Head and neck squamous cell carcinoma （HNSCC） is one of the ten most common cancers worldwide and is one of the refractory cancers with a poor prognosis in otorhinolaryngology-head and neck surgery. Cetuximab is widely used in the clinical treatment of HNSCC and has been approved by the FDA as a first-line chemotherapeutic agent. However, its efficacy varies significantly among different individuals. Therefore, exploring the resistance mechanisms of cetuximab in the treatment of HNSCC and screening for sensitive populations are essential for the precision treatment of head and neck cancer. This article summarizes the research progress on cetuximab resistance mechanisms in HNSCC, and the main aspects include: alterations in epidermal growth factor receptor （EGFR） and its ligands, changes in downstream effectors of EGFR, bypass activation and crosstalk, epithelial-mesenchymal transition, epigenetic modifications, and immunosuppression in the tumor microenvironment.
Humans ; Cetuximab/therapeutic use* ; Drug Resistance, Neoplasm ; Squamous Cell Carcinoma of Head and Neck/drug therapy* ; Head and Neck Neoplasms/drug therapy* ; ErbB Receptors/metabolism* ; Tumor Microenvironment ; Epithelial-Mesenchymal Transition ; Molecular Targeted Therapy ; Antineoplastic Agents, Immunological/therapeutic use*

Objective:To investigate the effect of inhibitory activity of high mobility group protein B1 (HMGB1), signal transduction and activator of transcription 3 (STAT3) on myocardial ischemia-reperfusion injury in rats.Methods:In vivo and in vitro models of MIRI were established. SD rats were randomly divided into a sham group, a model group, a glycyrrhizic acid group, and a NSC74859 group, with 6 rats in each group. Rats in the sham group were not ligation, and rats in the sham group and model group were not given medication. The rats in the glycyrrhizic acid group and the NSC74859 group were injected with HMGB1 antagonist glycyrrhizic acid or STAT3 inhibitor NSC74859 5 mg/kg in the tail vein at 12 h 30 min before ischemia/reperfusion and 30 min after ischemia, respectively. Left ventricular shortening fraction (FS) and left ventricular ejection fraction (EF) were evaluated by echocardiography, and apoptosis of cardiomyocytes was evaluated by hematoxylin-eosin (HE) and TUNEL staining. The expression levels of HMGB1, STAT3, and phosphorylated STAT3 (p-STAT3) were detected by real-time fluorescence quantitative PCR and Western Blot. The viability of H9C2 cells was determined by the MTS assay, intracellular ATP content was determined, and the mitochondrial membrane potential of H9C2 cells was measured by flow cytometry to evaluate the survival of cardiomyocytes. The action mode of HMGB1/STAT3 was studied by the immunoprecipitation method. The expression and migration of HMGB1/STAT3 in the nucleus and cytoplasm were detected by immunostaining. Results:After inhibiting the expression of HMGB1 or STAT3, EF and FS were increased, and immune infiltration and apoptosis of cardiomyocytes were decreased. Inhibition of HMGB1 expression could decrease the expression of STAT3, but inhibition of STAT3 expression didn’t affect the expression of HMGB1. Hypoxia could lead to increased expression of HMGB1 and p-STAT3, and decreased expression of STAT3. After 8 hours of hypoxia, the expression level of STAT3 suddenly increased. After reoxygenation, the expression of HMGB1 and STAT3 decreased, and the expression of p-STAT3 increased, but p-STAT3 (Ser 727) didn’t participate in this process. After ischemia-reperfusion injury, HMGB1 and STAT3 binded firmly in cardiomyocytes, but inhibition of STAT3 or HMGB1 weakened this binding. Inhibition of HMGB1 or STAT3 expression could reduce myocardial ischemia-reperfusion injury. The expression of HMGB1 in reoxygenated cardiomyocytes increased after hypoxia, and HMGB1 migrated from the nucleus to the cytoplasm.Conclusions:Inhibiting the activity of the HMGB1/STAT3 axis effectively reduces MIRI in rats.

