Miracle-dz/UniFAR-FTUs huggingface dataset:
Investigation of the Interplay between Circulating Lipids and IGF-I and Relevance to Breast Cancer Risk: An Observational and Mendelian Randomization Study

Background: Circulating lipids and insulin-like growth factor 1 (IGF-I) have been reliably associated with breast cancer. Observational studies suggest an interplay between lipids and IGF-I, however, whether these relationships are causal and if pathways from these phenotypes to breast cancer overlap is unclear. Methods: Mendelian randomization (MR) was conducted to estimate the relationship between lipids or IGF-I and breast cancer risk using genetic summary statistics for lipids (low-density lipoprotein cholesterol, LDL-C; high-density lipoprotein cholesterol, HDL-C; triglycerides, TGs), IGF-I and breast cancer from GLGC/UKBB (N = 239,119), CHARGE/UKBB (N = 252,547), and Breast Cancer Association Consortium (N = 247,173), respectively. Cross-sectional observational and MR analyses were conducted to assess the bi-directional relationship between lipids and IGF-I in SHIP (N = 3,812) and UKBB (N = 422,389), and using genetic summary statistics from GLGC (N = 188,577) and CHARGE/UKBB (N = 469,872). Results: In multivariable MR (MVMR) analyses, the OR for breast cancer per 1-SD increase in HDL-C and TG was 1.08 [95% confidence interval (CI), 1.04–1.13] and 0.94 (95% CI, 0.89–0.98), respectively. The OR for breast cancer per 1-SD increase in IGF-I was 1.09 (95% CI, 1.04–1.15). MR analyses suggested a bi-directional TG–IGF-I relationship (TG–IGF-I β per 1-SD: −0.13; 95% CI, −0.23 to −0.04; and IGF-I–TG β per 1-SD: −0.11; 95% CI, −0.18 to −0.05). There was little evidence for a causal relationship between HDL-C and LDL-C with IGF-I. In MVMR analyses, associations of TG or IGF-I with breast cancer were robust to adjustment for IGF-I or TG, respectively. Conclusions: Our findings suggest a causal role of HDL-C, TG, and IGF-I in breast cancer. Observational and MR analyses support an interplay between IGF-I and TG; however, MVMR estimates suggest that TG and IGF-I may act independently to influence breast cancer. Impact: Our findings should be considered in the development of prevention strategies for breast cancer, where interventions are known to modify circulating lipids and IGF-I.
Symptom trajectories in breast cancer survivors: growth mixture analysis of patient-reported pain, fatigue, insomnia, breast and arm symptoms

Abstract Background Variations in symptom development among breast cancer (BC) survivors are understudied. We examined: (Q1) Symptom trajectories of pain, fatigue, insomnia, breast, and arm symptoms in BC survivors, (Q2) possible patterns or cluster-like associations between trajectory classification of different symptoms, and (Q3) characteristics of survivors assigned to high-burden symptom trajectories. Material and methods Participants were 968 women (mean age = 59.6 years) treated for early-stage BC and followed across a three-year postoperative period. As part of routine follow-up procedures, patients reported symptom burden and functioning levels at each hospital visit using the European Organisation for Research and Treatment of Cancer (EORTC) Quality of Life Questionnaire (QLQ-C30) and the BC-specific module (QLQ-BR-23). Growth mixture modeling (GMM) analysis was used to differentiate potential subgroups of individuals with similar longitudinal symptom patterns, i.e., symptom trajectories (Q1). With this approach, groups experiencing persistent, highly distressing cancer- and treatment-related late effects (LEs) may be identified. Latent class analysis (LCA) was used for Q2 and logistic regression analysis for Q3. Results GMM identified two relatively parallel trajectories across the tested symptoms: The majority of the sample exhibited a low-burden symptom trajectory (74.4–89.2%) and a minority by a high-burden symptom trajectory (10.8–25.6%). LCA revealed that approximately one in five women (18.8%) were likely to be members of the high-burden symptom trajectory across all tested symptoms. In addition to a high probability of being burdened over time across multiple symptoms, these women were also characterized by poorer self-reported physical and social functioning. Conclusion A substantial minority followed a high-burden symptom trajectory for several years following BC treatment. Associations were found in trajectory classification across symptoms, indicating that cancer-related LEs appear in clusters of multiple concurrent symptoms.
Bile acid metabolism dysregulation associates with cancer cachexia: roles of liver and gut microbiome

