Publications

Introduction: 5-ethylamino-9-diethylaminobenzo[a]phenoselenazinium (EtNBSe) is a novel synthetic bipolar photosensitizer with many promising applications. This study investigated the impact of EtNBSe-mediated photodynamic therapy (EtNBSe-PDT) on the autophagy and endoplasmic reticulum (ER) stress of squamous carcinoma cells (A-431 cells), as well as the related molecular mechanisms. Methods: The potency of EtNBSe-PDT against squamous cell carcinoma was evaluated in BALB/c nude mice. Cell viability was evaluated using MTT. Western blotting and immunofluorescence were used to determine the expression levels of ER stress- and autophagy-related proteins. Results: Both morphological and microscopic findings showed that the tumor on the xenograft mice exhibited an apparent reduction in volume and was replaced with fibrosis 20 days after EtNBSe-PDT. Additionally, in an in vitro study using A-431 cells, EtNBSe-PDT was found to inhibit A-431 cell survival in an EtNBSe concentration- and light dose- dependent manner, and to induce ER stress via the PERK-eIF2α signaling pathway. Additionally, EtNBSe-PDT could also induce autophagy of A-431 cells. Furthermore, the ER stress inhibitor 4-PBA and the eIF2α inhibitor salubrinal were found to inhibit the autophagy induced by EtNBSe-PDT. Conclusion: This study demonstrated that the PERK-eIF2α signaling pathway was involved in the ER stress induced by EtNBSe-PDT. Meanwhile, the ER stress via the PERK-eIF2α pathway promoted the occurrence of autophagy in A-431 cells. Keywords: photodynamic therapy, endoplasmic reticulum stress, squamous cell carcinoma, autophagy

<p>Plotting a) the median spread of coverage per-gene, from the pooled reference data and b) the per-gene standard deviations for duplicated samples shows that some genes are less reliable than others.</p>

182 Background: IPATential150 is a randomized trial comparing Ipat + Abi vs placebo + Abi in patients (pts) with 1L mCRPC (NCT03072238). We evaluated the potential associations between PTEN loss, genomic alterations, and country of enrollment (East Asian [EAS] vs non-EAS). Methods: Before randomization, tumor samples (archival > 90%) were centrally tested for PTEN loss by VENTANA PTEN (SP218) immunohistochemistry (IHC) assay (N = 1101). Tumor genetic alterations were profiled by Foundation Medicine FoundationOne CDx (F1CDx) NGS assay (n = 735). Results: Of 1101 pts enrolled, 521 (47%) had PTEN loss by IHC. An overall 76% agreement was observed between PTEN IHC and F1CDx. TMPRSS2 fusion, alterations in TP53 and PTEN were most frequent (28%-32%). Alterations in PIK3CA, SPOP, APC, MYC, RAD21, and genes involved in DNA damage repair, including BRCA2, CDK12, ATM, had a 5%-8% prevalence. PTEN loss (IHC) tended to co-occur with genetic alterations in TP53 and TMPRSS2. The prevalence of PTEN loss in EAS vs non-EAS pts was 35% vs 50% by IHC and 15% vs 31% by F1CDx. Alterations in CDK12, BRCA2, SPOP, and MYC were more prevalent in EAS pts, whereas alterations in TMPRSS2, PTEN, and TP53 were more prevalent in non-EAS pts. Conclusions: This analysis reveals molecular heterogeneity in prostate cancer and association between potentially actionable targets. It also suggests that EAS pts with mCRPC have a genetic profile that may be at least quantitatively different from non-EAS pts. Clinical trial information: NCT03072238. [Table: see text]

What is known and objective Since the beginning of the COVID-19 outbreak in China in December 2019, the epidemic has continued to spread globally. Despite continuous reports of clinical trials being launched, no studies have yet systematically summarized and analysed their characteristics. Our objective is to do this by reviewing trials registered at ClinicalTrials.gov. Methods We searched the ClinicalTrials.gov database and retrieved all clinical trials on COVID-19 registered up to and including 3 April 2020. We summarized the characteristics of the trials, presenting the results of all trials, all intervention trials and drug intervention (including vaccines and traditional Chinese medicine) trials. Results and discussion We identified 306 COVID-19-related clinical trials. Seven of the studies had been withdrawn, leaving 299 active trials. Of the trials, 28.8% were planned to be conducted in Asia, 26.8% in Europe and 18.7% in North America. Most (73.0%) proposed trials expected to recruit fewer than 500 people, and only 22.1% of the studies included children (aged <18 years). About two-thirds (67.2%) of the studies were funded by the own resources of medical or research institutions. Of intervention trials, 73.9% used random allocation, and 73.4% used parallel assignment. Only 36.7% of the intervention trials used blinding. In terms of drug trials, 147 trials were drug intervention studies, covering 80 conventional drugs and seven traditional Chinese medicine drugs. Antiviral drugs and antimalarial drugs were the most commonly studied drugs with 52 and 45 trials registered, respectively. Five registered clinical trials were on vaccines. What is new and conclusion A large number of COVID-19-related trials have been registered within the first 4 months since the first infection was reported. These involve a large number of different drugs, the most common being antiviral drugs and antimalarial drugs. More attention should be paid to adequate blinding in future trials.

