Drug Resistance in Hepatocellular Carcinoma: Theoretical Basis and Therapeutic Aspects.

Primary liver cancer is one of the most common malignant tumors with high mortality and increasing incidence worldwide. Currently, chemotherapy is an important comprehensive treatment for moderate or advanced liver cancer. Despite the effective therapeutic effects initially achieved by chemotherapy, the high phenotypic and molecular heterogeneity of liver cancer cells facilitates resistance to conventional chemotherapy or targeted therapy and even leads to multidrug resistance (MDR), which is one of the major obstacles for clinical chemotherapy. Drug resistance exhibits multiple and complex molecular mechanisms to antagonize therapy under pharmacological pressure, including overexpression of drug efflux transporters, downstream adaptive response (such as apoptosis, autophagy, and endoplasmic reticulum stress), dysfunction of DNA damage repair (DDR), epigenetic modification, tumor microenvironment (TME) as well as extracellular matrix (ECM). In this paper, we summarize the recent research progress and intervention strategies for drug resistance in hepatocellular carcinoma (HCC), which will provide a promising therapeutic strategy for overcoming MDR in liver cancer.

NAMPT promotes the malignant progression of HBV-associated hepatocellular carcinoma through activation of SREBP1-mediated lipogenesis.

Metabolic reprogramming is a hallmark of cancer. The nicotinamide phosphoribosyltransferase (NAMPT)-mediated salvage pathway maintains sufficient cellular NAD levels and is required for tumorigenesis and development. However, the molecular mechanism by which NAMPT contributes to HBV-associated hepatocellular carcinoma (HCC) remains not fully understood. In the present study, our results showed that NAMPT protein was obviously upregulated in HBV-positive HCC tissues compared with HBV-negative HCC tissues. NAMPT was positively associated with aggressive HCC phenotypes and poor prognosis in HBV-positive HCC patients. NAMPT overexpression strengthened the proliferative, migratory, and invasive capacities of HBV-associated HCC cells, while NAMPT-insufficient HCC cells exhibited decreased growth and mobility. Mechanistically, we demonstrated that NAMPT activated SREBP1 (sterol regulatory element-binding protein 1) by increasing the expression and nuclear translocation of SREBP1, leading to the transcription of SREBP1 downstream lipogenesis-related genes and the production of intracellular lipids and cholesterol. Altogether, our data uncovered an important molecular mechanism by which NAMPT promoted HBV-induced HCC progression through the activation of SREBP1-triggered lipid metabolism reprogramming and suggested NAMPT as a promising prognostic biomarker and therapeutic target for HBV-associated HCC patients.

Roles of entrapped bubbles in methanogenic granules under oscillating pressure: Respiration and embolization for intra-granular transport.

Anaerobic granular sludge plays a pivotal role in the treatment of concentrated organic wastewater. However, previous studies on intra- granular transport have generally overlooked lung-like respiration that expedites transport in response to fluctuating pressure. This study explored the activities of calcified and normal granules under simulated hydrostatic pressure oscillations. The results revealed a significant enhancement in the bioactivity of calcified granules under oscillating pressure, contrasting with the comparatively lower bioactivity observed in normal granules. The hypothesis posited that the gas pockets in calcified granules facilitated respiration as the functional structure. The presence of tiny bubbles exhibited a propensity for inducing clogging, thereby diminishing the capillary connectivity essential for substrate diffusion. The proposed respiration and embolization concepts decipher the distinct roles of entrapped bubbles in the granular bioactivity across diverse fluid states. This study offers valuable insights into the impact of fluidization on microscopic transport within granule-based bed reactors.

The expression of CD86 in CD3+CD56+ NKT cells is associated with the occurrence and prognosis of sepsis-associated encephalopathy in sepsis patients: a prospective observational cohort study.

