Search Results (81)

PARP inhibitors (PARPi), alone or in combination with androgen receptor signaling inhibitors (ARSi), have shown clinical benefit in metastatic castration-resistant prostate cancer (mCRPC), particularly in tumors with homologous recombination repair (HRR) gene alterations. Recent data from the TALAPRO-2 trial complete the current evidence on PARPi–ARSi combination strategies in this setting. Background/Objectives: To evaluate the efficacy and safety of PARPi-based therapies—monotherapy and combination with ARSi—in patients with mCRPC, focusing on molecular subgroups defined by DNA repair alterations. Methods: We conducted a systematic review and meta-analysis of phase III randomized controlled trials (RCTs) assessing PARPi as monotherapy or in combination with ARSi. Searches were performed in PubMed, EMBASE, the Cochrane Library, and oncology conference proceedings up to February 2025. Outcomes included radiographic progression-free survival (rPFS), overall survival (OS), second progression-free survival (PFS2), and grade ≥3 adverse events (AEs). Data were pooled using a random-effects model, with subgroup analyses by DNA repair status. Results: Five RCTs (n = 2921) were I confirmincluded: three on combination therapy (n = 2271) and two on monotherapy (n = 650). Combination therapy improved rPFS in the ITT (HR = 0.64; 95% CI: 0.56–0.74), HRRm (HR = 0.55; 95% CI: 0.44–0.68), and BRCAm (HR = 0.33; 95% CI: 0.18–0.58) subgroups. OS was also improved in the ITT (HR = 0.80; 95% CI: 0.70–0.92), HRRm (HR = 0.68; 95% CI: 0.55–0.83), and BRCAm (HR = 0.54; 95% CI: 0.34–0.85) groups. No benefit was observed in non-HRRm patients. PFS2 favored combination therapy (HR = 0.77; 95% CI: 0.64–0.91). Grade ≥3 AEs were more frequent (RR = 1.44; 95% CI: 1.20–1.73). Monotherapy improved rPFS in ITT (HR = 0.46; 95% CI: 0.20–0.81) and BRCAm (HR = 0.33; 95% CI: 0.15–0.75); OS benefit was seen only in BRCAm (HR = 0.73; 95% CI: 0.57–0.95). Conclusions: PARPi therapies improve outcomes mainly in HRR- and BRCA-mutated mCRPC. Molecular selection is key to optimizing benefit and minimizing toxicity. Further research on the activity of PARPi combinations in non-HRR mutated mCRPC is needed to better understand the underlying mechanisms of efficacy. Full article

Background: The management of metastatic hormone-sensitive prostate cancer (mHSPC) has evolved with the integration of androgen receptor signaling inhibitors (ARSIs) and metastasis-directed therapies (MDTs). Stereotactic body radiotherapy (SBRT) offers precise local control, yet real-world data on its combination with apalutamide remain limited. Methods: We conducted a multicenter retrospective cohort study including 134 patients with mHSPC treated with apalutamide and SBRT between February 2021 and December 2024. The primary endpoints were progression-free survival (PFS), local control (LC), and treatment safety. PSA kinetics and radiologic response were evaluated, and outcomes were analyzed according to PSA thresholds and treatment timing. Results: Most patients (93.3%) had low-volume disease; 97.1% presented with ≤5 metastases. At a median follow-up of 28 months, LC was 99.3% and 95.5% of patients were progression-free. Complete radiological response was achieved in 87.5% of patients, and 68.4% attained ultralow PSA levels (≤0.02 ng/mL). Undetectable PSA and radiologic complete response were independently associated with improved PFS (p = 0.010 and p = 0.011, respectively). Treatment was well tolerated, with grade ≥3 toxicity occurring in only 2.2% of patients. Conclusions: The combination of apalutamide and SBRT in mHSPC is associated with high local and systemic disease control and minimal toxicity in a real-world setting. This approach may delay systemic treatment intensification and the onset of castration resistance. Prospective studies are warranted to confirm these findings. Full article

