were used to evaluate the proliferation of SW982 synovial cells. ELISA, western blot and immunofluorescence staining were used to investigate the anti-inflammatory mechanisms of SGE on IL-1β-induced SW982 cells and joint muscles of CIA rats. Results: SGE attenuated the collagen-induced hind paw swelling, cartilage damage and bone erosion. SGE inhibited the synovial hyperplasia to the articular cavity in the toe joint and ankle. Moreover, SGE decreased the production of C-reactive protein in serum and the expression of IL-6, IL-1β, cyclooxygenase-2 (COX-2) and phosphorylation of NF-κB p65 in the joint muscles. SGE also recovered the decreased Tregs. Results from the in vitro experiments showed that SGE not only inhibited the proliferation and migration of human synovial cell but also inhibited the IL-1β-induced expression of IL-6 and IL-8. Similarly, SGE inhibited the activation of NF-κB and the expression of COX-2. Conclusions: SGE attenuated the collagen-induced arthritis through inhibiting the synovial hyperplasia and inflammation. [ABSTRACT FROM AUTHOR]

Background: Glycerophospholipids were the main components of cerebral cortex lipids, and there was a close association between lipid homeostasis and human health. It has been reported that dietary DHA-enriched phosphatidylcholine (DHA-PC) and phosphatidylserine (DHA-PS) could improve brain function. However, it was unclear that whether supplementation of DHA-PC and DHA-PS could change lipid profiles in the brain of dementia animals. Methods: SAMP8 mice was fed with different diet patterns for 2 months, including high-fat diet and low-fat diet. After intervention with DHA-PC and DHA-PS for another 2 months, the lipid profile in cerebral cortex was determined by lipidomics in dementia mice. Results: High-fat diet could significantly decrease the levels of DHA-containing PS/pPE, DPA-containing PS, and AA-containing PE, which might exhibit the potential of lipid biomarkers for the prevention and diagnosis of AD. Notably, DHA-PC and DHA-PS remarkably recovered the lipid homeostasis in dementia mice. These might provide a potential novel therapy strategy and direction of dietary intervention for patients with cognitive decline. Conclusions: DHA-PC and DHA-PS could recover the content of brain DHA-containing PS and pPE in SAMP8 mice fed with high-fat diet. [ABSTRACT FROM AUTHOR]

Circular RNAs, as hopeful diagnosis markers and therapeutic molecules, have been studied, probed and applied into several diseases, such as cardiovascular diseases, systemic lupus erythematosus, leukemia, pulmonary tuberculosis, and cancer especially. Recently, mounting evidence has supported that circRNAs play a key role in the tumorigenesis, progress, invasion and metastasis in lung cancer. Its special structure—3′–5′ covalent loop—allow it to execute several special functions in both normal eukaryotic cells and cancer cells. Our review summaries the latest studies on characteristics and biogenesis of circRNAs, and highlight the regulatory functions about miRNA sponge of lung-cancer-related circRNAs. In addition, the interaction of the circRNA-miRNA-mRNA regulatory network will also be elaborated in detail in this review. Therefore, this review can provide a new idea or strategy for further development and application in clinical setting in terms of early-diagnosis and better treatment. [ABSTRACT FROM AUTHOR]

Background: Neutrophils form the first line of innate host defense against invading microorganisms. We previously showed that F0F1 ATP synthase (F-ATPase), which is widely known as mitochondrial respiratory chain complex V, is expressed in the plasma membrane of human neutrophils and is involved in regulating cell migration. Whether F-ATPase performs cellular functions through other pathways remains unknown. Methods: Blue native polyacrylamide gel electrophoresis followed by nano-ESI-LC MS/MS identification and bioinformatic analysis were used to identify protein complexes containing F-ATPase. Then, the identified protein complexes containing F-ATPase were verified by immunoblotting, immunofluorescence colocalization, immunoprecipitation, real-time RT-PCR and agarose gel electrophoresis. Immunoblotting, flow cytometry and a LPS-induced mouse lung injury model were used to assess the effects of the F-ATPase-containing protein complex in vitro and in vivo. Results: We found that the voltage-gated calcium channel (VGCC) α2δ-1 subunit is a binding partner of cell surface F-ATPase in human neutrophils. Further investigation found that the physical connection between the two proteins may exist between the F1 part (α and β subunits) of F-ATPase and the α2 part of VGCC α2δ-1. Real-time RT-PCR and PCR analyses showed that Cav2.3 (R-type) is the primary type of VGCC expressed in human neutrophils. Research on the F-ATPase/Cav2.3 functional complex indicated that it can regulate extracellular Ca2+ influx, thereby modulating ERK1/2 phosphorylation and reactive oxygen species production, which are typical features of neutrophil activation. In addition, the inhibition of F-ATPase can reduce neutrophil accumulation in the lungs of mice that were intratracheally instilled with lipopolysaccharide, suggesting that the inhibition of F-ATPase may prevent neutrophilic inflammation-induced tissue damage. Conclusions: In this study, we identified a mechanism by which neutrophil activity is modulated, with simultaneous regulation of neutrophil-mediated pulmonary damage. These results show that surface F-ATPase of neutrophils is a potential innate immune therapeutic target. [ABSTRACT FROM AUTHOR]

