Search

There are increasing numbers of synchronous multiple primary lung cancer (SMPLC) patients in clinical practice, with most lesions presenting as ground-glass opacity (GGO). For SMPLC patients, surgical resection should be a prior option for all lesions suspected of being malignant, if medically and technically feasible. However, it is frequently a dilemma for the management of residual GGO lesions that were unresected simultaneously with the main tumor in SMPLC patients. We report a case of SMPLC, in which the patient underwent surgical resection of the major lesion with EGFR mutation and then received compelling EGFR-TKI treatment for one enlarging residual GGO lesion after 12 months since operation. Furthermore, a comprehensive literature review about the risk for the progress of GGOs unresected simultaneously with the main lesion and the management of these residual GGOs was also summarized. With the treatment of EGFR-TKI gefitinib for 3 months, the biggest residual GGO lesion (more than 10mm) achieved a complete response (CR), three lesions reduced in size, and the other three lesions remained stable in this case. Surgical resection for major lesion and EGFR-TKI treatment on unresected GGOs might bring favorable outcome for patients with EGFR-mutated multifocal lung cancer. This strategy is safe and effective, which could be a promising therapeutic approach for unresectable GGO lesions in EGFR-mutated SMPLC patients after primary surgery. Notably, folate receptor-positive circulating tumor cell (FR+-CTC) for therapeutic monitoring was more sensitive for GGO-featured lung adenocarcinoma than serum markers.

Background The addition of chemotherapy to a programmed death 1/programmed death ligand 1 (PD-L1) inhibitor is a more effective option as a first-line treatment for advanced non-small cell lung cancer (NSCLC). It might also inhibit an overactive immune response and thereby reduce immune-related adverse events (irAEs). This meta-analysis assessed the rate of irAEs with a PD-(L)1 inhibitor plus chemotherapy (I+C) versus a PD-(L)1 inhibitor alone (I) and evaluated the indirect relative risk (RR) of I+C versus I. Methods The protocol of this study was registered with PROSPERO (CRD42020139923). The pooled rates of irAEs at different grades were calculated by a single-arm meta-analysis weighted by sample size, and RRs were determined by direct meta-analysis and indirect treatment comparison. Results Overall, I+C had a lower rate of grade 3 or higher irAEs than I (7.1% vs 10.6%; indirect RR, 0.516; 95% confidence interval [CI], 0.291-0.916), although irAEs of any grade were similar. The rate of pneumonitis with I+C was lower than the rate with I for any grade (5.9% vs 7.1%; indirect RR, 0.217; 95% CI, 0.080-0.588) and for grade 3 or higher. In the endocrine system, I+C was associated with a lower overall ratein comparison with I (16.1% vs 20.1%; indirect RR, 0.260; 95% CI, 0.120-0.564), whereas irAEs of the digestive system were similar with I+C and I. In other systems, I+C decreased the rate of skin reactions, including rash, in comparison with I (10.4% vs 12.9%; indirect RR, 0.474; 95% CI, 0.299-0.751). The rate of grade 3 or higher skin reactions (excluding rash) also decreased with I+C versus I (1.1% vs 2.0%) with an indirect RR of 0.158 (95% CI, 0.032-0.765), whereas other included irAEs were similar. Conclusions In comparison with a PD-(L)1 inhibitor alone, a combination with chemotherapy for the first-line treatment of NSCLC decreased the rates of most irAEs, such as pneumonitis and endocrine and skin reactions, and the overall rate. Lay summary In the first-line treatment of advanced non-small cell lung cancer (NSCLC), the addition of chemotherapy to a programmed death 1/programmed death ligand 1 (PD-(L)1) inhibitor is a more effective option. Adding chemotherapy might reduce immune-related adverse events (irAEs). Thus, this article assesses the rate of irAEs with a PD-(L)1 inhibitor plus chemotherapy (I+C) in comparison with a PD-(L)1 inhibitor alone (I) and evaluates the indirect relative risk (RR) with I+C versus I. The key finding is that in comparison with a PD-(L)1 inhibitor alone, a combination with chemotherapy for the first-line treatment of NSCLC decreases the rates of most irAEs, such as pneumonitis and endocrine and skin reactions, and the overall rate.

We performed a meta‐analysis to determine cancer risks at multiple sites and their associations with tumor mutation burden (TMB), an index for immunogenicity, in heart or lung transplant recipients. A comprehensive search of PubMed, Web of Science, EMBASE, and Medline was conducted. Random effects models were used to calculate standardized incidence ratios (SIRs) versus the general population and to determine the risks of different cancers. Weighted linear regression (WLR) was used to analyze the associations between the SIRs and TMBs. (PROSPERO CRD42020159599). Data from 21 studies including 116,438 transplant recipients (51,173 heart transplant recipients and 65,265 lung transplant recipients) with a total follow‐up of 601,330.7 person‐years were analyzed. Compared with the general population, heart transplant recipients displayed a 3.13‐fold higher cancer risk [SIR: 3.13; 95% confidence interval (CI): 2.38–4.13; p, Our study demonstrated that both heart and lung transplant recipients displayed a higher risk of certain site‐specific cancers. These findings can provide individualized guidance for clinicians for detection of cancer among heart or lung transplantation recipients. In addition, we provided evidence that increased risks of post‐transplant cancers can be attributed to immunosuppression.

Objective Differences in efficacy of epidermal growth factor receptor-tyrosine kinase inhibitors (EGFR-TKI) have been observed between non-small cell lung cancer (NSCLC) patients with 19 exon deletion (19Del) and L858R mutation. We explored whether the total number or pattern of concomitant mutations of 19Del and L858R may explain their different sensitivities. Patients and methods This study contained the mutational profiles of EGFR-mutated NSCLC patients from two cohorts: Guangzhou (G1) and database (G2). Concomitant mutation status and EGFR-TKI response information were retrieved. Results A total of 403 patients covered 283 genes in the G1 and 803 patients with a different gene set in the G2 were included. Similar prevalence of total concomitant mutation number was observed in both G1 (19Del 32.48% vs L858R 30.45%; P=0.68) and G2 (19Del 74.9% vs L858R 73.2%; P=0.65) cohorts. Only HGF/c-Met pathway same more related to L858R mutation. EGFR-TKI response information was recorded for 134 patients in the G2 cohort. 19Del showed a higher objective response (OR) rate compared with L858R, regardless of concomitant mutations. Compared to patients with OR, non-OR patients had more concomitant mutations, both in 19Del (53.8% vs 83.3%; P=0.021) and L858R (51.4% vs 77.8%; P=0.029). In particular, total concomitant mutations (OR=0.27; P=0.03), sensitive EGFR mutations (OR=2.21; P=0.04), and T790M (OR=0.244; P=0.02) significantly affected the TKI response. Conclusion Concomitant mutations were widespread in 19Del and L858R and were associated with poorer OR to EGFR-TKIs. However, 19Del and L858R had similar numbers and patterns of concomitant mutations, which might not explain the different sensitivity to EGFR-TKI.

