Search

Purpose: We aim to explore the predictive value of neuroendocrine differentiation (NED) in patients with metastatic castration-resistant prostate cancer (mCRPC) receiving abiraterone or docetaxel as first-line therapy. Methods: We retrospectively analyzed data of 262 mCRPC patients receiving abiraterone or docetaxel as first-line mCRPC treatment. NED was evaluated using prostate biopsy samples at the time of mCRPC by immunohistochemical staining. Kaplan–Meier curves and Cox regression were used to assess the association between NED and treatment outcomes including PSA progression-free survival (PSA-PFS), radiographic progression-free survival (rPFS), and overall survival (OS). Results: NED was confirmed in 100/262 (38.2%) mCRPC patients, with 76/100 (76.0%) and 24/100 (24.0%) men harboring NED < 10% and NED ≥ 10%, respectively. 203/262 (77.5%) and 59/262 (22.5%) patients received abiraterone and docetaxel, respectively. In abiraterone treatment, NED was associated with a significantly shorter median PSA-PFS (mPSA-PFS, 7.5 vs. 10.3-Mo, P < 0.001), median rPFS (mrPFS, 15.9 vs. 19.5-Mo, P = 0.010), and median OS (mOS, 23.2 vs. 34.3-Mo, P = 0.014)). Likewise, for mCRPC patients receiving docetaxel, the positive detection of NED also predicted shorter mPSA-PFS (3.8 vs. 5.9-Mo, P = 0.052), mrPFS (8.4 vs. 20.4-Mo, P = 0.016) and mOS (13.6 vs. 29.0-Mo, P = 0.033). The adverse prognostic trait of NED is consistent in most subgroups. Additionally, patients' survival outcomes deteriorated as the NED proportion grew in both therapies. After propensity score matching, NED-positive patients showed comparable prognosis in abiraterone and docetaxel therapy. Conclusion: For mCRPC patients receiving abiraterone or docetaxel, NED and its proportion were critical predictive factors. NED detection at mCRPC might aid in predicting patients' outcomes and optimizing treatment decisions. [ABSTRACT FROM AUTHOR]

Background: Intraductal carcinoma of the prostate (IDC-P) is a subtype of prostate cancer featured by poor prognosis. Previous studies suggested IDC-P could have a potentially unstable genome. Homologous recombination deficiency (HRD) score is a result-oriented method to describe the genomic instability status. This study investigates the association of HRD scores with IDC-P and other clinicopathological factors and the prognostic implication of HRD scores in an aggressive prostate cancer cohort. Methods: This study involved 123 PCa patients, including high-risk localized (M0) and de novo metastatic (M1) diseases. HRD score is calculated based on over 10,000 single-nucleotide polymorphisms distributed across the human genome. We explored the association between HRD scores and clinicopathological characteristics, genomic alterations, and patients' prognoses using rank-sum tests, chi-square tests, Kaplan-Meier curves, and Cox proportional hazards method. Results: The median HRD score of this cohort is 21.0, with 65 (52.8%) patients showing HRD score≥21. Tumors with IDC-P displayed higher HRD scores than adenocarcinoma (P=0.002); other high HRD score-related factors included M1 (P =0.008) and high ISUP grades (4–5) (P=0.001). MYC mutations were associated with high HRD scores (P<0.001) in the total cohort. TP53 mutations (P=0.010) and HRR pathway mutations (P=0.028) corresponded to high HRD scores in IDC-P positive and non-IDC-P patients, respectively, but not vice versa. HRD scores higher than 21 indicated significantly worse survival in the total cohort. Conclusions: M1, high Gleason score, and IDC-P pathology represent higher HRD scores in PCa. Tumors with IDC-P might have different driven mechanisms for high HRD scores than non-IDC-P. HRD score displayed prognostic value in this aggressive prostate cancer cohort. [ABSTRACT FROM AUTHOR]

Background: Intraductal carcinoma of the prostate (IDC-P) is a subtype of prostate cancer featured by poor prognosis. Previous studies suggested IDC-P could have a potentially unstable genome. Homologous recombination deficiency (HRD) score is a result-oriented method to describe the genomic instability status. This study investigates the association of HRD scores with IDC-P and other clinicopathological factors and the prognostic implication of HRD scores in an aggressive prostate cancer cohort.Methods: This study involved 123 PCa patients, including high-risk localized (M0) and de novo metastatic (M1) diseases. HRD score is calculated based on over 10,000 single-nucleotide polymorphisms distributed across the human genome. We explored the association between HRD scores and clinicopathological characteristics, genomic alterations, and patients' prognoses using rank-sum tests, chi-square tests, Kaplan-Meier curves, and Cox proportional hazards method.Results: The median HRD score of this cohort is 21.0, with 65 (52.8%) patients showing HRD score≥21. Tumors with IDC-P displayed higher HRD scores than adenocarcinoma (P=0.002); other high HRD score-related factors included M1 (P =0.008) and high ISUP grades (4-5) (P=0.001). MYC mutations were associated with high HRD scores (P<0.001) in the total cohort. TP53 mutations (P=0.010) and HRR pathway mutations (P=0.028) corresponded to high HRD scores in IDC-P positive and non-IDC-P patients, respectively, but not vice versa. HRD scores higher than 21 indicated significantly worse survival in the total cohort.Conclusions: M1, high Gleason score, and IDC-P pathology represent higher HRD scores in PCa. Tumors with IDC-P might have different driven mechanisms for high HRD scores than non-IDC-P. HRD score displayed prognostic value in this aggressive prostate cancer cohort. [ABSTRACT FROM AUTHOR]