Cancer cachexia is a multifactorial metabolic syndrome in which bile acid (BA) metabolism might be involved. The aim of the present study was to clarify the contribution of liver and gut microbiota to BA metabolism disturbance in cancer cachexia and to check the possibility of targeting BA metabolism using agents such as tauroursodeoxycholic acid (TUDCA) for cancer cachexia therapy.
A comparative study of AJCC and the modified staging system in pT2/pT3 penile squamous cell carcinoma – a validation on an external data set

The recent changes in the American Joint Commission on Cancer, 8th edition (AJCC‐8E) pT2 and pT3 tumour definitions for penile cancer need robust validation studies. A recent study redefined and modified the pT2 and pT3 stages incorporating the histopathological variables (tumour grade, lymphovascular invasion, perineural invasion) similar to that used in the current AJCC‐8E pT1 stage tumour subclassification. In this study, we validate and compare this proposed staging with the AJCC staging systems on an external data set.
Extended Lung Ultrasound to Differentiate Between Pneumonia and Atelectasis in Critically Ill Patients: A Diagnostic Accuracy Study

OBJECTIVES: To determine the diagnostic accuracy of extended lung ultrasonographic assessment, including evaluation of dynamic air bronchograms and color Doppler imaging to differentiate pneumonia and atelectasis in patients with consolidation on chest radiograph. Compare this approach to the Simplified Clinical Pulmonary Infection Score, Lung Ultrasound Clinical Pulmonary Infection Score, and the Bedside Lung Ultrasound in Emergency protocol. DESIGN: Prospective diagnostic accuracy study. SETTING: Adult ICU applying selective digestive decontamination. PATIENTS: Adult patients that underwent a chest radiograph for any indication at any time during admission. Patients with acute respiratory distress syndrome, coronavirus disease 2019, severe thoracic trauma, and infectious isolation measures were excluded. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: Lung ultrasound was performed within 24 hours of chest radiograph. Consolidated tissue was assessed for presence of dynamic air bronchograms and with color Doppler imaging for presence of flow. Clinical data were recorded after ultrasonographic assessment. The primary outcome was diagnostic accuracy of dynamic air bronchogram and color Doppler imaging alone and within a decision tree to differentiate pneumonia from atelectasis. Of 120 patients included, 51 (42.5%) were diagnosed with pneumonia. The dynamic air bronchogram had a 45% (95% CI, 31–60%) sensitivity and 99% (95% CI, 92–100%) specificity. Color Doppler imaging had a 90% (95% CI, 79–97%) sensitivity and 68% (95% CI, 56–79%) specificity. The combined decision tree had an 86% (95% CI, 74–94%) sensitivity and an 86% (95% CI, 75–93%) specificity. The Bedside Lung Ultrasound in Emergency protocol had a 100% (95% CI, 93–100%) sensitivity and 0% (95% CI, 0–5%) specificity, while the Simplified Clinical Pulmonary Infection Score and Lung Ultrasound Clinical Pulmonary Infection Score had a 41% (95% CI, 28–56%) sensitivity, 84% (95% CI, 73–92%) specificity and 68% (95% CI, 54–81%) sensitivity, 81% (95% CI, 70–90%) specificity, respectively. CONCLUSIONS: In critically ill patients with pulmonary consolidation on chest radiograph, an extended lung ultrasound protocol is an accurate and directly bedside available tool to differentiate pneumonia from atelectasis. It outperforms standard lung ultrasound and clinical scores.
Dual blocking of PI3K and mTOR signaling by DHW‐221, a novel benzimidazole derivative, exerts antitumor activity in human non‐small cell lung cancer

