SomaLogic proteomics reveals new biomarkers and provides mechanistic, clinical insights into Acetyl coA Carboxylase (ACC) inhibition in Non-alcoholic Steatohepatitis (NASH).

Non-alcoholic Fatty Liver Disease (NAFLD) and Non-alcoholic Steatohepatitis (NASH) are major metabolic diseases with increasing global prevalence and no approved therapies. There is a mounting need to develop biomarkers of diagnosis, prognosis and treatment response that can effectively replace current requirements for liver biopsies, which are invasive, error-prone and expensive. We performed SomaLogic serum proteome profiling with baseline (n = 231) and on-treatment (n = 72, Weeks 12 and 16, Placebo and 25 mg PF-05221304) samples from a Phase 2a trial (NCT03248882) with Clesacostat (PF-05221304), an acetyl coA carboxylase inhibitor (ACCi) in patients with NAFLD/NASH.

Inhibition of lysine acetyltransferase KAT6 in ERHER2 metastatic breast cancer: a phase 1 trial.

Inhibition of histone lysine acetyltransferases (KATs) KAT6A and KAT6B has shown antitumor activity in estrogen receptor-positive (ER) breast cancer preclinical models. PF-07248144 is a selective catalytic inhibitor of KAT6A and KAT6B. In the present study, we report the safety, pharmacokinetics (PK), pharmacodynamics, efficacy and biomarker results from the first-in-human, phase 1 dose escalation and dose expansion study (n = 107) of PF-07248144 monotherapy and fulvestrant combination in heavily pretreated ER human epidermal growth factor receptor-negative (HER2) metastatic breast cancer (mBC).

Molecular alterations associated with improved outcome in patients with glioblastoma treated with Tumor-Treating Fields.

Background: The genomic and overall biologic landscape of glioblastoma (GB) has become clearer over the past 2 decades, as predictive and prognostic biomarkers of both de novo and transformed forms of GB have been identified. The oral chemotherapeutic agent temozolomide (TMZ) has been integral to standard-of-care treatment for nearly 2 decades. More recently, the use of non-pharmacologic interventions, such as application of alternating electric fields, called Tumor-Treating Fields (TTFields), has emerged as a complementary treatment option that increases overall survival (OS) in patients with newly diagnosed GB.

Family Rank: a graphical domain knowledge informed feature ranking algorithm.

Motivation: When designing prediction models built with many features and relatively small sample sizes, feature selection methods often overfit training data, leading to selection of irrelevant features. One way to potentially mitigate overfitting is to incorporate domain knowledge during feature selection. Here, a feature ranking algorithm called 'Family Rank' is presented in which features are ranked based on a combination of graphical domain knowledge and feature scores computed from empirical data.

Pan-cancer analysis of RNA expression of ANGIOTENSIN-I-CONVERTING ENZYME 2 reveals high variability and possible impact on COVID-19 clinical outcomes.

Patients with cancer demonstrate particularly poor outcomes from COVID-19. To provide information essential for understanding the biologic underpinnings of this association, we analyzed whole-transcriptome RNA expression data obtained from a large cohort of cancer patients to characterize expression of ACE2, TMPRSS2, and other proteases that are involved in viral attachment to and entry into target cells. We find substantial variability of expression of these factors across tumor types and identify subpopulations expressing ACE2 at very high levels.

Molecular profiling of melanoma brain metastases compared to primary cutaneous melanoma and to extracranial metastases.

Background: Brain metastases are a significant cause of mortality and morbidity for patients with melanoma. We hypothesize that the development of brain metastases may be explained by molecular heterogeneity between primary cutaneous melanoma (PCM) or extracranial (ECM) and brain (MBM) melanoma metastases.

Materials And Methods: We compared next-generation sequencing, tumor mutational burden (TMB), and immunohistochemical staining for PD-L1 expression, among 132 MBM, 745 PCM, and 1190 ECM.

Population bias in somatic measurement of microsatellite instability status.

Microsatellite instability (MSI) is a key secondary effect of a defective DNA mismatch repair mechanism resulting in incorrectly replicated microsatellites in many malignant tumors. Historically, MSI detection has been performed by fragment analysis (FA) on a panel of representative genomic markers. More recently, using next-generation sequencing (NGS) to analyze thousands of microsatellites has been shown to improve the robustness and sensitivity of MSI detection.

An Emerging Landscape for Canonical and Actionable Molecular Alterations in Primary and Metastatic Prostate Cancer.

Patients with prostate cancer with tumors harboring defects in DNA-repair genes (DRD) generally do not respond well to AR-directed therapy. Furthermore, canonical pathways evolve during disease progression and may affect treatment with existing therapies. Due to the limited treatment options after failure of hormonal and taxane therapy, and the tumor heterogeneity induced by DRD, we sought to characterize the alterations in primary and metastatic prostate cancer.

Patterns and genomic correlates of PD-L1 expression in patients with biliary tract cancers.

Background: Patients with biliary tract cancer (BTC) have a dismal prognosis and limited treatment options. Given the potential for immunotherapy in patients with BTC, we studied the expression of programmed death ligand-1 (PD-L1)/programmed death-1 (PD-1) and evaluated for associated genetic alterations in patients with BTC.

Methods: By immunohistochemistry (IHC), PD-L1 (SP142 antibody; ≥2+ and/or ≥5% staining on tumor cells considered positive) and PD-1 [NAT105 antibody; ≥1+ staining of tumor infiltrating lymphocytes (TILs) considered positive] expression was studied and next-generation sequencing (NGS) was performed using Caris Life Sciences' sequencing panel of 592 genes.

Expression and purification of sea raven type II antifreeze protein from Drosophila melanogaster S2 cells.

We present a system for the expression and purification of recombinant sea raven type II antifreeze protein, a cysteine-rich, C-type lectin-like globular protein that has proved to be a difficult target for recombinant expression and purification. The cDNAs encoding the pro- and mature forms of the sea raven protein were cloned into a modified pMT Drosophila expression vector. These constructs produced N-terminally His(6)-tagged pro- and mature forms of the type II antifreeze protein under the control of a metallothionein promoter when transfected into Drosophila melanogaster S2 cells.