Objectives: To investigate the genetic alterations of patients with prostate cancer (PCa) with and without intraductal carcinoma of the prostate (IDC‐P). Patients and Methods: We performed targeted sequencing of plasma cell‐free DNA on 161 patients with prostate adenocarcinoma (PAC) with IDC‐P and 84 without IDC‐P. Genomic alterations were compared between these two groups. The association between genetic alterations and patients' survival outcomes was also explored. Results: We identified that 29.8% (48/161) and 21.4% (18/84) of patients with and without IDC‐P harboured genomic alterations in DNA repair pathways, respectively (P = 0.210). Pathogenic germline DNA repair alterations were frequently detected in IDC‐P carriers compared to IDC‐P non‐carriers (11.8% [19/161] vs 2.4% [two of 84], P = 0.024). Germline BReast CAncer type 2 susceptibility protein (BRCA2) and somatic cyclin‐dependent kinase 12 (CDK12) defects were specifically identified in IDC‐P carriers relative to PAC (BRCA2: 8.7% [14/161] vs 0% and CDK12: 6.8% [11/161] vs 1.2% [one of 84]). Patients with IDC‐P had a distinct androgen receptor (AR) pathway alteration, characterised by an enrichment of nuclear receptor corepressor 2 (NCOR2) mutations compared with patients with pure PAC (21.1% [34/161] vs 6.0% [five of 84], P = 0.004). Increased AR alterations were detected in patients harbouring tumours with an IDC‐P proportion of ≥10% vs those with an IDC‐P proportion of <10% (6.4% [five of 78] vs 18.1% [15/83], P = 0.045). For IDC‐P carriers, tumour protein p53 (TP53) mutation was associated with shorter castration‐resistant‐free survival (median 10.9 vs 28.9 months, P = 0.026), and BRCA2 alteration was related to rapid prostate‐specific antigen progression for those receiving abiraterone treatment (median 9.1 vs 11.9 months, P = 0.036). Conclusion: Our findings provide genomic evidence explaining the aggressive phenotype of tumours with IDC‐P, highlighting the potential therapeutic strategies for this patient population. [ABSTRACT FROM AUTHOR]

Objectives: To develop and validate a prediction model for identifying non-prostate cancer (non-PCa) in biopsy-naive patients with PI-RADS category ≥ 4 lesions and PSA ≤ 20 ng/ml to avoid unnecessary biopsy. Patients and methods: Eligible patients who underwent transperineal biopsies at West China Hospital between 2018 and 2022 were included. The patients were randomly divided into training cohort (70%) and validation cohort (30%). Logistic regression was used to screen for independent predictors of non-PCa, and a nomogram was constructed based on the regression coefficients. The discrimination and calibration were assessed by the C-index and calibration plots, respectively. Decision curve analysis (DCA) and clinical impact curves (CIC) were applied to measure the clinical net benefit. Results: A total of 1580 patients were included, with 634 non-PCa. Age, prostate volume, prostate-specific antigen density (PSAD), apparent diffusion coefficient (ADC) and lesion zone were independent predictors incorporated into the optimal prediction model, and a corresponding nomogram was constructed (https://nomogramscu.shinyapps.io/PI-RADS-4-5/). The model achieved a C-index of 0.931 (95% CI, 0.910–0.953) in the validation cohort. The DCA and CIC demonstrated an increased net benefit over a wide range of threshold probabilities. At biopsy-free thresholds of 60%, 70%, and 80%, the nomogram was able to avoid 74.0%, 65.8%, and 55.6% of unnecessary biopsies against 9.0%, 5.0%, and 3.6% of missed PCa (or 35.9%, 30.2% and 25.1% of foregone biopsies, respectively). Conclusion: The developed nomogram has favorable predictive capability and clinical utility can help identify non-PCa to support clinical decision-making and reduce unnecessary prostate biopsies. [ABSTRACT FROM AUTHOR]

Objectives: To develop nomograms predicting the incidence of castration‐resistant prostate cancer (CRPC) and overall survival (OS) for de novo metastatic prostate cancer (PCa). Patients and Methods: Data from 449 patients with de novo metastatic PCa were retrospectively analysed. Patients were randomly divided into a training (n = 314, 70%) and a validation cohort (n = 135, 30%). Predictive factors were selected using a Cox proportional hazards model and were further used for building predictive models. The outcomes were incidence of CRPC and OS. Results: Predictive factors included: Gleason score (GS), intraductal carcinoma of the prostate (IDC‐P), Eastern Cooperative Oncology Group status, and alkaline phosphatase, haemoglobin and prostate‐specific antigen levels. IDC‐P and GS were the strongest prognosticators for both the incidence of CRPC and OS. Nomograms for predicting CRPC and OS had an internal validated concordance index of 0.762 and 0.723, respectively. Based on the β coefficients of the final model, risk classification systems were constructed. For those with favourable, intermediate and poor prognosis, the median time to CRPC was 62.6, 28.0 and 13.0 months (P < 0.001), respectively; and the median OS was not reached, 55.0 and 33.0 months, respectively (P < 0.001). Conclusions: We developed two novel nomograms to predict the incidence of CRPC and OS for patients with de novo metastatic PCa. These tools may assist in physician decision‐making and the designing of clinical trials. [ABSTRACT FROM AUTHOR]

In this manuscript, a disposable paper-based analytical device comprised of a closed bipolar electrode (BPE) was fabricated for the ultrasensitive electrochemiluminescence (ECL) detection of intracellular H 2 O 2 and the number of cancer cells. In this approach, wax printing was used to fabricated reaction zone, and carbon ink-based BPE and driving electrodes were screen-printed into the paper. AuPd nanoparticles (NPs), which served as a carrier of the capture aptamer and as the catalyst for the ECL reaction of luminol and H 2 O 2 , were used to modify the BPE. Luminol/Au NPs were attached to the surface of the captured cells via hybridation chain reaction with two hairpin structure DNA labelled luminol/Au NPs. In the stimulation of phorbol myristate acetate, The coreactant H 2 O 2 was released from the target cells. The ECL response of the luminol-H 2 O 2 system was related to the number of cancer cells in the testing buffer, which served as a quantitative signal for the determination of cancer cells and the concentration of H 2 O 2 . In order to decrease the external voltage, K 3 [Fe(CN) 6 ] was introduced in the cathode resevoir of BPE because it gained electrons at the cathode more easily than oxygen. The ECL intensity was quantitatively related to the concentration of MCF-7 in the range of 1.0 × 10 2 –1.0 × 10 7 cells/mL. The detection limit was 40 cells/mL and it showed good specificity for cells with high overexpression of mucin-1 receptor, it was concluded that the developed protocol could be effectively utilized for the detection of MCF-7 cells. [ABSTRACT FROM AUTHOR]

