Gastrectomy for stage IV gastric cancer. A comparison of different treatment strategies from the SEER database

In the West, more than one third of newly diagnosed subjects show metastatic disease in gastric cancer (mGC) with few care options available. Gastrectomy has recently become a subject of debate, with some evidence showing advantages in survival beyond the sole purpose of treatment tumor-related complications. We investigated the survival benefit of different strategies in mGC patients, focusing on the role and timing of gastrectomy. Data were extracted from the SEER database. Groups were determined according to whether patients received gastrectomy, chemotherapy, supportive care. Patients receiving a multimodality treatment were further divided according to timing of surgery, whether performed before (primary gastrectomy, PG) or after chemotherapy (secondary gastrectomy, SG). 16,596 patients were included. Median OS was significantly higher (p<0.001) in the SG (15months) than in the PG (13months), gastrectomy alone (6months), and chemotherapy (7months) groups. In the multivariate analysis, SG showed better OS (HR=0.22, 95%CI=0.18-0.26, p<0.001) than PG (HR=0.25, 95%CI=0.23-0.28, p<0.001), gastrectomy (HR=0.40, 95%CI=0.36-0.44, p<0.001), and chemotherapy (HR=0.42, 95%CI=0.4-0.44, p<0.001). The survival benefits persisted even after the PSM analysis. This study shows survival advantages of gastrectomy as multimodality strategy after chemotherapy. In selected patients, SG can be proposed to improve the management of stage IV disease

Patient-derived xenografts and organoids model therapy response in prostate cancer.

Therapy resistance and metastatic processes in prostate cancer (PCa) remain undefined, due to lack of experimental models that mimic different disease stages. We describe an androgen-dependent PCa patient-derived xenograft (PDX) model from treatment-naïve, soft tissue metastasis (PNPCa). RNA and whole-exome sequencing of the PDX tissue and organoids confirmed transcriptomic and genomic similarity to primary tumor. PNPCa harbors BRCA2 and CHD1 somatic mutations, shows an SPOP/FOXA1-like transcriptomic signature and microsatellite instability, which occurs in 3% of advanced PCa and has never been modeled in vivo. Comparison of the treatment-naïve PNPCa with additional metastatic PDXs (BM18, LAPC9), in a medium-throughput organoid screen of FDA-approved compounds, revealed differential drug sensitivities. Multikinase inhibitors (ponatinib, sunitinib, sorafenib) were broadly effective on all PDX- and patient-derived organoids from advanced cases with acquired resistance to standard-of-care compounds. This proof-of-principle study may provide a preclinical tool to screen drug responses to standard-of-care and newly identified, repurposed compounds

Transcriptional Enhancer Factor Domain Family member 4 Exerts an Oncogenic Role in Hepatocellular Carcinoma by Hippo-Independent Regulation of Heat Shock Protein 70 Family Members.

Transcriptional enhancer factor domain family member 4 (TEAD4) is a downstream effector of the conserved Hippo signaling pathway, regulating the expression of genes involved in cell proliferation and differentiation. It is up-regulated in several cancer types and is associated with metastasis and poor prognosis. However, its role in hepatocellular carcinoma (HCC) remains largely unexplored. Using data from The Cancer Genome Atlas, we found that TEAD4 was overexpressed in HCC and was associated with aggressive HCC features and worse outcome. Overexpression of TEAD4 significantly increased proliferation and migration rates in HCC cells in vitro as well as tumor growth in vivo. Additionally, RNA sequencing analysis of TEAD4-overexpressing HCC cells demonstrated that TEAD4 overexpression was associated with the up-regulation of genes involved in epithelial-to-mesenchymal transition, proliferation, and protein-folding pathways. Among the most up-regulated genes following TEAD4 overexpression were the 70-kDa heat shock protein (HSP70) family members HSPA6 and HSPA1A. Chromatin immunoprecipitation-quantitative real-time polymerase chain reaction experiments demonstrated that TEAD4 regulates HSPA6 and HSPA1A expression by directly binding to their promoter and enhancer regions. The pharmacologic inhibition of HSP70 expression in TEAD4-overexpressing cells reduced the effect of TEAD4 on cell proliferation. Finally, by overexpressing TEAD4 in yes-associated protein (YAP)/transcriptional coactivator with PDZ binding motif (TAZ)-knockdown HCC cells, we showed that the effect of TEAD4 on cell proliferation and its regulation of HSP70 expression does not require YAP and TAZ, the main effectors of the Hippo signaling pathway. Conclusion: A novel Hippo-independent mechanism for TEAD4 promotes cell proliferation and tumor growth in HCC by directly regulating HSP70 family members

