Androgen-deprivation therapy-induced aggressive prostate cancer with neuroendocrine differentiation

Most prostate cancers （PCas） are classified as acinar type （conventional） adenocarcinoma which are composed of tumor cells with luminal differentiation including the expression of androgen receptor （AR） and prostate-specific antigen （PSA）. There are also scattered neuroendocrine （NE） cells in every case of adenocarcinoma. The NE cells are quiesecent, do not express AR or PSA, and their function remains unclear. We have demonstrated that IL8-CXCR2-P53 pathway provides a growth-inhibitory signal and keeps the NE cells in benign prostate and adenocarcinoma quiescent. Interestingly, some patients with a history of adenocarcinoma recur with small cell neuroendocrine carcinoma （SCNC） after hormonal therapy, and such tumors are composed of pure NE cells that are highly proliferative and aggressive, due to P53 mutation and inactivation of the IL8-CXCR2-P53 pathway. The incidence of SCNC will likely increase due to the widespread use of novel drugs that further inhibit AR function or intratumoral androgen synthesis. A phase II trial has demonstrated that platinum-based chemotherapy may be useful for such therapy-induced tumors.

Proinflammatory cytokine TNFα promotes HPV-associated oral carcinogenesis by increasing cancer stemness

High-risk human papillomaviruses(HPVs) are involved in the development of several human cancers, including oropharyngeal squamous cell carcinomas. However, many studies have demonstrated that HPV alone is not sufficient for the oncogenic transformation of normal human epithelial cells, indicating that additional cofactors are required for the oncogenic conversion of HPV-infected cells. Inasmuch as chronic inflammation is also closely associated with carcinogenesis, we investigated the effect of chronic exposure to tumor necrosis factor α(TNFα), the major proinflammatory cytokine, on oncogenesis in two immortalized oral keratinocyte cell lines, namely, HPV16-immortalized and human telomerase reverse transcriptase(h TERT)-immortalized cells. TNFαtreatment led to the acquisition of malignant growth properties in HPV16-immortalized cells, such as(1) calcium resistance,(2)anchorage independence, and(3) increased cell proliferation in vivo. Moreover, TNFα increased the cancer stem cell-like population and stemness phenotype in HPV16-immortalized cells. However, such transforming effects were not observed in h TERTimmortalized cells, suggesting an HPV-specific role in TNFα-promoted oncogenesis. We also generated h TERT-immortalized cells that express HPV16 E6 and E7. Chronic TNFα exposure successfully induced the malignant growth and stemness phenotype in the E6-expressing cells but not in the control and E7-expressing cells. We further demonstrated that HPV16 E6 played a key role in TNFα-induced cancer stemness via suppression of the stemness-inhibiting micro RNAs mi R-203 and mi R-200 c. Overexpression of mi R-203 and mi R-200 c suppressed cancer stemness in TNFα-treated HPV16-immortalized cells. Overall, our study suggests that chronic inflammation promotes cancer stemness in HPV-infected cells, thereby promoting HPV-associated oral carcinogenesis.

Neuroendocrine differentiation of prostate cancer

Benign prostate and prostatic adeno- carcinoma contain rare quiescentneuroendocrine cells while small cell neu- roendocrine carcinoma （SCNC）, a variant form of prostate cancer, contains highly proliferative neuroendocrine tumor cells. We provide evidence that IL-8-CXCR2- P53 pathway keeps the NE cells in a quiescent state normally. P53 mutation inactivates this pathway, resulting in hyper-proliferation and aggressive beha- vior of the NE cells in SCNC. Therefore, we have identified potential cells of origin and a molecular target for prostatic SCNC that are different from those of adenocarci- noma, which explains SCNC＇s distinct bio- logy and the clinical observation that it does not respond to hormonal therapy.