Dear Editor, We previously designed and synthesized a novel benzimidazole compound, DHW-221.1 Here, we evaluated its antiNSCLC activity as a PI3K/mTOR dual-target inhibitor and comprehensively described for the first time the mechanismunderlying the PI3K/AKT/mTOR signaling pathwaymediated antitumor effects of DHW-221. Our findings indicated that the antitumor activity of DHW-221 was significantly stronger than that of NVP-BEZ235, a dual PI3K/mTOR inhibitor currently undergoing a phase II clinical trial. The PI3K/AKT/mTOR pathway is a key mediator of receptor tyrosine kinase signal transduction. The PI3K family can be divided into three categories.2 Class I PI3K and mTOR, sharing structural homology in the kinase domain,3 are considered important targets for malignancy therapy.4 Thus, the thought of blocking the PI3K/AKT/mTOR pathway by double inhibition of PI3K/mTORwas proposed.5 Herein,we systematically elucidated the anti-NSCLC effects associated with DHW-221mediated dual PI3K/mTOR inhibition and identified the mechanism underlying this effect both in vitro and in vivo. First, we identified potential targets of DHW-221. Molecular docking indicated that DHW-221 fitted well into the PI3K-ATP binding pocket and formed hydrogen bonds with Gln859 and Arg770. For mTOR, DHW-221 precisely overlapped with it and formed two more hydrogen bonds (Val2240 and Thr2245) than NVP-BEZ235 (Figure 1A). Docking results with PI3Kβ/γ/δ are shown in Figure S1. Subsequent kinase assay suggested that DHW-221 significantly inhibits the kinase activity of the main PI3K isoforms1 (IC50: PI3Kα,0.5 nM; PI3Kβ,1.9 nM; PI3Kγ,1.8 nM; PI3Kδ,0.74 nM), as well as that of mTOR (IC50: 3.9 nM) (Table S1). Cellular thermal shift assay was used to further evaluate the binding mode, the thermal stability of DHW-221 combined with PI3K/mTOR was concentration-dependently enhanced (Figure 1B).
Efficacy evaluation of acupotomy combined with platelet-rich plasma in the treatment of early and middle osteoarthritis.

OBJECTIVE To investigate the efficacy of traditional Chinese medicine acupotomy combined with platelet-rich plasma (PRP) in the treatment of early and middle osteoarthritis. METHODS Eighty cases of early and middle knee joint pain patients admitted in our hospital were selected in this retrospective study. They were divided into the control group and observation group according to treatment methods, with 40 cases in each group. The control group was treated with PRP, and the observation group was treated with acupotomy + PRP. Clinical response rate, visual analogue scale (VAS) pain score, Lequesne score, Western Ontario and McMaster Universities Osteoarthritis (WOMAC) index and SF-36 quality of life score were compared between the two groups. RESULTS The total clinical response rate in the observation group was higher than that in control group (P<0.01). VAS pain score, knee joint WOMAC index and Lequesne score in the two groups after treatment were lower than those before treatment, and those in the observation group were lower than those in the control group (all P<0.05). SF-36 quality of life score was significantly higher in the observation group than in the control group (all P<0.001). CONCLUSION Acupotomy combined with PRP in the treatment of early and middle osteoarthritis can relieve pain and improve joint function, which is worthy of clinical promotion.
Beneficial Effect of Prone Positioning During Venovenous Extracorporeal Membrane Oxygenation for Coronavirus Disease 2019*

Supplemental Digital Content is available in the text. OBJECTIVES: The study investigated the impact of prone positioning during venovenous extracorporeal membrane oxygenation support for coronavirus disease 2019 acute respiratory failure on the patient outcome. DESIGN: An observational study of venovenous extracorporeal membrane oxygenation patients. We used a multistate survival model to compare the outcomes of patients treated with or without prone positioning during extracorporeal membrane oxygenation, which incorporates the dynamic nature of prone positioning and adjusts for potential confounders. SETTING: Seventy-two international institutions participating in the Coronavirus Disease 2019 Critical Care Consortium international registry. PATIENTS: Coronavirus disease 2019 patients who were supported by venovenous extracorporeal membrane oxygenation during the study period. INTERVENTION: None. MEASUREMENTS AND MAIN RESULTS: There were 232 coronavirus disease 2019 patients at 72 participating institutions who were supported with venovenous extracorporeal membrane oxygenation during the study period from February 16, 2020, to October 31, 2020. Proning was used in 176 patients (76%) before initiation of extracorporeal membrane oxygenation and in 67 patients (29%) during extracorporeal membrane oxygenation. Survival to hospital discharge was 33% in the extracorporeal membrane oxygenation prone group versus 22% in the extracorporeal membrane oxygenation supine group. Prone positioning during extracorporeal membrane oxygenation support was associated with reduced mortality (hazard ratio, 0.31; 95% CI, 0.14–0.68). CONCLUSIONS: Our study highlights that prone positioning during venovenous extracorporeal membrane oxygenation support for refractory coronavirus disease 2019-related acute respiratory distress syndrome is associated with reduced mortality. Given the observational nature of the study, a randomized controlled trial of prone positioning on venovenous extracorporeal membrane oxygenation is needed to confirm these findings.
Surgical mediastinal lymph node staging for non-small-cell lung carcinoma

