ZFYVE19 deficiency: a ciliopathy involving failure of cell division, with cell death.

BACKGROUND AND AIMS: Variants in ZFYVE19 underlie a disorder characterised by progressive portal fibrosis, portal hypertension and eventual liver decompensation. We aim to create an animal model to elucidate the pathogenic mechanism. METHODS: Zfyve19 knockout (Zfyve19-/- ) mice were generated and exposed to different liver toxins. Their livers were characterised at the tissue, cellular and molecular levels. Findings were compared with those in wild-type mice and in ZFYVE19-deficient patients. ZFYVE19 knockout and knockdown retinal pigment epithelial-1 cells and mouse embryonic fibroblasts were generated to study cell division and cell death. RESULTS: The Zfyve19-/- mice were normal overall, particularly with respect to hepatobiliary features. However, when challenged with α-naphthyl isothiocyanate, Zfyve19-/- mice developed changes resembling those in ZFYVE19-deficient patients, including elevated serum liver injury markers, increased numbers of bile duct profiles with abnormal cholangiocyte polarity and biliary fibrosis. Failure of cell division, centriole and cilia abnormalities, and increased cell death were observed in knockdown/knockout cells. Increased cell death and altered mRNA expression of cell death-related signalling pathways was demonstrated in livers from Zfyve19-/- mice and patients. Transforming growth factor-ß (TGF-ß) and Janus kinase-Signal Transducer and Activator of Transcription 3 (JAK-STAT3) signalling pathways were upregulated in vivo, as were chemokines such as C-X-C motif ligands 1, 10 and 12. CONCLUSIONS: Our findings demonstrated that ZFYVE19 deficiency is a ciliopathy with novel histological features. Failure of cell division with ciliary abnormalities and cell death activates macrophages and may thus lead to biliary fibrosis via TGF-ß pathway in the disease.

Metastatic site influences driver gene function in pancreatic cancer.

Driver gene mutations can increase the metastatic potential of the primary tumor1-3, but their role in sustaining tumor growth at metastatic sites is poorly understood. A paradigm of such mutations is inactivation of SMAD4 - a transcriptional effector of TGFß signaling - which is a hallmark of multiple gastrointestinal malignancies4,5. SMAD4 inactivation mediates TGFß's remarkable anti- to pro-tumorigenic switch during cancer progression and can thus influence both tumor initiation and metastasis6-14. To determine whether metastatic tumors remain dependent on SMAD4 inactivation, we developed a mouse model of pancreatic ductal adenocarcinoma (PDAC) that enables Smad4 depletion in the pre-malignant pancreas and subsequent Smad4 reactivation in established metastases. As expected, Smad4 inactivation facilitated the formation of primary tumors that eventually colonized the liver and lungs. By contrast, Smad4 reactivation in metastatic disease had strikingly opposite effects depending on the tumor's organ of residence: suppression of liver metastases and promotion of lung metastases. Integrative multiomic analysis revealed organ-specific differences in the tumor cells' epigenomic state, whereby the liver and lungs harbored chromatin programs respectively dominated by the KLF and RUNX developmental transcription factors, with Klf4 depletion being sufficient to reverse Smad4's tumor-suppressive activity in liver metastases. Our results show how epigenetic states favored by the organ of residence can influence the function of driver genes in metastatic tumors. This organ-specific gene-chromatin interplay invites consideration of anatomical site in the interpretation of tumor genetics, with implications for the therapeutic targeting of metastatic disease.

A transient protein folding response targets aggregation in the early phase of TDP-43-mediated neurodegeneration.