The role of CD3+CD56+ natural killer T (NKT) cells and its co-signaling molecules in patients with sepsis-associated encephalopathy (SAE) is unknown. In this prospective observational cohort study, we initially recruited 260 septic patients and eventually analyzed 90 patients, of whom 57 were in the SAE group and 37 were in the non-SAE group. Compared to the non-SAE group, 28-day mortality was significantly increased in the SAE group (33.3% vs. 12.1%, p = 0.026), while the mean fluorescence intensity (MFI) of CD86 in CD3+CD56+ NKT cells was significantly lower (2065.8 (1625.5 ~ 3198.8) vs. 3117.8 (2278.1 ~ 5349), p = 0.007). Multivariate analysis showed that MFI of CD86 in NKT cells, APACHE II score, and serum albumin were independent risk factors for SAE. Furthermore, the Kaplan-Meier survival analysis indicated that the mortality rate was significantly higher in the high-risk group than in the low-risk group (χ2 = 14.779, p < 0.001). This study showed that the decreased expression of CD86 in CD3+CD56+ NKT cells is an independent risk factor of SAE; thus, a prediction model including MFI of CD86 in NKT cells, APACHE II score, and serum albumin can be constructed for diagnosing SAE and predicting prognosis.

Current therapy and drug resistance in metastatic castration-resistant prostate cancer.

Castration-resistant prostate cancer (CRPC), especially metastatic castration-resistant prostate cancer (mCRPC) is one of the most prevalent malignancies and main cause of cancer-related death among men in the world. In addition, it is very difficult for clinical treatment because of the natural or acquired drug resistance of CRPC. Mechanisms of drug resistance are extremely complicated and how to overcome it remains an urgent clinical problem to be solved. Thus, a comprehensive and thorough understanding for mechanisms of drug resistance in mCRPC is indispensable to develop novel and better therapeutic strategies. In this review, we aim to review new insight of the treatment of mCRPC and elucidate mechanisms governing resistance to new drugs: taxanes, androgen receptor signaling inhibitors (ARSIs) and poly (ADP-ribose) polymerase (PARP) inhibitors (PARPi). Most importantly, in order to improve efficacy of these drugs, strategies of overcoming drug resistance are also discussed based on their mechanisms respectively.

CircSMARCC1 facilitates tumor progression by disrupting the crosstalk between prostate cancer cells and tumor-associated macrophages via miR-1322/CCL20/CCR6 signaling.

BACKGROUND: Circular RNAs (circRNAs) mediate the infiltration of tumor-associated macrophages (TAMs) to facilitate carcinogenesis and development of various types of cancers. However, the role of circRNAs in regulating macrophages in prostate cancer (PCa) remains uncertain. METHODS: Differentially expressed circRNAs in PCa were identified by RNA sequencing. The expression of circSMARCC1 was recognized and evaluated using fluorescence in situ hybridization and quantitative real-time PCR. The oncogenic role of circSMARCC1 in PCa tumor proliferation and metastasis was investigated through a series of in vitro and in vivo assays. Finally, Western blot, biotin-labeled RNA pulldown, luciferase assay, rescue experiments, and co-culture experiments with TAMs were conducted to reveal the mechanistic role of circSMARCC1. RESULTS: CircSMARCC1 was dramatically up-regulated in PCa cells, plasma and tissues. Overexpression of circSMARCC1 promotes tumor proliferation and metastasis both in vitro and in vivo, whereas knockdown of circSMARCC1 exerts the opposite effects. Mechanistically, circSMARCC1 regulates the expression of CC-chemokine ligand 20 (CCL20) via sponging miR-1322 and activate PI3K-Akt signaling pathway involved in the proliferation and epithelial mesenchymal transformation. More importantly, high expression of circSMARCC1 was positively associated with colonization of CD68+/CD163+/CD206+ TAMs in tumor microenvironment. In addition, overexpression of circSMARCC1 facilitates the expression of CD163 in macrophages through the CCL20-CCR6 axis, induces TAMs infiltration and M2 polarization, thereby leading to PCa progression. CONCLUSIONS: CircSMARCC1 up-regulates the chemokine CCL20 secretion by sponging miR-1322, which is involved in the crosstalk between tumor cells and TAMs by targeting CCL20/CCR6 signaling to promote progression of PCa.

Identification of UAP1L1 as a critical factor for prostate cancer and underlying molecular mechanism in tumorigenicity.

