AMIGO2 attenuates innate cisplatin sensitivity by suppression of GSDME-conferred pyroptosis in non-small cell lung cancer.

Non-small cell lung cancer (NSCLC) accounts for approximately 85% of lung cancer. Cisplatin is commonly used in the treatment of many malignant tumours including NSCLC. The innate drug sensitivity greatly affects the clinical efficacy of cisplatin-based chemotherapy. As a plasma membrane adhesion molecule, amphoterin-induced gene and ORF-2 (AMIGO2) initially identified as a neurite outgrowth factor has been recently found to play a crucial role in cancer occurrence and progression. However, it is still unclear whether AMIGO2 is involved in innate cisplatin sensitivity. In the present study, we provided the in vitro and in vivo evidences indicating that the alteration of AMIGO2 expression triggered changes of innate cisplatin sensitivity as well as cisplatin-induced pyroptosis in NSCLC. Further results revealed that AMIGO2 might inhibit cisplatin-induced activation of (caspase-8 and caspase-9)/caspase-3 via stimulating PDK1/Akt (T308) signalling axis, resulting in suppression of GSDME cleavage and the subsequent cell pyroptosis, thereby decreasing the sensitivity of NSCLC cells to cisplatin treatment. The results provided a new insight that AMIGO2 regulated the innate cisplatin sensitivity of NSCLC through GSDME-mediated pyroptosis.

Association between post-stroke smoking and stroke recurrence in first-ever ischemic stroke survivors: based on a 10-year prospective cohort.

BACKGROUND: Whether smoking is a risk factor for ischemic stroke (IS) recurrence in IS survivors is still uncovered, and evidences are sparse. Meanwhile, an add-on effect of clopidogrel was observed in myocardial infarction patients who smoked, but whether the paradox exists in IS patients is still unsolved. The objectives of this study are to explore the association between smoking behavior after index stroke and IS recurrence and to explore whether the paradox exists. METHODS: A prospective cohort of first-ever IS patients was conducted between 2010 and 2019. The prognosis and smoking features of enrolled patients were obtained via telephone follow-up every 3 months. Fine-gray model with interaction terms was applied to measure the relationships between stroke recurrence and smoking behaviors after index stroke and to explore the add-on effect of clopidogrel in smoking patients. RESULTS: There were 171 (24.26%) recurrences and 129 (18.30%) deaths during follow-up in 705 enrolled IS patients. One hundred forty-six (20.71%) patients smoked after index stroke. The hazard ratios (HRs) and 95% confidence intervals (CIs) of interaction terms between antiplatelet drug and follow-up smoking (smoking status and daily smoking amount) were 1.092 (95% CI: 0.524, 2.276) and 0.985 (95% CI: 0.941, 1.031), respectively. A significantly higher risk of recurrence was observed in patients with a higher daily smoking amount during follow-up (per cigarette), with HR being 1.027 (95% CI: 1.003, 1.052). CONCLUSIONS: Smoking could elevate the risk of IS recurrence, and IS survivor should be advised to quit or smoke less. Add-on effect of clopidogrel may not exist in smoking strokers taking clopidogrel.

Immune-Related Pneumonitis Was Decreased by Addition of Chemotherapy with PD-1/L1 Inhibitors: Systematic Review and Network Meta-Analysis of Randomized Controlled Trials (RCTs).

PURPOSE: Immune-related pneumonitis (IRP) has attracted extensive attention, owing to its increased mortality rate. Conventional chemotherapy (C) has been considered as an immunosuppressive agent and may thus reduce IRP's risk when used in combination with PD-1/L1 inhibitors. This study aimed to assess the risk of IRP with PD-1/L1 inhibitors plus chemotherapy (I+C) versus PD-1/L1 inhibitors alone (I) in solid cancer treatment. METHOD: Multiple databases were searched for RCTs before January 2021. This NMA was performed among I+C, I, and C to investigate IRP's risk. Subgroup analysis was carried out on the basis of different PD-1/L1 inhibitors and cancer types. RESULTS: Thirty-one RCTs (19,624 patients) were included. The I+C group exhibited a lower risk of IRP in any grade (RR, 0.60; 95% CI, 0.38-0.95) and in grade 3-5 (RR, 0.44; 95% CI, 0.21-0.92) as opposed to the I group. The risk of any grade IRP with PD-1 plus chemotherapy was lower than that with PD-1 monotherapy (RR, 0.50; 95% CI, 0.28-0.89), although grade 3-5 IRP was similar. There was no statistically meaningful difference in the risk of any grade IRP between PD-L1 plus chemotherapy and PD-L1 inhibitors monotherapy (RR, 0.95; 95% CI, 0.43-2.09) or grade 3-5 IRP (RR, 0.71;95% CI, 0.24-2.07). In addition, compared with the I group, the I+C group was correlated with a decreased risk in IRP regardless of cancer type, while a substantial difference was only observed in NSCLC patients for grade 3-5 IRP (RR, 0.39; 95% CI, 0.15-0.98). CONCLUSION: In comparison to PD-1/L1 inhibitor treatment alone, combining chemotherapy with PD-1/L1 inhibitors might reduce the risk of IRP in the general population. Furthermore, PD-1 inhibitors in combination with chemotherapy were correlated with a decreased risk of IRP compared to PD-1 inhibitor treatment alone. In contrast to the I group, the I+C group exhibited a lower risk of IRP, especially for NSCLC patients.

