Emerging treatment options for BRAF-mutant colorectal cancer.

The personalization of cancer care is rooted in the premise that there are subsets of patients with tumors harboring clinically relevant targets for patient-specific treatments. Colorectal cancer (CRC) is a disease that has historically been notable for its dearth of biomarkers that are predictive of response to targeted therapies. In recent years, BRAFV600E-mutated CRC has emerged as a distinct biologic entity, typically refractory to standard chemotherapy regimens approved for the treatment of metastatic CRC and associated with a dismal prognosis. Multiple clinical trials sought to replicate the successes of targeted therapies seen in BRAFV600E-mutated melanoma without success; metastatic BRAFV600E-mutated CRC is clearly a distinct biologic entity. We review a number of recent studies demonstrating the evidence of modest responses to combinations of BRAF, EGFR, and/or MEK inhibition in patients with metastatic BRAFV600E-mutated CRC; however, despite advances, overall survival remains far inferior for these patients compared to their BRAF-wild-type counterparts. Development of combination therapies to impede signaling through the MAPK pathway through alternate targets remains an area of active investigation. Reflecting the rapid evolution of efforts for this small subset of CRC patients, the first-ever Phase III study is now underway evaluating the combination of BRAF, EGFR, and MEK inhibition. Immunotherapies are also an area of active research, particularly for the subset of patients with tumors that are also microsatellite instability (MSI) high. Here, we summarize the current landscape and emerging data on the molecular, clinical, and therapeutic aspects of BRAF-mutant CRC

Vitamin D Levels in Patients with Colorectal Cancer and Matched Household Members.

BackgroundVitamin D levels, as measured by 25-hydroxyvitamin-D [25(OH) D], are inversely related to the risk of developing colorectal cancer (CRC). Given shared demographic and lifestyle factors among members of the same household, we sought to examine vitamin D levels and associated lifestyle factors in household members of CRC patients.MethodsThirty patients with pathologically confirmed CRC were enrolled prior to oncologic therapy along with unrelated household members who were matched for age (+/- 5 years) and race. In addition to serum blood draws for 25(OH)D levels at baseline and six-month follow-up, questionnaires collected gender, vitamin use, body mass index, family history of CRC, race, dietary vitamin D, UV exposure, and exercise.ResultsMedian serum 25(OH) D levels were 26.8 ng/mL for CRC patients versus 27.3 for household members (P=0.89). Vitamin-D associated factors such as dietary vitamin D intake, UV exposure, gender, multivitamin use, vitamin D supplement use, and family history of CRC were not significantly different between CRC patients and paired household members (P>0.05). Household members were more likely than CRC patients to be overweight and to exercise more.ConclusionsVitamin D levels and many associated lifestyle factors were not significantly different between CRC patients and unrelated paired household members. Given comparable vitamin D levels, further investigation into whether age-matched household members of CRC patients may be at increased risk for CRC is warranted

Quality Evaluation of Data Management Plans at a Research University

With the emergence of the National Science Foundation (NSF) requirement for data management plans (DMPs), academic librarians have increasingly aided researchers in developing DMPs and disseminating research data. To determine the overall quality of DMPs at Wayne State University, the Library System’s Research Data Services (RDS) team evaluated the content of 119 DMPs from NSF grant proposals submitted between 2012 and 2014. The results of our content analysis indicate that, while most researchers understand the need to share data, many DMPs fail to adequately describe the data generated by the project, how data will be managed during the project, or how data will be preserved and shared after the completion of the project. Our results also show that DMP deficiencies vary across academic units, suggesting the need for differentiated outreach services to improve the strength of DMPs in future NSF grant proposals

Characteristics of Esophageal Cancer Cases in Tanzania.

PurposeAge-standardized incidence rates for esophageal cancer (EC) in East Africa have been reported as disproportionately high compared with the worldwide incidence of nine per 100,000 population. This study aimed to characterize EC cases seen at Muhimbili National Hospital and Ocean Road Cancer Institute in Dar es Salaam, Tanzania.MethodsDemographic, clinical, and treatment variables were abstracted from charts of patients who received care for a diagnosis of EC at one or both institutions between 2011 and 2013. Categorical data were summarized as frequency counts and percentages. Continuous data were presented as medians and ranges. To compare men and women, Pearson's χ2 and two-sample t tests were applied.ResultsSeven hundred thirty-eight unique cases of EC were identified, of whom 68% were men and the median age was 60 years (range, 19 to 95 years). Notably, 93 cases (13%) were ≤ 40 years old at diagnosis. Squamous cell carcinoma was the dominant histology, comprising 90% of cases with documented histopathology. However, 34% of cases with a diagnosis of EC were not pathologically confirmed. The stage was documented as locoregional in 4% of cases, locally advanced in 20% of cases, metastatic in 14% of cases, and unknown in 63% of cases. Of 430 patients who received treatment at Ocean Road Cancer Institute, 76% were treated with radiation, 44% were treated with chemotherapy, 3% underwent a cancer-related surgical procedure, and 10% of cases received no cancer-directed therapy. The median overall survival for all patients was 6.9 months (95% CI, 5.0 to 12.8), regardless of stage at presentation.ConclusionBetween 2011 and 2013, cases of EC represented a large clinical burden at both institutions

25-Hydroxyvitamin D Levels and Survival in Advanced Pancreatic Cancer: Findings From CALGB 80303 (Alliance)