BACKGROUND: Prostate cancer is the second most common cancer in men, and some new target genes are needed to predict the risk of prostate cancer progression and the treatment. METHODS: In this study, the effects of UAP1L1 (UAP1-like-1) on prostate cancer were investigated by detecting the proliferation, migration, invasion and apoptosis of prostate cancer cells in vitro using MTT, wound healing, Transwell and flow cytometry assay, and the tumor growth in vivo. The downstream genes and pathways of UAP1L1 were explored using Ingenuity Pathway Analysis (IPA), and screened by qRT-PCR and western blot. The effects of CDCA8 on prostate cancer cells were also verified in vitro, which was through detecting the change of proliferation, migration, invasion and apoptosis of prostate cancer cells after CDCA8 knockdown. RESULTS: The results indicated that UAP1L1 promoted the proliferation, migration and invasion of prostate cancer cells, which was inhibited by downregulating CDCA8. Furthermore, the promotion of CDCA8 knockdown on cell apoptosis was reduced when UAP1L1 was simultaneously overexpressed. CONCLUSIONS: In conclusion, the results in this study revealed that UAP1L1 promoted the progression of prostate cancer through the downstream gene CDCA8.

Hsa_circ_0003258 promotes prostate cancer metastasis by complexing with IGF2BP3 and sponging miR-653-5p.

BACKGROUND: More and more studies have shown that circular RNAs (circRNAs) play a critical regulatory role in many cancers. However, the potential molecular mechanism of circRNAs in prostate cancer (PCa) remains largely unknown. METHODS: Differentially expressed circRNAs were identified by RNA sequencing. The expression of hsa_circ_0003258 was evaluated using quantitative real-time PCR and RNA in situ hybridization. The impacts of hsa_circ_0003258 on the metastasis of PCa cells were investigated by a series of in vitro and in vivo assays. Lastly, the underlying mechanism of hsa_circ_0003258 was revealed by Western blot, biotin-labeled RNA pulldown, RNA immunoprecipitation, luciferase assays and rescue experiments. RESULTS: Increased expression of hsa_circ_0003258 was found in PCa tissues and was associated with advanced TNM stage and ISUP grade. Overexpression of hsa_circ_0003258 promoted PCa cell migration by inducing epithelial mesenchymal transformation (EMT) in vitro as well as tumor metastasis in vivo, while knockdown of hsa_circ_0003258 exerts the opposite effect. Mechanistically, hsa_circ_0003258 could elevate the expression of Rho GTPase activating protein 5 (ARHGAP5) via sponging miR-653-5p. In addition, hsa_circ_0003258 physically binds to insulin like growth factor 2 mRNA binding protein 3 (IGF2BP3) in the cytoplasm and enhanced HDAC4 mRNA stability, in which it activates ERK signalling pathway, then triggers EMT programming and finally accelerates the metastasis of PCa. CONCLUSIONS: Upregulation of hsa_circ_0003258 drives tumor progression through both hsa_circ_0003258/miR-653-5p/ARHGAP5 axis and hsa_circ_0003258/IGF2BP3 /HDAC4 axis. Hsa_circ_0003258 may act as a promising biomarker for metastasis of PCa and an attractive target for PCa intervention.

Biallelic mutations in spermatogenesis and centriole-associated 1 like (SPATC1L) cause acephalic spermatozoa syndrome and male infertility / 亚洲男科学杂志(英文版)

Acephalic spermatozoa syndrome is a rare type of teratozoospermia that severely impairs the reproductive ability of male patients, and genetic defects have been recognized as the main cause of acephalic spermatozoa syndrome. Spermatogenesis and centriole-associated 1 like (SPATC1L) is indispensable for maintaining the integrity of sperm head-to-tail connections in mice, but its roles in human sperm and early embryonic development remain largely unknown. Herein, we conducted whole-exome sequencing (WES) of 22 infertile men with acephalic spermatozoa syndrome. An in silico analysis of the candidate variants was conducted, and WES data analysis was performed using another cohort consisting of 34 patients with acephalic spermatozoa syndrome and 25 control subjects with proven fertility. We identified biallelic mutations in SPATC1L (c.910C>T:p.Arg304Cys and c.994G>T:p.Glu332X) from a patient whose sperm displayed complete acephalia. Both SPATC1L variants are rare and deleterious. SPATC1L is mainly expressed at the head-tail junction of elongating spermatids. Plasmids containing pathogenic variants decreased the level of SPATC1L in vitro. Moreover, none of the patient's four attempts at intracytoplasmic sperm injection (ICSI) resulted in a transplantable embryo, which suggests that SPATC1L defects might affect early embryonic development. In conclusion, this study provides the first identification of SPATC1L as a novel gene for human acephalic spermatozoa syndrome. Furthermore, WES might be applied for patients with acephalic spermatozoa syndrome who exhibit reiterative ICSI failures.