The achievement of efficient structure-function unification involves the reasonable structure design of molecules and the application-oriented function regulation. DNA aptamer possesses feathers of high specificity, high stability, and easily flexible structure design, making it a promising candidate for access to specific functions. Inspired by the typical Y-shaped structure, a smart antibody-mimic Y probe (Y probe) composed of dual-aptamer recognition segments and rigid stem was designed for boosting the specific molecular recognition of β-amyloid oligomer (AβO). The spatial structure match of Y probe and AβO, as well as binding sites of AβO exposed to Y probe attributed to the enhanced specific targeting for AβO. As expected, Y probe specifically captured AβO but not Aβ monomer and fibril. For further investigation the reliability and applicability of Y probe, an electrochemical aptasensor based on Y probe was constructed and its performance was comprehensively tested. In particular, the aptasensor achieved a low limit of detection of 0.6 fM for AβO detection in a wide detection range (1 fM-5 nM). This work provided a universal method to promote specific interactions through the practical structure design of recognition molecules. Moreover, Y probe has positive implications for developing AβO biosensing platform in Alzheimer's disease early diagnosis. [Display omitted] • Antibody-mimic Y probe for boosting specific recognition of β-amyloid oligomer. • Design strategy of considering spatial structure match and exposed binding sites. • A method to promote specific interactions by the structure design of aptamers. • Sensitive and specific detection of β-amyloid oligomer by Y probe-based aptasensor. • Positive implications for a biosensing platform in Alzheimer's disease diagnosis. [ABSTRACT FROM AUTHOR]

Four N -fluorenyl indoline sensitizers were designed and synthesized to compare the influence of vinyl bond and aryl ring on the cell efficiency based on the cyanoacrylic acid acceptor. Compared with vinyl bond, the introduction of aryl ring enlarges the conjugation system of the whole molecule and brings out the improvement of the absorption spectra favoring the improvement of J SC . Among three kinds of aryl rings, benzene unit favors the photovoltage due to a reduction of electron recombination while the photocurrent more benefit from thiophene unit. Due to the best J SC , dye with thiophene π-bridge shows the most efficient photoelectricity conversion efficiency and has the maximum η value of 5.89% ( V OC = 650 mV, J SC = 13.88 mA cm −2 , ff = 0.71) under simulated AM 1.5 G irradiation (100 mW cm −2 ). [ABSTRACT FROM AUTHOR]

Highlights: [•] We design a two-step Kalman filter which is suitable for the embedded system. [•] We divide the typical Kalman filter into two sub Kalman filters. [•] We separately deal with the gravity acceleration vector and geomagnetic vector. [•] The outputs of filters are adjusted based on variance matching of fuzzy logic. [•] The mathematical model is simplified and the speed of computation is improved. [Copyright &y& Elsevier]

Background: Inflammation plays a pivotal role in the progression of prostate cancer (PCa). Several immune-inflammatory indices, including neutrophil to lymphocyte ratio (NLR), derived neutrophil to lymphocyte ratio (dNLR), lymphocyte to monocyte ratio (LMR) and platelet to lymphocyte ratio (PLR), lung immune prognostic index (LIPI), systemic inflammation response index (SIRI) and systemic immune inflammation index (SII), have demonstrated their prognostic values in several solid malignancies. However, Comparisons of superiority with these seven indices' predictive efficacy within metastatic hormone-sensitive PCa (mHSPC) and metastatic castration-resistant PCa (mCRPC) remain uncertain. Methods: We retrospectively included 407 patients diagnosed with mHSPC and 158 patients with mCRPC at West China Hospital from 2005 to 2022. The seven immune-inflammatory indices were computed based on hematological data of mHSPC at initial diagnosis and mCRPC at progression to CRPC. Prognostic value for castration-resistant prostate cancer-free survival (CFS), overall survival (OS), prostate-specific antigen progression-free survival (PSA-PFS) and prostate-specific antigen (PSA) response was assessed using Kaplan–Meier curves, Cox regression models, and chi-square tests. The predictive performance of each immune-inflammatory index was assessed using the area under the curve (AUC) in time-dependent receiver operating characteristic curve (ROC) analysis and C-index calculation. Results: All seven immune-inflammatory indices were significantly associated with CFS and OS in the mHSPC cohort, as well as with PSA response, PSA-PFS, and OS in the mCRPC cohort. In the mHSPC cohort, LIPI consistently exhibited higher AUC values compared to NLR, dNLR, LMR, PLR, SII, and SIRI for predicting CFS and OS. This indicates that LIPI had a superior discriminative ability compared to the other indices (C-index of LIPI: 0.643 and 0.686 for CFS and OS, respectively). Notably, the predictive advantage of LIPI over other indices in the mHSPC stage diminished in the mCRPC stage. Conclusions: This study firstly confirmed the prognostic value of SII, SIRI and LIPI in mHSPC and mCRPC, and revealed that LIPI had a higher predictive power than NLR, dNLR, LMR, PLR, SII and SIRI in mHSPC. These non-invasive indices can enable clinicians to quickly assess the prognosis of patients. [ABSTRACT FROM AUTHOR]

• Co 3 O 4 -Au polyhedron as mimic peroxidase and electronic extinguisher for amplify signal response. • TiO 2 /Bi 2 S 3 heterostructure with high photoelectric conversion efficiency. • Cascade enzyme-assisted cycling process for miRNA detection to improve the sensitivity. A photoelectrochemical (PEC) biosensor was constructed based on cascade enzyme-assisted cycling process and Co 3 O 4 -Au polyhedron for miRNA-141 detection. The biotin-modified DNA was immobilized on ITO/TiO 2 /Bi 2 S 3 to link streptomycin-modified Co 3 O 4 -Au through the specific interaction between streptavidin and biotin. The Co 3 O 4 -Au with the competitive consumption effect of electron donor and excitation light energy could effectively reduce the photocurrent signal. Additionally, Co 3 O 4 -Au as peroxidase mimetics enzyme could catalyze the formation of benzo-4-chlorohexanedione (4-CD) precipitate on the electrode surface, which could efficiently prevent electron transfer and decrease the photocurrent signal of PEC biosensor. In the cascade enzyme-assisted cycling process, a small amount of miRNA-141 triggered the double-strand specific endonucleases-assisted cycling process, which could generate DNA fragment for next step experiment. Then the biotin-modified DNA was decomposed by Exonuclease III (Exo III) in the Exo III-assisted cycling process, resulting in the separation of biotin from the electrode surface and the reduction in the loading of streptomycin-modified Co 3 O 4 -Au. The fabricated PEC biosensor with a wide linear range and a low detection limit has potential applications in highly accurate and ultrasensitive monitoring of bioanalysis and disease diagnostics. [ABSTRACT FROM AUTHOR]