Background The current preferred approach for surgical mediastinal staging of non-small-cell lung carcinoma is video-assisted mediastinoscopy. An alternative technique in which lymph nodes are resected instead of biopsied is video-assisted mediastinoscopic lymphadenectomy (VAMLA) that is suggested to be superior in detecting N2 disease. Yet, evidence is conflicting and furthermore limited by sample size. The objective was to compare mediastinal staging through VAMLA and video-assisted mediastinoscopy. Methods A single-center cohort study was conducted. All consecutive patients that underwent surgical mediastinal staging of non-small-cell lung carcinoma by VAMLA (2011 to 2018) were compared to historic video-assisted mediastinoscopy controls (2007 to 2011). Patients with negative surgical mediastinal staging underwent subsequent anatomical resection with systematic regional lymphadenectomy. Primary outcome was the sensitivity and negative predictive value for detecting N2 disease. Results Two-hundred-sixty-nine video-assisted mediastinoscopic lymphadenectomies and 118 video-assisted mediastinoscopies were performed. The prevalence of N2 disease was 20% and 26% respectively in the VAMLA and video-assisted mediastinoscopy group, while the rate of unforeseen pN2 resulting from lymph node dissection during anatomical resection was 4% and 11%, respectively. Invasive staging using VAMLA demonstrated superior sensitivity of 0.82 and a negative predictive value of 0.96 when compared to video-assisted mediastinoscopy (0.62 and 0.89, respectively), offering a 64% decrease in risk of unforeseen pN2 following anatomical resection. However, VAMLA is also associated with a 75% risk increase on complications (P=0.36). Conclusions We conclude that performing invasive mediastinal lymph node assessment for staging of non-small-cell lung carcinoma, VAMLA should be the preferred technique with superior sensitivity and negative predictive value in detecting N2 disease. Though, VAMLA is also associated with an increased risk of complications.
Shedding light on the mechanisms of absorption and transport of ZnO nanoparticles by plants via in vivo X-ray spectroscopy

Several factors have contributed to bring pressure on agriculture. In this context, nanomaterial properties can be explored to design more efficient fertilizers and therefore increase productivity. In the present study, the roots of Phaseolus vulgaris were immersed in several nano ZnO dispersions for 48 h. The absorption and transport phenomena were in vivo monitored by X-ray fluorescence spectroscopy (XRF) and X-ray absorption spectroscopy (XAS). The nanoparticle size, concentration and coating with surfactants affected the rate of Zn release and therefore its uptake. In vivo X-ray absorption spectroscopy showed that Phaseolus vulgaris takes up Zn bound to both citrate and malate, while entire nanoparticles were only absorbed when roots were injured. X-ray fluorescence microanalysis unravelled that besides xylem bundles, root to shoot Zn transport can take place through the cortex.
Autonomous clocks that regulate organelle biogenesis, cytoskeletal organization, and intracellular dynamics

How do cells perceive time? Do cells use temporal information to regulate the production/degradation of their enzymes, membranes, and organelles? Does controlling biological time influence cytoskeletal organization and cellular architecture in ways that confer evolutionary and physiological advantages? Potential answers to these fundamental questions of cell biology have historically revolved around the discussion of ‘master’ temporal programs, such as the principal cyclin-dependent kinase/cyclin cell division oscillator and the circadian clock. In this review, we provide an overview of the recent evidence supporting an emerging concept of ‘autonomous clocks,’ which under normal conditions can be entrained by the cell cycle and/or the circadian clock to run at their pace, but can also run independently to serve their functions if/when these major temporal programs are halted/abrupted. We begin the discussion by introducing recent developments in the study of such clocks and their roles at different scales and complexities. We then use current advances to elucidate the logic and molecular architecture of temporal networks that comprise autonomous clocks, providing important clues as to how these clocks may have evolved to run independently and, sometimes at the cost of redundancy, have strongly coupled to run under the full command of the cell cycle and/or the circadian clock. Next, we review a list of important recent findings that have shed new light onto potential hallmarks of autonomous clocks, suggestive of prospective theoretical and experimental approaches to further accelerate their discovery. Finally, we discuss their roles in health and disease, as well as possible therapeutic opportunities that targeting the autonomous clocks may offer.
Iron intake and multiple health outcomes: Umbrella review

