The immune escape mechanism of nasopharyngeal carcinoma.

Tumor cells are known for being able to evade immune system surveillance, a hallmark of malignancy. Complicated immune escape mechanisms in the tumor microenvironment (TME) provide favorable conditions for tumor invasion, metastasis, treatment resistance, and recurrence. Epstein-Barr virus (EBV) infection is closely related to the pathogenesis of nasopharyngeal carcinoma (NPC), and the co-existence of EBV-infected NPC cells and tumor-infiltrating lymphocytes represents a distinctive, highly heterogeneous, and suppressive TME that supports immune escape and promotes tumorigenesis. Understanding the complex interaction between EBV and NPC host cells and focusing on the immune escape mechanism of TME may help to identify specific immunotherapy targets and to develop effective immunotherapy drugs.

Causal inference for recurrent events via aggregated marginal odds ratio.

Researchers often work with treatments and outcomes that vary over time. For example, psychologists are interested in the curative effect of cognitive behavior therapies on patients' recurrent depression symptoms. While there are various causal effect measures designed for one-time treatment, the causal effect measures for time-varying treatment and recurrent events are relatively under-developed. In this article, a new causal measure is proposed to quantify the causal effect of time-varying treatments on recurrent events. We suggest estimators with robust standard errors that are based on various weight models for both conventional causal measures and the proposed measure in different time settings. We outline the approaches and describe how using some stabilized inverse probability weight models are more advantageous than others. We demonstrate that the proposed causal estimand can be consistently estimated for study periods of moderate length, and the estimation results are compared under different treatment settings with various weight models. We also find that the proposed method is suitable for both absorbing and nonabsorbing treatments. The methods are applied to the 1997 National Longitudinal Study of Youth as an illustrative example.

Anatomy of the internal iliac vein around the sacral promontory based on CT three-dimensional (3D) reconstruction.

INTRODUCTION AND HYPOTHESIS: The area around the sacral promontory (SP) is the targeted location of various pelvic operations. We examined the internal iliac vein (IIV) configurations around the SP by computed tomography angiography (CTA) three-dimensional (3D) reconstruction to describe its anatomy and provide accurate anatomical parameters for relevant operations to reduce intraoperative vascular injury. METHODS: We retrospectively studied 2078 CTA 3D model datasets from Nanfang Hospital patients examined for gynecological diseases from December 2009 to October 2020. The IIVs of the above cases were divided into standard and variant IIVs, and variant IIVs were subdivided into different subtypes. To compare the size of the avascular area around the SP between standard and variant IIVs, we selected the two subtypes with the highest variation rate for comparison with the standard IIV type. RESULTS: The most common types of variant IIVs were 5a (5.15%) and 3a (5.05%). The results showed larger values in the standard group than in the 3a and 5a groups for the confluence of common iliac vein (CCIV) height (37.73±12.05 vs. 28.93±10.17 vs. 27.27±7.58 mm, P < 0.05), distance between the iliac vessels (49.47±9.47 mm vs. 37.08±9.36 vs. 37.73±8.94 mm, P < 0.05), and SP exposure width (44.94±6.39 mm vs. 36.83±8.29 vs. 36.93±7.91, P < 0.05). CONCLUSIONS: Variant IIVs may increase the risk of surgery by reducing the avascular area compared with standard IIVs. Therefore, when operating around the SP, special attention should be given to variant IIVs and avoiding vascular injury.

Unassisted Clinicians Versus Deep Learning-Assisted Clinicians in Image-Based Cancer Diagnostics: Systematic Review With Meta-analysis.

