Cancer-associated fibroblasts promote enzalutamide resistance and PD-L1 expression in prostate cancer through CCL5-CCR5 paracrine axis.

Cancer-associated fibroblasts (CAFs) have been shown to play a key role in prostate cancer treatment resistance, but the role of CAFs in the initial course of enzalutamide therapy for prostate cancer remains unclear. Our research revealed that CAFs secrete CCL5, which promotes the upregulation of androgen receptor (AR) expression in prostate cancer cells, leading to resistance to enzalutamide therapy. Furthermore, CCL5 also enhances the expression of tumor programmed death-ligand 1 (PD-L1), resulting in immune escape. Mechanistically, CCL5 binds to the receptor CCR5 on prostate cancer cells and activates the AKT signaling pathway, leading to the upregulation of AR and PD-L1. The CCR5 antagonist maraviroc to inhibit the CAFs mediated CCL5 signaling pathway can effectively reduce the expression of AR and PD-L1, and improve the efficacy of enzalutamide. This study highlights a promising therapeutic approach targeting the CCL5-CCR5 signaling pathway to improve the effectiveness of enzalutamide.

The Experiences of Female Partners of Patients With Erectile Dysfunction Due to Prostate Cancer Treatment in China: A Qualitative Exploration.

BACKGROUND: Because of sociocultural factors, Chinese female partners of patients with prostate cancer (PC) may have perspectives and needs that differ from the more published reports of female partners living in Western cultures. OBJECTIVES: The aim of this study was to explore the experiences of female partners of patients with PC experiencing erectile dysfunction in China. INTERVENTIONS/METHODS: In this interpretive descriptive design, qualitative data were collected from semistructured telephone interviews with purposively sampled participants from the urology outpatient unit in a hospital in South China. The interviews were audiotaped, transcribed, and analyzed using a constant comparison approach. RESULTS: Three themes emerged from the analysis of the participants' narratives: (a) acceptance of ceasing sex; (b) preserving intimacy through caregiving; and (c) the need for sexual health-related information. CONCLUSION: Participants in this study reported that their own sexuality and intimacy were affected by their partner's erectile dysfunction, but they adjusted to sexuality and intimacy changes through their caregiving of their husbands owing to Chinese traditional perspectives on women's obligations. They also reported having unmet informational needs in improving sexual well-being for the sake of their partners, lending further support to the likely benefit of couple-based educational interventions addressing sexual wellness in dyads affected by PC and erectile dysfunction. IMPLICATIONS FOR PRACTICE: The present study findings highlighted the need for more research attention to the support of Chinese female partners of patients with PC regarding sexual and intimate topics.

Virtual computed-tomography system for deep-learning-based material decomposition.

Objective.Material decomposition (MD) evaluates the elemental composition of human tissues and organs via computed tomography (CT) and is indispensable in correlating anatomical images with functional ones. A major issue in MD is inaccurate elemental information about the real human body. To overcome this problem, we developed a virtual CT system model, by which various reconstructed images can be generated based on ICRP110 human phantoms with information about six major elements (H, C, N, O, P, and Ca).Approach.We generated CT datasets labelled with accurate elemental information using the proposed generative CT model and trained a deep learning (DL)-based model to estimate the material distribution with the ICRP110 based human phantom as well as the digital Shepp-Logan phantom. The accuracy in quad-, dual-, and single-energy CT cases was investigated. The influence of beam-hardening artefacts, noise, and spectrum variations were analysed with testing datasets including elemental density and anatomical shape variations.Main results.The results indicated that this DL approach can realise precise MD, even with single-energy CT images. Moreover, noise, beam-hardening artefacts, and spectrum variations were shown to have minimal impact on the MD.Significance.Present results suggest that the difficulty to prepare a large CT database can be solved by introducing the virtual CT system and the proposed technique can be applied to clinical radiodiagnosis and radiotherapy.

Review of Deep Learning Based Automatic Segmentation for Lung Cancer Radiotherapy.

