[Role of liver sinusoidal endothelial cell damage in the developmental process of hepatic sinusoidal obstruction syndrome: a focus on the research progress of immune inflammatory mechanisms].

Hepatic sinusoidal obstruction syndrome (HSOS) is a type of secondary vascular disease of the liver that is mainly associated with the ingestion of pyrrole alkaloids (PAs) and hematopoietic stem cell transplantation (HSCT) treatment, resulting in severe liver dysfunction, multiple organ failure, and even death. Hepatic sinusoidal dilatation and obstruction, hepatocyte coagulative necrosis, and hepatic lobular inflammation are the main pathological manifestations of HSOS. The key initiating process for the pathogenesis of HSOS is damage to liver sinusoidal endothelial cells (LSECs). Currently, it is believed that LSECs are damaged by the involvement of multiple etiologies and mechanisms, and secondary coagulation and fibrinolysis disorders, oxidative stress, and inflammatory responses are the occurrence contributors to HSOS; however, the mechanism has not been fully elucidated. Therefore, the role of immune-inflammatory mechanisms has received increasing attention in LSEC damage. This article provides an overview of the epidemiology, etiology, and pathological changes of HSOS and reviews the physiological functions, common etiological damage mechanisms, and the key role of LSEC damage in the pathogenesis of HSOS, with a special focus on the role and research progress of immune-inflammatory mechanisms for LSEC damage in recent years. Furthermore, we believe that in-depth study and elucidation of the role of immune-inflammatory mechanisms in LSEC damage and the pathogenesis of HSOS and diagnosis will provide feasible research and development ideas for the screening and identification of new markers and drug treatment targets for HSOS.

[Research progress on non-alcoholic fatty liver disease animal models].

In recent years, with the changes in living standards and dietary structure, the incidence of non-alcoholic fatty liver disease has been increasing year by year in China, and the incidence rate in the general population is as high as 29.81%. An increasingly epidemiological evidence suggests that non-alcoholic fatty liver disease has become one of the causes of increasing liver cirrhosis and liver cancer. However, its etiology and pathogenesis are complex and have not yet been fully elucidated. Therefore, establishing an appropriate non-alcoholic fatty liver disease animal models for pre-clinical research is essential to elucidate its pathogenesis. This article summarizes the latest research progress of non-alcoholic fatty liver disease animal models, which are common at home and abroad in recent years.

[Analysis of the reported data of National Cervical Cancer Screening Program in Rural Areas in China from 2009 to 2018].

Objective: To analyze the effectiveness of the National Cervical Cancer Screening Program in Rural Areas (NCCSPRA) in China. Methods: Data were collected in the form of quarterly statistical tables reported by NCCSPRA counties in 30 provinces (Hong Kong, Macao and Taiwan province of China were not included into the NCCSPRA, and Tibet Autonomous Region carried out the program but did not reported the data) from 2009 to 2018. The women aged 35-64 years with sexual behavior and the identity (Hukou) of rural area in these project counties were included into the NCCSPRA, and women receiving hysterectomy for non-cervical cancer or non-cervical lesions were excluded. The following indicators were analyzed: the positive rates of different screening methods, the abnormality rates of colposcopy and histopathology, the detection rate of precancerous lesions, the detection rate of cervical cancer and the rate of early diagnosis. Results: A total of 85 041 490 women aged 35-64 in rural areas received free cervical cancer screening and diagnosis if necessary. On the whole, the abnormality rate of cytology, HPV testing, VIA/VILI, colposcopy and histopathology was 3.71%(2 567 610), 9.91%(331 158), 10.10%(1 167 930), 28.85%(1 420 847), and 21.20%(303 068) respectively. The detection rate of cervical precancerous lesions was 153.88/100 000, and increased from 106.85/100 000 in 2012 to 223.89/100 000 in 2018 (P<0.001). Regionally, the east (207.37/100 000) reached higher rate than the middle (177.65/100 000), and the middle higher than the west (108.65/100 000) (P<0.001). The detection rate of invasive cervical cancer was 21.58/100 000, and increased from 18.02/100 000 in 2012 to 26.54/100 000 in 2018 (P<0.001). Regionally, the middle of China (25.46/100 000) reached the higher rate than the east (19.62/100 000) and the west (19.30/100 000) (P<0.001). The rate of early detection was 91.24%(136 140), which increased from 89.60% (11 883)in 2012 to 92.80%(26 962) in 2018 (P<0.001). Regionally, the east of China (94.02%, 37 600) reached the higher rate than the middle(91.06%, 56 488), and the middle higher than the west (89.12%, 42 052) (P<0.001). Conclusions: There are obvious difference in terms of the detection rate of cervical precancerous lesions and the rate of early diagnosis reflecting cervical cancer screening capacity among the eastern, middle and western regions,which showed service inequity among different areas indirectly. The middle and western regions, especially the western regions, are still the focus of future works.

