Durvalumab plus tremelimumab for the treatment of advanced neuroendocrine neoplasms of gastroenteropancreatic and lung origin

Single immune checkpoint blockade has shown limited activity in patients with neuroendocrine neoplasms (NENs). Here the authors report the results of a phase II clinical trial of durvalumab (anti-PD-L1) and tremelimumab (anti CTLA-4) in patients with advanced NENs of gastroenteropancreatic and lung origin. Single immune checkpoint blockade in advanced neuroendocrine neoplasms (NENs) shows limited efficacy; dual checkpoint blockade may improve treatment activity. Dune (NCT03095274) is a non-randomized controlled multicohort phase II clinical trial evaluating durvalumab plus tremelimumab activity and safety in advanced NENs. This study included 123 patients presenting between 2017 and 2019 with typical/atypical lung carcinoids (Cohort 1), G1/2 gastrointestinal (Cohort 2), G1/2 pancreatic (Cohort 3) and G3 gastroenteropancreatic (GEP) (Cohort 4) NENs; who progressed to standard therapies. Patients received 1500 mg durvalumab and 75 mg tremelimumab for up to 13 and 4 cycles (every 4 weeks), respectively. The primary objective was the 9-month clinical benefit rate (CBR) for cohorts 1-3 and 9-month overall survival (OS) rate for Cohort 4. Secondary endpoints included objective response rate, duration of response, progression-free survival according to irRECIST, overall survival, and safety. Correlation of PD-L1 expression with efficacy was exploratory. The 9-month CBR was 25.9%/35.5%/25% for Cohorts 1, 2, and 3 respectively. The 9-month OS rate for Cohort 4 was 36.1%, surpassing the futility threshold. Benefit in Cohort 4 was observed regardless of differentiation and Ki67 levels. PD-L1 combined scores did not correlate with treatment activity. Safety profile was consistent with that of prior studies. In conclusion, durvalumab plus tremelimumab is safe in NENs and shows modest survival benefit in G3 GEP-NENs; with one-third of these patients experiencing a prolonged OS

Point mutations affecting yeast prion propagation change the structure of its amyloid fibrils

We investigated the effect of the point substitutions in the N-terminal domain of the yeast prion protein Sup35 (Sup35NMp) on the structure of its amyloid fibrils. As the objects of the study, proteins with mutations that have different influence on the [PSI+] prion propagation, but do not prevent the aggregation of Sup35NMp in vitro were chosen. The use of the wide range of physico-chemical methods allowed us to show significant differences in the structure of these aggregates, their physical size, clumping tendency. Also we demonstrated that the fluorescent probe thioflavin T (ThT) can be successfully used for investigation of subtle changes in the structural organization of fibrils formed from various Sup35NMp. The obtained results and our theoretical predictions allowed us to conclude that some of selected amino acid substitutions delimit the region of the protein that forms the core of amyloid fibrils, and change the fibrils structure. The relationship of structural features of in vitro Sup35NMp amyloid aggregates with the stability of the [PSI+] prion in vivo allowed us to suggest that oligopeptide repeats (R) of the amyloidogenic N-terminal domain of Sup35NMp from R0 to R2 play a key role in protein aggregation. Their arrangement rather than just presence is critical for propagation of the strong [PSI+] prion variants. The results confirm the suitability of the proposed combination of theoretical and empirical approaches for identifying changes in the amyloid fibrils structure, which, in turn, can significantly affect both the functional stability of amyloid fibrils and their pathogenicity.Laboratorio de Investigación y Desarrollo de Bioactivo

Signals: I. Survey description

SIGNALS, the Star formation, Ionized Gas, and Nebular Abundances Legacy Survey, is a large observing programme designed to investigate massive star formation and H II regions in a sample of local extended galaxies. The programme will use the imaging Fourier transform spectrograph SITELLE at the Canada–France–Hawaii Telescope. Over 355 h (54.7 nights) have been allocated beginning in fall 2018 for eight consecutive semesters. Once completed, SIGNALS will provide a statistically reliable laboratory to investigate massive star formation, including over 50 000 resolved H II regions: the largest, most complete, and homogeneous data base of spectroscopically and spatially resolved extragalactic H II regions ever assembled. For each field observed, three datacubes covering the spectral bands of the filters SN1 (363–386 nm), SN2 (482–513 nm), and SN3 (647–685 nm) are gathered. The spectral resolution selected for each spectral band is 1000, 1000, and 5000, respectively. As defined, the project sample will facilitate the study of small-scale nebular physics and many other phenomena linked to star formation at a mean spatial resolution of ∼20 pc. This survey also has considerable legacy value for additional topics, including planetary nebulae, diffuse ionized gas, and supernova remnants. The purpose of this paper is to present a general outlook of the survey, notably the observing strategy, galaxy sample, and science requirements

Glucolipotoxicity initiates pancreatic beta-cell death through TNFR5/CD40-mediated STAT1 and NF-kappa B activation

Funded by Diabetes UK, NovoNordisk UK Research Foundation, and St. Bartholomew’s & The Royal London Charitable Foundation grant awards