In this work, a peptide-based photoelectrochemical (PEC) biosensor was constructed based on CdTe/TiO 2 sensitized structure as electrode and CuS nanocrystals as signal amplifier for the ultrasensitive detection of protein. After peptide was fixed to the CdTe/TiO 2 electrode surface, the double-helix DNA (dsDNA) was immobilized at the end of the peptide and used as a carrier to immobilize the doxorubicin-copper sulfide nanocrystals (Dox-CuS) conjugates. As a proof of concept, prostate specific antigen (PSA) has been chosen as the model. In absence of PSA, CuS nanocrystals could consume electron donors and exciting light energy. Additionally, the steric hindrance effect of biomacromolecules hindered the movement of electron donors to the photoelectrode. Eventually, the photoelectric response signal was reduced, and the biosensor was in a "signal off" state. When PSA existed, the PSA specifically cleaved the peptide, and DNA/Dox-CuS probes were released from the electrode surface, resulting in a "signal on" state. The PEC biosensor revealed good specificity, stability, and reproducibility, and it exhibited excellent application in PSA analysis with a linear range from 0.005 to 20 ng mL−1 and a low detection limit of 0.0015 ng mL−1. This PEC biosensor may have potential applications in bioanalysis, disease diagnostics, and clinical biomedicine. ● Peptide cleavage-mediated photoelectrochemical signal on-off with PSA. ● Double-stranded DNA loaded a large number of CuS nanocrystals via Dox. ● CuS nanocrystals as electronic extinguisher for amplify response signals. [ABSTRACT FROM AUTHOR]

Background: TFE3-rearranged renal cell carcinoma (TFE3-rRCC) is a rare but highly heterogeneous renal cell carcinoma (RCC) entity, of which the clinical treatment landscape is largely undefined. This study aims to evaluate and compare the efficacy of different systemic treatments and further explore the molecular correlates. Methods: Thirty-eight patients with metastatic TFE3-rRCC were enrolled. Main outcomes included progression-free survival (PFS), overall survival, objective response rate (ORR) and disease control rate. RNA sequencing was performed on 32 tumors. Results: Patients receiving first-line immune checkpoint inhibitor (ICI) based combination therapy achieved longer PFS than those treated without ICI (median PFS: 11.5 vs. 5.1 months, P = 0.098). After stratification of fusion partners, the superior efficacy of first-line ICI based combination therapy was predominantly observed in ASPSCR1-TFE3 rRCC (median PFS: not reached vs. 6.5 months, P = 0.01; ORR: 67.5% vs. 10.0%, P = 0.019), but almost not in non-ASPSCR1-TFE3 rRCC. Transcriptomic data revealed enrichment of ECM and collagen-related signaling in ASPSCR1-TFE3 rRCC, which might interfere with the potential efficacy of anti-angiogenic monotherapy. Whereas angiogenesis and immune activities were exclusively enriched in ASPSCR1-TFE3 rRCC and promised the better clinical outcomes with ICI plus tyrosine kinase inhibitor combination therapy. Conclusions: The current study represents the largest cohort comparing treatment outcomes and investigating molecular correlates of metastatic TFE3-rRCC based on fusion partner stratification. ICI based combination therapy could serve as an effective first-line treatment option for metastatic ASPSCR1-TFE3 rRCC patients. Regarding with other fusion subtypes, further investigations should be performed to explore the molecular mechanisms to propose pointed therapeutic strategy accordingly. [ABSTRACT FROM AUTHOR]

Background: Poly (ADP- ribose) polymerase inhibitors (PARPi) has been increasingly adopted for metastatic castration-resistance prostate cancer (mCRPC) patients with homologous recombination repair deficiency (HRD). However, it is unclear which PARPi is optimal in mCRPC patients with HRD in 2nd -line setting. Method: We conducted a systematic review of trials regarding PARPi- based therapies on mCRPC in 2nd -line setting and performed a Bayesian network meta-analysis (NMA). Radiographic progression-free survival (rPFS) was assessed as primary outcome. PSA response and adverse events (AEs) were evaluated as secondary outcomes. Subgroup analyses were performed according to specific genetic mutation. Results: Four RCTs comprised of 1024 patients (763 harbored homologous recombination repair (HRR) mutations) were identified for quantitative analysis. Regarding rPFS, olaparib monotherapy, rucaparib and cediranib plus olaparib showed significant improvement compared with ARAT. Olaparib plus cediranib had the highest surface under cumulative ranking curve (SUCRA) scores (87.5%) for rPFS, followed by rucaparib, olaparib and olaparib plus abiraterone acetate prednisone. For patients with BRCA 1/2 mutations, olaparib associated with the highest probability (98.1%) of improved rPFS. For patients with BRCA-2 mutations, olaparib and olaparib plus cediranib had similar efficacy. However, neither olaparib nor rucaparib showed significant superior effectiveness to androgen receptor-axis-targeted therapy (ARAT) in patients with ATM mutations. For safety, olaparib showed significantly lower ≥ 3 AE rate compared with cediranib plus olaparib (RR: 0.72, 95% CI: 0.51, 0.97), while olaparib plus cediranib was associated with the highest risk of all-grade AE. Conclusion: PARPi-based therapy showed considerable efficacy for mCRPC patients with HRD in 2nd -line setting. However, patients should be treated accordingly based on their genetic background as well as the efficacy and safety of the selected regimen. Trial registration: : CRD42023454079. [ABSTRACT FROM AUTHOR]

