Dongguan People’s Hospital

Cancer-derived exosomes are considered a major driver of cancer-induced pre-metastatic niche formation at foreign sites, but the mechanisms remain unclear. Here, we show that miR-25-3p, a metastasis-promoting miRNA of colorectal cancer (CRC), can be transferred from CRC cells to endothelial cells via exosomes. Exosomal miR-25-3p regulates the expression of VEGFR2, ZO-1, occludin and Claudin5 in endothelial cells by targeting KLF2 and KLF4, consequently promotes vascular permeability and angiogenesis. In addition, exosomal miR-25-3p from CRC cells dramatically induces vascular leakiness and enhances CRC metastasis in liver and lung of mice. Moreover, the expression level of miR-25-3p from circulating exosomes is significantly higher in CRC patients with metastasis than those without metastasis. Our work suggests that exosomal miR-25-3p is involved in pre-metastatic niche formation and may be used as a blood-based biomarker for CRC metastasis.

Chemotherapy is still one of the principal treatments for gastric cancer, but the clinical application of 5-FU is limited by drug resistance. Here, we demonstrate that ferroptosis triggered by STAT3 inhibition may provide a novel opportunity to explore a new effective therapeutic strategy for gastric cancer and chemotherapy resistance. We find that ferroptosis negative regulation (FNR) signatures are closely correlated with the progression and chemoresistance of gastric cancer. FNR associated genes (GPX4, SLC7A11, and FTH1) and STAT3 are upregulated in 5-FU resistant cells and xenografts. Further evidence demonstrates that STAT3 binds to consensus DNA response elements in the promoters of the FNR associated genes (GPX4, SLC7A11, and FTH1) and regulates their expression, thereby establishing a negative STAT3-ferroptosis regulatory axis in gastric cancer. Genetic inhibition of STAT3 activity triggers ferroptosis through lipid peroxidation and Fe2+ accumulation in gastric cancer cells. We further develop a potent and selective STAT3 inhibitor, W1131, which demonstrates significant anti-tumor effects in gastric cancer cell xenograft model, organoids model, and patient-derived xenografts (PDX) model partly by inducing ferroptosis, thus providing a new candidate compound for advanced gastric cancer. Moreover, targeting the STAT3-ferroptosis circuit promotes ferroptosis and restores sensitivity to chemotherapy. Our finding reveals that STAT3 acts as a key negative regulator of ferroptosis in gastric cancer through a multi-pronged mechanism and provides a new therapeutic strategy for advanced gastric cancer and chemotherapy resistance.