Background: The tick Haemaphysalis longicornis exhibits two separate reproductive populations: bisexual and parthenogenetic, which have diploid and triploid karyotypes, respectively. The parthenogenetic population can undergo engorgement without copulation and produce viable female-only offspring with a longer incubation period than the bisexual population. Three enzymes, cathepsin B, cathepsin D and acid phosphatase, were found to be involved in vitellin degradation during the embryonic development of bisexual H. longicornis. However, the expression and activity profiles of these enzymes during the embryonic development of parthenogenetic ticks remain unknown. In the present study, the transcriptional expression profile, enzyme activity and roles in embryogenesis of the three enzymes during the embryonic development of parthenogenetic H. longicornis were investigated. Methods: Quantitative real-time polymerase chain reaction (qPCR) and fluorescence detection were used to analyze the dynamic changes in the three enzymes during embryogenesis. The roles of the three enzymes during embryogenesis were also explored using RNA interference (RNAi). Results: The three enzymes were all expressed during embryonic development in parthenogenetic H. longicornis. The expression of cathepsin B was highest on day 15, whereas that of cathepsin D was highest on day 3 and the peak of acid phosphatase expression occurred on day 9. The activity of cathepsin B was highest on day 3 and lowest on day 5, then gradually increased and remained stable. Cathepsin D activity was highest on day 1 and showed a gradually decreasing trend, whereas acid phosphatase showed the opposite trend and reached a peak on day 23. RNA interference experiments in engorged female ticks revealed that there was no significant difference in the number of eggs laid, but the hatching rate of the eggs was significantly decreased. Conclusion: The three enzymes all play important roles in embryonic development of H. longicornis, but the expression patterns and changes in the activity of the enzymes in the bisexual and parthenogenetic populations are different. The results will help a better understanding of the similarities and differences underlying embryonic development in the bisexual and parthenogenetic populations and contribute to the future exploration of the development of the parthenogenetic population of H. longicornis. [ABSTRACT FROM AUTHOR]

Background: Whether hypothyroidism is an independent risk factor for cardiovascular events is still disputed. We aimed to assess the association between hypothyroidism and risks of cardiovascular events and mortality.Methods: We searched PubMed and Embase from inception to 29 February 2016. Cohort studies were included with no restriction of hypothyroid states. Priori main outcomes were ischemic heart disease (IHD), cardiac mortality, cardiovascular mortality, and all-cause mortality.Results: Fifty-five cohort studies involving 1,898,314 participants were identified. Patients with hypothyroidism, compared with euthyroidism, experienced higher risks of IHD (relative risk (RR): 1.13; 95% confidence interval (CI): 1.01-1.26), myocardial infarction (MI) (RR: 1.15; 95% CI: 1.05-1.25), cardiac mortality (RR: 1.96; 95% CI: 1.38-2.80), and all-cause mortality (RR: 1.25; 95% CI: 1.13-1.39); subclinical hypothyroidism (SCH; especially with thyrotropin level ≥10 mIU/L) was also associated with higher risks of IHD and cardiac mortality. Moreover, cardiac patients with hypothyroidism, compared with those with euthyroidism, experienced higher risks of cardiac mortality (RR: 2.22; 95% CI: 1.28-3.83) and all-cause mortality (RR: 1.51; 95% CI: 1.26-1.81).Conclusions: Hypothyroidism is a risk factor for IHD and cardiac mortality. Hypothyroidism is associated with higher risks of cardiac mortality and all-cause mortality compared with euthyroidism in the general public or in patients with cardiac disease. [ABSTRACT FROM AUTHOR]

