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A randomized trial tested whether the addition of apalutamide, an androgen receptor blocker, to androgen-deprivation therapy might improve radiographic (including MRI-detected) progression–free survival and overall survival. Apalutamide was significantly more effective than placebo for both end points.

Src kinase-mediated interactions between prostate cancer cells and osteoclasts might promote bone metastasis. Dasatinib inhibits tyrosine kinases, including Src kinases. Data suggests that dasatinib kinase inhibition leads to antitumour activity, affects osteoclasts, and has synergy with docetaxel, a first-line chemotherapy for metastatic castration-resistant prostate cancer. We assessed whether dasatinib plus docetaxel in chemotherapy-naive men with metastatic castration-resistant prostate cancer led to greater efficacy than with docetaxel alone. In this double-blind, randomised, placebo-controlled phase 3 study, we enrolled men of 18 years or older with chemotherapy-naive, metastatic, castration-resistant prostate cancer, and adequate organ function from 186 centres across 25 countries. Eligible patients were randomly assigned (1:1) via an interactive voice response system to receive docetaxel (75 mg/m2 intravenously every 3 weeks, plus oral prednisone 5 mg twice daily), plus either dasatinib (100 mg orally once daily) or placebo until disease progression or unacceptable toxicity. Randomisation was stratified by Eastern Cooperative Oncology Group performance status (0–1 vs 2), bisphosphonate use (yes vs no), and urinary N-telopeptide (uNTx) value (<60 μmol/mol creatinine vs ≥60 μmol/mol creatinine). All patients, investigators, and personnel involved in study conduct and data analyses were blinded to treatment allocation. The primary endpoint was overall survival, analysed by intention to treat. The trial is registered with ClinicalTrials.gov, number NCT00744497. Between Oct 30, 2008, and April 11, 2011, 1522 eligible patients were randomly assigned to treatment; 762 patients were assigned to dasatinib and 760 to placebo. At final analysis, median follow-up was 19·0 months (IQR 11·2–25·1) and 914 patients had died. Median overall survival was 21·5 months (95% CI 20·3–22·8) in the dasatinib group and 21·2 months (20·0–23·4) in the placebo group (stratified hazard ratio [HR] 0·99, 95·5% CI 0·87–1·13; p=0·90). The most common grade 3–4 adverse events included diarrhoea (58 [8%] patients in the dasatinib group vs 27 [4%] patients in the placebo group), fatigue (62 [8%] vs 42 [6%]), and asthenia (40 [5%] vs 23 [3%]); grade 3–4 pleural effusions were uncommon (ten [1%] vs three [<1%]). The addition of dasatinib to docetaxel did not improve overall survival for chemotherapy-naive men with metastatic castration-resistant prostate cancer. This study does not support the combination of dasatinib and docetaxel in this population of patients. Bristol-Myers Squibb.

Background Adult ovarian granulosa cell tumours (GCT) are the most common subtype of ovarian sex cord‐stromal tumours. Forkhead transcription factor FOXL2 is required for development and function of normal granulosa cells, including proliferation and ovarian hormone synthesis. A single somatic missense mutation in FOXL2, c.402C > G (p.Cys134Trp), has previously been identified in the majority of GCT and is a pathognomonic marker for this tumour type. NOTCH activation contributes to GCT survival in preclinical models, and NOTCH2 and NOTCH3 are critical for embryonic development of the ovary and function of the ovarian follicle. Nirogacestat is a potent, selective, noncompetitive inhibitor of gamma secretase, which inhibits NOTCH pathway signalling. Treatment of GCT with nirogacestat was predicted to inhibit granulosa cell survival. Methods A Phase II clinical trial was conducted to assess antitumour activity of nirogacestat in adult patients with relapsed/refractory ovarian GCT (NCT05348356). This study enrolled 53 patients; all were evaluable for efficacy and safety. Endpoints included objective response rate by Response Evaluation Criteria in Solid Tumors v1.1 and 6‐month progression‐free survival (PFS6). Fresh or archival tumour samples were analysed for mutational profiling. Results Patients received a median of 5 prior lines of therapy (range, 1–13) and a median of 3.7 months of treatment (range, 0–20 months). A decrease in tumour burden was seen in 16 (30%) patients; however, there were no confirmed objective responses. Thirty‐one (58%) patients had stable disease; 18 (34%) had progressive disease. Eleven (21%) patients achieved PFS6. No correlations with disease stability were found with baseline clinical characteristics. All 3 patients who had an activating NOTCH1 mutation achieved PFS6. Conclusions In patients with heavily pretreated GCT, nirogacestat treatment resulted in durable disease stabilisation of at least 7 weeks for 58% of patients, with 21% achieving PFS6, including the 3 patients whose tumours had an activating NOTCH1 mutation. Key points This Phase II clinical trial of a rare tumour achieved its enrolment target in under 1 year and completed primary analysis within 2 years. 87% (46 of 53 patients who received nirogacestat) had fresh or archival biopsies that were analysed by next‐generation sequencing for mutational profiling. Of the 3 patients with activating NOTCH1 mutations, all achieved 6‐month progression‐free survival (PFS6); 8 other patients also achieved PFS6 but did not share a common mutation. Evidence suggests NOTCH activation is among the survival and proliferation pathways interacting with FOXL2 c.402C > G (p.Cys134Trp) mutation in granulosa cell tumours (GCT). This Phase II clinical trial of nirogacestat in GCT achieved its enrolment target in < 1 year and primary analysis within 2 years. Activating NOTCH1 mutation was associated with 6‐month progression‐free survival in 3 patients.