As of March 24, 2020, novel severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has been responsible for 379,661 infection cases with 16,428 deaths globally, and the number is still increasing rapidly. Herein, we present four critically ill patients with SARS-CoV-2 infection who received supportive care and convalescent plasma. Although all four patients (including a pregnant woman) recovered from SARS-CoV-2 infection eventually, randomized trials are needed to eliminate the effect of other treatments and investigate the safety and efficacy of convalescent plasma therapy. As of March 24, 2020, novel severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has been responsible for 379,661 infection cases with 16,428 deaths globally, and the number is still increasing rapidly. Herein, we present four critically ill patients with SARS-CoV-2 infection who received supportive care and convalescent plasma. Although all four patients (including a pregnant woman) recovered from SARS-CoV-2 infection eventually, randomized trials are needed to eliminate the effect of other treatments and investigate the safety and efficacy of convalescent plasma therapy. An outbreak of novel severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection first appeared in Wuhan, China,1Guan WJ, Ni ZY, Hu Y, et al. Clinical characteristics of coronavirus disease 2019 in China [published online ahead of print February 28, 2020]. N Engl J Med. https://doi.org/10.1056/NEJMoa2002032.Google Scholar and rapidly spread to 171 countries. As of March 24, 2020, the virus has been responsible for 379,661 confirmed cases and 16,428 deaths worldwide. To date, no specific treatment has been recommended for SARS-CoV-2 infection except for meticulous supportive care.2Chen N. Zhou M. Dong X. et al.Epidemiological and clinical characteristics of 99 cases of 2019 novel coronavirus pneumonia in Wuhan, China: a descriptive study.Lancet. 2020; 395: 507-513Abstract Full Text Full Text PDF PubMed Scopus (13646) Google Scholar Numerous therapeutics have been explored or developed during the outbreak. A recent trial showed lopinavir-ritonavir has no treatment benefit for severe illness caused by SARS-CoV-2.3Cao B, Wang Y, Wen D, et al. A trial of lopinavir-ritonavir in adults hospitalized with severe Covid-19 [published online ahead of print March 18, 2020]. N Engl J Med. https://doi.org/10.1056/NEJMe2005477.Google Scholar Immunotherapy with virus-specific antibodies in convalescent plasma had been used as a last resort to improve the survival rate of patients with serious infectious diseases, such as severe acute respiratory syndrome, middle east respiratory syndrome coronavirus, Ebola virus disease, pandemic influenza A, and avian-origin influenza A.4Chen L, Xiong J, Bao L, et al. Convalescent plasma as a potential therapy for COVID-19 [published online ahead of print February 27, 2020]. Lancet Infect Dis. https://doi.org/10.1016/S1473-3099(20)30141-9.Google Scholar Previous reports have shown treatment with convalescent plasma collated from recovered patients could reduce the hospital stay and mortality of patients.5Soo Y.O. Cheng Y. Wong R. et al.Retrospective comparison of convalescent plasma with continuing high-dose methylprednisolone treatment in SARS patients.Clin Microbiol Infect. 2004; 10: 676-678Abstract Full Text Full Text PDF PubMed Scopus (309) Google Scholar, 6Cheng Y. Wong R. Soo Y.O. et al.Use of convalescent plasma therapy in SARS patients in Hong Kong.Eur J Clin Microbiol Infect Dis. 2005; 24: 44-46Crossref PubMed Scopus (728) Google Scholar, 7Lai S.T. Treatment of severe acute respiratory syndrome.Eur J Clin Microbiol Infect Dis. 2005; 24: 583-591Crossref PubMed Scopus (92) Google Scholar However, the efficacy of convalescent plasma in critically ill patients with SARS-CoV-2 infection remains unclear. Herein, we report the disease course on four critically ill patients infected with SARS-CoV-2 and treated with supportive care and convalescent plasma. Figure 1 shows the clinical course of four critically ill patients infected with SARS-CoV-2. The first case is a 69-year-old woman with a history of hypertension who presented with fever for 2 days and clear sputum for 5 days. On January 30, the patient was admitted to Dongguan Ninth People’s Hospital because of positive reverse transcriptase polymerase chain reaction (RT-PCR) test of throat swab by Dongguan Center for Disease Control (CDC). A chest CT scan revealed bilateral ground-glass opacities primarily distributed along the pleura. Treatment with arbidol (200 mg three times daily), lopinavir-ritonavir (400 mg twice daily), interferon alpha inhalation (50 μg twice daily), and other supportive therapies was started. At 4 pm on February 4, the patient’s Po2 decreased to 56.5 mm Hg with an oxygenation index (OI) (Po2/Fio2) of 94 mm Hg. Significantly increased consolidation was observed in the right lung. The patient was transferred to the ICU of Dongguan People’s Hospital (a designated center for critical illness treatment) on February 5 and received invasive mechanical ventilation. Apart from antiviral drugs (lopinavir-ritonavir, oseltamivir, and interferon alpha), human albumin, zadaxin and immunoglobulin, and antibacterial and antifungal drugs were administrated because of coinfection with bacteria and Aspergillus. At 6:30 pm on February 11, the patient’s Po2 was 58 mm Hg. She experienced septic shock with BP of 89/44 mm Hg 5 h later. Hypohemoglobin (92 g/L) and bloody sputum under bronchoscopy suggested pneumorrhagia. A bedside chest radiograph showed obvious progression of disease. Although the patient was successfully rescued, follow-up chest radiographs showed continuous progression of pneumonia. A total of 900 mL O-compatible convalescent plasma was transfused to the patient in three batches; the first batch was given at 8 am on February 17 (200 mL), the second one was at 8 am on February 27 (400 mL), and the last one was at 8 am on February 28 (300 mL). The virus load of the patient on February 18 was 55 × 105 copies/mL, which significantly decreased to 3.9 × 104 copies/mL on February 28, and further decreased to 180 copies/mL on March 5. The patient was extubated and noninvasion ventilation was given on March 3. Chest CT scans obtained on February 27, March 6, and March 15 showed persistent absorption of consolidation. The results of two repeat RT-PCR tests of oropharyngeal swabs (with at least 1-day interval) performed on March 9 and 11 were negative. The patient was discharged on March 13. The second case was a 55-year-old man with a history of COPD who was admitted to a fever clinic of Xiangtan Central Hospital on February 5, 2020. He had nausea, poor appetite, and cough with clear sputum for 4 days. The results of RT-PCR assay of throat swab were positive for SARS-CoV-2 infection. A chest CT scan obtained on February 6 revealed interlobular septal thickening with honeycombing change in the right upper lung. The patient started to receive antiviral treatment, including arbidol (200 mg three times daily), lopinavir-ritonavir (500 mg twice daily), and interferon alpha-2b (5 million units twice daily). After 2 days, he complained of shortness of breath and his Po2 decreased to 50 mm Hg with an OI of 135 mm Hg. The patient was therefore diagnosed with ARDS and began to receive noninvasive mechanical ventilation and oxygen therapy through high-flow nasal cannula alternately. However, the conditions of the patient continued to deteriorate despite treatment with pulsed methylprednisolone. His Po2 oscillated between 46 and 83 mm Hg, and symptoms were not improved. Follow-up chest CT scans obtained on February 9 to 16 showed interstitial pneumonia extended to both lungs. At 3 pm on February 16, 200 mL convalescent plasma obtained from a patient recovered from SARS-CoV-2 infection in January 2020 was transfused to the patient. No adverse reactions were observed. One day later, his Po2 increased to 97 mm Hg with an OI of 198 mm Hg. All drugs were discontinued except for methylprednisolone. Chest images obtained on February 17 to 21 showed obvious absorption of interstitial pneumonia. Three repetitive RT-PCR test results were negative from February 20 to 22. The patient recovered and was discharged on February 23. He was asked to continue the quarantine at home for 14 days and receive home oxygen therapy. The third case was a 73-year-old man who was admitted to Dongguan Ninth People’s Hospital on February 2 because of self-reported dry cough for 4 days. He had a history of hypertension and chronic renal failure. On February 3, the patient was confirmed as being infected with SARS-CoV-2 by a virus RNA detection kit. At 11:30 pm, the patient developed acute respiratory failure with Po2 of 53 mm Hg and OI of 124 mm Hg; high-flow oxygen through face mask was given. He was then transferred to the isolation wards of the ICU of Dongguan People’s Hospital for further treatment. A chest radiograph showed bilateral infiltrative shadows. The viral load of the patient was as high as 85 × 105 copies/mL. The patient was treated with arbidol (200 mg three times daily), lopinavir-ritonavir (400 mg twice daily), oseltamivir (75 mg twice daily), and ribavirin and interferon alpha-2b (5 million units twice daily). On February 5, the patient was given tracheal intubation because of dyspnea and consistent decrease of oxygen saturation. On February 11, continuous renal replacement therapy (CRRT) was started on the patient. Laboratory tests obtained on February 14 showed significantly increased WBCs of 33.93 × 109/L and neutrophils of 31.08 × 109/L. He was diagnosed with multiple organ failure by clinical examination. On February 15, the patient developed septic shock and his BP decreased to 90/68 mm Hg with heart rate of 149 beat/min and respiratory rate of 30 breaths/min. A chest radiograph showed bilateral white lung. At 12:55 pm on February 15, the patient started to receive veno-venous extracorporeal membrane oxygenation, whereas the OI was unstable and symptoms were not improved. High-throughput DNA sequencing of sputum suggested Aspergillus infection. The patient was therefore treated with caspofungin and voriconazole. Eight transfusions of B-compatible convalescent plasma (2,400 mL) were given to the patient from February 16 to March 13. On February 21, the patient was confirmed positive for active pneumorrhagia, cystorrhagia, and GI bleeding. Antibody testing on February 27 indicated positive anti-SARS-CoV-2 IgG. The viral load was reduced (detailed values were not available). Follow-up chest radiographs showed absorbed infiltrative lesions but pneumothorax. Two repeat RT-PCR tests of sputum in deep lungs on March 16 and 17 (with at least 1-day interval) were negative and the serum IgM level decreased to the normal range. On March 22, the patient was transferred to the unfenced ICU for further treatment of underlying diseases and multiple organ failure. The fourth case was a 31-year-old pregnant woman (35 weeks and 2 days) who was admitted to Xiaolan People’s Hospital of Zhongshan on February 1 because of pharyngalgia for 4 days and fever (39.3°C) and difficulty breathing for half-day. The patient was confirmed as being infected with SARS-CoV-2 by Zhongshan CDC. A chest CT scan showed opacities in the lower lobe of the left lung. After admission, the patient developed severe ARDS, multiple organ dysfunction syndrome, and septic shock. Invasive ventilation and caesarean section were therefore given to the patient. Unfortunately, the newborn died of endouterine asphyxia. After the conditions turned stable, she was transferred to the Second People’s Hospital of Zhongshan (a designated hospital for SARS-CoV-2 treatment) at 1:04 am on February 2. Amounts of frothy sputum was observed under bronchofiberscope. Cardiac ultrasound suggested left ventricular enlargement with decreased systolic function. The patient received invasive ventilation and CRRT. Treatment with lopinavir-ritonavir (400 mg twice daily) and ribavirin (500 mg every 12 h) was started on February 2. Gram-positive bacteria were detected by blood culture, and imipenem and vancomycin were given to the patient. A chest radiograph showed increased consolidation and extended opacities. Oxygen saturation oscillated between 85% and 92% with an OI between 60 and 75 mm Hg. At 12 am on February 6, the patient started to receive veno-venous extracorporeal membrane oxygenation (flow rate: 3 L/min). Her OI was significantly improved (with a maximum of 200 mm Hg). Follow-up chest radiographs showed partial absorption of opacities. Left ventricular systolic function returned to normal. At 11:30 am on February 19, a 300-mL transfusion of convalescent plasma was given to the patient. On February 27, CRRT and extracorporeal membrane oxygenation (ECMO) were removed. On March 11, trachea cannula was removed and nasal oxygen was given to the patient. On March 6, 8, and 11, anti-SARS-CoV-2 IgM changed from positive to weakly positive to negative, whereas anti-SARS-CoV-2 IgG was persistently positive. Follow-up chest CT scan showed near-complete absorption of opacities. The results of two continual RT-PCR tests of BAL fluid on March 11 and 14 were both negative. The patient recovered from SARS-CoV-2 infection and was discharged on March 17. A recent retrospective review of 72,314 SARS-CoV-2-infected cases by the China CDC showed that 5% of cases were critical illness characterized by respiratory failure, septic shock, and/or multiple organ dysfunction or failure.8Zunyou W, McGoogan JM. Characteristics of and important lessons from the coronavirus disease 2019 (COVID-19) outbreak in China: summary of a report of 72 314 cases from the Chinese Center for Disease Control and Prevention [published online ahead of print February 24, 2020]. JAMA. https://doi.org/10.1001/jama.2020.2648.Google Scholar Around 48% of patients infected with SARS-CoV-2 had comorbid conditions, commonly cardiovascular diseases and diabetes.9Zhou F, Yu T, Du R, et al. Clinical course and risk factors for mortality of adult inpatients with COVID-19 in Wuhan, China: a retrospective cohort study [published online ahead of print March 11, 2020]. Lancet. https://doi.org/10.1016/S0140-6736(20)30566-3.Google Scholar Older adults with underlying diseases were more likely to have a higher Sequential Organ Failure Assessment score and higher risk of death. The treatment of SARS-CoV-2 infection faces compelling challenges. To date, no therapeutics have yet been proven effective for the treatment of the critical illness except for supportive care, including treatment with antiviral drugs, corticosteroids, immunoglobulins, and noninvasive or invasive mechanical ventilation. The most critically ill patients infected with SARS-CoV-2 have elevated levels of infection-related biomarkers and inflammatory cytokines, indicating potential bacterial coinfection caused by a dysregulated immune system.10Qin C, Zhou L, Hu Z, et al. Dysregulation of immune response in patients with COVID-19 in Wuhan, China [published online ahead of print March 12, 2020]. Clin Infect Dis. https://doi.org/10.1093/cid/ciaa248.Google Scholar Antibacterial drugs are therefore given to these patients. Management of critical SARS-CoV-2 infection is not different from management of most viral pneumonia causing respiratory failure. The principal feature of patients with the critical illness is the development of ARDS. ECMO is recommended by World Health Organization interim guidelines to support eligible patients with ARDS, while the use of which is restricted to specialized centers globally and technology challenges.11Ramanathan K, Antognini D, Combes A, et al. Planning and provision of ECMO services for severe ARDS during the COVID-19 pandemic and other outbreaks of emerging infectious diseases [published online ahead of print March 20, 2020]. Lancet Respir Med. https://doi.org/10.1016/S2213-2600(20)30121-1.Google Scholar In this study, two patients were treated with ECMO, but the efficacy was mixed. Apart from ARDS, other life-threatening conditions including septic shock and multiple organ dysfunction or failure may occur in a substantial proportion of patients with SARS-CoV-2-related critical illness, the management of which is according to current evidence-based guidelines.12De Backer D. Dorman T. Surviving sepsis guidelines: a continuous move toward better care of patients with sepsis.JAMA. 2017; 317: 807-808Crossref PubMed Scopus (67) Google Scholar In China, if the current therapeutic strategies are not satisfactory for critically ill patients, physicians might turn to convalescent plasma transfusion based on the Pneumonitis Diagnosis and Treatment Program for SARS-CoV-2 infection (Trial Version 7). Convalescent plasma has been used as a last resort to improve the survival rate of patients with severe acute respiratory syndrome infection. Previous evidence has proven that convalescent plasma treatment can significantly reduce the relative risk of mortality of patients,13Hung I.F. To K.K. Lee C.K. et al.Convalescent plasma treatment reduced mortality in patients with severe pandemic influenza A (H1N1) 2009 virus infection.Clin Infect Dis. 2011; 52: 447-456Crossref PubMed Scopus (534) Google Scholar which may be because antibodies from convalescent plasma might suppress viremia. The level of SARS-CoV-2 neutralizing antibodies in donor plasma could be important for the effectiveness of intervention. However, the level of neutralizing antibodies in donor plasma before transfusion cannot be determined. In this study, three patients were tested for either virus load or antibodies IgM and IgG. In the first case, SARS-CoV-2 virus load after convalescent plasma transfusion significantly dropped (from 55 × 105 to 3.9 × 104 to 180 copies/mL). Among the four patients, the time from transfusion to negative RT-PCR test results ranged from 3 to 22 days. The third and fourth cases produced anti-SARS-CoV-2 IgG approximately 14 days after convalescent plasma transfusion. Patients who survive critical illness might mount higher antibody responses, which can persist for longer periods compared with those with nonsevere disease.14Chen J. Zhu H. Horby P.W. et al.Specificity, kinetics and longevity of antibody responses to avian influenza A (H7N9) virus infection in humans.J Infect. 2020; 80: 310-319Abstract Full Text Full Text PDF PubMed Scopus (8) Google Scholar The antibody levels, however, are confounded by other treatments, such as antiviral drugs, steroids, and IV immunoglobulin.15Luke T.C. Kilbane E.M. Jackson J.L. Hoffman S.L. Meta-analysis: convalescent blood products for Spanish influenza pneumonia: a future H5N1 treatment?.Ann Intern Med. 2006; 145: 599-609Crossref PubMed Scopus (487) Google Scholar A recent animal model indicated that antibodies produced from SARS-CoV-2 infection could protect from subsequent exposures.16Bao L, Deng W, Gao H, et al. Reinfection could not occur in SARS-CoV-2 infected rhesus macaques [published online ahead of print March 13, 2020]. bioRxiv. https://doi.org/10.1101/2020.03.13.990226.Google Scholar Our results indicate convalescent plasma might be a potential therapy for critically ill patients infected with SARS-CoV-2. We observed no serious adverse reactions associated with the transfusion of convalescent plasma. However, the relative contributions of supportive care, investigational therapies, and patient’s immune response on survival could not be determined. Whether convalescent plasma and/or supportive care provide any clinical benefit is unknown. The safety and efficacy of convalescent plasma transfusion in patients infected with SARS-CoV-2 should be studied within the context of a well-designed clinical trial.