BACKGROUND: A number of publications have demonstrated that deep learning (DL) algorithms matched or outperformed clinicians in image-based cancer diagnostics, but these algorithms are frequently considered as opponents rather than partners. Despite the clinicians-in-the-loop DL approach having great potential, no study has systematically quantified the diagnostic accuracy of clinicians with and without the assistance of DL in image-based cancer identification. OBJECTIVE: We systematically quantified the diagnostic accuracy of clinicians with and without the assistance of DL in image-based cancer identification. METHODS: PubMed, Embase, IEEEXplore, and the Cochrane Library were searched for studies published between January 1, 2012, and December 7, 2021. Any type of study design was permitted that focused on comparing unassisted clinicians and DL-assisted clinicians in cancer identification using medical imaging. Studies using medical waveform-data graphics material and those investigating image segmentation rather than classification were excluded. Studies providing binary diagnostic accuracy data and contingency tables were included for further meta-analysis. Two subgroups were defined and analyzed, including cancer type and imaging modality. RESULTS: In total, 9796 studies were identified, of which 48 were deemed eligible for systematic review. Twenty-five of these studies made comparisons between unassisted clinicians and DL-assisted clinicians and provided sufficient data for statistical synthesis. We found a pooled sensitivity of 83% (95% CI 80%-86%) for unassisted clinicians and 88% (95% CI 86%-90%) for DL-assisted clinicians. Pooled specificity was 86% (95% CI 83%-88%) for unassisted clinicians and 88% (95% CI 85%-90%) for DL-assisted clinicians. The pooled sensitivity and specificity values for DL-assisted clinicians were higher than for unassisted clinicians, at ratios of 1.07 (95% CI 1.05-1.09) and 1.03 (95% CI 1.02-1.05), respectively. Similar diagnostic performance by DL-assisted clinicians was also observed across the predefined subgroups. CONCLUSIONS: The diagnostic performance of DL-assisted clinicians appears better than unassisted clinicians in image-based cancer identification. However, caution should be exercised, because the evidence provided in the reviewed studies does not cover all the minutiae involved in real-world clinical practice. Combining qualitative insights from clinical practice with data-science approaches may improve DL-assisted practice, although further research is required. TRIAL REGISTRATION: PROSPERO CRD42021281372; https://www.crd.york.ac.uk/prospero/display_record.php?RecordID=281372.

Correction: Unassisted Clinicians Versus Deep Learning-Assisted Clinicians in Image-Based Cancer Diagnostics: Systematic Review With Meta-analysis.

[This corrects the article DOI: 10.2196/43832.].

Associations between congenital heart disease and air pollutants at different gestational weeks: a time-series analysis.

Exposure to air pollution during pregnancy has been linked to birth defects. But the directions of studies on the associations between air pollutants exposure and effect on the incidence of congenital heart disease (CHDs) were inconsistent. To date, few studies were concentrated on the effects of both particulate matter and gaseous air pollutant exposure on CHDs across the full gestational week simultaneously. Our study aimed to investigate the critical exposure windows for each air pollutant throughout 40 gestational weeks. Data on CHDs, air pollution, and meteorological factors from 2013 to 2019 were collected in Lanzhou, China. A distributed lag nonlinear model combined with a quasi-Poisson regression model was applied to evaluate the weekly exposure-lag-response association between air pollutants levels and CHDs, and the subgroup analyses were conducted by gender (baby boy and baby girl). The study included 1607 mother-infant pairs. The results demonstrated that exposure of pregnant women to particulate matter ≤ 5 µm (PM2.5) at lag 1-4 weeks was significantly associated with the risk of CHDs, and the strongest effects were observed in the lag 1 week (1.150, 95%CI 1.059-1.248). For exposure to particulate matter ≤ 10 µm (PM10) at lag 1-3 weeks, the strongest effects were observed in the lag 1 week (1.075, 95% CI 1.026-1.128). For exposure to sulfur dioxide (SO2) at lag 1-4 weeks, the strongest effects were observed in the lag 1 week (1.154, 95% CI 1.025-1.299). For exposure to carbon monoxide (CO) at lag 1-3 weeks, the strongest effects were observed in the lag 1 week (1.089, 95% CI 1.002-1.183). For exposure to ozone (O3) concentration at lag 9-15 weeks, the strongest effects were observed in the lag 15 weeks (1.628, 95% CI 1.001-2.649). The cumulative effects of PM2.5, PM10, SO2, and CO along weeks with a maximum of 1.609 (95%CI 1.000-2.589), 1.286 (95%CI 1.007-1.641), 1.648 (95%CI 1.018-2.668), and 1.368 (95%CI 1.003, 1.865), respectively. The effects were obvious in the initial gestational weeks too. Through the gender stratification analysis, the air pollutants with significant effects were PM2.5 for baby boys and PM2.5, PM10, SO2, CO, NO2, and O3 for baby girl. For the relationship between CHDs and air pollution in Lanzhou, PM2.5, PM10, SO2, CO, and O3 played an important role in the initial gestational weeks, especially for baby girl.

