Targeting undruggable phosphatase overcomes trastuzumab resistance by inhibiting multi-oncogenic kinases.

AIMS: Resistance to targeted therapy is one of the critical obstacles in cancer management. Resistance to trastuzumab frequently develops in the treatment for HER2+ cancers. The role of protein tyrosine phosphatases (PTPs) in trastuzumab resistance is not well understood. In this study, we aim to identify pivotal PTPs affecting trastuzumab resistance and devise a novel counteracting strategy. METHODS: Four public datasets were used to screen PTP candidates in relation to trastuzumab responsiveness in HER2+ breast cancer. Tyrosine kinase (TK) arrays were used to identify kinases that linked to protein tyrosine phosphate receptor type O (PTPRO)-enhanced trastuzumab sensitivity. The efficacy of small activating RNA (saRNA) in trastuzumab-conjugated silica nanoparticles was tested for PTPRO upregulation and resistance mitigation in cell models, a transgenic mouse model, and human cancer cell line-derived xenograft models. RESULTS: PTPRO was identified as the key PTP which influences trastuzumab responsiveness and patient survival. PTPRO de-phosphorated several TKs, including the previously overlooked substrate ERBB3, thereby inhibiting multiple oncogenic pathways associated with drug resistance. Notably, PTPRO, previously deemed "undruggable," was effectively upregulated by saRNA-loaded nanoparticles. The upregulated PTPRO simultaneously inhibited ERBB3, ERBB2, and downstream SRC signaling pathways, thereby counteracting trastuzumab resistance. CONCLUSIONS: Antibody-conjugated saRNA represents an innovative approach for targeting "undruggable" PTPs.

Folylpolyglutamate synthetase inactivation in relapsed ALL induces a druggable folate metabolic vulnerability.

AIMS: The antifolate methotrexate (MTX) is an anchor drug used in acute lymphoblastic leukemia (ALL) with poorly understood chemoresistance mechanisms in relapse. Herein we find decreased folate polyglutamylation network activities and inactivating FPGS mutations, both of which could induce MTX resistance and folate metabolic vulnerability in relapsed ALL. METHODS: We utilized integrated systems biology analysis of transcriptomic and genomic data from relapse ALL cohorts to infer hidden ALL relapse drivers and related genetic alternations during clonal evolution. The drug sensitivity assay was used to determine the impact of relapse-specific FPGS mutations on sensitivity to different antifolates and chemotherapeutics in ALL cells. We used liquid chromatography-mass spectrometry (LC-MS) to quantify MTX and folate polyglutamate levels in folylpoly-γ-glutamate synthetase (FPGS) mutant ALL cells. Enzymatic activity and protein degradation assays were also conducted to characterize the catalytic properties and protein stabilities of FPGS mutants. An ALL cell line-derived mouse leukemia xenograft model was used to evaluate the in vivo impact of FPGS inactivation on leukemogenesis and sensitivity to the polyglutamatable antifolate MTX as well as non-polyglutamatble lipophilic antifolate trimetrexate (TMQ). RESULTS: We found a significant decrease in folate polyglutamylation network activities during ALL relapse using RNA-seq data. Supported by functional evidence, we identified multifactorial mechanisms of FPGS inactivation in relapsed ALL, including its decreased network activity and gene expression, focal gene deletion, impaired catalytic activity, and increased protein degradation. These deleterious FPGS alterations induce MTX resistance and inevitably cause marked intracellular folate shrinkage, which could be efficiently targeted by a polyglutamylation-independent lipophilic antifolate TMQ in vitro and in vivo. CONCLUSIONS: MTX resistance in relapsed ALL relies on FPGS inactivation, which inevitably induces a folate metabolic vulnerability, allowing for an efficacious antifolate ALL treatment strategy that is based upon TMQ, thereby surmounting chemoresistance in relapsed ALL.

Characterization and trajectories of hematological parameters prior to severe COVID-19 based on a large-scale prospective health checkup cohort in western China: a longitudinal study of 13-year follow-up.

