Machine Learning-Assisted Nanoenzyme/Bioenzyme Dual-Coupled Array for Rapid Detection of Amyloids.

Array-based sensing methods offer significant advantages in the simultaneous detection of multiple amyloid biomarkers and thus have great potential for diagnosing early-stage Alzheimer's disease. Yet, detecting low concentrations of amyloids remains exceptionally challenging. Here, we have developed a fluorescent sensor array based on the dual coupling of a nanoenzyme (AuNPs) and bioenzyme (horseradish peroxidase) to detect amyloids. Various ss-DNAs were bound to the nanoenzyme for regulating enzymatic activity and recognizing amyloids. A simplified sensor array was generated from a screening model via machine learning algorithms and achieved signal amplification through a two-step enzymatic reaction. As a result, our sensing system could discriminate the aggregation species and aggregation kinetics at 200 nM with 100% accuracy. Moreover, AD model mice and healthy mice were distinguished with 100% accuracy through the sensor array, providing a powerful sensing platform for diagnosing AD.

Evaluation of progression-free survival as a surrogate end point in primary CNS lymphoma: a systematic review and meta-analysis.

Purpose: To evaluate progression-free survival (PFS) as early surrogate endpoints for overall survival (OS) in primary CNS lymphoma (PCNSL). Methods: PubMed, Embase and Cochrane Central Library were searched up to 7 June 2022. Trial-level analyses were performed by weighted linear regression of logarithmic hazard ratios for PFS and OS. Treatment arm-level analyses were performed between PFS rates and 3- or 5-year OS rates. Results: 1471 PCNSL patients in nine randomized control trials were included. PFS was associated with OS (r = 0.750; 95% CI: 0.228-0.937). Strong linear correlations existed between 1-, 2- and 3-year PFS and 3-year OS (r = 0.896-0.928), moderate or weak correlations existed between 3- to 6-month PFS and 3-year OS, 3-month to 5-year PFS and 5-year OS. Conclusion: Short-term PFS can validly substitute for long-term OS in PCNSL.

Optimizing the therapeutic window of sirolimus by monitoring blood concentration for the treatment of immune thrombocytopenia.

Previous studies have demonstrated that sirolimus (SRL) is an effective agent for the treatment of refractory/relapsed (R/R) ITP. However, the therapeutic window of sirolimus in the treatment of ITP has not been established. As the toxicity of sirolimus increases with higher blood concentrations, it is crucial to determine the optimal therapeutic concentration of SRL for the treatment of ITP. Thus, in this study, we used a retrospective cohort of ITP patients treated with sirolimus to propose the therapeutic dosage window for sirolimus. A total of 275 laboratory results of SRL blood concentration from 63 ITP patients treated with SRL were analyzed retrospectively. The ITP patients were divided into five groups based on their SRL blood concentration: 0-4 ng/ml, 4-8 ng/ml, 8-12 ng/ml, 12-16 ng/ml and ≥16 ng/ml. In addition to the SRL blood concentration, platelet counts and adverse events that occurred during the first 6 weeks of SRL treatment were analyzed. These findings were then used to establish the decision matrix tables and ROC curves, which helped identify the therapeutic window of SRL. Based on the values and trends of true-positive rate (TPR) and false-positive rate (FPR) in the ROC curve, patients who achieved a SRL blood concentration of 4-12 ng/ml displayed a higher response rate compared to those with a SRL concentration of 0-4 ng/ml or ≥16ng/ml. Additionally, the response rate was better for patients with a SRL concentration of 8-12 ng/ml compared to 4-8 ng/ml. Adverse events were related to the concentration of SRL; however, there was no significant difference in the incidence of adverse events between the concentrations of 4-8 ng/ml and 8-12 ng/ml (P > .05). Regression analysis suggested that the concentration of SRL correlated with the patient's age, PLT count at the start of SRL administration, and the dose of SRL. It is suggested that the optimal blood concentration of SRL monotherapy for managing ITP is 8-12 ng/ml. This range may achieve a favorable balance between clinical efficacy and the severity of adverse events.

Although sirolimus (SRL) has been proven to be an effective alternative agent for refractory/relapsed immune thrombocytopenia (R/R ITP), there is currently no recommended optimal blood concentration during its administration. We collected data on SRL drug concentration, platelet response, and drug side effects in ITP patients, constructed ROC curves to evaluate the relationship between the SRL concentration and both efficacy and side effects, and finally suggested a most appropriate SRL blood concentration (8­12ng/ml). This concentration window ensured optimal efficacy of SRL in the treatment of ITP while maintaining tolerable side effects. Additionally, we conducted a multivariate analysis to explore factors that may influence SRL blood concentration. The present study made an important contribution to the precision therapy of ITP with sirolimus by clarifying the optimal blood concentration range.