[Global guidelines for cervical cancer screening: a systematic review].

Objective: To systematically summarize and evaluate the current cervical cancer screening guidelines worldwide. Methods: "Cervical cancer/cervical intraepithelial neoplasia", "screening", and "guidelines/recommendations" were searched as keywords in PubMed, Embase, China National Knowledge Infrastructure (CNKI), Wanfang Data for cervical cancer screening guidelines. The language was limited to Chinese and English. A total of 29 guidelines were included before September 1, 2020. The basic information and recommendations of the guidelines issued were summarized. Results: Among the 29 cervical cancer screening guidelines, most guidelines targeted on the population aged 25-65 years. Cytology and human papillomavirus (HPV) testing are two commonly used methods for the cervical cancer screening, and HPV testing is increasingly recommended as the primary screening methods. Most guidelines recommended five years interval for the HPV testing-based screening or co-testing (HPV testing and cytology) based screening and three years for the cytology-based. For managing population with abnormal cervical cancer screening, triage or screening repeatedly to identify high-risk populations were more recommended. Direct colposcopy or treatment were allowed for women with higher risk of cervical intraepithelial neoplasia (CIN) during the screening procedure. Several guidelines involving HPV vaccination population recommended them the same strategy as the general population without vaccination. Conclusion: Currently, most of the cervical cancer screening guidelines applied to the population with the average risk of the CINs and were issued by the developed countries. Primary methods for the cervical cancer screening have gradually changed from the cytology to the HPV testing. There is a lack of recommendations targeting special population on cervical cancer screening in the current guidelines.

[Accelerating the elimination of cervical cancer in China and building a paradigm for "Healthy China" cancer prevention].

Cervical cancer is a common malignant tumor that seriously threatens the health of Chinese women. The situation of prevention and control is still serious. In the past decade, the Chinese government has made great efforts to cervical cancer prevention and control and achieved remarkably in HPV vaccine development, sound health screening system, and treatment capacity of early cervical cancer and precancerous lesions. However, due to the large population base, unequal allocation of health resources, and uneven service quality across regions, there is still a significant gap to achieve the WHO's goal of eliminating cervical cancer by 2030. In order to fulfill the Global Strategy to accelerate the elimination of cervical cancer, China urgently needs to learn from the international experience, combined with the real situation of cervical cancer prevention and control and the latest research progress in China and to put forward appropriate action recommendations and implementation approaches, which will contribute to promote the cervical cancer elimination process and to build a paradigm for "Healthy China" cancer prevention.

[Breast ultrasound optimization process analysis based on breast cancer screening for 1 501 753 rural women in China].