Long non-coding RNAs are involved in alternative splicing and promote cancer progression.

Alternative splicing (AS) is a key process in which precursor RNAs produce different mature RNAs, and the disorder of AS is a key factor in promoting cancer development. Compared with coding RNA, studies on the functions of long non-coding RNAs (lncRNAs) are far from enough. In fact, lncRNA is an important participant and regulator in the process of AS. On the one hand, lncRNAs regulate cancer progression as AS products of precursor messenger RNA (mRNA), but on the other hand, precursor lncRNA generates cancer-related abnormal splicing variants through AS. In addition, lncRNAs directly or indirectly regulate the AS events of downstream target genes, thus affecting the occurrence and development of cancer. Here, we reviewed how lncRNAs regulate AS and influence oncogenesis in different ways.

Cohort Profile Update: the China Metal-Exposed workers Cohort Study (Jinchang Cohort).

The Jinchang Cohort was an ongoing 20-year ambispective cohort with unique metal exposures to an occupational population. From January 2014 to December 2019, the Jinchang Cohort has completed three phases of follow-up. The baseline cohort was completed from June 2011 to December 2013, and a total of 48 001 people were included. Three phases of follow-ups included 46 713, 41 888, and 40 530 participants, respectively. The death data were collected from 2001 to 2020. The epidemiological, physical examination, physiological, and biochemical data of the cohort were collected at baseline and during follow-up. Biological specimens were collected on the baseline to establish a biological specimen bank. The concentrations of metals in urine and serum were detected by inductively coupled plasma mass spectrometry (ICP-MS). The new areas of research aim to study the all-cases mortality, the burden of diseases, heavy metals and diseases, and the course of the chain from disease to high-risk outcomes using a combination of macro and micro means, which provided a scientific basis to explore the pathogenesis of multi-etiology and multi-disease and to evaluate the effects of the intervention measures in the population.

Colorectal cancer prompted adipose tissue browning and cancer cachexia through transferring exosomal miR-146b-5p.

Cancer cachexia is a complex syndrome that is associated with thermogenic gene regulation. Currently, although some studies have reported the link between exosomes and cancer cachexia in a few types of cancer, the underlying mechanisms remain poorly understood. In this study, we tried to identify whether exosomes derived from colorectal cancer could affect lipolysis in vitro and in vivo. Here, we collected the tissue samples from 48 patients with colorectal cancer (47.91% females and mean age 55 ± 8.20) and 48 healthy people at the First Affiliated Hospital of Nanjing Medical University to detect the miR-146-5p expression. Here, we found that cancer cells released exosomes induced white adipose tissues (WATs) browning and accelerated lipolysis. We also demonstrated that miR-146b-5p was enriched in cancer-related exosomes. Overexpression miR-146b-5p resulted in increased WAT browning, decreased oxygen consumption, and fat mass loss (14.57%). The further study identified that miR-146b-5p could directly repress the downstream gene homeodomain-containing gene C10 (HOXC10), thereby regulating lipolysis. Therefore, our results indicated that cancer cells derived from exosomal miR-146b-5p played an essential role in WAT browning. Inhibition of cancer-related exosomes might be necessary for improving the cachexia condition.

Comparison of survival outcomes with or without Para-aortic lymphadenectomy in surgical patients with stage IB1-IIA2 cervical cancer in China from 2004 to 2016.