Lung cancer is the leading cause of cancer-related mortality for males and females. Radiation therapy (RT) is one of the primary treatment modalities for lung cancer. While delivering the prescribed dose to tumor targets, it is essential to spare the tissues near the targets-the so-called organs-at-risk (OARs). An optimal RT planning benefits from the accurate segmentation of the gross tumor volume and surrounding OARs. Manual segmentation is a time-consuming and tedious task for radiation oncologists. Therefore, it is crucial to develop automatic image segmentation to relieve radiation oncologists of the tedious contouring work. Currently, the atlas-based automatic segmentation technique is commonly used in clinical routines. However, this technique depends heavily on the similarity between the atlas and the image segmented. With significant advances made in computer vision, deep learning as a part of artificial intelligence attracts increasing attention in medical image automatic segmentation. In this article, we reviewed deep learning based automatic segmentation techniques related to lung cancer and compared them with the atlas-based automatic segmentation technique. At present, the auto-segmentation of OARs with relatively large volume such as lung and heart etc. outperforms the organs with small volume such as esophagus. The average Dice similarity coefficient (DSC) of lung, heart and liver are over 0.9, and the best DSC of spinal cord reaches 0.9. However, the DSC of esophagus ranges between 0.71 and 0.87 with a ragged performance. In terms of the gross tumor volume, the average DSC is below 0.8. Although deep learning based automatic segmentation techniques indicate significant superiority in many aspects compared to manual segmentation, various issues still need to be solved. We discussed the potential issues in deep learning based automatic segmentation including low contrast, dataset size, consensus guidelines, and network design. Clinical limitations and future research directions of deep learning based automatic segmentation were discussed as well.

kV-kV and kV-MV DECT based estimation of proton stopping power ratio - a simulation study.

PURPOSE: This study aims to estimate the proton stopping power ratio (SPR) by using 80-120 kV and 120 kV-6 MV dual-energy CT (DECT) in a fully simulation-based approach for proton therapy dose calculations. METHODS: Based on a virtual CT system, a two-step approach is applied to obtain the reference attenuation coefficient for image reconstruction. The effective atomic number (EAN) and electron density ratio (EDR) are estimated from two CT scans. The SPR is estimated using a calibration based on known materials to obtain a piecewise linear relationship between the EAN and the logarithm of the mean excitation energy, lnIm. The calibration phantoms are constructed from reference tissue materials taken from ICRU Report 44. Our approach is evaluated through using the ICRP110 human phantom. The respective influences of noise and beam hardening effects are studied. RESULTS: With the beam hardening correction applied, the results of 120 kV-6 MV DECT are comparable to those of 80-120 kV DECT in predicting the EAN, but the former demonstrated a clear improvement in predicting the EDR and SPR. The 120 kV-6 MV DECT is able to predict the SPR within an accuracy of 10% for lung tissue and 5% for pelvis tissue, thereby outperforming the 80-120 kV DECT. CONCLUSIONS: The 120 kV-6 MV DECT is less sensitive to noise but more susceptible to beam hardening effects. By applying beam hardening correction, the 120 kV-6 MV DECT can predict the SPR more accurately than the 80-120 kV DECT. To utilize our DECT approach most effectively, high-quality reconstructed images are required.

HHLA2 and PD-L1 co-expression predicts poor prognosis in patients with clear cell renal cell carcinoma.

