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Introduction:\ud Malignant pleural mesothelioma (MPM) is difficult to diagnose. An accurate blood biomarker could prompt specialist referral or be deployed in future screening. In earlier retrospective studies, SOMAscan proteomics (Somalogic, Boulder, CO) and fibulin-3 seemed highly accurate, but SOMAscan has not been validated prospectively and subsequent fibulin-3 data have been contradictory.\ud \ud Methods:\ud A multicenter prospective observational study was performed in 22 centers, generating a large intention-to-diagnose cohort. Blood sampling, processing, and diagnostic assessment were standardized, including a 1-year follow-up. Plasma fibulin-3 was measured using two enzyme-linked immunosorbent assays (CloudClone [used in previous studies] and BosterBio, Pleasanton, CA). Serum proteomics was measured using the SOMAscan assay. Diagnostic performance (sensitivity at 95% specificity, area under the curve [AUC]) was benchmarked against serum mesothelin (Mesomark, Fujirebio Diagnostics, Malvern, PA). Biomarkers were correlated against primary tumor volume, inflammatory markers, and asbestos exposure.\ud \ud Results:\ud A total of 638 patients with suspected pleural malignancy (SPM) and 110 asbestos-exposed controls (AECs) were recruited. SOMAscan reliably differentiated MPM from AECs (75% sensitivity, 88.2% specificity, validation cohort AUC 0.855) but was not useful in patients with differentiating non-MPM SPM. Fibulin-3 (by BosterBio after failed CloudClone validation) revealed 7.4% and 11.9% sensitivity at 95% specificity in MPM versus non-MPM SPM and AECs, respectively (associated AUCs 0.611 [0.557–0.664], p = 0.0015) and 0.516 [0.443–0.589], p = 0.671), both inferior to mesothelin. SOMAscan proteins correlated with inflammatory markers but not with asbestos exposure. Neither biomarker correlated with tumor volume.\ud \ud Conclusions:\ud SOMAscan may prove useful as a future screening test for MPM in asbestos-exposed persons. Neither fibulin-3 nor SOMAscan should be used for diagnosis or pathway stratification.

Oncogenic KRAS mutations and inactivation of the APC tumor suppressor co-occur in colorectal cancer (CRC). Despite efforts to target mutant KRAS directly, most therapeutic approaches focus on downstream pathways, albeit with limited efficacy. Moreover, mutant KRAS alters the basal metabolism of cancer cells, increasing glutamine utilization to support proliferation. We show that concomitant mutation of Apc and Kras in the mouse intestinal epithelium profoundly rewires metabolism, increasing glutamine consumption. Furthermore, SLC7A5, a glutamine antiporter, is critical for colorectal tumorigenesis in models of both early- and late-stage metastatic disease. Mechanistically, SLC7A5 maintains intracellular amino acid levels following KRAS activation through transcriptional and metabolic reprogramming. This supports the increased demand for bulk protein synthesis that underpins the enhanced proliferation of KRAS-mutant cells. Moreover, targeting protein synthesis, via inhibition of the mTORC1 regulator, together with Slc7a5 deletion abrogates the growth of established Kras-mutant tumors. Together, these data suggest SLC7A5 as an attractive target for therapy-resistant KRAS-mutant CRC.

Volatile organic compounds (VOCs) are potential biomarkers for diagnosing colorectal cancer (CRC). We characterized urinary VOCs from CRC patients, their spouses/cohabitors (spouses) and first-degree relatives (relatives) to determine any differences. Correlation with stool-derived microbiomes was also undertaken.Urine from 56 CRC patients, 45 spouses and 37 relatives was assayed using liquid chromatography, field asymmetric ion mobility spectrometry (FAIMS), mass spectrometer technology. Analysis was performed using five-fold cross-validation and a random forest classifier. Faecal microbiome 16S rRNA was sequenced using Illumina MiSeq protocols and analysed using UPARSE and QIIME pipelines. VOC and microbiome profiles were also compared before and after cancer treatment.Urinary VOC profiles of CRC patients were indistinguishable from either spouses or relatives. When spouses and relatives were grouped together to form a larger non-cancer control group (n = 82), their VOC profiles became distinguishable from those of CRC patients (n = 56) with 69% sensitivity and specificity, area under the curve 0.72 (P 0.001). Microbiome analysis identified 1300 operational taxonomic units across all groups. The analysis of similarity R value was 0.067 (P 0.001), with significantly different bacterial abundances in 82 operational taxonomic units (6.2%) by Kruskal-Wallis testing. CRC patients' VOC or stool microbiome profiles were unchanged after treatment.Although CRC patients' urinary VOC profiles cannot be differentiated from those of spouses or relatives they can be differentiated from a larger non-cancer control group. Comparison of the groups' microbiomes confirmed differences in bacterial species abundance. The current FAIMS-based assay can detect a unique, but modest, signal in CRC patients' urinary VOCs, which remains unaltered after treatment.