Understanding the mechanisms that drive TDP-43 pathology is integral to combating amyotrophic lateral sclerosis (ALS), frontotemporal lobar degeneration (FTLD) and other neurodegenerative diseases. Here we generated a longitudinal quantitative proteomic map of the cortex from the cytoplasmic TDP-43 rNLS8 mouse model of ALS and FTLD, and developed a complementary open-access webtool, TDP-map ( https://shiny.rcc.uq.edu.au/TDP-map/ ). We identified distinct protein subsets enriched for diverse biological pathways with temporal alterations in protein abundance, including increases in protein folding factors prior to disease onset. This included increased levels of DnaJ homolog subfamily B member 5, DNAJB5, which also co-localized with TDP-43 pathology in diseased human motor cortex. DNAJB5 over-expression decreased TDP-43 aggregation in cell and cortical neuron cultures, and knockout of Dnajb5 exacerbated motor impairments caused by AAV-mediated cytoplasmic TDP-43 expression in mice. Together, these findings reveal molecular mechanisms at distinct stages of ALS and FTLD progression and suggest that protein folding factors could be protective in neurodegenerative diseases.

Characteristics and duties of clinical research nurses: a scoping review.

Introduction: The characteristics and duties of clinical research nurses (CRNs) are constantly developing and changing with the progress of medical technology and increasing needs in patient care. With the continuous deepening and standardization of clinical trials, the importance and status of CRNs during the whole process of clinical trials are also increasingly valued. Methods: A scoping review of studies related to the characteristics and duties of CRNs was conducted to clarify relevant roles and concepts. An electronic search was conducted on three English databases (PubMed, Web of Science, Embase) and two Chinese databases (CNKI and Wanfang database) in December 2023. Two authors independently screened the literature, extracted information from the included literature, and summarized and reported the findings. Results: A total of 26 articles published between 1991 and 2023 were analyzed, and four characteristics of CRNs were identified as participants and managers of clinical trials, caregivers and protectors of subjects, coordinators of research teams, and educators. Basic knowledge, skills and literacy, communication and coordination ability, and advanced research ability are the competencies required for CRNs. Conclusion: Further studies should focus on the importance of various characteristics of CRNs, so as to improve the quality of clinical trials and promote clinical evidence-based practice.

Generation of precision preclinical cancer models using regulated in vivo base editing.

Although single-nucleotide variants (SNVs) make up the majority of cancer-associated genetic changes and have been comprehensively catalogued, little is known about their impact on tumor initiation and progression. To enable the functional interrogation of cancer-associated SNVs, we developed a mouse system for temporal and regulatable in vivo base editing. The inducible base editing (iBE) mouse carries a single expression-optimized cytosine base editor transgene under the control of a tetracycline response element and enables robust, doxycycline-dependent expression across a broad range of tissues in vivo. Combined with plasmid-based or synthetic guide RNAs, iBE drives efficient engineering of individual or multiple SNVs in intestinal, lung and pancreatic organoids. Temporal regulation of base editor activity allows controlled sequential genome editing ex vivo and in vivo, and delivery of sgRNAs directly to target tissues facilitates generation of in situ preclinical cancer models.

Social isolation, depression, nutritional status and quality of life during COVID-19 among Chinese community-dwelling older adults: a cross-sectional study.

OBJECTIVE: This survey investigated the relationship between social isolation, depression, nutritional status and quality of life among community-dwelling older adults during COVID-19. DESIGN: This was a cross-sectional survey study. SETTING: Communities in Pudong New Area, Shanghai, China that have contracted with Renji Hospital, affiliated with Shanghai Jiao Tong University School of Medicine. PARTICIPANTS: From May to July 2022, 406 community-dwelling older adults were selected by convenience sampling in Shanghai, China. PRIMARY AND SECONDARY OUTCOME MEASURES: The Lubben Social Network Scale, Geriatric Depression Scale, 36-item Short Form Health Survey Scale and risk assessment of malnutrition were used in older adults. Mediation models were constructed to determine the mediating role of depression and nutritional status on social isolation and quality of life among older adults. RESULTS: The prevalence of social isolation among older adults in the community was 44.3%. The total social isolation score in community-dwelling older adults was positively associated with the total malnutrition risk and quality of life scores, and negatively associated with depression (p<0.01). Logistic regression demonstrated that living alone, loss of families or friends during COVID-19 and depression were risk factors for social isolation among community-dwelling older adults (p<0.05). Social isolation could directly affect the quality of life (ß=0.306). In addition, depression (ß=0.334) and nutritional status (ß=0.058) had a significant mediating effect on the relationship between social isolation and quality of life. CONCLUSIONS: Our findings showed that the prevalence of social isolation among older adults increased during COVID-19. Depression and nutritional status played parallel mediating roles on the effect of social isolation on quality of life. Community workers and healthcare providers should develop intervention plans to improve the status of social isolation in older adults, eliminating existing and ongoing adverse effects.