Novel genetic loci associated with prostate cancer in the rapanese population

Takata et al.1 recently reported in Nature Genetics that they have identified five novel genetic loci that are associated with prostate cancer in the Japanese population. Using most updated Illumina Quad BeadChip to genotype 3001 prostate cancer patients and 5415 control subjects,

Identification, characterization and targeting of Docetaxel-resistant prostate cancer cells

Men with castration-resistant pro- state cancer exhibit resistance tochemotherapeutic agents such as Docetaxel. Defining the mechanisms of resistance to Docetaxel is critical for treating advanced disease. In a new study, Carlos Cordon-Cardo and colleagues determine that Docetaxel-resistant prostate cancer cells rely on the Notch and Hedgehog signaling pathways for their survival. These findings provide a rationale for the inhibition of Notch and Hedgehog pathways in Docetaxel-resistant prostate cancer.

Periodontitis-induced systemic inflammation exacerbates atherosclerosis partly via endothelial–mesenchymal transition in mice

Growing evidence suggests close associations between periodontitis and atherosclerosis.To further understand the pathological relationships of these associations,we developed periodontitis with ligature placement around maxillary molars or ligature placement in conjunction with Porphyromonas gingivalis lipopolysaccharide injection at the ligature sites (ligature/P.g.LPS) in Apolipoprotein E knock out mice and studied the atherogenesis process in these animals.The mice were fed with high fat diet for 11 weeks and sacrificed for analyzing periodontitis,systemic inflammation,and atherosclerosis.Controls did not develop periodontitis or systemic inflammation and had minimal lipid deposition in the aortas,but mice receiving ligature or ligature/P.g.LPS showed severe periodontitis,systemic inflammation,and aortic plaque formation.The aortic plaque contained abundant macrophages and cells expressing both endothelial and mesenchymal cell markers.The severity of periodontitis was slightly higher in mice receiving ligature/P.g.LPS than ligature alone,and the magnitude of systemic inflammation and aortic plaque formation were also notably greater in the mice with ligature/P.g.LPS.These observations indicate that the development of atherosclerosis is due to systemic inflammation caused by severe periodontitis.In vitro,P.g.LPS enhanced the secretion of pro-inflammatory cytokines from macrophages and increased the adhesion of monocytes to endothelial cells by upregulating the expression of adhesion molecules from endothelial cells.Moreover,secretory proteins,such as TNF-α,from macrophages induced endothelial–mesenchymal transitions of the endothelial cells.Taken together,systemic inflammation induced by severe periodontitis might exacerbate atherosclerosis via,in part,causing aberrant functions of vascular endothelial cells and the activation of macrophages in mice.

Tumor microenvironment and immune evasion in head and neck squamous cell carcinoma

Head and neck squamous cell carcinoma(HNSCC),an aggressive malignancy,is characterized by high morbidity and low survival rates with limited therapeutic options outside of regional surgery,conventional cytotoxic chemotherapy,and irradiation.Increasing studies have supported the synergistic role of the tumor microenvironment(TME)in cancer advancement.The immune system,in particular,plays a key role in surveillance against the initiation,development,and progression of HNSCC.The understanding of how neoplastic cells evolve and evade the immune system whether through self-immunogenicity manipulation,or expression of immunosuppressive mediators,provides the foundation for the development of advanced therapies.Furthermore,the crosstalk between cancer cells and the host immune system have a detrimental effect on the TME promoting angiogenesis,proliferation,and metastasis.This review provides a recent insight into the role of the key inflammatory cells infiltrating the TME,with a focus on reviewing immunological principles related to HNSCC,as cancer immunosurveillance and immune escape,including a brief overview of current immunotherapeutic strategies and ongoing clinical trials.

From bulk, single-cell to spatial RNA sequencing

RNA sequencing(RNAseq)can reveal gene fusions,splicing variants,mutations/indels in addition to differential gene expression,thus providing a more complete genetic picture than DNA sequencing.This most widely used technology in genomics tool box has evolved from classic bulk RNA sequencing(RNAseq),popular single cell RNA sequencing(scRNAseq)to newly emerged spatial RNA sequencing(spRNAseq).Bulk RNAseq studies average global gene expression,scRNAseq investigates single cell RNA biology up to 20,000 individual cells simultaneously,while spRNAseq has ability to dissect RNA activities spatially,representing next generation of RNA sequencing.This article highlights these technologies,characteristic features and suitable applications in precision oncology.