SMARCC1 Suppresses Tumor Progression by Inhibiting the PI3K/AKT Signaling Pathway in Prostate Cancer.

BACKGROUND: SWI/SNF-related, matrix-associated, actin-dependent regulator of chromatin subfamily C member 1 (SMARCC1) protein is a potential tumor suppressor in various cancers. However, its role in prostate cancer (PCa) remains controversial. The aim of this study was to determine the biological function of SMARCC1 in PCa and explore the underlying regulatory mechanisms. METHODS: The expression of SMARCC1 was validated in PCa tissues by immunohistochemistry. Meanwhile, function experiments were used to evaluate the regulatory role on cell proliferation and metastasis in PCa cells with SMARCC1 depletion both in vitro and in vivo. The expression levels of relevant proteins were detected by Western blotting. RESULTS: Our finding showed that SMARCC1 was significantly downregulated in prostate adenocarcinoma, with a higher Gleason score (GS) than that in low GS. The decreased expression of SMARCC1 was significantly correlated with a higher GS and poor prognosis. Additionally, we found that silencing of SMARCC1 dramatically accelerated cell proliferation by promoting cell cycle progression and enhancing cell migration by inducing epithelial mesenchymal transition (EMT). Furthermore, depletion of SMARCC1 facilitated PCa xenograft growth and lung metastasis in murine models. Mechanistically, the loss of SMARCC1 activated the PI3K/AKT pathway in PCa cells. CONCLUSION: SMARCC1 suppresses PCa cell proliferation and metastasis via the PI3K/AKT signaling pathway and is a novel therapeutic target.

The role of androgen therapy in prostate cancer: from testosterone replacement therapy to bipolar androgen therapy.

Testosterone replacement therapy (TRT) is the primary treatment for male testosterone deficiency. This therapy raises concerns over the risk of prostate cancer (PC), because testosterone has historically been considered the fuel for PC. We discuss the re-evaluation of the relationship between androgen and PC, and highlight the safety of TRT in the treatment of symptomatic men with testosterone deficiency who have low-risk disease after treatment for localized PC with surgery or radiation. Furthermore, we review the clinical application and potential mechanisms of bipolar androgen therapy (BAT) in the treatment of castration-resistant PC, emphasizing that much remains to be done before BAT can be broadly applied.

A 14-year multi-institutional collaborative study of Chinese pelvic floor surgical procedures related to pelvic organ prolapse / 中华医学杂志(英文版)

BACKGROUND@#It has been a global trend that increasing complications related to pelvic floor surgeries have been reported over time. The current study aimed to outline the development of Chinese pelvic floor surgeries related to pelvic organ prolapse (POP) over the past 14 years and investigate the potential influence of enhanced monitoring conducted by the Chinese Association of Urogynecology since 2011.@*METHODS@#A total of 44,594 women with POP who underwent pelvic floor surgeries between October 1, 2004 and September 30, 2018 were included from 22 tertiary academic medical centers. The data were reported voluntarily and obtained from a database. We compared the proportion of each procedure in the 7 years before and 7 years after September 30, 2011. The data were analyzed by performing Z test (one-sided).@*RESULTS@#The number of different procedures during October 1, 2011-September 30, 2018 was more than twice that during October 1, 2004-September 30, 2011. Regarding pelvic floor surgeries related to POP, the rate of synthetic mesh procedures increased from 38.1% (5298/13,906) during October 1, 2004-September 30, 2011 to 46.0% (14,107/30,688) during October 1, 2011-September 30, 2018, whereas the rate of non-mesh procedures decreased from 61.9% (8608/13,906) to 54.0% (16,581/30,688) (Z = 15.53, P < 0.001). Regarding synthetic mesh surgeries related to POP, the rates of transvaginal placement of surgical mesh (TVM) procedures decreased from 94.1% (4983/5298) to 82.2% (11,603/14,107) (Z = 20.79, P < 0.001), but the rate of laparoscopic sacrocolpopexy (LSC) procedures increased from 5.9% (315/5298) to 17.8% (2504/14,107).@*CONCLUSIONS@#The rate of synthetic mesh procedures increased while that of non-mesh procedures decreased significantly. The rate of TVM procedures decreased while the rate of LSC procedures increased significantly.@*TRIAL REGISTRATION NUMBER@#NCT03620565, https://register.clinicaltrials.gov.