BACKGROUND: Current opinions on whether surgical patients with cervical cancer should undergo para-aortic lymphadenectomy at the same time are inconsistent. The present study examined differences in survival outcomes with or without para-aortic lymphadenectomy in surgical patients with stage IB1-IIA2 cervical cancer. METHODS: We retrospectively compared the survival outcomes of 8802 stage IB1-IIA2 cervical cancer patients (FIGO 2009) who underwent abdominal radical hysterectomy + pelvic lymphadenectomy (n = 8445) or abdominal radical hysterectomy + pelvic lymphadenectomy + para-aortic lymphadenectomy (n = 357) from 37 hospitals in mainland China. RESULTS: Among the 8802 patients with stage IB1-IIA2 cervical cancer, 1618 (18.38%) patients had postoperative pelvic lymph node metastases, and 37 (10.36%) patients had para-aortic lymph node metastasis. When pelvic lymph nodes had metastases, the para-aortic lymph node simultaneous metastasis rate was 30.00% (36/120). The risk of isolated para-aortic lymph node metastasis was 0.42% (1/237). There were no significant differences in the survival outcomes between the para-aortic lymph node unresected and resected groups. No differences in the survival outcomes were found before or after matching between the two groups regardless of pelvic lymph node negativity/positivity. CONCLUSION: Para-aortic lymphadenectomy did not improve 5-year survival outcomes in surgical patients with stage IB1-IIA2 cervical cancer. Therefore, when pelvic lymph node metastasis is negative, the risk of isolated para-aortic lymph node metastasis is very low, and para-aortic lymphadenectomy is not recommended. When pelvic lymph node metastasis is positive, para-aortic lymphadenectomy should be carefully selected because of the high risk of this procedure.

EBV-miR-BART12 accelerates migration and invasion in EBV-associated cancer cells by targeting tubulin polymerization-promoting protein 1.

Epstein-Barr virus (EBV) infection leads to cancers with an epithelial origin, such as nasopharyngeal cancer and gastric cancer, as well as multiple blood cell-based malignant tumors, such as lymphoma. Interestingly, EBV is also the first virus found to carry genes encoding miRNAs. EBV encodes 25 types of pre-miRNAs which are finally processed into 44 mature miRNAs. Most EBV-encoded miRNAs were found to be involved in the occurrence and development of EBV-related tumors. However, the function of EBV-miR-BART12 remains unclear. The findings of the current study revealed that EBV-miR-BART12 binds to the 3'UTR region of Tubulin Polymerization-Promoting Protein 1 (TPPP1) mRNA and downregulates TPPP1, thereby promoting the invasion and migration of EBV-related cancers, such as nasopharyngeal cancer and gastric cancer. The mechanism underlying this process was found to be the inhibition of TPPP1 by EBV-miRNA-BART12, which, in turn, inhibits the acetylation of α-tubulin, and promotes the dynamic assembly of microtubules, remodels the cytoskeleton, and enhances the acetylation of ß-catenin. ß-catenin activates epithelial to mesenchymal transition (EMT). These two processes synergistically promote the invasion and metastasis of tumor cells. To the best of our knowledge, this is the first study to reveal the role of EBV-miRNA-BART12 in the development of EBV-related tumors as well as the mechanism underlying this process, and suggests potential targets and strategies for the treatment of EBV-related tumors.

Mitochondria-associated endoplasmic reticulum membranes: At the crossroad between familiar and sporadic Alzheimer's disease.

Alzheimer's disease (AD) is the leading cause of dementia and is incurable. The widely accepted amyloid hypothesis failed to produce efficient clinical therapies. In contrast, there is increasing evidence suggesting that the disruption of mitochondria-associated endoplasmic reticulum (ER) membranes (MAM) is a critical upstream event of AD pathogenesis. Here, we review MAM's role in some AD symptoms such as plaque formation, tau hyperphosphorylation, synaptic loss, aberrant lipid synthesis, disturbed calcium homeostasis, and abnormal autophagy. At last, we proposed that MAM plays a central role in familial AD (FAD) and sporadic AD (SAD).

Exploration of the safe suture area of the presacral space in sacrocolpopexy by 3-dimensional (3D) models reconstructed from CT.