Objective: To evaluate the effectiveness and quality of ultrasound-based (BUS) process optimization in breast cancer screening. Methods: The program collected the first to fourth quarterly breast cancer screening statistic data and case report data from 30 provinces, autonomous regions and municipalities in 2015 by the online report system of national key service program of women and children's public health. The call rate, mammography (MG) subsequent screen rate, biopsy rate, detection rate, early diagnosis rate, carcinoma in situ rate, missing detection rate, false positive rate and positive predictive value (PPV) of breast cancer were calculated. Results: A total of 1 501 753 rural women attended the BUS process optimization screening. The nationwide recall rate was 3.01%(45 156/1 501 753), and in the eastern and central area were 3.41%(17 173/503 130) and 3.56%(14 499/407 739), respectively, higher than 2.28% (13 484/590 884) of western area (P<0.05). The nationwide MG subsequent screen rate was 2.78%(41 694/1 501 753), and in the eastern and central area were 3.19%(16 036/503 130) and 3.29% (13 421/407 739), respectively, higher than 2.07%(12 237/590 884) of western area (P<0.05). The nationwide biopsy rate was 0.23%(3 462/1 501 753), and in the central area were 0.26%(1 078/407 739), respectively, higher than 0.21%(1 247/590 884) of western area and 0.23% (1 137/503 130) of eastern area (P<0.05). The nationwide biopsy PPV was 37.00%(1 281/3 462). The biopsy PPV of eastern area was (34.30%, 390/1 137), lower than 39.33% (424/1 078) of central area (P<0.05). A total of 1 281 cases of breast cancer were detected, the detection rate was 0.85‰(1 281/1 501 753), and the detection rates of central area was 1.04‰ (424/407 739), higher than 0.79‰(467/590 884) of western area and 0.78‰(390/503 130) of eastern area (P<0.05). The BUS initiate screening positive rate from detected breast cancer cases was 96.96%(1 242/1 281), the MG subsequent screening positive rate was 2.42%(31/1 281). The nationwide early diagnosis rate was 85.25%(1 092/1 281), and in the eastern and central areas were 87.95%(343/390) and 88.21%(374/424), higher than 80.30%(375/467) of western area (P<0.05). The screening rate of on or above stage Ⅱ breast cancer in eastern area was 55.64%(217/390), lower than 64.62%(374/424) of central area and 62.31%(291/467) of western area. The missing detection rate was 0.62%(8/1 281) and false positive rate was 1.20%(17 528/1 464 149). Conclusions: The BUS process optimization of breast cancer screening scheme is reasonable and applicable to China rural women. The effectiveness and quality of eastern area are superior to those of central and western area.

[Diagnosis and therapeutic strategies for non-alcoholic fatty liver disease in children].

Non-alcoholic fatty liver disease (NAFLD) is a common chronic liver disease in children and adults, and is closely related to obesity and metabolic factors. In recent years, with the changes in living standards and dietary structure, the incidence of NAFLD has been increasing year by year. Pediatric NAFLD has many similarities with adult NAFLD in terms of epidemiology, etiology, pathogenesis, and diagnosis and treatment strategies; however it has its own unique characteristics. This paper reviews the latest research progress of pediatric NAFLD in recent years at home and abroad.

Association between hsa_circ_0006156 expression and incidence of gastric cancer.

OBJECTIVE: To screen the differentially expressed circular ribonucleic acids (circRNAs) related to gastric cancer and to explore their associations with the clinicopathological features of gastric cancer. PATIENTS AND METHODS: Cancer tissues of 50 gastric cancer patients undergoing surgical resection in our hospital from April 2015 to December 2018 were collected as an experimental group, while the para-carcinoma tissues were used as the control group. First, the differentially expressed circRNAs were screened by analyzing the circRNA profile in the microarray. Then, the expression of hsa_circ_0006156 in tissues was detected via Reverse Transcription-quantitative Polymerase Chain Reaction (RT-qPCR) in both groups. The potential associations of the relative expression level of hsa_circ_0006156 with clinicopathological features and prognosis were analyzed according to the clinical data of gastric cancer patients. RESULTS: Six significantly downregulated circRNAs in gastric cancer patients were screened out. The results of RT-qPCR showed that the expression level of hsa_circ_0006156 was significantly lower in gastric cancer tissues than that in para-carcinoma tissues (p<0.05). Accordingly, 50 gastric cancer patients were divided into hsa_circ_0006156 high expression group and hsa_circ_0006156 low expression group based on the fold change of hsa_circ_0006156 in para-carcinoma tissues than that of gastric cancer tissues (fold change>3). The expression level of hsa_circ_0006156 was not correlated with the age and gender of gastric cancer patients (p>0.05) but correlated with the lymph node metastasis (p<0.05), nerve invasion (p<0.05), and degree of tumor differentiation (p<0.05). The expression level of hsa_circ_0006156 was also significantly associated with the progression-free survival (PFS) and overall survival (OS) of patients (p<0.05). According to the multivariate analysis of variance, the PFS of gastric cancer patients was associated with nerve invasion, lymph node metastasis, and hsa_circ_0006156 expression (relative risk coefficient=1.742, 2.329, and 3.003). Meanwhile, the OS was associated with lymph node metastasis, nerve invasion, degree of tumor differentiation, and hsa_circ_0006156 expression (relative risk coefficient =1.604, 2.405, 2.114, and 2.004). Moreover, the survival analysis revealed that PFS was markedly prolonged in the hsa_circ_0006156 high expression group compared with that in the hsa_circ_0006156 low expression group. CONCLUSIONS: The expression of hsa_circ_0006156 substantially declines in gastric cancer tissues, which is related to the differentiation degree, presence, or absence of lymph node metastasis and prognosis of gastric cancer patients. Therefore, hsa_circ_0006156 may clinically serve as a biomarker for the prognostic prediction of gastric cancer patients.

