Search Results (11)

Objectives: The objective of this study was to investigate the prognostic value of systemic inflammatory markers (SIMs)—namely, the neutrophil-to-lymphocyte ratio (NLR) and platelet-to-lymphocyte ratio (PLR)—on survival outcomes and treatment responses in patients with metastatic castration-resistant prostate cancer (mCRPC) receiving abiraterone (ABI) or enzalutamide (ENZA) therapy. Methods: In this two-center retrospective observational study, researchers analyzed clinical data from 106 patients diagnosed with mCRPC. The cut-offs for NLR and PLR were determined to be 2.83 and 156, respectively, and their effects on progression-free survival (PFS) and overall survival (OS) were evaluated using Kaplan–Meier and Cox regression analyses. Changes in SIMs before and after ABI/ENZA treatment were assessed using the Wilcoxon signed-rank test. Results: Lower NLR (≤2.83) and PLR (≤156) were significantly associated with longer PFS and OS; however, in multivariate analysis, only high PLR emerged as an independent adverse prognostic factor for OS (HR: 2.01; p = 0.026). Meanwhile, treatment response was an independent predictor of PFS, and no significant changes were observed in the mean platelet volume (MPV), platelet distribution width (PDW), or platelet–large cell ratio (P-LCR) after treatment. Conclusions: SIMs, such as NLR and especially PLR, may serve as practical and accessible tools for predicting survival in mCRPC patients; however, further prospective studies are warranted. Full article

We conducted a retrospective evaluation of the clinical outcomes and prognostic factors in patients with nonmetastatic castration-resistant prostate cancer (nmCRPC) treated with first-line androgen receptor signaling inhibitors (ARSI) in real-world clinical practice in Japan. Between 2012 and 2023, a total of 127 consecutive patients with nmCRPC received ARSI treatment. Overall survival (OS), metastatic-free survival (MFS), and prostate-specific antigen–progression-free survival (PSA–PFS) from ARSI initiation were assessed using the Kaplan–Meier methodology. Clinical factors associated with OS in nmCRPC were analyzed using the Cox proportional hazards model. Among the patients, 72, 26, 12, and 17 received enzalutamide (ENZ), abiraterone (ABI), apalutamide (APA), and darolutamide (DARO) as first-line therapy. The median OS and MFS for all patients were 79.0 and 42.0 months, respectively. Median PSA–PFS was 27.0, 20.0, 10.0, and 14.0 months for patients treated with ENZ, ABI, APA, and DARO, respectively (p = 0.33). Multivariate analysis revealed that a baseline PSA level ≥ 3.67 ng/mL at ARSI initiation was significantly associated with poorer OS (p = 0.002). ARSI demonstrated favorable efficacy in nmCRPC patients. There were no significant differences in clinical outcomes among different types of ARSI therapy for nmCRP. Elevated baseline PSA at ARSI initiation was significantly associated with poorer OS. Full article

Introduction: In the United States, a total of 268,490 men were found to have prostate cancer in 2022, thus making it the most common cancer in men, accounting for 27% of all cancers in the male population. Among all cancers in men, it was the fifth leading cause of death, with 34,500 deaths and a mortality rate of 11%. In 2019, the total number of cases was 94,748, making it the leading cancer in males, accounting for 11% of all male cancers. In terms of mortality, it ranked seventh, with 13,217 deaths and a mortality rate of 1.6%. However, new treatment options for metastatic castration-sensitive prostate cancer (mCSPC) have emerged. Docetaxel has been shown to be effective for both mCSPC and castration-resistant prostate cancer (CRPC). Upfront docetaxel has not been approved in Japan, nor has it been validated in large-scale studies. Furthermore, several agents can be used after docetaxel treatment, but it is unclear which is the most effective. We used a large Japanese health insurance database to determine which agent would be the most effective as a next-line therapy in patients who had received docetaxel. Materials and Methods: We used data from medical institutions using the Diagnosis Procedure Combination (DPC), which provides a comprehensive evaluation of medical classifications. The Medical Data Vision database covers approximately 23% of DPC hospitals in Japan. This study analyzed 2938 patients with mCSPC who received docetaxel, followed by CRPC, between April 2008 and December 2021. The study focused on three agents: enzalutamide, abiraterone acetate, and cabazitaxel. Other agents were excluded due to the small number of patients. The following data were analyzed: age, date of CRPC diagnosis, presence of bone metastasis, drug type, and prognosis. Results: This study included 1997 patients with CRPC after upfront docetaxel therapy for mCSPC (enzalutamide [ENZ] group, n = 998; abiraterone acetate [ABI] group, n = 617; and cabazitaxel [CBZ] group, n = 382). The overall survival (OS) time from drug initiation was 456 days in the enzalutamide group, which was significantly longer than that in the cabazitaxel group (p = 0.017, HR 0.94) (ENZ: ABI p = 0.54, HR 0.94; ABI: CBZ p = 0.14, HR 0.75). OS was also compared for the third-line drug in the group that received enzalutamide as the second-line drug, the group that used abiraterone acetate as the third-line drug (ENZ-ABI group), and the group that used abiraterone acetate as the second-line drug. OS from the start of the third-line drug was compared between the ENZ–ABI group and the ABI–ENZ group, which received enzalutamide as the third-line drug, but showed no significant difference (269 vs. 281 days, p = 0.85; HR 1.03). Conclusion: ENZ was shown to prolong OS relative to cabazitaxel after the cessation of docetaxel. ENZ was associated with a longer duration of drug use than ABI and CBZ. Full article