Epigenetic plasticity cooperates with cell-cell interactions to direct pancreatic tumorigenesis.

The response to tumor-initiating inflammatory and genetic insults can vary among morphologically indistinguishable cells, suggesting as yet uncharacterized roles for epigenetic plasticity during early neoplasia. To investigate the origins and impact of such plasticity, we performed single-cell analyses on normal, inflamed, premalignant, and malignant tissues in autochthonous models of pancreatic cancer. We reproducibly identified heterogeneous cell states that are primed for diverse, late-emerging neoplastic fates and linked these to chromatin remodeling at cell-cell communication loci. Using an inference approach, we revealed signaling gene modules and tissue-level cross-talk, including a neoplasia-driving feedback loop between discrete epithelial and immune cell populations that was functionally validated in mice. Our results uncover a neoplasia-specific tissue-remodeling program that may be exploited for pancreatic cancer interception.

EZH2 inhibition remodels the inflammatory senescence-associated secretory phenotype to potentiate pancreatic cancer immune surveillance.

Immunotherapies that produce durable responses in some malignancies have failed in pancreatic ductal adenocarcinoma (PDAC) due to rampant immune suppression and poor tumor immunogenicity. We and others have demonstrated that induction of the senescence-associated secretory phenotype (SASP) can be an effective approach to activate anti-tumor natural killer (NK) cell and T cell immunity. In the present study, we found that the pancreas tumor microenvironment suppresses NK cell and T cell surveillance after therapy-induced senescence through enhancer of zeste homolog 2 (EZH2)-mediated epigenetic repression of proinflammatory SASP genes. EZH2 blockade stimulated production of SASP chemokines CCL2 and CXCL9/10, leading to enhanced NK cell and T cell infiltration and PDAC eradication in mouse models. EZH2 activity was also associated with suppression of chemokine signaling and cytotoxic lymphocytes and reduced survival in patients with PDAC. These results demonstrate that EZH2 represses the proinflammatory SASP and that EZH2 inhibition combined with senescence-inducing therapy could be a powerful means to achieve immune-mediated tumor control in PDAC.

LWJ-M30, a conjugate of DM1 and B6, for the targeted therapy of colorectal cancer with improved therapeutic effects.

Colorectal cancer (CRC) is one of the most prevalent cancers worldwide as well as a significant cause of mortality. The conventional treatment could cause serious side effects and induce drug resistance, recurrence and metastasis of cancers. Hence, specific targeting of cancer cells without affecting the normal tissues is currently an urgent necessity in cancer therapy. The emerging of peptide-drug conjugates (PDC) is regarded as a promising approach to address malignant tumors. LWJ-M30, a conjugate of DM1 and B6 peptide, targeted transferrin receptors (TfRs) on the surface of the CRC cells, showing a powerful anti-cancer effect. LWJ-M30 significantly inhibited the HCT116 cells proliferation and migration in vitro. LWJ-M30 also dramatically decreased the level of polymeric tubulin, while the disruption of microtubules caused the cell cycle to be arrested in the G2/M phase. LWJ-M30 induced the HCT116 cells apoptosis both in vivo and in vitro. The results in vivo demonstrated that LWJ-M30 could inhibit the HCT116 growth without affecting the mouse body weight. Taking these results together, our data indicated that LWJ-M30 could improve the therapeutic effects of DM1 while reducing the systemic toxicity in normal tissues.

Early activation of cellular stress and death pathways caused by cytoplasmic TDP-43 in the rNLS8 mouse model of ALS and FTD.