BACKGROUND: Although clear cell renal cell carcinoma (ccRCC) is well known as a highly immunogenic tumor, only a small subset of patients could benefit from current immunotherapy, which might be due to the heterogeneity of immune microenvironment in ccRCC. So, it is meaningful to explore novel immunotherapy or combination therapy for improving therapeutic efficacy. HHLA2, a newly discovered B7 family member, is prevalently expressed in numerous tumors, including ccRCC. This study aimed to investigate the prognostic impact of HHLA2/PD-L1 co-expression and its relationship with tumor-infiltrating lymphocytes (TILs). METHODS: The expression levels of HHLA2, PD-L1, CD8, and CD4 in cancer tissues from cases (206 in the training cohort and 197 in the validation cohort) with surgically resectable primary ccRCC were evaluated by immunohistochemistry. RESULTS: The positive rates of HHLA2 were much higher than those of PD-L1 in ccRCC tissues. HHLA2-positive expression was significantly associated with necrosis, microvascular invasion, advanced Fuhrman nuclear, and TNM stage and indicated a shorter progression-free survival (PFS) and overall survival (OS) in both cohorts. Moreover, patients with HHLA2/PD-L1 co-expression suffered the highest risk of disease progression and death by a significant margin. Besides, HHLA2/PD-L1 co-expression was significantly associated with a high density of CD8+ and CD4+ TILs. Notably, a new immune classification, based on HHLA2/PD-L1 co-expression and TILs, successfully stratified PFS and OS, especially in patients with TILs positivity. CONCLUSIONS: The expression of HHLA2 is more frequent than PD-L1 in ccRCC. HHLA2/PD-L1 co-expression had an adverse impact on the prognoses of patients with ccRCC; this finding provides a rationale for combination immunotherapy with anti-HHLA2 and PD-L1 blockage for patients with ccRCC in the future.

High Prevalence of HBV Lamivudine-Resistant Mutations in HBV/HIV Co-Infected Patients on Antiretroviral Therapy in the Area with the Highest Prevalence of HIV/HBV Co-Infection in China.

OBJECTIVES: We aimed to determine the prevalence of hepatitis B virus (HBV) drug-resistant mutations in patients co- infected with HBV/human immunodeficiency virus (HIV), including both drug-naïve subjects and those who received antiretroviral therapy (ART) in Guangxi, where the prevalence of HIV/HBV co-infection is highest in China. METHODS: Two hundred and three subjects co-infected with HBV/HIV were recruited, including 123 drug-naïve patients (group 1) and 80 who received ART (group 2). The polymerase gene of HBV in the serum of all study subjects was analysed. RESULTS: The results showed that the prevalence of HBV drug-resistant mutations in group 2 (76.5%, 95% CI 56.3-96.7) was significantly higher than that in group 1 (1.4%, 95% CI -1.4 to 4.2; χ2 = 50.955, p < 0.05). The major pattern of lamivudine (3TC)-resistant mutations is L180M+M204I+L80I (35.7%). In total, 95% of subjects with resistant mutations had cross-resistance to telbivudine and entecavir. No putative tenofovir disoproxil fumarate (TDF) resistance change was found. Five subjects (6.5%) in group 2 had HBV viral loads over 10 × 106 copies/mL. Four of them had 3TC-resistant mutations. Multivariate analysis showed that ART was the only factor associated with the development of drug-resistant mutations. CONCLUSION: Treating HIV in HIV/HBV co-infection with antiretroviral agents may result in a very high prevalence of HBV 3TC-resistant mutations. TDF could not completely suppress HBV replication.

Des-γ carboxyprothrombin may not be a good biomarker for hepatocellular carcinoma in those chronically infected with hepatitis B virus with basal core promoter double mutations (T

BACKGROUND: The accuracy of des-γ -carboxyprothrombin (DCP) in the detection of hepatocellular carcinoma (HCC) in those infected hepatitis B virus (HBV) from cross-sectional or case-control studies is contradictory. OBJECTIVE: To resolve this contradiction using a prospective study. METHODS: Three hundred male individuals persistently infected with HBV were recruited from the Chinese cohort and followed up once per year from 2012 to 2015. Each subject was screened for HCC by measurements of serum alpha-fetoprotein (AFP), lectin-bound α -fetoprotein (AFP-L3), DCP concentrations and ultrasonographic examinations. RESULTS: Nineteen HCC cases were identified. The area under receiver operating characteristic (AUROC) at first, second and third visit for AFP, AFP-L3 and DCP ranges from 0.710-0.897, 0.566-0.637 and 0.520-0.595, respectively. The rate of elevated DCP is not significantly different between the HCC cases and controls (52.6% vs. 47.4%) (P > 0.05). The incidence of HCC in subjects with elevated DCP is not significantly higher than that of those with normal DCP (9.5% vs. 4.6%) (P > 0.05). The AUROC of combinations of these biomarkers was higher than that of AFP alone at the first visit. However, it was reduced at the second visit. At the third visit, the AUROCs of AFP + DCP and AFP + AFP-L3 + DCP, but not that of AFP + AFP-L3, were higher than that of AFP alone. CONCLUSIONS: AFP but DCP or AFP-L3 remains a valuable biomarker for HCC in those chronically infected with HBV. The combination with AFP-L3 and DCP may not increase the accuracy of AFP in differentiating HCC cases from controls, among those infected with HBV.