Feasibility of utilizing ultra-low-dose contrast medium for pancreatic artery depiction using the combination of advanced virtual monoenergetic imaging and high-concentration contrast medium: an intra-patient study.

OBJECTIVES: The least amount of contrast medium (CM) should be used under the premise of adequate diagnosis. The purpose of this study is to evaluate the feasibility of utilizing ultra-low-dose (224 mgI/kg) CM for pancreatic artery depiction using the combination of advanced virtual monoenergetic imaging (VMI+) and high-concentration (400 mgI/mL) CM. MATERIALS AND METHODS: 41 patients who underwent both normal dose CM (ND-CM, 320 mgI/kg) and low dose CM (LD-CM, 224 mgI/kg) thoracoabdominal enhanced CT for tumor follow-up were prospectively included. The VMI+ at the energy level of 40-kev for LD-CM images was reconstructed. CT attenuation, signal-to-noise ratios (SNRs), and contrast-to-noise ratios (CNRs) of the abdominal artery, celiac artery, and superior mesenteric artery (SMA) and qualitative scores of pancreatic arteries depiction were recorded and compared among the three groups (ND-CM, LD-CM, and VMI+ LD-CM images). ANOVA and Friedman tests were used for statistical analysis. RESULTS: All quantitative and qualitative parameters on LD-CM images were lower than that on ND-CM images (all p < 0.01). There were no significant differences of all arteries' qualitative scores between ND-CM and VMI+ LD-CM images (all p > 0.05). VMI+ LD-CM images had the highest mean CT and CNR values of all arteries (all p < 0.0001). The CM volume was 52.6 ± 9.4 mL for the ND-CM group and 37.0 ± 6.7 mL for the LD-CM group. CONCLUSION: Ultra-low-dose CM (224 mgI/kg) was feasible for depicting pancreatic arteries. Inferior angiographic image quality could be successfully compensated by VMI+ and high-concentration CM.

Identification of a crucial amino acid responsible for the loss of specifying FGFR1-KLB affinity of the iodinated FGF21.

Previous studies suggest that specific binding to the complex consisting of fibroblast growth factor receptor-1 (FGFR1) and the coreceptor beta-Klotho (KLB) is the premise for human FGF19 and FGF21 activating the downstream signaling cascades, and regulating the metabolic homeostasis. However, it was found that human FGF21 loses its ability to bind to FGFR1-KLB after iodination with Na125 I and chloramine T, whereas human FGF19 retained its affinity for FGFR1-KLB even after iodination. The molecular mechanisms underlying these differences remained elusive. In this study, we first demonstrated that an intramolecular disulfide bond was formed between cysteine-102 and cysteine-121 in FGF21, implying that the oxidation of the cysteine to cysteic acid, which may interfere with the active conformation of FGF21, did not occur during the iodination procedures, and thus ruled out the possibility of the two conserved cysteine residues mediating the loss of FGF21 binding affinity to FGFR1-KLB upon iodination. Site-directed mutagenesis and molecular modeling were further applied to determine the residue(s) responsible for the loss of FGFR1-KLB affinity. The results showed that mutation of a single tyrosine-207, but not the other five tyrosine residues in FGF21, to a phenylalanine retained the FGFR1-KLB affinity of FGF21 even after iodination, whereas replacing the corresponding phenylalanine residue with tyrosine in FGF19 did not alter its binding affinity to FGFR1-KLB, but decreased the receptor binding ability of the iodinated protein, suggesting that tyrosine-207 is the crucial amino acid responsible for the loss of specifying FGFR1-KLB affinity of the iodinated FGF21.

