Translational insights and overall survival in the U31402-A-U102 study of patritumab deruxtecan (HER3-DXd) in EGFR-mutated NSCLC.

BACKGROUND: Human epidermal growth factor receptor 3 (HER3) is broadly expressed in non-small-cell lung cancer (NSCLC) and is the target of patritumab deruxtecan (HER3-DXd), an antibody-drug conjugate consisting of a HER3 antibody attached to a topoisomerase I inhibitor payload via a tetrapeptide-based cleavable linker. U31402-A-U102 is an ongoing phase I study of HER3-DXd in patients with advanced NSCLC. Patients with epidermal growth factor receptor (EGFR)-mutated NSCLC that progressed after EGFR tyrosine kinase inhibitor (TKI) and platinum-based chemotherapy (PBC) who received HER3-DXd 5.6 mg/kg intravenously once every 3 weeks had a confirmed objective response rate (cORR) of 39%. We present median overall survival (OS) with extended follow-up in a larger population of patients with EGFR-mutated NSCLC and an exploratory analysis in those with acquired genomic alterations potentially associated with resistance to HER3-DXd. PATIENTS AND METHODS: Safety was assessed in patients with EGFR-mutated NSCLC previously treated with EGFR TKI who received HER3-DXd 5.6 mg/kg; efficacy was assessed in those who also had prior PBC. RESULTS: In the safety population (N = 102), median treatment duration was 5.5 (range 0.7-27.5) months. Grade ≥3 adverse events occurred in 76.5% of patients; the overall safety profile was consistent with previous reports. In 78/102 patients who had prior third-generation EGFR TKI and PBC, cORR by blinded independent central review (as per RECIST v1.1) was 41.0% [95% confidence interval (CI) 30.0% to 52.7%], median progression-free survival was 6.4 (95% CI 4.4-10.8) months, and median OS was 16.2 (95% CI 11.2-21.9) months. Patients had diverse mechanisms of EGFR TKI resistance at baseline. At tumor progression, acquired mutations in ERBB3 and TOP1 that might confer resistance to HER3-DXd were identified. CONCLUSIONS: In patients with EGFR-mutated NSCLC after EGFR TKI and PBC, HER3-DXd treatment was associated with a clinically meaningful OS. The tumor biomarker characterization comprised the first description of potential mechanisms of resistance to HER3-DXd therapy.

[Influencing factors of mild cognitive impairment among the Chinese elderly: a meta-analysis].

Objective: To conduct a meta-analysis on the influencing factors of mild cognitive impairment (MCI) in the Chinese elderly. Methods: The literature related to the influencing factors of MCI in Chinese elderly population was retrieved through CNKI, Wanfang, VIP, PubMed, Embase and Web of Science databases up to March 13, 2022. Stata17.0 software was used to calculate the combined risk ratio (RR) with the 95% confidence interval (CI), test the heterogeneity, and assess the publication bias. Results: A total of 2 450 articles were retrieved, and 49 articles met the inclusion criteria, including 5 cohort studies and 44 case-control studies. Meta-analysis results showed that male (RR=0.778, 95%CI: 0.696-0.870, I2=73.1), education>6years (RR=0.428, 95%CI: 0.374-0.490, I2=86.9) and regular exercise (RR=0.496, 95%CI: 0.421-0.585, I2=81.5) were protective factors for MCI, while age≥70 years (RR=2.431, 95%CI: 2.086-2.833, I2=79.3), family history of dementia (RR=3.228, 95%CI: 2.140-4.867, I2=0.0), smoking (RR=1.214, 95%CI: 1.098-1.342, I2=78.8), alcohol consumption (RR=1.165, 95%CI: 1.047-1.297, I2=68.2), solitary living (RR=2.816, 95%CI: 2.123-3.736, I2=42.0), insomnia (RR=1.402, 95%CI: 1.093-1.799, I2=41.3), overweight/obesity (RR=1.431, 95%CI: 1.207-1.696, I2=75.9), hypertension (RR=1.731, 95%CI: 1.589-1.886, I2=67.1), hyperlipidemia (RR=1.722, 95%CI: 1.541-1.924, I2=63.9), diabetes mellitus (RR=1.495, 95%CI: 1.341-1.666, I2=71.6), cardiovascular diseases (RR=1.671, 95%CI: 1.446-1.932, I2=74.6) and cerebrovascular diseases (RR=2.309, 95%CI: 2.040-2.613, I2=76.3) were risk factors of MCI. Conclusion: The present study indicates that male, junior high school education or above and regular exercise are protective factors of MCI, while age≥70 years, family history of dementia, smoking, alcohol consumption, living alone, insomnia, overweight/obesity, hypertension, hyperlipidemia, diabetes, cardiovascular diseases and cerebrovascular diseases are risk factors of MCI.

Mass Measurement of Upper fp-Shell N=Z-2 and N=Z-1 Nuclei and the Importance of Three-Nucleon Force along the N=Z Line.

Using a novel method of isochronous mass spectrometry, the masses of ^{62}Ge, ^{64}As, ^{66}Se, and ^{70}Kr are measured for the first time, and the masses of ^{58}Zn, ^{61}Ga, ^{63}Ge, ^{65}As, ^{67}Se, ^{71}Kr, and ^{75}Sr are redetermined with improved accuracy. The new masses allow us to derive residual proton-neutron interactions (δV_{pn}) in the N=Z nuclei, which are found to decrease (increase) with increasing mass A for even-even (odd-odd) nuclei beyond Z=28. This bifurcation of δV_{pn} cannot be reproduced by the available mass models, nor is it consistent with expectations of a pseudo-SU(4) symmetry restoration in the fp shell. We performed ab initio calculations with a chiral three-nucleon force (3NF) included, which indicate the enhancement of the T=1 pn pairing over the T=0 pn pairing in this mass region, leading to the opposite evolving trends of δV_{pn} in even-even and odd-odd nuclei.