INTRODUCTION AND HYPOTHESIS: The objective of this study, a digital in vivo anatomical study based on patient-specific three-dimensional (3D) models reconstructed from computed tomography (CT) scans, was to clarify the anatomy of the presacral space and suggest a safe area for complication-free graft or mesh fixation. METHODS: We retrospectively studied 182 CT angiography (CTA) datasets from Han Chinese women examined for gynecological diseases from January 2018-June 2020; we used Mimics 21.0 to create 176 3D models of the female presacral space. The distances of pelvic structures from the presacral vessels and ureters were standardized and measured in 3D mode. RESULTS: The distances from the median sacral artery (MSA) to the bilateral great vessels and bilateral ureters at the sacral promontory (SP) level were similar to the respective distances from the midpoint of the SP (MSP) to those four structures (p > 0.05). At the level of the first transverse line, when the MSA was right of the midline, the MSA was 20.74 ± 3.86 mm from the medial edge of the left first anterior sacral foramen. When the MSA was left of the midline, its average distance from the medial edge of the right first anterior sacral foramen was 20.89 ± 4.92 mm. The SP was 9.71 ± 4.49 mm and 40.39 ± 6.74 mm, respectively, from the first and second sacral transverse veins along the midline. CONCLUSIONS: To preserve important vasculature, we recommend a 30 × 20-mm (L × W) avascular rectangular-shaped area, 10 mm below the SP and alongside the MSA, for safe graft or mesh attachment during sacrocolpopexy.

mRNA microarray profiling identifies a novel circulating HTRA2 for detection of gastric cancer.

BACKGROUND: mRNAs have been shown to be critical biomarkers or therapeutic targets for human diseases. However, only a few of them have been studied as blood-based biomarkers for gastric carcinoma (GC) detection. METHODS: mRNA expression profiles for GC were screened using plasma samples from 10 GC patients with different TNM stages and 5 healthy individuals as controls. One candidate tumor-related mRNA named HTRA2 was then evaluated in GC samples with quantitative real-time polymerase chain reaction (qRT-PCR). TCGAportal, UALCAN, and TISCH database were used to explore the function of HTRA2 in GC. Finally, the effect generated by HTRA2 expression on cell proliferating, invading, and migrating processes was assessed in vitro with knockdown and over-expression strategies. RESULTS: HTRA2 displayed noticeable increase inside GC plasma compared with control cases. Higher expression of HTRA2 displayed a correlation to higher clinicopathological stage and worse prognosis. HTRA2 knocking down down-regulated GC cells' proliferating, invading, and migrating states, while HTRA2 over-expression exerted the inconsistent influence. HTRA2 protein, which may interact with PINK1, PARL, and CYCS, was mainly located in the mitochondria of cells and primarily involved cellular response and metabolic signaling pathway. Immune factors may interact with HTRA2 in GC, and HTRA2 was found noticeably linked with immunosuppressor such as CD274, IDO1, and TIGIT. CONCLUSION: One plasma HTRA2 can be an emerging diagnosis-related biomarker to achieve GC detecting process, but the particular regulatory effect still needs to be further explored.

Inhibition of LONP1 protects against erastin-induced ferroptosis in Pancreatic ductal adenocarcinoma PANC1 cells.

Ferroptosis is identified as a regulated cell death mediated by iron accumulation and lipid peroxidation. The disturbances of mitochondrial morphology and function have been shown in this process. Mitochondrial Lon peptidase 1 (LONP1) is one of the main multi-function enzymes in regulating the mitochondrial function and cytological stability. To evaluate whether LONP1 take a role in ferroptosis, we applied erastin to initiate the ferroptosis in human pancreatic ductal adenocarcinoma (PDAC) cells. Here we show that erastin triggers cell death in both of oncogenic RAS mutant PANC1 cells and wild KRAS BxPC3 cells and the expression of LONP1 was up-regulated in this process. Gene inhibition of LONP1 only negatively regulates erastin-induced cell death and the alterations of molecular indicators in PANC1 cells. Furthermore, we show that inhibition of LONP1 activates the Nrf2/Keap1 signal pathway and up-regulates the expression of GPX4, a key peroxidase in regulating ferroptosis. Together, our results uncover a previously unappreciated mechanism coupling LONP1 to ferroptosis.

APLNR is involved in ATRA-induced growth inhibition of nasopharyngeal carcinoma and may suppress EMT through PI3K-Akt-mTOR signaling.