Down-regulation of hsa_circ_0092125 is related to the occurrence and development of oral squamous cell carcinoma.

Circular RNA plays an important role in regulating tumour development and progression and can serve as a biomarker for cancer. This study was performed to investigate the clinical significance of hsa_circ_0092125 expression in oral squamous cell carcinoma (OSCC). The expression of hsa_circ_0092125 in OSCC tissues and cell lines was determined by reverse transcription-quantitative PCR analysis. The association between hsa_circ_0092125 expression and clinicopathological data was determined by χ2 test. Overall survival (OS) curves were created using Kaplan-Meier survival analysis, and the differences were examined by log-rank test. Moreover, univariate and multivariate Cox analysis were employed to evaluate the risk factors of the OSCC prognosis. The expression of hsa_circ_0092125 was significantly down-regulated in OSCC tissues and cell lines. A low expression of hsa_circ_0092125 was associated with clinicopathological factors in OSCC patients, including tumour size, TNM stage, and lymph node metastasis. Kaplan-Meier survival analysis indicated that the OS time was shorter in OSCC patients with a lower hsa_circ_0092125 expression level than in those with a higher expression level. In addition, univariate and multivariate Cox analysis identified lower hsa_circ_0092125 expression, tumour size, TNM stage, and lymph node metastasis as independent risk factors for the OSCC prognosis. Thus, down-regulated expression of hsa_circ_0092125 might serve as a biomarker of the OSCC prognosis.

Comparison of endoscope-assisted versus conventional resection of parotid tumors.

Endoscopically-assisted partial parotidectomy for benign tumours has been reported, but we have evaluated its feasibility through different concealed incisions compared with conventional parotidectomy. A total of 124 patients with parotid tumours were enrolled in this retrospective study: an endoscopically-assisted group (n=37) compared with a group operated on conventionally (n=87). The incision for endoscopically-assisted partial, total parotidectomy and selective neck dissection was based on location and pathological characters of the parotid tumour. The sex and age of the patients, diameter of the tumour, and histopathological features were comparable between the two groups. The mean length of the incision in the endoscopic group was significantly shorter than that in the conventional group. However, intraoperative blood loss, operating time, and duration of hospital stay were significantly reduced, and postoperative secretion of saliva was significantly improved in the endoscopic group, among whom there were no recurrences of tumour. More importantly, all patients who had endoscopically-assisted operations were satisfied with the cosmetic result. Endoscopically-assisted parotidectomy is superior to conventional resection as judged by postoperative cosmetic and functional outcomes. It is noteworthy that the site of incision depends mainly on location, and on the suspected low grade of malignancy of the parotid tumour seen on preoperative computed tomography and magnetic resonance images.

[Functional and supraomohyoid neck dissection in stage cN0/N1 oral squamous cell carcinoma].

Objective: To evaluate the clinical effects of functional neck dissection (FND) and supraomohyoid neck dissection (SOND) in patients with cN0/N1 oral squamous cell carcinoma (OSCC). Methods: A total of 210 patients with stage cN0/N1 OSCC underwent FND and SOND between January 2012 and May 2015 were retrospectively reviewed, among which, 147 patients were male and 63 were female, with an age range of 23-82 years and mean age of (62.2±10.2) years. There were 112 and 98 patients in FND and SOND groups, respectively. The follow-up data included cervical lymph node metastasis, movement of shoulder joint, great auricular nerve function, recurrence rate of cervical lymph nodes. Results: There was no significant difference in gender, age, tumor location, T stage, N stage, histological grades between the two groups (all P>0.05). Compared to patients in FND group, the activities of shoulder joint and earlobe numbness improved significantly in SOND group. Of the 210 patients, 17 patients (8.1%) had cervical recurrence, with 9 patients (8.0%) in FND group and 8 patients (8.2%) in SOND group. No significant difference was observed for neck recurrence between the two groups (P=0.973). Conclusion: SOND can be safely performed in cN0 or cN1 OSCC patients, which avoids major complications of FND, and improves postoperative quality of life in those patients.

