Systematic Identification of Combinatorial Drivers and Targets in Cancer Cell Lines

There is an urgent need to elicit and validate highly efficacious targets for combinatorial intervention from large scale ongoing molecular characterization efforts of tumors. We established an in silico bioinformatic platform in concert with a high throughput screening platform evaluating 37 novel targeted agents in 669 extensively characterized cancer cell lines reflecting the genomic and tissue-type diversity of human cancers, to systematically identify combinatorial biomarkers of response and co-actionable targets in cancer. Genomic biomarkers discovered in a 141 cell line training set were validated in an independent 359 cell line test set. We identified co-occurring and mutually exclusive genomic events that represent potential drivers and combinatorial targets in cancer. We demonstrate multiple cooperating genomic events that predict sensitivity to drug intervention independent of tumor lineage. The coupling of scalable in silico and biologic high throughput cancer cell line platforms for the identification of co-events in cancer delivers rational combinatorial targets for synthetic lethal approaches with a high potential to pre-empt the emergence of resistance

Erratum to: 36th International Symposium on Intensive Care and Emergency Medicine

[This corrects the article DOI: 10.1186/s13054-016-1208-6.]

Prognostic factors in 264 adults with invasive Scedosporium spp. and Lomentospora prolificans infection reported in the literature and FungiScope

Invasive Scedosporium spp. and Lomentospora prolificans infections are an emerging threat in immunocompromised and occasionally in healthy hosts. Scedosporium spp. is intrinsically resistant to most, L. prolificans to all the antifungal drugs currently approved, raising concerns about appropriate treatment decisions. High mortality rates of up to 90% underline the need for comprehensive diagnostic workup and even more for new, effective antifungal drugs to improve patient outcome. For a comprehensive analysis, we identified cases of severe Scedosporium spp. and L. prolificans infections from the literature diagnosed in 2000 or later and the FungiScopeVR registry. For 208 Scedosporium spp. infections solid organ transplantation (n¼58, 27.9%) and for 56 L. prolificans infection underlying malignancy (n¼28, 50.0%) were the most prevalent risk factors. L. prolificans infections frequently presented as fungemia (n¼26, 46.4% versus n¼12, 5.8% for Scedosporium spp.). Malignancy, fungemia, CNS and lung involvement predicted worse outcome for scedosporiosis and lomentosporiosis. Patients treated with voriconazole had a better overall outcome in both groups compared to treatment with amphotericin B formulations. This review discusses the epidemiology, prognostic factors, pathogen susceptibility to approved and investigational antifungals, and treatment strategies of severe infections caused by Scedosporium spp. and L. prolificans

Heterogeneous activation of the TGFβ pathway in glioblastomas identified by gene expression-based classification using TGFβ-responsive genes

<p>Abstract</p> <p>Background</p> <p>TGFβ has emerged as an attractive target for the therapeutic intervention of glioblastomas. Aberrant TGFβ overproduction in glioblastoma and other high-grade gliomas has been reported, however, to date, none of these reports has systematically examined the components of TGFβ signaling to gain a comprehensive view of TGFβ activation in large cohorts of human glioma patients.</p> <p>Methods</p> <p>TGFβ activation in mammalian cells leads to a transcriptional program that typically affects 5–10% of the genes in the genome. To systematically examine the status of TGFβ activation in high-grade glial tumors, we compiled a gene set of transcriptional response to TGFβ stimulation from tissue culture and <it>in vivo </it>animal studies. These genes were used to examine the status of TGFβ activation in high-grade gliomas including a large cohort of glioblastomas. Unsupervised and supervised classification analysis was performed in two independent, publicly available glioma microarray datasets.</p> <p>Results</p> <p>Unsupervised and supervised classification using the TGFβ-responsive gene list in two independent glial tumor gene expression data sets revealed various levels of TGFβ activation in these tumors. Among glioblastomas, one of the most devastating human cancers, two subgroups were identified that showed distinct TGFβ activation patterns as measured from transcriptional responses. Approximately 62% of glioblastoma samples analyzed showed strong TGFβ activation, while the rest showed a weak TGFβ transcriptional response.</p> <p>Conclusion</p> <p>Our findings suggest heterogeneous TGFβ activation in glioblastomas, which may cause potential differences in responses to anti-TGFβ therapies in these two distinct subgroups of glioblastomas patients.</p