[Research advances of adipose stem cell matrix gel in promoting wound healing].

In recent years, with the problem of aging population in China being prominant, the number of patients with chronic wounds such as diabetic foot, pressure ulcer, and vascular ulcer is increasing. Those diseases seriously affect the life quality of patients and increase the economy and care burden of the patients' family, which have been one of the most urgent clinical problems. Many researches have confirmed that adipose stem cells can effectively promote wound healing, while exogenous protease is needed, and there are ethical and many other problems, which limit the clinical application of adipose stem cells. Adipose stem cell matrix gel is a gel-like mixture of biologically active extracellular matrix and stromal vascular fragment obtained from adipose tissue by the principle of fluid whirlpool and flocculation precipitation. It contains rich adipose stem cells, hematopoietic stem cells, endothelial progenitor cells, and macrophages, etc. The preparation method of adipose stem cell matrix gel is simple and the preparation time is short, which is convenient for clinical application. Many studies at home and abroad showed that adipose stem cell matrix gel can effectively promote wound healing by regulating inflammatory reaction, promoting microvascular reconstruction and collagen synthesis. Therefore, this paper summarized the preparation of adipose stem cell matrix gel, the mechanism and problems of the matrix gel in promoting wound repair, in order to provide new methods and ideas for the treatment of chronic refractory wounds in clinic.

Challenges in oncology career: are we closing the gender gap? Results of the new ESMO Women for Oncology Committee survey.

BACKGROUND: Following a European Society for Medical Oncology Women for Oncology (ESMO W4O) survey in 2016 showing severe under-representation of female oncologists in leadership roles, ESMO launched a series of initiatives to address obstacles to gender equity. A follow-up survey in October 2021 investigated progress achieved. MATERIALS AND METHODS: The W4O questionnaire 2021 expanded on the 2016 survey, with additional questions on the impact of ethnicity, sexual orientation and religion on career development. Results were analysed according to respondent gender and age. RESULTS: The survey sample was larger than in 2016 (n = 1473 versus 482), especially among men. Significantly fewer respondents had managerial or leadership roles than in 2016 (31.8% versus 51.7%). Lack of leadership development for women and unconscious bias were considered more important in 2021 than in 2016. In 2021, more people reported harassment in the workplace than in 2016 (50.3% versus 41.0%). In 2021, ethnicity, sexual orientation and religion were considered to have little or no impact on professional career opportunities, salary setting or related potential pay gap. However, gender had a significant or major impact on career development (25.5% of respondents), especially in respondents ≤40 years of age and women. As in 2016, highest ranked initiatives to foster workplace equity were promotion of work-life balance, development and leadership training and flexible working. Significantly more 2021 respondents (mainly women) supported the need for culture and gender equity education at work than in 2016. CONCLUSIONS: Gender remains a major barrier to career progression in oncology and, although some obstacles may have been reduced since 2016, we are a long way from closing the gender gap. Increased reporting of discrimination and inappropriate behaviour in the workplace is a major, priority concern. The W4O 2021 survey findings provide new evidence and highlight the areas for future ESMO interventions to support equity and diversity in oncology career development.

[Evaluation of safety and clinical efficacy of bilateral percutaneous kyphoplasty in treatment of osteoporotic thoraco-lumbar burst fractures].

Objective: To evaluate the safety and clinical efficacy of bilateral percutaneous kyphoplasty (PKP) in the treatment of osteoporotic vertebral burst fractures. Methods: It was a prospective study, 28 patients with osteoporotic thoraco-lumbar burst fractures who were treated in Beijing Chao-Yang Hospital from January 2021 to July 2021 were included, including 10 males and 18 females, with a median age of 73.6 years (range: 56.0-87.0 years). The X-ray radiographs, bone mineral density (BMD), CT three-dimensional reconstruction scan and MRI were taken and measured before operation to observe the fracture location and the posterior wall of the vertebral body, and further to determine the diagnosis. The X-ray radiographs and CT three-dimensional reconstruction scans were taken on the first day after operation and the last follow-up to observe whether there were bone cement leakage or not. The changes of kyphosis angle (KA), the height of anterior wall (HAW) and the height of posterior wall (HPW) before the operation, on the 1st day post operation and at the last follow-up were recorded. The visual analogue scale (VAS) of back pain and Oswestry dysfunction index (ODI) before the operation, 1 day post operation and at the last follow-up were used to evaluate the clinical effect of the operation. Results: All the patients were followed up for (12.2±6.0) months. The HAW on the 1st day post operation [(22.5±2.0) mm] was significantly increased as compared with that before the operation [(21.2±2.4) mm] (P<0.05). The HAW at the last follow-up [(18.9±1.6) mm] decreased signficantly as compared with that on the 1st day post opertion [(22.5±2.0) mm] (P<0.05). The HPW was also significantly corrected after surgery (P<0.05). At the end of the follow-up, the HPW [(27.2±1.3) mm] was comparable with that on the 1st day after surgery [(27.5±1.6) mm] (P>0.05). The KA on the 1st day after the operation (14.2°±1.5°) decreased significantly when compared with that before the operation (18.8°±1.3°) (P<0.05), but it was increased to 17.6°±1.4° at the last follow-up and was higher than that on the 1st day after the operation (P<0.05). There were bone cement leakage in 5 cases and adjacent vertebral fracture in 1 case. The VAS and ODI scores were all significantly lower on the 1st day and at last follow-up than that before the operation (all P<0.05). Conclusions: Bilateral PKP is effective, safe and reliable in the treatment of osteoporotic vertebral burst fracture. Careful evaluation of preoperative imaging data, accurate puncture and timing of bone cement injection are the key factors to ensure the success of the operation.