BACKGROUND: The relaxation of the "zero-COVID" policy on Dec. 7, 2022, in China posed a major public health threat recently. Complete blood count test was discovered to have complicated relationships with COVID-19 after the infection, while very few studies could track long-term monitoring of the health status and identify the characterization of hematological parameters prior to COVID-19. METHODS: Based on a 13-year longitudinal prospective health checkup cohort of ~ 480,000 participants in West China Hospital, the largest medical center in western China, we documented 998 participants with a laboratory-confirmed diagnosis of COVID-19 during the 1 month after the policy. We performed a time-to-event analysis to explore the associations of severe COVID-19 patients diagnosed, with 34 different hematological parameters at the baseline level prior to COVID-19, including the whole and the subtypes of white and red blood cells. RESULTS: A total of 998 participants with a positive SARS-CoV-2 test were documented in the cohort, 42 of which were severe cases. For white blood cell-related parameters, a higher level of basophil percentage (HR = 6.164, 95% CI = 2.066-18.393, P = 0.001) and monocyte percentage (HR = 1.283, 95% CI = 1.046-1.573, P = 0.017) were found associated with the severe COVID-19. For lymphocyte-related parameters, a lower level of lymphocyte count (HR = 0.571, 95% CI = 0.341-0.955, P = 0.033), and a higher CD4/CD8 ratio (HR = 2.473, 95% CI = 1.009-6.059, P = 0.048) were found related to the risk of severe COVID-19. We also observed that abnormality of red cell distribution width (RDW), mean corpuscular hemoglobin concentration (MCHC), and hemoglobin might also be involved in the development of severe COVID-19. The different trajectory patterns of RDW-SD and white blood cell count, including lymphocyte and neutrophil, prior to the infection were also discovered to have significant associations with the risk of severe COVID-19 (all P < 0.05). CONCLUSIONS: Our findings might help decision-makers and clinicians to classify different risk groups of population due to outbreaks including COVID-19. They could not only optimize the allocation of medical resources, but also help them be more proactive instead of reactive to long COVID-19 or even other outbreaks in the future.

Rare variations within the serine/arginine-rich splicing factor PtoRSZ21 modulate stomatal size to determine drought tolerance in Populus.

Rare variants contribute significantly to the 'missing heritability' of quantitative traits. The genome-wide characteristics of rare variants and their roles in environmental adaptation of woody plants remain unexplored. Utilizing genome-wide rare variant association study (RVAS), expression quantitative trait loci (eQTL) mapping, genetic transformation, and molecular experiments, we explored the impact of rare variants on stomatal morphology and drought adaptation in Populus. Through comparative analysis of five world-wide Populus species, we observed the influence of mutational bias and adaptive selection on the distribution of rare variants. RVAS identified 75 candidate genes correlated with stomatal size (SS)/stomatal density (SD), and a rare haplotype in the promoter of serine/arginine-rich splicing factor PtoRSZ21 emerged as the foremost association signal governing SS. As a positive regulator of drought tolerance, PtoRSZ21 can recruit the core splicing factor PtoU1-70K to regulate alternative splicing (AS) of PtoATG2b (autophagy-related 2). The rare haplotype PtoRSZ21hap2 weakens binding affinity to PtoMYB61, consequently affecting PtoRSZ21 expression and SS, ultimately resulting in differential distribution of Populus accessions in arid and humid climates. This study enhances the understanding of regulatory mechanisms that underlie AS induced by rare variants and might provide targets for drought-tolerant varieties breeding in Populus.

Exploring the impact of gut microbiota on abdominal aortic aneurysm risk through a bidirectional Mendelian randomization analysis.