Introduction: Androgen receptor pathway inhibitors (ARPIs) have been increasingly offered to older patients with prostate cancer (PC). However, prognostic factors relevant to their outcome with ARPIs are still little investigated. Methods and Materials: The Meet-URO network ADHERE was a prospective multicentre observational cohort study evaluating and monitoring adherence to ARPIs metastatic castrate-resistant PC (mCRPC) patients aged ≥70. Cox regression univariable and multivariable analyses for radiographic progression-free (rPFS) and overall survival (OS) were performed. Unsupervised median values and literature-based thresholds where available were used as cut-offs for quantitative variables. Results: Overall, 234 patients were enrolled with a median age of 78 years (73–82); 86 were treated with abiraterone (ABI) and 148 with enzalutamide (ENZ). With a median follow-up of 15.4 months (mo.), the median rPFS was 26.0 mo. (95% CI, 22.8–29.3) and OS 48.8 mo. (95% CI, 36.8–60.8). At the MVA, independent prognostic factors for both worse rPFS and OS were Geriatric G8 assessment ≤ 14 (p < 0.001 and p = 0.004) and PSA decline ≥50% (p < 0.001 for both); time to castration resistance ≥ 31 mo. and setting of treatment (i.e., post-ABI/ENZ) for rPFS only (p < 0.001 and p = 0.01, respectively); age ≥78 years for OS only (p = 0.008). Conclusions: Baseline G8 screening is recommended for mCRPC patients aged ≥70 to optimise ARPIs in vulnerable individuals, including early introduction of palliative care. Full article

Drought has become one of the environmental threats to agriculture and food security. Applications of melatonin (MT) serve as an effective way to alleviate drought stress, but the underlying mechanism remains poorly understood. Here, we found that foliar spray of 100-µM MT greatly mitigated the severe drought stress-induced damages in rice seedlings, including improved survival rates, enhanced antioxidant system, and adjusted osmotic balance. However, mutation of the suppressor of the G2 allele of skp1 (OsSGT1) and ABSCISIC ACID INSENSITIVE 5 (OsABI5) abolished the effects of MT. Furthermore, the upregulated expression of OsABI5 was detected in wild type (WT) under drought stress, irrespective of MT treatment, whereas OsABI5 was significantly downregulated in sgt1 and sgt1abi5 mutants. In contrast, no change of the OsSGT1 expression level was detected in abi5. Moreover, mutation of OsSGT1 and OsABI5 significantly suppressed the expression of genes associated with the antioxidant system. These results suggested that the functions of OsSGT1 in the MT-mediated alleviation of drought stress were associated with the ABI5-mediated signals. Collectively, we demonstrated that OsSGT1 was involved in the drought response of rice and that melatonin promoted SGT1-involved signals to ameliorate drought stress adaption. Full article