[Clinical characteristics of 272 437 patients with different histopathological subtypes of primary esophageal malignant tumors].

Objective: To characterize the histopathological subtypes and their clinicopathological parameters of gender and onset age by common, rare and sparse primary esophageal malignant tumors (PEMT). Methods: A total of 272 437 patients with PEMT were enrolled in this study, and all of the patients were received radical surgery. The clinicopathological information of the patients was obtained from the database established by the State Key Laboratory of Esophageal Cancer Prevention & Treatment from September 1973 to December 2020, which included the clinical treatment, pathological diagnosis and follow-up information of esophagus and gastric cardia cancers. All patients were diagnosed and classified by the criteria of esophageal tumor histopathological diagnosis and classification (2019) of the World Health Organization (WHO). The esophageal tumors, which were not included in the WHO classification, were analyzed separately according to the postoperative pathological diagnosis. The χ2 test was performed by the SPSS 25.0 software on count data, and the test standard α=0.05. Results: A total of 32 histopathological types were identified in the enrolled PEMT patients, of which 10 subtypes were not included in the WHO classification. According to the frequency, PEMT were divided into common (esophageal squamous cell carcinoma, ESCC, accounting for 97.1%), rare (esophageal adenocarcinoma, EAC, accounting for 2.3%) and sparse (mainly esophageal small cell carcinoma, malignant melanoma, etc., accounting for 0.6%). All the common, rare, and sparse types occurred predominantly in male patients, and the gender difference of rare type was most significant (EAC, male∶ female, 2.67∶1), followed with common type (ESCC, male∶ female, 1.78∶1) and sparse type (male∶ female, 1.71∶1). The common type (ESCC) mainly occurred in the middle thoracic segment (65.2%), while the rare type (EAC) mainly occurred in the lower thoracic segment (56.8%). Among the sparse type, malignant melanoma and malignant fibrous histiocytoma were both predominantly located in the lower thoracic segment (51.7%, 66.7%), and the others were mainly in the middle thoracic segment. Conclusion: ESCC is the most common type among the 32 histopathological types of PEMT, followed by EAC as the rare type, and esophageal small cell carcinoma and malignant melanoma as the major sparse type, and all of which are mainly occur in male patients. The common type of ESCC mainly occur in the middle thoracic segment, while the rare type of EAC mainly in the lower thoracic segment. The mainly sparse type of malignant melanoma and malignant fibrous histiocytoma predominately occur in the lower thoracic segment, and the remaining sparse types mainly occur in the middle thoracic segment.

[Assessment of quality of systematic reviews and Meta-analyses on efficacy and safety of COVID-19 vaccines].

Objective: To evaluate the methodology of the published systematic reviews and Meta-analyses (SR/MA) on efficacy and safety of coronavirus disease 2019 (COVID-19) vaccines. Methods: We conducted a retrieval for literatures published as of December 10, 2021 in English databases (Medline, Embase, Cochrane Library, Web of science) and Chinese databases (CNKI, Wanfang data, VIP, Sinomed). Two reviewers independently screened literatures and extracted data. The methodology of included SR/MA papers was assessed by A MeaSurement Tool to Assess systematic Review-2 (AMSTAR-2) tool in 16 items. Results: A total 22 SR/MA papers were included, in which 3 (13.6%) had low quality and 19 (86.4%) had very low quality. The main problems of these SR/MA included having no definite PICO (Participants, intervention, control and outcome), providing no preliminary research protocol, no list of excluded studies and justify the exclusions, making no evaluation and explanation or discussion of the risk of bias of original studies, no adequate evaluation of publication bias and discuss its likely impact on the results, etc. Conclusion: SR/MA for the efficacy and safety of COVID-19 vaccines had varied methodological deficiencies, further improvements are needed.

Correlation between treatment effects on response rate and progression-free survival and overall survival in trials of targeted therapies in molecularly enriched populations.

BACKGROUND: The number of randomized trials of agents targeting oncogene-addicted tumors has surged in the past 10 years. Using a meta-analysis, we explored whether improvements in objective response rate (ORR) in comparative trials using targeted agents could serve as a potential surrogate endpoint for improvements in progression-free survival (PFS) or overall survival (OS) in populations with oncogene-addicted cancer. PATIENTS AND METHODS: Using commercial text mining software I2E, we searched ClinicalTrials.gov and MEDLINE databases for randomized, phase III trials based on prospectively defined criteria, including (i) use of agents targeting EGFR activating mutations, ALK rearrangements, BRAF V600E or V600K mutations, and BCR-ABL fusion protein; (ii) molecularly enriched trial population or subpopulation; (iii) control arm only randomized to chemo/cytotoxic therapy. Correlative analyses were performed using ORR, OS, and PFS data from trials that met these criteria. RESULTS: A total of 62 trials were identified; 15 met all of the prespecified criteria. The ORR effect size (both the difference in ORR between arms and the log odds ratio) and log PFS hazard ratio were strongly correlated: -0.78 (P = 0.0007) for the ORR difference model; -0.74 (P = 0.0017) for the log odds ratio model. ORR effect size was positively correlated with the log OS hazard ratio, but more weakly: -0.67 (P = 0.013) for the ORR difference model and -0.58 (P = 0.036) for the log odds ratio model. Analysis of the treatment effects between OS and PFS found no correlation. CONCLUSIONS: These analyses identified a strong correlation between treatment effects on ORR and PFS in randomized clinical trials investigating agents targeting oncogene-driven cancers. A weaker correlation was observed between ORR and OS. These meta-analysis results support the use of a high ORR forming the basis of an initial regulatory approval in biomarker-driven studies.

