Photoactivatable nanoagonists chemically programmed for pharmacokinetic tuning and in situ cancer vaccination.

Immunotherapy holds great promise for the treatment of aggressive and metastatic cancers; however, currently available immunotherapeutics, such as immune checkpoint blockade, benefit only a small subset of patients. A photoactivatable toll-like receptor 7/8 (TLR7/8) nanoagonist (PNA) system that imparts near-infrared (NIR) light-induced immunogenic cell death (ICD) in dying tumor cells in synchrony with the spontaneous release of a potent immunoadjuvant is developed here. The PNA consists of polymer-derived proimmunoadjuvants ligated via a reactive oxygen species (ROS)-cleavable linker and polymer-derived photosensitizers, which are further encapsulated in amphiphilic matrices for systemic injection. In particular, conjugation of the TLR7/8 agonist resiquimod to biodegradable macromolecular moieties with different molecular weights enabled pharmacokinetic tuning of small-molecule agonists and optimized delivery efficiency in mice. Upon NIR photoirradiation, PNA effectively generated ROS not only to ablate tumors and induce the ICD cascade but also to trigger the on-demand release of TLR agonists. In several preclinical cancer models, intravenous PNA administration followed by NIR tumor irradiation resulted in remarkable tumor regression and suppressed postsurgical tumor recurrence and metastasis. Furthermore, this treatment profoundly shifted the tumor immune landscape to a tumoricidal one, eliciting robust tumor-specific T cell priming in vivo. This work highlights a simple and cost-effective approach to generate in situ cancer vaccines for synergistic photodynamic immunotherapy of metastatic cancers.

MZINBVA: variational approximation for multilevel zero-inflated negative-binomial models for association analysis in microbiome surveys.

As our understanding of the microbiome has expanded, so has the recognition of its critical role in human health and disease, thereby emphasizing the importance of testing whether microbes are associated with environmental factors or clinical outcomes. However, many of the fundamental challenges that concern microbiome surveys arise from statistical and experimental design issues, such as the sparse and overdispersed nature of microbiome count data and the complex correlation structure among samples. For example, in the human microbiome project (HMP) dataset, the repeated observations across time points (level 1) are nested within body sites (level 2), which are further nested within subjects (level 3). Therefore, there is a great need for the development of specialized and sophisticated statistical tests. In this paper, we propose multilevel zero-inflated negative-binomial models for association analysis in microbiome surveys. We develop a variational approximation method for maximum likelihood estimation and inference. It uses optimization, rather than sampling, to approximate the log-likelihood and compute parameter estimates, provides a robust estimate of the covariance of parameter estimates and constructs a Wald-type test statistic for association testing. We evaluate and demonstrate the performance of our method using extensive simulation studies and an application to the HMP dataset. We have developed an R package MZINBVA to implement the proposed method, which is available from the GitHub repository https://github.com/liudoubletian/MZINBVA.

Development and validation of a clinical-radiomics model for prediction of prostate cancer: a multicenter study.

PURPOSE: To develop an early diagnosis model of prostate cancer based on clinical-radiomics to improve the accuracy of imaging diagnosis of prostate cancer. METHODS: The multicenter study enrolled a total of 449 patients with prostate cancer from December 2017 to January 2022. We retrospectively collected information from 342 patients who underwent prostate biopsy at Minhang Hospital. We extracted T2WI images through 3D-Slice, and used mask tools to mark the prostate area manually. The radiomics features were extracted by Python using the "Pyradiomics" module. Least Absolute Shrinkage and Selection Operator (LASSO) regression was used for data dimensionality reduction and feature selection, and the radiomics score was calculated according to the correlation coefficients. Multivariate logistic regression analysis was used to develop predictive models. We incorporated the radiomics score, PI-RADS, and clinical features, and this was presented as a nomogram. The model was validated using a cohort of 107 patients from the Xuhui Hospital. RESULTS: In total, 110 effective radiomics features were extracted. Finally, 9 features were significantly associated with the diagnosis of prostate cancer, from which we calculated the radiomics score. The predictors contained in the individualized prediction nomogram included age, fPSA/tPSA, PI-RADS, and radiomics score. The clinical-radiomics model showed good discrimination in the validation cohort (C-index = 0.88). CONCLUSION: This study presents a clinical-radiomics model that incorporates age, fPSA/PSA, PI-RADS, and radiomics score, which can be conveniently used to facilitate individualized prediction of prostate cancer before prostate biopsy.