In this work, an ultrasensitive photoelectrochemical (PEC) biosensor was proposed to detect nucleic acids on the basis of cascaded photoactive materials and triple-helix molecular switch. DNA sequence of human immunodeficiency virus type 1 (HIV-1) was chosen as the target DNA (T-DNA). Cascaded photoactive structure was formed via different sizes of CdTe quantum dots (QDs) sensitized ZnO nanorods (ZnO NRs), which was employed as a cascaded photoactive interface to amplify the photocurrent signal. A hairpin structure DNA (H-DNA) as capture probe was conjugated onto the photoactive interface through amide bond, and then a single-stranded DNA modified with gold nanoparticles labeled alkaline phosphatase (ALP-Au NPs-DNA) at each end was introduced to hybridize with the H-DNA to form a triple-helix conformation. The T-DNA detection was based on the photocurrent response change resulted from conformation change of the triple-helix molecule after hybridization with T-DNA. In the absence of T-DNA, the triple-helix molecule was in a closed state and the ALP of ALP-Au NPs-DNA could specifically catalyze the ascorbic acid 2-phosphate (AAP) to generate ascorbic acid (AA) as electron donors, which resulted in a significant photocurrent response due to the rapid electron transfer process. However, in the presence of T-DNA, the T-DNA hybridized with the ALP-Au NPs-DNA molecule, which caused triple-helix molecule in an opened state and compelled ALP-Au NPs-DNA away from the electrode surface, resulting in the absence of ALP which could catalyze AAP to generate AA. Subsequently, the photocurrent response significantly decreased. The proposed PEC biosensor not only had a wide detection range of 1fM-1nM and low detection limit (0.65 fM), but also showed excellent reproducibility, specificity and stability, which had great application prospect and opened up a new research method in the early clinical diagnosis and cancer research. • DNA Triple-helix molecular switch regulates the signal-on and signal-off. • Cascaded photoactive materials was used to enhance the current signals. • An ultrasensitive photoelectrochemical biosensor is constructed for HIV-1 detection. [ABSTRACT FROM AUTHOR]

Background: Fumarate hydratase–deficient renal cell carcinoma (FH-RCC) is a rare highly aggressive subtype of kidney cancer for which the distinct genomic, transcriptomic, and evolutionary relationships between metastatic and primary lesions are still unclear. Methods: In this study, whole-exome, RNA-seq, and DNA methylation sequencing were performed on primary-metastatic paired specimens from 19 FH-RCC cases, including 23 primary and 35 matched metastatic lesions. Phylogenetic and clonal evolutionary analyses were used to investigate the evolutionary characteristics of FH-RCC. Transcriptomic analyses, immunohistochemistry, and multiple immunofluorescence experiments were performed to identify the tumor microenvironmental features of metastatic lesions. Results: Paired primary and metastatic lesions generally showed similar characteristics of tumor mutation burden, tumor neoantigen burden, microsatellite instability score, CNV burden, and genome instability index. Notably, we identified an FH-mutated founding MRCA (the most recent common ancestor) clone that dominated the early evolutionary trajectories in FH-RCC. Although both primary and metastatic lesions manifested high immunogenicity, metastatic lesions exhibited higher enrichment of T effector cells and immune-related chemokines, together with upregulation of PD-L1, TIGIT, and BTLA. In addition, we found that concurrent NF2 mutation may be associated with bone metastasis and upregulation of cell cycle signature in metastatic lesions. Furthermore, although in FH-RCC metastatic lesions in general shared similar CpG island methylator phenotype with primary lesions, we found metastatic lesions displaying hypomethylated chemokine and immune checkpoints related genomic loci. Conclusions: Overall, our study demonstrated the genomic, epigenomic, and transcriptomic features of metastatic lesions in FH-RCC and revealed their early evolutionary trajectory. These results provided multi-omics evidence portraying the progression of FH-RCC. [ABSTRACT FROM AUTHOR]

In this work, we designed a facile and label-free electrochemical biosensor based on intrinsic topological insulator (TI) Bi 2 Se 3 and peptide for the detection of immune checkpoint molecules. With topological protection, Bi 2 Se 3 could have robust surface states with low electronic noise, which was beneficial for the stable and sensitive electron transport between electrode and electrolyte interface. The peptides are easily synthesized and chemically modified, and have good biocompatibility and bioavailability, which is a suitable candidate as the recognition units for immune checkpoint molecules. Therefore, the peptide/Bi 2 Se 3 was developed as a suitable working electrode for the electrochemical biosensor. The basic performance of the designed peptide/Bi 2 Se 3 biosensor was investigated to determine the Anti-HA Tag Antibody and PD-L1 molecules. The linear detection range was from 3.6 × 10−10 mg mL−1 to 3.6 × 10−5 mg mL−1, and the detection limit was 1.07 × 10−11 mg mL−1. Moreover, the biosensor also displayed good selectivity and stability. [Display omitted] • Sensitive electrochemical biosensors combined with topological materials and peptides. • High-quality and large-scale topological crystal with few defects as electrodes. • Effective recognition units of peptides for the immune checkpoint. • A large detection range, good selectivity and stability with low detection limit of the sensing assay. • Excellent discernment in the complicated serum environment for clinical application. [ABSTRACT FROM AUTHOR]

As a key approach to mediate cholesterol metabolism, the role of the CYP27A1/27‐HC axis in renal cell carcinoma (RCC) remains unclear. Analysis of CYP27A1 expression from public databases and metastatic cases in our center suggested that CYP27A1 was obviously downregulated in RCC tissues, and survival analysis further showed its correlation with favorable clinicopathological features and prognosis. In vitro, up and downregulation of CYP27A1 expression in RCC cell lines could definitely illustrate its anticipation involving apoptosis, proliferation, invasion, migration, and clonality. This could be achieved through upregulation of 27‐HC concentration, which mediates the activation of signaling pathways of apoptosis and cell cycle arrest. Further, recovery of CYP27A1 expression could definitely inhibit the proliferation of RCC tumors in vivo. This is the first study to explore the role of the CYP27A1/27‐HC axis in RCC. Attempts to maintain the normal function of the axis may be a potential strategy in the treatment of RCC, and the predictive value of CYP27A1 detection on the efficacy of targeted therapy in metastatic RCC is also worthy of attention. [ABSTRACT FROM AUTHOR]

CDK12 (Cyclin-Dependent Kinase 12)-mutated prostate cancer patients often respond badly to current therapies. Immunotherapy and platinum-based chemotherapy are recommended based on the molecular features of CDK12-mutated tumors, but the reported patient outcomes are still unsatisfying. Here we report a prostate cancer patient with CDK12 somatic mutation who received multiple therapy options, including platinum-based chemotherapy and immunotherapy. His sequential circulating tumor DNA (ctDNA) -based liquid biopsy tests showed that his original CDK12 mutation fell undetectable twice. This phenomenon was observed only when he was responding well to platinum-based chemotherapy. His responses to immunotherapy were not satisfying. This case indicates that platinum-based chemotherapy can be a good option for treating patients with CDK12 mutation. More importantly, dynamic ctDNA-based liquid biopsies to monitor patients' CDK12 mutation status are critical in evaluating patients' response and tolerance during platinum-based chemotherapy, therefore may lead to a better overall prognosis. In conclusion, CDK12-mutated prostate cancer patients are likely to benefit from platinum-based chemotherapy, especially with the help of dynamic ctDNA-based liquid biopsies to monitor their CDK12 mutation status. [ABSTRACT FROM AUTHOR]