Common hallmarks of cancer include the dysregulation of cell cycle progression and the acquisition of genome instability. In tumors, G1 cell cycle checkpoint induction is often lost. This increases the reliance on a functional G2/M checkpoint to prevent progression through mitosis with damaged DNA, avoiding the introduction of potentially aberrant genetic alterations. Treatment of tumors with ionizing radiation (IR) utilizes this dependence on the G2/M checkpoint. Therefore, identification of factors which regulate this process could yield important biomarkers for refining this widely used cancer therapy. Leucine zipper and ICAT domain containing (LZIC) downregulation has been associated with the development of IR-induced tumors. However, despite LZIC being highly conserved, it has no known molecular function. We demonstrate that LZIC knockout (KO) cell lines show a dysregulated G2/M cell cycle checkpoint following IR treatment. In addition, we show that LZIC deficient cells competently activate the G1 and early G2/M checkpoint but fail to maintain the late G2/M checkpoint after IR exposure. Specifically, this defect was found to occur downstream of PIKK signaling. The LZIC KO cells demonstrated severe aneuploidy indicative of genomic instability. In addition, analysis of data from cancer patient databases uncovered a strong correlation between LZIC expression and poor prognosis in several cancers. Our findings suggest that LZIC is functionally involved in cellular response to IR, and its expression level could serve as a biomarker for patient stratification in clinical cancer practice.

A whole genome in vivo CRISPR/Cas9 screen identifies TCEAL1 as a potential target to sensitise prostate cancer cells to docetaxel to improve the efficacy of chemotherapy., Docetaxel chemotherapy in metastatic prostate cancer offers only a modest survival benefit because of emerging resistance. To identify candidate therapeutic gene targets, we applied a murine prostate cancer orthograft model that recapitulates clinical invasive prostate cancer in a genome-wide CRISPR/Cas9 screen under docetaxel treatment pressure. We identified 17 candidate genes whose suppression may enhance the efficacy of docetaxel, with transcription elongation factor A–like 1 (Tceal1) as the top candidate. TCEAL1 function is not fully characterised; it may modulate transcription in a promoter dependent fashion. Suppressed TCEAL1 expression in multiple human prostate cancer cell lines enhanced therapeutic response to docetaxel. Based on gene set enrichment analysis from transcriptomic data and flow cytometry, we confirmed that loss of TCEAL1 in combination with docetaxel leads to an altered cell cycle profile compared with docetaxel alone, with increased subG1 cell death and increased polyploidy. Here, we report the first in vivo genome-wide treatment sensitisation CRISPR screen in prostate cancer, and present proof of concept data on TCEAL1 as a candidate for a combinational strategy with the use of docetaxel.

Escalating costs of health care and the realization that home care is an alternative to hospitaliza tion has resulted in an increase in patients receiving home intravenous (IV) therapy. At St. Elizabeth Home Infusion, Dayton, Ohio, stage III or IV congestive heart failure (CHF) patients must be stabilized on dobutamine prior to acceptance. Dobutamine therapy in the home causes less interruption in the patient's lifestyle and provides convenience for the patient with CHF at a decreased cost of treatment. Although patient survival may not be prolonged, quality of life may be improved, and the number of hospitalizations are reduced. Key words: dobutamine, heart failure, inotropic, intermittent therapy