Background This Bayesian network meta-analysis (NMA) was conducted to compare efficacy and safety of programmed death 1/ligand 1 (PD-1/L1) inhibitors in previous untreated advanced non-small cell lung cancer (NSCLC) patients. Methods Eligible studies evaluating first-line anti-PD-1/L1 based regimens in advanced NSCLC patients were included. Overall survival (OS), progression free survival (PFS), objective response rate (ORR), as well as treatment-related severe adverse events (tr-SAE) were synthesized within the Bayesian framework. Subgroup analysis was conducted according to PD-L1 expression. Results Twelve studies including 7,490 patients and 9 treatment strategies were enrolled in this study. For the PD-L1 expression non-selective patients, all chemo-immunotherapies were significantly better than chemotherapy for prolonging OS and PFS, except for caremlizumab plus chemotherapy (HR =0.72) failed to show advantages for OS. In addition, pembrolizumab plus chemotherapy showed better PFS than nivolumab plus ipilimumab (HR =0.66). In PD-L1 ≥50% patients, all immunotherapy was better than chemotherapy for OS, except for nivolumab (HR =0.83) and nivolumab plus ipilimumab (HR =0.70). For PFS, pembrolizumab plus chemotherapy (HR =0.39), atezolizumab plus chemotherapy (HR =0.47) and pembrolizumab (HR =0.67) were significantly better than chemotherapy. In PD-L1 1-49% patients, pembrolizumab plus chemotherapy (HR =0.52) and atezolizumab plus chemotherapy (HR =0.70) were better than chemotherapy for PFS. In the PD-L1 positive or negative group, all included corresponding regimens were equivalence according to OS and PFS. Conclusions We conducted a systematic comparison of first line immunotherapy for advanced NSCLC. Chemo-immunotherapies were better than chemotherapy and mono-immunotherapies in most patients. Pembrolizumab might have better efficacy than other PD-1/L1 inhibitors.

Background Lymph node (LN) metastasis status is the most important prognostic factor and determines treatment strategy. Methylation alteration is an optimal candidate to trace the signal from early stage tumors due to its early existence, multiple loci and stability in blood. We built a diagnostic tool to screen and identify a set of plasma methylation markers in early stage occult LN metastasis. Methods High-throughput targeted methylation sequencing was performed on tissue and matched plasma samples from a cohort of 119 non-small cell lung cancer (NSCLC) patients with a primary lesion of less than 3.0 cm in diameter. The methylation profiles were compared between patients with and without occult LN metastases. We carried out a set of machine-learning analyses on our discovery cohort to evaluate the utility of cell free DNA methylation profiles in early detection of LN metastasis. Two preliminary prognostic models predictive of LN metastasis were built by random forest with differentially methylated markers shared by plasma and tissue samples and markers present either in plasma or tissue samples respectively. The performance of these models was then evaluated using receiver operating characteristic (ROC) statistics derived from ten-fold cross validation repeated ten times. Results Within this cohort, 27 cases (27/119, 22.7%) were found to have occult LN metastases found by pathological examination. Compared with those without metastases, 878 and 52 genes were differentially methylated in terms of tissue (MTA3, MIR548H4, HIST3H2A, etc.) and plasma (CIRBP, CHGB, FCHO1, etc.) respectively. 19 of these genes (ICAM1, EPH4, COCH, etc.) were overlapped. We selected 22 pairs of cases with or without occult LN metastasis by matching gender, age, smoking history and tumor histology to build and test the plasma model. The AUC of the preliminary prediction model using markers shared by plasma and tissue samples and markers present either in plasma or tissue samples is 88.6% (95% CI, 87.8-89.4%) and 74.9% (95% CI, 72.2-77.6%) respectively. Conclusions We identified a set of specific plasma methylation markers for early occult LN metastasis of NSCLC and established a preliminary non-invasive blood diagnostic tool.

Background The generation of subclonal (low-frequency) mutations is driven by tumor mutations and the relationship between the heterogeneity of tumor mutation abundance and non-small cell lung cancer (NSCLC) remains unknown. We investigate the role of allele frequency heterogeneity (AFH) defined by circulating tumor DNA (ctDNA) profiling in predicting prognosis in advanced NSCLC patients. Methods Publicly available data set of POPLAR (N=211) and OAK (N=642) trials were used for analyzing. A low ratio of allele frequency (AF) of a mutation to the maximum-somatic-allele-frequency (MSAF) was used to define the presence of AFH. The prognostic value of AF/MSAF ratio that was below a defined cutoff point in overall survival (OS) was evaluated using Cox-proportional hazards regression; and the structural break point was determined by LOESS regression and Chow test. The derived AFH was also explored in an independent cohort (N=259) of advanced NSCLC receiving first-line EGFR-TKIs from the First Affiliated Hospital of Guangzhou Medical University. Results In the POPLAR and OAK cohort, low AF/MSAF ratio was found to be significantly associated with unfavorable OS in univariate and multivariate analysis. The structural break point analysis demonstrated that AF/MSAF

Autophagy-mediated lipotoxicity plays a critical role in the progression of diabetic nephropathy (DN), but the precise mechanism is not fully understood. Whether lipophagy, a selective type of autophagy participates in renal ectopic lipid deposition (ELD) and lipotoxicity in the kidney of DN is unknown. Here, decreased lipophagy, increased ELD and lipotoxcity were observed in tubular cells of patients with DN, which were accompanied with reduced expression of AdipoR1 and p-AMPK. Similar results were found in db/db mice, these changes were reversed by AdipoRon, an adiponectin receptor activator that promotes autophagy. Additionally, a significantly decreased level of lipophagy was observed in HK-2 cells, a human proximal tubular cell line treated with high glucose, which was consistent with increased lipid deposition, apoptosis and fibrosis, while were partially alleviated by AdipoRon. However, these effects were abolished by pretreatment with ULK1 inhibitor SBI-0206965, autophagy inhibitor chloroquine and enhanced by AMPK activator AICAR. These data suggested by the first time that autophagy-mediated lipophagy deficiency plays a critical role in the ELD and lipid-related renal injury of DN.

BACKGROUND: Several randomized controlled trials have suggested that adjuvant epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs) were associated with prolonged disease-free survival (DFS) in EGFR-mutated NSCLC patients after radical resection, comparing with chemotherapy or placebo. We aimed to compare the effectiveness of different first-generation EGFR-TKIs as adjuvant treatment in real-world setting. METHODS: Early-stage EGFR mutated NSCLC patients who underwent radical resection and treated with first-generation EGFR-TKIs (gefitinib, erlotinib, icotinib) as adjuvant therapy between Feb 2010 and Jan 2019 were retrieved from a prospectively-maintained database in our center. The primary endpoint was DFS in stage II/III (TNM 8th) patients with exploratory endpoint regarding DFS in stage I patients. Sensitivity analyses were based on propensity score matched (PSM) cohorts. Treatment failure patterns among different TKIs were also compared. RESULTS: Of 588 eligible patients, 198 patients (33.7%) received gefitinib, 106 patients (17.9%) received erlotinib, and 284 patients (48.2%) received icotinib. The median DFS of stage II/III patients in the gefitinib, erlotinib and icotinib group were 36.1 months (95% CI, 23.9–49.4), 42.8 months (95% CI, 29.6–97.8), and 32.5 months (95% CI, 23.9–49.4), respectively, with no significant difference (log-rank test P=0.22). There was also no significant difference in DFS among stage I patients receiving different TKIs (P=0.12). PSM adjustments and multivariate analyses adjusting for other confounders revealed similar results. In addition, there were no significant differences in treatment failure pattens in different EGFR-TKI arms, especially in terms of brain metastases (6.1% in gefitinb, 7.5% in erlotinib, 3.9% in icotinib) and bone metastases (8.6% in gefitinb, 9.4% in erlotinib, 7.0% in icotinib). CONCLUSIONS: This first and largest real-world study showed that gefitinib, erlotinib, and icotinib demonstrated comparable clinical effectiveness as adjuvant therapy for patients with early-stage EGFR mutated NSCLC.