Microsphere-Based Microsensor for Miniature Motors' Vibration Measurement.

We present a microsphere-based microsensor that can measure the vibrations of the miniature motor shaft (MMS) in a small space. The microsensor is composed of a stretched fiber and a microsphere with a diameter of 5 µm. When a light source is incident on the microsphere surface, the microsphere induces the phenomenon of photonic nanojet (PNJ), which causes light to pass through the front. The PNJ's full width at half maximum is narrow, surpassing the diffraction limit, enables precise focusing on the MMS surface, and enhances the scattered or reflected light emitted from the MMS surface. With two of the proposed microsensors, the axial and radial vibration of the MMS are measured simultaneously. The performance of the microsensor has been calibrated with a standard vibration source, demonstrating measurement errors of less than 1.5%. The microsensor is expected to be used in a confined space for the vibration measurement of miniature motors in industry.

Reforming the Uniformity of Solid Electrolyte Interphase by Nanoscale Structure Regulation for Stable Lithium Metal Batteries.

The stability of high-energy-density lithium metal batteries depends on the uniformity of solid electrolyte interphase (SEI) on lithium metal anodes. Rationally improving SEI uniformity is hindered by poorly understanding the effect of structure and components of SEI on its uniformity. Herein, a bilayer structure of SEI formed by isosorbide dinitrate (ISDN) additives in localized high-concentration electrolytes was demonstrated to improve SEI uniformity. In the bilayer SEI, LiNx Oy generated by ISDN occupies top layer and LiF dominates bottom layer next to anode. The uniformity of lithium deposition is remarkably improved with the bilayer SEI, mitigating the consumption rate of active lithium and electrolytes. The cycle life of lithium metal batteries with bilayer SEI is three times as that with common anion-derived SEI under practical conditions. A prototype lithium metal pouch cell of 430 Wh kg-1 undergoes 173 cycles. This work demonstrates the effect of a reasonable structure of SEI on reforming SEI uniformity.

Psychological health status among thyroid cancer patients during the COVID-19 epidemic in China.

OBJECTIVES: To investigate the psychological health status and explore the impact of different factors among thyroid cancer patients during the peak period of the COVID-19 epidemic in China. METHODS: With thyroid cancer patients who had attended Peking Union Medical College Hospital included, we collected their demographic and clinical characteristics, COVID-19-related factors, and outcomes of 4 psychological scales (Insomnia Severity Index [ISI], Generalized Anxiety Disorder Questionnaire [GAD-7], Patient Health Questionnaire [PHQ-9], and Impact of Events Scale-Revised [IES-R]) through an online questionnaire and used multiple linear regression to find independent risk factors for each psychological symptom. RESULTS: A total of 219 patients were included. Insomnia, anxiety, depression, and clinically relevant post-traumatic stress symptoms (PTSS) were reported by 69 (31.5%), 87 (39.7%), 74 (33.8%), and 44 (20.1%) patients, respectively. Based on multiple linear regression, being single/divorced/widowed, having a lower level of education, receiving resources of science lectures during the epidemic, and experiencing disruption of routine treatment or follow-up were associated with poorer psychological health among patients with thyroid cancer. CONCLUSIONS: High rates of psychological symptoms and potential risk factors were found in thyroid cancer patients during the peak period of COVID-19 in China. Based on these findings, the psychological status of these patients should be a focus, and the psychological support systems need to be strengthened for the prevention of psychological crises during the epidemic.

[Updated studies on the immunotherapy of prostate cancer].

Prostate cancer (PCa) is a common urogenital malignancy in elderly men, for which current treatment strategies include surgery, radiotherapy, chemotherapy and androgen-deprivation therapy. However, PCa patients with recurrence or metastasis may ultimately develop therapeutic resistance. Recent studies show that PCa is an immunosensitive tumor and immunotherapy is a feasible option for its treatment, which involves therapeutic vaccination, immune checkpoint inhibitors, tumor microenvironment regulators, bi-specific antibodies, and adoptive cell metastasis. The application of immunotherapy, however, has been hindered by the adverse reactions of the patients and limited effects of single-drug medication. Individualized treatment and combination therapy are expected to be the alternatives in the development of the treatments of PCa.