OBJECTIVE: The abdominal aortic aneurysm (AAA) is associated with alterations in the composition of the gut microbiota; however, the precise causal relationship remains unclear. Elucidating this complex interplay could provide new insights into the pathogenesis of AAA. METHODS: A bidirectional two-sample Mendelian randomization analysis was conducted using genome-wide association study summary data on the gut microbiota (n = 18,340) and AAA (n = 353,087). A total of 196 gut microbial taxa across taxonomic levels were examined for their potential causal effects on AAA risk. Conversely, the effect of AAA on these microbial taxa was also analyzed. RESULTS: Nine microbial taxa were identified as having a causal influence on AAA risk. Specifically, increased risk were associated with genus Bilophila (odds ratio [OR], 1.359; P = .0119), genus Catenibacterium (OR, 1.348; P = .0058), genus family XIII AD3011 group (OR, 1.507; P = .004), genus Oxalobacter (OR, 1.157; P = .0449), and genus Prevotella 7 (OR, 1.194; P = .0306), whereas decreased risks were linked to class Lentisphaeria (OR, 0.829; P = .0361), order Victivallales (OR, 0.829; P = .0361), family Victivallaceae (OR, 0.814; P = .0057), and genus Anaerotruncus (OR, 0.773; P = .0497). Furthermore, AAA was found to influence the abundance of 14 microbial taxa across various taxonomic levels. Notably, bidirectional associations were observed with the class Lentisphaeria and the order Victivallales. CONCLUSIONS: This study provides novel evidence for a reciprocal causal relationship between gut microbiota and AAA risk, thereby offering new insights into the pathogenesis of AAA. These findings also suggest promising avenues for microbiome-based therapeutic interventions.

Time-dependent risk of fracture in adults with type 2 diabetes receiving anti-diabetic drug: A one-stage network meta-analysis.

AIMS: To assess the time-dependent risk of fracture in adults with type 2 diabetes receiving anti-diabetic drugs. MATERIALS AND METHODS: We searched MEDLINE, EMBASE, and Cochrane Library up to 18 November 2021, for randomized controlled trials (RCTs) and propensity-score-matched non-randomized studies (NRSs) comparing all anti-diabetic drugs with standard treatment or with each other on fracture in adults with type 2 diabetes. The study performed a one-stage network meta-analysis using discrete-time hazard regression with reconstructed individual time-to-event data. RESULTS: This network meta-analysis involved seven RCTs (65,051 adults with type 2 diabetes) with a median follow-up of 36 months and three propensity-score-based NRSs (17,954 participants) with a median follow-up of 27.3 months. Among anti-diabetic drugs, thiazolidinediones increased the overall hazard of fracture by 42% (95% credible interval [CrI], 3%-97%) and almost tripled the risk after 4 years (hazard ratio [HR], 2.74; 95% CrI, 1.53-4.80). Credible subgroup analysis suggested that thiazolidinediones increased the hazard of fracture only in females (HR, 2.19; 95% CrI, 1.26-3.74) but not among males (HR, 0.81; 95% CrI, 0.45-1.40). Moderate certainty evidence established that thiazolidinediones increase 92 fractures in five years per 1000 female patients. We did not find the risk of fractures with other anti-diabetic drugs including metformin, sulfonylureas, sodium-glucose cotransporter-2 (SGLT2) inhibitors, and dipeptidyl peptidase-4 (DPP-4) inhibitors. CONCLUSIONS: Long-term use of thiazolidinediones elevates the risk of fracture among females with type 2 diabetes. There is no evidence eliciting fracture risk associated with other anti-diabetic drugs.

Association between TB delay and TB treatment outcomes in HIV-TB co-infected patients: a study based on the multilevel propensity score method.

BACKGROUND: HIV-tuberculosis (HIV-TB) co-infection is a significant public health concern worldwide. TB delay, consisting of patient delay, diagnostic delay, treatment delay, increases the risk of adverse anti-TB treatment (ATT) outcomes. Except for individual level variables, differences in regional levels have been shown to impact the ATT outcomes. However, few studies appropriately considered possible individual and regional level confounding variables. In this study, we aimed to assess the association of TB delay on treatment outcomes in HIV-TB co-infected patients in Liangshan Yi Autonomous Prefecture (Liangshan Prefecture) of China, using a causal inference framework while taking into account individual and regional level factors. METHODS: We conducted a study to analyze data from 2068 patients with HIV-TB co-infection in Liangshan Prefecture from 2019 to 2022. To address potential confounding bias, we used a causal directed acyclic graph (DAG) to select appropriate confounding variables. Further, we controlled for these confounders through multilevel propensity score and inverse probability weighting (IPW). RESULTS: The successful rate of ATT for patients with HIV-TB co-infection in Liangshan Prefecture was 91.2%. Total delay (OR = 1.411, 95% CI: 1.015, 1.962), diagnostic delay (OR = 1.778, 95% CI: 1.261, 2.508), treatment delay (OR = 1.749, 95% CI: 1.146, 2.668) and health system delay (OR = 1.480 95% CI: (1.035, 2.118) were identified as risk factors for successful ATT outcome. Sensitivity analysis demonstrated the robustness of these findings. CONCLUSIONS: HIV-TB co-infection prevention and control policy in Liangshan Prefecture should prioritize early treatment for diagnosed HIV-TB co-infected patients. It is urgent to improve the health system in Liangshan Prefecture to reduce delays in diagnosis and treatment.