PURPOSE Lenvatinib (LEN) is a first-line therapy for patients with advanced hepatocellular carcinoma (HCC); however, it has shown modest survival benefits. Therefore, we aimed to compare clinical outcomes of LEN combined with transarterial chemoembolization (LEN-TACE) versus LEN monotherapy in patients with advanced HCC. MATERIALS AND METHODS This was a multicenter, randomized, open-label, parallel group, phase III trial. Patients with primary treatment-naive or initial recurrent advanced HCC after surgery were randomly assigned (1:1) to receive LEN plus on-demand TACE (LEN-TACE) or LEN monotherapy. LEN was initiated within 3 days after random assignment (initial dose: 12 mg once daily for patients ≥ 60 kg; 8 mg once daily for patients < 60 kg). TACE was initiated one day after LEN initiation. The primary end point was overall survival (OS). RESULTS Between June 2019 and July 2021, a total of 338 patients underwent random assignment at 12 centers in China: 170 to LEN-TACE and 168 to LEN. At a prespecified event-driven interim analysis after a median follow-up of 17.0 months, the median OS was significantly longer in the LEN-TACE group (17.8 v 11.5 months; hazard ratio, 0.45; P < .001). The median progression-free survival was 10.6 months in the LEN-TACE group and 6.4 months in the LEN group (hazard ratio, 0.43; P < .001). Patients in the LEN-TACE group had a higher objective response rate according to the modified RECIST (54.1% v 25.0%, P < .001). Multivariable analysis revealed that portal vein tumor thrombus and treatment allocation were independent risk factors for OS. CONCLUSION The addition of TACE to LEN improves clinical outcomes and is a potential first-line treatment for patients with advanced HCC.

