Efficacy and safety of GST-HG171 in adult patients with mild to moderate COVID-19: a randomised, double-blind, placebo-controlled phase 2/3 trial.

Background: GST-HG171 is a potent, broad-spectrum, orally bioavailable small-molecule 3C like protease inhibitor that has demonstrated greater potency and efficacy compared to Nirmatrelvir in pre-clinical studies. We aimed to evaluate the efficacy and safety of orally administered GST-HG171 plus Ritonavir in patients with coronavirus disease 2019 (COVID-19) infected with emerging XBB and non-XBB variants. Methods: This randomised, double-blind, placebo-controlled phase 2/3 trial was conducted in 47 sites in China among adult patients with mild-to-moderate COVID-19 with symptoms onset ≤72 h. Eligible patients were randomised 1:1 to receive GST-HG171 (150 mg) plus Ritonavir (100 mg) or corresponding placebo tablets twice daily for 5 days, with stratification factors including the risk level of disease progression and vaccination status. The primary efficacy endpoint was time to sustained recovery of clinical symptoms within 28 days, defined as a score of 0 for 11 COVID-19-related target symptoms for 2 consecutive days, assessed in the modified intention-to-treat (mITT) population. This trial was registered at ClinicalTrials.gov (NCT05656443) and Chinese Clinical Trial Registry (ChiCTR2200067088). Findings: Between Dec 19, 2022, and May 4, 2023, 1525 patients were screened. Among 1246 patients who underwent randomisation, most completed basic (21.2%) or booster (74.9%) COVID-19 immunization, and most had a low risk of disease progression at baseline. 610 of 617 who received GST-HG171 plus Ritonavir and 603 of 610 who received placebo were included in the mITT population. Patients who received GST-HG171 plus Ritonavir showed shortened median time to sustained recovery of clinical symptoms compared to the placebo group (13.0 days [95.45% confidence interval 12.0-15.0] vs. 15.0 days [14.0-15.0], P = 0.031). Consistent results were observed in both SARS-CoV-2 XBB (45.7%, 481/1053 of mITT population) and non-XBB variants (54.3%, 572/1053 of mITT population) subgroups. Incidence of adverse events was similar in the GST-HG171 plus Ritonavir (320/617, 51.9%) and placebo group (298/610, 48.9%). The most common adverse events in both placebo and treatment groups were hypertriglyceridaemia (10.0% vs. 14.7%). No deaths occurred. Interpretation: Treatment with GST-HG171 plus Ritonavir has demonstrated benefits in symptom recovery and viral clearance among low-risk vaccinated adult patients with COVID-19, without apparent safety concerns. As most patients were treated within 2 days after symptom onset in our study, confirming the potential benefits of symptom recovery for patients with a longer duration between symptom onset and treatment initiation will require real-world studies. Funding: Fujian Akeylink Biotechnology Co., Ltd.

First-line penpulimab combined with paclitaxel and carboplatin for metastatic squamous non-small-cell lung cancer in China (AK105-302): a multicentre, randomised, double-blind, placebo-controlled phase 3 clinical trial.