Objective: To analyze the relationship between new surrogate marks of insulin resistance (IR) and bone mineral content (BMC) in adolescents, and predictive value of the new surrogate marks on low bone mass, so as to provide scientific basis for early identification and prevention of skeletal related diseases in adolescents. Methods: A total of 1 594 adolescents aged 12-18 years in Yinchuan City were selected by convenience sampling and stratified cluster random sampling from September 2017 to September 2020, and triglyceride and glucose index (TyG), triglyceride glucose-body mass index (TyG-BMI) and triglyceride/high density lipoprotein cholesterol (TG/HDL-C) were calculated as new simplified IR index. The correlation between different simplified IR indexes and BMC level was analyzed by partial correlation. Binary Logistic regression was used to analyze the relationship between IR index and low bone mass, and receiver operating characteristic (ROC) curve was constructed to analyze its evaluation effect on low bone mass. Results: After adjusting for confounding factors such as gender, age, smoking, drinking, family history of hypertension, systolic blood pressure (SBP) and diastolic blood pressure (DBP), the new surrogate marks of IR were positively correlated with BMC level (TyG: r =0.11, TyG-BMI: r =0.58, TG/HDL-C: r =0.21, P <0.01). After further adjustment of body mass index (BMI), fat mass (FM) and lean mass (LM), the relationship between IR indexes and BMC turned into negative correlation (TyG: r =-0.20, TyG-BMI: r =-0.18, TG/HDL-C: r=-0.14, P <0.01). After adjusting for confounding factors such as gender, age, smoking, drinking, family history of hypertension, SBP and DBP, Logistic regression results showed that the increase of TyG, TyG-BMI and TG/HDL-C levels reduced the possibility of low bone mass in adolescents (TyG: OR=0.63, 95%CI = 0.40-0.98, TyG-BMI: OR=0.94, 95%CI =0.93-0.96, TG/HDL-C: OR=0.31, 95%CI=0.17-0.58, P <0.01). After adjusting BMI, FM and LM, the above results were completely reversed. Girls with high TyG and TG/HDL-C levels were 4.95 and 4.38 times more likely to have low bone mass than those with low TyG and TG/HDL-C levels (TyG: OR=4.95, 95%CI =1.29- 18.95 , TG/HDL-C: OR=4.38, 95%CI=1.04-18.50, P <0.05). ROC curve showed that TyG-BMI had the best predictive value on low bone mass (AUC=0.80, 95% CI=0.77-0.83, P <0.01). Conclusion The new surrogate marks of IR in adolescents are negatively correlated with adolescent BMC, of which TyG-BMI is the best for assessing of low bone mass and can serving as a reliable indicator for early identification of low bone mass.

Objective:To provide evidence for optimizing the screening strategy for gastric cancer (GC), we evaluated the risk of incident GC for individuals with different precancerous gastric lesions in a prospective cohort study.Methods:Based on the National Upper Gastrointestinal Cancer Early Detection Program launched in Linqu, Shandong, a high-risk area of gastric cancer in China, we included a total of 14 087 subjects diagnosed with different gastric lesions stages by endoscopic screening from 2012 to 2018. Study subjects were prospectively followed up until December 31, 2019. The incidence of GC during the follow-up was ascertained by repeated endoscopic examinations, cancer, death registry reports, and active follow-up of study subjects and was confirmed by reviewing medical records extracted from the hospital information management system. The Poisson regression model was applied to calculate the relative risk ( RR) and 95% CI for GC occurrence among subjects with different gastric lesions. Results:Among 14 087 subjects with different gastric lesions as determined by their first endoscopic examination in 2012-2018, 7 608 (54.00%) had a global diagnosis of superficial gastritis (SG), 2 848 (20.22%) had chronic atrophic gastritis (CAG), 3 103 (22.03%) had intestinal metaplasia (IM), and 520 (3.69%) had low-grade intestinal neoplasia (LGIN). During the follow-up, 109 subjects were diagnosed with GC, including 63 with high-grade intestinal neoplasia (HGIN) and 46 with invasive GC. Compared to subjects having normal gastric mucosa or SG, those with CAG ( RR=3.85, 95% CI: 2.04-7.28), IM ( RR=5.18, 95% CI: 2.79-9.60), and LGIN ( RR=19.08, 95% CI: 9.97-36.53) had significantly increased risk of progression to GC. Individuals with these gastric lesions had an elevated risk of developing HGIN and invasive GC. For subjects with LGIN, the RR was 22.96 (95% CI: 9.71-54.27) for developing HGIN and 14.64 (95% CI: 5.37-39.93) for developing invasive GC. Subgroup analyses found that all age group subjects with LGIN diagnosed during the initial endoscopic examination had a significantly increased risk of developing the GC. Conclusions:Our large-scale prospective study on a high-risk area of GC showed that most residents aged 40-69 years had gastric lesions of different stages. Subjects with more advanced gastric lesions had a significantly increased risk of progression to GC.