Androgen receptor signaling regulates the transcriptome of prostate cancer cells by modulating global alternative splicing

Androgen receptor (AR), is a transcription factor and a member of a hormone receptor superfamily. AR plays a vital role in the progression of prostate cancer and is a crucial target for therapeutic interventions. While the majority of advanced-stage prostate cancer patients will initially respond to the androgen deprivation, the disease often progresses to castrate-resistant prostate cancer (CRPC). Interestingly, CRPC tumors continue to depend on hyperactive AR signaling and will respond to potent second-line antiandrogen therapies, including bicalutamide (CASODEX®) and enzalutamide (XTANDI®). However, the progression-free survival rate for the CRPC patients on antiandrogen therapies is only 8–19 months. Hence, there is a need to understand the mechanisms underlying CRPC progression and eventual treatment resistance. Here, we have leveraged next-generation sequencing and newly developed analytical methodologies to evaluate the role of AR signaling in regulating the transcriptome of prostate cancer cells. The genomic and pharmacologic stimulation and inhibition of AR activity demonstrates that AR regulates alternative splicing within cancer-relevant genes. Furthermore, by integrating transcriptomic data from in vitro experiments and in prostate cancer patients, we found that a significant number of AR-regulated splicing events are associated with tumor progression. For example, we found evidence for an inadvertent AR-antagonist-mediated switch in IDH1 and PL2G2A isoform expression, which is associated with a decrease in overall survival of patients. Mechanistically, we discovered that the epithelial-specific splicing regulators (ESRP1 and ESRP2), flank many AR-regulated alternatively spliced exons. And, using 2D invasion assays, we show that the inhibition of ESRPs can suppress AR-antagonist-driven tumor invasion. Our work provides evidence for a new mechanism by which AR alters the transcriptome of prostate cancer cells by modulating alternative splicing. As such, our work has important implications for CRPC progression and development of resistance to treatment with bicalutamide and enzalutamide

Prognostic molecular markers with no impact on decision-making: the paradox of gliomas based on a prospective study

This study assessed the prognostic value of several markers involved in gliomagenesis, and compared it with that of other clinical and imaging markers already used. Four-hundred and sixteen adult patients with newly diagnosed glioma were included over a 3-year period and tumour suppressor genes, oncogenes, MGMT and hTERT expressions, losses of heterozygosity, as well as relevant clinical and imaging information were recorded. This prospective study was based on all adult gliomas. Analyses were performed on patient groups selected according to World Health Organization histoprognostic criteria and on the entire cohort. The endpoint was overall survival, estimated by the Kaplan–Meier method. Univariate analysis was followed by multivariate analysis according to a Cox model. p14ARF, p16INK4A and PTEN expressions, and 10p 10q23, 10q26 and 13q LOH for the entire cohort, hTERT expression for high-grade tumours, EGFR for glioblastomas, 10q26 LOH for grade III tumours and anaplastic oligodendrogliomas were found to be correlated with overall survival on univariate analysis and age and grade on multivariate analysis only. This study confirms the prognostic value of several markers. However, the scattering of the values explained by tumour heterogeneity prevents their use in individual decision-making

Diffuse glioma growth: a guerilla war

In contrast to almost all other brain tumors, diffuse gliomas infiltrate extensively in the neuropil. This growth pattern is a major factor in therapeutic failure. Diffuse infiltrative glioma cells show some similarities with guerilla warriors. Histopathologically, the tumor cells tend to invade individually or in small groups in between the dense network of neuronal and glial cell processes. Meanwhile, in large areas of diffuse gliomas the tumor cells abuse pre-existent “supply lines” for oxygen and nutrients rather than constructing their own. Radiological visualization of the invasive front of diffuse gliomas is difficult. Although the knowledge about migration of (tumor)cells is rapidly increasing, the exact molecular mechanisms underlying infiltration of glioma cells in the neuropil have not yet been elucidated. As the efficacy of conventional methods to fight diffuse infiltrative glioma cells is limited, a more targeted (“search & destroy”) tactic may be needed for these tumors. Hopefully, the study of original human glioma tissue and of genotypically and phenotypically relevant glioma models will soon provide information about the Achilles heel of diffuse infiltrative glioma cells that can be used for more effective therapeutic strategies