UNLABELLED: Our study aimed to investigate the short-term efficacy and long-term prognosis of liver failure patients caused by hepatitis B after a single transplantation with autologous marrow mesenchymal stem cells (MMSCs). A total of 527 inpatients with liver failure caused by hepatitis B were recruited and received the same medical treatments, among whom 53 patients underwent a single transplantation with autologous MMSCs. A total of 105 patients matched for age, sex, and biochemical indexes, including alanine aminotransferase (ALT), albumin, total bilirubin (TBIL), prothrombin time (PT), and Model for End-Stage Liver Disease (MELD), comprised the control group. A total of 120 mL of bone marrow was obtained from each patient and then diluted and separated. Then, the MMSC suspension was slowly transfused into the liver through the proper hepatic artery. The success rate of transplantation was 100%, without serious side effects or complications. Levels of ALB, TBIL, and PT and MELD score of patients in the transplantation group were markedly improved from 2-3 weeks after transplantation, compared with those in the control group. At 192 weeks of follow-up, there were no dramatic differences in incidence of hepatocellular carcinoma (HCC) or mortality between the two groups. Additionally, there were no significant differences in the incidence of HCC or mortality between patients with and without cirrhosis in the transplantation group. CONCLUSION: Autologous MMSC transplantation is safe for liver failure patients caused by chronic hepatitis B. Short-term efficacy was favorable, but long-term outcomes were not markedly improved. In respect to several parameters, this method is preferable for patients with liver cirrhosis and may have potential for reducing their incidence of HCC and mortality.