Renal anatomical classification systems cannot predict the occurrence of vascular complications after partial nephrectomy.

OBJECTIVES: To determine the relationship between renal tumor complexity and vascular complications after partial nephrectomy using PADUA, RENAL, and ZS scores. METHODS: Between January 2007 and December 2018, a total of 1917 patients with available cross-sectional imaging were enrolled in the study. Logistic regressions were used to identify independent predictors of vascular complications. RESULTS: Of 1917 patients, 31 (1.6%) developed vascular complications, including 10 females and 21 males. The high-complexity category was significantly associated with a decreased risk of vascular complication in PADUA (OR = 0.256; 95%CI = 0.086-0.762; P = 0.014) and ZS score (OR = 0.279; 95%CI = 0.083-0.946; P = 0.040). Laparoscopic partial nephrectomy and robot-assisted laparoscopic partial nephrectomy were independent risk factors for vascular complications. Meanwhile, the incidence was significantly reduced in the recent 4 years in the high score tumor group alone in PADUA (0.2% [1/474] vs. 2.2% [3/139], P = 0.038) and ZS score (0.2% [1/469] vs. 2.7% [3/112], P = 0.024). In the first 8 years, laparoscopic partial nephrectomy and robot-assisted laparoscopic partial nephrectomy were the only two independent risk factors for vascular complications. In the recent 4 years, only the high-complexity category was significantly associated with a decreased risk of vascular complication in the PADUA score (OR = 0.110; 95%CI = 0.013-0.938; P = 0.044). CONCLUSION: The renal anatomic classification system cannot predict the occurrence of vascular complications after partial nephrectomy.

Deoxynivalenol induces m6A-mediated upregulation of p21 and growth arrest of mouse hippocampal neuron cells in vitro.

Hippocampal neurons maintain the ability of proliferation throughout life to support neurogenesis. Deoxynivalenol (DON) is a mycotoxin that exhibits brain toxicity, yet whether and how DON affects hippocampal neurogenesis remains unknown. Here, we use mouse hippocampal neuron cells (HT-22) as a model to illustrate the effects of DON on neuron proliferation and to explore underlying mechanisms. DON exposure significantly inhibits the proliferation of HT-22 cells, which is associated with an up-regulation of cell cycle inhibitor p21 at both mRNA and protein levels. Global and site-specific m6A methylation levels on the 3'UTR of p21 mRNA are significantly increased in response to DON treatment, whereas inhibition of m6A hypermethylation significantly alleviates DON-induced cell cycle arrest. Further mechanistic studies indicate that the m6A readers YTHDF1 and IGF2BP1 are responsible for m6A-mediated increase in p21 mRNA stability. Meanwhile, 3'UTR of E3 ubiquitin ligase TRIM21 mRNA is also m6A hypermethylated, and another m6A reader YTHDF2 binds to the m6A sites, leading to decreased TRIM21 mRNA stability. Consequently, TRIM21 suppression impairs ubiquitin-mediated p21 protein degradation. Taken together, m6A-mediated upregulation of p21, at both post-transcriptional and post-translational levels, contributes to DON-induced inhibition of hippocampal neuron proliferation. These results may provide new insights for epigenetic therapy of neurodegenerative diseases.

Peroral endoscopic myotomy is an effective treatment for achalasia combined with hiatal hernia.