BackgroundTo increase locoregional and systemic tumor control, a portion of patients with stage III (N2, N3) non-small cell lung cancer (NSCLC) received pulmonary resection after immunochemotherapy in our center. Herein, we assessed the real-world downstage (T, N stage) effectiveness of immunochemotherapy as induction treatment and explored the proper cycle number for stage III (N2, N3) NSCLC.MethodsBiopsy confirmed stage III (N2, N3) NSCLC patients who underwent immunochemotherapy between January 1st, 2018, to August 30th, 2019, were identified. Tumor radiologic regression, lymph node down-staging, and pathological response information were collected.ResultsIn total, 16 patients with stage IIIA NSCLC, 30 with stage IIIB NSCLC, 9 with stage IIIC NSCLC (N2, N3 metastasis) were included. After immunochemotherapy, 25/55 (45.5%) patients achieved an objective response. Ultimately, 33/55 (60.0%) patients received lobectomy plus systemic lymphadenectomy, of whom 18/33 (54.5%) obtained major pathological response (MPR) of the primary lesion, and 24 (72.7%) had pathological-confirmed lymph node downstage (N2-3 to N0-1). Notably, four patients had MPR of the primary lesion but without lymph node downstage. At the time of data cutoff (December 30th, 2020), the median follow-up duration was 9.2 months (IQR 8.0-11.7), 24/33 (72.7%) of patients that had pulmonary resection were progression-free, with 30 of them alive. Binary logistics analysis showed that 3-4 induction cycles were favorably associated with MPR than 1-2 cycles (p = 0.017).ConclusionsImmunochemotherapy as induction treatment showed encouraging MPR and lymph nodes down-staging rates in stage III (N2, N3) NSCLC in this study. Prolonged (3-4) cycles of immunochemotherapy were recommended for a better pathological response.

ObjectivesThis study aimed to establish a noninvasive radiomics model based on computed tomography (CT), with favorable sensitivity and specificity to predict EGFR mutation status in GGO-featured lung adenocarcinoma that subsequently guiding the administration of targeted therapy.MethodClinical-pathological information and preoperative CT-images of 636 lung adenocarcinoma patients (464, 100, and 72 in the training, internal, and external validation sets, respectively) that underwent GGO lesions resection were included. A total of 1476 radiomic features were extracted with gradient boosting decision tree (GBDT).ResultsThe established radiomics model containing 252 selected features showed an encouraging discrimination performance of EGFR mutation status (mutant or wild-type), and the predictive ability was superior to that of the clinical model (AUC: 0.901 vs. 0.674, 0.813 vs. 0.730, and 0.801 vs. 0.746 the training, internal, and external validation sets, respectively). The combined radiomics plus clinical model showed no additional benefit over the radiomics model in predicting EGFR status (AUC: 0.909 vs. 0.901, 0.803 vs. 0.813, 0.808 vs. 0.801, respectively, in three cohorts). Uniquely, this model was validated in a cohort of lung adenocarcinoma patients who undertaken adjuvant EGFR-TKIs and harbored unresected GGOs, leading to a significantly improved potency of EGFR-TKIs (response rate: 33.9% vs. 62.5%, P =0.04; before- and after-prediction, respectively).ConclusionThis presented radiomics model can be served as a noninvasive and time-saving approach for predicting the EGFR mutation status in lung adenocarcinoma presenting as GGO.Key pointsWe developed a GGO-specific radiomics model containing 252 radiomics features for EGFR mutation status differentiation.An AUC of 0.813 and 0.801 in the internal and external validation cohort, respectively, were achieved.The radiomics model was utilized in clinical translation in an adjuvant EGFR-TKIs cohort with unresected GGOs. A significant improvement in the potency of EGFR-TKIs was achieved (response rate: 33.9% vs. 62.5%, P =0.04; before- and after-prediction).

HYPOTHESIS The anterior cingulate cortex (ACC) participates in sodium salicylate (SS)-induced tinnitus through alteration of the disordered neural activity and modulates the neuronal changes in the auditory cortex (AC). BACKGROUND Although the mechanism underlying tinnitus remains unclear, the crucial roles of the auditory center and limbic system in this process have been elucidated. Recent reports suggest that dysfunction of the ACC, an important component of the limbic system that regulates and controls the conduction of multiple sensations, is involved in tinnitus. Although altered functional connectivity between the ACC and the auditory system has been observed in humans with tinnitus, the underlying neuronal mechanism remains unexplored. METHODS SS (350 mg/kg, 10%, i.p.) was used to yield tinnitus model in rats, followed by comparison of the alteration in the spontaneous firing rate (SFR), local field potential (LFP), and extracellular glutamic acid in the ACC. The responses of neurons in the AC to electrical stimulation from the ACC were also observed. RESULTS We determined significant increases in the neuronal SFR and extracellular glutamate level in the ACC after SS injection (p

Background Several articles have been published about the reorganization of surgical activity during the coronavirus disease 2019 (COVID-19) pandemic but little is known about the operative volume, distribution of cases, or capacity of The Department of Thoracic Surgery to deliver surgical services in the time of COVID-19. Methods A retrospective operative logbook review was completed in department of thoracic in a designated COVID-19 hospital. We reviewed and analyzed the operative logbook and discussed our countermeasures during the outbreak. A prediction model was established to discuss the time consuming about delayed surgeries during the pandemic. Results One thousand two hundred and seventy-five operation records were collected. The thoracic surgeries of this year has decreased (43.4%) during the Wuhan lockdown. From Jan 23rd to Apr 8th in 2020, there were 461 surgeries performed in The Department of Thoracic in our hospital with 0 cases of nosocomial COVID-19 infection. Prediction model showed that it will take 6 weeks to solve the backlog if department can reach the 85% of maximum of operations per week. Conclusions An understanding of operative case volume and distribution is essential in facilitating targeted interventions to strengthen surgical capacity in the time of COVID-19. A proper guideline is imperative to ensure access to safe, timely surgical care. By developing a scientific and effective management of hospital, it is possible to ensure optimal surgical safety during this crisis. Regular updates and a further study include multicenter is required. Clinical trial registry number ChiCTR2000034346.

Although diffusion-weighted imaging (DWI) is reported to be accurate in detecting bowel inflammation in Crohn’s disease (CD), its ability to assess bowel fibrosis remains unclear. This study assessed the role of DWI in the characterization of bowel fibrosis using surgical histopathology as the reference standard. Abdominal DWI was performed before elective surgery in 30 consecutive patients with CD. The apparent diffusion coefficients (ADCs) in pathologic bowel walls were calculated. Region-by-region correlations between DWI and the surgical specimens were performed to determine the histologic degrees of bowel fibrosis and inflammation. ADCs correlated negatively with bowel inflammation (r = − 0.499, p

Perianal abscess is a common disease in anorectal surgery. If the diagnosis is not clear and the cure is thoroughly cleared, the recurrence and spread of anal fistula will cause life-long pain. Objective: To investigate the application of 3.0T MRI 3D CUBE T2WI lipid suppression sequence in the diagnosis of perianal abscess. Methods: Thirty-six patients with perianal abscess confirmed by operation were examined with 2D T2WI and 3D CUBE T2WI lipid suppression sequences before operation. Two imaging techniques were evaluated to show the types of perianal abscess, the number of abscesses, the number of internal orifices of abscess, and the number of fistula branches with anal fistula in abscess. Results: Among 36 cases of perianal abscess, there were 5 cases of anal subcutaneous abscess, 12 cases of ischiorectal space abscess (8 cases complicated with anal fistula), 6 cases of posterior anal space abscess, 5 cases of anal sphincter abscess (3 cases complicated with anal fistula), 2 cases of high intermuscular abscess, 2 cases of rectal submucosal abscess, 3 cases of complex abscess (3 cases complicated with anal fistula), 1 case of misdiagnosis, 2D T2WI lipid suppression sequence and 3D CUBE T2WI suppression. The accuracy of lipid sequence abscess typing was 80.6% (29/36) and 88.9% (32/36), respectively, with no significant difference (P > 0.05). Thirty-six patients were surgically diagnosed as having 32 internal orifices, 68.8% (22/32) and 93.8% (30/32) of 2D T2WI and 3D CUBE T2WI lipid-suppressing sequences, respectively, with significant difference (P < 0.05); among the 36 patients, 14 had perianal abscess complicated with anal fistula, and 21 fistulas were found during the operation, 21 cases were found fistula, 61.9% (13/21) of fistula branches were found by 2D T2WI lipid-suppressing sequence and 90.5% (19/21) of 3D CUBE T2WI lipid-suppressing sequence. The difference was statistically significant (P < 0.05). The number of perianal abscesses was identical between the two scanning techniques. Conclusion: 3D CUBE T2WI lipid suppression sequence is superior to 2D T2WI lipid suppression sequence in the classification of perianal abscess, the number of internal orifices of abscess and the number of fistula branches of abscess complicated with anal fistula. It can also determine the number of internal orifices of abscess complicated with anal fistula, the number of fistula branches, the shape of primary and branch fistula and the relationship among pelvic floor muscle tissues. It can provide more accurate images for preoperative and intraoperative clinical surgery.