BACKGROUND: Penpulimab is a novel programmed death (PD)-1 inhibitor. This study aimed to establish the efficacy and safety of first line penpulimab plus chemotherapy for advanced squamous non-small-cell lung cancer. METHODS: This multicentre, randomised, double-blind, placebo-controlled, phase 3 clinical trial enrolled patients with locally advanced or metastatic squamous non-small-cell lung cancer from 74 hospitals in China. Eligible participants were aged 18-75 years, had histologically or cytologically confirmed locally advanced (stage IIIb or IIIc) or metastatic (stage IV) squamous non-small-cell lung cancer, were ineligible to complete surgical resection and concurrent or sequential chemoradiotherapy, had an Eastern Cooperative Oncology Group (ECOG) performance status of 0-1, did not have previous systemic chemotherapy for locally advanced or metastatic non-small-cell lung cancer, and had one or more measurable lesions according to RECIST (version 1.1). Participants were randomly assigned (1:1) to receive intravenous penpulimab 200 mg or placebo (excipient of penpulimab injection), plus paclitaxel 175 mg/m2 and carboplatin AUC of 5 intravenously on day 1 every 3 weeks for four cycles, followed by penpulimab or placebo as maintenance therapy. Stratification was done according to the PD-L1 tumour proportion score (<1% vs 1-49% vs ≥50%) and sex (male vs female). The participants, investigators, and other research staff were masked to group assignment. The primary outcome was progression-free survival assessed by the masked Independent Radiology Review Committee in the intention-to-treat population and patients with a PD-L1 tumour proportion score of 1% or more (PD-L1-positive subgroup). The primary analysis was based on the intention-to-treat analysis set (ie, all randomly assigned participants) and the PD-L1-positive subgroup. The safety analysis included all participants who received at least one dose of study drug after enrolment. This trial was registered with ClinicalTrials.gov (NCT03866993). FINDINGS: Between Dec 20, 2018, and Oct 10, 2020, 485 patients were screened, and 350 participants were randomly assigned (175 in the penpulimab group and 175 in the placebo group). Of 350 participants, 324 (93%) were male and 26 (7%) were female, and 347 (99%) were of Han ethnicity. In the final analysis (June 1, 2022; median follow-up, 24·7 months [IQR 0-41·4]), the penpulimab group showed an improved progression-free survival compared with the placebo group, both in the intention-to-treat population (median 7·6 months, 95% CI 6·8--9·6 vs 4·2 months, 95% CI 4·2-4·3; HR 0·43, 95% CI 0·33-0·56; p<0·0001) and in the PD-L1-positive subgroup (8·1 months, 5·7-9·7 vs 4·2 months, 4·1-4·3; HR 0·37, 0·27-0·52, p<0·0001). Grade 3 or worse treatment-emergent adverse events occurred in 120 (69%) 173 patients in the penpulimab group and 119 (68%) of 175 in the placebo group. INTERPRETATION: Penpulimab plus chemotherapy significantly improved progression-free survival in patients with advanced squamous non-small-cell lung cancer compared with chemotherapy alone. The treatment was safe and tolerable. Penpulimab combined with paclitaxel and carboplatin is a new option for first-line treatment in patients with this advanced disease. FUNDING: The National Natural Science Foundation of China, Shanghai Municipal Health Commission, Chia Tai Tianqing Pharmaceutical, Akeso.

Clinical characteristics and predictors of delayed discharge among children with SARS­CoV­2 Omicron variant infection.

The present study investigated the epidemiology and clinical characteristics of infection with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) Omicron variant and determined the risk factors for delayed discharge or release from isolation for pediatric patients in Quanzhou, China in 2022. There were 145, 254 and 23 patients in the asymptomatic, mildly symptomatic and moderately symptomatic categories, respectively. The proportion of pediatric patients in the moderately symptomatic category increased with increasing age. No child aged <1 year and 9.02% of patients aged 13-18 years were in the moderately symptomatic category. The proportion of patients with asymptomatic infection did not differ significantly by vaccination status. The median days until the first negative conversion of viral RNA was 11 days, and the median hospitalization duration was 16 days. Most symptoms appeared in the upper respiratory tract. Notably, ~33.23% of patients showed elevated aspartate aminotransferase levels. C-reactive protein and interleukin-6 (IL-6) levels, and lymphocyte counts were consistently lower in asymptomatic patients than those in in symptomatic patients. Adjusted logistic regression analyses indicated that IL-6 levels and time to the first negative conversion of viral RNA were independent risk factors for delayed discharge. The area under the curve of the regression model for predicting delayed discharge was 0.760. In conclusion, these results could facilitate the formulation of global epidemic prevention policies for pediatric patients.

Epidemiological and clinical features of SARS-CoV-2 Omicron variant infection in Quanzhou, Fujian province: a retrospective study.

Epidemiological and clinical data of patients infected with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) Omicron variant (BA.2) admitted to three designated hospitals in Quanzhou City, Fujian Province, China, were collected and analyzed. Overall, 2,541 patients infected with BA.2, comprising 1,060 asymptomatic, 1,287 mild, and 194 moderate infections, were enrolled. The percentage of moderate infections was higher in patients aged ≥ 60 years than in those aged < 18 years and 18-59 years. The median hospitalization duration was 17 days. Among the 2,541 patients, 43.52% had a clear history of close contact. The vaccination rate was 87.92%, and the percentage of asymptomatic infections was higher in vaccinated than in unvaccinated patients. Moreover, patients with underlying diseases, including hypertension and diabetes mellitus, had more moderate infections than those without underlying diseases. The three most common clinical manifestations were fever, dry cough, and sore throat. The albumin-to-globulin (A/G) ratio and lymphocyte count decreased in cases with mild and moderate infections, while procalcitonin, erythrocyte sedimentation rate, interleukin-6, D-dimer, and C4 levels increased. Advanced age, non-vaccination, and underlying comorbid diseases were high-risk factors for disease progression in patients. However, dynamic monitoring of blood routine parameters, A/G ratio, and inflammatory indicators facilitated the prediction of disease progression.