Diagnostic Targeted Sequencing Panel for Hepatocellular Carcinoma Genomic Screening

Commercially available targeted panels miss genomic regions frequently altered in hepatocellular carcinoma (HCC). We sought to design and benchmark a sequencing assay for genomic screening of HCC. We designed an AmpliSeq custom panel targeting all exons of 33 protein-coding and two long noncoding RNA genes frequently mutated in HCC, TERT promoter, and nine genes with frequent copy number alterations. By using this panel, the profiling of DNA from fresh-frozen (n = 10, 1495×) and/or formalin-fixed, paraffin-embedded (FFPE) tumors with low-input DNA (n = 36, 530×) from 39 HCCs identified at least one somatic mutation in 90% of the cases. Median of 2.5 (range, 0 to 74) and 3 (range, 0 to 76) mutations were identified in fresh-frozen and FFPE tumors, respectively. Benchmarked against the mutations identified from Illumina whole-exome sequencing (WES) of the corresponding fresh-frozen tumors (105×), 98% (61 of 62) and 100% (104 of 104) of the mutations from WES were detected in the 10 fresh-frozen tumors and the 36 FFPE tumors, respectively, using the HCC panel. In addition, 18 and 70 somatic mutations in coding and noncoding genes, respectively, not found by WES were identified by using our HCC panel. Copy number alterations between WES and our HCC panel showed an overall concordance of 86%. In conclusion, we established a cost-effective assay for the detection of genomic alterations in HCC

Advancing drug discovery through assay development: a survey of tool compounds within the human solute carrier superfamily

With over 450 genes, solute carriers (SLCs) constitute the largest transporter superfamily responsible for the uptake and efflux of nutrients, metabolites, and xenobiotics in human cells. SLCs are associated with a wide variety of human diseases, including cancer, diabetes, and metabolic and neurological disorders. They represent an important therapeutic target class that remains only partly exploited as therapeutics that target SLCs are scarce. Additionally, many small molecules reported in the literature to target SLCs are poorly characterized. Both features may be due to the difficulty of developing SLC transport assays that fulfill the quality criteria for high-throughput screening. Here, we report one of the main limitations hampering assay development within the RESOLUTE consortium: the lack of a resource providing high-quality information on SLC tool compounds. To address this, we provide a systematic annotation of tool compounds targeting SLCs. We first provide an overview on RESOLUTE assays. Next, we present a list of SLC-targeting compounds collected from the literature and public databases; we found that most data sources lacked specificity data. Finally, we report on experimental tests of 19 selected compounds against a panel of 13 SLCs from seven different families. Except for a few inhibitors, which were active on unrelated SLCs, the tested inhibitors demonstrated high selectivity for their reported targets. To make this knowledge easily accessible to the scientific community, we created an interactive dashboard displaying the collected data in the RESOLUTE web portal (https://re-solute.eu). We anticipate that our open-access resources on assays and compounds will support the development of future drug discovery campaigns for SLCs

Alterations in homologous recombination repair genes in prostate cancer brain metastases

Improved survival rates for prostate cancer through more effective therapies have also led to an increase in the diagnosis of metastases to infrequent locations such as the brain. Here we investigate the repertoire of somatic genetic alterations present in brain metastases from 51 patients with prostate cancer brain metastases (PCBM). We highlight the clonal evolution occurring in PCBM and demonstrate an increased mutational burden, concomitant with an enrichment of the homologous recombination deficiency mutational signature in PCBM compared to non-brain metastases. Focusing on known pathogenic alterations within homologous recombination repair genes, we find 10 patients (19.6%) fulfilling the inclusion criteria used in the PROfound clinical trial, which assessed the efficacy of PARP inhibitors (PARPi) in homologous recombination deficient prostate cancer. Eight (15.7%) patients show biallelic loss of one of the 15 genes included in the trial, while 5 patients (9.8%) harbor pathogenic alterations in BRCA1/2 specifically. Uncovering these molecular features of PCBM may have therapeutic implications, suggesting the need of clinical trial enrollment of PCBM patients when evaluating potential benefit from PARPi

Alterations in homologous recombination repair genes in prostate cancer brain metastases.