Aboveground biomass models are useful for assessing vegetation conditions and providing valuable information on the availability of ecosystem goods and services, including carbon stock and forest/rangeland products. This study aimed to develop aboveground biomass estimation models for the common woody species found in Borana woodland. Multispecies and species-specific models for aboveground biomass were developed using 114 destructively sampled trees representing five species. The dendrometric variables selected as predictors of the trees’ aboveground dry biomass for both multispecies and species-specific models were diameter at breast height, tree height, wood basic density (ρ), crown area (ca) and crown diameter (cd). The distribution of biomass across trees’ aboveground components was estimated using destructively sampled trees. Most tree biomass is allocated to branches, followed by the stems. The tree diameter, wood basic density, and crown diameter were significant predictors in generic and species-specific biomass models across all tree components. Incorporating wood basic density into the model significantly improved prediction accuracy, while tree height had a minimal effect on biomass estimation. The stem and twig biomasses were the highest and least predictable plant parts, respectively. Compared with the existing models, our newly developed models significantly reduced prediction errors, reinforcing the importance of location-specific models for accurate biomass estimation. Hence, this study fills the geographic and ecological gaps by developing models tailored with the unique conditions of the Borana lowland forest. The accuracy of species-specific biomass models varied among tree species, indicating the need for species-specific models that account for variations in growth architecture, ecological factors, and bioclimatic conditions. Full article

Metastatic hormone-sensitive prostate cancer (mHSPCa) presents de novo or represents significant disease progression and requires systemic treatment. However, progression to castration resistance is inevitable. The treatment landscape has evolved with the introduction of intensified systemic therapy, including androgen deprivation therapy (ADT) combined with either androgen receptor signaling inhibitors (ARSIs) or cytotoxic chemotherapy (doublet therapy) or combined therapy with both agents (triplet therapy). Landmark trials such as CHAARTED, STAMPEDE, LATITUDE, ENZAMET, and TITAN have established combination therapies as the standard of care, demonstrating significant overall survival benefits. More recently, triplet therapy—integrating ADT, docetaxel, and an ARSI—has emerged as an effective approach, particularly in high-volume metastatic disease, as supported by ARASENS and PEACE-1. Advances in imaging, such as PSMA PET-CT, have improved disease detection, allowing earlier detection of metastasis and appropriate therapy. Similarly, genomic profiling has enabled biomarker-driven, personalized treatment strategies. The role of treatment of the primary tumor, by either radiation therapy or cytoreductive prostatectomy, in low-volume disease continues to be explored. As novel therapies, targeted agents, and immunotherapies undergo investigation, optimizing treatment selection based on disease burden, molecular characteristics, and patient factors will be essential. The future of mHSPCa management lies in multidisciplinary, precision-based approaches to improve patient outcomes while balancing treatment efficacy and tolerability. Full article

Background: Gleason scores of 8 or higher indicate a poorer prognosis in metastatic castration-sensitive prostate cancer (mCSPC). This study aims to perform a systematic review and network meta-analysis (NMA) to compare overall survival (OS) and progression-free survival (PFS) among combination therapies with androgen receptor signaling inhibitors (ARSIs) in mCSPC patients, stratified by Gleason score ≥8 and <8. Methods: A literature search was conducted across PubMed, Embase, and Web of Science, using a PRISMA-guided systematic search strategy, covering January 2013 to June 2024. Results: Twelve studies including 12,652 patients were included in the NMAs. In the overall population, most ARSI combination therapies improved survival outcomes, except for orteronel + androgen deprivation therapy (ADT). In the Gleason score ≥8 subgroup, all ARSI combination therapies improved OS, with rezvilutamide showing the highest probability of being the best treatment for OS (HR 0.48, 95% CI 0.31–0.76, P-scores 0.88). In the Gleason score <8 subgroup, only darolutamide + docetaxel + ADT (HR 0.49, 95% CI 0.29–0.81) and apalutamide + ADT (HR 0.67, 95% CI 0.46–0.98) improved OS. Conclusions: ARSI combination therapy is effective for mCSPC patients with Gleason score ≥8, but further investigation is needed to confirm its efficacy in patients with Gleason score <8. Full article

The role of neoadjuvant and adjuvant hormonal or chemotherapy-based treatments before or after radical prostatectomy in localized or locally advanced high-risk prostate cancer (PCa) is currently debatable. European guidelines recommend adjuvant androgen deprivation therapy (ADT) only in pN1 patients after extended pelvic lymph node dissection based on outdated evidence on standard hormonal agents. The introduction of new-generation androgen receptor targeting agents (ARTAs) has revolutionized the treatment of metastatic PCa and might also impact the perioperative management of patients with high-risk localized disease. In the last years, a renewed interest has also arisen in chemotherapy-based neoadjuvant or adjuvant treatments alone or in combination with ADT and/or ARTAs. In the present review, we gathered the current evidence on the oncological outcomes of neoadjuvant and adjuvant systemic treatments in surgically treated patients with localized or locally advanced PCa. Despite mild benefits in terms of pathologic responses or oncological outcomes reported in some studies investigating ADT and/or chemotherapy in this setting of patients, strong evidence to support their use in clinical practice is lacking. Promising data in favor of ARTAs have been gathered from phase II trials and prospective series, but definitive results from phase III trials are awaited to confirm these findings. Full article