Chaperones in hepatitis C virus infection

The hepatitis C virus(HCV) infects approximately 3% of the world population or more than 185 million people worldwide. Each year, an estimated 350000-500000 deaths occur worldwide due to HCV-associated diseases including cirrhosis and hepatocellular carcinoma. HCV is the most common indication for liver transplantation in patients with cirrhosis worldwide. HCV is an enveloped RNA virus classified in the genus Hepacivirus in the Flaviviridae family. The HCV viral life cycle in a cell can be divided into six phases:(1) binding and internalization;(2) cytoplasmic release and uncoating;(3) viral polyprotein translation and processing;(4) RNA genome replication;(5) encapsidation(packaging) and assembly; and(6) virus morphogenesis(maturation) and secretion. Many host factors are involved in the HCV life cycle. Chaperones are an important group of host cytoprotective molecules that coordinate numerous cellular processes including protein folding, multimeric protein assembly, protein trafficking, and protein degradation. All phases of the viral life cycle require chaperone activity and the interaction of viral proteins with chaperones. This review will present our current knowledge and understanding of the role of chaperones in the HCV life cycle. Analysis of chaperones in HCV infection will provide further insights into viral/host interactions and potential therapeutic targets for both HCV and other viruses.

关注和跟踪表观遗传研究在眼科疾病诊治中的应用

不涉及修改基因编码序列的、可遗传的基因表达变化称为表观遗传改变,眼科表观遗传学是当前生物医学研究的热点之一.表观遗传机制主要包括DNA甲基化、组蛋白修饰、染色质重排及非编码RNA.异常的DNA甲基化和组蛋白修饰与许多年龄相关性疾病密切关联,如癌症、自身免疫性疾病和其他疾病.近年来,表观遗传对眼科疾病发生和发展的调控机制及其在治疗中的作用日益引起研究者的关注,不仅加深了人们对相关眼病发病机制的理解,而且由于表观遗传性改变是可逆的,因此对与相关眼病有关的基因标志进行修饰也为这些疾病的预防、早期诊断和治疗提供了新的思路.我们讨论眼科表观遗传学的机制及表观遗传改变在眼病发生和发展过程中的作用,希望眼科研究人员重视基因表达改变与环境因素的相互作用及其对眼部发育和眼部疾病发病过程的影响,更重要的是应将这些研究成果更好地用于眼科疾病的预防和治疗.

Metabolic syndrome does not affect sustained virologic response of direct-acting antivirals while hepatitis C clearance improves hemoglobin A1c

AIM To determine whether successful treatment with direc-tacting antivirals(DAA) is associated with improvements in hemoglobin A1 c(HbA1 c) and if type 2 diabetes mellitus(T2 DM) or metabolic syndrome affects sustained virologic response(SVR).METHODS We performed a retrospective analysis of all hepatitis C virus(HCV) patients at the VA Greater Los Angeles Healthcare System treated with varying DAA therapy between 2014-2016. Separate multivariable logistic regression was performed to determine predictors of HbA1 c decrease ≥ 0.5 after DAA treatment and predictors of SVR 12-wk post treatment(SVR12).RESULTS A total of 1068 patients were treated with DAA therapy between 2014-2016. The presence of T2 DM or metabolic syndrome did not adversely affect SVR12. 106 patients had both HCV and T2 DM. Within that cohort,patients who achieved SVR12 had lower mean HbA1 c pre treatment(7.35 vs 8.60,P = 0.02),and lower mean HbA1 c post-treatment compared to non-responders(6.55 vs 8.61,P = 0.01). The mean reduction in HbA1 c after treatment was greater for those who achieved SVR12 than for non-responders(0.79 vs 0.01,P = 0.03). In adjusted models,patients that achieved SVR12 were more likely to have a HbA1 c decrease of ≥ 0.5 than those that did not achieve SVR12(adjusted OR = 7.24,95%CI: 1.22-42.94). CONCLUSION In HCV patients with T2 DM,successful treatment with DAA was associated with a significant reduction in HbA1 c suggesting that DAA may have a role in improving insulin sensitivity. Furthermore,the presence of T2 DM or metabolic syndrome does not adversely affect SVR12 rates in patients treated with DAA.