Introduction: To assess the role of the 21-gene recurrence score (RS) assay on decision-making of postoperative radiotherapy (RT) following breast-conserving surgery (BCS) in elderly women with early-stage breast cancer. Methods: The 21-gene RS for elderly (≥65 years) women with stage T1–2N0M0 estrogen receptor-positive breast cancer who underwent BCS from 2004 to 2015 was obtained from the Surveillance, Epidemiology, and End Results program. We estimated the association of 21-gene RS and adjuvant RT related to breast cancer-specific survival (BCSS) using propensity score matching (PSM). Results: We identified 18,456 patients, of which 15,326 (83.0%) received postoperative RT. Of identified patients, 58.9%, 34.0%, and 7.1% of patients had a low-, intermediate-, and high-risk RS, respectively. Receipt of postoperative RT was not related to the year of diagnosis according to the 21-gene RS groups. Multivariate analysis suggested that receipt of postoperative RT was an independent predictor of better BCSS before (hazard ratio [HR] 0.587, 95% confidence interval [CI] 0.426–0.809, P = 0.001) and after (HR 0.613, 95%CI 0.390–0.963, P = 0.034) PSM. However, subgroups analyses indicated that receipt of postoperative RT was related to better BCSS in women with intermediate-risk RS before (HR 0.467, 95%CI 0.283–0.772, P = 0.003) and after (HR 0.389, 95%CI 0.179–0.846, P = 0.017) PSM, but not in women with low- and high-risk RS groups before and after PSM. Conclusions: Although causation cannot be implied, adjuvant RT in elderly women was associated with a greater effect size in patients with an intermediate-risk RS.

Human-machine interaction (HMI) technology shows an important application prospect in rehabilitation medicine, but it is greatly limited by the unsatisfactory recognition accuracy and wearing comfort. Here, this work develops a fully flexible, conformable, and functionalized multimodal HMI interface consisting of hydrogel-based sensors and a self-designed flexible printed circuit board. Thanks to the component regulation and structural design of the hydrogel, both electromyogram (EMG) and forcemyography (FMG) signals can be collected accurately and stably, so that they are later decoded with the assistance of artificial intelligence (AI). Compared with traditional multichannel EMG signals, the multimodal human-machine interaction method based on the combination of EMG and FMG signals significantly improves the efficiency of human-machine interaction by increasing the information entropy of the interaction signals. The decoding accuracy of the interaction signals from only two channels for different gestures reaches 91.28%. The resulting AI-powered active rehabilitation system can control a pneumatic robotic glove to assist stroke patients in completing movements according to the recognized human motion intention. Moreover, this HMI interface is further generalized and applied to other remote sensing platforms, such as manipulators, intelligent cars, and drones, paving the way for the design of future intelligent robot systems.

OBJECTIVE: To identify an optimal lifestyle profile to protect against memory loss in older individuals. DESIGN: Population based, prospective cohort study. SETTING: Participants from areas representative of the north, south, and west of China. PARTICIPANTS: Individuals aged 60 years or older who had normal cognition and underwent apolipoprotein E (APOE) genotyping at baseline in 2009. MAIN OUTCOME MEASURES: Participants were followed up until death, discontinuation, or 26 December 2019. Six healthy lifestyle factors were assessed: a healthy diet (adherence to the recommended intake of at least 7 of 12 eligible food items), regular physical exercise (≥150 min of moderate intensity or ≥75 min of vigorous intensity, per week), active social contact (≥twice per week), active cognitive activity (≥twice per week), never or previously smoked, and never drinking alcohol. Participants were categorised into the favourable group if they had four to six healthy lifestyle factors, into the average group for two to three factors, and into the unfavourable group for zero to one factor. Memory function was assessed using the World Health Organization/University of California-Los Angeles Auditory Verbal Learning Test, and global cognition was assessed via the Mini-Mental State Examination. Linear mixed models were used to explore the impact of lifestyle factors on memory in the study sample. RESULTS: 29 072 participants were included (mean age of 72.23 years; 48.54% (n=14 113) were women; and 20.43% (n=5939) were APOE ε4 carriers). Over the 10 year follow-up period (2009-19), participants in the favourable group had slower memory decline than those in the unfavourable group (by 0.028 points/year, 95% confidence interval 0.023 to 0.032, P<0.001). APOE ε4 carriers with favourable (0.027, 95% confidence interval 0.023 to 0.031) and average (0.014, 0.010 to 0.019) lifestyles exhibited a slower memory decline than those with unfavourable lifestyles. Among people who were not carriers of APOE ε4, similar results were observed among participants in the favourable (0.029 points/year, 95% confidence interval 0.019 to 0.039) and average (0.019, 0.011 to 0.027) groups compared with those in the unfavourable group. APOE ε4 status and lifestyle profiles did not show a significant interaction effect on memory decline (P=0.52). CONCLUSION: A healthy lifestyle is associated with slower memory decline, even in the presence of the APOE ε4 allele. This study might offer important information to protect older adults against memory decline. TRIAL REGISTRATION: ClinicalTrials.gov NCT03653156.