COVID-19 infection in adult patients with hematological malignancies: a European Hematology Association Survey (EPICOVIDEHA)

Background: Patients with hematological malignancies (HM) are at high risk of mortality from SARS-CoV-2 disease 2019 (COVID-19). A better understanding of risk factors for adverse outcomes may improve clinical management in these patients. We therefore studied baseline characteristics of HM patients developing COVID-19 and analyzed predictors of mortality. Methods: The survey was supported by the Scientific Working Group Infection in Hematology of the European Hematology Association (EHA). Eligible for the analysis were adult patients with HM and laboratory-confirmed COVID-19 observed between March and December 2020. Results: The study sample includes 3801 cases, represented by lymphoproliferative (mainly non-Hodgkin lymphoma n = 1084, myeloma n = 684 and chronic lymphoid leukemia n = 474) and myeloproliferative malignancies (mainly acute myeloid leukemia n = 497 and myelodysplastic syndromes n = 279). Severe/critical COVID-19 was observed in 63.8% of patients (n = 2425). Overall, 2778 (73.1%) of the patients were hospitalized, 689 (18.1%) of whom were admitted to intensive care units (ICUs). Overall, 1185 patients (31.2%) died. The primary cause of death was COVID-19 in 688 patients (58.1%), HM in 173 patients (14.6%), and a combination of both COVID-19 and progressing HM in 155 patients (13.1%). Highest mortality was observed in acute myeloid leukemia (199/497, 40%) and myelodysplastic syndromes (118/279, 42.3%). The mortality rate significantly decreased between the first COVID-19 wave (March–May 2020) and the second wave (October–December 2020) (581/1427, 40.7% vs. 439/1773, 24.8%, p value < 0.0001). In the multivariable analysis, age, active malignancy, chronic cardiac disease, liver disease, renal impairment, smoking history, and ICU stay correlated with mortality. Acute myeloid leukemia was a higher mortality risk than lymphoproliferative diseases. Conclusions: This survey confirms that COVID-19 patients with HM are at high risk of lethal complications. However, improved COVID-19 prevention has reduced mortality despite an increase in the number of reported cases.EPICOVIDEHA has received funds from Optics COMMITTM (COVID-19 Unmet Medical Needs and Associated Research Extension) COVID-19 RFP program by GILEAD Science, United States (Project 2020-8223)

Clinical and organizational factors associated with mortality during the peak of first COVID-19 wave: the global UNITE-COVID study

Purpose: To accommodate the unprecedented number of critically ill patients with pneumonia caused by coronavirus disease 2019 (COVID-19) expansion of the capacity of intensive care unit (ICU) to clinical areas not previously used for critical care was necessary. We describe the global burden of COVID-19 admissions and the clinical and organizational characteristics associated with outcomes in critically ill COVID-19 patients. Methods: Multicenter, international, point prevalence study, including adult patients with SARS-CoV-2 infection confirmed by polymerase chain reaction (PCR) and a diagnosis of COVID-19 admitted to ICU between February 15th and May 15th, 2020. Results: 4994 patients from 280 ICUs in 46 countries were included. Included ICUs increased their total capacity from 4931 to 7630 beds, deploying personnel from other areas. Overall, 1986 (39.8%) patients were admitted to surge capacity beds. Invasive ventilation at admission was present in 2325 (46.5%) patients and was required during ICU stay in 85.8% of patients. 60-day mortality was 33.9% (IQR across units: 20%–50%) and ICU mortality 32.7%. Older age, invasive mechanical ventilation, and acute kidney injury (AKI) were associated with increased mortality. These associations were also confirmed specifically in mechanically ventilated patients. Admission to surge capacity beds was not associated with mortality, even after controlling for other factors. Conclusions: ICUs responded to the increase in COVID-19 patients by increasing bed availability and staff, admitting up to 40% of patients in surge capacity beds. Although mortality in this population was high, admission to a surge capacity bed was not associated with increased mortality. Older age, invasive mechanical ventilation, and AKI were identified as the strongest predictors of mortality