&lt;p&gt;Genomic regions used for the targeted panel sequencing in this study.&lt;/p&gt;

Metastatic castration-resistant prostate cancer (mCRPC) remains a lethal disease with current standard-of-care therapies. Homologous recombination repair (HRR) gene alterations, including

Whether immune-related adverse events (irAEs) indicate drug activity in patients treated with immune checkpoint inhibitors remains unknown.To investigate the association between irAEs and recurrence-free survival (RFS) in the double-blind EORTC 1325/KEYNOTE-054 clinical trial comparing pembrolizumab therapy and placebo for the treatment of patients with high-risk stage III melanoma.A total of 1019 adults with stage III melanoma were randomly assigned on a 1:1 ratio to receive treatment with pembrolizumab therapy or placebo. Eligible patients were adults 18 years and older with complete resection of cutaneous melanoma metastatic to lymph nodes, classified with stage IIIA (at least 1 micrometastasis measuring >1 mm in greatest diameter), IIIB, or IIIC (without in-transit metastasis) cancer. Patients were randomized from August 26, 2015, to November 14, 2016. The clinical cutoff for the data set was October 2, 2017. Analyses were then performed on the database, which was locked on November 28, 2017.Participants were scheduled to receive 200 mg of pembrolizumab or placebo every 3 weeks for a total of 18 doses for approximately 1 year or until disease recurrence, unacceptable toxic effects, major protocol violation, or withdrawal of consent.The association between irAEs and RFS was estimated using a Cox model adjusted for sex, age, and AJCC-7 stage, with a time-varying covariate that had a value of 0 before irAE onset and 1 after irAE onset.Of 1011 patients who began treatment with pembrolizumab therapy or placebo, 622 (61.5%) were men and 389 (38.5%) were women; 386 patients (38.2%) were aged 50 to 64 years, 377 (37.3%) were younger than 50 years, and 248 (24.5%) were 65 years and older. Consistent with the reported main analysis in the intent-to-treat population, RFS was longer in the pembrolizumab arm compared with the placebo arm (hazard ratio [HR], 0.56; 98.4% CI, 0.43-0.74) among patients who started treatment. The incidence of irAEs was 190 (37.4%) in the pembrolizumab arm (n = 509) and 45 (9.0%) in the placebo arm (n = 502); in each treatment group, the incidence was similar for men and women. The occurrence of an irAE was associated with a longer RFS in the pembrolizumab arm (HR, 0.61; 95% CI, 0.39-0.95; P = .03) in both men and women. However, in the placebo arm, this association was not significant. Compared with the placebo arm, the reduction in the hazard of recurrence or death in the pembrolizumab arm was greater after the onset of an irAE than without or before an irAE (HR, 0.37; 95% CI, 0.24-0.57 vs HR, 0.61; 95% CI, 0.49-0.77, respectively; P = .03).In this study, the occurrence of an irAE was associated with a longer RFS in the pembrolizumab arm.ClinicalTrials.gov identifier: NCT02362594; EudraCT identifier: 2014-004944-37.

This paper explores the lateral load-carrying behaviour of coupled steel-concrete composite (SCC) wall-frame structures, which comprise concrete-filled steel tubular (CFST) columns, composite beams and composite walls. Both experimental and numerical studies were conducted. The experimental programme includes one single-storey bare frame structure and three single-storey coupled SCC wall-frame structures. The experimental results showed that applying the composite wall can significantly increase the lateral load-carrying capacity of the entire structure. It was also evident that increasing the wall width and lowering the structural height can effectively enhance the lateral load-carrying capacity. The modelling approaches in ABAQUS and OpenSees were proposed to conduct the finite element (FE) analysis. In particular, ABAQUS was used to build single-storey coupled SCC wall-frame structures to assess the effects of several parameters, such as beam stiffness, the thickness of steel tubes and wall faceplates, wall width, concrete grade, steel grade and axial load ratio. It was found that increasing the thickness of steel tubes and wall faceplates as well as wall width can effectively increase the lateral performance of the structure but increasing the steel beam stiffness only results in limited improvement. Increasing the steel grade can improve the lateral performance of the structure much more significantly than the concrete grade. When the axial load ratio reaches 0.6, the lateral strength of the structure is greatly reduced owing to the P-Δ effect. Moreover, one multi-storey bare frame structure and three multi-storey coupled SCC wall-frame structures were constructed in OpenSees as a case study. The multi-storey coupled SCC wall-frame structures display extraordinary lateral load-carrying capacity by analysing the curves of base shear force versus roof drift ratio. Besides that, instead of the nominal inter-storey drift ratio, the destructive inter-storey drift ratio together with the roof drift ratio are recommended to assess the multi-storey coupled SCC wall-frame structures in order to avoid overconservative design.