[Clinical features of severe acute respiratory syndrome coronavirus 2 Omicron variant infection in children: an analysis of 201 cases]. / 201ä¾‹å„¿ç«¥æ–°åž‹å† çŠ¶ç— æ¯’Omicronå˜å¼‚æ ªæ„ŸæŸ“çš„ä¸´åºŠç‰¹å¾åˆ†æž.

OBJECTIVES: To study the clinical features of children with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) Omicron variant infection. METHODS: A retrospective analysis was performed on the medical data of 201 children with coronavirus disease 2019 (COVID-19) who were hospitalized and diagnosed with SARS-CoV-2 Omicron variant infection in Quanzhou First Hospital from March 14 to April 7, 2022. Among the 201 children, there were 34 children with asymptomatic infection and 167 with symptomatic infection. The two groups were compared in terms of clinical features, results of experimental examinations, and outcome. RESULTS: Of all the 201 children, 161 (80.1%) had a history of exposure to COVID-19 patients and 132 (65.7%) had a history of COVID-19 vaccination. Among the 167 children with symptomatic infections, 151 had mild COVID-19 and 16 had common COVID-19, with no severe infection or death. Among the 101 children who underwent chest CT examination, 16 had ground glass changes and 20 had nodular or linear opacities. The mean time to nucleic acid clearance was (14±4) days for the 201 children with Omicron variant infection, and the symptomatic infection group had a significantly longer time than the asymptomatic infection group [(15±4) days vs (11±4) days, P<0.05]. The group vaccinated with one or two doses of COVID-19 vaccine had a significantly higher positive rate of IgG than the group without vaccination (P<0.05). The proportions of children with increased blood lymphocyte count in the symptomatic infection group was significantly lower than that in the asymptomatic infection group (P<0.05). Compared with the asymptomatic infection group, the symptomatic infection group had significantly higher proportions of children with increased interleukin-6, increased fibrinogen, and increased D-dimer (P<0.05). CONCLUSIONS: Most of the children with Omicron variant infection have clinical symptoms, which are generally mild. The children with symptomatic infection are often accompanied by decreased or normal blood lymphocyte count and increased levels of interleukin-6, fibrinogen, and D-dimer, with a relatively long time to nucleic acid clearance. Some of them had ground glass changes on chest CT.

Clinical characteristics of patients infected with novel coronavirus wild strain, Delta variant strain and Omicron variant strain in Quanzhou: A real­world study.

This study aimed to investigate the clinical features of patients infected with novel coronavirus wild strains, Delta variant strains and Omicron variant strains to provide a reference for early clinical diagnosis and prognostic assessment. The demographic, clinical symptoms and ancillary examination data of 47 patients with novel coronavirus wild type strain infection, 18 with Delta variant infection and 20 with Omicron variant infection admitted to the First Hospital of Quanzhou affiliated with Fujian Medical University were collected and analyzed. The novel coronavirus wild strain and Delta strain were the predominant clinical types; patients infected with the Omicron strain were mainly asymptomatic. Fever and fatigue were the main clinical manifestations in the wild strain and Delta strain groups, whereas dry cough, nasal congestion, sore throat and fever were common clinical manifestations in the Omicron strain group. The Delta strain and Omicron variant groups had fewer comorbidities than the wild-type strain group, but no significant reduction was observed in the negative conversion time of nucleic acids. Significant differences were found in the neutrophil count/lymphocyte count ratio, lymphocyte count, eosinophil count, red blood cell count, hemoglobin level, erythrocyte sedimentation rate, C-reactive protein, prothrombin time, international normalized ratio and plasma D-dimer, PH, PaO2, lactic acid and albumin levels among the three groups. Patients infected with the Omicron strain in Quanzhou presented with mild symptoms of the upper respiratory tract as the primary clinical manifestation and had few comorbidities and a good prognosis; however, the negative conversion time of the new coronavirus nucleic acid was still considerably long.