Drosophila Genome-Wide RNAi Screen Identifies Multiple Regulators of HIF–Dependent Transcription in Hypoxia

Hypoxia-inducible factors (HIFs) are a family of evolutionary conserved alpha-beta heterodimeric transcription factors that induce a wide range of genes in response to low oxygen tension. Molecular mechanisms that mediate oxygen-dependent HIF regulation operate at the level of the alpha subunit, controlling protein stability, subcellular localization, and transcriptional coactivator recruitment. We have conducted an unbiased genome-wide RNA interference (RNAi) screen in Drosophila cells aimed to the identification of genes required for HIF activity. After 3 rounds of selection, 30 genes emerged as critical HIF regulators in hypoxia, most of which had not been previously associated with HIF biology. The list of genes includes components of chromatin remodeling complexes, transcription elongation factors, and translational regulators. One remarkable hit was the argonaute 1 (ago1) gene, a central element of the microRNA (miRNA) translational silencing machinery. Further studies confirmed the physiological role of the miRNA machinery in HIF–dependent transcription. This study reveals the occurrence of novel mechanisms of HIF regulation, which might contribute to developing novel strategies for therapeutic intervention of HIF–related pathologies, including heart attack, cancer, and stroke

Economic burden of neural tube defects and impact of prevention with folic acid: a literature review

Neural tube defects (NTDs) are the second most common group of serious birth defects. Although folic acid has been shown to reduce effectively the risk of NTDs and measures have been taken to increase the awareness, knowledge, and consumption of folic acid, the full potential of folic acid to reduce the risk of NTDs has not been realized in most countries. To understand the economic burden of NTDs and the economic impact of preventing NTDs with folic acid, a systematic review was performed on relevant studies. A total of 14 cost of illness studies and 10 economic evaluations on prevention of NTDs with folic acid were identified. Consistent findings were reported across all of the cost of illness studies. The lifetime direct medical cost for patients with NTDs is significant, with the majority of cost being for inpatient care, for treatment at initial diagnosis in childhood, and for comorbidities in adult life. The lifetime indirect cost for patients with spina bifida is even greater due to increased morbidity and premature mortality. Caregiver time costs are also significant. The results from the economic evaluations demonstrate that folic acid fortification in food and preconception folic acid consumption are cost-effective ways to reduce the incidence and prevalence of NTDs. This review highlights the significant cost burden that NTDs pose to healthcare systems, various healthcare payers, and society and concludes that the benefits of prevention of NTDs with folic acid far outweigh the cost. Further intervention with folic acid is justified in countries where the full potential of folic acid to reduce the risk of NTDs has not been realized

Cytotoxic Withanolide Constituents of Physalis longifolia

Fourteen new withanolides, 1–14, named withalongolides A–N, respectively, were isolated from the aerial parts of Physalis longifolia together with eight known compounds (15–22). The structures of compounds 1–14 were elucidated through spectroscopic techniques and chemical methods. In addition, the structures of withanolides 1, 2, 3, and 6 were confirmed by X-ray crystallographic analysis. Using a MTS viability assay, eight withanolides (1, 2, 3, 7, 8, 15, 16, and 19) and four acetylated derivatives (1a, 1b, 2a, and 2b) showed potent cytotoxicity against human head and neck squamous cell carcinoma (JMAR and MDA-1986), melanoma (B16F10 and SKMEL-28), and normal fetal fibroblast (MRC-5) cells with IC50 values in the range between 0.067 and 9.3 μM

Expression of minichromosome maintenance protein 2 as a marker for proliferation and prognosis in diffuse large B-cell lymphoma: a tissue microarray and clinico-pathological analysis

BACKGROUND: Minichromosome maintenance (MCM) proteins are essential for the initiation of DNA replication and have been found to be relevant markers for prognosis in a variety of tumours. The aim of this study was to assess the proliferative activity of diffuse large B-cell lymphoma (DLBCL) in tissue microarray (TMA) using one of the minichromosome maintenance proteins (Mcm2) and to explore its potential value to predict prognosis. METHODS: Immunohistochemistry for Mcm2 was performed on TMAs constructed from 302 cases of DLBCL. A monoclonal mouse antibody was used after heat induced antigen retrieval. Mcm2 expression was scored quantitatively. Positivity for Mcm2 was defined as presence of nuclear expression of Mcm2 in greater than or equal to 40 % of tumour cells. A statistical analysis was carried out of the association of Mcm2 and the clinico-pathological characteristics. RESULTS: Mcm2 expression was clearly evident in the nuclei of proliferating non-neoplastic cells and tumour cells. Positivity for Mcm2 was found in 46% (98/211) of analysable cases. A significant correlation existed between Mcm2 expression and presence of bulky disease (p = 0.003). Poor disease specific survival was observed in patients with DLBCL positive for Mcm2 expression in the univariate analysis (p = 0.0424). CONCLUSION: Mcm2 expression can be used to assess tumour proliferation and may be useful as an additional prognostic marker to refine the prediction of outcome in DLBCL