Gastrin-Releasing Peptide/Gastrin-Releasing Peptide Receptor Participation in Itch Sensation Signaling in the Spinal Cord of Uremic Pruritus Mice.

Background: Uremic pruritus is a prevalent clinical symptom in maintenance dialysis patients. Existing evidence establishes a connection between itch transmission and the gastrin-releasing peptide/gastrin-releasing peptide receptor signaling pathway. Objective: To investigate the involvement of the gastrin-releasing peptide/gastrin-releasing peptide receptor in itch sensation signaling within the spinal cord of uremic pruritus. Design: An animal study was conducted. Setting: The research was conducted at the First Hospital of Hebei Medical University. Participants: A total of 50 male C57BL/6J mice (weight: 30-40 g) were acquired from Beijing Weitonglihua Laboratory Animal Center. Interventions: Mice were categorized into five groups: normal, sham, Y, A, and B. The Y group received intrathecal injections of saline (5 ul). The A group received intrathecal injections of gastrin-releasing peptide (0.1 nmol, 5 ul), and the B group received intrathecal injections of the gastrin-releasing peptide receptor antagonist RC-3095 (0.3 mmol, 5 ul). Primary Outcome Measures: (1) Pruritus behavior of mice and (2) expression of gastrin-releasing peptide, gastrin-releasing peptide receptor, and inositol trisphosphate. Results: Scratching times in the Y group significantly surpassed those of normal and sham groups, increasing over time. Gastrin-releasing peptide and receptor expression rose in the uremic pruritus mouse model compared to normal and sham groups (P < .05). Expression of gastrin-releasing peptide and its receptor was significantly elevated in the uremic pruritus mouse model compared to the normal and sham groups (P < .05). Inositol trisphosphate expression in the dorsal spinal horn of Y group mice increased compared to normal and sham groups. Intrathecal gastrin-releasing peptide heightened inositol trisphosphate expression, while the peptide receptor antagonist RC-3095 reduced it. Y group scratching times were higher than normal and sham groups, increasing after intrathecal gastrin-releasing peptide but decreasing after RC-3095 injection. Conclusion: The gastrin-releasing peptide/gastrin-releasing peptide receptor signaling pathway is involved in the development of uremic pruritus.

Development of best performance evaluation indicators based on value-based healthcare for general hospital nursing: A Delphi study.

OBJECTIVE: To establish and validate a set of best nursing practice indicators for medical groups in Chinese general hospitals based on value-based healthcare (VBHC) theory. DESIGN: A modified Delphi method. METHODS: This study engaged experienced clinical nurses from public hospitals and multidisciplinary experts in operations management. Through a literature review and structured brainstorming, a comprehensive framework for assessing best nursing practices in Chinese general hospital medical groups was developed. A modified Delphi method was then employed to establish an indicator framework, followed by the Combined Empowerment-MABAC method to weight and validate the indicators using empirical data collected between June 2023 and October 2023. The CREDES checklist guided the reporting of this study. RESULTS: Sixteen experts, each with at least 10 years of experience in nurse management from nine healthcare organizations, participated in two rounds of consultation. The experts' responses and suggestions for rewording, deleting and adding items were incorporated into each round. Of the 34 proposed indicators, 25 were approved, covering healthcare service capacity, efficiency, quality and safety, patient experience and cost. CONCLUSION: The Delphi survey reached a consensus on necessary actions to improve nursing performance. The developed indicator system provides a foundational framework for standardizing the monitoring of care quality and performance assessment in Chinese clinical healthcare groups, with broad applicability. RELEVANCE TO CLINICAL PRACTICE: This study provides a reliable basis for developing a nursing performance assessment database, offering crucial insights for measuring quality of care and improving patient value. PATIENT OR PUBLIC CONTRIBUTION: No Patient or Public Contribution.