Study on the structure of eye anterior segment after laser treatment in ROP with Sirius anterior segment analysis system / 国际眼科杂志(Guoji Yanke Zazhi)

@#AIM: To observe the changes of the development of the anterior segment in children after the treatment of laser photocoagulation(LP)for retinopathy of prematurity(ROP)by corneal topographic. <p>METHODS: In this retrospective case study, 25 children(50 eyes)as ROP group and 23 children(46 eyes)born at term as control group had participated in the study. The best corrected visual acuity(BCVA)was examined in both groups, and converted to LogMAR vision when statistical analysis was performed. The observation indicators of the Sirius anterior segment analysis system in the study were as follows: the horizontal iris diameter(HVID), corneal radius of the thinnest point, the thinnest point of the cornea, the maximum curvature of the cornea, the maximum radius of cornea curvature, central corneal thickness(CCT), corneal volume(CV), anterior chamber depth(ACD), anterior chamber volume and the anterior chamber angle.<p>RESULTS: The HVID, the thinnest point of the cornea, ACD, and the anterior chamber volume in ROP group were smaller than that in the control group(all <i>P</i><0.05). The CV and the anterior chamber angle in ROP group were smaller than that in the control group, but there was no significant difference between the two groups(all <i>P</i>>0.05). The BCVA was significantly better in the control group than that in the ROP group(0.07±0.10 <i>vs</i> 0.24±0.25, <i>P</i><0.05). <p>CONCLUSION: The development of eye anterior ganglion tissues of the ROP group had changed with steeper cornea, shallower anterior chamber, smaller angle of the anterior chamber and poor BCVA. All of the changes above might make it easier for the development of refractive errors and glaucoma.

Visible-Light-Induced Regio- and Stereoselective C(sp2)-H Trifluoroethylation of Enamides with 2,2,2-Trifluoroethyl Iodide.

A photoredox-catalyzed regio- and stereoselective trifluoroethylation reaction of enamides using commercially available 2,2,2-trifluoroethyl iodide as trifluoroethylating agents has been developed, furnishing geometrically defined and synthetically and physiochemically pivotal ß-trifluoroethylated enamides bearing a diverse range of functional groups.

Discussion on the effect of comprehensive nursing in endoscopic treatment of esophageal and gastric varicose bleeding / 中国实用护理杂志

Objective@#To explore and analyze the effect of comprehensive nursing care in endoscopic treatment of esophageal and gastric varicose bleeding.@*Methods@#A retrospective analysis of 60 cases of patients with esophageal and gastric varicose hemorrhage admitted to the hospital was conducted. The patients were randomly divided into 30 cases of control group and 30 cases of observation group. Routine nursing and comprehensive nursing were adopted respectively to evaluate different nursing effects.@*Results@#Intraoperative and postoperative heart rate of the observation group (91.0 ± 4.0) times/min, (89.2 ± 4.2) times/min, which were lower than (98.0 ± 4.2) times/min, (94.7 ± 4.5) times/min of the control group. There was statistically significant difference (t values were 6.610, 4.894, P < 0.05). The bleeding prevention effectiveness rate of the observation group (93.33%, 28/30) was higher than the control group (73.33%, 22/30), The difference was statistically significant (χ2 value was 4.32, P < 0.05). The total nursing satisfaction rate (100.00%, 30/30) in the observation group was higher than that in the control group (86.70%, 26/30), the difference was statistically significant (χ2 value was 4.29, P< 0.05). Quality of life, disease cognition, compliance behavior, proper rest, self-protection, General Quality of life Inventory (GQOLI) score in the observation group were (33.5 ± 3.5), (21.5 ± 3.7), (32.5 ± 2.8), (21.5 ± 3.3), (22.0±4.2), (130.2 ± 17.4) points, which were higher than those in the control group (28.2 ± 3.2), (17.5 ± 2.5), (28.5 ± 3.0), (17.2 ± 3.0), (18.0 ± 3.0), and (110.2 ± 15.2) points. The differences were statistically significant (t values were 4.245-6.121, P<0.05).@*Conclusions@#Endoscopic treatment of esophageal and gastric varicose bleeding patients combined with comprehensive nursing intervention, can effectively prevent the occurrence of rebleeding, improve the quality of life of patients. The application effect is significant.