Improved survival rates for prostate cancer through more effective therapies have also led to an increase in the diagnosis of metastases to infrequent locations such as the brain. Here we investigate the repertoire of somatic genetic alterations present in brain metastases from 51 patients with prostate cancer brain metastases (PCBM). We highlight the clonal evolution occurring in PCBM and demonstrate an increased mutational burden, concomitant with an enrichment of the homologous recombination deficiency mutational signature in PCBM compared to non-brain metastases. Focusing on known pathogenic alterations within homologous recombination repair genes, we find 10 patients (19.6%) fulfilling the inclusion criteria used in the PROfound clinical trial, which assessed the efficacy of PARP inhibitors (PARPi) in homologous recombination deficient prostate cancer. Eight (15.7%) patients show biallelic loss of one of the 15 genes included in the trial, while 5 patients (9.8%) harbor pathogenic alterations in BRCA1/2 specifically. Uncovering these molecular features of PCBM may have therapeutic implications, suggesting the need of clinical trial enrollment of PCBM patients when evaluating potential benefit from PARPi

Measurement of Upsilon production in pp collisions at \sqrt{s} = 7 TeV

The production of Upsilon(1S), Upsilon(2S) and Upsilon(3S) mesons in proton-proton collisions at the centre-of-mass energy of sqrt(s)=7 TeV is studied with the LHCb detector. The analysis is based on a data sample of 25 pb-1 collected at the Large Hadron Collider. The Upsilon mesons are reconstructed in the decay mode Upsilon -> mu+ mu- and the signal yields are extracted from a fit to the mu+ mu- invariant mass distributions. The differential production cross-sections times dimuon branching fractions are measured as a function of the Upsilon transverse momentum pT and rapidity y, over the range pT < 15 GeV/c and 2.0 < y < 4.5. The cross-sections times branching fractions, integrated over these kinematic ranges, are measured to be sigma(pp -> Upsilon(1S) X) x B(Upsilon(1S)->mu+ mu-) = 2.29 {\pm} 0.01 {\pm} 0.10 -0.37 +0.19 nb, sigma(pp -> Upsilon(2S) X) x B(Upsilon(2S)->mu+ mu-) = 0.562 {\pm} 0.007 {\pm} 0.023 -0.092 +0.048 nb, sigma(pp -> Upsilon(3S) X) x B(Upsilon(3S)->mu+ mu-) = 0.283 {\pm} 0.005 {\pm} 0.012 -0.048 +0.025 nb, where the first uncertainty is statistical, the second systematic and the third is due to the unknown polarisation of the three Upsilon states.Comment: 22 pages, 7 figure

Observation of the B0 → ρ0ρ0 decay from an amplitude analysis of B0 → (π+π−)(π+π−) decays

Proton–proton collision data recorded in 2011 and 2012 by the LHCb experiment, corresponding to an integrated luminosity of 3.0 fb−1 , are analysed to search for the charmless B0→ρ0ρ0 decay. More than 600 B0→(π+π−)(π+π−) signal decays are selected and used to perform an amplitude analysis, under the assumption of no CP violation in the decay, from which the B0→ρ0ρ0 decay is observed for the first time with 7.1 standard deviations significance. The fraction of B0→ρ0ρ0 decays yielding a longitudinally polarised final state is measured to be fL=0.745−0.058+0.048(stat)±0.034(syst) . The B0→ρ0ρ0 branching fraction, using the B0→ϕK⁎(892)0 decay as reference, is also reported as B(B0→ρ0ρ0)=(0.94±0.17(stat)±0.09(syst)±0.06(BF))×10−6