[Application of Competing Risks Model in Predicting Smoking Relapse Following Ischemic Stroke].

OBJECTIVE: To determine factors associated with smoking relapse in men who survived from their first stroke. METHODS: Data were collected through face to face interviews with stroke patients in the hospital, and then repeated every three months via telephone over the period from 2010 to 2014. Kaplan-Meier method and competing risk model were adopted to estimate and predict smoking relapse rates. RESULTS: The Kaplan-Meier method estimated a higher relapse rate than the competing risk model. The four-year relapse rate was 43.1% after adjustment of competing risk. Exposure to environmental tobacco smoking outside of home and workplace (such as bars and restaurants) (P=0.01), single (P<0.01), and prior history of smoking at least 20 cigarettes per day (P=0.02) were significant predictors of smoking relapse. CONCLUSION: When competing risks exist, competing risks model should be used in data analyses. Smoking interventions should give priorities to those without a spouse and those with a heavy smoking history. Smoking ban in public settings can reduce smoking relapse in stroke patients.

[Sample Size Calculation using SAS for Phaseâ ¡in Two-stage Clinical Trials of Anti-tumor Drugs].

OBJECTIVE: To compare Gehan two-stage design and Simon two-stage design in sample size calculations for phase Ⅱ clinical trials of anti-tumor drugs. METHODS: We explained the sample size calculation methods with a single-stage design, Gehan two-stage design, and Simon optimal two-stage and minimax two-stage designs in line with the principle of exact binomial probability. By setting up different parameters in SAS macro program, the advantages and disadvantages of these designs were compared. RESULTS: The minimax two-stage design does not increase the maximum sample size compared with the single-stage design. Compared with the Gehan two-stage design, the Simon two-stage design has the advantage of being able to determine an early termination of trials when no or low anti-tumor activities are evident. CONCLUSION: Simon two-stage design is better than single-stage design and Gehan two-stage design. The minimax design is more popular than the optimal design.

Long-term trends and predictors of smoking behaviors among men following first-ever ischemic stroke.

Continued smoking following stroke is associated with adverse outcomes including increased risk of mortality and secondary stroke. The aim of this study was to examine the long-term trends in smoking behaviors and factors associated with smoking relapse among men who survived their first-ever stroke. Data collection for this longitudinal study was conducted at baseline through face-to-face interviews and follow-up was completed every 3 months via telephone, beginning in 2010 and continuing through 2014. Cox proportional hazard regression models were used to identify predictors of smoking relapse behavior. At baseline, 372 male patients were recruited into the study. Totally, 155 (41.7%) of these patients stopped smoking for stroke, and 61 (39.3%) began smoking again within 57 months after discharge with an increasing trend in the number of cigarettes smoked per day. Exposure to environmental tobacco smoke at places outside of home and work (such as bars, restaurants) (HR, 2.34; 95% CI, 1.04-5.29, P=0.04), not having a spouse (HR, 0.12; 95% CI, 0.04-0.36; P=0.0002) and smoking at least 20 cigarettes per day before stroke (HR, 2.42; 95% CI, 1.14-5.14, P=0.02) were predictors of smoking relapse. It was concluded that environmental tobacco smoke is an important determinant of smoking relapse among men who survive their first stroke. Environmental tobacco smoke should be addressed by smoke-free policies in public places.

Assessment of Utilization and Cost-Effectiveness of Telemedicine Program in Western Regions of China: A 12-Year Study of 249 Hospitals Across 112 Cities.

BACKGROUND: The imbalance in healthcare between urban and rural areas is still a problem in China. In recent decades, China has aimed to develop telemedicine. We assessed the implementation, utilization, and cost-effectiveness of a large telemedicine program across western China. MATERIALS AND METHODS: In 2002-2013, a government-sponsored major telemedicine program was established by West China Hospital of Sichuan University (hub), covering 249 spoke hospitals in 112 cities throughout western China and in 40 medical expertise areas. We analyzed the cross-sectional data from 11,987 consultations conducted at West China Hospital using the telemedicine network over a 12-year period. The types of diseases as well as the diagnosis and treatment changes were assessed. We also performed a cost-savings analysis and a one-way sensitivity analysis. RESULTS: Of the 11,987 teleconsultations, we noted that neoplasms (19.4%), injuries (13.9%), and circulatory diseases (10.3%) were the three most common diagnoses. Teleconsultations resulted in a change of diagnosis in 4,772 (39.8%) patients, and 3,707 (77.7%) of them underwent major diagnosis changes. Moreover, it led to a change of treatment in 6,591 (55.0%) patients, including 3,677 (55.8%) changes not linked to diagnosis changes. The telemedicine network resulted in an estimated net saving of $2,364,525 (if the patients traveled to the hub) or $3,759,014 (if the specialists traveled to the spoke hospitals). CONCLUSIONS: The introduction of telemedicine in China, linking highly specialized major hospitals (hub) with hundreds of small rural hospitals (spoke), can greatly improve the quality, efficiency, and cost-effectiveness of healthcare delivery and utilization. This new Internet-based healthcare model should be utilized more widely in developing countries.