Discussion on the effect of comprehensive nursing in endoscopic treatment of esophageal and gastric varicose bleeding / 中国实用护理杂志

Objective:To explore and analyze the effect of comprehensive nursing care in endoscopic treatment of esophageal and gastric varicose bleeding.Methods:A retrospective analysis of 60 cases of patients with esophageal and gastric varicose hemorrhage admitted to the hospital was conducted. The patients were randomly divided into 30 cases of control group and 30 cases of observation group. Routine nursing and comprehensive nursing were adopted respectively to evaluate different nursing effects.Results:Intraoperative and postoperative heart rate of the observation group (91.0 ± 4.0) times/min, (89.2 ± 4.2) times/min, which were lower than (98.0 ± 4.2) times/min, (94.7 ± 4.5) times/min of the control group. There was statistically significant difference ( t values were 6.610, 4.894, P < 0.05). The bleeding prevention effectiveness rate of the observation group (93.33%, 28/30) was higher than the control group (73.33%, 22/30), The difference was statistically significant ( χ 2 value was 4.32, P < 0.05). The total nursing satisfaction rate (100.00%, 30/30) in the observation group was higher than that in the control group (86.70%, 26/30), the difference was statistically significant ( χ 2 value was 4.29, P< 0.05). Quality of life, disease cognition, compliance behavior, proper rest, self-protection, General Quality of life Inventory (GQOLI) score in the observation group were (33.5 ± 3.5), (21.5 ± 3.7), (32.5 ± 2.8), (21.5 ± 3.3), (22.0±4.2), (130.2 ± 17.4) points, which were higher than those in the control group (28.2 ± 3.2), (17.5 ± 2.5), (28.5 ± 3.0), (17.2 ± 3.0), (18.0 ± 3.0), and (110.2 ± 15.2) points. The differences were statistically significant ( t values were 4.245-6.121, P<0.05). Conclusions:Endoscopic treatment of esophageal and gastric varicose bleeding patients combined with comprehensive nursing intervention, can effectively prevent the occurrence of rebleeding, improve the quality of life of patients. The application effect is significant.

The role of tyrosine phosphatase Shp2 in spermatogonial differentiation and spermatocyte meiosis / 亚洲男科学杂志(英文版)

The transition from spermatogonia to spermatocytes and the initiation of meiosis are key steps in spermatogenesis and are precisely regulated by a plethora of proteins. However, the underlying molecular mechanism remains largely unknown. Here, we report that Src homology domain tyrosine phosphatase 2 (Shp2; encoded by the protein tyrosine phosphatase, nonreceptor type 11 [Ptpn11] gene) is abundant in spermatogonia but markedly decreases in meiotic spermatocytes. Conditional knockout of Shp2 in spermatogonia in mice using stimulated by retinoic acid gene 8 (Stra8)-cre enhanced spermatogonial differentiation and disturbed the meiotic process. Depletion of Shp2 in spermatogonia caused many meiotic spermatocytes to die; moreover, the surviving spermatocytes reached the leptotene stage early at postnatal day 9 (PN9) and the pachytene stage at PN11-13. In preleptotene spermatocytes, Shp2 deletion disrupted the expression of meiotic genes, such as disrupted meiotic cDNA 1 (Dmc1), DNA repair recombinase rad51 (Rad51), and structural maintenance of chromosome 3 (Smc3), and these deficiencies interrupted spermatocyte meiosis. In GC-1 cells cultured in vitro, Shp2 knockdown suppressed the retinoic acid (RA)-induced phosphorylation of extracellular-regulated protein kinase (Erk) and protein kinase B (Akt/PKB) and the expression of target genes such as synaptonemal complex protein 3 (Sycp3) and Dmc1. Together, these data suggest that Shp2 plays a crucial role in spermatogenesis by governing the transition from spermatogonia to spermatocytes and by mediating meiotic progression through regulating gene transcription, thus providing a potential treatment target for male infertility.