Abstract Iron is an essential trace element, while excess iron can lead to different levels of physical abnormalities or diseases. This umbrella review aimed to conduct a systematic evaluation of the possible relationships between iron intake and various health outcomes. We retrieved PubMed, Embase, Web of Science, Scopus, and the Cochrane Database of Systematic Reviews from inception through May 2021. A total of 34 meta-analyses with 46 unique health outcomes were identified. Heme iron intake was positively associated with nine outcomes, including colorectal cancer, type 2 diabetes mellitus, and cardiovascular disease mortality, while dietary total iron intake could decrease the risk of colorectal adenoma, esophageal cancer, coronary heart disease, and depression. Iron supplementation was a protective factor against eight outcomes. However, it was associated with decreased length and weight gain. The quality of evidence for most outcomes was “low” or “very low” with the remaining eleven as “high” or “moderate”. All outcomes were categorized as class III, IV, or NS based on evidence classification. Although high iron intake has been identified to be significantly associated with a range of outcomes, firm universal conclusions about its beneficial or negative effects cannot be drawn given the low quality of evidence for most outcomes.
Utility of Hepatic 2D Shear-Wave Elastography in Monitoring Response to Image-Guided Intervention in Children With Chronic Budd-Chiari Syndrome: A Prospective Study.

Background: Image-guided interventions for Budd-Chiari syndrome (BCS) reduce hepatic congestion, thereby reducing liver stiffness. Liver stiffness measurements (LSM) by ultrasound may provide a noninvasive marker for assessing treatment response. Objective: To assess the utility of 2D shear-wave elastography (SWE) for monitoring response to image-guided intervention in children with BCS, with attention to changes in LSM in patients with disease recurrence. Materials and Methods: This prospective study included children with chronic BCS and planned image-guided intervention. Color Doppler ultrasound (CDUS) and 2D SWE were performed at baseline; at 24 hours, one month, and three months after intervention; and thereafter every three months or at the time of clinically suspected recurrence. Eighteen children underwent liver biopsy at the time of intervention for fibrosis staging using METAVIR criteria. Disease recurrence was diagnosed by CDUS. Statistical evaluation was performed using non-parametric tests. Results: A total of 32 children (28 boys, 4 girls; mean age: 9.0 years; range: 3-14 years) were included. Median LSM was at baseline 43.7 kPa [interquartile range (IQR): 33.0-65.4), at 24 hours 22.5 kPa (IQR: 16.8-32.0), at one month 18.7 kPa (IQR: 14.2-32.0), and at three months 16.7 kPa (IQR: 11.5-22.5) (p<.05 for all post-intervention time points vs baseline). Nine (28.1%) patients developed recurrence after intervention at mean of 4.4 months. In one patient with recurrence, LSM was higher at 24 hours (52.3 kPa) than at baseline (44.2 kPa). In the remaining eight patients with recurrence, LSM increased at the time of recurrence compared with the prior post-intervention LSM measurement [median absolute increase of 11.0 kPa (IQR: 6.1-24.4 kPa)]. Fibrosis stage was not significantly correlated with baseline LSM (r=0.11, 95% CI: -0.37, 0.54; p=.51) or 24-hour post-intervention LSM (r=0.39, 95% CI: -0.11, 0.73; p=.11). Conclusion: LSM decreased significantly after image-guided intervention for chronic BCS in children, showing a maximal decrease at 24 hours post-intervention. Disease recurrence was typically associated with an increase in LSM compared with the patient's prior measurement. Clinical Impact: LSM obtained by 2D SWE may serve as a useful quantitative adjunct to CDUS in monitoring children with chronic BCS for disease recurrence after percutaneous interventional treatment.
RNA–RNA interactions between SARS-CoV-2 and host benefit viral development and evolution during COVID-19 infection

Abstract Some studies reported that genomic RNA of SARS-CoV-2 can absorb a few host miRNAs that regulate immune-related genes and then deprive their function. In this perspective, we conjecture that the absorption of the SARS-CoV-2 genome to host miRNAs is not a coincidence, which may be an indispensable approach leading to viral survival and development in host. In our study, we collected five datasets of miRNAs that were predicted to interact with the genome of SARS-CoV-2. The targets of these miRNAs in the five groups were consistently enriched immune-related pathways and virus-infectious diseases. Interestingly, the five datasets shared no one miRNA but their targets shared 168 genes. The signaling pathway enrichment of 168 shared targets implied an unbalanced immune response that the most of interleukin signaling pathways and none of the interferon signaling pathways were significantly different. Protein–protein interaction (PPI) network using the shared targets showed that PPI pairs, including IL6-IL6R, were related to the process of SARS-CoV-2 infection and pathogenesis. In addition, we found that SARS-CoV-2 absorption to host miRNA could benefit two popular mutant strains for more infectivity and pathogenicity. Conclusively, our results suggest that genomic RNA absorption to host miRNAs may be a vital approach by which SARS-CoV-2 disturbs the host immune system and infects host cells.