Background: Clear cell renal cell carcinoma (ccRCC) is the most common and highly heterogeneous subtype of renal cell carcinoma. Dysregulated basal cell adhesion molecule (BCAM) gene is associated with poor prognosis in various cancers. However, the dysregulated functions and related multi-omics features of BCAM in ccRCC stay unclear. Results: BCAM expression was aberrantly downregulated in ccRCC and correlated with adverse pathological parameters and poor prognosis. Low mRNA expression of BCAM was remarkably associated with its CpG methylation levels and BAP1 mutation status. Patients with lower-expressed BCAM concomitant with BAP1 mutation had a worse prognosis. Using RNA-seq data from The cancer genome atlas, we found that compared to the BCAM-high expression subgroup, ccRCC patients in the BCAM-low expression subgroup had significantly higher levels of immune infiltration, higher immune checkpoint expression levels and lower TIDE (tumor immune dysfunction and exclusion) score, indicating potential better response to immunotherapy. Data from the Clinical Proteomic Tumor Analysis Consortium further validated the association between low BCAM expression and CD8 + inflamed phenotype at protein level. Meanwhile, our results suggested that the angiogenesis-related pathways were enriched in the BCAM-high expression subgroup. More importantly, according to the data from the GDSC database, we revealed that the BCAM-high expression subgroup should be more sensitive to anti-angiogenetic therapies, including sorafenib, pazopanib and axitinib. Conclusions: These results suggest that BCAM could serve as a biomarker distinguishing different tumor microenvironment phenotypes, predicting prognosis and helping therapeutic decision-making for patients with ccRCC. [ABSTRACT FROM AUTHOR]

Background: To use ddPCR to quantify plasma exosomal class III β‐tubulin (βIII‐tubulin, TUBB3, encoded by the TUBB3 gene) mRNA expression in metastatic castration‐resistant prostate cancer (mCRPC) patients, and study the association of this expression with abiraterone efficacy. Methods: Blood samples were prospectively collected from 52 mCRPC patients using abiraterone as first‐line therapy to measure plasma exosomal TUBB3 mRNA expression value before the initiation of abiraterone. Study endpoints were PSA response rate, PSA‐progression‐free survival (PSA‐PFS), and overall survival (OS, from CRPC to death). Results: Patients with positive exosomal TUBB3 expression showed shorter PSA‐PFS (negative TUBB3 vs. positive TUBB3: 11.0 vs. 7.9 months; p = 0.014). Further analysis demonstrated that patients with strongly positive exosomal TUBB3 (>20 copies/20 µl) was associated with even shorter PSA‐PFS (negative TUBB3 vs. positive TUBB3 [<20 copies/20 µl] vs. strongly positive TUBB3 [>20 copies/20 µl]: 11.0 vs. 8.3 vs. 3.6 months, p = 0.005). In multivariate analyzes, TUBB3 (+) (HR: 2.114, p = 0.033) and ECOG score >2 (HR: 3.039, p = 0.006) were independent prognosticators of poor PSA‐PFS. PSA response and OS did not present significant differences. Conclusion: The exosomal TUBB3 mRNA expression level is associated with poor PSA‐PFS of abiraterone in mCRPC patients. The detection of exosomal TUBB3 can be valuable in their management. [ABSTRACT FROM AUTHOR]

Pelvic lymph node dissection (PLND) represents the gold standard for nodal staging in PCa and is recommended for patients with a probability of lymph node invasion (LNI) >5%. However, the therapeutic role of PLND and its extent remains a debate. In this study, data of 20,668 patients treated with radical prostatectomy (RP) with and without PLND from SEER database between 2010 and 2015 were retrospectively analyzed. All patients had a risk of LNI >5% according to 2012-Briganti nomogram. Propensity score matching (PSM) was performed to balance baseline characteristics between patients with and without PLND. Kaplan-Meier curves and Cox regression were used to evaluate the impacts of the PLND and its extent on cancer-specific survival (CSS) and overall survival (OS). In overall cohort, patients with PLND were associated with more aggressive clinicopathologic characteristics and had poorer survival compared to those without PLND (5-year CSS rate: 98.4% vs. 99.7%, p < 0.001; 5-year OS rate: 96.3% vs. 97.8%, p < 0.001). In the post-PSM cohort, no significant difference in survival was found between patients with and without PLND (5-year CSS rate: 99.4% vs. 99.7%, p = 0.479; 5-year OS rate: 97.3% vs. 97.8%, p = 0.204). In addition, the extent of PLND had no impact on prognosis (all p > 0.05). Subgroup analyses reported similar negative findings. In conclusion, neither PLND nor its extent was associated with survival in North American patients with a risk of LNI >5%. The cut-off point of 5% probability of LNI might be too low to show benefits in survival in patients underwent PLND. [ABSTRACT FROM AUTHOR]

Background: The optimal treatment for patients with high-risk prostate cancer (PCa) remains a debate and selection of patients to receive proper therapy is still an unsettled question. This systematic review was conducted to compare the effectiveness of prostatectomy (RP) and radiotherapy (RT) in patients with high-risk PCa and to select candidates for optimal treatment. Methods: PubMed, EMBASE, and Cochrane Central Register of Controlled Trials were searched for eligible studies. We extracted hazard ratios (HRs) and 95% confidence interval (CI) of all included studies. The primary outcomes were overall survival (OS) and cancer-specific survival (CSS); the secondary outcomes were biochemical recurrence-free survival (BRFS), metastasis-free survival (MFS) and clinical recurrence-free survival (CRFS). The meta-analysis was performed using Review Manager 5.3. Subgroup analyses were conducted according to Gleason score (GS), T stage and RT types. Quality of life (QoL) was compared with these two treatments. Results: A total of 25 studies were included in this meta-analysis. Overall, RP showed more survival benefits than RT on CSS (P = 0.003) and OS (P = 0.002); while RT was associated with better BRFS (P = 0.002) and MFS (P = 0.004). Subgroup analyses showed RT was associated with similar or even better survival outcomes compared to RP in patients with high GS, high T stage or received external beam radiotherapy plus brachytherapy (EBRT + BT). As for QoL, RP was associated with poorer urinary and sexual function but better performance in the bowel domain. Conclusion: RP could prolong the survival time of patients with high-risk PCa; however, RT could delay the disease progression, and combined RT (EBRT + BT) even brought preferable CSS and similar OS compared to RP. RT might be the prior choice for patients with high T stage or high GS. RP could lead to poorer urinary and sexual function, while bringing better performance in the bowel domain. [ABSTRACT FROM AUTHOR]