For nearly a century, fundamental observations that prostate cancer (PCa) cells nearly always require AR stimulation for sustained proliferation have led to a unidirectional quest to abrogate such a pathway. Similarly focused have been efforts to understand AR-driven processes in the context of elevated expression of its target genes, and much less so on products that become overexpressed when AR signaling is suppressed. Treatment with ARSI results in an increased expression of the TLK1B splice variant via a ‘translational’ derepression driven by the compensatory mTOR activation and consequent activation of the TLK1 > NEK1 > ATR > Chk1 and NEK1 > YAP axes. In due course, this results first in a pro-survival quiescence and then adaptation to ADT and CRPC progression. This constitutes a novel liability for PCa that we have targeted for several years and novel approaches. Full article

Background: Reproductive performance is critical in the pig industry, and improved sow performance could lead to increased economic benefits. GWAS and ROH analyses based on SNP array data were conducted to identify the breed-specific genetic architecture underlying the variation in NBA and TNB. Methods: A total of 7488 breeding pigs with phenotypic data from 1586 Duroc, 2256 Landrace, and 3646 Yorkshire breeds, along with 76,756 SNP markers from Korean grand-grand-parent (GGP) breeding farms, were used. Results: In the Duroc breeds, SNPs on SSC 9 and 17 were found to be associated with the SIDT2 and TGM2 genes, respectively. In the Landrace breed, PPP1R9A, LMTK2, and GTF2H3 on SSCs 9, 3, and 14, respectively, were associated with both TNB and NBA. With the Yorkshire breed genome, GRID1, DLGAP2, ZZEF1, PARG, RNF17, and NDUFAF5 in SSCs 14, 15, 12, 14, 11, and 17, respectively, were associated with NBA and TNB traits. These genes have distinct functions, ranging from synaptic transmission and cytoskeletal organization to DNA repair and cellular energy production. In the Duroc breed, six genes identified in the ROH islands were associated with various biological pathways, molecular functions, and cellular components. NT5DC1 was associated with metaphyseal chondrodysplasia, CRTAC1 with ion binding, CFAP43 with spermatogenic failure, CASC3 with intracellular mRNA localization, ERC2 with cellular component organization, and FOCAD with Focadhesin. In the Landrace and Yorkshire breeds, PDE6D was associated with GTPase inhibitor activity. Conclusions: Through GWAS and ROH analyses, we identified breed-specific SNP markers associated with NBA and TNB in three breed genotypes, providing insights for improving reproductive performance efficiency and contributing to future breeding strategies. Full article

Broiler chicken lameness caused by bacterial chondronecrosis with osteomyelitis (BCO) is presently amongst the most important economic and animal welfare issues faced by the poultry industry, and the estimated economic loss is around USD 150 million. BCO lameness is associated with multiple opportunistic bacterial pathogens inhabiting the respiratory and gastrointestinal tracts. In cases of immune deficiency resulting from stress, injury, or inflammation of the tissue, opportunistic pathogens, mainly Staphylococcus spp., can infiltrate the respiratory or gastrointestinal mucosa and migrate through the bloodstream to eventually colonize the growth plates of long bones, causing necrosis that leads to lameness. This is the first report of developing a Staphylococcus vaccine against BCO lameness disease in broiler chickens. Electron beam (eBeam) technology causes irreparable DNA damage, preventing bacterial multiplication, while keeping the epitopes of the cell membrane intact, helping the immune system generate a more effective response. Our results show a 50% reduction of lameness incidence in the eBeam-vaccinated chicken group compared to the control. Additionally, the eBeam-vaccinated chickens present higher titer of anti-Staphylococcus IgA, signifying the development of an efficient and more specific humoral immune response. Our data establish the eBeam-killed Staphylococcus vaccine as an effective approach to reducing the incidence of lameness in broiler chickens. Full article