Impact of the uniaxial strain on terahertz modulation characteristics in flexible epitaxial VO2 film across the phase transition.

Exploring flexible electronics is on the verge of innovative breakthroughs in terahertz (THz) communication technology. Vanadium dioxide (VO2) with insulator-metal transition (IMT) has excellent application potential in various THz smart devices, but the associated THz modulation properties in the flexible state have rarely been reported. Herein, we deposited an epitaxial VO2 film on a flexible mica substrate via pulsed-laser deposition and investigated its THz modulation properties under different uniaxial strains across the phase transition. It was observed that the THz modulation depth increases under compressive strain and decreases under tensile strain. Moreover, the phase-transition threshold depends on the uniaxial strain. Particularly, the rate of the phase transition temperature depends on the uniaxial strain and reaches approximately 6 °C/% in the temperature-induced phase transition. The optical trigger threshold in laser-induced phase transition decreased by 38.9% under compressive strain but increased by 36.7% under tensile strain, compared to the initial state without uniaxial strain. These findings demonstrate the uniaxial strain-induced low-power triggered THz modulation and provide new insights for applying phase transition oxide films in THz flexible electronics.

Evaluating Upstaging in Ductal Carcinoma In Situ Using Preoperative MRI-Based Radiomics.

BACKGROUND: About 20%-40% of patients diagnosed with ductal carcinoma in situ (DCIS) by core needle biopsy (CNB) will develop invasive cancer at the time of excision. Improving the preoperative diagnosis of DCIS is important for surgical planning. PURPOSE: To establish an MRI-based radiomics nomogram for preoperatively evaluating the upstaging of DCIS patients and help with risk stratification. STUDY TYPE: Retrospective. POPULATION: A total of 227 patients (50.5 ± 9.7 years; 67 upstaged DCIS) were divided into training (n = 109), internal (n = 47), and external (n = 71) validation cohort. FIELD STRENGTH/SEQUENCE: 1.5-T or 3-T, dynamic contrast-enhanced (DCE) imaging, and diffusion-weighted imaging (DWI). ASSESSMENT: DCIS lesions were manually segmented using ITK-SNAP software and 1304 radiomic features were extracted from DCE, DWI, and apparent diffusion coef-ficient (ADC) maps, respectively. A radscore was calculated by a random forest algo-rithm based on DCIS upstaging-related radiomic features, which selected by a coarse-to-fine method including interclass correlation coefficient, single-factor anal-ysis, and the least absolute shrinkage and selection operator (LASSO) method. Uni-variate and multivariate logistic regression was used to analyze the independent risk factors, including age, location, lesion size, estrogen receptor (ER) status, and other clinico-pathologic factors. Finally, Mann-Whitney U tests were performed to com-pare the differences in radscore between low/intermediate and high nuclear grade groups for pure DCIS patients. STATISTICAL TESTS: Student's t-tests or Mann-Whitney U tests, chi-square-tests, or Fisher's-tests, univariate and multivariate logistic regression analysis, calibration curve, Youden index, the area under the curve (AUC), Delong test, net reclassification improvement (NRI), and integrated discrimination improvement (IDI) analyses. RESULTS: Eight important radiomic features (two from ADC, three from DWI, and three from DCE) were selected for calculating radscore. Clinical model including age and ER was established with AUCs of 0.747 and 0.738 in the internal and external validation cohorts, respectively. A combined model integrating age, estrogen receptor (ER), and radscore were also constructed with AUCs of 0.887 and 0.881. Further subgroup analysis showed that pure DCIS patients with different nuclear grade have significant differences in radscore. DATA CONCLUSION: Multisequence MRI radiomics may preoperatively evaluate the upstaging of DCIS and might provide personalized image-based clinical decision support. EVIDENCE LEVEL: 4. TECHNICAL EFFICACY: Stage 2.

Red/processed meat consumption and non-cancer-related outcomes in humans: umbrella review.