TAR DNA binding protein 43 (TDP-43) pathology is a key feature of over 95% of amyotrophic lateral sclerosis (ALS) and nearly half of frontotemporal dementia (FTD) cases. The pathogenic mechanisms of TDP-43 dysfunction are poorly understood, however, activation of cell stress pathways may contribute to pathogenesis. We, therefore, sought to identify which cell stress components are critical for driving disease onset and neurodegeneration in ALS and FTD. We studied the rNLS8 transgenic mouse model, which expresses human TDP-43 with a genetically-ablated nuclear localisation sequence within neurons of the brain and spinal cord resulting in cytoplasmic TDP-43 pathology and progressive motor dysfunction. Amongst numerous cell stress-related biological pathways profiled using qPCR arrays, several critical integrated stress response (ISR) effectors, including CCAAT/enhancer-binding homologous protein (Chop/Ddit3) and activating transcription factor 4 (Atf4), were upregulated in the cortex of rNLS8 mice prior to disease onset. This was accompanied by early up-regulation of anti-apoptotic gene Bcl2 and diverse pro-apoptotic genes including BH3-interacting domain death agonist (Bid). However, pro-apoptotic signalling predominated after onset of motor phenotypes. Notably, pro-apoptotic cleaved caspase-3 protein was elevated in the cortex of rNLS8 mice at later disease stages, suggesting that downstream activation of apoptosis drives neurodegeneration following failure of early protective responses. Unexpectedly, suppression of Chop in the brain and spinal cord using antisense oligonucleotide-mediated silencing had no effect on overall TDP-43 pathology or disease phenotypes in rNLS8 mice. Cytoplasmic TDP-43 accumulation therefore causes very early activation of ISR and both anti- and pro-apoptotic signalling that switches to predominant pro-apoptotic activation later in disease. These findings suggest that precise temporal modulation of cell stress and death pathways may be beneficial to protect against neurodegeneration in ALS and FTD.

Senescence Rewires Microenvironment Sensing to Facilitate Antitumor Immunity.

Cellular senescence involves a stable cell-cycle arrest coupled to a secretory program that, in some instances, stimulates the immune clearance of senescent cells. Using an immune-competent liver cancer model in which senescence triggers CD8 T cell-mediated tumor rejection, we show that senescence also remodels the cell-surface proteome to alter how tumor cells sense environmental factors, as exemplified by type II interferon (IFNγ). Compared with proliferating cells, senescent cells upregulate the IFNγ receptor, become hypersensitized to microenvironmental IFNγ, and more robustly induce the antigen-presenting machinery-effects also recapitulated in human tumor cells undergoing therapy-induced senescence. Disruption of IFNγ sensing in senescent cells blunts their immune-mediated clearance without disabling the senescence state or its characteristic secretory program. Our results demonstrate that senescent cells have an enhanced ability to both send and receive environmental signals and imply that each process is required for their effective immune surveillance. SIGNIFICANCE: Our work uncovers an interplay between tissue remodeling and tissue-sensing programs that can be engaged by senescence in advanced cancers to render tumor cells more visible to the adaptive immune system. This new facet of senescence establishes reciprocal heterotypic signaling interactions that can be induced therapeutically to enhance antitumor immunity. See related article by Marin et al., p. 410. This article is highlighted in the In This Issue feature, p. 247.

Prediction model for the pretreatment evaluation of mortality risk in anti-melanoma differentiation-associated gene 5 antibody-positive dermatomyositis with interstitial lung disease.

