Centaurus A, with its gas-rich elliptical host galaxy, NGC 5128, is the nearest radio galaxy at a distance of 3.8 Mpc. Its proximity allows us to study the interaction among an active galactic ...nucleus, radio jets, and molecular gas in great detail. We present ALMA observations of low-J transitions of three CO isotopologues, HCN, HCO+, HNC, CN, and CCH toward the inner projected 500 pc of NGC 5128. Our observations resolve physical sizes down to 40 pc. By observing multiple chemical probes, we determine the physical and chemical conditions of the nuclear interstellar medium of NGC 5128. This region contains molecular arms associated with the dust lanes and a circumnuclear disk (CND) interior to the molecular arms. The CND is approximately 400 pc by 200 pc and appears to be chemically distinct from the molecular arms. It is dominated by dense gas tracers while the molecular arms are dominated by 12CO and its rare isotopologues. The CND has a higher temperature, elevated CN/HCN and HCN/HNC intensity ratios, and much weaker 13CO and C18O emission than the molecular arms. This suggests an influence from the AGN on the CND molecular gas. There is also absorption against the AGN with a low velocity complex near the systemic velocity and a high velocity complex shifted by about 60 km s−1. We find similar chemical properties between the CND in emission and both the low and high velocity absorption complexes, implying that both likely originate from the CND. If the HV complex does originate in the CND, then that gas would correspond to gas falling toward the supermassive black hole.
In eukaryotes, post-translational modification of histones is critical for regulation of chromatin structure and gene expression. EZH2 is the catalytic subunit of the polycomb repressive complex 2 ...(PRC2) and is involved in repressing gene expression through methylation of histone H3 on lysine 27 (H3K27). EZH2 overexpression is implicated in tumorigenesis and correlates with poor prognosis in several tumour types. Additionally, somatic heterozygous mutations of Y641 and A677 residues within the catalytic SET domain of EZH2 occur in diffuse large B-cell lymphoma (DLBCL) and follicular lymphoma. The Y641 residue is the most frequently mutated residue, with up to 22% of germinal centre B-cell DLBCL and follicular lymphoma harbouring mutations at this site. These lymphomas have increased H3K27 tri-methylation (H3K27me3) owing to altered substrate preferences of the mutant enzymes. However, it is unknown whether specific, direct inhibition of EZH2 methyltransferase activity will be effective in treating EZH2 mutant lymphomas. Here we demonstrate that GSK126, a potent, highly selective, S-adenosyl-methionine-competitive, small-molecule inhibitor of EZH2 methyltransferase activity, decreases global H3K27me3 levels and reactivates silenced PRC2 target genes. GSK126 effectively inhibits the proliferation of EZH2 mutant DLBCL cell lines and markedly inhibits the growth of EZH2 mutant DLBCL xenografts in mice. Together, these data demonstrate that pharmacological inhibition of EZH2 activity may provide a promising treatment for EZH2 mutant lymphoma.
Seprehvir (HSV1716) is an oncolytic herpes simplex virus-1 (HSV-1) previously demonstrated to be well tolerated in pediatric patients when administered intratumorally. To determine the safety of ...administering Seprehvir systemically, we conducted the first-in-human phase I trial of intravenous injection in young patients with relapsed or refractory extra-cranial solid cancers. We delivered a single dose of 5 × 104 infectious units (iu)/kg (maximum dose of 2 × 106) or 2.5 × 105 iu/kg (maximum dose of 1 × 107 iu) of Seprehvir via the peripheral vein, monitored adverse events, and measured tumor responses by imaging. We monitored HSV-1 serology as well as viremia and shedding by PCR and culture. We administered a single dose of Seprehvir to seven patients and multiple doses to two patients. We did not observe any dose-limiting toxicities. All five HSV-1 seronegative patients seroconverted by day 28. Four of nine patients had detectable HSV-1 genomes in peripheral blood appearing on day +4 consistent with de novo virus replication. Two patients had stable disease in response to Seprehvir. Intravenous Seprehvir is well tolerated without viral shedding in children and young adults with late-stage cancer. Viremia consistent with virus replication holds promise for future Seprehvir studies at higher doses and/or in combination with other anti-neoplastic therapies.