Thermally Stable Polymer-Rich Solid Electrolyte Interphase for Safe Lithium Metal Pouch Cells.

Serious safety risks caused by the high reactivity of lithium metal against electrolytes severely hamper the practicability of lithium metal batteries. By introducing unique polymerization site and more fluoride substitution, we built an in situ formed polymer-rich solid electrolyte interphase upon lithium anode to improve battery safety. The fluorine-rich and hydrogen-free polymer exhibits high thermal stability, which effectively reduces the continuous exothermic reaction between electrolyte and anode/cathode. As a result, the critical temperature for thermal safety of 1.0 Ah lithium-LiNi0.5 Co0.2 Mn0.3 O2 pouch cell can be increased from 143.2 °C to 174.2 °C. The more dangerous "ignition" point of lithium metal batteries, the starting temperature of battery thermal runaway, has been dramatically raised from 240.0 °C to 338.0 °C. This work affords novel strategies upon electrolyte design, aiming to pave the way for high-energy-density and thermally safe lithium metal batteries.

Operando Quantified Lithium Plating Determination Enabled by Dynamic Capacitance Measurement in Working Li-Ion Batteries.

The access to full performance of state-of-the-art Li-ion batteries (LIBs) is hindered by the mysterious lithium plating behavior. A rapid quantified lithium plating determination method compatible with actual working conditions is an urgent necessity for safe working LIBs. In this contribution, the relationship between electrical double layer (EDL) capacitance and electrochemical active surface area (ECSA) of graphite anodes during the Li-ion intercalation and Li plating processes is unveiled. We propose an operando lithium plating determination method based on the dynamic capacitance measurement (DCM) test. Reasonable selection of alternating current (AC) frequency protects the anodic responses from the interference of cathodic responses, which allows DCM to be applied in practical LIBs. The onset of lithium plating can be quantitatively traced, demonstrating the promise for real-time operando determination for lithium plating in a working battery.

Umbilical cord-derived mesenchymal stem cells promote myeloid-derived suppressor cell enrichment by secreting CXCL1 to prevent graft-versus-host disease after hematopoietic stem cell transplantation.

BACKGROUND AIMS: Human mesenchymal stem cells (MSCs) from various tissues have emerged as attractive candidates for the prevention and treatment of graft-versus-host disease (GVHD). However, the molecular machinery that defines and channels the behavior of these cells remains poorly understood. METHODS: In this study, the authors compared the efficacy of four tissue-derived MSC types in controlling GVHD in a murine model and investigated their immunomodulatory effects. RESULTS: Human umbilical cord-derived mesenchymal stem cells (hUCMSCs) effectively decreased the incidence and severity of GVHD, which was mediated by the enrichment of myeloid-derived suppressor cells in GVHD target tissues. RNA sequencing results showed that hUCMSCs highly expressed CXCL1. CONCLUSIONS: These results suggest a novel prophylactic application of hUCMSCs for controlling GVHD after allogeneic hematopoietic stem cell transplantation.

Cadmium exposure, fasting blood glucose changes, and type 2 diabetes mellitus: A longitudinal prospective study in China.

BACKGROUND: Cadmium is a recognized human carcinogen, raising global concern for its ubiquitously environmental exposure on public health. Diabetogenic effects of cadmium have been suggested in previous studies, but the longitudinal associations of chronic cadmium exposure with fasting blood glucose changes and type 2 diabetes mellitus have not been fully elucidated. OBJECTIVE: To investigate the effects of long-term cadmium exposure on the fasting blood glucose changes and type 2 diabetes mellitus risk in a longitudinal prospective study of China. METHODS: A total of 3521 urban adults were included as baseline study population from the Wuhan-Zhuhai cohort, and followed up three years later. Urinary cadmium concentrations were determined repeatedly during the follow-up of a three-year period. The within-person and between-person variability of urinary cadmium concentrations over three years was estimated using multilevel random-effects mixed models. Multivariate regression models were performed to evaluate the associations of cadmium exposure with fasting blood glucose changes and type 2 diabetes mellitus risk. RESULTS: The geometric means of creatinine-corrected urinary cadmium concentration at baseline were 1.13 µg/g creatinine, which were close to the levels of follow-up (1.14 µg/g creatinine). The intra-class correlation coefficient of creatinine-corrected urinary cadmium concentrations was 0.71, achieving good reproducibility of cadmium over three years. With adjustment for potential confounders, each one-unit increase in log10-transformed cadmium was associated with a 0.11 (95%CI: 0.03 to 0.19) elevation in fasting blood glucose concentration, and was associated with a 42% (95%CI: 1.16 to 1.73) increase in risk of prevalent type 2 diabetes mellitus. Upward trends of fasting blood glucose changes and type 2 diabetes mellitus incidence were observed with increasing cadmium exposure. Individuals with the highest urinary cadmium exposure had a significant increase in fasting blood glucose change at follow-up [ß (95% CI): 0.49 (0.31-0.67)]. Risk of incident type 2 diabetes mellitus were gradually elevated across increasing quartiles of cadmium exposure, though associations did not reach statistical significance (P = 0.15). CONCLUSIONS: Our findings suggested that relatively high chronic cadmium exposure for general population adults might contribute to elevated changes of fasting blood glucose resulting in the development of type 2 diabetes mellitus.

