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Cyclic high-dose testosterone administration, known as bipolar androgen therapy (BAT), is a treatment strategy for patients with metastatic castration-resistant prostate cancer (mCRPC). Here, we report the results of a multicenter, single arm Phase 2 study (NCT03554317) enrolling 45 patients with heavily pretreated mCRPC who received BAT (testosterone cypionate, 400 mg intramuscularly every 28 days) with the addition of nivolumab (480 mg intravenously every 28 days) following three cycles of BAT monotherapy. The primary endpoint of a confirmed PSA 50 response rate was met and estimated at 40% ( N  = 18/45, 95% CI: 25.7–55.7%, P  = 0.02 one-sided against the 25% null hypothesis). Sixteen of the PSA 50 responses were achieved before the addition of nivolumab. Secondary endpoints included objective response rate (ORR), median PSA progression-free survival, radiographic progression-free survival (rPFS), overall survival (OS), and safety/tolerability. The ORR was 24% ( N  = 10/42). Three of the objective responses occurred following the addition of nivolumab. After a median follow-up of 17.9 months, the median rPFS was 5.6 (95% CI: 5.4–6.8) months, and median OS was 24.4 (95% CI: 17.6–31.1) months. BAT/nivolumab was well tolerated, resulting in only five (11%) drug related, grade-3 adverse events. In a predefined exploratory analysis, clinical response rates correlated with increased baseline levels of intratumoral PD-1 + T cells. In paired metastatic tumor biopsies, BAT induced pro-inflammatory gene expression changes that were restricted to patients achieving a clinical response. These data suggest that BAT may augment antitumor immune responses that are further potentiated by immune checkpoint blockade. Bipolar androgen therapy (BAT) is a treatment option for patients with metastatic castration-resistant prostate cancer (mCRPC). Here the authors report the results of a phase 2 trial of BAT plus nivolumab (anti-PD1) in patients with advanced mCRPC.

In this study, the compostability of treatment sludge sourced from the food industry (TS) and cattle manure (CM) was investigated. For this purpose, sunflower stalks (SS) were added as a bulking agent and composting experiments were performed. Different mixtures (R 1 , R 2 , R 3 ) were prepared in order to determine the individual and co-compostability of the raw materials used. In the R 1 reactor, TS and SS in the ratio of 70:30, in the R 2 reactor, CM and SS in the ratio of 70:30, and in the R 3 reactor, TS, CM and SS in the ratio of 35:35:30 were mixed, respectively. Temperature, organic matter, pH, electrical conductivity (EC) and C/N ratio parameters were monitored during the 21-day process. The highest temperatures during the composting process were determined as 43.9°C, 43.9°C and 53.7°C in the R 1 , R 2 and R 3 reactors, respectively. When the C/N ratios are examined, R 3 , in which the C/N ratio had decreased at a rate of 18.5% by the end of the process and which had the highest temperature rise, can be defined as the best reactor. It has been found that the efficiency of the composting process of food industry treatment sludge and cattle manure is high.

This study aimed to investigate the compostability of treatment sludge and to determine the effects of adding different animal manures (cattle, pig, horse, and chicken) and agricultural waste (sunflower stalks) on the composting process. Five different compost reactors (M1, M2, M3, M4, and M5) were operated. Sunflower stalks were added to all reactors as a bulking agent at the rate of 20%. Treatment sludge (80%) and bulking agent were added to the M1 reactor, where animal manure was not added, while 40% treatment sludge and 40% animal manure were added to the other reactors. In the reactors where animal manure was added, cattle (M2), pig (M3), horse (M4), and chicken (M5) manure were used, respectively. The temperature, pH, electrical conductivity, organic matter (OM), carbon to nitrogen ratio (C/N), total Kjeldahl nitrogen, and total phosphorus were monitored during the 21-day process. The highest OM loss (64.8%) occurred in the M2 reactor, and the maximum temperature (62.7 °C) was achieved. The high temperatures reached in the reactor increased microbial activity, resulting in rapid decomposition of OM and elimination of pathogens. With a maximum reduction in the C/N ratio (40%), carbon and nitrogen balance was achieved, thus obtaining a more stable and higher quality compost for plants in this reactor. In the M1 reactor, where only treatment sludge was composted, lower microbiological activity occurred compared to the other mixtures due to the lack of substrate. It can be said that composting treatment sludge together with animal manures will provide higher quality end products.