Higher prevalence of cancer related mutations 1762T/1764A and PreS deletions in hepatitis B virus (HBV) isolated from HBV/HIV co-infected compared to HBV-mono-infected Chinese adults.

In the era of combination therapy for human immunodeficiency virus (HIV), liver disease including hepatocellular carcinoma (HCC), are the major causes of death for patients co-infected with hepatitis B virus (HBV) and HIV. However, the mechanisms remain obscure. We aimed to determine whether HCC-related HBV mutations including 1762T/1764A double mutation and pre-S deletions occur more frequently in HBV/HIV co-infected individuals compared to HBV mono-infected individuals. In this study, the basic core promoter (BCP) and the preS/S regions of HBV isolated from 61 pairs of HBV/HIV co-infected and HBV mono-infected participants were analyzed. We found that the prevalence of HBV isolates with 1762T/1764A and/or preS deletion mutations was 37.7% (95% CI: 29.1-46.3). The prevalence of these mutations in HBV/HIV co-infected group (52.5%, 95% CI: 40.0-65.0) was significantly higher than in the HBV mono-infected group (23.0%, 95% CI: 12.4-33.6) (X2=11.307, P<0.05). HBV/HIV co-infection was associated with higher viral loads but these higher viral loads were not associated with the higher prevalence of HCC-related HBV mutations. Individually 1762T1764A (44.3%) or preS deletions (23%) occurred more frequently in isolates from co-infected compared to mono-infected individuals (21.3%, 4.9%, respectively) (X2=7.290, P<0.05; X2=8.270, P<0.05). Moreover, 1762T/1764A and preS deletions occurred more frequently in genotypes C and I compared to genotype B (p<0.05). Multivariate analysis revealed that co-infection with HIV was associated with the development of both 1762T/1764A ((RR: 2.932(1.325-6.488)) and preS deletions ((RR: 5.759(1.562-21.235)). These results demonstrate that co-infection with HIV was associated with increased prevalence of HCC-related mutations in HBV isolates from Chinese patients.

Hepatitis B Virus Core Promoter Double Mutations (A1762T, G1764A) Are Associated with Lower Levels of Serum Dihydrolipoyl Dehydrogenase.

OBJECTIVES: The aim of this study was to identify serum proteins with differential concentrations between hepatocellular carcinoma (HCC) patients and HBsAg asymptomatic carriers among individuals infected with hepatitis B virus (HBV) with basal core promoter (BCP) double mutations (A1762T, G1764A). METHODS: iTRAQ and liquid chromatography-tandem mass spectrometry were used to identify differentially expressed protein, and an ELISA test was used for the validation test. RESULTS: The total number of proteins identified was 1,125, of which 239 showed statistically significant differences in their expression. The relative concentrations of serum dihydrolipoyl dehydrogenase (DLD), which showed the most significant correlation with liver diseases and infection, were significantly lower in HCC patients than asymptomatic HBsAg carriers and individuals negative for HBsAg. However, only the difference between HCC patients with BCP double mutations and HBsAg-negative individuals could be confirmed by ELISA. Meanwhile, we found that the concentrations of serum DLD in those infected with HBV with BCP double mutations were significantly lower than in individuals with the wild-type BCP. However, the difference in the concentrations of serum DLD between individuals with wild-type BCP and those negative for HBsAg was not significant. CONCLUSIONS: HBV with BCP double mutations are associated with lower concentrations of serum DLD.