Background: The treatment strategy for metastatic castration-sensitive prostate cancer (mCSPC) has changed significantly in recent years. Based on various guidelines, an upfront androgen receptor signaling inhibitor (ARSI) is the first choice, but in patients of Asian descent, including Japanese patients, there are a certain number of cases in which androgen deprivation therapy (ADT) and CAB are more effective. If patients can be identified who show a marked response to ADT within 12 weeks after the initiation of ADT, which is the inclusion criterion for ARSI clinical trials targeting mCSPC, it would be valuable from an economic standpoint. Methods: A total of 218 patients with pure prostate adenocarcinoma and treated with ADT at the Kanazawa University Hospital between January 2000 and December 2020 were included in this study. As a risk classification for mCSPC, in addition to the LATITUDE and CHAARTED criteria, we used the castration-sensitive prostate cancer classification proposed by Kanazawa University (Canazawa), developed by the Department of Urology of Kanazawa University. The Canazawa classification was based on three factors: Gleason pattern 5, bone scan index (BSI) ≥ 1.5, and lactate dehydrogenase (LDH) ≥ 300 IU/L. It defined patients with one factor or less as low-risk and patients with two or three factors as high-risk. The overall survival (OS) and time to castration resistance (TTCR) were estimated retrospectively using the Kaplan–Meier method, and factors associated with TTCR were identified using univariate and multivariate analyses. Results: The median follow-up period was 40.4 months, the median OS period was 85.2 months, and the median TTCR period was 16.4 months. The Canazawa risk classification provided the clearest distinction between the OS and TTCR in mCSPC patients. Multivariate analysis revealed a decrease in PSA levels of <95% at 12 weeks after ADT initiation and was a predictor of short TTCR in low-risk, low-volume patients across all risk classifications. Conclusion: The Canazawa classification differentiated the prognosis of mCSPC patients more clearly. A PSA reduction rate of <95% at 12 w after starting ADT in low-risk, low-volume patients of all risk classifications was significantly shorter than the TTCR. We propose a new treatment strategy, in which patients with low-risk mCSPC are treated with ADT and switched to ARSIs based on the rate of PSA reduction at 12 w. Full article

The purpose of this study was to estimate the homozygosity distribution and compute genomic and conventional inbreeding coefficients in three genetically diverse pig breed populations. The genomic and pedigree data of Duroc (1586), Landrace (2256), and Yorkshire (3646) were analyzed. We estimated and compared various genomic and pedigree inbreeding coefficients using different models and approaches. A total of 709,384 ROH segments in Duroc, 816,898 in Landrace, and 1,401,781 in Yorkshire, with average lengths of 53.59 Mb, 56.21 Mb, and 53.46 Mb, respectively, were identified. Relatively, the Yorkshire breed had the shortest ROH segments, whereas the Landrace breed had the longest mean ROH segments. Sus scrofa chromosome 1 (SSC1) had the highest chromosomal coverage by ROH across all breeds. Across breeds, an absolute correlation (1.0) was seen between F_ROH total and F_ROH1–2Mb, showing that short ROH were the primary contributors to overall F_ROH values. The overall association between genomic and conventional inbreeding was weak, with values ranging from 0.058 to 0.140. In contrast, total genomic inbreeding (F_ROH) and ROH classes showed a strong association, ranging from 0.663 to 1.00, across the genotypes. The results of genomic and conventional inbreeding estimates improve our understanding of the genetic diversity among genotypes. Full article

Despite some advances in controlling the progression of prostate cancer (PCa) that is refractory to the use of ADT/ARSI, most patients eventually succumb to the disease, and there is a pressing need to understand the mechanisms that lead to the development of CRPC. A common mechanism is the ability to integrate AR signals from vanishing levels of testosterone, with the frequent participation of YAP as a co-activator, and pointing to the deregulation of the Hippo pathway as a major determinant. We have recently shown that YAP is post-transcriptionally activated via the TLK1>NEK1 axis by stabilizing phosphorylation at Y407. We are now solidifying this work by showing the following: (1) The phosphorylation of Y407 is critical for YAP retention/partition in the nuclei, and J54 (TLK1i) reverses this along with YAP-Y407 dephosphorylation. (2) The enhanced degradation of (cytoplasmic) YAP is increased by J54 counteracting its Enzalutamide-induced accumulation. (3) The basis for all these effects, including YAP nuclear retention, can be explained by the stronger association of pYAP-Y407 with its transcriptional co-activators, AR and TEAD1. (4) We demonstrate that ChIP for GFP-YAP-wt, but hardly for the GFP-YAP-Y407F mutant, at the promoters of typical ARE- and TEAD1-driven genes is readily detected but becomes displaced after treatment with J54. (5) While xenografts of LNCaP cells show rapid regression following treatment with ARSI+J54, in the VCaP model, driven by the TMPRSS2-ERG oncogenic translocation, tumors initially respond well to the combination but subsequently recur, despite the continuous suppression of pNek1-T141 and pYAP-Y407. This suggests an alternative parallel pathway for CRPC progression for VCaP tumors in the long term, which may be separate from the observed ENZ-driven YAP deregulation, although clearly some YAP gene targets like PD-L1, that are found to accumulate following prolonged ENZ treatment, are still suppressed by the concomitant addition of J54. 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