PURPOSE: To explore the feasibility of peroral endoscopic myotomy (POEM) in patients with achalasia and hiatal hernia. MATERIALS AND METHODS: We performed a retrospective review of 2136 patients with achalasia between January 2016 and December 2022. Patients with achalasia and hiatal hernia were assigned into study group, and matched patients with achalasia but no hiatal hernia were assigned into control group. The preoperative baseline information, procedure-related adverse events (AEs) and follow-up data were compared between the two groups. RESULTS: Hiatal hernia was identified in 56/1564 (3.6%) patients with achalasia. All of these patients underwent POEM with success. The preoperative baseline characteristics were similar between the study and control group. The study group presented with a similar rate of mucosal injury (12.5% vs 16.1, P = 0.589), pneumothorax (3.6% vs 1.8%, P = 1.000), pleural effusion (8.9% vs 12.5%, P = 0.541) and major AEs (1.8% vs 1.8%, P = 1.000) compared with the control group. As for the follow-up data, no significant differences were observed in clinical success (96.4% vs 92.9%, P = 0.679; 93.6% vs 94.0%, P = 1.000; 86.5% vs 91.4%, P = 0.711) clinical reflux (25.0% vs 19.6%, P = 0.496; 31.9% vs 26.0%, P = 0.521; 35.1% vs 31.4%, P = 0.739) and proton pump inhibitor usage (17.9% vs 16.1%, P = 0.801; 29.8% vs 24.0%, P = 0.520; 32.4% vs 25.7%, P = 0.531) between the study group and control group at 1-year, 2-year and 3-year follow-ups. CONCLUSIONS: POEM is a safe and effective treatment for achalasia combined with hiatal hernia.

Evaluation of the safety and efficacy of perform enterectomy in colorectal cancer patients aged 80 or older. A meta-analysis and a systematic review.

BACKGROUND: Colorectal cancer (CRC) is one of the four most common cancers in the world. At present, human beings have stepped into an aging society, and the number of over eighties colorectal cancer patients has increased year by year. However, few high-quality studies focused on the post-operation complications and long-term outcomes of octogenarian patients with colorectal cancer. This meta-analysis, based on published studies, aims to assess the safety of treating octogenarian CRC patients with surgery. METHODS: Databases, including PubMed, Embase, and Cochrane Library were searched until July 2022. The incidence of preoperative comorbidities, postoperative complications, and mortality was assessed using odds ratios (ORs) with corresponding 95% confidence intervals (CIs). Furthermore, the hazard ratios (HRs) with 95% CIs were applied for survival outcomes. RESULTS: A total of 13,790 patients with CRC in 21 studies were included. Our results demonstrated that octogenarian patients were associated with a higher burden of comorbidities (OR = 3.03; 95% CI: 2.03, 4.53; P = .000), high incidences of overall postoperative complications (OR = 1.63; 95% CI: 1.29, 2.06; P = .000), high internal medicine postoperative complications (OR = 2.38; 95% CI: 1.76, 3.21; P = .000), high in-hospital mortality (OR = 4.01; 95% CI: 3.06, 5.27; P = .000) and poor overall survival (OR = 2.13; 95% CI: 1.78, 2.55; P = .000). But there is no statistical difference in surgery-related postoperative complications(OR = 1.16; 95% CI: 0.94, 1.43; P = .16) and DFS (OR = 1.03; 95% CI: 0.83, 1.29; P = .775). CONCLUSIONS: Extremely elderly patients with colorectal cancer have the high burden of comorbidities, high postoperative complications and mortality. However, survival outcomes (DFS) in patients 80 years and older are similar to younger patients. Clinicians should administer individualized treatment for such patients. Physiologic age rather than chronological age should determine cancer management for each individual.

Circ_0020123, a New Circular RNA Biomarker for Deep Vein Thrombosis in Pregnant Women.

BACKGROUND: Deep vein thrombosis (DVT) commonly occurs among vascular diseases globally, for which circular RNAs (circRNAs) are becoming a promising option by mediating functions of human umbilical vein endothelial cells (HUVECs). Therefore, this study focuses on whether circ_0020123 plays a role in HUVECs. METHODS: Pregnant women with DVT (n = 39) and without DVT (n = 39) were selected as the observation group and control group, respectively. Circ_0020123 expression in serum of pregnant women with DVT was assessed by RT-qPCR. The risk factors of DVT in pregnant women were analyzed by single factor logistic regression. HUVECs were treated with oxidized low-density lipoprotein (ox-LDL) to construct an in vitro model. Cell proliferation, tube formation ability, migration, and apoptosis were determined by cell counting kit-8, tube formation assay, Transwell assay, and flow cytometry. The levels of oxidative stress, inflammatory factors, endothelin-1 (ET-1), and von Willebrand factor (VWF) in cell supernatant were detected. RESULTS: The mode of delivery (cesarean delivery), postpartum hemorrhage (yes), puerperal bedtime (> 72 hours), and increased circ_0020123 were independent risk factors for DVT in pregnant women. Knockdown of circ_0020123 promoted HUVEC proliferation and angiogenesis in vitro. CONCLUSIONS: Clinical analysis of risk factors for DVT in pregnant women and positive measures for prevention can effectively avoid the formation of DVT. Circ_0020123 is a new circRNA biomarker for DVT in pregnant women.