BACKGROUND: Neuroinflammation-induced injury is intimately associated with poor prognosis in patients with cerebral venous sinus thrombosis (CVST). The cyclic GMP-AMP synthase-stimulator of interferon gene (cGAS-STING) axis is a cytoplasmic double-stranded DNA (dsDNA) sensing pathway has recently emerged as a crucial mediator of neuroinflammation in ischemic stroke. However, the role of the cGAS-STING pathway in modulating post-CVST inflammation and the underlying mechanisms involved remain unclear. METHODS: A CVST model was induced by ferric chloride in male C57BL/6J mice. The selective cGAS inhibitor RU.521, STING agonist 2'3'-cGAMP, and STING siRNA were delivered by intranasal administration or intraventricular injection. Post-CVST assessments included rotarod test, TUNEL staining, Fluoro-Jade C staining, dihydroethidium staining, western blotting, qPCR, immunofluorescence, immunohistochemistry, ELISA and flow cytometry. RESULTS: cGAS, STING, NLRP3 and GSDMD were significantly upregulated after CVST and mostly in the microglia of the mouse brain. CVST triggered the release of dsDNA into the cytoplasm and elicited an inflammatory response via activating the cGAS-STING axis. RU.521 decreased the levels of 2'3'-cGAMP, STING and downstream inflammatory cytokines, and suppressed the expressions of NLRP3 inflammasome and pyroptosis-pertinent components containing cleaved caspase-1, GSDMD, GSDMD-C, pro- and cleaved IL-1β, and cleaved IL-1β/pro-IL-1β. Besides, RU.521 treatment also reduced oxidative stress, lessened the numbers of microglia and neutrophils, and ameliorated neuronal apoptosis, degeneration along with neurological deficits post-CVST. 2'3'-cGAMP delivery enhanced the expressions of STING and related inflammatory mediators, NLRP3 inflammasome and pyroptosis-relevant proteins, whereas these alterations were significantly abrogated by the silencing of STING by siRNA. CONCLUSIONS: Our data demonstrate that repression of the cGAS-STING pathway diminishes the neuroinflammatory burden of CVST and highlight this approach as a potential therapeutic tactic in CVST-mediated pathologies.

Abstract Hard carbon is considered as one of the most promising anodes in sodium‐ion batteries due to its high capacity, low cost, and abundant resources. However, the available capacity and low initial Coulombic efficiency (ICE) limits the practical application of hard carbon anode. This issue results from the unclear understanding of the Na + storage mechanism in hard carbon. In this work, a series of hard carbons with different microstructures are synthesized through an “up to down” approach by using a simple ball‐milling method to illustrate the sodium‐ion storage mechanism. The results demonstrate that ball‐milled hard carbon with more defects and smaller microcrystalline size shows less low‐potential‐plateau capacity and lower ICE, which provides further evidence to the “adsorption–insertion” mechanism. This work might give a new perspective to design hard carbon material with a proper structure for efficient sodium‐ion storage to develop high‐performance sodium‐ion batteries.

fibroblasts show potential anti-tumor functions in adjacent non-cancerous regions. Fibroblast-subtype compositions define patient subtypes with distinct clinical outcomes. This study advances our understanding of fibroblast biology and suggests potential therapeutic strategies for targeting specific fibroblast subsets in cancer treatment.

Hemoglobinopathies are among the most common autosomal-recessive disorders worldwide. A comprehensive next-generation sequencing (NGS) test would greatly facilitate screening and diagnosis of these disorders. An NGS panel targeting the coding regions of hemoglobin genes and four modifier genes was designed. We validated the assay by using 2522 subjects affected with hemoglobinopathies and applied it to carrier testing in a cohort of 10,111 couples who were also screened through traditional methods. In the clinical genotyping analysis of 1182 β-thalassemia subjects, we identified a group of additional variants that can be used for accurate diagnosis. In the molecular screening analysis of the 10,111 couples, we detected 4180 individuals in total who carried 4840 mutant alleles, and identified 186 couples at risk of having affected offspring. 12.1% of the pathogenic or likely pathogenic variants identified by our NGS assay, which were undetectable by traditional methods. Compared with the traditional methods, our assay identified an additional at-risk 35 couples. We describe a comprehensive NGS-based test that offers advantages over the traditional screening/molecular testing methods. To our knowledge, this is among the first large-scale population study to systematically evaluate the application of an NGS technique in carrier screening and molecular diagnosis of hemoglobinopathies.

OBJECTIVE: Development of proteinuria in lupus nephritis (LN) is associated with podocyte dysfunction. The NLRP3 inflammasome has been implicated in the pathogenesis of LN. The purpose of this study was to investigate whether NLRP3 inflammasome activation is involved in the development of podocyte injury in LN. METHODS: A fluorescence-labeled caspase 1 inhibitor probe was used to detect the activation of NLRP3 inflammasomes in podocytes derived from lupus-prone NZM2328 mice and from renal biopsy tissues obtained from patients with LN. MCC950, a selective inhibitor of NLRP3, was used to treat NZM2328 mice. Proteinuria, podocyte ultrastructure, and renal pathology were evaluated. In vitro, sera from diseased NZM2328 mice were used to stimulate a podocyte cell line, and the cells were analyzed by flow cytometry. RESULTS: NLRP3 inflammasomes were activated in podocytes from lupus-prone mice and from patients with LN. Inhibition of NLRP3 with MCC950 ameliorated proteinuria, renal histologic lesions, and podocyte foot process effacement in lupus-prone mice. In vitro, sera from diseased NZM2328 mice activated NLRP3 inflammasomes in the podocyte cell line through the production of reactive oxygen species. CONCLUSION: NLRP3 inflammasomes were activated in podocytes from lupus-prone mice and from LN patients. Activation of NLRP3 is involved in the pathogenesis of podocyte injuries and the development of proteinuria in LN.