PLAGL2 promotes the stemness and is upregulated by transcription factor E2F1 in human lung cancer.

This study mainly focuses on revealing the role of PLAGL2 in lung cancer stemness. In vitro and in vivo experiments were performed to evaluate the effects of PLAGL2 on lung cancer cell stemness. Mechanistic analysis using luciferase reporter and ChIP assays were implemented to reveal the underlying mechanisms. The transcriptional factor E2F1 transcriptionally activated PLAGL2 expression via directly binding to PLAGL2 promoter in lung cancer cells. Moreover, PLAGL2 promoted the stemness of lung cancer cells dependent on E2F1-mediated transcriptional activation. This study provides a potential target for lung cancer progression.

Landscape of B Cell Receptor Repertoires in COVID-19 Patients Revealed Through CDR3 Sequencing of Immunoglobulin Heavy and Light Chains.

The outbreak and persistence of coronavirus disease 2019 (COVID-19) threaten human health. B cells play a vital role in fighting the infections caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Despite many studies on the immune responses in COVID-19 patients, it is still unclear how B cell receptor (BCR) constituents, including immunoglobulin heavy (IGHs) and light chains (IGLs), respond to SARS-CoV-2 in patients with varying symptoms. In this study, we conducted complementarity-determining region 3 (CDR3) sequencing of BCR IGHs and IGLs from the peripheral blood of COVID-19 patients and healthy donors. The results showed significantly reduced clonal diversity, more expanded clones, and longer CDR3 lengths of IGH and IGL in COVID-19 patients than those in healthy individuals. The IGLs had a much higher percentage of VJ skew usage (47.83% IGLV and 42.86% IGLJ were significantly regulated) than the IGHs (12.09% IGHV and 0% IGHJ) between the healthy individuals and patients, which indicated the importance of BCR light chains. Furthermore, we found a largely expanded IGLV3-25 gene cluster mostly pairing with IGLJ1 and ILGJ2 in COVID-19 patients and a newly identified upregulated IGLJ1 gene and IGLJ2+IGLV13-21 recombination, both of which are potential sources of SARS-CoV-2-targeting antibodies. Our findings on specific immune B-cell signatures associated with COVID-19 have clinical implications for vaccine and biomarker development for disease diagnosis.

The Association of Human Leukocyte Antigen and COVID-19 in Southern China.

Human leukocyte antigen (HLA) polymorphism is hypothesized to be associated with diverse immune responses toward infectious diseases. Herein, by comparing against multiple subpopulation groups as control, we confirmed that HLA-B*15:27 and HLA-DRB1*04:06 were associated with coronavirus disease 2019 susceptibility in China. Both alleles were predicted to have weak binding affinities toward viral proteins.

Serum neuron-specific enolase: A promising biomarker of silicosis.

BACKGROUND: Silicosis is a type of chronic pulmonary fibrosis caused by long-term inhalation of silica dust particles. There has been no ideal biomarker for the diagnosis and differential diagnosis of silicosis until now. Studies have found that elevated neuron-specific enolase (NSE) concentration in the serum of silicosis patients is helpful for diagnosis and severity assessment of the disease. However, the number of cases in these studies was not enough to arouse attention. AIM: To investigate the clinical significance of serum NSE in the diagnosis and staging of silicosis. METHODS: From January 2017 to June 2019, 326 cases of silicosis confirmed in Quanzhou First Hospital Affiliated to Fujian Medical University were included in the silicosis group. A total of 328 healthy individuals or medical patients without silicosis were included in the control group. Serum NSE concentrations of all subjects were determined by electrochemical luminescence. RESULTS: There were no significant differences in sex, age, smoking index and complications between the silicosis and control groups. The mean serum NSE concentration was 26.57 ± 20.95 ng/mL in the silicosis group and 12.42 ± 2.68 ng/mL in the control group. The difference between the two groups was significant (U = 15187, P = 0.000). Among the 326 patients with silicosis, 103 had stage I silicosis, and the mean serum NSE concentration was 15.55 ± 6.23 ng/mL. The mean serum NSE concentration was 21.85 ± 12.05 ng/mL in 70 patients with stage II silicosis. The mean serum NSE concentration was 36.14 ± 25.72 ng/mL in 153 patients with stage III silicosis. Kruskal-Wallis H test suggested that the difference in serum NSE concentration in silicosis patients in the three groups was significant (H = 130.196, P = 0.000). Receiver operating characteristic curve analysis indicated that the area under the curve was 0.858 (95% confidence interval: 0.828-0.888; P = 0.000). When the NSE concentration was 15.82 ng/mL, the Jorden index was the largest, the sensitivity was 72%, and the specificity was 90%. CONCLUSION: Serum NSE concentration may be a promising biomarker for the diagnosis and assessment of severity of silicosis.