[Virtual planning and 3D printing modeling for mandibular reconstruction with fibula free flap].

Objective: To evaluate the use of virtual planning and 3D printing modeling in mandibular reconstruction and compare the operation time and surgical outcome of this technique with conventional method. Methods: Between June 2013 and June 2017, A total of 18 patients underwent the mandibular reconstruction with fibula free flap in the Affiliated Hospital of Qingdao University.Among 18 patients, there were 11 males and 7 females with an average age of 36.5 years (21-73 years). Nine patients underwent vascularized fibula flap mandibular reconstruction using virtual planning and 3D printing modeling.Titanium plates were pre-bent using the models and cutting guides which were used for osteotomies.Another 9 patients who underwent mandibular reconstruction using fibula flap without aid of virtual planning and 3D printing models were selected as control group. The operation time was recorded and compared in two groups. Accuracy of reconstruction was measured by superimposing the preoperative image onto the postoperative image of mandible. The selected bony landmark, distance and angle were measured. Results: The mean total operation time were 4.7-6.2(5.5±0.5) h in computer-assisted group and 5.6-7.5(6.6±0.7) h in conventional group, respectively. The operation time was shorter in computer-assisted group. The difference between the preoperative and postoperative intercondylar distances, intergonial angle distances, anteroposterior distances were(2.6±1.4)vs(4.4±1.6)mm, (2.9±1.2)vs(4.7±1.7)mm, (4.2±1.4) vs(5.9±1.8)mm in the computer-assisted and conventional group, respectively. The differences between the preoperative and postoperative mandible were smaller in the computer-assisted group. Conclusions: Virtual planning and 3D printing modeling have the potential to increase mandibular reconstruction accuracy and reduce operation time. We believe that this technology for mandibular reconstruction in selected patients can significantly improve the quality of reconstruction.

[Long-term outcomes of implanting drug-eluting stents for unprotected left main coronary artery disease patients with left ventricular systolic dysfunction].

Objective: To analyze the clinical characteristics and prognosis of implanting drug-eluting stents (DES) for unprotected left main (ULM) coronary artery disease patients with left ventricular systolic dysfunction (LVSD). Methods: A total of 511 ULM coronary artery disease patients who underwent DES implantation from January 2005 to January 2012 in Department of Cardiology, Beijing Anzhen Hospital were included in the study. Based on left ventricular ejection fraction (LVEF), the patients were divided into three groups: LVEF≤40% (n=104), 41%≤LVEF≤49% (n=137), and LVEF≥50% (n=270). The clinical characteristics of patients undergoing DES implantation were retrospectively compared, and the effects of LVSD on ULM coronary artery disease were analyzed. Results: After comparison of clinical baseline data among three different LVEF groups, the incidence of peripheral vascular diseases, old myocardial infarction (OMI), multi-vessel lesions, complete revascularization and chronic total occlusion (CTO) was statistically different (P=0.002, P<0.001, P<0.001, P=0.049, P=0.001, respectively). However, there was no significant difference in the incidence of other clinical characteristics (all P>0.05). In terms of survival analysis, total mortality and cardiac mortality were both remarkably higher in LVEF≤40% group than those in LVEF≥50% group (both P<0.001). There was no statistical difference of total mortality between 41%≤LVEF≤49% group and LVEF≥50% group (P>0.05), while cardiac mortality was higher in LVEF≥50% group (P=0.027) . Besides, there was no significant difference among three groups in major adverse cardiac and cerebral events (MACCE), myocardial infarction(MI), cerebral infarction and target vessel revascularization (TVR) (all P>0.05). After adjusting for multiple clinical factors, total mortality and cardiac mortality were both remarkably higher in LVEF≤40% group than those in LVEF≥50% group (P=0.002, P<0.001), while there were no statistical differences of total mortality and cardiac mortality between 41%≤LVEF≤49% group and LVEF≥50% group (both P>0.05). In terms of MACCE, MI, cerebral infarction and TVR, there were also no significant differences among three groups (all P>0.05). Conclusion: For ULM coronary artery disease patients with LVSD, implanting DES is safe and effective, but for those with severe LVSD (LVEF≤40%), DES implantation showed an increased risk of long-term death and therefore should be selected with great care.