BACKGROUND: Although maternal deaths are rare in developed regions, the morbidity associated with severe postpartum hemorrhage (SPPH) remains a major problem. To determine the prevalence and risk factors of SPPH, we analyzed data of women who gave birth in Guangzhou Medical Centre for Critical Pregnant Women, which received a large quantity of critically ill obstetric patients who were transferred from other hospitals in Southern China. METHODS: In this study, we conducted a retrospective case-control study to determine the prevalence and risk factors for SPPH among a cohort of women who gave birth after 28 weeks of gestation between January 2015 and August 2019. SPPH was defined as an estimated blood loss ≥1000 mL and total blood transfusion≥4 units. Logistic regression analysis was used to identify independent risk factors for SPPH. RESULTS: SPPH was observed in 532 mothers (1.56%) among the total population of 34,178 mothers. Placenta-related problems (55.83%) were the major identified causes of SPPH, while uterine atony without associated retention of placental tissues accounted for 38.91%. The risk factors for SPPH were maternal age < 18 years (adjusted OR [aOR] = 11.52, 95% CI: 1.51-87.62), previous cesarean section (aOR = 2.57, 95% CI: 1.90-3.47), history of postpartum hemorrhage (aOR = 4.94, 95% CI: 2.63-9.29), conception through in vitro fertilization (aOR = 1.78, 95% CI: 1.31-2.43), pre-delivery anemia (aOR = 2.37, 95% CI: 1.88-3.00), stillbirth (aOR = 2.61, 95% CI: 1.02-6.69), prolonged labor (aOR = 5.24, 95% CI: 3.10-8.86), placenta previa (aOR = 9.75, 95% CI: 7.45-12.75), placenta abruption (aOR = 3.85, 95% CI: 1.91-7.76), placenta accrete spectrum (aOR = 8.00, 95% CI: 6.20-10.33), and macrosomia (aOR = 2.30, 95% CI: 1.38-3.83). CONCLUSION: Maternal age < 18 years, previous cesarean section, history of PPH, conception through IVF, pre-delivery anemia, stillbirth, prolonged labor, placenta previa, placental abruption, PAS, and macrosomia were risk factors for SPPH. Extra vigilance during the antenatal and peripartum periods is needed to identify women who have risk factors and enable early intervention to prevent SPPH.

Objective: To investigate the prevalence, characteristics, and preventive status of skin injuries caused by personal protective equipment (PPE) in medical staff. Approach: A cross-sectional survey was conducted online for understanding skin injuries among medical staff fighting COVID-19 in February 8–22, 2020. Participants voluntarily answered and submitted the questionnaire with cell phone. The questionnaire items included demographic data, grade of PPE and daily wearing time, skin injury types, anatomical sites, and preventive measures. Univariable analyses and logistic regression analyses were used to explore the risk factors associated with skin injuries. Results: A total of 4,308 respondents were collected from 161 hospitals and 4,306 respondents were valid. The overall prevalence of skin injuries was 42.8% (95% confidence interval [CI] 41.30–44.30) with three types of device-related pressure injuries, moist-associated skin damage, and skin tear. Co-skin injuries and multiple location injuries were 27.4% and 76.8%, respectively. The logistic regression analysis indicated that sweating (95% CI for odds ratio [OR] 87.52–163.11), daily wearing time (95% CI for OR 1.61–3.21), male (95% CI for OR 1.11–2.13), and grade 3 PPE (95% CI for OR 1.08–2.01) were associated with skin injuries. Only 17.7% of respondents took prevention and 45.0% of skin injuries were treated. Innovation: This is the first cross-sectional survey to understand skin injuries in medical staff caused by PPE, which is expected to be a benchmark. Conclusion: The skin injuries among medical staff are serious, with insufficient prevention and treatment. A comprehensive program should be taken in the future.

// Dong Ren 1, 2, * , Bihua Lin 1, * , Xin Zhang 1, 3 , Yao Peng 4 , Ziyu Ye 1 , Yan Ma 1 , Yangfang Liang 5 , Longbin Cao 4 , Xiangyong Li 1 , Ronggang Li 3 , Lixia Sun 3 , Qiongru Liu 3 , Jinhua Wu 6 , Keyuan Zhou 1 and Jincheng Zeng 1 1 Guangdong Provincial Key Laboratory of Medical Molecular Diagnostics, Key Laboratory of Medical Bioactive Molecular Research for Department of Education of Guangdong Province, Guangdong Medical University, Dongguan, Guangdong Province, 523808, China 2 Department of Orthopedic Surgery, The First Affiliated Hospital of Sun Yat-Sen University, Guangzhou, Guangdong Province, 510080, China 3 Department of Pathology, Jiangmen Central Hospital, Affiliated Jiangmen Hospital of Sun Yat-Sen University, Jiangmen, Guangdong Province, 529030, China 4 Department of Gastroenterology, The First Affiliated Hospital of Sun Yat-Sen University, Guangzhou, Guangdong Province, 510080, China 5 Department of Pathology, Dongguan Hospital Affiliated to Medical College of Jinan University, The Fifth People&rsquo;s Hospital of Dongguan, Dongguan, Guangdong Province, 523905, China 6 Department of Clinical Laboratory, Jiangmen Central Hospital, Affiliated Jiangmen Hospital of Sun Yat-Sen University, Jiangmen, Guangdong Province, 529030, China * These authors contributed equally to this work Correspondence to: Jincheng Zeng, email: zengjc@gdmu.edu.cn Keywords: miR-196b-5p, cancer stem cell, chemotherapeutic resistance, STAT3 signaling pathway, CRC Received: October 27, 2016&nbsp;&nbsp;&nbsp;&nbsp;&nbsp; Accepted: May 04, 2017&nbsp;&nbsp;&nbsp;&nbsp;&nbsp; Published: May 18, 2017 ABSTRACT Emerging studies indicated that cancer stem cells represent a subpopulation of cells within the tumor that is responsible for chemotherapeutic resistance. However, the underlying mechanism is still not clarified yet. Here we report that miR-196b-5p is dramatically upregulated in CRC tissues and high expression of miR-196b-5p correlates with poor survival in CRC patients. Moreover, recurrent gains (amplification) contribute to the miR-196b-5p overexpression in CRC tissues. Silencing miR-196b-5p suppresses spheroids formation ability, the fraction of SP cells, expression of stem cell factors and the mitochondrial potential, and enhances the apoptosis induced by 5-fluorouracil in CRC cells; while ectopic expression of miR-196b-5p yields an opposite effect. In addition, downregulation of miR-196b-5p resensitizes CRC cells to 5-fluorouracil in vivo . Our results further demonstrate that miR-196b-5p promotes stemness and chemoresistance of CRC cells to 5-fluorouracil via targeting negative regulators SOCS1 and SOCS3 of STAT3 signaling pathway, giving rise to activation of STAT3 signaling. Interestingly, miR-196b-5p is highly enriched in the serum exosomes of patients with CRC compared to the healthy control subjects. Thus, our results unravel a novel mechanism of miR-196b-5p implicating in the maintenance of stem cell property and chemotherapeutic resistance in CRC, offering a potential rational registry of anti-miR-196b-5p combining with conventional chemotherapy against CRC.