BACKGROUND: An increasing number and proportion of younger lung cancer patients have been observed worldwide, raising concerns on the optimal age to begin screening. This study aimed to investigate the association between age and findings in initial CT scans. METHODS: We searched for low-dose CT screening cohorts from electronic databases. Single-arm syntheses weighted by sample size were performed to calculate the detection rates of pulmonary nodules, lung cancers (all stages and stage I), and the proportion of stage I diseases in lung cancers. In addition, we included patients who underwent chest CT in our center as a supplementary cohort. The correlation between the detection rates and age was evaluated by the Pearson Correlation Coefficient. RESULTS: A total of 37 studies involving 163,442 participants were included. We found the detection rates of pulmonary nodules and lung cancers increased with age. However, the proportion of stage I diseases in lung cancers declined with increased starting age and was significantly higher in the 40-year group than in other groups (40 vs. 45, 50, 55, P

BACKGROUND: A survival benefit was observed in metastatic non-small cell lung cancer (NSCLC) patients that underwent surgical resection of the primary tumor. We developed a model testing the hypothesis that only certain stage IV patients would benefit from surgery and the potential benefit would vary based on primary tumor characteristics. METHODS: Patients with stage IV NSCLC were identified in the Surveillance, Epidemiology and End Results (SEER) database and then divided into surgery and non-surgery groups. A 1:1 Propensity score matching (PSM) was performed to balance characters. We assumed that patients received primary tumor surgery that lived longer than median cancer specific survival (CSS) time of those who didn’t underwent surgery could benefit from the operation. Multivariable Cox model was used to explore the independent factors of CSS in two groups (beneficial and non-beneficial group). Logistic regression was used to build a nomogram based on the significant predictive factors. RESULTS: A total of 30,342 patients with stage IV NSCLC were identified; 8.03% (2,436) received primary tumor surgery. After PSM, surgical intervention was independently correlated with longer median CSS time (19 vs. 9 months, P

Background: The response of cancer patients to immune checkpoint inhibitors (ICIs) vary in success. CD8+ tumor infiltrating lymphocytes (TILs) play a key role in killing cancer cells. This study aimed to evaluate the prognostic role of CD8+ TILs in cancer patients treat with immune checkpoint inhibitors (ICIs).Methods: We systematically searched all publications from PubMed, EMBASE, and Cochrane Library until 31 Jan 2021 without any restriction of language or article types. Studies assessing high versus low CD8+ TILs in predicting survival of various cancer patients were included. The outcomes included overall survival (OS), progression-free survival (PFS), objective response rate (ORR). Findings: A total of 32 studies consisting of 2546 cancer patients were included . The result showed that high CD8+ TILs was significantly associated with better OS (HR, 0.52; 95% confidence interval: 0.41-0.67; P < 0.001), PFS (HR, 0.54; 95% confidence interval: 0.42-0.70; P < 0.001) and ORR (OR = 3.88; 95% confidence interval: 2.59-5.82;P < 0.001) in patients treated with ICIs. Subgroup analyses suggested that patients with high CD8+ TILs had better clinical benefit regardless of different treatment (ICI monotherapy, or combination therapy), cancer types (NSCLC, melanoma and other), and CD8+ T cells location (intratumor, stroma, and invasive margin). Higher baseline circulating CD8+ T cells from peripheral blood did not contribute to improved OS (HR, 0.93; 95% confidence interval: 0.67-1.29; P = 0.67) and PFS (HR, 0.89; 95% confidence interval: 0.60-1.32;P = 0.56) when compared with low baseline. Interpretation: The result showed that high intratumoral, stromal, or invasive marginal, but not circulating CD8+ TILs can predict treatment outcomes in patients with ICIs therapy across different cancer , in either single-agent ICIs or combination with other therapies. Funding: China National Science Foundation (Grant No. 82022048, 81871893), Key Project of Guangzhou Scentific Research Project (Grant No. 201804020030), High-level university construction project of Guangzhou medical university (Grant No. 20182737, 201721007, 201715907, 2017160107); National key R & D Program (Grant No. 2017YFC0907903 & 2017YFC0112704) and the Guangdong high level hospital construction "reaching peak" plan. Declaration of Interest: No potential conflicts of interest were disclosed.

BackgroundFamily socioeconomic position (SEP) in childhood is an important factor to predict some chronic diseases. However, the association between family SEP in childhood and the risk of lung cancer is not clear. MethodsA systematic search was performed to explore their relationship. We selected education level, socioeconomic positions of parents and childhood housing conditions to represent an individual family SEP. Hazard ratios (HRs) of lung cancer specific-mortality were synthesized using a random effects model. Two-sample Mendelian randomization (MR) was carried out with summary data from published genome-wide association studies of SEP to assess the possible causal relationship of SEP and risk of lung cancer. ResultsThrough meta-analysis of 13 studies, we observed that poorer SEP was associated with increased lung cancer risk (HR: 1.25, 95% CI: 1.10, 1.43). In addition, the dose-response analysis revealed a negative correlation between SEP in childhood and lung cancer in adulthood. Same conclusion was reached in MR [(education level) OR 0.50, 95% CI: 0.39, 0.63; P: ConclusionsThis study indicates that poor family SEP in childhood is a causal risk factor for lung cancer. We believe this population may receive greater benefit from lung cancer screening programs.Systematic review registrationProspero ID: 159082

Objectives In diabetic nephropathy (DN), hypoxia‐inducible factor‐1α (HIF‐1α) activation in tubular cells plays an important protective role against kidney injury. The effects may occur via the target genes of HIF‐1α, such as haem oxygenase‐1 (HO‐1), but the exact mechanisms are incompletely understood. Materials and methods Mice with proximal tubule‐specific knockout of HIF‐1α (PT‐HIF‐1α−/− mice) were generated, and diabetes was induced in these mice by streptozotocin (STZ) injection. In addition, to mimic a hypoxic state, cobaltous chloride (CoCl2) was applied to HK‐2 cells. Results Our study first verified that conditional knockout of HIF‐1α worsened tubular injury in DN; additionally, aggravated kidney dysfunction, renal histopathological alterations, mitochondrial fragmentation, ROS accumulation and apoptosis were observed in diabetic PT‐HIF‐1α−/− mice. In vitro study showed that compared to control group, HK‐2 cells cultured under hypoxic ambiance displayed increased mitochondrial fragmentation, ROS production, mitochondrial membrane potential loss and apoptosis. These increases were reversed by overexpression of HIF‐1α or treatment with a HO‐1 agonist. Importantly, cotreatment with a HIF‐1α inhibitor and a HO‐1 agonist rescued the HK‐2 cells from the negative impacts of the HIF‐1α inhibitor. Conclusions These data revealed that HIF‐1α exerted a protective effect against tubular injury in DN, which could be mediated via modulation of mitochondrial dynamics through HO‐1 upregulation., HIF‐1α is a transcription factor that regulates HO‐1 gene expression, and HO‐1 facilitates mitochondrial fusion (Mfn1 and Mfn2) and inhibits mitochondrial fission (Drp1 and Fis1), which maintains mitochondrial homeostasis. Under diabetic conditions, kidney tissues are in hypoxia, which induces the expression of HIF‐1α through an impaired compensatory response. However, tubular‐specific deletion of HIF‐1α in the kidneys of diabetic mice exaggerated the mitochondrial dysfunction and ROS accumulation and then caused tubular damage, thereby leading to diabetic kidney injury.