Biochemical recurrence (BCR) after primary treatments for prostate cancer (PC) is an extremely heterogeneous phase and at least a stratification into low- and high-risk cases for early progression in metastatic disease is necessary. At present, PSA-DT represents the best parameter to define low- and high-risk BCR PC, but real precision medicine is strongly suggested to define tailored management for patients with BCR. Before defining management, it is necessary to exclude the presence of low-volume metastasis associated with PSA progression using new-generation imaging, preferably with PSMA PET/CT. Low-risk BCR cases should be actively observed without early systemic therapies. Early treatment of low-risk BCR with continuous androgen deprivation therapy (ADT) can produce disadvantages such as the development of castration resistance before the appearance of metastases (non-metastatic castration-resistant PC). Patients with high-risk BCR benefit from early systemic therapy. Even with overall survival (OS) as the primary treatment endpoint, metastasis-free survival (MFS) should be used as a surrogate endpoint in clinical trials, especially in long survival stages of the disease. The EMBARK study has greatly influenced the management of high-risk BCR, by introducing the concept of anticipation and intensification through the use of androgen receptor signaling inhibitors (ARSIs) and ADT combination therapy. In high-risk (PSA-DT ≤ 9 months) BCR cases, the combination of enzalutamide with leuprolide significantly improves MFS when compared to leuprolide alone, maintaining an unchanged quality of life in the asymptomatic phase of the disease. The possibility of using ARSIs alone in this early disease setting is suggested by the EMBARK study (arm with enzalutamide alone) with less evidence than with the intensification of the combination therapy. Continued use versus discontinuation of enzalutamide plus leuprolide intensified therapy upon reaching undetectable PSA levels needs to be better defined with further analysis. Real-world analysis must verify the significant results obtained in the context of a phase 3 study. Full article

Segmentation of Agricultural Remote Sensing Images (ARSIs) stands as a pivotal component within the intelligent development path of agricultural information technology. Similarly, quick and effective delineation of urban green spaces (UGSs) in high-resolution images is also increasingly needed as input in various urban simulation models. Numerous segmentation algorithms exist for ARSIs and UGSs; however, a model with exceptional generalization capabilities and accuracy remains elusive. Notably, the newly released Segment Anything Model (SAM) by META AI is gaining significant recognition in various domains for segmenting conventional images, yielding commendable results. Nevertheless, SAM’s application in ARSI and UGS segmentation has been relatively limited. ARSIs and UGSs exhibit distinct image characteristics, such as prominent boundaries, larger frame sizes, and extensive data types and volumes. Presently, there is a dearth of research on how SAM can effectively handle various ARSI and UGS image types and deliver superior segmentation outcomes. Thus, as a novel attempt in this paper, we aim to evaluate SAM’s compatibility with a wide array of ARSI and UGS image types. The data acquisition platform comprises both aerial and spaceborne sensors, and the study sites encompass most regions of the United States, with images of varying resolutions and frame sizes. It is noteworthy that the segmentation effect of SAM is significantly influenced by the content of the image, as well as the stability and accuracy across images of different resolutions and sizes. However, in general, our findings indicate that resolution has a minimal impact on the effectiveness of conditional SAM-based segmentation, maintaining an overall segmentation accuracy above 90%. In contrast, the unsupervised segmentation approach, SAM, exhibits performance issues, with around 55% of images (3 m and coarser resolutions) experiencing lower accuracy on low-resolution images. Whereas frame size exerts a more substantial influence, as the image size increases, the accuracy of unsupervised segmentation methods decreases extremely fast, and conditional segmentation methods also show some degree of degradation. Additionally, SAM’s segmentation efficacy diminishes considerably in the case of images featuring unclear edges and minimal color distinctions. Consequently, we propose enhancing SAM’s capabilities by augmenting the training dataset and fine-tuning hyperparameters to align with the demands of ARSI and UGS image segmentation. Leveraging the multispectral nature and extensive data volumes of remote sensing images, the secondary development of SAM can harness its formidable segmentation potential to elevate the overall standard of ARSI and UGS image segmentation. Full article