The impact of Adult Comorbidity Evaluation-27 on the clinical outcome of elderly nasopharyngeal carcinoma patients treated with chemoradiotherapy or radiotherapy: a matched cohort analysis.

Objectives: To evaluate the prognostic significance of Adult Comorbidity Evaluation-27 (ACE-27) for elderly patients (age ≥70 years) with locoregionally advanced nasopharyngeal carcinoma (NPC) treated with Intensity-Modulated Radiotherapy (IMRT), with or without chemotherapy. Methods: 206 elderly patients with locoregionally advanced NPC treated from December 2006 to December 2016 were involved into analysis as the training cohort. Besides, a separate cohort of 72 patients from the same cancer center collected between January 2003 and October 2006 served as the validation cohort. By using propensity score matching (PSM), we created a balanced cohort by matching patients who received chemoradiotherapy with patients who received IMRT alone. Treatment toxicities were calculated between CRT and RT groups using the χ2 test. The primary endpoint was cancer-specific survival (CSS). Multivariate analysis was performed to assess the relative risk for each factor by using a Cox's proportional hazards regression model. Results: The median follow-up was 39.0 months (range = 3-137 months). In the PSM cohort, patients in the CRT group achieved comparable survival compared with patients in the RT group. The 3-year CSS rate was 64.3% and 65.2%, respectively (P =0.764). In multivariate analysis, the addition of chemotherapy to IMRT was not an independent prognostic factor for CSS, whereas a high ACE-27 score was an independent risk factor. In subgroup analysis with ACE-27 score ≥ 2, the 3-year CSS rate was worse in patients from the CRT group (63.5% vs. 46.3%, P = 0.041). Conclusions: CRT is comparable to IMRT alone for elderly patients with locoregionally advanced NPC. The ACE-27 tool may help to identify high-risk subgroup for poor disease outcome and tailor individualized treatment.

HMGB1 Promotes Prostate Cancer Development and Metastasis by Interacting with Brahma-Related Gene 1 and Activating the Akt Signaling Pathway.

Background and Aim: We have previously shown that high-mobility group box 1 (HMGB1) is an independent biomarker for shortened survival of prostate cancer (PCa) patients. However, the specific role of HMGB1 in tumor development and progression remains largely unknown. In this study, we investigated the molecular mechanisms of HMGB1 in PCa tumorigenesis. Methods: Gain-of-function and loss-of-function experiments were used to determine the biological functions of HMGB1 both in vitro and in vivo. Bioinformatic analysis, immunoprecipitation, and immunofluorescence assays were applied to discern and examine the relationship between HMGB1 and its potential targets. Specimens from 64 patients with PCa were analyzed for the expression of HMGB1 and its relationship with Brahma-related gene 1 (BRG1) was examined by immunohistochemistry. Results: The results demonstrated that ectopic expression of HMGB1 facilitated growth and metastasis of PCa by enhancing Akt signaling pathway and promoting epithelial-mesenchymal transition (EMT), while silencing of HMGB1 showed the opposite effects. Mechanistically, HMGB1 exerted these functions through its interaction with BRG1 which may augment BRG1 function and activate the Akt signaling pathway thereby promoting EMT. Importantly, both HMGB1 and BRG1 expression was markedly increased in human PCa tissues. Conclusions: Taken together, these findings indicate that upregulation of HMGB1 promotes PCa development via activation of Akt and accelerates metastasis through regulating BRG1-mediated EMT. HMGB1 could be used as a novel potential target for the treatment of PCa.