The apelin receptor (APLNR) is a GPCR involved in many pathophysiological processes; however, the correlation between APLNR expression and nasopharyngeal carcinoma (NPC) has not been reported. In this study, we used cDNA microarray data to determine APLNR expression levels in NPC tissues. We found that APLNR expression was reduced in NPC tissues compared with noncancerous nasopharyngeal epithelial tissues. Subsequently, a large-scale sample of 1015 tissues was used to validate this discovery and explore the relationship between APLNR expression and prognosis of NPC. Expression levels of APLNR in NPC tissues were indeed down-regulated. Furthermore, positive expression of APLNR in NPC predicted a better prognosis (disease-free survival: P = 0.001; overall survival: P < 0.001). Moreover, ingenuity pathway analysis revealed that an indirect interaction existed between APLNR and retinoic acid (RA) in the cancer regulatory network. Consistently, after treatment with all-trans-RA (ATRA), we found that APLNR was significantly up-regulated in NPC cell lines (5-8F and HNE1), and proliferation of NPC cells was inhibited. Cell cycle arrest occurred in the G0/G1 phase. In contrast, knockdown of APLNR diminished ATRA-induced growth inhibition of NPC cells. In addition, we surprisingly found that APLNR also played an important role in migration and invasion of NPC. Wound-healing and Transwell assays revealed that APLNR overexpression led to reduced migratory and invasive properties in 2 NPC cell lines. Western blot results revealed that hallmarks of epithelial-mesenchymal transition (EMT) were altered as well, suggesting that APLNR was capable of inhibiting EMT in NPC cells. Our study further demonstrated that low expression of APLNR promoted EMT in NPC cells by activating the PI3K-protein kinase B-mammalian target of rapamycin signaling pathway. Taken together, our data suggest that APLNR could potentially predict prognosis for patients with NPC and inhibit proliferation, migration, invasion, and EMT in nasopharyngeal cancer cells.-Liu, Y., Liu, Q., Chen, S., Liu, Y., Huang, Y., Chen, P., Li, X., Gao, G., Xu, K., Fan, S., Zeng, Z., Xiong, W., Tan, M., Li, G., Zhang, W. APLNR is involved in ATRA-induced growth inhibition of nasopharyngeal carcinoma and may suppress EMT through PI3K-Akt-mTOR signaling.

Increased Expression of Sema3C Indicates a Poor Prognosis and Is Regulated by miR-142-5p in Glioma.

Sema3C has been reported to promote glioma stem cells self-renewal and glioblastoma growth. However, the prognostic value and the regulatory mechanism for its abnormal expression in glioma remain poorly understood. In the current study, the immunohistochemistry results demonstrated that Sema3C was overexpressed in 169 of 216 (78.2%) interpretable glioma patients compared with 3 of 15 (20.0%) interpretable non-neoplastic brain cases (p = 0.0001). Sema3C overexpression was significantly associated with histologic type (p = 0.008), high Ki67 labeling index (p = 0.02), tumor grade (p = 0.002) and wild type IDH1 (p = 0.0001). Importantly, its overexpression predicts the shorter overall survival of glioma patients (p = 0.0017), especially the ones with high grade (p = 0.0124). Functionally, Sema3C silencing significantly reduced the proliferation and invasion of glioma cells, indicating an oncogenic role of Sema3C in glioma in vitro. To elucidate the reason accounting for its overexpression, it is identified miR-142-5p as a tumor suppressor that directly targets Sema3C in glioma cells. miR-142-5p and Sema3C were co-regulators of epithelial-mesenchymal transition. Clinically, miR-142-5p expression was conversely related with Sema3C expression in glioma samples. Together, we identified that Sema3C could promote the progression of glioma and its expression was negatively regulated by miR-142-5p in vitro. Thus, the miR-142-5p-Sema3C axis plays importantly in glioma and holds potential to be therapeutic targets as well.

Study on amniotic fluid metabolism in the second trimester of Trisomy 21.