Delayed discharge is associated with higher complement C3 levels and a longer nucleic acid-negative conversion time in patients with COVID-19.

To determine factors associated with delayed discharge of hospitalized patients with coronavirus disease (COVID-19). This retrospective cohort study included 47 patients with COVID-19 admitted to three hospitals in Quanzhou City, Fujian Province, China, between January 21, 2020 and March 6, 2020. Univariate and multivariate logistic regression analyses were conducted to identify factors associated with delayed discharge. The median length of hospital stay was 22 days. Patients in the delayed discharge group (length of hospital stay ≥ 21 days, n = 27) were more likely to have diarrhea, anorexia, decreased white blood cell counts, increased complement C3 and C-reactive protein levels, air bronchograms, undergo thymalfasin treatment, and take significantly longer to convert to a severe acute respiratory syndrome coronavirus (SARS-CoV-2) RNA-negative status than those in the control group (length of hospital stay, < 21 days; n = 20). In multivariate logistic regression analysis, the time to SARS-CoV-2 RNA-negative conversion (odds ratio [OR]: 1.48, 95% confidence interval [CI] 1.09-2.04, P = 0.01) and complement C3 levels (OR 1.14 95% CI 1.02-1.27, P = 0.03) were the only risk factors independently associated with delayed discharge from the hospital. Dynamic monitoring of complement C3 and SARS-CoV-2 RNA levels is useful for predicting delayed discharge of patients.

A Retrospective Study of the Epidemiologic and Clinical Characteristics of COVID-19 Among Hospitalized Patients in Quanzhou, China.

Coronavirus disease 2019 (COVID-19) has spread throughout China. However, information about COVID-19 in cities and regions outside Wuhan is limited and the indicators that predict the length of hospital stay for patients with COVID-19 are unclear. Therefore, we collected clinical data from 47 patients with COVID-19 in Quanzhou City. The median age was 38 years [interquartile range (IQR): 31-50 years], and 24 (51%) were male. There were 8 mild, 36 moderate, and 3 severe/critical cases. The median interval from exposure to disease onset was 13 days (IQR: 8-18 days). The incidence of severe/critical cases was 33% (3/10) in patients with hypertension. Common symptoms included fever (83%), cough (77%), fatigue (40%), a sore, dry throat (28%), and diarrhea (21%). One patient (2%) developed respiratory distress syndrome on day 13 of inpatient treatment. Six patients had leukopenia, 17 had elevated C-reactive protein (CRP), and 8 had lymphocytopenia and elevated lactate dehydrogenase (LDH). The median length of hospitalization was 22 days (IQR: 16-30 days). Dynamic monitoring of LDH, CRP, and neutrophil-lymphocyte ratio predicted whether length of hospitalization would exceed 21 days. Most patients presented with mild and moderate disease. Patients with hypertension were more likely to become severe or critical. Dynamic monitoring of LDH, CRP, and neutrophil-lymphocyte ratio levels can help predict delayed discharge from the hospital.

Clinical characteristics of 199 discharged patients with COVID-19 in Fujian Province: A multicenter retrospective study between January 22nd and February 27th, 2020.