There is a heated debate on whether the cancer survivors have worse outcomes in corona virus disease 2019 (COVID-2019). This study showed that both cancer survivors and cancer patients have decreased lymphocytes, partially explaining why these patients were associated with poorer prognosis in severe acute respiratory syndrome coronavirus 2 infection (SARS-CoV-2) in principle. Therefore, patients with cancer history, whether they are going active treatment or not, deserve special attention.

Endoplasmic reticulum (ER) stress has been reported to play a pivotal role in diabetic nephropathy (DN). AdipoRon is a newly developed adiponectin receptor agonist that provides beneficial effects for diabetic mice; however, its underlying mechanism remains to be delineated. Here, we demonstrated increased expression levels of ER stress markers, accompanied by upregulated levels of proinflammatory cytokines and increased expression of collagen I, fibronectin, Bax, and cleaved caspase 3 in the kidneys of db/db mice compared with control mice. Decreased expression of adiponectin receptor 1 (AdipoR1) and phosphorylated 5′AMP-activated kinase (p-AMPK) was also observed in the kidneys of db/db mice. However, these alterations were partially reversed by intragastric gavage with AdipoRon. In vitro, AdipoRon alleviated high-glucose-induced ER stress, oxidative stress, and apoptosis in HK-2 cells, a human tubular cell line. Moreover, AdipoRon restored the expression of AdipoR1 and p-AMPK in HK-2 cells exposed to high-glucose conditions. Additionally, these effects were partially abrogated by pretreatment with AdipoR1 siRNA, but this abrogation was ameliorated by cotreatment with AICAR, an AMPK activator. Furthermore, the effects of AdipoRon were also partially abolished by cotreatment with compound C. Together, these results suggest that AdipoRon exerts favorable effects on diabetes-induced tubular injury in DN by inhibiting ER stress mediated by the AdipoR1/p-AMPK pathway.

Background: Epidermal growth factor receptor (EGFR) mutation testing in plasma cell-free DNA (cfDNA) from advanced lung cancer patients is an emerging clinical tool. This meta-analysis was designed to determine the diagnostic accuracy of two common PCR systems, droplet digital PCR (ddPCR) and amplification refractory mutation system PCR (ARMS-PCR), for detecting EGFR mutation in cfDNA. Materials and methods: A systematic search was carried out based on PubMed, Web of science, Embase and the Cochrane library. Data from eligible studies were extracted and pooled to calculate the sensitivity, specificity, diagnostic odds ratio (DOR), area under the summary receiver-operating characteristic curve (AUROC), using tissue biopsy results as the standard method. Subgroup analyses were performed regarding EGFR mutation type, tumor stage, and EGFR-TKI treatment. Results: Twenty-five studies involving 4,881 cases were included. The plasma testing sensitivity, specificity, DOR, and AUROC, compared with the matched tumor tissues, were 72.1%, 95.6%, 38.5, 0.89 for ddPCR, and 65.3%, 98.2%, 52.8, 0.71 for ARMS-PCR, respectively, through indirect comparison, significant differences were found in sensitivity (P = 0.003) and specificity (P = 0.007). Furthermore, significant difference was found in sensitivity between tumor stage subgroups (IIIB-IV subgroup vs. IA-IV subgroup) in ARMS-PCR (73.7 vs. 64.2%, P = 0.008), but not in ddPCR (72.5 vs. 71.2%, P = 0.756). Conclusions: This study demonstrates that ddPCR and ARMS-PCR have a high specificity with a practical sensitivity for detecting EGFR mutation in cfDNA, which supports their application as a supplement or a conditional-alternative to tissue biopsy in clinical practice for genotyping. It seems that ddPCR has a higher sensitivity than ARMS-PCR, especially in early stages.

In recent years, lung cancer has become the most common cancer and the leading cause of deaths attributed to cancer. In China, lung cancer is the third leading cause of death after strokes and ischemic heart disease. This review aimed to provide an up-to-date summary of studies in regard to lung cancer in 2019 and to present the remarkable progress seen in lung cancer clinical research. A systematic search of PubMed and Web of Science for research published in 2019 was conducted using the search terms "lung cancer", "early stage", "advanced", "diagnosis", "treatment", or any combination of these terms. We selected 56 studies that we considered to be significant and have presented their major findings. In summary, survival among lung cancer patients was significantly improved compared with historical controls, turning lung cancer from an incurable disease into a chronic disease. In addition, treating lung cancer has become increasingly comprehensive, diversified, and individualized. Exploring the accurate biomarkers in immunotherapy and the mechanism of drug resistance in targeted therapy constitutes the greatest challenge at this stage.

ObjectiveTo evaluate the spectrum of comorbidities and its impact on the clinical outcome in patients with coronavirus disease 2019 (COVID-19).DesignRetrospective case studiesSetting575 hospitals in 31 province/autonomous regions/provincial municipalities across ChinaParticipants1,590 laboratory-confirmed hospitalized patients. Data were collected from November 21st, 2019 to January 31st, 2020.Main outcomes and measuresEpidemiological and clinical variables (in particular, comorbidities) were extracted from medical charts. The disease severity was categorized based on the American Thoracic Society guidelines for community-acquired pneumonia. The primary endpoint was the composite endpoints, which consisted of the admission to intensive care unit (ICU), or invasive ventilation, or death. The risk of reaching to the composite endpoints was compared among patients with COVID-19 according to the presence and number of comorbidities.ResultsOf the 1,590 cases, the mean age was 48.9 years. 686 patients (42.7%) were females. 647 (40.7%) patients were managed inside Hubei province, and 1,334 (83.9%) patients had a contact history of Wuhan city. Severe cases accounted for 16.0% of the study population. 131 (8.2%) patients reached to the composite endpoints. 399 (25.1%) reported having at least one comorbidity. 269 (16.9%), 59 (3.7%), 30 (1.9%), 130 (8.2%), 28 (1.8%), 24 (1.5%), 21 (1.3%), 18 (1.1%) and 3 (0.2%) patients reported having hypertension, cardiovascular diseases, cerebrovascular diseases, diabetes, hepatitis B infections, chronic obstructive pulmonary disease, chronic kidney diseases, malignancy and immunodeficiency, respectively. 130 (8.2%) patients reported having two or more comorbidities. Patients with two or more comorbidities had significantly escalated risks of reaching to the composite endpoint compared with those who had a single comorbidity, and even more so as compared with those without (all PConclusionComorbidities are present in around one fourth of patients with COVID-19 in China, and predispose to poorer clinical outcomes.HighlightsWhat is already known on this topic-Since November 2019, the rapid outbreak of coronavirus disease 2019 (COVID-19) has recently become a public health emergency of international concern. There have been 79,331 laboratory-confirmed cases and 2,595 deaths globally as of February 25th, 2020-Previous studies have demonstrated the association between comorbidities and other severe acute respiratory diseases including SARS and MERS.-No study with a nationwide representative cohort has demonstrated the spectrum of comorbidities and the impact of comorbidities on the clinical outcomes in patients with COVID-19.What this study adds-In this nationwide study with 1,590 patients with COVID-19, comorbidities were identified in 399 patients. Comorbidities of COVID-19 mainly included hypertension, cardiovascular diseases, cerebrovascular diseases, diabetes, hepatitis B infections, chronic obstructive pulmonary disease, chronic kidney diseases, malignancy and immunodeficiency.-The presence of as well as the number of comorbidities predicted the poor clinical outcomes (admission to intensive care unit, invasive ventilation, or death) of COVID-19.-Comorbidities should be taken into account when estimating the clinical outcomes of patients with COVID-19 on hospital admission.