Cross-sectional and longitudinal associations between urinary zinc and lung function among urban adults in China.

BACKGROUND: Exposure to zinc was suggested to be associated with pulmonary damage, but whether zinc exposure affects lung function remains unclear. OBJECTIVES: To quantify the association between urinary zinc and lung function and explore the potential mechanisms. METHODS: Urinary zinc and lung function were measured in 3917 adults from the Wuhan-Zhuhai cohort and were repeated after 3 years of follow-up. Indicators of systemic inflammation (C reactive protein), lung epithelium integrity (club cell secretory protein-16) and oxidative damage (8-hydroxy-2'-deoxyguanosine and 8-isoprostane) were measured at baseline. Linear mixed models were used to estimate the exposure-response relationship between urinary zinc and lung function. Mediation analyses were conducted to assess mediating roles of inflammation and oxidative damage in above relationships. RESULTS: Each 1-unit increase in log-transformed urinary zinc values was associated with a 35.72 mL decrease in forced vital capacity (FVC) and a 24.89 mL decrease in forced expiratory volume in 1 s (FEV1) in the baseline analyses. In the follow-up analyses, there was a negative association between urinary zinc and FVC among participants with persistent high urinary zinc levels, with an estimated change of -93.31 mL (95% CI -178.47 to -8.14). Furthermore, urinary zinc was positively associated with restrictive ventilatory impairment. The mediation analyses suggested that C reactive protein mediated 8.62% and 8.71% of the associations of urinary zinc with FVC and FEV1, respectively. CONCLUSION: Urinary zinc was negatively associated with lung function, and the systemic inflammation may be one of the underlying mechanisms.

Oxidative damage mediates the association between polycyclic aromatic hydrocarbon exposure and lung function.

BACKGROUND: Exposure to polycyclic aromatic hydrocarbons (PAHs) is related to decreased lung function. However, whether oxidative damage is involved in this relationship remains unclear. This study was aimed to explore the potential mediating role of oxidative DNA or lipid damage in the association between PAH exposure and lung function. METHODS: The urinary levels of monohydroxy polycyclic aromatic hydrocarbon metabolites (OH-PAHs) and lung function parameters were measured among 3367 participants from the baseline of the Wuhan-Zhuhai cohort. Urinary 8-hydroxy-2'-deoxyguanosine (8-OHdG) and 8-isoprostane (8-iso-PGF2α) were determined to evaluate the individuals' oxidative DNA and lipid damage degrees, respectively. Linear mixed models were used to investigate the associations of urinary OH-PAHs, 8-OHdG and 8-iso-PGF2α with lung function parameters. Mediation analysis was further conducted to assess the potential role of oxidative damage in the association between urinary OH-PAHs and lung function. RESULTS: Each one-percentage increase in the sum of urinary OH-PAHs, high-molecular-weight or low-molecular-weight OH-PAHs (Æ©OH-PAHs, Æ©HMW OH-PAH or Æ©LMW OH-PAHs, respectively) was associated with a 0.2152-, 0.2076- or 0.1985- ml decrease in FEV1, and a 0.1891-, 0.2195- or 0.1634- ml decrease in FVC, respectively. Additionally, significantly positive dose-response relationships of Æ©OH-PAHs, Æ©HMW OH-PAH and Æ©LMW OH-PAHs with urinary 8-OHdG or 8-iso-PGF2α, as well as an inverse dose-response relationship between urinary 8-OHdG and FVC, were observed (all P for trend < 0.05). Mediation analysis indicated that urinary 8-OHdG mediated 14.22% of the association between Æ©HMW OH-PAH and FVC. CONCLUSION: Higher levels of oxidative DNA damage might be involved in the decreased levels of FVC caused by high-molecular-weight PAH exposure.

