GCOD - GeneChip Oncology Database

<p>Abstract</p> <p>Background</p> <p>DNA microarrays have become a nearly ubiquitous tool for the study of human disease, and nowhere is this more true than in cancer. With hundreds of studies and thousands of expression profiles representing the majority of human cancers completed and in public databases, the challenge has been effectively accessing and using this wealth of data.</p> <p>Description</p> <p>To address this issue we have collected published human cancer gene expression datasets generated on the Affymetrix GeneChip platform, and carefully annotated those studies with a focus on providing accurate sample annotation. To facilitate comparison between datasets, we implemented a consistent data normalization and transformation protocol and then applied stringent quality control procedures to flag low-quality assays.</p> <p>Conclusion</p> <p>The resulting resource, the GeneChip Oncology Database, is available through a publicly accessible website that provides several query options and analytical tools through an intuitive interface.</p

iBBiG: iterative binary bi-clustering of gene sets

Motivation: Meta-analysis of genomics data seeks to identify genes associated with a biological phenotype across multiple datasets; however, merging data from different platforms by their features (genes) is challenging. Meta-analysis using functionally or biologically characterized gene sets simplifies data integration is biologically intuitive and is seen as having great potential, but is an emerging field with few established statistical methods. Results: We transform gene expression profiles into binary gene set profiles by discretizing results of gene set enrichment analyses and apply a new iterative bi-clustering algorithm (iBBiG) to identify groups of gene sets that are coordinately associated with groups of phenotypes across multiple studies. iBBiG is optimized for meta-analysis of large numbers of diverse genomics data that may have unmatched samples. It does not require prior knowledge of the number or size of clusters. When applied to simulated data, it outperforms commonly used clustering methods, discovers overlapping clusters of diverse sizes and is robust in the presence of noise. We apply it to meta-analysis of breast cancer studies, where iBBiG extracted novel gene set—phenotype association that predicted tumor metastases within tumor subtypes

Spartalizumab or placebo in combination with dabrafenib and trametinib in patients with BRAF\textit{BRAF}V600-mutant melanoma: exploratory biomarker analyses from a randomized phase 3 trial (COMBI-i)

BackgroundThe randomized phase 3 COMBI-i trial did not meet its primary endpoint of improved progression-free survival (PFS) with spartalizumab plus dabrafenib and trametinib (sparta-DabTram) vs placebo plus dabrafenib and trametinib (placebo-DabTram) in the overall population of patients with unresectable/metastatic $\textit{BRAF}$V600-mutant melanoma. This prespecified exploratory biomarker analysis was performed to identify subgroups that may derive greater treatment benefit from sparta-DabTram.MethodsIn COMBI-i (ClinicalTrials.gov, NCT02967692), 532 patients received spartalizumab 400 mg intravenously every 4 weeks plus dabrafenib 150 mg orally two times daily and trametinib 2 mg orally one time daily or placebo-DabTram. Baseline/on-treatment pharmacodynamic markers were assessed via flow cytometry-based immunophenotyping and plasma cytokine profiling. Baseline programmed death ligand 1 (PD-L1) status and T-cell phenotype were assessed via immunohistochemistry; $\textit{BRAF}$V600 mutation type, tumor mutational burden (TMB), and circulating tumor DNA (ctDNA) via DNA sequencing; gene expression signatures via RNA sequencing; and CD4$^{+}$/CD8$^{+}$ T-cell ratio via immunophenotyping.ResultsExtensive biomarker analyses were possible in approximately 64% to 90% of the intention-to-treat population, depending on sample availability and assay. Subgroups based on PD-L1 status/TMB or T-cell inflammation did not show significant differences in PFS benefit with sparta-DabTram vs placebo-DabTram, although T-cell inflammation was prognostic across treatment arms. Subgroups defined by $\textit{BRAF}$V600K mutation (HR 0.45 (95% CI 0.21 to 0.99)), detectable ctDNA shedding (HR 0.75 (95% CI 0.58 to 0.96)), or CD4$^{+}$/CD8$^{+}$ ratio above median (HR 0.58 (95% CI 0.40 to 0.84)) derived greater PFS benefit with sparta-DabTram vs placebo-DabTram. In a multivariate analysis, ctDNA emerged as strongly prognostic (p=0.007), while its predictive trend did not reach significance; in contrast, CD4$^{+}$/CD8$^{+}$ ratio was strongly predictive (interaction p=0.0131).ConclusionsThese results support the feasibility of large-scale comprehensive biomarker analyses in the context of a global phase 3 study. T-cell inflammation was prognostic but not predictive of sparta-DabTram benefit, as patients with high T-cell inflammation already benefit from targeted therapy alone. Baseline ctDNA shedding also emerged as a strong independent prognostic variable, with predictive trends consistent with established measures of disease burden such as lactate dehydrogenase levels. CD4$^{+}$/CD8$^{+}$ T-cell ratio was significantly predictive of PFS benefit with sparta-DabTram but requires further validation as a biomarker in melanoma. Taken together with previous observations, further study of checkpoint inhibitor plus targeted therapy combination in patients with higher disease burden may be warranted