BACKGROUND: Coronavirus disease 2019 (COVID-19) has quickly spread throughout the country and the world since first broke out in Wuhan, China. The outbreak that started from January 22, 2020, in Fujian Province has been controlled as the number of indigenous cases has not increased since March. We aimed to describe the clinical characteristics of patients with COVID-19 in Fujian Province, China. METHODS: In this retrospective, multicenter study, we collected and analyzed the epidemiological, clinical, and laboratory data of all cases confirmed by nucleic acid tests in five designated hospitals in Fujian Province between January 22 and February 27, 2020. All patients were followed up until discharge. COVID-19 severity was classified as mild, moderate, severe, or critical. RESULTS: Of 199 discharged patients with COVID-19, 105 patients were male, with a median age of 46.3 years, and 17 patients were severe, and 5 patients were critical on admission. Hypertension and diabetes were the most common comorbidities. The symptoms at illness onset were mainly fever (76.4%), cough (60.8%), and myalgia or fatigue (27.6%). A total of 96.5% of patients had abnormal imaging findings on chest computed tomography. Lymphopenia (37.2%) and hypoxemia (13.6%) were observed. Acute respiratory distress syndrome and respiratory failure occurred in 9 patients (4.5%) and 8 patients (4.0%) respectively. One patient died and the others were cured and discharged with the median hospital stay of 19 days. Old age was negatively correlated with lymphocyte count (r = - 0.296, p < 0.001) and oxygenation index (r = - 0.263, p = 0.001). Bivariate regression analysis revealed that old age (≥ 75 years), hypertension, diabetes, and lymphopenia were correlated with the severity of COVID-19. CONCLUSIONS: Patients in Fujian Province were mostly nonsevere cases with mild or moderate symptoms, and had a lower mortality than patients in Wuhan (4.3%-15%). Older age, hypertension, diabetes, and lymphopenia were risk factors for severity of COVID-19.

Expression of CCL-18 and CX3CL1 in Serum, and Their Potential Roles as Two Diagnostic and Prognostic Markers in Chronic Obstructive Pulmonary Disease and Chronic cor Pulmonale (COPD&CCP): a Pilot Study.

BACKGROUND: CC chemokine ligand-18 (CCL-18) and CX3 chemokine ligand 1 (CX3CL1) are key factors of vascular and tissue injury in chronic respiratory diseases. Here, we investigated the value of CCL-18 and CX3CL1 in diagnosis and prognosis of patients with chronic obstructive pulmonary disease and chronic cor pulmonale (COPD&CCP). METHODS: First, we investigated the expression profile of CCL-18 and CX3CL1 in serum of COPD&CCP patients. Then the relationship of the level of CCL-18 and CX3CL1 with clinicopathological characteristics was analyzed. Subsequently, we evaluated the diagnostic accuracy of CCL-18 and CX3CL1 to discriminate COPD&CCP. The prognostic value and therapy outcome were also evaluated. RESULTS: Compared to healthy subjects, the level of CCL-18 (8.01 ± 2.01 ng/mL) and CX3CL1 (2,096.11 ± 306.09 ng/mL) was significantly increased in COPD&CCP patients (p < 0.05). The upregulation of CCL-18 and CX3CL1 was significantly correlated with clinicopathological characteristics including CRP, IL-6, FIB, NT-proBNP, FEV1, FEV1/FVC, PASP, LVEF, and T wave anomaly. The combination of CCL-18 and CX3CL1 showed high precision for discriminating COPD&CCP with high AUC values (0.828), sensitivity (66.1%), and specificity (92.5%). Furthermore, CCL-18 and CX3CL1 acted as independent factors which lead to poor clinical benefits and indicated poor prognosis of COPD&CCP patients. CONCLUSIONS: Taken together, our results indicated that CCL-18 and CX3CL1 could act as suitable biomarkers in prognosis and prognostic evaluation of COPD&CCP.

The diagnostic value of D-dimer with simplified Geneva score (SGS) pre-test in the diagnosis of pulmonary embolism (PE).

BACKGROUND: Pulmonary embolism (PE) is the third most common cardiovascular syndrome with an average annual incidence rate of 77 per 100,000 population in the worldwide. The diagnose algorithms for suspected PE are generally include clinical scoring assessment and plasma D-dimer evaluation, patients with high risk of PE require computed tomographic pulmonary angiogram (CTPA) detection for confirmation. METHODS: In this retrospective analysis, 1035 patients with suspected PE were recruited. All the patients were clinically received simplified Geneva score (SGS) pre-test, determination of plasma D-dimer level, and CTPA detection. All enrolled patients were grouped according to the CTPA results: PE patients and non-PE patients. Then, receiver operating characteristic (ROC) curve were constructed to determine the optimal D-dimer cutoff point value which is based on Yonden's index (YI). RESULTS: 294 (28.4%) patients were confirmed with PE and 741(71.6%) individuals were regarded as non-PE cases by CTPA detection. Using the SGS pre-test, 829 (80.1%) patients were classified PE-unlikely (SGS ≤ 2) and 206 (19.9%) patients were PE-likely (SGS ≥ 3). Patients with D-dimer levels above 1.96 mg/L had a significant risk to suffer from PE (area under curve (AUC), 0.707; 95% CI, 0.678-0.735; p < 0.05). Meanwhile, in patients with SGS ≥ 3, the D-dimer cutoff point value moved to 2.2 mg/L (AUC, 0.644; 95% CI, 0.574-0.709; p < 0.05). CONCLUSION: D-dimer test in combination with SGS pre-test could improve the accuracy of PE diagnosis. Patients with D-dimer levels over 1.96 mg/L (4 times of the normal level) have a significant risk for PE. In patients with SGS ≥ 3, the D-dimer cutoff point concentration for PE risk moves to the levels of 2.2 mg/L.