Data from animal and cell-line models suggest that vitamin D metabolism plays an important role in pancreatic tumor behavior. Although vitamin D deficiency has been implicated in numerous cancers, the vitamin D status of patients with advanced pancreatic cancer and the effect of baseline vitamin D levels on survival are unknown

First Results from the HerschelHerschel and ALMA Spectroscopic Surveys of the SMC: The Relationship Between [CII]-bright Gas and CO-bright Gas at Low Metallicity

The Small Magellanic Cloud (SMC) provides the only laboratory to study the structure of molecular gas at high resolution and low metallicity. We present results from the Herschel Spectroscopic Survey of the SMC (HS$^{3}$), which mapped the key far-IR cooling lines [CII], [OI], [NII], and [OIII] in five star-forming regions, and new ALMA 7m-array maps of $^{12}$CO and $^{13}$CO $(2-1)$ with coverage overlapping four of the five HS$^{3}$ regions. We detect [CII] and [OI] throughout all of the regions mapped. The data allow us to compare the structure of the molecular clouds and surrounding photodissociation regions using $^{13}$CO, CO, [CII], and [OI] emission at $<10$" ($<3$ pc) scales. We estimate Av using far-IR thermal continuum emission from dust and find the CO/[CII] ratios reach the Milky Way value at high A$_{V}$ in the centers of the clouds and fall to $\sim{1/5-1/10}\times$ the Milky Way value in the outskirts, indicating the presence of translucent molecular gas not traced by bright CO emission. We estimate the amount of molecular gas traced by bright [CII] emission at low A$_{V}$ and bright CO emission at high A$_{V}$. We find that most of the molecular gas is at low A$_{V}$ and traced by bright [CII] emission, but that faint CO emission appears to extend to where we estimate the H$_{2}$-to-HI transition occurs. By converting our H$_{2}$ gas estimates to a CO-to-H$_{2}$ conversion factor ($X_{CO}$), we show that $X_{CO}$ is primarily a function of A$_{V}$, consistent with simulations and models of low metallicity molecular clouds.Comment: Accepted for publication in Ap

The vitamin D receptor gene as a determinant of survival in pancreatic cancer patients: Genomic analysis and experimental validation

Purpose: Advanced pancreatic cancer is a highly refractory disease almost always associated with survival of little more than a year. New interventions based on novel targets are needed. We aim to identify new genetic determinants of overall survival (OS) in patients after treatment with gemcitabine using genome-wide screens of germline DNA. We aim also to support these findings with in vitro functional analysis. Patients and methods: Genome-wide screens of germline DNA in two independent cohorts of pancreatic cancer patients (from the Cancer and Leukemia Group B (CALGB) 80303 and the Mayo Clinic) were used to select new genes associated with OS. The vitamin D receptor gene (VDR) was selected, and the interactions of genetic variation in VDR with circulating vitamin D levels and gemcitabine treatment were evaluated. Functional effects of common VDR variants were also evaluated in experimental assays in human cell lines. Results: The rs2853564 variant in VDR was associated with OS in patients from both the Mayo Clinic (HR 0.81, 95% CI 0.70–0.94, p = 0.0059) and CALGB 80303 (HR 0.74, 0.63–0.87, p = 0.0002). rs2853564 interacted with high pre-treatment levels of 25-hydroxyvitamin D (25(OH)D, a measure of endogenous vitamin D) (p = 0.0079 for interaction) and with gemcitabine treatment (p = 0.024 for interaction) to confer increased OS. rs2853564 increased transcriptional activity in luciferase assays and reduced the binding of the IRF4 transcription factor. Conclusion: Our findings propose VDR as a novel determinant of survival in advanced pancreatic cancer patients. Common functional variation in this gene might interact with endogenous vitamin D and gemcitabine treatment to determine improved patient survival. These results support evidence for a modulatory role of the vitamin D pathway for the survival of advanced pancreatic cancer patients.</p

Different Domains of the RNA Polymerase of Infectious Bursal Disease Virus Contribute to Virulence

BACKGROUND: Infectious bursal disease virus (IBDV) is a pathogen of worldwide significance to the poultry industry. IBDV has a bi-segmented double-stranded RNA genome. Segments A and B encode the capsid, ribonucleoprotein and non-structural proteins, or the virus polymerase (RdRp), respectively. Since the late eighties, very virulent (vv) IBDV strains have emerged in Europe inducing up to 60% mortality. Although some progress has been made in understanding the molecular biology of IBDV, the molecular basis for the pathogenicity of vvIBDV is still not fully understood. METHODOLOGY, PRINCIPAL FINDINGS: Strain 88180 belongs to a lineage of pathogenic IBDV phylogenetically related to vvIBDV. By reverse genetics, we rescued a molecular clone (mc88180), as pathogenic as its parent strain. To study the molecular basis for 88180 pathogenicity, we constructed and characterized in vivo reassortant or mosaic recombinant viruses derived from the 88180 and the attenuated Cu-1 IBDV strains. The reassortant virus rescued from segments A of 88180 (A88) and B of Cu-1 (BCU1) was milder than mc88180 showing that segment B is involved in 88180 pathogenicity. Next, the exchange of different regions of BCU1 with their counterparts in B88 in association with A88 did not fully restore a virulence equivalent to mc88180. This demonstrated that several regions if not the whole B88 are essential for the in vivo pathogenicity of 88180. CONCLUSION, SIGNIFICANCE: The present results show that different domains of the RdRp, are essential for the in vivo pathogenicity of IBDV, independently of the replication efficiency of the mosaic viruses