Growth differentiation factor 6,a repressive target of EZH2,promotes the commitment of human embryonic stem cells to mesenchymal stem cells

Mesenchymal stem cells(MSCs)derived from human embryonic stem cells(hESCs)have significant potential for cell-mediated bone regeneration.Our recent study revealed that inhibiting the epigenetic regulator EZH2 plays a key role in promoting the mesodermal differentiation of hESCs.In this study,an epigenome-wide analysis of hESCs and MSCs revealed that growth differentiation factor 6(GDF6),which is involved in bone formation,was the most upregulated gene associated with MSCs compared to hESCs.Furthermore,we identified GDF6 as a repressive target of EZH2 and found that ectopic GDF6 selectively promoted hESC differentiation towards the mesodermal lineage and enriched the MSC population.Our results provide molecular insights governing the mesenchymal commitment of hESCs and identify an inducing factor that offers strong promise for the future of regenerative medicine.

Racial/ethnic disparities in hepatocellular carcinoma treatment and survival in California, 1988-2012

AIM To describe racial/ethnic differences in treatment and survival among liver cancer patients in a populationbased cancer registry.METHODS Invasive cases of primary hepatocellular carcinoma, n = 33270, diagnosed between January 1, 1988-December 31, 2012 and reported to the California Cancer Registry were analyzed by race/ethnicity, age, gender, geographical region, socio-economic status, time period of diagnosis, stage, surgical treatment, and survival. Patients were classified into 15 racial/ethnic groups: non-Hispanic White(White, n = 12710), Hispanic(n = 8500), Chinese(n = 2723), non-Hispanic Black(Black, n = 2609), Vietnamese(n = 2063), Filipino(n = 1479), Korean(n = 1099), Japanese(n = 658), American Indian/Alaskan Native(AIAN, n = 281), Laotian/Hmong (n = 244), Cambodian(n = 233), South Asian(n = 190), Hawai`ian/Pacific Islander(n = 172), Thai(n = 95), and Other Asian(n = 214). The main outcome measures were receipt of surgical treatment, and cause-specific and all-cause mortality.RESULTS After adjustment for socio-demographic characteristics, time period, and stage of disease, compared to Whites, Laotian/Hmong [odds ratio(OR) = 0.30, 95%CI: 0.17-0.53], Cambodian(OR = 0.65, 95%CI: 0.45-0.96), AIAN(OR = 0.66, 95%CI: 0.46-0.93), Black(OR = 0.76, 95%CI: 0.67-0.86), and Hispanic(OR = 0.78, 95%CI: 0.72-0.84) patients were less likely, whereas Chinese(OR = 1.58, 95%CI: 1.42-1.77), Koreans(OR = 1.45, 95%CI: 1.24-1.70), Japanese(OR = 1.41, 95%CI: 1.15-1.72), and Vietnamese(OR = 1.26, 95%CI: 1.12-1.42) were more likely to receive surgical treatment. After adjustment for the same covariates and treatment, cause-specific mortality was higher for Laotian/Hmong [(hazard ratio(HR) = 1.50, 95%CI: 1.29-1.73)], Cambodians(HR = 1.35, 95%CI: 1.16-1.58), and Blacks(HR = 1.07, 95%CI: 1.01-1.13), and lower for Chinese(HR = 0.82, 95%CI: 0.77-0.86), Filipinos(HR = 0.84, 95%CI: 0.78-0.90), Vietnamese(HR = 0.85, 95%CI: 0.80-0.90), Koreans(HR = 0.90, 95%CI: 0.83-0.97), and Hispanics(HR = 0.91, 95%CI: 0.88-0.94); results were similar for all-cause mortality.CONCLUSION Disaggregated data revealed substantial racial/ethnic differences in liver cancer treatment and survival, demonstrating the need for development of targeted interventions to mitigate disparities.