The associations of red/processed meat consumption and cancer-related health outcomes have been well discussed. The umbrella review aimed to summarise the associations of red/processed meat consumption and various non-cancer-related outcomes in humans. We systematically searched the systematic reviews and meta-analyses of associations between red/processed meat intake and health outcomes from PubMed, Embase, Web of Science and the Cochrane Library databases. The umbrella review has been registered in PROSPERO (CRD 42021218568). A total of 40 meta-analyses were included. High consumption of red meat, particularly processed meat, was associated with a higher risk of all-cause mortality, CVD and metabolic outcomes. Dose-response analysis revealed that an additional 100 g/d red meat intake was positively associated with a 17 % increased risk of type 2 diabetes mellitus (T2DM), 15 % increased risk of CHD, 14 % of hypertension and 12 % of stroke. The highest dose-response/50 g increase in processed meat consumption at 95 % confident levels was 1·37, 95 % CI (1·22, 1·55) for T2DM, 1·27, 95 % CI (1·09, 1·49) for CHD, 1·17, 95 % CI (1·02, 1·34) for stroke, 1·15, 95 % CI (1·11, 1·19) for all-cause mortality and 1·08, 95 % CI (1·02, 1·14) for heart failure. In addition, red/processed meat intake was associated with several other health-related outcomes. Red and processed meat consumption seems to be more harmful than beneficial to human health in this umbrella review. It is necessary to take the impacts of red/processed meat consumption on non-cancer-related outcomes into consideration when developing new dietary guidelines, which will be of great public health importance. However, more additional randomised controlled trials are warranted to clarify the causality.

Effects of dialysis modality on mortality in patients with end-stage renal disease: A cohort study.

METHODS: Using a retrospective 15-year cohort, stratified by age, this study aimed to analyze the effect of dialysis modality on mortality of ESRD patients in a city of China. Study data were from the medical insurance information system of Kunshan, Jiangsu Province of China, and 1484 patients with ESRD, enrolled from 1 January 2005 to 31 December 2019 were included in this study. The primary outcome event was all-cause mortality, which was calculated in months. Dialysis modalities included hemodialysis (HD) and peritoneal dialysis (PD). Survival analysis and competing-risk regression model were performed in this study. RESULTS: HD costs significantly higher medical expense than the PD treatment regimen. The mean survival time was 121.28 (SE = 3.020) months for HD patients, while that was 94.68 (SE = 3.534) months for the PD. Ten-year survival rates of the young, middle-aged, and elderly were 0.82, 0.56, and 0.26, respectively. For the young (SHR = 0.869, 95% CI: 0.525-1.436) and middle-aged (SHR = 0.715, 95% CI: 0.484-1.057) ESRD patients, different dialysis modalities exhibited no statistical significance on the survival, but for the elderly, HD had a lower risk of mortality than PD (SHR = 0.747, 95% CI: 0.581-0.961). CONCLUSION: Survival of the young and middle-aged ESRD patients was superior to that of the elderly. Considering both survival time and direct medical costs, we recommend that PD could be a better choice for young and middle-aged ESRD patients, while HD may be suitable for older patients.

The Underappreciated Placebo Effects and Responses in Randomized Controlled Trials on Neck Pain: A Systematic Review With Meta-analysis.

OBJECTIVE: To quantify placebo effects and responses in randomized controlled trials (RCTs) on neck pain and explore how they would influence the treatment of neck pain. DATA SOURCES: We searched MEDLINE (PubMed), EMBASE (Ovid), CINAHL (EBSCO), Physiotherapy Evidence Database (PEDro), and World Health Organization International Clinical Trials Registry Platform from the inception of August 15, 2021, to identify relevant RCTs. STUDY SELECTION AND DATA EXTRACTION: The abstracts and full texts of potential studies were independently screened, and data extraction was also independently performed by 2 researchers. Scales of the score measuring neck pain and the scores both at baseline and the endpoint were extracted. DATA SYNTHESIS: A total of 60 RCTs were included. The mean improvement in the pain score after placebo treatment was 15.65 (mean difference [MD]=-15.65, 95% confidence interval; CI [-19.19, -12.12]; P<.05), which we defined as the placebo response. In the active groups, it was 25.91 (MD=-25.91, 95% CI [-29.15, -22.68]; P<.05), and in the no-treatment groups, it was 5.80 (MD=-5.80, 95% CI [13.28, 1.69]; P=.13). Using the 3 MDs from the 3 groups, the placebo effect was calculated to account for 38.0% of the pain score improvement in the active group. CONCLUSIONS: The pain scores of patients with neck pain were reduced after treatment with placebos, but the magnitude of pain score reduction was not clinically significant enough. The 38.0% amount of pain score reduction in patients treated with active interventions was caused by placebo. Interventions with considerable clinically significance for neck pain were still required.