Background: Many gynecological cancer survivors (GCS) have comorbid chronic diseases (CCD). This study was to estimate the impacts of CCD on quality of life (QOL) in GCS.Methods: We collected cross-sectional self-reported survey data from 598 GCS between April and July 2013, in Shanghai, China. All the subjects were asked to complete a questionnaire containing the European Organization for Research and Treatment quality of life version 3 questionnaire (EORTC QLQ-C30) and questions on socio-demographic characteristics and CCD. In order to mitigate the bias caused by confounding factors, multiple linear models were employed to calculate adjusted means of QOL scores.Results: Approximately three-quarters of subjects reported at least one CCD. The highest overall prevalence of all CCD was found in endometrial cancer survivors. Subjects with CCD generally reported lower scores for most EORTC QLQ-C30 scales when compared to subjects without CCD, indicating poorer QOL, particularly for cardiovascular diseases, respiratory diseases, digestive diseases, and musculoskeletal disease.Conclusions: The CCD are common health problems among GCS. CCD have significantly negative influence on QOL, and GCS with CCD generally reported lower QOL scores. These findings suggested comprehensive cares for GCS. [ABSTRACT FROM AUTHOR]

Background: Dual anti-human epidermal growth factor receptor 2 (HER2) therapies have been shown to improve outcomes of HER2-positive breast cancer patients. We undertook a systematic review to compare treatment outcomes for patients who received single or combined anti-HER2 therapies.Methods: We identified randomized control trials that compared dual anti-HER2 therapy and anti-HER2 monotherapy in patients with HER2-positive breast cancer. Outcomes included pathologic complete response (pCR), overall survival (OS), progression-free survival (PFS), and adverse events. Included in the analysis were seven trials that recruited 2,609 patients.Results: In the neoadjuvant setting, the pooled pCR rate in the dual anti-HER2 therapy and monotherapy groups in combination with chemotherapy was 54.8% and 36%, respectively. This difference was statistically significant (relative risk, 1.56; 95% confidence interval (CI), 1.23-1.97; p < 0.001). In the metastatic setting, dual anti-HER2 therapy demonstrated significant benefits in both PFS (hazard ratio (HR), 0.71; 95% CI, 0.62-0.81; p < 0.001) and OS (HR, 0.68; 95% CI, 0.57-0.82; p < 0.001). Subgroup analyses indicated that the addition of chemotherapy to dual anti-HER2 therapy could greatly improve pCR in the neoadjuvant settings. However, in the metastatic setting, similar PFS and OS were found in patients receiving dual anti-HER2 therapy with or without chemotherapy. Dual anti-HER2 therapy was associated with more frequent adverse events than monotherapy, but no statistical differences were observed in cardiac toxicity.Conclusions: This systematic review provides a summary of all the data currently available, and confirms the benefits and risks of dual anti-HER2 therapy for HER2-positive breast cancer. [ABSTRACT FROM AUTHOR]

Metastatic castration-resistant prostate cancer (mCRPC) remains a terminal diagnosis with an aggressive disease course despite currently approved therapeutics. The recent successful development of poly ADP-ribose polymerase (PARP) inhibitors for patients with mCRPC and mutations in DNA damage repair genes has added to the treatment armamentarium and improved personalized treatments for prostate cancer. Other promising therapeutic agents currently in clinical development include the radiotherapeutic 177-lutetium-prostate-specific membrane antigen (PSMA)-617 targeting PSMA-expressing prostate cancer and combinations of immunotherapy with currently effective treatment options for prostate cancer. Herein, we have highlighted the progress in systemic treatments for mCRPC and the promising agents currently in ongoing clinical trials. [ABSTRACT FROM AUTHOR]

Background: In 1997, the Radiation Therapy Oncology Group (RTOG) put forward the recursive partitioning analysis classification for the prognosis of brain metastases (BMs), but this system does not take into account the epidermal growth factor receptor (EGFR) mutations. The aim of the study is to assess the prognosis of patients with EGFR-mutated non-small cell lung cancer (NSCLC) and BMs in the era of tyrosine kinase inhibitor (TKI) availability.Methods: This was a retrospective study of consecutive patients with EGFR-mutated (exon 19 or 21) NSCLC diagnosed between 01/2011 and 12/2014 at the Tianjin Medical University Cancer Institute & Hospital and who were ultimately diagnosed with BMs. The patients were stage I-III at initial presentation and developed BMs as the first progression. Overall survival (OS), OS after BM diagnosis (mOS), intracranial progression-free survival (iPFS), response to treatment, and adverse reactions were analyzed.Results: Median survival was 35 months, and the 1- and 2- year survival rates were 95.6% (108/113) and 74.3% (84/113). The 3-month CR + PR rates of radiotherapy(R), chemotherapy(C), targeted treatment(T), and targeted treatment + radiotherapy(T+R) after BMs were 63.0% (17/27), 26.7% (4/15), 50.0% (7/14), and 89.7% (35/39), respectively. The median survival of the four treatments was 20, 9, 12, and 25 months after BMs, respectively (P = 0.001). Multivariable analysis showed that < 3 BMs (odds ratio (OR) = 3.34, 95% confidence interval (CI): 1.89-5.91, P < 0.001) and treatment after BMs (OR = 0.68, 95%CI: 0.54-0.85, P = 0.001) were independently associated with better prognosis.Conclusions: The prognosis of patients with NSCLC and EGFR mutation in exon 19 or 21 after BM is associated with the number of brain metastasis and the treatment method. Targeted treatment combined with radiotherapy may have some advantages over other treatments, but further study is warranted to validate the results. [ABSTRACT FROM AUTHOR]