Increased mitochondrial function may render some cancers vulnerable to mitochondrial inhibitors. Since mitochondrial function is regulated partly by mitochondrial DNA copy number (mtDNAcn), accurate measurements of mtDNAcn could help reveal which cancers are driven by increased mitochondrial function and may be candidates for mitochondrial inhibition. However, prior studies have employed bulk macrodissections that fail to account for cell type-specific or tumor cell heterogeneity in mtDNAcn. These studies have often produced unclear results, particularly in prostate cancer. Herein, we developed a multiplex in situ method to spatially quantify cell type-specific mtDNAcn. We show that mtDNAcn is increased in luminal cells of high-grade prostatic intraepithelial neoplasia (HGPIN), is increased in prostatic adenocarcinomas (PCa), and is further elevated in metastatic castration-resistant prostate cancer. Increased PCa mtDNAcn was validated by 2 orthogonal methods and is accompanied by increases in mtRNAs and enzymatic activity. Mechanistically, MYC inhibition in prostate cancer cells decreases mtDNA replication and expression of several mtDNA replication genes, and MYC activation in the mouse prostate leads to increased mtDNA levels in the neoplastic prostate cells. Our in situ approach also revealed elevated mtDNAcn in precancerous lesions of the pancreas and colon/rectum, demonstrating generalization across cancer types using clinical tissue samples.

Over the last few decades, fine needle aspiration cytology (FNA) has emerged as a SAFE (Simple, Accurate, Fast, Economical) diagnostic tool based on the morphologic evaluation of cells. The first and most important step in obtaining accurate results from FNA is to procure sufficient and representative material from the lesion and to appropriately transfer this material to the laboratory. Unfortunately, the most important aspect of this task occurs beyond the control of the cytopathologist, a key reason for obtaining unsatisfactory results with FNA. There is growing interest in the field of cytology in \"cytopathologist-performed ultrasound (US)-guided FNA,\" which has been reported to yield accurate results. The first author has been applying FNA in his own private cytopathology practice with a radiologist and under the guidance of US for more than 20 years. This study retrospectively reviews the utility of this practice. We present a selection of didactic examples under different headings that highlight the application of FNA by a cytopathologist, accompanied by US, under the guidance of a radiologist, in the form of an \"outpatient FNA clinic.\" The use of this technique enhances diagnostic accuracy and prevents pitfalls. The highlights of each case are also outlined as \"take-home messages.\"

Understanding the intricacies of lethal prostate cancer poses specific challenges due to difficulties in accurate modeling of metastasis in vivo. Here we show that mice (for - ) develop prostate cancer with a high penetrance of metastasis to bone, thereby enabling detection and tracking of bone metastasis in vivo and ex vivo. Transcriptomic and whole-exome analyses of bone metastasis from these mice revealed distinct molecular profiles conserved between human and mouse and specific patterns of subclonal branching from the primary tumor. Integrating bulk and single-cell transcriptomic data from mouse and human datasets with functional studies in vivo unravels a unique MYC/RAS co-activation signature associated with prostate cancer metastasis. Finally, we identify a gene signature with prognostic value for time to metastasis and predictive of treatment response in human patients undergoing androgen receptor therapy across clinical cohorts, thus uncovering conserved mechanisms of metastasis with potential translational significance.

Prostate adenocarcinoma is the second most commonly diagnosed cancer in men worldwide, and the initiating factors are unknown. Oncogenic TMPRSS2:ERG (ERG+) gene fusions are facilitated by DNA breaks and occur in up to 50% of prostate cancers. Infection-driven inflammation is implicated in the formation of ERG+ fusions, and we hypothesized that these fusions initiate in early inflammation-associated prostate cancer precursor lesions, such as proliferative inflammatory atrophy (PIA), prior to cancer development. We investigated whether bacterial prostatitis is associated with ERG+ precancerous lesions in unique cases with active bacterial infections at the time of radical prostatectomy. We identified a high frequency of ERG+ non–neoplastic-appearing glands in these cases, including ERG+ PIA transitioning to early invasive cancer. These lesions were positive for ERG protein by immunohistochemistry and ERG messenger RNA by in situ hybridization. We additionally verified TMPRSS2:ERG genomic rearrangements in precursor lesions using tricolor fluorescence in situ hybridization. Identification of rearrangement patterns combined with whole-prostate mapping in three dimensions confirmed multiple (up to eight) distinct ERG+ precancerous lesions in infected cases. We further identified the pathogen-derived genotoxin colibactin as a potential source of DNA breaks in clinical cases as well as cultured prostate cells. Overall, we provide evidence that bacterial infections can initiate driver gene alterations in prostate cancer. In addition, our observations indicate that infection-induced ERG+ fusions are an early alteration in the carcinogenic process and that PIA may serve as a direct precursor to prostate cancer.