Background: The appropriate timing of radiotherapy (RT) for patients after radical prostatectomy (RP) with adverse pathological features (APFs) remains controversial. This systematic review was conducted to compare the efficacy of adjuvant radiotherapy (ART) and salvage radiotherapy (SRT).Methods: PubMed, EMBASE, Web of Science and the Cochrane Library electronic databases were searched to retrieve the required. The hazard ratio (HR) and corresponding 95% confidence interval (CI) of overall survival (OS), biochemical recurrence-free survival (BRFS) and distant metastases-free survival (DMFS) were extracted. The survival benefits of ART with SRT (including early salvage radiotherapy (ESRT)) were analyzed. The process of the meta-analysis was performed with RevMan version 5.3.Results: A total of fifteen retrospective studies were finally included in the final analysis including 5586 patients. The pooled analysis indicated that ART could achieve better control of prostate cancer and improve OS (p = 0.0006), BRFS (p < 0.0001) and DMFS (p < 0.0001), when compared to SRT. The subgroup analysis of the 5-year OS rate demonstrated that the ART group still had survival advantages compared to the SRT group (p = 0.0006). However, ART and SRT were comparable in 10-year OS rate (p = 0.07). ART had advantages over SRT in both 5-year (p = 0.0003) and 10-year BRFS (p = 0.0003). The subgroup analysis with different follow-up starting points from RP or RT was essentially consistent with the above results. The pooled analysis also showed that ART was superior to ESRT on OS (p = 0.008) and DMFS (p = 0.03), and comparable to ESRT on BRFS (p = 0.1).Conclusions: According to this meta-analysis, ART could be served as a preferential treatment for patients with APFs after RP to improve prognosis. Certainly, high-quality, multicenter randomized controlled trials (RCTs) are expecting to confirm the outcomes of our meta-analysis in the future. [ABSTRACT FROM AUTHOR]

The survival of patients diagnosed with metastatic renal cell carcinoma (RCC) is still limited and the current targeted therapies are only partially effective. Herein, we investigated the clinical value and functions of adiponectin receptors (AdipoR1 and AdipoR2) in metastatic renal cell carcinoma (RCC) patients treated with tyrosine kinase inhibitors (TKIs). A total of 127 mRCC patients treated with first-line TKIs between 2008 and 2017 at a single institution were collected. AdipoR1 and AdipoR2 expression was assessed by immunohistochemistry. AdipoR1 was positively expressed in 87.4% (111/127) of tumors, especially, highly expressed in pulmonary and bone lesions. Patients with low-AdipoR1 expression in primary tumor tissues were more likely to suffer from progressive disease during TKIs treatment (40.0% vs. 11.1%, P = 0.02), and with decreased progression-free survival (PFS: 19.5 vs. 37.8 mo, P =.001) and overall survival (OS: 62.3 vs 101.1 mo, P =.004) compared to those with high-AdipoR1 expression. Moreover, low-AdipoR1 expression in metastatic tissues was also associated with poor PFS (P =.006) and OS (P =.037). In contrast, AdipoR2 expression was neither associated with sunitinib response nor patient survival. In vitro, we found that adiponectin inhibited migration, invasion and sensitized RCC cells to sunitinib though interacting with AdipoR1, but not AdipoR2. Furthermore, we demonstrated that adiponentin-AdipoR1 axis inhibits tumor cells migration and invasion by blocking the GSK3β/β-Catenin pathway and enhances sunitinib sensitivity via abrogating PI3K/AKT/NF-κB signaling. Our results suggest that adiponentin-AdipoR1 axis may serve as a predictor of TKIs response and could be a potential therapeutic target in the future treatment for metastatic RCC. [ABSTRACT FROM AUTHOR]

Background: In clinical practice, the detection of biomarkers is mostly based on primary tumors for its convenience in acquisition. However, immune checkpoints may express differently between primary and metastatic tumor. Therefore, we aimed to compare the differential expressions of PD-1, PD-L1 and PD-L2 between the primary and metastatic sites of renal cell carcinoma (RCC).Methods: Patients diagnosed with RCC by resection or fine needle aspiration of metastasis were included. Immunohistochemistry (IHC) was applied to detect PD-1, PD-L1 and PD-L2 expressions. SPSS 22.0 was applied to conduct Chi-square, consistency tests and Cox's proportional hazards regression models. GraphPad Prism 6 was used to plot survival curves and R software was used to calculate Predictive accuracy (PA).Results: In the whole cohort (N = 163), IHC results suggested a higher detection rate of PD-L1 in the metastasis than that of the primary site (χ2 = 4.66, p = 0.03), with a low consistent rate of 32.5%. Among different metastatic tumors, PD-1 was highly expressed in the lung/lymph node (65.3%) and poorly expressed in the brain (10.5%) and visceral metastases (12.5%). PD-L1 was highly expressed in lung/lymph node (37.5%) and the bone metastases (12.2%) on the contrary. In terms of survival analysis, patients with PD-1 expression either in the primary or metastasis had a shorter overall survival (OS) (HR: 1.59, 95% CI 1.08-2.36, p = 0.02). Also, PD-L1 expression in the primary was associated with a shorter OS (HR 2.55, 95% CI 1.06-6.15, p = 0.04). In the multivariate analysis, the predictive accuracy of the whole model for PFS was increased from 0.683 to 0.699 after adding PD-1.Conclusion: PD-1, PD-L1 and PD-L2 were differentially expressed between primary and metastatic tumors. Histopathological examination of these immune check points in metastatic lesions of mRCC should be noticed, and its accurate diagnosis may be one of the effective ways to realize the individualized treatment. [ABSTRACT FROM AUTHOR]