Preliminary Exploration of the Application of Vesical Imaging-Reporting and Data System (VI-RADS) in Post-treatment Patients With Bladder Cancer: A Prospective Single-Center Study.

BACKGROUND: Vesical Imaging-Reporting and Data System (VI-RADS) has been shown to be effective in diagnosing muscle invasion of bladder cancer (BC) in primary patients. PURPOSE: To evaluate the diagnostic efficacy of VI-RADS in a BC target population which included post-treatment patients, and to determine the repeatability. STUDY TYPE: Prospective. POPULATION: Seventy-three patients (42 with primary BC, 31 with post-treatment BC). FIELD STRENGTH/SEQUENCE: 3.0 T MRI with propeller fast spin-echo T2 WI, echo planer imaging diffusion-weighted imaging (DWI), and dynamic contrast-enhanced imaging (DCEI). ASSESSMENT: VI-RADS scores were independently assessed by five radiologists with different levels of experience. The diagnostic efficiency in each group (primary and post-treatment) and of each radiologist was assessed. STATISTICAL TESTS: Sensitivity, specificity, positive predictive value (PPV), and negative predictive value (NPV), and area under the curve (AUC) in receiver operating characteristic curve analysis were calculated to evaluate VI-RADS diagnostic performance. Interobserver agreement was assessed using weighted Kappa statistics. A P value <0.05 was considered statistically significant. RESULTS: At the corresponding cut-off, AUC values of three groups range from 0.936 to 0.947 and AUC values of five observers range from 0.901 to 0.963. There was no significant difference between the AUCs in the primary and post-treatment groups (P = 0.870). The cut-off of the whole group and the post-treatment group was ≥4, and the cut-off of the primary group was ≥3. The Kappa values of interobserver agreements range from 0.709 to 0.923. CONCLUSIONS: After expanding the target population to include post-treatment patients, VI-RADS still has good diagnostic efficacy and repeatability. VI-RADS could potentially be a preoperative staging tool for post-treatment patients. LEVEL OF EVIDENCE: 1 TECHNICAL EFFICACY STAGE: 2.

Does intraoperative cyst rupture of malignant cystic renal masses really have no negative impact on oncologic outcomes?

BACKGROUND: To assess the impact of malignant cystic renal masses (CRM) rupture on oncologic outcomes. METHODS: The study included 406 cases with partial nephrectomy (PN) and 17 cases with cyst decortication confirmed as malignant CRM by pathology. Recurrence-free survival (RFS), metastasis-free survival (MFS), cancer-specific survival (CSS), and overall survival (OS) were analyzed by the Kaplan-Meier method and log-rank test. Cox regression was used to identify risk factors associated with RFS, MFS, CSS, and OS. Logistic regression was performed to explore predictors of rupture. RESULTS: Tumor rupture occurred in 32 of 406 cases (7.9%). With median follow-up of 43 months, 4 (12.5%) and 5 (1.3%) cases experienced recurrence in rupture and non-rupture group, respectively (P = 0.003). Estimated RFS, MFS, and CSS were shorter in cyst ruptured (CR) group than non-ruptured (nonCR) cases (P < 0.001; P = 0.001; P < 0.001). Cox regression analysis indicated that CR was an independent prognostic factor for RFS (HR = 7.354; 95% CI = 1.839-29.413; P = 0.005), MFS (HR = 8.069; 95% CI = 1.804-36.095; P = 0.006), and CSS (HR = 9.643; 95% CI = 2.183-42.599; P = 0.003). Multivariable logistic regression showed that Bosniak IV was a protective factor for CR (OR = 0.065; 95% CI = 0.018-0.239; P < 0.001). However, compared to Bosniak III and I-IIF, Bosniak IV CRMs showed higher rate of clear cell renal cell carcinoma (ccRCC) (76.8% vs 36.5% vs 81.4%) (P < 0.001) and lower rate of Fuhrman I staging (11.2% vs 66.7% vs 7.4%) (P < 0.001). Therefore, in ruptured cases, the recurrence rate was higher in CRM with Bosniak IV (50%, 2/4) than Bosniak I-III (4.4%, 2/45) (P = 0.029). CONCLUSIONS: Intraoperative malignant CRM rupture had negative impacts on oncologic outcomes. Bosniak IV was more aggressive than Bosniak I-III and had a higher risk of recurrence after rupture. However, Bosniak IV had a lower risk of rupture, which could weaken even cover-up of the true effect of tumor rupture on oncologic outcomes.