Oncolytic viruses hold promise for the field of oncology as novel targeted therapies. Streby et al. report the first-in-human intravenous administration of an oncolytic herpes simplex virus and demonstrate its safety in young patients with relapsed or refractory extra-cranial solid cancers.
Summary Background Follicular lymphoma is a clinically and genetically heterogeneous disease, but the prognostic value of somatic mutations has not been systematically assessed. We aimed to improve ...risk stratification of patients receiving first-line immunochemotherapy by integrating gene mutations into a prognostic model. Methods We did DNA deep sequencing to retrospectively analyse the mutation status of 74 genes in 151 follicular lymphoma biopsy specimens that were obtained from patients within 1 year before beginning immunochemotherapy consisting of rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone (R-CHOP). These patients were recruited between May 4, 2000, and Oct 20, 2010, as part of a phase 3 trial (GLSG2000). Eligible patients had symptomatic, advanced stage follicular lymphoma and were previously untreated. The primary endpoints were failure-free survival (defined as less than a partial remission at the end of induction, relapse, progression, or death) and overall survival calculated from date of treatment initiation. Median follow-up was 7·7 years (IQR 5·5–9·3). Mutations and clinical factors were incorporated into a risk model for failure-free survival using multivariable L1-penalised Cox regression. We validated the risk model in an independent population-based cohort of 107 patients with symptomatic follicular lymphoma considered ineligible for curative irradiation. Pretreatment biopsies were taken between Feb 24, 2004, and Nov 24, 2009, within 1 year before beginning first-line immunochemotherapy consisting of rituximab, cyclophosphamide, vincristine, and prednisone (R-CVP). Median follow-up was 6·7 years (IQR 5·7–7·6). Findings We established a clinicogenetic risk model (termed m7-FLIPI) that included the mutation status of seven genes ( EZH2, ARID1A, MEF2B, EP300, FOXO1, CREBBP , and CARD11 ), the Follicular Lymphoma International Prognostic Index (FLIPI), and Eastern Cooperative Oncology Group (ECOG) performance status. In the training cohort, m7-FLIPI defined a high-risk group (28%, 43/151) with 5-year failure-free survival of 38·29% (95% CI 25·31–57·95) versus 77·21% (95% CI 69·21–86·14) for the low-risk group (hazard ratio HR 4·14, 95% CI 2·47–6·93; p<0·0001; bootstrap-corrected HR 2·02), and outperformed a prognostic model of only gene mutations (HR 3·76, 95% CI 2·10–6·74; p<0·0001; bootstrap-corrected HR 1·57). The positive predictive value and negative predictive value for 5-year failure-free survival were 64% and 78%, respectively, with a C -index of 0·80 (95% CI 0·71–0·89). In the validation cohort, m7-FLIPI again defined a high-risk group (22%, 24/107) with 5-year failure-free survival of 25·00% (95% CI 12·50–49·99) versus 68·24% (58·84–79·15) in the low-risk group (HR 3·58, 95% CI 2·00–6·42; p<0.0001). The positive predictive value for 5-year failure-free survival was 72% and 68% for negative predictive value, with a C -index of 0·79 (95% CI 0·69–0·89). In the validation cohort, risk stratification by m7-FLIPI outperformed FLIPI alone (HR 2·18, 95% CI 1·21–3·92), and FLIPI combined with ECOG performance status (HR 2·03, 95% CI 1·12–3·67). Interpretation Integration of the mutational status of seven genes with clinical risk factors improves prognostication for patients with follicular lymphoma receiving first-line immunochemotherapy and is a promising approach to identify the subset at highest risk of treatment failure. Funding Deutsche Krebshilfe, Terry Fox Research Institute.