Background: Anti-melanoma differentiation-associated gene 5 antibody-positive dermatomyositis with interstitial lung disease (anti-MDA5 DM-ILD) is a disease with high mortality. We sought to develop an effective and convenient prediction tool to estimate mortality risk in patients with anti-MDA5 DM-ILD and inform clinical decision-making early. Methods: This prognostic study included Asian patients with anti-MDA5 DM-ILD hospitalized at the Nanjing Drum Hospital from December 2016 to December 2020. Candidate laboratory indicators were retrospectively collected. Patients hospitalized from 2016 to 2018 were used as the discovery cohort and applied to identify the optimal predictive features using a least absolute shrinkage and selection operator (LASSO) logistic regression model. A risk score was determined based on these features and used to construct the mortality risk prediction model in combination with clinical characteristics. Results were verified in a temporal validation comprising patients treated between 2019 and 2020. The primary outcome was mortality risk within one year. The secondary outcome was overall survival. The prediction model's performance was assessed in terms of discrimination, calibration, and clinical usefulness. Results: This study included 127 patients, (72 men [56.7%]; median age, 54 years [interquartile range, 48-63 years], split into discovery (n = 87, 70%) and temporal validation (n=37, 30%) cohorts. Five optimal features were selected by LASSO logistic regression in the discovery cohort (n = 87) and used to construct a risk score, including lymphocyte counts, CD3+CD4+ T-cell counts, cytokeratin 19 fragment (CYFRA21-1), oxygenation index, and anti-Ro52 antibody. The retained predictive variables in the final prediction model were age, Heliotrope, fever, and risk score, and the most predictive factor was the risk score. The prediction model showed good discrimination (AUC: 0.915, 95% CI: 0.846-0.957), good calibration (Hosmer-Lemeshow test, P = 0.506; Brier score, 0.12), and fair clinical usefulness in the discovery cohort. The results were verified among patients in the temporal validation cohort (n = 38). We successfully divided patients into three risk groups with very different mortality rates according to the predictive score in both the discovery and validation cohorts (Cochran-Armitage test for trend, P < 0.001). Conclusions: We developed and validated a mortality risk prediction tool with good discrimination and calibration for Asian patients with anti-MDA5 DM-ILD. This tool can offer individualized mortality risk estimation and inform clinical decision-making.

Correlation Between the Frailty of Elderly Patients on Regular Haemodialysis and the Quality of Life of Their Family Caregivers: A Cross-Sectional Evaluation.

Objective: To investigate the correlation between the frailty status of elderly patients on regular haemodialysis and the quality of life of their family caregivers. Methods: 90 elderly patients with regular haemodialysis and 90 family caregivers of the respective patients were selected from January 2020 to April 2021. The influencing factors of the caregivers' quality of life and correlation between patient debility and caregiver quality of life were analyzed by general information questionnaire, Tilburg debility index scale, self-care ability scale, family caregiver-related quality-of-life scale and social support scale. Results: The quality of life of the family caregivers of elderly patients on regular haemodialysis is at the medium level (4.50 ± 2.96). Multiple linear stepwise regression analysis shows that the ability of patients to take care of themselves, the degree of patients' weaknesses, whether they care for non-dialysis patients, the time to care for patients, social support and the type of current residence have significant impacts on the quality of life of the caregivers (p < 0.001). Variance analysis showed that the fitting degree of linear regression equation is relatively high, and the regression equation is significant (F = 9.195, p < 0.001, R = 0.595, R2 = 0.315). The quality of life of caregivers is positively correlated with the ability of the patients to take care of themselves, the length of care, social support and type of current residence (p < 0.05). The degree of weakness in patients is negatively correlated with taking care of non-regular dialysis patients (p < 0.05). Conclusion: The ability of patients to take care of themselves, the degree of weakness of the patients, social support and the type of current residence are the influencing factors of the burden on the family caregivers of maintenance haemodialysis patients.

Research progress on digital health literacy of older adults: A scoping review.

With the rapid development of digital health today, the lack of digital health literacy in older adults is an urgent problem. It is crucial that older adults adapt to the digital reform in medical treatment, pension, health management, and other fields. Therefore, we reviewed the current development status of digital health literacy among older adults. A total of 47 articles were included in this scoping review. Our findings revealed that research on digital health literacy in older adults is still in its infancy. Further development is warranted especially in terms of assessment tools and intervention methods.

Prenatal hypoxia alters the early ontogeny of dopamine neurons.

