Proteogenomic data and resources for pan-cancer analysis.

The National Cancer Institute's Clinical Proteomic Tumor Analysis Consortium (CPTAC) investigates tumors from a proteogenomic perspective, creating rich multi-omics datasets connecting genomic aberrations to cancer phenotypes. To facilitate pan-cancer investigations, we have generated harmonized genomic, transcriptomic, proteomic, and clinical data for >1000 tumors in 10 cohorts to create a cohesive and powerful dataset for scientific discovery. We outline efforts by the CPTAC pan-cancer working group in data harmonization, data dissemination, and computational resources for aiding biological discoveries. We also discuss challenges for multi-omics data integration and analysis, specifically the unique challenges of working with both nucleotide sequencing and mass spectrometry proteomics data.

Pan-cancer proteogenomics connects oncogenic drivers to functional states.

Cancer driver events refer to key genetic aberrations that drive oncogenesis; however, their exact molecular mechanisms remain insufficiently understood. Here, our multi-omics pan-cancer analysis uncovers insights into the impacts of cancer drivers by identifying their significant cis-effects and distal trans-effects quantified at the RNA, protein, and phosphoprotein levels. Salient observations include the association of point mutations and copy-number alterations with the rewiring of protein interaction networks, and notably, most cancer genes converge toward similar molecular states denoted by sequence-based kinase activity profiles. A correlation between predicted neoantigen burden and measured T cell infiltration suggests potential vulnerabilities for immunotherapies. Patterns of cancer hallmarks vary by polygenic protein abundance ranging from uniform to heterogeneous. Overall, our work demonstrates the value of comprehensive proteogenomics in understanding the functional states of oncogenic drivers and their links to cancer development, surpassing the limitations of studying individual cancer types.

Pan-cancer analysis of post-translational modifications reveals shared patterns of protein regulation.

Post-translational modifications (PTMs) play key roles in regulating cell signaling and physiology in both normal and cancer cells. Advances in mass spectrometry enable high-throughput, accurate, and sensitive measurement of PTM levels to better understand their role, prevalence, and crosstalk. Here, we analyze the largest collection of proteogenomics data from 1,110 patients with PTM profiles across 11 cancer types (10 from the National Cancer Institute's Clinical Proteomic Tumor Analysis Consortium [CPTAC]). Our study reveals pan-cancer patterns of changes in protein acetylation and phosphorylation involved in hallmark cancer processes. These patterns revealed subsets of tumors, from different cancer types, including those with dysregulated DNA repair driven by phosphorylation, altered metabolic regulation associated with immune response driven by acetylation, affected kinase specificity by crosstalk between acetylation and phosphorylation, and modified histone regulation. Overall, this resource highlights the rich biology governed by PTMs and exposes potential new therapeutic avenues.

Genomic and transcriptomic analysis of checkpoint blockade response in advanced non-small cell lung cancer.

Anti-PD-1/PD-L1 agents have transformed the treatment landscape of advanced non-small cell lung cancer (NSCLC). To expand our understanding of the molecular features underlying response to checkpoint inhibitors in NSCLC, we describe here the first joint analysis of the Stand Up To Cancer-Mark Foundation cohort, a resource of whole exome and/or RNA sequencing from 393 patients with NSCLC treated with anti-PD-(L)1 therapy, along with matched clinical response annotation. We identify a number of associations between molecular features and outcome, including (1) favorable (for example, ATM altered) and unfavorable (for example, TERT amplified) genomic subgroups, (2) a prominent association between expression of inducible components of the immunoproteasome and response and (3) a dedifferentiated tumor-intrinsic subtype with enhanced response to checkpoint blockade. Taken together, results from this cohort demonstrate the complexity of biological determinants underlying immunotherapy outcomes and reinforce the discovery potential of integrative analysis within large, well-curated, cancer-specific cohorts.

Fabrication of milled removable partial dentures using a custom plate with prefabricated artificial teeth.

PURPOSE: Although digital removable partial dentures have been previously described, there have been no reports on how to fabricate them in one piece. This study proposes a new method for fabricating patient-specific digital removable partial dentures using a custom plate. METHODS: First, a gypsum model was scanned using a laboratory scanner and a removable partial denture was designed using computer-aided design (CAD) software based on standard tessellation language data. The metal clasp was fabricated from Ti-6Al-4V using a 3D printer. For custom plate fabrication, a resin plate frame was designed using computer-aided design (CAD) software and fabricated using a 3D printer. An artificial tooth and metal clasp were fixed on the base surface of the frame, an auto-polymerizing resin was poured into the frame for the denture base, and the artificial tooth and metal clasp were packed to form a custom plate. The plate was cut using a milling machine. Subsequently, the support attached to the denture was removed and polished for complete fabrication of the denture. CONCLUSIONS: Our novel removable partial denture fabrication method is more efficient than the conventional method. The obtained removable partial dentures demonstrated satisfactory accuracy.

Fully Digital Workflow for the Fabrication of Three-Dimensionally Printed Surgical Splints for Preventing Postoperative Bleeding: A Case Report.

The management of postoperative bleeding is mandatory in patients receiving anticoagulants. In this case report, we introduce a fully digital workflow for surgical splint fabrication to prevent postoperative bleeding in patients receiving anticoagulants and/or at risk of inadvertent extraction of a mobile tooth during impression making. An 87-year-old woman using apixaban had a left mandibular canine that required extraction due to chronic apical periodontitis. A digital impression was obtained using an intraoral scanner. First, the tooth to be extracted was deleted using three-dimensional (3D) computer-aided design (CAD) software (Geomagic Freeform, 3D Systems) and a stereolithography (STL) file was exported. This modified STL file was imported into another CAD software (3Shape Dental System, 3Shape) and a surgical splint was designed. The splint was fabricated using a 3D printer (Form 3; Formlabs) and light-curable resin (Dental LT Clear, Formlabs) and was delivered after the tooth extraction. The patient was followed-up 2 days after the extraction; no postoperative bleeding was detected and the surgical splint was removed. The additively manufactured surgical splint fabricated using a fully digital workflow was efficacious for managing postoperative bleeding after a dental extraction.

Novel ALK inhibitor AZD3463 inhibits neuroblastoma growth by overcoming crizotinib resistance and inducing apoptosis.

ALK receptor tyrosine kinase has been shown to be a therapeutic target in neuroblastoma. Germline ALK activating mutations are responsible for the majority of hereditary neuroblastoma and somatic ALK activating mutations are also frequently observed in sporadic cases of advanced NB. Crizotinib, a first-line therapy in the treatment of advanced non-small cell lung cancer (NSCLC) harboring ALK rearrangements, demonstrates striking efficacy against ALK-rearranged NB. However, crizotinib fails to effectively inhibit the activity of ALK when activating mutations are present within its kinase domain, as with the F1174L mutation. Here we show that a new ALK inhibitor AZD3463 effectively suppressed the proliferation of NB cell lines with wild type ALK (WT) as well as ALK activating mutations (F1174L and D1091N) by blocking the ALK-mediated PI3K/AKT/mTOR pathway and ultimately induced apoptosis and autophagy. In addition, AZD3463 enhanced the cytotoxic effects of doxorubicin on NB cells. AZD3463 also exhibited significant therapeutic efficacy on the growth of the NB tumors with WT and F1174L activating mutation ALK in orthotopic xenograft mouse models. These results indicate that AZD3463 is a promising therapeutic agent in the treatment of NB.