Indigenous microbiota protects development of medication-related osteonecrosis induced by periapical disease in mice

Bacterial infection is a common finding in patients,who develop medication-related osteonecrosis of the jaw(MRONJ)by the longterm and/or high-dose use of anti-resorptive agents such as bisphosphonate(BPs).However,pathological role of bacteria in MRONJ development at the early stage remains controversial.Here,we demonstrated that commensal microbiota protects against MRONJ development in the pulp-exposed periapical periodontitis mouse model.C57/BL6 female mice were treated with intragastric broadspectrum antibiotics for 1 week.Zoledronic acid(ZOL)through intravenous injection and antibiotics in drinking water were administered for throughout the experiment.Pulp was exposed on the left maxillary first molar,then the mice were left for 5 weeks after which bilateral maxillary first molar was extracted and mice were left for additional 3 weeks to heal.All mice were harvested,and cecum,maxilla,and femurs were collected.ONJ development was assessed usingμCT and histologic analyses.When antibiotic was treated in mice,these mice had no weight changes,but developed significantly enlarged ceca compared to the control group(CTL mice).Periapical bone resorption prior to the tooth extraction was similarly prevented when treated with antibiotics,which was confirmed by decreased osteoclasts and inflammation.ZOL treatment with pulp exposure significantly increased bone necrosis as determined by empty lacunae and necrotic bone amount.Furthermore,antibiotics treatment could further exacerbate bone necrosis,with increased osteoclast number.Our findings suggest that the commensal microbiome may play protective role,rather than pathological role,in the early stages of MRONJ development.

Loss of KDM4B impairs osteogenic differentiation of OMSCs and promotes oral bone aging

Aging of craniofacial skeleton significantly impairs the repair and regeneration of trauma-induced bony defects,and complicates dental treatment outcomes.Age-related alveolar bone loss could be attributed to decreased progenitor pool through senescence,imbalance in bone metabolism and bone-fat ratio.Mesenchymal stem cells isolated from oral bones(OMSCs)have distinct lineage propensities and characteristics compared to MSCs from long bones,and are more suited for craniofacial regeneration.However,the effect of epigenetic modifications regulating OMSC differentiation and senescence in aging has not yet been investigated.In this study,we found that the histone demethylase KDM4B plays an essential role in regulating the osteogenesis of OMSCs and oral bone aging.Loss of KDM4B in OMSCs leads to inhibition of osteogenesis.Moreover,KDM4B loss promoted adipogenesis and OMSC senescence which further impairs bone-fat balance in the mandible.Together,our data suggest that KDM4B may underpin the molecular mechanisms of OMSC fate determination and alveolar bone homeostasis in skeletal aging,and present as a promising therapeutic target for addressing craniofacial skeletal defects associated with age-related deteriorations.

Risk factors for liver disease among adults of Mexican descent in the United States and Mexico

AIM To compare the prevalence of chronic liver disease(CLD) risk factors in a representative sample of MexicanAmericans born in the United States(US) or Mexico, to a sample of adults in Mexico.METHODS Data for Mexican-Americans in the US were obtained from the 1999-2014 National Health and Nutrition Examination Survey(NHANES), which includes persons of Mexican origin living in the US(n = 4274). The NHANES sample was restricted to Mexican-American participants who were 20 years and older, born in the US or Mexico, not pregnant or breastfeeding, and with medical insurance.The data in Mexico were obtained from the 2004-2013 Health Worker Cohort Study in Cuernavaca, Mexico(n =9485). The following known risk factors for liver disease/cancer were evaluated: elevated aminotransferase levels(elevated alanine aminotransferase was defined as > 40 IU/L for males and females; elevated aspartate aminotransferase was defined as > 40 IU/L for males and females), infection with hepatitis B or hepatitis C,metabolic syndrome, high total cholesterol, diabetes,obesity, abdominal obesity, and heavy alcohol use. The main independent variables for this study classified individuals by country of residence(i.e., Mexico vs the US) and place of birth(i.e., US-born vs Mexico-born).Regression analyses were used to investigate CLD risk factors.RESULTS After adjusting for socio-demographic characteristics,Mexican-American males were more likely to be obese,diabetic, heavy/binge drinkers or have abdominal obesity than males in Mexico. The adjusted multivariate results for females also indicate that Mexican-American females were significantly more likely to be obese, diabetic, be heavy/binge drinkers or have abdominal obesity than Mexican females. The prevalence ratios and prevalence differences mirror the multivariate analysis findings for the aforementioned risk factors, showing a greater risk among US-born as compared to Mexico-born MexicanAmericans. CONCLUSION In this study, Mexican-Americans in the US had more risk factors for CLD than their counterparts in Mexico.These findings can be used to design and implement more effective health promotion policies and programs to address the specific factors that put Mexicans at higher risk of developing CLD in both countries.