GeneSigDB: a manually curated database and resource for analysis of gene expression signatures

GeneSigDB (http://www.genesigdb.org or http://compbio.dfci.harvard.edu/genesigdb/) is a database of gene signatures that have been extracted and manually curated from the published literature. It provides a standardized resource of published prognostic, diagnostic and other gene signatures of cancer and related disease to the community so they can compare the predictive power of gene signatures or use these in gene set enrichment analysis. Since GeneSigDB release 1.0, we have expanded from 575 to 3515 gene signatures, which were collected and transcribed from 1604 published articles largely focused on gene expression in cancer, stem cells, immune cells, development and lung disease. We have made substantial upgrades to the GeneSigDB website to improve accessibility and usability, including adding a tag cloud browse function, facetted navigation and a ‘basket’ feature to store genes or gene signatures of interest. Users can analyze GeneSigDB gene signatures, or upload their own gene list, to identify gene signatures with significant gene overlap and results can be viewed on a dynamic editable heatmap that can be downloaded as a publication quality image. All data in GeneSigDB can be downloaded in numerous formats including .gmt file format for gene set enrichment analysis or as a R/Bioconductor data file. GeneSigDB is available from http://www.genesigdb.org

A Phase 2, Multicenter, Open-Label Study of Anti-Lag-3 Ieramilimab in Combination With Anti-Pd-1 Spartalizumab in Patients With Advanced Solid Malignancies

Ieramilimab, a humanized anti-LAG-3 monoclonal antibody, was well tolerated in combination with the anti-PD-1 antibody spartalizumab in a phase 1 study. This phase 2 study aimed to further investigate the efficacy and safety of combination treatment in patients with selected advanced (locally advanced or metastatic) solid malignancies. Eligible patients with non-small cell lung cancer (NSCLC), melanoma, renal cell carcinoma (RCC), mesothelioma, and triple-negative breast cancer (TNBC) were grouped depending on prior anti-PD-1/L1 therapy (anti-PD-1/L1 naive or anti-PD-1/L1 pretreated). Patients received ieramilimab (400 mg) followed by spartalizumab (300 mg) every 3 weeks. The primary endpoint was objective response rate (ORR), along with safety, pharmacokinetics, and biomarker assessments. Of 235 patients, 142 were naive to anti-PD-1/L1 and 93 were pretreated with anti-PD-1/L1 antibodies. Durable responses (\u3e24 months) were seen across all indications for patients naive to anti-PD-1/L1 and in melanoma and RCC patients pretreated with anti-PD1/L1. The most frequent study drug-related AEs were pruritus (15.5%), fatigue (10.6%), and rash (10.6%) in patients naive to anti-PD-1/L1 and fatigue (18.3%), rash (14.0%), and nausea (10.8%) in anti-PD-1/L1 pretreated patients. Biomarker assessment indicated higher expression of T-cell-inflamed gene signature at baseline among responding patients. Response to treatment was durable (\u3e24 months) in some patients across all enrolled indications, and safety findings were in accordance with previous and current studies exploring LAG-3/PD-1 blockade

A novel, integrated in vitro carcinogenicity test to identify genotoxic and non-genotoxic carcinogens using human lymphoblastoid cells