"Four-Step Procedure" of laparoscopic exploration for gastric cancer in West China Hospital: a retrospective observational analysis from a high-volume institution in China.

BACKGROUND: The preoperative work-up has limitations on finding peritoneal dissemination (PD) in gastric cancer patients. Laparoscopic exploration (LE) can discover radiographically occult PD, obtain accurate stage and avert futile laparotomy. The aim of our study was to introduce "Four-Step Procedure" LE in West China Hospital and further evaluate its safety and feasibility. METHODS: We conducted a retrospective analysis on 165 patients from July 2016 to December 2017 who underwent "Four-Step Procedure" LE in gastrointestinal surgery department of West China Hospital. All the patients were diagnosed with gastric adenocarcinoma without explicit distant metastasis through Computed Tomography and/or Gastrointestinal Ultrasonography. Peritoneal lavage cytological examination (CY) was routinely performed during LE in our research. The "Four-Step" technical process of LE was introduced comprehensively. The clinicopathologic features and the presence of PD or CY at LE were analyzed, and the stratified analysis by cT and cN stages on the proportion of P1 and/or CY1 was also reported in this study. RESULTS: Total of 165 patients accepted LE in our study, among these patients: 27 (16.4%) patients with P1 and/or CY1: 19 (11.5%) patients were found PD (P1), 17 (10.3%) patients with positive cytological examination (CY1) and 9 (3.6%) patients with P1Cy1. The stratified analysis by cT stage indicated that there was no P1 and/or Cy1 in cT1-cT2 stages, 1 (2.7%) patient with P1 and 1 (2.7%) with Cy1 in cT3 stage, 18 (20.0%) patients with P1 and 16 (17.8%) with Cy1 in cT4 stage. After LE, there were 74 (44.8%) patients underwent laparoscopic assistant gastrectomy, 25 (15.2%) patients with open gastrectomy, 50 (30.3%) patients with neoadjuvant chemotherapy and 16 (9.7%) patients with palliative chemotherapy and/or conversion therapy. CONCLUSION: "Four-Step Procedure" LE is reliable and feasible for gastric cancer. From our study, LE has unique superiority on ascertaining PD and cytological examination and LE should be recommended in cT4 stage gastric cancer before resection.

Chronic Intermittent Hypobaric Hypoxia Pretreatment Ameliorates Ischemia-Induced Cognitive Dysfunction Through Activation of ERK1/2-CREB-BDNF Pathway in Anesthetized Mice.

Chronic intermittent hypobaric hypoxia (CIHH) has protective effects on heart and brain against ischemia injury through mobilizing endogenous adaptive mechanisms. However, whether CIHH prevents against cognitive impairment was not elucidated. The present study aimed to investigate the effect and mechanism of CIHH treatment on ischemia/reperfusion (IR)-induced cognitive dysfunction. Mice were randomly divided into 8 groups: Control, Sham, CIHH (simulating 5000 m high-altitude for 28 days, 6 h per day), IR (three 16-min occlusions of bilateral common carotid arteries interrupted by two 10-min intervals), CIHH + IR, PD98059 (inhibitor of MEK1/2) + CIHH + IR, PD98059 + Sham and PD98059 + IR group. Morris water maze and step-down passive avoidance tests were performed to evaluate the capability of learning and memory 1 month after ischemia. Thionine dyeing was to examine histological manifestations of pyramidal neurons in hippocampus CA1 region. Western blotting assay was for measurement of the protein expressions in ERK1/2-CREB-BDNF signaling pathway. There were a shorter escape latency and a longer percentage of time retaining in the target quadrant in Morris water maze test, fewer times of errors in the step-down avoidance test and a higher neuronal density of the hippocampal CA1 subfield in CIHH + IR group than in IR group. CIHH upregulated the expressions of BDNF, phosphorylated CREB, ERK1/2 and TrkB with or without ischemia. The protective effects of CIHH were abolished by PD98059 administration 15 min before ischemia. CIHH ameliorated ischemia-induced cognitive dysfunction through activation of ERK1/2-CREB-BDNF signaling pathway.