ESMO expert consensus statements on the management of EGFR mutant non-small-cell lung cancer.

The European Society for Medical Oncology (ESMO) held a virtual consensus-building process on epidermal growth factor receptor (EGFR)-mutant non-small-cell lung cancer in 2021. The consensus included a multidisciplinary panel of 34 leading experts in the management of lung cancer. The aim of the consensus was to develop recommendations on topics that are not covered in detail in the current ESMO Clinical Practice Guideline and where the available evidence is either limited or conflicting. The main topics identified for discussion were: (i) tissue and biomarkers analyses; (ii) early and locally advanced disease; (iii) metastatic disease and (iv) clinical trial design, patient's perspective and miscellaneous. The expert panel was divided into four working groups to address questions relating to one of the four topics outlined above. Relevant scientific literature was reviewed in advance. Recommendations were developed by the working groups and then presented to the entire panel for further discussion and amendment before voting. This manuscript presents the recommendations developed, including findings from the expert panel discussions, consensus recommendations and a summary of evidence supporting each recommendation.

Female leadership in oncology-has progress stalled? Data from the ESMO W4O authorship and monitoring studies.

BACKGROUND: Exploratory research showed that female oncologists are frequently under-represented in leadership roles. European Society for Medical Oncology (ESMO) Women for Oncology (W4O) therefore implemented gender equality programs in career development and established international studies on female representation at all stages of the oncology career pathway. METHODS: For 2017-2019, data were collected on (i) first and last authorship of publications in five major oncology journals and (ii) representation of women in leadership positions in oncology-as invited speakers at National/International congresses, board members or presidents of National/International societies and ESMO members. The 2015/2016 data from the first published W4O Study were incorporated for comparisons. RESULTS: Across 2017-2019, female oncologists were significantly more likely to be first than last authors (P < 0.001). The proportion of female first authors was similar across years: 38.0% in 2017, 37.1% in 2018, 41.0% in 2019 (P = 0.063). The proportion of female last authors decreased from 30.4% in 2017 to 24.2% in 2018 (P = 0.0018) and increased to 28.5% in 2019 (P = 0.018). Across 2015-2019, invited speakers at International/National oncology congresses were significantly less likely to be female than male (P < 0.001; 29.7% in 2015 to 36.8% in 2019). Across 2016-2019, board members of International/National oncology societies were significantly less likely to be female than male (P < 0.001; 26.8% in 2016 to 35.8% in 2019). There were statistically significant increasing trends in female speakers and board members across the study periods (P < 0.001 for both). Societies with a female president had a higher proportion of female board members across these periods (P = 0.026). CONCLUSIONS: Reported progress towards gender equality in career development in oncology is real but slow. Women in leadership positions are essential for encouraging young women to aspire to and work towards similar or greater success. Therefore, continued monitoring is needed to inform ESMO W4O initiatives to promote gender balance at all stages of the career pathway.

Has COVID-19 had a greater impact on female than male oncologists? Results of the ESMO Women for Oncology (W4O) Survey.

BACKGROUND: European Society for Medical Oncology Women for Oncology (ESMO W4O) research has previously shown under-representation of female oncologists in leadership roles. As early reports suggested disproportionate effects of the COVID-19 pandemic on women, the ESMO W4O Committee initiated a study on the impact of the pandemic on the lives of female and male oncologists. METHODS: A questionnaire was sent to ESMO members and put on the ESMO website between 8 June 2020 and 2 July 2020. Questions focused on the working (hospital tasks, laboratory tasks, science) and home (household management, childcare, parent care, personal care) lives of oncologists during and after COVID-19-related lockdowns. RESULTS: Of 649 respondents, 541 completed the questionnaire. Of these, 58% reported that COVID-19 had affected their professional career, 83% of whom said this was in a negative way (85% of women versus 76% of men). Approximately 86% reported that COVID-19 had changed their personal life and 82% their family life. Women were again significantly more affected than men: personal life (89% versus 78%; P = 0.001); family life (84% versus 77%; P = 0.037). During lockdowns, women reported increased time spent on hospital and laboratory tasks compared with men (53% versus 46% and 33% versus 26%, respectively) and a significantly higher proportion of women than men spent less time on science (39% versus 25%) and personal care (58% versus 39%). After confinement, this trend remained for science (42% versus 23%) and personal care (55% versus 36%). CONCLUSIONS: The COVID-19 pandemic has adversely affected the professional and home lives of oncologists, especially women. Reduced research time for female oncologists may have long-lasting career consequences, especially for those at key stages in their career. The gender gap for promotion to leadership positions may widen further as a result of the pandemic.

[Mechanism study of dendritic epidermal T lymphocytes in promoting healing of full-thickness skin defects wound on mice by regulating the proliferation and differentiation of epidermal stem cells in mice].