Enhanced Antitumor Efficacy of Docetaxel-Loaded Monomethoxy Poly(ethylene glycol)-Poly(D, L-lactide-co-glycolide) Amphiphilic Copolymer Against Non-Small Cell Lung Cancer.

Lung cancer, including non-small cell lung cancer (NSCLC), is one of the mainly diagnosed cancer and becomes as the leading cause of death induced by cancer worldwide. Conventional antitumor drugs, such as docetaxel (DTX), exhibit excellent therapeutic efficacy, however, serious adverse effects have occurred due to their side effect, which limits their clinical use. Therefore, it is necessary to develop the novel drug delivery systems for antitumor therapy. Herein, we successfully developed mPEG-PLGA nanoparticles for the encapsulation of the clinically relevant drug DTX (NP-DTX) via an improved green method by emulsion. The mPEG-PLGA nanoparticles could target A549 and increased the cytotoxicity of DTX, NP-DTX showed significantly enhanced antitumor effect and therapeutic efficacy on NSCLC in vitro and in vivo. Compared with free DTX, NP-DTX significantly inhibited tumor growth and reduced the side effect of DTX. Therefore, we have shown a promising strategy to construct a novel therapeutic platform for targeted anti-tumor drug delivery.

Preliminary study on the clinical significance of kinesin Kif18a in nonsmall cell lung cancer: An analysis of 100 cases.

The aim of this study was to investigate the expression of Kif18A in cancerous and paracancerous tissues from 100 patients with nonsmall cell lung cancer (NSCLC).This was a prospective study of 100 patients with pathologically confirmed NSCLC (adenocarcinoma and squamous cell carcinoma [SCC], n = 50/group) that were operated at the Quanzhou First Hospital Affiliated to Fujian Medical University between June 2015 and December 2016. Kif18A protein expression in cancerous and paracancerous normal tissues was detected by western blot and immunohistochemistry.The expression of the Kif18A protein was higher in adenocarcinoma and SCC tissues than in the corresponding paracancerous normal tissues. The expression of the Kif18A protein was higher in highly differentiated tumors, in patients with lymph node metastasis (vs no lymph node metastasis), adenocarcinoma, and in stage III NSCLC. There were no associations between Kif18A expression and age, gender, and pathologic type.The expression of the Kif18A protein by immunohistochemistry was higher in NSCLC tissues than in normal tissues, and was associated with tumor differentiation, lymph node metastasis, and TNM staging. These results could provide a theoretical basis for novel molecular targeted therapies against NSCLC.

Correlated low IGF2BP1 and FOXM1 expression predicts a good prognosis in lung adenocarcinoma.

IGF2BP1 and FOXM1 are shown to be critical in the regulation of caner progression. However, the prognostic value of IGF2BP1 in lung adenocarcinoma and its relationship with FOXM1 still remains unclear. In this study, the expression and biological significance of both IGF2BP1 and FOXM1 were evaluated in 188 lung adenocarcinoma, at mRNA and protein levels. We showed that mRNA and protein levels of IGF2BP1 and FOXM1 were upregulated in lung adenocarcinoma compared to adjacent non-cancerous tissues. High IGF2BP1 expression was correlated with a poor prognosis for lung adenocarcinoma patients. Moreover, IGF2BP1 expression was positively associated with FOXM1 expression. Meanwhile, the findings indicated that low IGF2BP1 combined with low FOXM1 expression, was negatively correlated with pathological stage and lymph node metastasis, predicted good outcomes for lung adenocarcinoma patients. Additionally, low IGF2BP1 and FOXM1 expression status, is an independent prognostic factor for lung adenocarcinoma after surgical resection. We demonstrate that low IGF2BP1 and FOXM1 expression can serve as a potential factor for the clinical diagnosis and prognosis of lung adenocarcinoma, and targeted inhibition of IGF2BP1 and FOXM1 might be an alternative strategy for the management of lung adenocarcinoma.