Dopaminergic (DA) dysfunction is a significant feature in the pathophysiology of schizophrenia. Established developmental risk factors for schizophrenia such as maternal immune activation (MIA) or developmental vitamin D (DVD) deficiency, when modelled in animals, reveal the differentiation of early DA neurons in foetal brains is delayed suggesting this may be a convergent aetiological pathway. Here we have assessed the effects of prenatal hypoxia, another well-known developmental risk factor for schizophrenia, on developing DA systems. Pregnant mice were exposed to a hypoxic environment of 10% oxygen for 48 h from embryonic day 10 (E10) to E12. Embryonic brains were collected and the positioning of mesencephalic cells, expression of DA specification and maturation factors were examined along with the expression of factors that may govern the migration of these neurons. We show that prenatal hypoxia results in a decrease in dopaminergic progenitors retards early DA neuron lateral migration and reduces expression of the receptors known to govern this process. A second time-point, postnatal day 10 (P10) was also examined in order to assess whether prenatal hypoxia alters early presynaptic architecture in the developing striatum. We show reduced expression of tyrosine hydroxylase (TH) in the postnatal striatum along with increases in the density of high-probability DA release sites within TH varicosities. These findings add to the emerging literature showing that multiple epidemiologically validated environmental risk factors for schizophrenia may induce early alterations to develop DA systems. This may represent a possible convergent mechanism in the onset of presynaptic DA dysfunction in patients.

A preclinical platform for assessing antitumor effects and systemic toxicities of cancer drug targets.

Anticancer drug development campaigns often fail due to an incomplete understanding of the therapeutic index differentiating the efficacy of the agent against the cancer and its on-target toxicities to the host. To address this issue, we established a versatile preclinical platform in which genetically defined cancers are produced using somatic tissue engineering in transgenic mice harboring a doxycycline-inducible short hairpin RNA against the target of interest. In this system, target inhibition is achieved by the addition of doxycycline, enabling simultaneous assessment of efficacy and toxicity in the same animal. As proof of concept, we focused on CDK9­a cancer target whose clinical development has been hampered by compounds with poorly understood target specificity and unacceptable toxicities. We systematically compared phenotypes produced by genetic Cdk9 inhibition to those achieved using a recently developed highly specific small molecule CDK9 inhibitor and found that both perturbations led to robust antitumor responses. Remarkably, nontoxic levels of CDK9 inhibition could achieve significant treatment efficacy, and dose-dependent toxicities produced by prolonged CDK9 suppression were largely reversible upon Cdk9 restoration or drug withdrawal. Overall, these results establish a versatile in vivo target validation platform that can be employed for rapid triaging of therapeutic targets and lend support to efforts aimed at advancing CDK9 inhibitors for cancer therapy.

Correlation between nutritional status and oral health quality of life, self-efficacy of older inpatients and the influencing factors.

OBJECTIVE: This study explores the relationship between nutritional status and oral health quality of life, the self-efficacy of older inpatients and the correlative factors. METHODS: In this study, the convenience sampling method was used to select 307 older inpatients in the southern section of the Renji Hospital affiliated to Shanghai Jiao Tong University School of Medicine from October to December 2020 as the main research participants. A mini nutritional assessment questionnaire was used to assess nutritional status, and the Chinese version of a geriatric oral health assessment index questionnaire was used to determine the oral health quality of life. Self-efficacy was assessed by a general self-efficacy scale questionnaire. Descriptive statistics were used to analyse data using the SPSS 22.0 software. Pearson correlation and multiple linear regression analysis were applied to explore the correlation between variables and factors concerned with nutritional status, respectively. RESULTS: The results of this study showed that the self-efficacy and oral health quality of life of older inpatients were at a moderate level. Among the patients, 263 had one or more tooth defects, and only 128 had oral restorations or wore dentures. The risk of malnutrition in hospitalised older patients was 37.1%, and the incidence of malnutrition was 13.4%. The risk factors of nutritional status of older patients were age, oral-related quality of life, prealbumin index, self-efficacy, chronic disease, monthly income and tooth defect (P < 0.05). CONCLUSION: The incidence of malnutrition and malnutrition risk in hospitalised older patients is relatively high. The main associated factors include age, tooth defect, oral health quality of life, self-efficacy, chronic disease status and monthly income. Therefore, older inpatients, especially those with prosthodontic problems, should carry out nutritional assessments, intervention and graded management as soon as possible to improve their self-efficacy, improve their nutrition and health status and reduce the incidence of a poor prognosis.