Automatic detection of significant areas for functional data with directional error control.

In this paper, we propose a large-scale multiple testing procedure to find the significant sub-areas between two samples of curves automatically. The procedure is optimal in that it controls the directional false discovery rate at any specified level on a continuum asymptotically. By introducing a nonparametric Gaussian process regression model for the two-sided multiple test, the procedure is computationally inexpensive. It can cope with problems with multidimensional covariates and accommodate different sampling designs across the samples. We further propose the significant curve/surface, giving an insight on dynamic significant differences between two curves. Simulation studies demonstrate that the proposed procedure enjoys superior performance with strong power and good directional error control. The procedure is also illustrated with the application to two executive function studies in hemiplegia.

Responses of bladder smooth muscle to the stretch go through extracellular signal-regulated kinase (ERK)/p90 ribosomal S6 protein kinase (p90RSK)/Nuclear factor-κB (NF-κB) Pathway.

AIMS: The present study was designed to study changes and its potential mechanisms in human bladder smooth muscle subjected to stretch. METHODS: Bioinformatics analyses including differential expression analysis, overrepresentation enrichment analysis, principal component analysis, and weighted gene coexpression network analysis were used to analyze a microarray dataset (GSE47080) of partial bladder outlet obstruction (pBOO) in rat to find the potential changes of gene expressions. Bladder from pBOO model and human bladder smooth muscle cells (HBSMCs) subjected to sustained prolonged stretch were collected for Western blot analysis, real-time polymerase chain reaction, and fluorescence analysis to verify the changes of gene expressions and preliminarily study the potential role of signaling pathway regulation in treatment of pBOO. RESULTS: The bioinformatics analysis showed that chronic obstruction activated mitogen-activated protein kinase pathway and changed cytoskeleton structure in bladder smooth muscle. In in vivo experiments in mice, pBOO was verified by cystometry. Partial BOO activated the extracellular signal-regulated kinase (ERK)/p90 ribosomal S6 protein kinase (p90RSK)/nuclear factor-κB (NF-κB) signaling pathway in DM. The messenger RNA (mRNA) expressions of contractile phenotypic proteins increased after pBOO. In in vitro experiments of HBSMCs, mechanical stretch activated ERK/p90RSK/NF-κB in HBSMCs in a time-dependent manner. The mRNA expressions of α-smooth muscle actin and SM22 also increased and filamentous actin (F-actin) polymerization was enhanced as well. Inhibition of ERK/p90RSK/NF-κB pathway reversed mechanical stretch-induced changes of contractile phenotypic expression and F-action polymerization. CONCLUSIONS: Continuous stretch increases expressions of contractile phenotypic proteins and promotes the polymerization of F-actin. This process partially goes through ERK/p90RSK/NF-κB pathway.

Preliminary evaluation for Bit1 as a potential biomarker for squamous cell carcinoma and adenocarcinoma of esophagus.