Objective: To explore the mechanism of dendritic epidermal T lymphocytes (DETCs) in promoting healing of full-thickness skin defect wound on mice by regulating the proliferation and differentiation of epidermal stem cells (ESCs) in mice. Methods: (1) Ten 8-week-old wild type (WT) male C57BL/6 mice (the same sex and kind below) were sacrificed to collect the skin of back for extracting DETCs to culture. Five WT and five 8-week-old T cell receptor (TCR) δ(-)/(-) mice were selected and enrolled in WT control group and TCR δ(-)/(-) control group, respectively. A full-thickness skin defect wound with diameter of 6 mm was made on both sides of spinal line on the back of mice without any treatment after injury. Another fifteen 8-week-old TCR δ(-)/(-) mice were selected and divided into phosphate buffer solution (PBS), DETC, and insulin-like growth factor-Ⅰ(IGF-Ⅰ) groups according to the random number table (the same grouping method below), with 5 mice in each group, and the same full-thickness skin defect wound was made on each mouse. Immediately after injury, mice in PBS, DETC, and IGF-Ⅰ groups were injected subcutaneously around each wound with 10 µL sterile PBS , DETCs (cell concentration of 1×10(6)/mL), and 5 mg/mL recombinant mice IGF-Ⅰ, respectively. The percentage of the residual wound area was calculated on post injury day (PID) 2, 4, 6, and 8. (2) Three 8-week-old WT mice were enrolled in WT control group and nine 8-week-old TCR δ(-)/(-) mice were divided into TCR δ(-)/(-) control group, PBS group, and DETC group, with 3 mice in each group. The full-thickness skin defect wound was made as in experiment (1) . On PID 3, the protein expression of IGF-Ⅰ in the epidermis tissue of wound margin was detected by chemiluminescence imaging analyzer. (3) Three 8-week-old WT mice were enrolled in WT control group and six 8-week-old TCR δ(-)/(-) mice were divided into PBS and DETC groups, with 3 mice in each group, and the full-thickness skin defect wound was made as in experiment (1). On PID3, DETCs were extracted from the wound margin epidermis tissue to detect the percentage of DETCs expressing IGF-Ⅰ by flow cytometer. (4) The mice were taken as in experiment (2) and divided into WT control, PBS, DETC, and IGF-Ⅰ groups. A straight full-thickness skin defect incision with length of 3 cm was made in the direction of one inner ear. Mice in WT control group didn't have any other treatment after injury, and immediately after injury, mice in PBS, DETC, and IGF-Ⅰ groups were injected subcutaneously around each wound with 10 µL sterile PBS, DETCs (cell concentration of 1×10(6)/mL), and 5 mg/mL recombinant mice IGF-Ⅰ, respectively. On PID 12, epidermis tissue of wound margin was collected, and immunofluorescence staining was performed to observe the number of keratin 15 positive cells. (5) The same mice were collected, grouped, and treated as in experiment (4). On PID12, the epidermis tissue of wound margin was collected and immunofluorescence staining was performed to observe the number of keratin 10 positive cells. (6) Twenty 3-day-old WT mice (the same below) were sacrificed to collect the whole skin, which was used to extract ESCs, with 5 mice detecting one index. The ESCs were divided into DETC co-culture group and control group, which were added with 1 mL DETCs (cell concentration of 1.25×10(6)/mL) and DETC medium, respectively. The percentage of 5-ethynyl-2'-deoxyuridine (EdU) positive cell on culture day (CD) 3, the percentages of CD49f(+) CD71(-) and keratin 14 positive cells on CD 5, and the percentage of keratin 10 positive cell on CD 10 in 2 groups were detected by flow cytometer. (7) Twenty mice were taken to extract ESCs, with 5 mice detecting one index. The ESCs were divided into control group and IGF-Ⅰ group, which were added with 1 mL sterile PBS and 10 ng/mL recombinant mice IGF-Ⅰ, respectively. The percentages of EdU positive cell, CD49f(+) CD71(-) cell, keratin10 positive cell, and keratin 14 positive cell were detected as in experiment (6). The sample in each group of experiments (6) and (7) was three. Data were statistically analyzed with analysis of variance for repeated measurement, one-way analysis of variance, and t test. Results: (1) On PID 4, 6, and 8, the percentage of residual wound area in TCR δ(-)/(-) control group was significantly higher than that in WT control group (t=2.78, 3.39, 3.66, P<0.05 or P<0.01). The percentage of residual wound area in DETC group and IGF-Ⅰgroup on PID 4, 6, and 8 was apparently lower than that in PBS group (t=2.61, 3.21, 3.88, 2.84, 2.91, 2.49, P<0.05 or P<0.01). (2) On PID 3, the protein expression of IGF-Ⅰ in the epidermis tissue of wound margin of mice in TCR δ(-)/(-) control group was significantly lower than that in WT control group (t=17.34, P<0.01). The protein expression of IGF-Ⅰ in the epidermis tissue of wound margin of mice in DETC group was significantly higher than that in PBS group (t=11.71, P<0.01). (3) On PID 3, the percentage of DETCs expressing IGF-Ⅰ in the epidermis tissue of wound margin of mice in PBS group was significantly lower than that in WT control group and DETC group (t=24.95, 27.23, P<0.01). (4) On PID 12, the number of keratin 15 positive cells in the epidermis tissue of wound margin of mice in PBS group was significantly lower than that in WT control group, DETC group, and IGF-Ⅰ group (t=17.97, 11.95, 7.63, P<0.01). (5) The number of keratin 10 positive cells in the epidermis tissue of wound margin of mice in PBS group was significantly higher than that in WT control group, DETC group, and IGF-Ⅰ group (t=11.59, 9.51, 3.48, P<0.05 or P<0.01). (6) The percentages of EdU positive cells on CD 3, CD49f(+) CD71(-) cells on CD 5, and keratin 14 positive cells on CD 5 in DETC co-culture group were respectively (43.5±0.6)%, (66.5±0.5)%, (69.3±1.7)%, apparently higher than (32.3±1.3)%, (56.4±0.3)%, (54.9±1.3)% in control group (t=7.97, 17.10, 6.66, P<0.01). The percentage of keratin 10 positive cells on CD 10 in DETC co-culture group was (55.7±0.7)%, significantly lower than (67.1±1.2)% in control group (t=8.34, P<0.01). (7) The percentages of EdU positive cells on CD 3, CD49f(+) CD71(-) cells on CD 5, and keratin 14 positive cells on CD 5 in IGF-Ⅰ group were respectively (42.1±0.9)%, (81.1±1.3)%, (66.8±1.0)%, apparently higher than (32.4±0.7)%, (74.9±0.7)%, (52.0±1.9)% in control group (t=8.39, 4.24, 7.25, P<0.05 or P<0.01). The percentage of keratin 10 positive cells on CD 10 in IGF-Ⅰ group was (53.5±1.1)% , significantly lower than (58.2±0.3)% in control group (t=3.99, P<0.05). Conclusions: DETCs can promote the proliferation and anti-apoptotic potential of ESCs and inhibit their differentiation into end-stage by secreting IGF-Ⅰ, thus promoting wound healing of full-thickness skin defects in mice.