Overexpression of forkhead box protein M1 (FOXM1) plays a critical role in colorectal cancer.

BACKGROUND: The forkhead box M1 (FOXM1), an important regulator of cell differentiation and proliferation, is overexpressed in a number of aggressive human carcinomas. However, the clinical significance of FOXM1 signaling in human colorectal cancer (CRC) pathogenesis remains unknown. The aim of this study was to evaluate the role of FOXM1 in CRC tumorigenesis. METHODS: We investigated FOXM1 expression in 103 cases of primary CRC and matched normal tissue specimens and explored the underlying mechanisms of altered FOXM1 expression and the impact of this altered expression on CRC proliferation and metastasis using in vitro models of CRC. RESULTS: The results showed that high expression of FOXM1 staining was 85.44% (88/103) in 103 cases of CRC and 20.39% (21/103) in 103 cases of adjacent non-cancerous tissue samples; the difference of FOXM1 expression between two groups was statistically significant (P < 0.001). Silencing of FOXM1 inhibited the proliferation of CRC cells, and the invasion and migration of CRC cells were distinctly suppressed. Furthermore, FOXM1 knockdown led to substantial reductions in VEGF-A levels in CRC cell lines. CONCLUSIONS: Our data suggest that the pathogenesis of CRC maybe mediated by FOXM1, and FOXM1 could represent selective targets for the molecularly targeted treatments of CRC.

Circulating miR-125b as a biomarker of Ewing's sarcoma in Chinese children.

Previous studies indicated that microRNA-125b (miR-125b) has an important role in the progression of Ewing's sarcoma (ES). The purpose of the current study was to examine expression changes of miR-125b in the serum of ES patients and evaluate if the expression level of miR-125b could serve as a new biomarker for ES. This study was performed on patients who underwent surgical resection at our hospital between 2005 and 2013 after an initial diagnosis of ES. We measured serum miR-125b levels in 63 patients with ES and 126 healthy control patients using a real-time quantitative reverse transcriptase-PCR (qRT-PCR) method. Expression levels of serum miR-125b were distinctly decreased in ES patients when compared with healthy controls (P < 0.001). ES cases that had a poor response to chemotherapy presented a significant down-regulation of miR-125b (P = 0.001). The ROC curve showed that the serum miR-125b could serve as a valuable biomarker for differentiating ES patients from healthy controls with an AUC of 0.879 (95%CI = 0.817-0.924; P < 0.001). At a cut-off value of 2.203 for miR-125b, the sensitivity was 72.8% and the specificity was 87.2% in discriminating ES from the controls. Our results indicate that serum miR- 125b may serve as a useful noninvasive biomarker for ES.

Meta-analysis of associations between the TP53 Arg72Pro polymorphism with risk of head and neck carcinomas based on case-control studies.

Genetic factors have been shown to play a role in the development of head and neck cancers (HNCs). However, studies investigating the association between the TP53 Arg72Pro polymorphism and HNCs susceptibility have yielded conflicting results. Hence, we performed a meta-analysis of all eligible studies (up to January 1, 2012) to derive a more precise estimation of this association in order to increase understanding of the possible risk factors of HNCs. Twenty-seven case-control studies involving 3966 cases and 4387 controls were included in our analysis. Overall, no evidence of association was observed between the TP53 Arg72Pro single nucleotide polymorphism (SNP) and the risk of HNCs in any genetic model (Arg/Arg vs Pro/Pro: odds ratio (OR) = 0.83, 95% confidence interval (CI): 0.65-1.06; Arg/Pro vs Pro/Pro: OR = 0.88, 95%CI= 0.70-1.10; Arg/Arg+Arg/Pro vs Pro/Pro: OR = 0.87, 95%CI= 0.70-1.09; Arg/Arg vs Arg/Pro+Pro/Pro: OR = 0.95, 95%CI= 0.82-1.11). Nevertheless, the TP53 Arg72Pro polymorphism shows diverse effects across different subtypes of HNCs. For example, there was a lack of association of this polymorphism with oral cavity cancer, whereas a significant association with nasopharyngeal cancer was observed. Results of this meta-analysis suggest that the TP53 Arg72Pro polymorphism might have different effects on the risk of various subtypes of HNCs.