Low temperature is a critical environmental factor restricting the physiology of organisms across kingdoms. In prokaryotes, cold shock induces the expression of various genes and proteins involved in cellular processes. Here, a cold-shock protein (ArCspA) from the South Pole-dwelling soil bacterium Arthrobacter sp. A2-5 was introduced into rice, a monocot model plant species. Four-week-old 35S:ArCspA transgenic rice plants grown in a cold chamber at 4 °C survived for 6 days. Cold stress significantly decreased the chlorophyll content in WT plants after 4 days compared with that in 35S:ArCspA transgenic plants. RNA-seq analysis was performed on WT and 35S:ArCspA transgenic rice with/without cold stress. GO terms such as “response to stress (GO:0006950)”, “response to cold (GO:0009409)”, and “response to heat (GO:0009408)” were significantly enriched among the upregulated genes in the 35S:ArCspA transgenic rice under normal conditions, even without cold-stress treatment. The expression of five cold stress-related genes, Rab16B (Os11g0454200), Rab21 (Os11g0454300), LEA22 (Os01g0702500), ABI5 (Os01 g0859300), and MAPK5 (Os03g0285800), was significantly upregulated in the transgenic rice compared with the WT rice. These results indicate that the ArCspA gene might be involved in the induction of cold-responsive genes and provide cold tolerance. Full article

Kelch-like ECH-associated protein 1 (KEAP1)–nuclear factor E2-related factor 2 (NRF2) is the key antioxidant system in animals. In a previous study, we identified a probable KEAP1 ortholog in rice, OsKEAP1, and demonstrated that the downregulation of OsKEAP1 could alter the redox system and impair plant growth, as well as increase the susceptibility to abscisic acid (ABA) in seed germination. However, no NRF2 orthologs have been identified in plants and the mechanism underlying the phenotype changes of downregulated oskeap1 mutants is yet unknown. An in silico search showed that OsABI5 is the gene that encodes a protein with the highest amino acid identity score (38.78%) to NRF2 in rice. In this study, we demonstrated that, via yeast two-hybrids analysis and bimolecular fluorescence complementation assays, OsKEAP1 interacted with OsABI5 via its Kelch repeat domain in the nucleus. In germinating seeds, the expression of OsKEAP1 was significantly downregulated in oskeap1-1 (39.5% that of the wild-type (WT)) and oskeap1-2 (64.5% that of WT), while the expression of OsABI5 was significantly increased only in oskeap1-1 (247.4% that of WT) but not in oskeap1-2 (104.8% that of WT). ABA (0.5 μM) treatment significantly increased the expression of OsKEAP1 and OsABI5 in both the oskeap1 mutants and WT, and 4 days post treatment, the transcription level of OsABI5 became significantly greater in oskeap1-1 (+87.2%) and oskeap1-2 (+55.0%) than that in the WT. The ABA-responsive genes (OsRab16A and three late embryogenesis abundant genes), which are known to be activated by OsABI5, became more responsive to ABA in both oskeap1 mutants than in the WT. The transcript abundances of genes that regulate OsABI5, e.g., OsSnRK2 (encodes a kinase that activates OsABI5), OsABI1, and OsABI2 (both encode proteins binding to OsSnRK2 and are involved in ABA signaling) were not significantly different between the two oskeap1 mutants and the WT. These results demonstrated that OsKEAP1 played a role in the ABA response in rice seed germination via regulating OsABI5, which is the key player in the ABA response. In-depth analyses of the components and their action mode of the KEAP1–NRF2 and ABA signaling pathways suggested that OsKEAP1 likely formed a complex with OsABI5 and OsKEG, and OsABI5 was ubiquitinated by OsKEG and subsequently degraded under physiological conditions; meanwhile, under oxidative stress or with increased an ABA level, OsABI5 was released from the complex, phosphorylated, and transactivated the ABA response genes. Therefore, OsKEAP1–OsABI5 bore some resemblance to KEAP1–NRF2 in terms of its function and working mechanism. Full article

UDP-glycosyltransferases (UGTs) play key roles in modulating plant development and responses to environmental challenges. Previous research reported that the Arabidopsis UDP-glucosyltransferase 74E2 (AtUGT74E2), which transfers glucose to indole-3-butyric acid (IBA), is involved in regulating plant architecture and stress responses. Here, we show novel and distinct roles of UGT74E2 in rice. We found that overexpression of AtUGT74E2 in rice could enhance seed germination. This effect was also observed in the presence of IBA and abscisic acid (ABA), as well as salt and drought stresses. Further investigation indicated that the overexpression lines had lower levels of free IBA and ABA compared to wild-type plants. Auxin signaling pathway gene expression such as for OsARF and OsGH3 genes, as well as ABA signaling pathway genes OsABI3 and OsABI5, was substantially downregulated in germinating seeds of UGT74E2 overexpression lines. Consistently, due to reduced IBA and ABA levels, the established seedlings were less tolerant to drought and salt stresses. The regulation of rice seed germination and stress tolerance could be attributed to IBA and ABA level alterations, as well as modulation of the auxin/ABA signaling pathways by UGT74E2. The distinct roles of UGT74E2 in rice implied that complex and different molecular regulation networks exist between Arabidopsis and rice. Full article