Ribosome biosynthesis is a cancer vulnerability executed by targeting RNA polymerase I (Pol I) transcription. We developed advanced, specific Pol I inhibitors to identify drivers of this sensitivity. By integrating multi-omics features and drug sensitivity data from a large cancer cell panel, we discovered that frameshift mutation conferred Pol I inhibitor sensitivity in microsatellite instable cancers. Mechanistically, RPL22 directly interacts with 28S rRNA and mRNA splice junctions, functioning as a splicing regulator. RPL22 deficiency, intensified by 28S rRNA sequestration, promoted the splicing of its paralog RPL22L1 and p53 negative regulator MDM4. Chemical and genetic inhibition of rRNA synthesis broadly remodeled mRNA splicing controlling hundreds of targets. Strikingly, RPL22-dependent alternative splicing was reversed by Pol I inhibition revealing a ribotoxic stress-initiated tumor suppressive pathway. We identify a mechanism that robustly connects rRNA synthesis activity to splicing and reveals their coordination by ribosomal protein RPL22.

Increased mitochondrial function may render some cancers vulnerable to mitochondrial inhibitors. Since mitochondrial function is regulated partly by mitochondrial DNA copy number (mtDNAcn), accurate measurements of mtDNAcn could help reveal which cancers are driven by increased mitochondrial function and may be candidates for mitochondrial inhibition. However, prior studies have employed bulk macrodissections that fail to account for cell type-specific or tumor cell heterogeneity in mtDNAcn. These studies have often produced unclear results, particularly in prostate cancer. Herein, we developed a multiplex method to spatially quantify cell type specific mtDNAcn. We show that mtDNAcn is increased in luminal cells of high-grade prostatic intraepithelial neoplasia (HGPIN), is increased in prostatic adenocarcinomas (PCa), and is further elevated in metastatic castration-resistant prostate cancer. Increased PCa mtDNAcn was validated by two orthogonal methods and is accompanied by increases in mtRNAs and enzymatic activity. Mechanistically, MYC inhibition in prostate cancer cells decreases mtDNA replication and expression of several mtDNA replication genes, and MYC activation in the mouse prostate leads to increased mtDNA levels in the neoplastic prostate cells. Our approach also revealed elevated mtDNAcn in precancerous lesions of the pancreas and colon/rectum, demonstrating generalization across cancer types using clinical tissue samples.

Bu çalışmada, gıda endüstrisi kaynaklı oluşan evsel nitelikli arıtma çamurlarının (AÇ), geri kazanımı için farklı türden hayvan gübreleri (sığır, domuz, at, tavuk) ve düzenleyici katkı maddesi olarak ayçiçeği sapı (AS) ilavesi ile kompostlanabilirliğinin belirlenmesi amaçlanmıştır. Çalışma kapsamında on bir adet (R1, R2, R3, K1, K2, K3, K4, K5, K6, K7, K8) farklı karışım oluşturulmuştur. R1, R2 ve R3 reaktörlerinde %30 oranında ayçiçeği sapı kullanılırken diğer reaktörlerde bu oran %20 olarak belirlenmiştir. Reaktörler için farklı karışım reçeteleri oluşturulmuş olup bazı reaktörlerde sadece arıtma çamuru kullanılırken, bazı reaktörlerde sadece sığır gübresi (SG), at gübresi (AG), tavuk gübresi (TG) kullanılmış ve geri kalan diğer reaktörlerde hem arıtma çamuru hem de hayvan gübreleri birlikte kullanılmıştır. 21 günlük proses boyunca reaktörlerde sıcaklık, nem, organik madde, pH, elektriksel iletkenlik, toplam fosfor, karbon/azot oranı ve toplam kjeldahl azotu parametreleri izlenmiştir. En yüksek sıcaklıklar K3 (AÇ+SG) için 62,7℃, K6 (AÇ+TG) için 62,2℃ ve K5 (AÇ+AG) için 60,2℃ kaydedilmiştir. K6 reaktöründe, diğer reaktörlere oranla en fazla organik madde kaybı (%64,8) gerçekleşmiş ve en yüksek sıcaklığa (62,7℃) ulaşılmıştır. R1 reaktöründe ise arıtma çamurunun tek başına kompostlanması sırasında yeterli substrat bulamayan mikroorganizmalar erken inaktive olmuşlar ve en az OM kaybı (%0,8) ve en düşük sıcaklık (43,9℃) elde edilmiştir. Bu çalışmada arıtma çamurlarının substrat olarak farklı fizikokimyasal özelliklere sahip hayvan gübreleri ile birlikte kompostlanması sonucunda daha verimli kompost son ürünü elde edilebildiği belirlenmiştir.