[Clinical Trial of Intraoperative Tissue Identification for Breast-Conserving Surgery Using Bio-impedance Spectroscopy].

OBJECTIVE: To evaluate the effectiveness of bio-impedance spectroscopy (BIS) analysis for marginal tissue malignancy/benignancy identification during Breast-Conserving Surgery (BCS). METHODS: A multicenter parallel-group clinical trial was conducted with the patients who received breast conserving surgery in 2 hospitals. One hundred and fifty breast tissue specimens were collected and analyzed by BIS, frozen section biopsy and paraffin section biopsy respectively. Results were compared and statistical analysis was implemented. RESULTS: For BIS technique to identify malignant/benign marginal tissues, the sensitivity was 92.98%, and the specificity was 94.62%. The coherence of BIS results and frozen section biopsy results was significant, and the Kappa value was higher than 0.75. The mean measuring time of BIS was 2.63 min, which was shorter than frozen section biopsy (18.97 min) and paraffin section biospy (1.12 d). CONCLUSION: BIS technique likely has high accuracy in tissue identification so has potential to be adopted as a real-time indicator for marginal tissue malignancy/benignancy identification during breast-conserving surgery.

Identification of galectin-1 as a novel mediator for chemoresistance in chronic myeloid leukemia cells.

Multidrug resistance protein-1 (MDR1) has been proven to be associated with the development of chemoresistance to imatinib (Glivec, STI571) which displays high efficacy in treatment of BCR-ABL-positive chronic myelogenous leukemia (CML). However, the possible mechanisms of MDR1 modulation in the process of the resistance development remain to be defined. Herein, galectin-1 was identified as a candidate modulator of MDR1 by proteomic analysis of a model system of leukemia cell lines with a gradual increase of MDR1 expression and drug resistance. Coincidently, alteration of galectin-1 expression triggers the change of MDR1 expression as well as the resistance to the cytotoxic drugs, suggesting that augment of MDR1 expression engages in galectin-1-mediated chemoresistance. Moreover, we provided the first data showing that NF-κB translocation induced by P38 MAPK activation was responsible for the modulation effect of galectin-1 on MDR1 in the chronic myelogenous leukemia cells. Galectin-1 might be considered as a novel target for combined modality therapy for enhancing the efficacy of CML treatment with imatinib.

[Determination of the Association Between Smoking and Recurrence of Ischemic Stroke using a Competing Risks Model].

OBJECTIVE: To determine the association between smoking and ischemic stroke recurrence. METHODS: We conducted a prospective follow-up study of patients with first incidence of stroke. A competing risks model was used to establish the association between smoking and stroke recurrence. RESULTS: A total of 594 stroke patients were recruited. Among the 361 male patients, 59 recurrent events and 13 competing events occurred. Among the 233 female patients (all were non-smokers), 49 recurrent events and 11 competing events occurred. Adjusted for confounding factors, male nonsmokers exposed to passive smoking had a SHR of 3. 040 in comparison with those without exposure to smoking and the P value was borderline significant. Those who smoked 100-200 cigarettes a year had a SHR of 0. 947. The other groups with exposure to smoking had a greater than 1 SHR, but without statistical significance. Moreover, no significant associations between recurrence of ischemic stroke and smoking index/cumulative smoking were found. The female nonsmokers who had exposure to passive smoking only at follow-ups had a SHR of 1. 4 (and all other groups had less than 1 SHR). But no statistical significances were found in the comparisons. CONCLUSION: Further research with a larger sample size is needed to establish the association between smoking and recurrence of ischemic stroke.

Association of increased circulating catecholamine and glucocorticoid levels with risk of psychological problems in oral neoplasm patients.