251 Background: Immune checkpoint inhibitors (CPIs) (anti-CTLA4, anti-PD-1/PD-L1 mAbs) have had limited monotherapy activity in prostate cancer (PC) compared to urothelial cancer (UC). Recent biomarker studies revealed molecular features associated w/ better efficacy/resistance to CPIs in UC. 1 Here we examined the tumor immune microenvironment (iTME) of hormone naïve/sensitive (HSPC) &amp; castrate resistant prostate (CRPC) specimens from primary &amp; metastatic sites, to determine if parallels to UC molecular correlates exist that will allow us to predict subsets of PC pts who are more likely to benefit from rational combination therapies w/ CPIs. Methods: Tumor FFPE archival tissues (HSPC, n = 98; CRPC, n = 46; Unk, n = 6) were sourced from a Royal Melbourne Hospital cohort of PC patients. Tissues were evaluated by H&amp;E for TILs &amp; IHC performed for PD-L1 (clones SP142 &amp; SP263) &amp; CD8. RNAseq was conducted &amp; Lund bladder molecular subtyping performed during bioinformatics analyses. TCGA PRAD dataset was used for further validation. Results: We first applied Lund molecular subtyping to broadly categorize this cohort into luminal/basal subtypes. CRPC tumors were almost entirely luminal, whereas HSPC tumors were mainly basal. Luminal PC tumors enriched for Wnt gene sets (p = 0.026) &amp; enriched for a genomically unstable (GU) subtype w/ higher expression of DNA damage repair (DDR) &amp; cell cycle gene sets (p = 0.082). Compared to CRPC, HSPCs had higher numbers of infiltrating CD8s (p = 4.37e-004), increased expression of T-effector, MHC-I antigen presentation machinery, immune checkpoints, macrophages &amp; activated stromal biology, including the fibroblast TGFβ response signature. PD-L1 on immune cells by SP142 &amp; SP263 was 30% &amp; 17% respectively &amp; was enriched in HSPC samples (SP142: CRPC 18% vs. HSPC 34%, p = 0.08). Within patients w/ CRPC, differences were minimal between primary &amp; metastatic samples. Conclusions: These analyses on the iTME contexture of PC reveal potentially actionable biological nodes for targeted therapies. These findings could inform future clinical strategies to improve CPI responses in CRPC &amp; HSPC w/ rationale combinations.1. Mariathasan et al. Nature 2018.

&lt;div&gt;Abstract&lt;p&gt;&lt;b&gt;Purpose:&lt;/b&gt; The MYC oncogene is frequently overexpressed in prostate cancer. Upregulation of ribosome biogenesis and function is characteristic of MYC-driven tumors. In addition, PIM kinases activate MYC signaling and mRNA translation in prostate cancer and cooperate with MYC to accelerate tumorigenesis. Here, we investigate the efficacy of a single and dual approach targeting ribosome biogenesis and function to treat prostate cancer.&lt;/p&gt;&lt;p&gt;&lt;b&gt;Experimental Design:&lt;/b&gt;The inhibition of ribosomal RNA (rRNA) synthesis with CX-5461, a potent, selective, and orally bioavailable inhibitor of RNA polymerase I (Pol I) transcription, has been successfully exploited therapeutically but only in models of hematologic malignancy. CX-5461 and CX-6258, a pan-PIM kinase inhibitor, were tested alone and in combination in prostate cancer cell lines, in Hi-MYC- and PTEN-deficient mouse models and in patient-derived xenografts (PDX) of metastatic tissue obtained from a patient with castration-resistant prostate cancer.&lt;/p&gt;&lt;p&gt;&lt;b&gt;Results:&lt;/b&gt; CX-5461 inhibited anchorage-independent growth and induced cell-cycle arrest in prostate cancer cell lines at nanomolar concentrations. Oral administration of 50 mg/kg CX-5461 induced TP53 expression and activity and reduced proliferation (MKI67) and invasion (loss of ductal actin) in Hi-MYC tumors, but not in PTEN-null (low MYC) tumors. While 100 mg/kg CX-6258 showed limited effect alone, its combination with CX-5461 further suppressed proliferation and dramatically reduced large invasive lesions in both models. This rational combination strategy significantly inhibited proliferation and induced cell death in PDX of prostate cancer.&lt;/p&gt;&lt;p&gt;&lt;b&gt;Conclusions:&lt;/b&gt; Our results demonstrate preclinical efficacy of targeting the ribosome at multiple levels and provide a new approach for the treatment of prostate cancer. &lt;i&gt;Clin Cancer Res; 22(22); 5539–52. ©2016 AACR&lt;/i&gt;.&lt;/p&gt;&lt;/div&gt;