Mounting evidence has demonstrated that Bit1 has been investigated as an etiological factor for certain cancers, including esophageal squamous cell carcinoma reported in our previous study, but data regarding possible roles of Bit1 in esophageal squamous cell carcinoma and esophageal adenocarcinoma remain to be elucidated. The purpose of this study was to examine whether Bit1 can be a novel diagnostic marker for the patients with esophageal squamous cell carcinoma and esophageal adenocarcinoma. The results revealed that Bit1 level in esophageal squamous cell carcinoma was significantly higher than that in esophageal adenocarcinoma tissues ( p < 0.05); notably, Bit1 level in esophageal adenocarcinoma tissues was lower than that in paired normal tissues but no difference was found ( p > 0.05). Bit1 expression patterns were completely in accordance with matrix metalloproteinase 2 and Bcl-2 in esophageal squamous cell carcinoma and esophageal adenocarcinoma. In addition, Bit1, Bcl-2, and matrix metalloproteinase 2 expression patterns in different differentiated esophageal squamous cell carcinoma were higher than those in corresponding normal esophageal tissues. Bit1 expression in poorly differentiated esophageal squamous cell carcinoma was significantly higher than that in normal esophageal tissues ( p < 0.05) but not in moderately and well-differentiated esophageal squamous cell carcinoma. Matrix metalloproteinase 2 expression patterns in poorly and moderately differentiated esophageal squamous cell carcinoma were significantly higher than those in corresponding normal esophageal tissues ( p < 0.01) but not in well-differentiated esophageal squamous cell carcinoma tissue ( p > 0.05). Bcl-2 expression patterns in various differentiated esophageal squamous cell carcinoma were higher than those in corresponding normal esophageal tissues with no statistical differences ( p > 0.05). Importantly, Bit1 expression was positively correlated with both matrix metalloproteinase 2 and Bcl-2 expression in esophageal squamous cell carcinoma and esophageal adenocarcinoma tissues ( p < 0.05). Collectively, these preliminary data support further investigation of Bit1 as an important diagnostic factor for esophageal squamous cell carcinoma and esophageal adenocarcinoma.

Bit1 knockdown contributes to growth suppression as well as the decreases of migration and invasion abilities in esophageal squamous cell carcinoma via suppressing FAK-paxillin pathway.

BACKGROUND: There is growing evidence that Bit1 exerts different roles in the development and progression of human cancers. Although Bit1 was highly exhibited in ESCC tissues in our previous study, its roles and molecular mechanisms implicated in development and progression of ESCC remain unknown. METHODS: Bit1 protein expression in ESCC cell lines and normal esophageal epithelial cell was detected by Western blotting. Bit1 protein expression mediated by Bit1 shRNA was investigated by Western blotting. MTT, migration assay, invasion experiment, ELISA and Flow cytometry were utilized to determine the effects of Bit1 knockdown on cell proliferation, migration, invasion and apoptosis, respectively. A xenograft model was used to examine in vivo tumourigenicity, and immunohistochemistry and TUNEL were utilized to evaluate the related protein expression and apoptosis. Gene microarray was determined by Agilent SurePrint G3 Human GE 8 × 60 K Microarray, the interaction of Bit1 and FAK proteins were detected by Immunoprecipitation and the key protein expressions of FAK-paxillin pathway were detected by Western blotting. RESULTS: We found Bit1 expression in all human ESCC cell lines tested was significantly higher than that in normal esophageal epithelial cell Het-1A (P < 0.05), in which EC9706 presented the highest Bit1 level. Bit1 protein level was significantly downregulated at day 1 after transfection with specific shRNA against Bit1 (P < 0.05). At days 2 and 3, Bit1 level reached the lowest value after transfection with Bit1 shRNA. Moreover, Bit1 depletion contributed to growth inhibition in vitro and in vivo, reduced cell migration and invasion abilities, and induced cell apoptosis in EC9706 and TE1 cells. More importantly, Bit1 downregulation significantly lowered Bcl-2 and MMP-2 levels in EC9706 xenografted tumor tissues, meanwhile triggered apoptosis after treatment with different doses of Bit1 shRNA. Further gene microarray revealed that 23 genes in Bit1-RNAi group were markedly downregulated, whereas 16 genes were obviously upregulated. Notably, Bit1 intrinsically interacted with FAK protein in EC9706 cells. Moreover, paxillin was downregulated at mRNA and protein levels in Bit1 shRNA group, coupled with the decreases of FAK mRNA and protein expressions. CONCLUSION: Bit1 may be an important regulator in cell growth, apoptosis, migration and invasion of ESCC via targeting FAK-paxillin pathway, and thereby combinative manipulation of Bit1 and FAK-paxillin pathway may be the novel and promising therapeutic targets for the patients with ESCC.

Ultrahigh dimensional time course feature selection.