Human exposure to carcinogens occurs via a plethora of environmental sources, with 70–90% of cancers caused by extrinsic factors. Aberrant phenotypes induced by such carcinogenic agents may provide universal biomarkers for cancer causation. Both current in vitro genotoxicity tests and the animal-testing paradigm in human cancer risk assessment fail to accurately represent and predict whether a chemical causes human carcinogenesis. The study aimed to establish whether the integrated analysis of multiple cellular endpoints related to the Hallmarks of Cancer could advance in vitro carcinogenicity assessment. Human lymphoblastoid cells (TK6, MCL-5) were treated for either 4 or 23 h with 8 known in vivo carcinogens, with doses up to 50% Relative Population Doubling (maximum 66.6 mM). The adverse effects of carcinogens on wide-ranging aspects of cellular health were quantified using several approaches; these included chromosome damage, cell signalling, cell morphology, cell-cycle dynamics and bioenergetic perturbations. Cell morphology and gene expression alterations proved particularly sensitive for environmental carcinogen identification. Composite scores for the carcinogens’ adverse effects revealed that this approach could identify both DNA-reactive and non-DNA reactive carcinogens in vitro. The richer datasets generated proved that the holistic evaluation of integrated phenotypic alterations is valuable for effective in vitro risk assessment, while also supporting animal test replacement. Crucially, the study offers valuable insights into the mechanisms of human carcinogenesis resulting from exposure to chemicals that humans are likely to encounter in their environment. Such an understanding of cancer induction via environmental agents is essential for cancer prevention

Zwei neue Andrena-Arten aus den Vereinigten Arabischen Emiraten (Hymenoptera, Apidae)

Scheuchl, E., Gusenleitner, F., A, United (2007): Zwei neue Andrena-Arten aus den Vereinigten Arabischen Emiraten (Hymenoptera, Apidae). Linzer biologische Beiträge 39 (1): 543-552, DOI: http://doi.org/10.5281/zenodo.541055

Pterocheilus persicus Gusenleitner & Fallahzadeh & Haghighi & Dousti 2013, nov.sp.

Pterocheilus persicus GUSENLEITNER & FALLAHZADEH nov.sp. (Figs 1-4) H o l o t y p e: Iran, Fars, Larestan, 870m, 27°32’N 54°22’E, &female;, 5.7.201 2, leg. A. Falahatpishe, coll. OLM. P a r a t y p e s: Iran, Fars, Niriz, 1795m, 29°16’N 54°19’E, &female;, 16.9.201 2, leg. M. Khosroabadi; Fars, Darab-Fathol Mobin, 1511m, 28°40’N 54°50’E, &female;, 8.7.291 2, leg. A. Haghighi; both coll. Dept. Entom., Jahrom Branch, Islamic Azad Univ., Jahrom, Iran. D i a g n o s i s: Pterocheilius persicus (fig. 1) is similar to Pterocheilus dives RADOSZKOWSKI 1876 (fig. 5), but differs in colouration; the pronotum is longer, the first tergite is stronger and the second sternite is more densely punctured than in P. dives. The occipital carina is lamellated in P. persicus. D e s c r i p t i o n: Primary colour black, with yellow colouring distributed as follows: mandibles nearly completely, labrum, clypeus (except for translucent anterior margin), and orbital bands from sinus to clypeus; one small dot above the antennae; antennal scape except for apical end; big dots present on the temples and the dorsal surface of the pronotum; patches on the upper part of the mesopleurae; tegulae except for the translucent margins and the disk; two dots on scutellum; a transverse band on postscutellum; claps on the sides of the scutellum and postscutellum present to tegulae; two patches on the metanotum; legs (the base of femora III and the trochanters black except for small yellow dots); broad, laterally enlarged apical bands on first and second tergites; a bisinuate narrow band on third tergite; tergites 4 to 6 totally, and the first sternite and other sternites almost completely yellow. Three red spots present in the middle of second sternite (fig. 4). Wings pale, with dusky radial cells. Clypeus (fig. 2) much broader than long (5,0: 3,0) and the straight „emargination“ is longer than distance between the antennal grooves. Disc of clypeus strongly punctured; spaces between the dots are glossy and similar in size to the punctures. Clypeus covered with microscopical white pubescence. Frons very densely punctured with small spots. Vertex and temples slightly punctured. On pronotum, mesonotum, mesopleurae and scutellum the dots are coarser and fewer than on the face. The posterior part of postscutellum has no punctures. Lateral edges of pronotum with spikes. Mesonotum has a prescutal furrow (extending from scutellum to close to middle of mesonotum). Propodeum sides rounded and uniformly punctured; only the lower part of each side is finely cross-striped. Discs of tegulae and legs glossy, without punctures. Dots on the first tergite (fig. 3) not as coarse as those on mesonotum; the intervals between the dots have microscopical dots. Second tergite has a few, not very coarse, microscopical dots. Tergites 3 to 6 also have fine microsopical dots. Sternites 2 to 6 glossy, with scattered punctures (fig. 4). Head and thorax with long, wavy, white hairs; abdomen with only microscopical pubescence. Body length: 9 mm. Male unknown. Etymology: The name is derived from Persia, the area of origin.Published as part of Gusenleitner, J., Fallahzadeh, M., Haghighi, A. & Dousti, A. F., 2013, Two new species of Eumeninae from Iran (Hymenoptera: Vespidae), pp. 109-116 in Linzer biologische Beiträge 45 (1) on pages 109-110, DOI: 10.5281/zenodo.452608