Still today, cancer remains a threat to human health. Possible common treatments to cure this disease include chemotherapy (CT), radiotherapy (RT), photothermal therapy (PTT), and surgical resection, which give unreasonable results because of their limited efficiency and also lead to side-effects. Hence, different strategies are now being exploited to not only enhance the efficiency of these traditional therapeutic methods or treat the tumor cells but also curtail the side effects. A latest method with authentic proof of chemodynamic therapy (CDT) utilizing the Fenton reaction is now gaining importance. This approach, which is developed based on the high level of hydrogen peroxide (H2O2) in a tumor microenvironment (TME), can be used to catalyze the Fenton reaction to generate cancer cell-killing reactive oxygen species (ROS). The selection of materials is extremely important and nanomaterials offer the most likely method to facilitate CDT. Among various materials, metal-organic frameworks (MOFs) which have been extensively applied in medical areas are regarded as a promising material and possess potential for the next generation of nanotechnology. This review focuses on summarizing the use of MOFs in CDT and their synergetic therapeutics as well as the challenges, obstacles, and development.

With the development of society, traumatic bone defects caused by accidents, diseases and surgeries have become common, eventually resulting in an increase in bone defects. The treatment of bone defects is characterized by a long period of treatment, high cost and uncontrollable outcomes. Also, it results in complications such as infection and bone discontinuity. Hence, due to this situation, the physical, mental and financial aspects of the patient are severely affected. What's more, such outcomes pose a challenge to orthopaedic surgeons. As a result, bone therapy and bone repair have become a hot topic of interest. In repairing bone defects, materials other than autogenous bone are still unable to provide good biocompatibility, osteogenesis, osteoconductivity and osteoinduction properties at the same time. In addition, the scarcity of autologous bone sources has forced the search for new autologous bone replacement materials. Metal organic frameworks (MOFs) are a new class of developed functional materials that have been widely used in the biomedical field during the recent years due to their porous nature, large specific surface area and diverse structures. With the progress in the investigation into bone treatment and repair, more and more investigators are using MOFs in bone therapy and bone repair. With these viewpoints, in the present perspective, the use of MOFs in bone therapy and bone repair has been summarized, and an insight into the future of MOFs in bone therapy and bone repair has been provided.

Cancer-secreted exosomes are critical mediators of cancer-host crosstalk. In the present study, we showed the delivery of miR-21-5p from colorectal cancer (CRC) cells to endothelial cells via exosomes increased the amount of miR-21-5p in recipient cells. MiR-21-5p suppressed Krev interaction trapped protein 1 (KRIT1) in recipient HUVECs and subsequently activated β-catenin signaling pathway and increased their downstream targets VEGFa and Ccnd1, which consequently promoted angiogenesis and vascular permeability in CRC. A strong inverse correlation between miR-21-5p and KRIT1 expression levels was observed in CRC-adjacent vessels. Furthermore, miR-21-5p expression in circulating exosomes was markedly higher in CRC patients than in healthy donors. Thus, our data suggest that exosomal miR-21-5p is involved in angiogenesis and vascular permeability in CRC and may be used as a potential new therapeutic target.

The effects of berries consumption on cardiovascular disease (CVD) risk factors have not been systematically examined. Here, we aimed to conduct a meta-analysis with trial sequential analysis to estimate the effect of berries consumption on CVD risk factors. PubMed, Embase, and CENTRAL were searched for randomized controlled trials (RCTs) that regarding the effects of berries consumption in either healthy participants or patients with CVD. Twenty-two eligible RCTs representing 1,251 subjects were enrolled. The pooled result showed that berries consumption significantly lowered the low density lipoprotein (LDL)-cholesterol [weighted mean difference (WMD), -0.21 mmol/L; 95% confidence interval (CI), -0.34 to -0.07; P = 0.003], systolic blood pressure (SBP) (WMD, -2.72 mmHg; 95% CI, -5.32 to -0.12; P = 0.04), fasting glucose (WMD, -0.10 mmol/L; 95% CI, -0.17 to -0.03; P = 0.004), body mass index (BMI) (WMD, -0.36 kg/m(2); 95% CI, -0.54 to -0.18, P < 0.00001), Hemoglobin A1c (HbA1c) (WMD, -0.20%; 95% CI, -0.39 to -0.01; P = 0.04) and tumor necrosis factor-α (TNF-α) (WMD, -0.99 ρg/mL; 95% CI, -1.96 to -0.02; P = 0.04). However, no significant changes were seen in other markers. The current evidence suggests that berries consumption might be utilized as a possible new effective and safe supplementary option to better prevent and control CVD in humans.