Statistical challenges arise from modern biomedical studies that produce time course genomic data with ultrahigh dimensions. In a renal cancer study that motivated this paper, the pharmacokinetic measures of a tumor suppressor (CCI-779) and expression levels of 12,625 genes were measured for each of 33 patients at 8 and 16 weeks after the start of treatments, with the goal of identifying predictive gene transcripts and the interactions with time in peripheral blood mononuclear cells for pharmacokinetics over the time course. The resulting data set defies analysis even with regularized regression. Although some remedies have been proposed for both linear and generalized linear models, there are virtually no solutions in the time course setting. As such, a novel GEE-based screening procedure is proposed, which only pertains to the specifications of the first two marginal moments and a working correlation structure. Different from existing methods that either fit separate marginal models or compute pairwise correlation measures, the new procedure merely involves making a single evaluation of estimating functions and thus is extremely computationally efficient. The new method is robust against the mis-specification of correlation structures and enjoys theoretical readiness, which is further verified via Monte Carlo simulations. The procedure is applied to analyze the aforementioned renal cancer study and identify gene transcripts and possible time-interactions that are relevant to CCI-779 metabolism in peripheral blood.

Reprogramming of arachidonic acid metabolism using α-terpineol to alleviate asthma: insights from metabolomics.

Asthma is a chronic inflammatory disorder in airways with typical pathologic features of airway inflammation and mucus hypersecretion. α-Terpineol is a monocyclic terpene found in many natural plants and foods. It has been reported to possess a wide range of pharmacological activities including anti-inflammatory and expectorant effects. However, the role of α-terpineol in asthma and its potential protective mechanism have not been well elucidated. This study is designed to investigate the pharmacological effect and mechanism of α-terpineol on asthmatic mice using the metabolomics platform. A murine model of asthma was established using ovalbumin (OVA) sensitization and then challenged for one week. The leukocyte count and inflammatory cytokines in the bronchoalveolar lavage fluid (BALF), lung histopathology, inflammatory  infiltrate and mucus secretion were evaluated. An ultra-high performance liquid chromatography-tandem mass spectrometry (UPLC-MS/MS)-based metabolomics study was performed on lung tissues and serum to explore endogenous small molecule metabolites affected by α-terpineol in asthmatic mice. After α-terpineol treatment, leukocyte count, inflammatory cytokines in the BALF, and peribronchial inflammation infiltration were significantly downregulated. Goblet cell hyperplasia and mucus secretion were attenuated, with the level of Muc5ac in BALF decreased. These results proved the protective effect of α-terpineol against airway inflammation, mucus hypersecretion and Th1/Th2 immune imbalance. To further investigate the underlying mechanisms of α-terpineol in asthma treatment, UPLC-MS/MS-based metabolomics analysis was performed. 26 and 15 identified significant differential metabolites were found in the lung tissues and serum of the control, model and α-terpineol groups, respectively. Based on the above differential metabolites, enrichment analysis showed that arachidonic acid (AA) metabolism was reprogrammed in both mouse lung tissues and serum. 5-Lipoxygenase (5-LOX) and cysteinyl leukotrienes (CysLTs) are the key enzyme and the end product of AA metabolism, respectively. In-depth studies have shown that pretreatment with α-terpineol can alleviate asthma by decreasing the AA level, downregulating the expression of 5-LOX and reducing the accumulation of CysLTs in mouse lung tissues. In summary, this study demonstrates that α-terpineol is a potential agent that can prevent asthma via regulating disordered AA metabolism.

Comparison of current treatment strategy for osteonecrosis of the femoral head from the perspective of cell therapy.

Aims: The purpose of our study is to compare the effects of core decompression (CD) and bone grafting (BG) on osteonecrosis of the femoral head (ONFH). And evaluate the efficacy of CD based on cell therapy to provide guidance for the dose and number of cells. Methods: We searched PubMed, Embase, and the Cochrane Library between 2012 and 2022, with keywords including "osteonecrosis of the femoral head", "core decompression" and "bone grafting". We selected comparative studies of CD and BG, and the comparison of CD combined with bone marrow (BM) transplantation and CD alone. Changes in hip pain were assessed by VAS, hip function were assessed by HHS and WOMAC, and THA conversion rate was used as an evaluation tool for femoral head collapse. From these three aspects, the dose of bone marrow and the number of cells transplantation were subgroup analyzed. Results: Eleven studies were used to compare the efficacy of CD and BG. There was no significant difference in HHS, and the THA conversion rate of BG was significantly lower than that of CD. Thirteen CD studies based on cell therapy were included in the meta-analysis. Bone marrow aspiration concentrate (BMAC) can significantly improve VAS (mean difference (MD), 10.15; 95% confidence intervals (CI) 7.35 to 12.96, p < 0.00001) and reduce THA conversion rate (odds ratio (OR), 2.38; 95% CI 1.26 to 4.47, p = 0.007). Medium dose bone marrow fluid has a lower p-value in THA conversion rate. The p values of bone marrow mononuclear cells (BMMC) of 109 magnitude in VAS score were lower. Conclusion: In general, there is no consensus on the use of BG in the treatment of ONFH. The enhancement of cell-based CD procedure shows promising results. Using 20 mL BMAC and 109 magnitude BMMC is likely to achieve better results.