BACKGROUND: Trisomy 21 is a common aneuploid condition in humans and accounts for approximately one quarter of all aneuploid live births. To date, early diagnosis of Trisomy 21 remains a challenging task. Metabolomics may prove an innovative tool to study the early pathophysiology of Trisomy 21 at a functional level. METHODS: Ultra-performance liquid chromatography coupled with mass spectrometer (UPLC-MS) was used for untargeted metabolomic analysis of amniotic fluid samples from women having normal and trisomy 21 fetuses. RESULTS: Many significantly changed metabolites were identified between amniotic fluid samples from Trisomy 21 pregnancies and normal euploid pregnancies, such as generally lower levels of several steroid hormones and their derivatives, higher levels of glutathione catabolites coupled with lower levels of gamma-glutamyl amino acids, and increased levels of phospholipid catabolites, sugars, and dicarboxylic acids. The identification of a human milk oligosaccharide in amniotic fluid may worth further investigation, since confirmation of this observation may have significant implications for regulation of fetal development. CONCLUSIONS: The metabolisms in amniotic fluid from Trisomy 21 and normal pregnancies are quite different, and some of the significantly changed metabolites may be considered as candidates of early diagnostic biomarkers for Trisomy 21.

Upregulation of cyclin D1 can act as an independent prognostic marker for longer survival time in human nasopharyngeal carcinoma.

BACKGROUND: Cyclin D1 is an essential part of oncogenic transformation. We previously proved that cyclin D1 was upregulated in nasopharyngeal carcinoma (NPC) and promoted the NPC cell proliferation. But the association between cyclin D1 and the clinical outcome of NPC has not yet been determined. The study explores the possible relevance between the cyclin D1 expression and clinical parameters and its predictive value of prognosis in NPC patients. METHODS: We analyzed the clinical data from 379 NPC patients and 112 non-NPC patients in our previous study, which made further statistics. Receiver operating curve (ROC) was applied to select the optimal cutoff points. By analyzing the clinical data from 101 NPC patients using Chi-squared test, we estimated the relationship between the cyclin D1 expression level and clinicopathological parameters. We also used Kaplan-Meier method and log-rank test assess and compared the disease-free survival (DFS) rate and overall survival (OS) rate. The Cox proportional hazards model was adopted to perform the univariate and multivariate analyses. RESULT: Receiver operating curve analysis reported that cyclin D1 was used to differentiate between NPC patients and non-NPC patients (P < .001, sensitivity: 53.6%, specificity: 85.7%, AUC = 0.752). Cyclin D1 was positively correlated with lymph node metastasis (P = .015). A survival analysis of the 101 NPC patients indicated that the positive expression of cyclin D1 was predictive of a good prognosis (DFS: P = .010, OS: P = .019). Multivariate analysis showed that cyclin D1 could be used independently to predict NPC patients' prognosis (DFS: P = .038). CONCLUSION: The overexpression of cyclin D1 is a good prognostic marker for NPC.

TSC22D2 identified as a candidate susceptibility gene of multi-cancer pedigree using genome-wide linkage analysis and whole-exome sequencing.

Cancer is a complex disease, which may involve multiple tumor susceptibility genes that mediate the occurrence and development of tumor molecular events. This study aimed to identify new genetic loci using genome-wide linkage analysis and whole-exome sequencing in a rare, large multi-cancer pedigree recently found in China. We performed high-throughput single-nucleotide polymorphism (SNP) array and linkage analyses of 24 core members of this pedigree and found that the disease susceptibility locus in the multi-cancer pedigree was mapped to chromosome 3q24-26. We also used microsatellites to further validate the results of the SNP locus linkage analysis. Furthermore, we sequenced the whole exome of three members in this pedigree and identified a novel mutant of transforming growth factor ß stimulated clone 22 domain family, member 2 (TSC22D2, c.-91T-C) cosegregated with the cancer phenotype. This change was at a highly conserved position, and the exome results were validated using linkage analysis. Moreover, we found the histone H4 transcription factor (HINFP) binds to the promoter region of TSC22D2 and may regulate its transcription. In conclusion, our findings are of great significance to the early pathogenesis of tumors and contribute to the search for molecular targets for the early prevention and treatment of tumors.