Aims To examine the association between 24 literature‐based single nucleotide polymorphisms and diabetic kidney disease in Chinese people with type 2 diabetes. Methods and results Twenty‐four candidate diabetic kidney disease‐susceptible single nucleotide polymorphisms were genotyped in 208 participants with type 2 diabetes and diabetic kidney disease and 200 participants with type 2 diabetes without diabetic kidney disease (case and control groups, respectively), together with 206 healthy participants using MassARRAY. Rs11643718 in the SLC12A3 gene was associated with diabetic kidney disease in the recessive model after adjusting for confounding factors, such as age and gender (adjusted odds ratio 2.056, 95% CI 1.120–3.776; P = 0.020). Meta‐analyses further confirmed the association (P = 0.002). In addition, participants with the GG genotype had worse renal function and more albuminuria than those with the AA+AG genotype (P < 0.05). Renal section immunohistochemistry was conducted in participants with type 2 diabetes, diabetic kidney disease and AA+AG or GG genotypes and in participants with glomerular minor lesions. Together with data from the Nephroseq database, it was shown that the abundance of SLC12A3 was reduced in patients with the GG genotype, while elevated expression of SLC12A3 was associated with better renal function. In addition, rs10951509 and rs1345365 in ELMO1, which were determined to be in high linkage disequilibrium by SHEsis software, were also associated with diabetic kidney disease (adjusted P = 0.010 and 0.015, respectively). Conclusions The G allele and GG genotype of SLC12A3 rs11643718 are associated with the development of diabetic kidney disease in a Chinese population with type 2 diabetes., What's new? Many diabetic kidney disease (DKD)‐susceptible single‐nucleotide polymorphims (SNPs) in type 2 diabetes have been identified; however, the relationship between some SNPs and DKD is still controversial. The effect of several SNPs on DKD in Chinese populations with type 2 diabetes is also unclear.This study found that the G allele and GG genotype in SLC12A3 rs11643718, as well as the G allele and GG+AG genotype in ELMO1 rs10951509 and rs1345365, may be risk factors for DKD in Chinese type 2 diabetes populations.Analysing these genotypes in people with type 2 diabetes will be helpful in identifying populations with high risk of DKD.

Nω-nitro-L-arginine methyl ester (L-NAME), an inhibitor of nitric oxide (NO) biosynthesis, results in hypertension and liver injury. This study aimed at investigating the changes of liver lipometabonomics and exploring the underlying mechanisms of liver injury in the L-NAME-treated rats. The male Sprague-Dawley (SD) rats were treated with L-NAME (40 mg/kg, p.o.) for 8 weeks. After that, the liver, aorta, fecal, and serum were collected for analysis. The results showed that L-NAME induced hypertension and disordered the endothelial nitric oxide synthase (eNOS)-NO pathway in the treated rats. L-NAME could also increase the levels of serum total cholesterol (TC), triglyceride (TG), alanine transaminase (ALT), and aspartate transaminase (AST). The multidimensional mass spectrometry-based shotgun lipidomics (MDMS-SL) analysis showed that L-NAME could induce significant changes of the total hepatic lipids and most hepatic triglycerides, as well as fatty acid (FA). A positive correlation was found between the blood pressure and TAG. Immunofluorescence and Western-Blot experiments indicated that the L-NAME treatment significantly influenced some FA β-oxidation, desaturation, and synthesis-related proteins. The increase of intestinal inflammation, decrease of microcirculation and tight junction proteins, as well as alterations of microbial communities were observed in the L-NAME induced hypertensive rats, as well as alterations of microbial communities were notable correlation to TAG and FA species. This study demonstrated that the L-NAME-induced hypertensive rats exhibiting liver injury were the joint action of hepatic abnormal fatty acid metabolism and microcirculation disorder. Furthermore, the gut microflora, as well as the changes of FA β-oxidation (ACOX, CPT1α), desaturation (SCD-1), and synthesis (FAS) may be the potential mechanisms for abnormal fatty acid metabolism.

Understanding the cancer risks in different transplant recipients helps early detection, evaluation, and treatment of post-transplant malignancies. Therefore, we performed a meta-analysis to determine the cancer risks at multiple sites for solid organ transplant recipients and their associations with tumor mutation burden (TMB), which reflects the immunogenicity. A comprehensive search of PubMed, Web of Science, EMBASE, Medline, and Cochrane Library was conducted. Random effects models were used to calculate the standardized incidence ratios (SIRs) versus the general population and determine the risks of different cancers. Linear regression (LR) was used to analyze the association between the SIRs and TMBs. Finally, seventy-two articles met our criteria, involving 2,105,122 solid organ transplant recipients. Compared with the general population, solid organ transplant recipients displayed a 2.68-fold cancer risk (SIR 2.68; 2.48–2.89; P

Background: As the COVID-19 pandemic continues to spread worldwide, there is still no accurate rapid diagnostic test for COVID-19, or monitoring tool for patient’s clinical course. An artificial-intelligence system (CoviDet) was therefore developed and applied on chest computed tomography (CT), to evaluate its application for rapid diagnosis and potential monitoring of COVID-19 patients. Methods: 1,201,074 CT slices from 2527 patients were grouped into 3 main groups: COVID-19 positive group, non-COVID-19 viral pneumonia group and control group. They were used to train and validate CoviDet novel stepwise diagnostic algorithm to diagnose COVID-19, with or without clinical data. A subset of COVID-19 patients with more than 3 consecutive CT images were selected for training and validation of the auto-segmentation and monitoring algorithm. Findings: CoviDet outperforms radiologists, and can diagnose COVID-19 based on CT alone with sensitivity of 0.93, specificity of 0.95 and AUC of 0.98 (95%CI 0.97-0.99; P

BackgroundThe coronavirus disease 2019 (COVID-19) outbreak is evolving rapidly worldwide.ObjectiveTo evaluate the risk of serious adverse outcomes in patients with COVID-19 by stratifying the comorbidity status.MethodsWe analysed data from 1590 laboratory confirmed hospitalised patients from 575 hospitals in 31 provinces/autonomous regions/provincial municipalities across mainland China between 11 December 2019 and 31 January 2020. We analysed the composite end-points, which consisted of admission to an intensive care unit, invasive ventilation or death. The risk of reaching the composite end-points was compared according to the presence and number of comorbidities.ResultsThe mean age was 48.9 years and 686 (42.7%) patients were female. Severe cases accounted for 16.0% of the study population. 131 (8.2%) patients reached the composite end-points. 399 (25.1%) reported having at least one comorbidity. The most prevalent comorbidity was hypertension (16.9%), followed by diabetes (8.2%). 130 (8.2%) patients reported having two or more comorbidities. After adjusting for age and smoking status, COPD (HR (95% CI) 2.681 (1.424–5.048)), diabetes (1.59 (1.03–2.45)), hypertension (1.58 (1.07–2.32)) and malignancy (3.50 (1.60–7.64)) were risk factors of reaching the composite end-points. The hazard ratio (95% CI) was 1.79 (1.16–2.77) among patients with at least one comorbidity and 2.59 (1.61–4.17) among patients with two or more comorbidities.ConclusionAmong laboratory confirmed cases of COVID-19, patients with any comorbidity yielded poorer clinical outcomes than those without. A greater number of comorbidities also correlated with poorer clinical outcomes.