Lignans are bioactive compounds that are especially abundant in the Norway spruce (Picea abies L. Karst.) knotwood. By combining a variety of chromatographic, spectroscopic and imaging techniques, we were able to quantify, qualify and localise the easily extractable lignans in the xylem tissue. The knotwood samples contained 15 different lignans according to the gas chromatography-mass spectrometry analysis. They comprised 16% of the knotwood dry weight and 82% of the acetone extract. The main lignans were found to be hydroxymatairesinols HMR1 and HMR2. Cryosectioned and resin-embedded ultrathin sections of the knotwood were analysed with scanning transmission X-ray microscopy (STXM). Cryosectioning was found to retain only lignan residues inside the cell lumina. In the resin-embedded samples, lignan was interpreted to be unevenly distributed inside the cell lumina, and partially confined in deposits which were either readily present in the lumina or formed when OsO₄ used in staining reacted with the lignans. Furthermore, the multi-technique characterisation enabled us to obtain information on the chemical composition of the structural components of knotwood. A simple spectral analysis of the STXM data gave consistent results with the gas chromatographic methods about the relative amounts of cell wall components (lignin and polysaccharides). The STXM analysis also indicated that a torus of a bordered pit contained aromatic compounds, possibly lignin. Full article

Sequential treatment of androgen receptor axis targeted agents (ARAT), abiraterone acetate (ABI) and enzalutamide (ENZA), in metastatic castration-resistant prostate cancer (mCRPC) demonstrated some positive effects, but cross-resistances between ABI and ENZA that reduce activity have been suggested. Therefore, we conducted a meta-analysis to compare oncologic outcomes between the treatment sequences of ABI-ENZA and ENZA-ABI in patients with mCRPC. The primary endpoint was a combined progression-free survival (PFS), and the secondary endpoint was overall survival (OS). A total of five trials on 553 patients were included in this study. Each of the included studies was retrospective. In two studies including both chemo-naïve and post-chemotherapy mCRPC patients, for ABI-ENZA compared with ENZA-ABI, pooled hazard ratios (HRs) for PFS and OS were 0.37 (p < 0.0001; 95% confidence intervals (CIs), 0.23–0.60) and 0.64 (p = 0.10; 95% CIs, 0.37–1.10), respectively. In three studies with chemo-naïve mCRPC patients only, for ABI-ENZA compared with ENZA-ABI, pooled HRs for PFS and OS were 0.57 (p = 0.02; 95% CIs, 0.35–0.92) and 0.86 (p = 0.39; 95% CIs, 0.61–1.21), respectively. The current meta-analysis revealed that ABI-ENZA had a significantly more favorable oncological outcome, but the level of evidence was low. Therefore, large-scale randomized trials may be needed. Full article

Testosterone plays a significant role in maintaining the tumor microenvironment. The role of the target serum testosterone (TST) level in enzalutamide- (Enza) and abiraterone (Abi)-treated castration-resistant prostate cancer (CRPC) patients was studied. In total, 107 patients treated with Enza and/or Abi at Chiba University Hospital and affiliated hospitals were studied. The relationships between progression-free survival (PFS), overall survival (OS), and clinical factors were studied by Cox proportional hazard and Kaplan–Meier models. In the Abi and Enza groups overall, TST ≥ 13 ng/dL (median) (Hazard Ratio (HR) 0.43, p = 0.0032) remained an independent prognostic factor for PFS. In the Enza group, TST ≥ 13 ng/dL (median) was found to be a significant prognostic factor (HR 0.28, p = 0.0044), while, in the Abi group, TST ≥ 12 ng/dL (median) was not significant (HR 0.40, p = 0.0891). TST showed significant correlation with PFS periods (r = 0. 32, p = 0.0067), whereas, for OS, TST ≥ 13 ng/dL (median) showed no significant difference in the Abi and Enza groups overall. According to Kaplan–Meier analysis, a longer PFS at first-line therapy showed a favorable prognosis in the Enza group (p = 0.0429), while no difference was observed in the Abi group (p = 0.6051). The TST level and PFS of first-line therapy may be considered when determining the treatment strategy for CRPC patients. Full article