Eustenancistrocerus (Parastenancistrocerus) iranicus Gusenleitner & Fallahzadeh & Haghighi & Dousti 2013, nov.sp.

Eustenancistrocerus (Parastenancistrocerus) iranicus GUSENLEITNER nov.sp. (Figs 6-9) H o l o t y p e: Iran, Fars, Larestan, 870m, 27°32’N 54°22’E, 3, 30.11.201 2, leg. A. Falahatpishe, coll. OLM. P a r a t y p e s: Same data as holotype, 13; Iran, Fars, Darab, 1124m, 28°42’N 54°34’E, 233, leg. A. Haghighi; all in coll. Dept. Entom., Jahrom Branch, Islamic Azad Univ., Jahrom, Iran. D i a g n o s i s: This species belongs to the group of Eustenancistrocerus (Parastenancistrocerus) amadanensis (DE SAUSSURE 1863) and is very similar to Eustenancistrocerus (Parastenancistrocerus) khuzestanicus GIORDANI SOIKA 1970. But the species described here differs in the form of the last segments of the antennae (Giordani Soika 1970, p. 98) and the second tergite is simply truncate and not extendedly rounded (fig. 10). The occipital carina narrowly lamellated but in P. kuzhestanicus not lamellated. D e s c r i p t i o n: E. iranicus (fig. 6) is black with nearly white markings, distributed as follows: mandibles except for black teeth; labrum; clypeus; top part of face up to the ocelli; antennal scape; first and last segments of the flagellum; temples and pronotum completely; a dot on mesonotum in front of scutellum; mesopleurae nearly completely; tegulae except for two translucent dots and a translucent margin; parategulae; scutellum and postscutellum completely; two large and two small patches on each side of propodeum; legs; first tergite except for the front; an apical band on second tergite, attached to big patches at the sides; bisinuate apical bands on tergites 3 to 6; first and second sternites completely, and sternites 3 to 6 with bisinuate apical bands. Wings pale, without dusky parts. Clypeus (fig. 7) wider than long (2,2: 1,7), emargination flat (length: depth = 1,5: 0,3), and broader than distance between antennal grooves (length: depth = 1,5: 1,2). Clypeus coarse and densely punctured, except for a sparsely punctured, narrow band at the base. Puncturation of frons, vertex and temples similar to that of clypeus. Antennal scapes glossy, with only a few microscopical punctures. Last segment of flagellum long and narrow (fig. 1). Pronotum, mesonotum, scutellum and mesopleurae much more coarsely punctured than face. Frontal border between horizontal and vertical part of pronotum lamellated like occipital carina. Postscutellum very finely sculptured. Propodeum with coarse punctures, only the concavity shows microscopical striation. Tegulae and legs glossy, without punctures. Puncturation of first tergite very similar to that of scutellum; transverse carina with a central depression. Second tergite uniform and densely punctured. Third tergite densely punctured and indented in the middle (fig. 8, 10); other tergites more finely but not as densely punctured. In profile, second sternite flat, sloping steeply to the basal furrow, with dense, deep puncturation similar to that on second tergite. Tergites 3 to 7 more finely punctured than second tergite, with glossier intervals. The whole insect has a microscopical pubescense that is difficult to see. Body length: 5 mm. F e m a l e: unknown. E t y m o l o g y: The name is derived from the country of origin, Iran.Published as part of Gusenleitner, J., Fallahzadeh, M., Haghighi, A. & Dousti, A. F., 2013, Two new species of Eumeninae from Iran (Hymenoptera: Vespidae), pp. 109-116 in Linzer biologische Beiträge 45 (1) on pages 110-111, DOI: 10.5281/zenodo.452608