Background: Myocardial fibrosis is a common pathophysiological process that is related to ventricular remodeling in congenital heart disease. However, the presence, characteristics, and clinical significance of myocardial fibrosis in Ebstein's anomaly have not been fully investigated. This study aimed to evaluate myocardial fibrosis using cardiovascular magnetic resonance (CMR) late gadolinium enhancement (LGE) and T1 mapping techniques, and to explore the significance of myocardial fibrosis in adolescent and adult patients with Ebstein's anomaly. Methods: Forty-four consecutive patients with unrepaired Ebstein's anomaly (34.0 ± 16.2 years; 18 males), and an equal number of age- and gender-matched controls, were included. A comprehensive CMR protocol consisted of cine, LGE, and T1 mapping by modified Look-Locker inversion recovery (MOLLI) sequences were performed. Ventricular functional parameters, native T1, extracellular volume (ECV), and LGE were analyzed. Associations between myocardial fibrosis and disease severity, ventricular function, and NYHA classification were analyzed. Results: LGE was found in 10 (22.7%) patients. Typical LGE in Ebstein's anomaly was located in the endocardium of the septum within the right ventricle (RV). The LV ECV of Ebstein's anomaly were significantly higher than those of the controls (30.0 ± 3.8% vs. 25.3 ± 2.3%, P < 0.001). An increased ECV was found to be independent of the existence of LGE. Positive LGE or higher ECV (≥30%) was associated with larger fRV volume, aRV volume, increased disease severity, and worse NYHA functional class. In addition, ECV was significantly correlated with the LV ejection fraction (P < 0.001). Conclusions: Both focal and diffuse myocardial fibrosis were observed in adolescent and adult patients with Ebstein's anomaly. Increased diffuse fibrosis is associated with worse LV function, increased Ebstein's severity, and worse clinical status. [ABSTRACT FROM AUTHOR]

Background: 2-Keto-l-gulonic acid (2-KGA), the precursor of vitamin C, is currently produced by two-step fermentation. In the second step, l-sorbose is transformed into 2-KGA by the symbiosis system composed of Ketogulonicigenium vulgare and Bacillus megaterium. Due to the different nutrient requirements and the uncertain ratio of the two strains, the symbiosis system significantly limits strain improvement and fermentation optimization. Results: In this study, Ketogulonicigenium robustum SPU_B003 was reported for its capability to grow well independently and to produce more 2-KGA than that of K. vulgare in a mono-culture system. The complete genome of K. robustum SPU_B003 was sequenced, and the metabolic characteristics were analyzed. Compared to the four reported K. vulgare genomes, K. robustum SPU_B003 contained more tRNAs, rRNAs, NAD and NADP biosynthetic genes, as well as regulation- and cell signaling-related genes. Moreover, the amino acid biosynthesis pathways were more complete. Two species-specific internal promoters, P1 (orf_01408 promoter) and P2 (orf_02221 promoter), were predicted and validated by detecting their initiation activity. To efficiently produce 2-KGA with decreased CO2 release, an innovative acetyl-CoA biosynthetic pathway (XFP-PTA pathway) was introduced into K. robustum SPU_B003 by expressing heterologous phosphoketolase (xfp) and phosphotransacetylase (pta) initiated by internal promoters. After gene optimization, the recombinant strain K. robustum/pBBR-P1_xfp2502-P2_pta2145 enhanced acetyl-CoA approximately 2.4-fold and increased 2-KGA production by 22.27% compared to the control strain K. robustum/pBBR1MCS-2. Accordingly, the transcriptional level of the 6-phosphogluconate dehydrogenase (pgd) and pyruvate dehydrogenase genes (pdh) decreased by 24.33 ± 6.67 and 8.67 ± 5.51%, respectively. The key genes responsible for 2-KGA biosynthesis, sorbose dehydrogenase gene (sdh) and sorbosone dehydrogenase gene (sndh), were up-regulated to different degrees in the recombinant strain. Conclusions: The genome-based functional analysis of K. robustum SPU_B003 provided a new understanding of the specific metabolic characteristics. The new XFP-PTA pathway was an efficient route to enhance acetyl-CoA levels and to therefore promote 2-KGA production. [ABSTRACT FROM AUTHOR]