间变性淋巴瘤激酶通路标签与乳腺癌细胞去分化、新辅助化疗反应及复发风险的相关性

背景与目的间变性淋巴瘤激酶(anaplastic lymphoma kinase,ALK)信号通路的异常激活参与了多种癌症的发生。本研究的目的是确定这一信号通路在乳腺癌发病中的作用。方法从42个芯片数据集共6381例乳腺癌样本中提取了ALK通路标签的数据并计算了ALK通路的活性,用logistic回归和生存分析检验了ALK通路标签的评分与临床因素之间的相关性。结果我们的结果表明,在这42个数据集中,高ALK通路活性是激素受体阴性、高级别乳腺癌的显著危险因素。注释了患者新辅助化疗反应信息的15个数据集的分析结果表明,ALK通路活性与病理完全缓解(pathological complete response,pCR)呈正相关(总OR=1.67,P<0.01),这种相关性在HER2阴性和1&2级乳腺癌中比HER2阳性和3级乳腺癌患者中更显著。注释了生存信息的30个数据集的分析结果表明,ALK通路活性与乳腺癌患者复发风险呈正相关(总HR=1.21,P<0.01),在年龄>50岁、淋巴结阳性或新辅助化疗后有残存病灶的患者中尤其显著。结论ALK可参与乳腺癌的发生,ALK通路标签评分可作为乳腺癌的预后生物标志物。

Fasting times in serum PSA assay

Prostate-specific antigen （PSA） test for prostate cancer is the only serum-based cancer screening test that is widely accepted. A large number of PSA tests are done in developed countries such as the United States due to the recommendation that men be screened annually starting at age 50. With the rapid economic development and increased access to healthcare, countries like China have also experienced a dramatic increase in the utilization of P SA test. This trend is unlikely to change significantly despite the recent recommendation against routine PSA screening by the US Preventive Health Task force.

代谢组学研究癌症代谢机制、纳米毒性和疾病标志物的开发

代谢组学是指对生物系统中特定类型的细胞、组织、器官、体液中存在的小分子代谢物进行系统的分析和研究。由于代谢分子与生物表型密切相关,因此代谢组学在生物医学方面有很多应用,例如发现临床上实用的疾病标志物、鉴定用于治疗的代谢酶靶向分子、探讨疾病中的代谢机制、确定基因功能以及代谢表型。在这篇综述文章中,我总结了我们在使用代谢组学研究癌症代谢、纳米毒性和生物标志物开发方面的最新进展。

Steimann Pin Repair of Zygomatic Complex Fractures

Purpose: To present the treatment of zygomaticomaxillary complex (ZMC) fractures with closed-reduction Steinmann-pin fixation and to compare it to the reduction and aesthetic outcomes of open-reduction techniques (ORIF). Materials and Methods: Case series. Charts for 23 patients with ZMC fractures presenting to the Head and Neck Surgery Department at Harbor-UCLA Medical Center from 2005 to 2009 were reviewed. Pre- and post-operative computed tomography (CT) scans were analyzed. Follow up ranged from 3 to 55 months. Interviews were conducted to evaluate the patient’s satisfaction. Patients were placed in two groups: those treated with ORIF and those treated with closed-reduction Steinmann-pin fixation. Results: Twelve patients had complete data for analysis. Average operative time was significantly lower for patients treated with closed-reduction as compared to open-reduction: 65.3 minutes vs. 162.5 minutes (p = 0.02). Bony realignment and aesthetic results were comparable in both groups. Additionally, only one 1cm facial incision was required with this repair system versus several incisions using traditional methods. Conclusions: Closed-reduction Steinmann-pin fixation of ZMC fractures provides adequate bony alignment and aesthetics. Our study supports this system in the repair of ZMC fractures as it requires significantly less operating time, one small incision, and excellent patient outcomes.