The outcome of patients with mucosal melanoma treated with ipilimumab is not defined. To assess the efficacy and safety of ipilimumab in this melanoma subset, we performed a multicenter, ...retrospective analysis of 33 patients with unresectable or metastatic mucosal melanoma treated with ipilimumab. The clinical characteristics, treatments, toxicities, radiographic assessment of disease burden by central radiology review at each site, and mutational profiles of the patients' tumors were recorded. Available peripheral blood samples were used to assess humoral immunity against a panel of cancer‐testis antigens and other antigens. By the immune‐related response criteria of the 30 patients who underwent radiographic assessment after ipilimumab at approximately week 12, there were 1 immune‐related complete response, 1 immune‐related partial response, 6 immune‐related stable disease, and 22 immune‐related progressive disease. By the modified World Health Organization criteria, there were 1 immune‐related complete response, 1 immune‐related partial response, 5 immune‐related stable disease, and 23 immune‐related progressive disease. Immune‐related adverse events (as graded by Common Terminology Criteria for Adverse Events version 4.0) consisted of six patients with rash (four grade 1, two grade 2), three patients with diarrhea (one grade 1, two grade 3), one patient with grade 1 thyroiditis, one patient with grade 3 hepatitis, and 1 patient with grade 2 hypophysitis. The median overall survival from the time of the first dose of ipilimumab was 6.4 months (range: 1.8–26.7 months). Several patients demonstrated serologic responses to cancer‐testis antigens and other antigens. Durable responses to ipilimumab were observed, but the overall response rate was low. Additional investigation is necessary to clarify the role of ipilimumab in patients with mucosal melanoma.
摘要
Ipilimumab 在粘膜黑色素瘤患者中的治疗结果还不清楚。为评估 ipilimumab 在这类黑色素瘤亚组中的疗效和安全性，我们针对33例 ipilimumab 治疗的不可切除或转移性粘膜黑色素瘤患者中开展了一项多中心回顾性研究。记录患者临床特征、治疗方案、毒性反应、每所研究中心统一放射学实验室对疾病负担进行的影像学评估，以及患者肿瘤的突变特征。收集外周血样本来评估针对癌症睾丸抗原与其他抗原的体液免疫。 Ipilimumab 治疗后约第12周时，利用免疫相关疗效标准分析30例接受影像学评估的患者，1例达到免疫相关完全缓解，1例为免疫相关的部分缓解，6例为免疫相关的疾病稳定，22例为免疫相关的疾病进展。根据改良的世界卫生组织标准，1例达到免疫相关的完全缓解，1例为免疫相关的部分缓解，5例为免疫相关的疾病稳定，23例为免疫相关的疾病进展。免疫相关的不良事件（基于通用不良事件术语标准4.0版进行分级），6例患者发生皮疹（4例为1级，2例为2级），3例发生腹泻（1例为1级，2例为3级），1例发生1级甲状腺炎，1例发生3级肝炎，1例发生2级下垂体炎。从 ipilimumab 第1剂次给药起计算的中位总生存期为6.4个月（范围，1.8∼26.7个月）。几例患者表现出对癌症睾丸抗原与其他抗原的血清学缓解。研究观察到对 ipilimumab 的持续缓解，但总缓解率偏低。有必要作进一步的研究，来明确 ipilimumab 在粘膜黑色素瘤患者中的治疗结果。The Oncologist 2013;18:726‐732
This multicenter, retrospective analysis assessed the efficacy and safety of ipilimumab in 33 patients with unresectable or metastatic mucosal melanoma. The study provides evidence that ipilimumab can result in durable antitumor effects in a subset of patients with mucosal melanoma, although the response rate was low.
Effectively monitoring the spread of SARS-CoV-2 mutants is essential to efforts to counter the ongoing pandemic. Predicting lineage abundance from wastewater, however, is technically challenging. We ...show that by sequencing SARS-CoV-2 RNA in wastewater and applying algorithms initially used for transcriptome quantification, we can estimate lineage abundance in wastewater samples. We find high variability in signal among individual samples, but the overall trends match those observed from sequencing clinical samples. Thus, while clinical sequencing remains a more sensitive technique for population surveillance, wastewater sequencing can be used to monitor trends in mutant prevalence in situations where clinical sequencing is unavailable.
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