A Multifunctional Contrast Agent for 19F-Based Magnetic Resonance Imaging.

Magnetic resonance imaging, MRI, relying on 19F nuclei has attracted much attention, because the isotopes exhibit a high gyromagnetic ratio (comparable to that of protons) and have 100% natural abundance. Furthermore, due to the very low traces of intrinsic fluorine in biological tissues, fluorine labeling allows easy visualization in vivo using 19F-based MRI. However, one of the drawbacks of the available fluorine tracers is their very limited solubility in water. Here, we detail the design and preparation of a set of water-compatible fluorine-rich polymers as contrast agents that can enhance the effectiveness of 19F-based MRI. The agents are synthesized using the nucleophilic addition reaction between poly(isobutylene-alt-maleic anhydride) copolymer and a mixture of amine-appended fluorine groups and polyethylene glycol (PEG) blocks. This allows control over the polymer architecture and stoichiometry, resulting in good affinity to water solutions. We further investigate the effects of introducing additional segmental mobility to the fluorine moieties in the polymer, by inserting a PEG linker between the moieties and the polymer backbone. We find that controlling the polymer stoichiometry and introducing additional segmental mobility enhance the NMR signals and narrow the peak profile. In particular, we assess the impact of the PEG linker on T2* and T1 relaxation times, using a series of gradient-recalled echo images with varying echo times, TE, or recovery time, TR, respectively. We find that for equivalent concentrations, the PEG linker greatly increases T2*, while maintaining high T1 values, as compared to polymers without this linker. Phantom images collected from these compounds show bright signals over a background with high intensities.

Is the CyberKnife© radiosurgery system effective and safe for patients? An umbrella review of the evidence.

Background: The CyberKnife© system combines real-time image guidance and a dynamic tracking system to implement frameless radiotherapy. This umbrella review is aimed to evaluate the effectiveness and safety of CyberKnife. Methods: A comprehensive search of health technology assessments and systematic reviews was performed among the Embase, PubMed and other grey databases until July 2020. Treatment outcomes were extracted, and the quality of included studies were assessed using AMSTAR-2. Results: Nineteen studies were eligible. CyberKnife not only had a wide range of applications, long overall survival and great local control, but also had a limited toxicity and good cost-effectiveness compared with other radiotherapy equipment. Conclusion: Despite the relatively low quality of the evidence, our findings can still provide a decision reference for policymakers.

An umbrella review on the effectiveness and safety of the CyberKnife^© system was performed by comprehensively searching for all related publications. The CyberKnife system had excellent effect on treatment of cancer and some noncancer diseases, with limited toxicity. Additionally, it was a cost-effective treatment compared with other types of radiotherapy. Despite the relatively low quality of the included evidence, our findings can still provide a comprehensive decision reference for policymakers of patients, government and hospitals.

Meta-analysis of alcohol consumption and venous thromboembolism.