[Study on mechanisms of interleukin-17A regulating the expressions of interleukin-1ß and interleukin-23 in mouse keratinocytes].

Objective: To investigate the mechanisms of interleukin-17A (IL-17A) regulating the expressions of IL-1ß and IL-23 in mouse keratinocytes (KCs). Methods: Primary KCs were isolated from the skin of 400 newborn male and female wild type C57BL/6 mice and cultured in 24-well plates with Roswell Park Memorial Institute 1640 medium containing fetal bovine serum in the volume fraction of 10% for the following experiments. (1) The cells were divided into phosphate buffer solution (PBS) control group and IL-17A stimulation group according to the random number table (the same grouping method below), which were cultured with 10 µL PBS or 10 µL IL-17A in the mass concentration of 100 ng/mL for 6 hours, respectively. The expression levels of IL-1ß and IL-23 mRNA in cells were detected by real-time fluorescence quantitative reverse transcription polymerase chain reaction (RT-PCR), with 3 samples in each group. (2) The cells were divided into dimethyl sulfoxide (DMSO) control group, IL-17A+ DMSO group, IL-17A+ nuclear factor κB (NF-κB) inhibitor group, IL-17A+ signal transduction and activator of transcription 3 (STAT3) inhibitor group, IL-17A+ extracellular signal-regulated kinase 1 (ERK1) inhibitor group, IL-17A+ ERK2 inhibitor group, and IL-17A+ c-Jun N-terminal kinase (JNK) inhibitor group. The reagents were added to cells in corresponding groups respectively and cultured for 6 hours. The volume of each reagent was 10 µL, the mass concentration of IL-17A was 100 ng/mL, and the molarity concentrations of NF-κB, STAT3, ERK1, ERK2, JNK signal pathway inhibitors PDTC, S3I-201, SCH772984, SCH772984, SP600125 were 5 µmol/L, 100 µmol/L, 4 nmol/L, 1 nmol/L, and 10 µmol/L, respectively. The expression levels of IL-1ß mRNA and IL-23 mRNA in cells were detected by real-time fluorescence quantitative RT-PCR, with 3 samples in each group. (3) The cells were grouped and treated the same as those in experiment (1). The levels of NF-κB phosphorylation, STAT3 phosphorylation, ERK phosphorylation, and JNK phosphorylation were detected by Western blotting, with 3 samples in each group. Data were statistically analyzed with two-tailed Student t test, one-way analysis of variance, t test, and Bonferroni correction. Results: (1) After culture of 6 hours, compared with those in PBS control group, the expression levels of IL-1ß and IL-23 mRNA in cells in IL-17A stimulation group were significantly increased (t=13.46, 6.72, P<0.01). (2) After culture of 6 hours, the expression levels of IL-1ß and IL-23 mRNA in cells in DMSO control group, IL-17A+ DMSO group, IL-17A+ NF-κB inhibitor group, IL-17A+ STAT3 inhibitor group, IL-17A+ ERK1 inhibitor group, IL-17A+ ERK2 inhibitor group, and IL-17A+ JNK inhibitor group were 1.00±0.11, 4.01±0.32, 0.32±0.06, 1.76±0.43, 3.62±0.24, 3.80±0.43, 4.26±0.74 and 1.03±0.29, 4.08±0.34, 4.76±0.38, 4.70±0.21, 1.06±0.42, 0.92±0.21, 0.39±0.05, respectively. Compared with those in DMSO control group, the expression levels of IL-1ß and IL-23 mRNA in cells in IL-17A+ DMSO group were significantly increased (t=9.24, 12.60, P<0.01). Compared with that in IL-17A+ DMSO group, the expression level of IL-1ß mRNA was significantly decreased in cells in IL-17A+ NF-κB inhibitor group and IL-17A+ STAT3 inhibitor group (t=11.34, 6.91, P<0.01). Compared with that in IL-17A+ DMSO group, the expression level of IL-23 mRNA was significantly decreased in cells in IL-17A+ ERK1 inhibitor group, IL-17A+ ERK2 inhibitor group, and IL-17A+ JNK inhibitor group (t=12.44, 13.03, 15.21, P<0.01). (3) After culture of 6 hours, compared with those in PBS control group, the levels of NF-κB phosphorylation, STAT3 phosphorylation, ERK phosphorylation, and JNK phosphorylation in cells in IL-17A stimulation group were significantly increased. Conclusions: IL-17A promotes the transcription of IL-1ß in mouse KCs through the phosphorylation of NF-κB and STAT3 pathways and IL-23 through the phosphorylation of ERK and JNK pathways.

Long non-coding RNA SNHG7 promotes migration and invasion of melanoma via upregulating SOX4.