The structural gene for cytochrome c2 (cycA) of the photosynthetic bacterium Rhodopseudomonas capsulata has been cloned, and the nucleotide and deduced polypeptide sequences have been determined. Compared with the known amino acid sequence of the purified cytochrome c2, the nucleotide sequence corresponding to the N-terminal part of the cycA gene product indicates the presence of a putative 21 amino acid signal sequence. Thus, cytochrome c2 may be synthesized as a precursor which is processed during its secretion to the periplasm. Insertion and insertion-deletion mutations were constructed in vitro and the chromosomal cycA+ allele of a wild-type strain was replaced with these mutations by homologous recombination to yield c2- mutants of R. capsulata. The c2- mutants are stable, and they can grow by photosynthesis and by respiration. Since cytochrome c2 is the primary electron donor to the reaction center during photosynthesis, the ability of these mutants to grow photosynthetically indicates that an alternative way(s) of reducing the oxidized reaction center must exist in R. capsulata. One candidate for this role may be the membrane-bound cytochrome c1.

SHRs function as hormone activated, sequence specific DNA binding transcription factors that recruit multiple coactivator and other proteins to specific genes and generally stimulate transcription of these genes. SHR may have further genomic actions, that do not involve direct DNA binding, through protein-protein interactions with other sequence specific transcription factors, although these may still involve weak binding to nonconsensus steroid responsive elements in vivo. SHRs also appear to have nongenomic effects mediated through interactions with cytoplasmic signaling proteins. The major functions of SHRs in normal adult tissues appear to involve stimulation of differentiation, rather than proliferation. In contrast, the ERα and AR directly stimulate the growth of breast and prostate cancers, respectively, indicating a critical change in their functions. The ERα and AR appear to undergo further adaptation in tumor cells in response to hormonal therapies, that render these therapies ineffective. Understanding the molecular basis for these changes in SHR function during cancer development and progression may provide new targets for the generation of drugs to prevent and treat steroid stimulated cancers.

Messenger RNA transcription, DNA amplification and progeny production of human papillomaviruses (HPVs) are closely linked to epithelial cell differentiation in patient papillomas. Since these cells have exited the cell cycle for weeks and viral DNA replication requires the host DNA replication machinery, HPVs must have a mechanism to reactivate these host genes. In this thesis, I show via retrovirus-mediated gene transfer that an intact E7 gene of high-risk or of low-risk HPV genotypes, each under the control of its respective native enhancer-E6 promoter, induced proliferating cell nuclear antigen (PCNA) expression in the suprabasal cells of epithelial raft cultures of acutely infected primary human foreskin keratinocytes. The differentiation program of the infected cells was not only unaltered, it was essential for high activity of the E6 promoter. I also show that extensive host DNA replication took place in differentiating cells of E7-containing raft cultures and of patient papillomas. These results suggest that the main function of the E7 protein is to reactivate host DNA replication machinery to support viral replication in differentiated, noncycling cells. I infer that the family of retinoblastoma proteins which E7 proteins inactivate play key roles in controlling all the cellular DNA replication genes. Their inactivation did not however promote progression through mitosis.

The structural gene for cytochrome c 2 ( cycA ) of the photosynthetic bacterium Rhodopseudomonas capsulata has been cloned, and the nucleotide and deduced polypeptide sequences have been determined. Compared with the known amino acid sequence of the purified cytochrome c 2 , the nucleotide sequence corresponding to the N-terminal part of the cycA gene product indicates the presence of a putative 21 amino acid signal sequence. Thus, cytochrome c 2 may be synthesized as a precursor which is processed during its secretion to the periplasm. Insertion and insertion-deletion mutations were constructed in vitro and the chromosomal cycA + allele of a wild-type strain was replaced with these mutations by homologous recombination to yield c 2 - mutants of R. capsulata . The c 2 - mutants are stable, and they can grow by photosynthesis and by respiration. Since cytochrome c 2 is the primary electron donor to the reaction center during photosynthesis, the ability of these mutants to grow photosynthetically indicates that an alternative way(s) of reducing the oxidized reaction center must exist in R. capsulata . One candidate for this role may be the membrane-bound cytochrome c 1 .

Porcine reproductive and respiratory syndrome virus (PRRSV) can infect pigs and cause enormous economic losses to the pig industry worldwide. Porcine sialoadhesin (pSN) and CD163 have been identified as key viral receptors on porcine alveolar macrophages (PAM), a main target cell infected by PRRSV. In this study, the protein structures of amino acids 1–119 from the pSN and cSN (cattle sialoadhesin) N-termini (excluding the 19-amino acid signal peptide) were modeled via homology modeling based on mSN (mouse sialoadhesin) template structures using bioinformatics tools. Subsequently, pSN and cSN homology structures were superposed onto the mSN protein structure to predict the binding sites of pSN. As a validation experiment, the SN N-terminus (including the wild-type and site-directed-mutant-types of pSN and cSN) was cloned and expressed as a SN-GFP chimera protein. The binding activity between SN and PRRSV was confirmed by WB (Western blotting), FAR-WB (far Western blotting), ELISA (enzyme-linked immunosorbent assay) and immunofluorescence assay. We found that the S107 amino acid residue in the pSN N-terminal played a crucial role in forming a special cavity, as well as a hydrogen bond for enhancing PRRSV binding during PRRSV infection. S107 may be glycosylated during PRRSV infection and may also be involved in forming the cavity for binding PRRSV along with other sites, including W2, Y44, S45, R97, R105, W106 and V109. Additionally, S107 might also be important for pSN binding with PRRSV. However, the function of these binding sites must be confirmed by further studies.