BACKGROUND: The associations of alcohol consumption and venous thromboembolism (VTE) have been investigated widely, but the conclusions were inconsistent. OBJECTIVE: To summarize the relationship of alcohol consumption and VTE. METHODS: This study has been registered in PROSPERO (ID: CRD42020164567). We searched the PubMed, Embase, Web of Science and the Cochrane Library databases from inception to September 2019 and reviewed the reference list of relevant articles to identify studies assessing the association between alcohol consumption and risk of VTE. RESULTS: Fourteen cohorts and four case-control studies were included in the meta-analysis. Compared with non-drinkers, the risk of VTE was decreased (RR: 0.93; 95% confidence interval [CI] 0.88-0.99) for alcohol drinkers. The pooled RRs of VTE were 0.91 (95% CI 0.84-0.99) for low to moderate alcohol intake (0.1-14.0 drinks/week) and 0.91 (95% CI 0.78-1.06) for high alcohol intake (>14.0 drinks/week) compared with non-drinker. Subgroup analysis showed liquor intake might slightly increase the risk of VTE (1.01; 95% CI 0.85-1.21) although the difference was not significant. CONCLUSIONS: Alcohol consumption in low to moderate was associated with a lower risk of VTE. However, precautions are needed when providing personal drinking advice considering the potential harm of alcohol. Further studies are warranted to determine whether moderate alcohol consumption has a causal role in VTE.

Hemostatic Agent May Improve Perioperative Outcomes in Partial Nephrectomy: A Systematic Review and Meta-Analysis.

BACKGROUND: Hemostatic agents (HAs) are used to achieve hemostasis and prevent postoperative complications in multiple surgeries, but the role of HAs is ambiguous during partial nephrectomy (PN), so this study aimed to assess the role of HAs in PN. METHODS: PubMed, Embase, CENTRAL and ClinicalTrials.gov were searched for randomized controlled trials and cohort studies regarding the comparison of HA use alone and standard suturing during PN on January 17, 2020. RevMan 5.3 was used to conduct meta-analysis. Sensitivity analyses and subgroup analyses were performed based on surgical procedures and HA types. RESULTS: Six studies involving 1,066 patients were included. The quality of studies was moderate to high. There were significant reductions in warm ischemia time (mean difference [MD] = -6.30 min, 95% confidence interval [CI] -7.70 to -4.90, p < 0.00001), operative time (MD = -19.81 min, 95% CI -27.54 to -12.08, p < 0.00001), and estimated blood loss (MD = -108.62 mL, 95% CI -177.27 to -39.9, p = 0.002) in the HA group, and HA use alone did not increase postoperative complications. The results were similar in the subgroup analyses and sensitivity analyses. CONCLUSION: HA may be an effective and safe surgical material in PN, which can improve postoperative outcomes. High-quality and randomly designed studies are needed to validate the applicability.

Microfluidic Synthesis of the Tumor Microenvironment-Responsive Nanosystem for Type-I Photodynamic Therapy.

Type I photosensitizers with aggregation-induced emission luminogens (AIE-gens) have the ability to generate high levels of reactive oxygen species (ROS), which have a good application prospect in cancer photodynamic therapy (PDT). However, the encapsulation and delivery of AIE molecules are unsatisfactory and seriously affect the efficiency of a practical therapy. Faced with this issue, we synthesized the metal-organic framework (MOF) in one step using the microfluidic integration technology and encapsulated TBP-2 (an AIE molecule) into the MOF to obtain the composite nanomaterial ZT. Material characterization showed that the prepared ZT had stable physical and chemical properties and controllable size and morphology. After being endocytosed by tumor cells, ZT was degraded in response to the acidic tumor microenvironment (TME), and then TBP-2 molecules were released. After stimulation by low-power white light, a large amount of •OH and H2O2 was generated by TBP-2 through type I PDT, thereby achieving a tumor-killing effect. Further in vitro cell experiments showed good biocompatibility of the prepared ZT. To the best of our knowledge, this report is the first on the microfluidic synthesis of multifunctional MOF for type I PDT in response to the TME. Overall, the preparation of ZT by the microfluidic synthesis method provides new insight into cancer therapy.

Publishing clinical prActice GuidelinEs (PAGE): Recommendations from editors and reviewers.

Transparency Ecosystem for Research and Journals in Medicine (TERM) working group summarized the essential recommendations that should be considered to review and publish a high-quality guideline. These recommendations from editors and reviewers included 10 components of essential requirements: systematic review of existing relevant guidelines, guideline registration, guideline protocol, stakeholders, conflicts of interest, clinical questions, systematic reviews, recommendation consensus, guideline reporting and external review. TERM working group abbreviates them as PAGE (essential requirements for Publishing clinical prActice GuidelinEs), and recommends guideline authors, editors, and peer reviewers to use them for high-quality guidelines.