Factors influencing the e-health literacy in cancer patients: a systematic review.

PURPOSE: As Internet technology evolves, electronic health (e-health) literacy gradually becomes a key factor in healthy behaviors and health-related decision-making. However, little is known about the influencing factors of e-health literacy among cancer survivors. Thus, the objective of this study was to systematically review the status quo, assessment tools, and influencing factors of e-health literacy in cancer patients. METHODS: We conducted a comprehensive search in several databases, including PubMed, MEDLINE, Embase, CINAHL, PsycInfo, Cochrane Library, China National Knowledge Infrastructure, Wanfang Database, Chinese BioMedical Literature Database, and Chinese Science and Technology Journal Database between January 2000 and December 2021. RESULTS: A total of nine articles were included in this review, all of which were cross-sectional studies. Following the JBI critical appraisal tool, seven of them were rated as high quality. The e-Health Literacy Scale (eHEALS) was the most commonly used measurement for e-health literacy in cancer patients. The level of e-health literacy in cancer survivors was not high, which was associated with a variable of factors. The behavioral model of health services use was adopted to summarize related influencing factors. From an individual's perspective, predisposing characteristics and enabling resources were the most significant factors, without factors related to needs characteristics. CONCLUSION: The study has identified the influencing factors of e-health literacy among cancer survivors, including age, gender, domicile place, education level, information-seeking behavior, and social support. In the future, e-health literacy lectures need to be carried out for elderly cancer patients, especially those who live in rural areas and have no access to the Internet. Families and friends of cancer survivors should also be encouraged to offer them more support. IMPLICATIONS FOR CANCER SURVIVORS: These findings of this review provide novel insights for both family members and medical workers to improve e-health literacy in cancer patients. Further research is required to develop easy-to-use electronic health information acquisition devices and establish propagable e-health literacy intervention programs for cancer survivors.

Predictive Factors for Acute Kidney Injury and Long-Term Renal Function Loss After Partial Nephrectomy: A Prospective Single-Center Study.

OBJECTIVE: To find factors related to postoperative acute kidney injury and long-term significant renal function (RF) loss after partial nephrectomy (PN) in Chinese population. METHODS: The main outcome was significant RF loss during the last follow-up, which was defined as >25% decrease in estimated glomerular filtration rate. RESULTS: A total of 416 patients were included with median age as 57 (interquartile ranges,IQR 49.8-65.0) year with body mass index as 24.2 (IQR 22.0-26.5) kg/m2 and preoperative estimated glomerular filtration rate as 90.5 (IQR 79.8-101) mL/min. Summarily, 259 (62.3%) patients were male, 54 (13%) had diabetes, 180 (43.3%) hypertension and 80 (19.2%) hyperuricemia. Median (IQR) tumor diameter was 3.1 (2.4-4.1) cm. All patients underwent PN, in which 135 (32.5%) by open PN approach, 109 (26.2%) by laparoscopic PN and 172 (41.3%) by robot assisted PN. RF was followed up for 16.88 (10.15-36.37) months, where 58 (13.9%) patients suffered significant RF loss. Multivariable analysis showed age (P = .0039), body mass index (P = .0049), diabetes (P = .0351), operative time > 110 minutes (P = .0034), diameter classification by Diameter-Axial-Polar score (diameter 2.4 cm-4.4 cm, P = .0225: diameter > 4.4 cm, P = .0207), postoperative acute kidney injury (P < .001) to be predictors of RF loss with area under the curve as 0.850. CONCLUSION: We prospectively found predictive factors of short and long-term significant RF loss in all operative methods and constructed a clinical nomogram for long-term Chinese patients RF loss.