Objective: To analyze the relationship between body fat distribution and bone mineral content (BMC) in adolescents and gender differences among Chinese adolescents, and to provide a scientific basis for the prevention and treatment of bone metabolic diseases. Methods: A total of 1 575 adolescents aged 12-18 years old were selected from Yinchuan by cluster random sampling. Body composition and bone mineral content were measured by bioelectrical impedance analysis(BIA). Multiple linear regression analysis was used to explore the relationship between body fat distribution and BMC after adjusting for confounding factors. Results: Except for LTFR, the levels of FM, AFM, TFM, TrTFR and TrLFR in boys were lower than those in girls( t =-13.52， -15.18 ，-12.47，-12.25，-7.96， P <0.05); After adjusting for age, sex and weight, FM, AFM, TFM, TrTFR and TrLFR were all negatively correlated with BMC level( P <0.05). For each increase of 1 standard deviation in TFM, BMC level decreased by 0.53 standard deviation(95% CI=-0.57--0.49, P<0.01]. LTFR had a linear negative correlation with BMC level in boys( B=0.07, P <0.01), no similar correlation was found in girls( B=0.01, P =0.74). There was a linear negative correlation between TrLFR and BMC level in girls( B=-0.06, P =0.03), but the correlation was of no significance in boys( B=-0.01, P =0.55). Conclusion Sex difference in body fat distribution in Chinese adolescents is observed. Body fat distribution is closely related to bone minerals content in adolescents.

Traditional survival methods have a wide application in the field of biomedical research. However, applying traditional survival methods requires data to meet a set of special assumptions while the Random Survival Forest model can overcome this inconvenience. Herein, we used the clinical data of Primary Biliary Cholangitis (PBC) from Mayo Clinic to introduce and demonstrate Random Survival Forest model from mathematical principles, model building, practical example and attentions, aiming to provide a novel method for doing survival analysis.

The liquid chromatography tandem mass spectrometry was used to detect the urinary proteomics of 223 residents aged 40-69 years old who participated in the National Upper Gastrointestinal Cancer Early Detection Program in Linqu County, Shandong Province from November 22 to December 7, 2018, and analyze the alcohol consumption related proteomic profiles and individual urinary protein. There were significant differences in urinary protein profiles between alcohol consumption group and non-alcohol consumption group. The expression of 26 urinary proteins was up-regulated and 20 urinary proteins were down-regulated in alcohol consumption group ( P<0.05). The differentially expressed proteins had enzyme inhibitor activity and phospholipid binding function, and mainly enriched in pathways involving proximal tubule bicarbonate regeneration, complement and coagulation cascade, and cholesterol metabolism. The protein expressions of complement factor I (CFI), angiotensin converting enzyme 2 (ACE2) and protein C inhibitor (SERPINA5) were positively correlated with daily alcohol consumption.

Traditional survival methods have a wide application in the field of biomedical research. However, applying traditional survival methods requires data to meet a set of special assumptions while the Random Survival Forest model can overcome this inconvenience. Herein, we used the clinical data of Primary Biliary Cholangitis (PBC) from Mayo Clinic to introduce and demonstrate Random Survival Forest model from mathematical principles, model building, practical example and attentions, aiming to provide a novel method for doing survival analysis.

The liquid chromatography tandem mass spectrometry was used to detect the urinary proteomics of 223 residents aged 40-69 years old who participated in the National Upper Gastrointestinal Cancer Early Detection Program in Linqu County, Shandong Province from November 22 to December 7, 2018, and analyze the alcohol consumption related proteomic profiles and individual urinary protein. There were significant differences in urinary protein profiles between alcohol consumption group and non-alcohol consumption group. The expression of 26 urinary proteins was up-regulated and 20 urinary proteins were down-regulated in alcohol consumption group ( P<0.05). The differentially expressed proteins had enzyme inhibitor activity and phospholipid binding function, and mainly enriched in pathways involving proximal tubule bicarbonate regeneration, complement and coagulation cascade, and cholesterol metabolism. The protein expressions of complement factor I (CFI), angiotensin converting enzyme 2 (ACE2) and protein C inhibitor (SERPINA5) were positively correlated with daily alcohol consumption.