Background: The responses of cancer patients to immune checkpoint inhibitors (ICIs) vary in success. CD8+ tumor infiltrating lymphocytes (TILs) play a key role in killing tumor cells. This study aims to evaluate the prognostic role of CD8+ TILs in cancer patients treated with ICIs. Methods: We systematically searched all publications from PubMed, EMBASE, and Cochrane Library until 12 Jul 2021 without any restriction of language or article types. Studies assessing high versus low CD8+ TILs in predicting efficacy and survival of various cancer patients were included. The outcomes included overall survival (OS), progression-free survival (PFS), and objective response rate (ORR). The study protocol is prospectively registered on PROSPERO (registration number CRD42021233654). Findings: Findings: A total of 33 studies consisting of 2559 cancer patients were included. The result showed that high CD8+ TILs were significantly associated with better OS (HR, 0.52; 95% confidence interval: 0.41–0.67; p

Epidermal growth factor receptor tyrosine kinase inhibitors (EGFR-TKIs) are treatments commonly used for lung cancer. The toxicity profile including toxicity incidence, severity, and spectrum (involving various specific adverse events) of each EGFR-TKI are of particular clinical interest and importance. Data from phase II and III randomized controlled trials comparing treatments among EGFR-TKIs (osimertinib, dacomitinib, afatinib, erlotinib, gefitinib, and icotinib) and chemotherapy for lung cancer were synthesized with Bayesian network meta-analysis. The primary outcome was systemic all-grade and grade ≥3 adverse events. The secondary outcome was specific all-grade adverse events including those of the skin, gastrointestinal tract, lung, etc. 40 trials randomizing 13,352 patients were included. Generally greater toxicity for dacomitinib and afatinib, and safety for icotinib were suggested. Furthermore, we found individual EGFR-TKIs had different toxicity spectrums. These findings provide a compelling safety reference for the individualized use of EGFR-TKIs for patients with lung cancer.

We aim to design a scoring model for differential diagnosis between diabetic nephropathy (DN) and nondiabetic renal disease (NDRD) in type 2 diabetic patients through a combination of clinical variables.A total of 170 patients with type 2 diabetes who underwent kidney biopsies were included and divided into three groups according to pathological findings: DN group (n = 46), MIX group (DN + NDRD, n = 54), NDRD group (n = 70). Clinical characteristics and laboratory data were collected and compared among groups. Variables with a significant statistical difference between DN and NDRD patients were analyzed by logistic regression to predict the presence of NDRD; then a scoring model was established based on the regression coefficient and further validated in an independent cohort of 67 patients prospectively.On biopsy, 72.9% of patients had NDRD, and the most common pathological type was membranous nephropathy. The established scoring model for predicting NDRD included five predictors: age, systolic blood pressure, hemoglobin, duration of diabetes, and absence of diabetic retinopathy. The model demonstrated good discrimination and calibration (area under curve [AUC] 0.863, 95% CI, 0.800-0.925; Hosmer-Lemeshow [H-L] P = .062). Furthermore, high prediction accuracy (AUC = 0.900; 95% CI, 0.815-0.985) in the validation cohort proved the stability of the model.We present a simple, robust scoring model for predicting the presence of NDRD with high accuracy (0.85) for the first time. This decision support tool provides a noninvasive method for differential diagnosis of DN and NDRD, which may help clinicians assess the risk-benefit ratio of kidney biopsy for type 2 diabetic patients with renal impairment.背景: 本研究旨在通过整合相关临床指标, 建立2型糖尿病患者中糖尿病肾病(diabetic nephropathy, DN)和非糖尿病肾病(non-diabetic renal disease, NDRD)的鉴别诊断评分模型。 方法: 纳入170例接受肾脏穿刺活检术的2型糖尿病患者, 根据病理结果分为三组: DN 组(n=46), MIX 组(DN+NDRD, n=54), NDRD 组(n=70), 比较分析三组患者的临床及实验室数据, 将DN与NDRD两组患者有显著差异的变量通过 logistic多元回归分析预测 NDRD, 基于回归系数建立诊断评分模型, 并在另一独立验证队列(n=67)中前瞻性地验证模型准确度。 结果: 活检患者中NDRD的检出率为72.9%, 其中最常见的病理类型为膜性肾病。NDRD诊断评分模型包括5个预测因素:年龄、收缩压、血红蛋白、糖尿病病程和排除糖尿病视网膜病变。该模型具有良好的区分度(曲线下面积[area under the curve, AUC]= 0.863; 95%CI 0.800-0.925)和校准度(H-L检验 P=0.062)。应用于验证队列时依然呈现出较高的准确率(AUC=0.900; 95% CI, 0.815-0.985), 提示其预测稳定性较好。 结论: 本研究首次建立了用于预测NDRD诊断的评分模型, 准确率为85%, 可以作为一种无创性鉴别诊断方法有效地区分DN和NDRD的工具, 因此有助于医生评估有肾脏损害的2型糖尿病患者肾活检的风险-收益比。.

Background Population-based cohort studies have indicated that systemic sclerosis (SSc) may be associated with an increased risk of lung cancer. However, there are few studies that comprehensively investigate their correlation and the causal effect remains unknown. Methods A systematic search of PubMed, Web of Science, Cochrane Library and Embase from the inception dates to December 1, 2019 was carried out. Meta-analysis was performed to calculate odds ratio (OR) and corresponding 95% confidence interval (CI) using random-effects models. Subgroup analyses were performed regarding gender. Two-sample Mendelian randomization (MR) was carried out with summary data from published genome-wide association studies of SSc (Neale Lab, 3871 individuals; UK Biobank, 463,315 individuals) and lung cancer (International Lung Cancer Consortium, 27,209 individuals; UK Biobank, 508,977 individuals). Study-specific estimates were summarized using inverse variance-weighted, weighted median, and MR-Egger method. Results Through meta-analysis of 10 population-based cohort studies involving 12,218 patients, we observed a significantly increased risk of lung cancer among patients with SSc (OR 2.80, 95% CI 1.55–5.03). In accordance with subgroup analysis, male patients (OR 4.11, 95% CI 1.92–8.79) had a 1.5-fold higher lung cancer risk compared with female patients (OR 2.73, 95% CI 1.41–5.27). However, using a score of 11 SSc-related single nucleotide polymorphisms (p Conclusions This study indicated an increased risk of lung cancer among patients with SSc by meta-analysis, whereas the MR study did not support a causality between the two diseases. Further studies are warranted to investigate the factors underlying the attribution of SSc to lung cancer risk.