BACKGROUND: Noradrenergic pathways and glucocorticoid-mediated signal pathways have been implicated in the growth and progression of oral cancer. Patients with oral neoplasms can have high psychological distress levels, but the effects of stress-related hormones on oral neoplasm growth are unknown. METHODS: We have investigated the relationships between pre-surgical measurements of psychological problems with Symptom Checklist-90-revised Inventory (SCL90-R), tumor histology, circulating blood catecholamine and glucocorticoid levels among 75 oral neoplasm patients, including 40 oral cancer patients and 35 benign oral tumor patients. RESULTS: The results showed that most dimension scores of SCL90-R did not show a significant difference between the two groups except depression (p = 0.0201) and obsessive-compulsion (p = 0.0093), with the scores for these symptoms being higher among oral cancer group versus the benign oral tumor group. The differences of total score, average score and other monomial factor scores were not statistically significant. The mean concentrations of catecholamine and glucocorticoid in peripheral blood of the oral cancer group were higher than those in benign oral tumor group (p<0.01). We also examined whether associations observed between biobehavioral measures and circulating blood catecholamine and glucocorticoid levels extended to other compartments in the oral cancer group. CONCLUSIONS: These findings suggest that stress hormones may affect oral cancer behavior by influencing the tumor micro-environment though the circulating blood.

[Assessment of mental health status in oral squamous cell carcinoma patients and its correlation with catecholamines level].

PURPOSE: To investigate the relationship between mental health status and catecholamines level in oral squamous cell carcinoma patients. METHODS: Forty patients with oral squamous carcinoma (OSCC) who were diagnosed in West China School of Stomatology between Dec. 2011 and Aug. 2012, were assessed with symptom checklist-90 (the 5-grade scoring of 0 to 4 points was used) independently according to their actual conditions. Blood sample was taken on the second admission day and fresh tumor tissue with the weight of 0.5 g was obtained. A method was developed for determination of catecholamine and glucocorticoid in serum using liquid chromatography-tandem mass spectrometry (HPLC-MS-MS). SPSS19.0 software package was used for statistical analysis. RESULTS: Forty patients were included in the study. Compared with the scores of SCL-90 in national norms, the scores were all higher in oral squamous carcinoma patients except the interpersonal relationship. Epinephrine(E) and norepinephrine(NE) in serum was (70.27±34.50) pg/mL and (316.73±109.22) pg/mL, respectively. E and NE in tumor tissues was (6.66±3.58) pg/mg and (12.67±5.27) pg/mg respectively. As the concentrations of NE and E from circulating serum increasing, the stage and grade of oral squamous carcinoma were promoted. CONCLUSIONS: Psychiatric factors have an important impact on OSCC patients. The increased level of catecholamines is closely related to clinical stage and grade of OSCC. Supported by National Natural Science Foundation of China (81172578) and Natural University Students Innovation Training Program (201210610096).

[Interobserver reproducibility in the pathologic diagnosis of borderline ductal proliferative breast diseases].

OBJECTIVE: The aim of this study involving general pathologists was to assess interobserver reproducibility in the pathologic diagnosis of borderline ductal proliferative breast diseases. METHODS: Ten general pathologists independently reviewed 43 specimens chosen to represent the spectrum of borderline ductal proliferative breast lesions. All slides were blindly reviewed without given standardized criteria, and were classified as either mild usual hyperplasia, moderate-severe usual hyperplasia, mild atypical hyperplasia, moderate-severe atypical hyperplasia, ductal carcinoma in situ, or ductal carcinoma in situ with invasion. According to the years of training, these 10 general pathologists were divided into the experienced group and the less trained group. Interobserver agreement was statistically analyzed using Kappa statistic. Then, by comparing all the diagnoses of individual pathologist with the consensus opinion confirmed by two breast pathologists in terms of Page standard, we acquired the diagnostic accuracy and ascertained the undue diagnosis. RESULTS: The ten general pathologists' interobserver reproducibility in the diagnosis of borderline ductal proliferative breast diseases was rather low, especially that in their diagnosis of atypical hyperplasia. The reproducibility and accuracy were slightly higher in the experienced pathologists than in the less trained pathologists. Some pathologists made over-diagnosis or under-diagnosis of the lesions to different degrees. However, when the categories of diagnostic terms were simplified, the interobserver reproducibility increased. CONCLUSION: The use of standardized criteria is an important approach to increasing the diagnostic reproducibility and accuracy.