Clinical features and therapeutic options in non-small cell lung cancer patients with concomitant mutations of EGFR, ALK, ROS1, KRAS or BRAF.

BACKGROUND: Although oncogenic driver mutations were thought to be mutually exclusive in non-small cell lung cancer (NSCLC), certain tumors harbor co-occurring mutations and represent a rare molecular subtype. The evaluation of the clinical features and therapeutic response associated with this NSCLC subtype will be vital for understanding the heterogeneity of treatment response and improving the management of these patients. METHODS: This retrospective study included 3774 samples from patients diagnosed with NSCLC. All samples were screened for EGFR, ALK, ROS1, KRAS, and BRAF mutation using the amplification-refractory mutation system. The relationship between concomitant driver mutations and clinicopathologic characteristics, and patient clinical outcomes were evaluated. RESULTS: Sixty-three (1.7%) samples had more than one driver gene mutation. Among these, 43 were coalterations with an EGFR mutation, 20 with an ALK rearrangement, and eight with an ROS1 rearrangement. Except for ROS1 concomitant mutations that were more frequent in male patients (87.5%, P = 0.020), the clinicopathological features of the concomitant mutation patients were not significantly different from those harboring a single EGFR, ALK, or ROS1 mutation. Furthermore, first-line EGFR-TKI treatment did not significantly improve the progression-free survival (PFS) of patients harboring EGFR concomitant mutation, compared to patients harboring a single EGFR mutation. However, for EGFR concomitant mutation patients, TKI therapy was more effective than chemotherapy (median PFS of 10.8 vs 5.2 months, P = 0.023). Lastly, KRAS mutations did not influence the EGFR-TKI therapy treatment effect. CONCLUSION: In this study, concomitant mutations were found in 1.7% of the NSCLC. EGFR-TKI therapy was more effective than chemotherapy for patients harboring EGFR concomitant mutation, and ROS1 concomitant mutations were more frequent in male patients. For patients harboring coalterations with an ALK or ROS1 rearrangement, we should be cautious when considering the therapeutic options.

Sulforaphane suppresses EMT and metastasis in human lung cancer through miR-616-5p-mediated GSK3ß/ß-catenin signaling pathways.

Sulforaphane is a common antioxidant selectively abundant in cruciferous plants, which exhibits effective anti-cancer actions in control of tumorigenesis or progression of various cancers. A recent study has shown that sulforaphane attenuates the EGFR signaling pathway in non-small cell lung cancer (NSCLC), suggesting its potential anti-metastatic effects. In this study we assessed the involvement of sulforaphane and miR-616-5p in epithelial-mesenchymal transition (EMT) and NSCLC metastasis. Sulforaphane suppressed the cell proliferation in human NSCLC cell lines H1299, 95C and 95D with IC50 values of 9.52±1.23, 9.04±1.90 and 17.35±2.03 µmol/L, respectively. At low concentrations (1-5 µmol/L), sulforaphane dose-dependently inhibited the migration and invasion of 95D and H1299 cells with relatively high metastatic potential. The anti-metastatic action of sulforaphane was confirmed in 95D and H1299 cell xenografts in vivo. In fresh NSCLC tissue samples from 179 patients, miR-616-5p levels were upregulated in late-stage NSCLCs, and strongly correlated with risk of NSCLC recurrence and metastasis. Consistent with the clinic observation, miR-616-5p levels in the 3 NSCLC cell lines were correlated with their metastatic ability, and were decreased by sulforaphane treatment. Silencing miR-616-5p markedly suppressed the migration and invasion of 95D cells in vitro and NSCLC metastasis in vivo. Further studies revealed that miR-616-5p directly targeted GSK3ß and decreased its expression, whereas sulforaphane decreased miR-616-5p levels by histone modification, and followed by inactivation of the GSK3ß/ß-catenin signaling pathway and inhibition of EMT, which was characterized by loss of epithelial markers and acquisition of a mesenchymal phenotype in NSCLC cells. Our findings suggest that sulforaphane is a potential adjuvant chemotherapeutic agent for the prevention of NSCLC recurrence and metastasis, and miR-616-5p can be clinically utilized as a biomarker or therapeutic target to inhibit metastasis.