Since this article has been suspected of research misconduct and the corresponding authors did not respond to our request to prove originality of data and figures, "Long non-coding RNA SNHG7 promotes migration and invasion of melanoma via upregulating SOX4, by C. Zhang, B. Zhu, X.-B. Li, Y.-Q. Cao, J.-C. Yang, X. Li, Y.-X. Liu, Y.-B. Wang, published in Eur Rev Med Pharmacol Sci 2019; 23 (11): 4828-4834-DOI: 10.26355/eurrev_201906_18069-PMID: 31210315" has been withdrawn. The Publisher apologizes for any inconvenience this may cause. https://www.europeanreview.org/article/18069.

[Current global development of screening guidelines for hepatocellular carcinoma: a systematic review].

Objective: The objective of the study was systematically summarized the current status of the hepatocellular carcinoma (HCC) screening guidelines, and evaluated the HCC screening guidelines according to the authoritative framework of cancer screening guidelines of authoritative institutions, which provided important value for the formulation of HCC screening evidence-based guidelines. Methods: Literature search was conducted in multiple databases from their inception dates to January 3, 2019. In addition, we sought relevant websites further was searched to identify potentially eligible studies. Two reviewers independently screened literature and extracted data. Qualitative description of the basic information, recommendations of HCC screening, source of evidence and update progress of the HCC screening guidelines was conducted. Results: At present, there were no independent HCC screening guidelines worldwide. There were only 17 clinical practice HCC guidelines briefly provided the recommendation of HCC screening. Current HCC screening guidelines only recommended screening for high-risk groups of HCC. All guidelines have identified patients with chronic hepatitis B, hepatitis C and cirrhosis as high-risk groups for HCC. Most of guidelines recommended screening intervals was 6 months. The latest guidelines in Europe and the United States recommended ultrasound for screening HCC. The combination of ultrasound and AFP was recommended in the Asian guidelines. Currently, HCC screening guidelines mainly recommended screening strategies based on factors such as risk of HCC, accuracy of screening modality, screening cost, etc.. The key factors such as screening efficacy and safety have not yet been considered comprehensively. Conclusions: There were no independent HCC screening guidelines worldwide. Only some clinical practice HCC guidelines briefly mentioned HCC screening. Currently, the guidelines only recommend screening for high-risk groups of HCC, with a screening interval of 6 months. There are differences in screening modalities recommended by European, American and Asian guidelines for screening HCC. It is suggested that the relevant institutions should formulate the evidence-based HCC screening guidelines by referring to the theoretical framework of other authoritative other cancer screening guidelines.

[Research advances in the mechanism of pulmonary fibrosis induced by coronavirus disease 2019 and the corresponding therapeutic measures].

Coronavirus disease 2019 (COVID-19) outbroke in Wuhan, China in December 2019 and the severe acute respiratory syndrome (SARS) outbroke in Guangzhou, China in 2003 were caused by highly pathogenic coronaviruses with high homology. Since the 2019 novel coronavirus is highly contagious and spreads rapidly. It has caused negative social effects and massive economic loss globaly. Currently there is no vaccine or effective drugs. Pulmonary fibrosis is a pulmonary disease with progressive fibrosis, which is the main factor leading to pulmonary dysfunction and declined quality of life in SARS survivors after recovery. Extensive epidemiological, viral immunological and current clinical evidences support the possibility that pulmonary fibrosis may be one of the major complications in COVID-19 patients. At present there is no report on the mechanism by which COVID-19 induces pulmonary fibrosis.With the existing theoretical basis, this article focuses on discussing the possible mechanism of COVID-19 sustained lung damaging, the key role of abnormal immune mechanism in the initiation and promotion of pulmonary fibrosis, and the corresponding therapeutic measures.

[Effects of dendritic epidermal T cells on proliferation and apoptosis of epidermal cells in wound margin of mice].