BackgroundDuring the outbreak of coronavirus disease 2019 (COVID-19), consistent and considerable differences in disease severity and mortality rate of patients treated in Hubei province compared to those in other parts of China have been observed. We sought to compare the clinical characteristics and outcomes of patients being treated inside and outside Hubei province, and explore the factors underlying these differences.MethodsCollaborating with the National Health Commission, we established a retrospective cohort to study hospitalised COVID-19 cases in China. Clinical characteristics, the rate of severe events and deaths, and the time to critical illness (invasive ventilation or intensive care unit admission or death) were compared between patients within and outside Hubei. The impact of Wuhan-related exposure (a presumed key factor that drove the severe situation in Hubei, as Wuhan is the epicentre as well the administrative centre of Hubei province) and the duration between symptom onset and admission on prognosis were also determined.ResultsAt the data cut-off (31 January 2020), 1590 cases from 575 hospitals in 31 provincial administrative regions were collected (core cohort). The overall rate of severe cases and mortality was 16.0% and 3.2%, respectively. Patients in Hubei (predominantly with Wuhan-related exposure, 597 (92.3%) out of 647) were older (mean age 49.7 versus 44.9 years), had more cases with comorbidity (32.9% versus 19.7%), higher symptomatic burden, abnormal radiologic manifestations and, especially, a longer waiting time between symptom onset and admission (5.7 versus 4.5 days) compared with patients outside Hubei. Patients in Hubei (severe event rate 23.0% versus 11.1%, death rate 7.3% versus 0.3%, HR (95% CI) for critical illness 1.59 (1.05–2.41)) have a poorer prognosis compared with patients outside Hubei after adjusting for age and comorbidity. However, among patients outside Hubei, the duration from symptom onset to hospitalisation (mean 4.4 versus 4.7 days) and prognosis (HR (95%) 0.84 (0.40–1.80)) were similar between patients with or without Wuhan-related exposure. In the overall population, the waiting time, but neither treated in Hubei nor Wuhan-related exposure, remained an independent prognostic factor (HR (95%) 1.05 (1.01–1.08)).ConclusionThere were more severe cases and poorer outcomes for COVID-19 patients treated in Hubei, which might be attributed to the prolonged duration of symptom onset to hospitalisation in the epicentre. Future studies to determine the reason for delaying hospitalisation are warranted.

Lung adenocarcinoma is a form of non-small-cell lung cancer with high mortality in the advanced stages, and is one of the most common histological subtypes of lung cancer in most countries. Prognosis of lung adenocarcinoma is generally poor, with a median survival of 4–13 months. We report a case of unusually prolonged survival of a patient with advanced lung adenocarcinoma complicated by hypothyroidism. A 71-year-old man with stage IV lung adenocarcinoma presented with hypothyroidism. Surprisingly, without any anti-tumor and anti-hypothyroidism therapy, he survived this lung cancer for longer than 2.5 years before his last follow-up visit. Patients with advanced lung adenocarcinoma rarely survive for longer than 2 years, even after therapy. We hypothesize that hypothyroidism is the cause for this discrepancy. Thyroid hormones can promote growth of carcinoma. Therefore, hypothyroidism appears to be beneficial to anti-cancer therapy. We believe that hypothyroidism, as an adverse event commonly occurring in anti-tumor therapy (e.g., an immune checkpoint inhibitor), might not be able to be completely eliminated.

Mouse-induced pluripotent stem cells (iPSCs) could differentiate into hair cell-like cells and spiral ganglion-like cells after transplantation into mouse cochleae, but it cannot improve the auditory brain response (ABR) thresholds in short term.To evaluate the potential of iPSCs for use as a source of transplants for the treatment of sensorineural hearing loss (SNHL).Establishing SNHL mice model, then injecting the iPSCs or equal volume DMEM basic medium into the cochleae, respectively. Immunofluorescence staining and reverse transcription-polymerase chain reaction (RT-PCR) were used to assess the survival, migration, differentiation of the transplanted iPSCs in cochleae and then recorded the ABR threshold in different time. Hematoxylin-eosin (HE) staining was used to observe the teratoma formation.Four weeks after transplantation, CM-Di1-labeled iPSCs could be found in the modiolus and Rosenthal's canal (RC), and some of them could expressed auditory hair cell markers or spiral ganglion neuron makers in group A, but not found in group B and C. As to the ABR threshold, no significance differences were found between pre- with postoperative in group A or B. In our study, no teratoma was observed in the cochleae.

Reduced bone mineral density and hip fracture are frequently observed in patients with Alzheimer's disease (AD). However, mechanisms underlying their association remain poorly understood. Amyloid precursor protein (APP) is a transmembrane protein that is ubiquitously expressed in bone marrow stromal cells (BMSCs), osteoblasts (OBs), macrophages (BMMs), and osteoclasts (OCs). Mutations in the APP gene identified in early-onset AD patients are believed to cause AD. But little is known about APP's role in bone remodeling. Here, we present evidence for Swedish mutant APP (APPswe) in suppression of OB differentiation and function in culture and in mouse. APP expression in BMSCs increases during aging. Ubiquitous expression of APPswe in young adult Tg2576 transgenic mice (under the control of a prion promoter) recaptured skeletal "aging-like" deficits, including decreased OB genesis and bone formation, increased adipogenesis and bone marrow fat, and enhanced OC genesis and bone resorption. Remarkably, selective expression of APPswe in mature OB-lineage cells in TgAPPswe-Ocn mice (under the control of osteocalcin [Ocn] promoter-driven Cre) also decreased OB genesis and increased OC formation, resulting in a trabecular bone loss. These results thus suggest a cell-autonomous role for APPswe in suppressing OB formation and function, but a nonautonomous effect on OC genesis. Notably, increased adipogenesis and elevated bone marrow fat were detected in young adult Tg2576 mice, but not in TgAPPswe-Ocn mice, implying that APPswe in BMSCs and/or multicell types in bone marrow promotes bone marrow adipogenesis. Intriguingly, the skeletal aging-like deficits in young adult Tg2576 mice were prevented by treatment with N-acetyl-L-cysteine (NAC), an antioxidant, suggesting that reactive oxygen species (ROS) may underlie APPswe-induced osteoporotic deficits. Taken together, these results demonstrate a role for APPswe in suppressing OB differentiation and bone formation, implicate APPswe as a detrimental factor for AD-associated osteoporotic deficit, and reveal a potential clinical value of NAC in the treatment of osteoporotic deficits. © 2013 American Society for Bone and Mineral Research.

Vps35 deficiency leads to impaired RANK trafficking, enhanced RANKL signaling, increased osteoclastogenesis and function, and osteoporotic deficits., Receptor activator of NF-κB (RANK) plays a critical role in osteoclastogenesis, an essential process for the initiation of bone remodeling to maintain healthy bone mass and structure. Although the signaling and function of RANK have been investigated extensively, much less is known about the negative regulatory mechanisms of its signaling. We demonstrate in this paper that RANK trafficking, signaling, and function are regulated by VPS35, a major component of the retromer essential for selective endosome to Golgi retrieval of membrane proteins. VPS35 loss of function altered RANK ligand (RANKL)–induced RANK distribution, enhanced RANKL sensitivity, sustained RANKL signaling, and increased hyperresorptive osteoclast (OC) formation. Hemizygous deletion of the Vps35 gene in mice promoted hyperresorptive osteoclastogenesis, decreased bone formation, and caused a subsequent osteoporotic deficit, including decreased trabecular bone volumes and reduced trabecular thickness and density in long bones. These results indicate that VPS35 critically deregulates RANK signaling, thus restraining increased formation of hyperresorptive OCs and preventing osteoporotic deficits.

SUMMARY Neogenin has been identified as a receptor for the neuronal axon guidance cues netrins and RGMs (repulsive guidance molecules). Here we provide evidence for neogenin in regulating endochondral bone development and BMP (bone morphogenetic protein) signaling. Neogenin-deficient mice were impaired in digit/limb development and endochondral ossification. BMP2 induction of Smad1/5/8 phosphorylation and Runx2 expression, but not noncanonical p38 MAPK activation, was reduced in chondrocytes from neogenin mutant mice. BMP receptor association with membrane microdomains, which is necessary for BMP signaling to Smad, but not p38 MAPK, was diminished in neogenin-deficient chondrocytes. Furthermore, RGMs appear to mediate neogenin interaction with BMP receptors in chondrocytes. Taken together, our results indicate that neogenin promotes chondrogenesis in vitro and in vivo, revealing an unexpected mechanism underlying neogenin regulation of BMP signaling.