Exosomal circ_0048856 derived from non-small cell lung cancer contributes to aggressive cancer progression through downregulation of miR-1287-5p.

AIM: Present study was aimed to explore the diagnostic value and mechanism of exosome derived circular RNA (circ)_0048856 in non-small cell lung cancer (NSCLC) development. METHODS: Exosomes protein markers, CD63 and CD9, were examined by Western blot. Real time quantitative reverse transcriptase - polymerase chain reaction (qRT-PCR) was used to detect the relative expression of circ_0048856 and miR-1287-5p. Proliferation of NSCLC cell was detected by MTT assay. Transwell assay was utilized to evaluated the migration and invasion of NSCLC cells. Apoptosis rate was examined by Flow cytometry. Double luciferase report assay was used to assess the targeting association between circ_0048856 and miR-1287-5p. Diagnostic value of circ_0048856 for NSCLC was estimated by receiver operating characteristic (ROC) curve. Animal models were constructed to explore the function of exosomal circ_0048856 in NSCLC. RESULTS: Diameter of exosomes in NSCLC serum was ranged between 75 and 150 nm. Exosomes circ_0048856 was enhanced in NSCLC serum and cell lines (P < 0.001). Exosome derived circ_0048856 had high diagnostic value for NSCLC. Area under the curve (AUC) was 0.943 (95%CI=0.904-0.982, P < 0.001). at the optimal cutoff value of 1.800, the sensitivity was 0.880, and specificity was 0.800. Exosome circ_0048856 facilitated proliferation, migration and invasion, inhibited apoptosis of NSCLC cells. MiR-1287-5p could be effaced by circ_0048856. MiR-1287-5p reversed the biological behavior changes of NSCLC cells which induced by circ_0048856. In vivo, exosomal circ_0048856 could significantly promote tumor growth (P < 0.001). CONCLUSION: Exosomes derived circ_0048856 was elevated in NSCLC serum and cell lines. Exosome circ_0048856 promoted the NSCLC development by targeting miR-1287-5p. Exosome circ_0048856 had high diagnostic value for NSCLC.

Improvement of Pulmonary Function in Arthrogryposis Multiplex Congenita Patients Undergoing Posterior Spinal Fusion Surgery for Concomitant Scoliosis: A Minimum of 3-Year Follow-up.

OBJECTIVE: We sought to investigate the long-term outcome of pulmonary function for arthrogryposis multiplex congenita (AMC) patients undergoing posterior spinal fusion (PSF) and to further determine influential factors. METHODS: Eighteen AMC patients with a minimum of 3-year follow-up after PSF were prospectively collected. All the patients underwent a pulmonary function test before surgery and at the final follow-up. The percentage predicted values of vital capacity (VC%) and forced vital capacity (FVC%) were recorded. The following radiographic parameters were collected including Cobb angle and thoracic kyphosis. The total lung volumes (TLV) were measured on the image of 3-dimensional computed tomography scan by the reconstruction software. RESULTS: There were 10 males and 8 females with a mean age of 13.8 ± 6.1 years. The mean preoperative VC% and FVC% were 40.5% ± 7.6% and 39.5% ± 4.7%, which were significantly increased to 52.0% ± 7.5% and 51.2% ± 6.8% at the final follow-up (P < 0.001). Besides, there was remarkable improvement in terms of TLV (1.57 ± 0.2 L vs. 2.39 ± 0.6 L, P < 0.001). Remarkable correlations were observed between TLV and pulmonary function tests (r = 0.79, P < 0.001 for VC%; r = 0.78, P < 0.001 for FVC%). Multiple regression analysis showed that 2 variables including Δ thoracic kyphosis and Δ Cobb angle were independently associated with the improvement of pulmonary function. CONCLUSIONS: The pulmonary function of AMC patients can be well improved through PSF surgery. It was remarkably associated with the correction of curve magnitude and restoration of thoracic kyphosis.