Objective: To explore the effects of dendritic epidermal T cells (DETC) on proliferation and apoptosis of epidermal cells in wound margin of mice and its effects on wound healing. Methods: Twenty-eight healthy specific pathogen free (SPF) C57BL/6 wild-type (WT) male mice aged 8-12 weeks and 60 SPF T lymphocyte receptor δ-knockout (TCR δ(-/-)) male mice aged 8-12 weeks were selected to conduct the following experiments. (1) Eight WT mice were selected to isolate epidermal cells and primarily culture DETC according to the random number table. Morphological observation and purity identification of DETC by flow cytometer were detected immediately after culture and on culture day (CD) 15 and 30, respectively. (2) According to the random number table, 5 WT mice and 5 TCR δ(-/-) mice were selected and enrolled into WT control group and TCR δ(-/-) group. Round full-thickness skin defect with diameter of 6 mm was made on the back of each mouse. The wound healing condition was observed immediately after injury and on post injury day (PID) 2, 4, 6, 8, 10, and the percentage of residual wound area was calculated. (3) Mice were selected to group and reproduce model of full-thickness skin defect as in experiment (2). On PID 3, the tissue of wound margin was collected for hematoxylin eosin staining, and the length of new epithelium was measured. (4) Mice were selected to group and reproduce model of full-thickness skin defect as in experiment (2). On PID 3, epidermal tissue of wound margin was collected to determine expression of proliferating cell nuclear antigen (PCNA) using Western blotting for evaluation of proliferation of epidermal cell. (5) Mice were selected to group and reproduce model of full-thickness skin defect as in experiment (2). On PID 3, epidermal tissue of wound margin was selected and digested into single-cell suspension, and apoptosis of cells was detected by flow cytometer. (6) Forty TCR δ(-/-) mice were selected to carry out the same treatment as in experiments (2)-(5). According to the random number table, these mice were enrolled into TCR δ(-/-) control group and TCR δ(-/-)+ DETC group, with 5 mice in each group for each experiment. Round full-thickness skin defect was made on the back of each mouse. DETC in the number of 1×10(5) (dissolution in 100 µL phosphate with buffer purity above 90%) were injected through multiple points of wound margin of mice in TCR δ(-/-)+ DETC group immediately after injury, and equal volume of phosphate buffer was injected into mice of TCR δ(-/-) control group with the same method as above. Data were processed with one-way analysis of variance for repeated measurement, t test, and Bonferroni correction. Results: (1) Along with the culture time elapse, the number of dendritic structures of DETC increased gradually. The percentage of T lymphocytes was 4.67% and 94.1% of these T lymphocytes were DETC. The purity of DETC on CD 15 was 18.50% and the purity of DETC on CD 30 was 98.70%. (2) Immediately after injury, the wound healing condition of mice in WT control group and TCR δ(-/-) group was similar. The wound healing speed of mice in TCR δ(-/-) group was slower than that in WT control group on PID 2-10. The percentages of residual wound area of mice in TCR δ(-/-) group on PID 2, 4, 6, 8, and 10 were increased significantly compared with those in WT control group (t=3.492, 4.425, 4.170, 4.780, 7.318, P<0.01). (3) The length of new epithelium of mice in TCR δ(-/-) group on PID 3 was (359 ± 15) µm, which was obviously shorter than that in WT control group [(462±26) µm, t=3.462, P<0.01]. (4) Immediately after injury, wound condition of mice in TCR δ(-/-)+ DETC group and TCR δ(-/-) control group was similar. Compared with TCR δ(-/-)+ DETC group, the wound healing speed of mice in TCR δ(-/-) control group were obviously slower on PID 2-10. The percentages of residual wound area of mice in TCR δ(-/-)+ DETC group on PID 2, 4, 6, 8, and 10 were decreased significantly compared with those in TCR δ(-/-) control group (t=2.308, 3.725, 2.698, 3.707, 6.093, P<0.05 or P<0.01). (5) On PID 3, the length of new epithelium of mice in TCR δ(-/-)+ DETC group was (465±31) µm, which was obviously longer than that in TCR δ(-/-) control group [(375±21) µm, t=2.390, P<0.05]. (6) On PID 3, PCNA expression of epidermal cell in wound margin of mice in TCR δ(-/-) group was 1.25±0.04, which was obviously lower than that in WT control group (2.01±0.09, t=7.415, P<0.01). (7) On PID 3, PCNA expression of epidermal cell in wound margin of mice in TCR δ(-/-)+ DETC group was 1.62±0.08, which was significantly higher than that in TCR δ(-/-) control group (1.05±0.14, t=3.561, P<0.05). (8) On PID 3, apoptosis rate of epidermal cell in wound margin of mice in TCR δ(-/-) group was (16.1±1.4)%, which was higher than that in WT control group [(8.1±0.6)%, t=5.363, P<0.01]. (9) On PID 3, apoptosis rate of epidermal cell in wound margin of mice in TCR δ(-/-)+ DETC group was (11.4±1.0)%, which was obviously lower than that in TCR δ(-/-) control group [(15.4±1.4)%, t=2.377, P<0.05]. Conclusions: DETC participates in the process of wound healing though promoting the proliferation of epidermal cells in wound margin and inhibit the apoptosis of these cells.

TATTON: a multi-arm, phase Ib trial of osimertinib combined with selumetinib, savolitinib, or durvalumab in EGFR-mutant lung cancer.

BACKGROUND: Osimertinib is a potent, third-generation epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor (TKI). The multi-arm phase Ib TATTON study (NCT02143466) was designed to assess the safety and tolerability of osimertinib in combination with other targeted therapies: selumetinib (MEK1/2 inhibitor), savolitinib (MET-TKI), or durvalumab [anti-programmed cell death ligand 1 (anti-PD-L1) monoclonal antibody]. PATIENTS AND METHODS: Patients with advanced EGFR-mutant non-small-cell lung cancer and disease progression on a prior EGFR-TKI were enrolled and allocated to dose-escalating cohorts combining osimertinib 80 mg orally (p.o.) once a day with selumetinib (25-75 mg p.o. twice a day; continuous or intermittent), savolitinib (600-800 mg p.o. once a day), or durvalumab (3-10 mg/kg intravenous every 2 weeks). RESULTS: At data cut-off (28 February 2018), 77 patients were enrolled and received osimertinib plus selumetinib (n = 36), savolitinib (n = 18), or durvalumab (n = 23). Most common adverse events (any grade), occurring in ≥20% of patients across dose groups, were: selumetinib arm-diarrhea (75%), rash (58%), nausea (47%); savolitinib arm-nausea (67%), rash (56%), vomiting (50%); durvalumab arm-rash (48%), vomiting (43%), diarrhea (39%). Dose-limiting toxicities were reported in the selumetinib 25 mg (n = 1), 50 mg (n = 1), and 75 mg (n = 4) continuous-dose groups, savolitinib 600 mg (n = 1) and 800 mg dose groups (n = 2), and durvalumab 10 mg/kg (n = 1) dose group. The objective response rate was 42% (95% confidence interval 26% to 59%), 44% (22% to 69%), and 43% (23% to 66%) in the selumetinib, savolitinib, and durvalumab arms, respectively. CONCLUSION: Our results demonstrate the feasibility of combining osimertinib 80 mg with selumetinib or savolitinib at identified tolerable, active doses. A combination of osimertinib with durvalumab was not feasible due to increased reporting of interstitial lung disease. Osimertinib-based combination therapies represent a compelling approach now being further investigated. CLINICAL TRIALS NUMBER: NCT02143466.