Background: Due to the significant heterogeneity of renal cell carcinoma (RCC), immune checkpoints may express differently between primary and metastatic tumor. We aimed to evaluate the differential expression of TIM-3 between the primary and metastatic sites of RCC.Methods: Cases of RCC with metastases resected or biopsied at West China Hospital between January 2009 and November 2016 were included. Clinicopathological parameters were retrospectively extracted. SPPS 22.0, GraphPad Prism 6 and R statistical software were applied for data analysis.Results: A total of 163 cases were included. Immunohistochemical results showed that the overall detection rate of TIM-3 was 56.4% (92/163). The detection rate of TIM-3 in the primary (53.0%, 44/83) was numerically higher than that of the metastasis (42.6%,79/174). Although the concordance rate of TIM-3 between the primary and metastasis was as high as 66.3% (55/83) in the paired cohort, a significant statistically difference of TIM-3 expression between the primary and metastasis was observed (χ2 = 4.664, p = 0.002), with a poor consistency (Kappa = 0.331, p = 0.002). Subsequent survival analysis suggested that TIM-3 expression either in the primary or metastatic tumor was associated with longer progression-free survival (PFS) (HR: 0.67, 95% CI 0.45-0.99, P = 0.02) and overall survival (OS) (HR: 0.52, 95% CI 0.33-0.82, P < 0.001). The expressions of TIM-3 in the primary, metastatic tumors and patients treated with targeted agents all played as favorable factors for PFS and OS. Further multivariate analysis showed that, in the whole cohort, TIM-3 expression in metastatic tumor increased the predicted accuracy (PA) of the whole model of PFS from 74.7 to 75.6% (P = 0.02). For OS, the PA of whole model was increased from 78.1 to 81.1% by adding TIM-3 expression in the metastasis (P = 0.005). The same trends were also observed in paired patients and patients treated with targeted agents. In conclusion, the expression difference between the primary and metastatic tumor of TIM-3 was significant. Biopsy or resection of the metastases may provide a more accurate biological information for clinician's decision-making and the patient's prognosis. What's more, the role of TIM-3 in the RCC still remains controversy, further study are needed to verify the conclusion. [ABSTRACT FROM AUTHOR]

We conducted a systematic network meta-analysis to review the relevant literature evaluating the therapeutic efficacy of upfront docetaxel (Doc) or abiraterone (Abi) plus androgen deprivation therapy (ADT) on oncological outcome in patients with castration-naïve prostate cancer (CNPC). An attempt to identify subgroups of patients who would benefit most either from Doc or Abi plus ADT and further compare the efficacy and safety between these two combination therapies was made. A comprehensive search of the PubMed/Medline, Embase databases, International Clinical Trial Registration Platform (ICTRP), Clinical Trial, and Cochrane Central Register of Controlled Trials to December 2017 was performed. Six studies, involving 6480 patients, were included in this meta-analysis, consisting of over 60% (4462/6480) of patients with metastatic CNPC (mCNPC, M1), and 31.1% (2018/6480) of patients with non-metastatic CNPC (M0). In total, combination therapies (ADT plus Doc or Abi) significantly improved overall survival (OS) and failure-free survival (FFS) for all CNPC patients. For M1 patients, combination therapies were dramatically associated with improved OS and FFS, but for M0 patients, only with moderate improvement in FFS. M1 patients < 70 years old, Eastern Cooperative Oncology Group (ECOG) performance status (ECOG PS) 0-1, Gleason score (< 8), or visceral metastases could realize better survival benefit from either combination therapy. In indirect comparisons among M1 patients with younger age (< 70 years), ECOG PS 0-1 or aggressive Gleason score (GS ≥ 8), upfront Abi showed superiority to Doc in prolonging FFS. The incidence of severe adverse events (AEs ≥ 3) was comparable between these two therapeutic regimens. In conclusion, upfront Doc or Abi plus ADT should be considered a standard of care in selected patients with mCNPC. For a subset of populations, Abi may be the first choice for men who start treatment for the first time. [ABSTRACT FROM AUTHOR]

Objective: The role of additional chemotherapy in the treatment of high-risk prostate cancer (PCa) remains a controversy. This meta-analysis aimed to investigate the effect of additional chemotherapy on high-risk PCa. Methods: Randomized controlled trials (RCTs) about additional chemotherapy for high-risk PCa were searched in PubMed, MEDLINE, EMBASE, and the Cochrane Central Register of Controlled Trials. We extracted HRs of overall survival (OS) and progression-free survival (PFS) for each trial and performed the meta-analysis using Review Manager 5.3.Results: Eight RCTs involving 4,007 patients were included. Data from four trials, which could collect OS, showed that additional chemotherapy could not significantly improve the OS in patients with high-risk PCa (HR: 0.93; 95% CI: 0.79–1.09; P=0.37). However, the pooled analysis suggested significantly longer PFS in high-risk PCa patients treated with additional chemotherapy (HR: 0.81; 95% CI: 0.74–0.90; P,0.0001). The meta-analysis showed additional chemotherapy to androgen-deprivation therapy improved PFS (HR: 0.82; 95% CI: 0.74–0.91; P=0.0002). Greater improvement in PFS was found in high-risk PCa patients treated with additional docetaxel-based chemotherapy (HR: 0.73; 95% CI: 0.64–0.83; P,0.00001). No pro-longed PFS was observed in high-risk PCa patients with non-docetaxel-based chemotherapy (HR: 0.97; 95% CI: 0.83–1.14; P=0.74).Conclusion: Additional chemotherapy, especially docetaxel-based chemotherapy, could significantly improve the PFS in high-risk PCa patients. More evidence about the effect of additional chemotherapy on OS is needed. Further investigations in PCa should also focus on the suitable population for chemotherapy as well as optimal use of chemotherapy. [ABSTRACT FROM AUTHOR]

The cover image is based on the Research Article Exosomal TUBB3 mRNA expression of metastatic castration‐resistant prostate cancer patients: Association with patient outcome under abiraterone by Hao Zeng et al., https://doi.org/10.1002/cam4.4168. [ABSTRACT FROM AUTHOR]