Genomic Markers of CDK 4/6 Inhibitor Resistance in Hormone Receptor Positive Metastatic Breast Cancer.

Cyclin-dependent kinase 4/6 inhibitors are the standard of care for hormone receptor-positive metastatic breast cancer. This retrospective study reports on genomic biomarkers of CDK 4/6i resistance utilizing genomic data acquired through routine clinical practice. Patients with HR+ MBC treated with palbociclib, ribociclib, or abemaciclib and antiestrogen therapy were identified.

A Phase I Clinical Trial of Trametinib in Combination with TAS-102 in Patients with Chemotherapy-Resistant RAS-Mutated (PIK3CA/PTEN-Wild Type) Metastatic Colorectal Cancer.

Purpose: We conducted a phase I study to evaluate the maximum tolerated dose (MTD), safety, and efficacy of trametinib in combination with TAS-102 in patients with chemotherapy-refractory KRAS-mutant, wild-type PIK3CA/PTEN metastatic colorectal cancer (mCRC).

Methods: A 3+3 dose de-escalation single arm phase I clinical trial was performed in patients with chemorefractory mCRC without priorTAS-102 exposure. Patients received fixed dosing of trametinib 2mg oral daily along with de-escalating doses of TAS-102 beginning at 35 mg/m twice daily on days 1-5 and days 8-12 every 28 days.

Phase II Trial of Neoadjuvant Carboplatin and Nab-Paclitaxel in Patients with Triple-Negative Breast Cancer.

Background: In this phase II clinical trial, we evaluated the efficacy of the nonanthracycline combination of carboplatin and nab-paclitaxel in early stage triple-negative breast cancer (TNBC).

Patients And Methods: Patients with newly diagnosed stage II-III TNBC (n = 69) were treated with neoadjuvant carboplatin (area under the curve 6) every 28 days for four cycles plus nab-paclitaxel (100 mg/m ) weekly for 16 weeks. Pathological complete response (pCR) and residual cancer burden (RCB) were analyzed with germline mutation status, tumor-infiltrating lymphocytes (TILs), TNBC molecular subtype, and GeparSixto immune signature (GSIS).

CCNE1 amplification is associated with poor prognosis in patients with triple negative breast cancer.

Background: Triple negative breast cancer (TNBC) is aggressive with limited treatment options upon recurrence. Molecular discordance between primary and metastatic TNBC has been observed, but the degree of biological heterogeneity has not been fully explored. Furthermore, genomic evolution through treatment is poorly understood.

Favorable impact of allogeneic stem cell transplantation in patients with therapy-related myelodysplasia regardless of mutational status.

Therapy-related myelodysplastic syndrome is a long-term complication of cancer treatment in patients receiving cytotoxic therapy, characterized by high-risk genetics and poor outcomes. Allogeneic hematopoietic cell transplantation is the only potential cure for this disease, but the prognostic impact of pre-transplant genetics and clinical features has not yet been fully characterized. We report here the genetic and clinical characteristics and outcomes of a relatively large cohort of patients with therapy-related myelodysplastic syndrome (n=67) who underwent allogeneic transplantation, comparing these patients to similarly treated patients with disease (n=199).

Stool Bacteriomic Profiling in Patients with Metastatic Renal Cell Carcinoma Receiving Vascular Endothelial Growth Factor-Tyrosine Kinase Inhibitors.

Purpose: Diarrhea occurs in approximately half of patients with metastatic renal cell carcinoma (mRCC) receiving vascular endothelial growth factor-tyrosine kinase inhibitors (VEGF-TKI). We evaluated the relationship between VEGF-TKI-related diarrhea and stool microbiota.

Experimental Design: Stool samples were collected from 20 mRCC patients receiving VEGF-TKIs.

Evaluating the role of epigenetic histone modifications in the metabolic memory of type 1 diabetes.

We assessed whether epigenetic histone posttranslational modifications are associated with the prolonged beneficial effects (metabolic memory) of intensive versus conventional therapy during the Diabetes Control and Complications Trial (DCCT) on the progression of microvascular outcomes in the long-term Epidemiology of Diabetes Interventions and Complications (EDIC) study. We performed chromatin immunoprecipitation linked to promoter tiling arrays to profile H3 lysine-9 acetylation (H3K9Ac), H3 lysine-4 trimethylation (H3K4Me3), and H3K9Me2 in blood monocytes and lymphocytes obtained from 30 DCCT conventional treatment group subjects (case subjects: mean DCCT HbA1c level >9.1% [76 mmol/mol] and progression of retinopathy or nephropathy by EDIC year 10 of follow-up) versus 30 DCCT intensive treatment subjects (control subjects: mean DCCT HbA1c level <7.

LRF-mediated Dll4 repression in erythroblasts is necessary for hematopoietic stem cell maintenance.

Hematopoietic stem cells (HSCs) are the most primitive cells in the hematopoietic system and are under tight regulation for self-renewal and differentiation. Notch signals are essential for the emergence of definitive hematopoiesis in mouse embryos and are critical regulators of lymphoid lineage fate determination. However, it remains unclear how Notch regulates the balance between HSC self-renewal and differentiation in the adult bone marrow (BM).

Transcriptome-wide survey of mouse CNS-derived cells reveals monoallelic expression within novel gene families.

Monoallelic expression is an integral component of regulation of a number of essential genes and gene families. To probe for allele-specific expression in cells of CNS origin, we used next-generation sequencing (RNA-seq) to analyze four clonal neural stem cell (NSC) lines derived from Mus musculus C57BL/6 (B6)×Mus musculus molossinus (JF1) adult female mice. We established a JF1 cSNP library, then ascertained transcriptome-wide expression from B6 vs.

A risk variant in an miR-125b binding site in BMPR1B is associated with breast cancer pathogenesis.

MicroRNAs regulate diverse cellular processes and play an integral role in cancer pathogenesis. Genomic variation within miRNA target sites may therefore be important sources for genetic differences in cancer risk. To investigate this possibility, we mapped HapMap single nucleotide polymorphisms (SNP) to putative miRNA recognition sites within genes dysregulated in estrogen receptor-stratified breast tumors and used local linkage disequilibrium patterns to identify high-ranking SNPs in the Cancer Genetic Markers of Susceptibility (CGEMS) breast cancer genome-wide association study for further testing.

Intraoperative spillage of favorable histology wilms tumor cells: influence of irradiation and chemotherapy regimens on abdominal recurrence. A report from the National Wilms Tumor Study Group.

Purpose: We undertook this study to determine (1) the frequency with which spilled tumor cells of favorable histology produced intra-abdominal disease in patients treated with differing chemotherapy regimens and abdominal radiation therapy (RT) and (2) the patterns of relapse and outcomes in such patients.

Methods And Materials: The influence of RT dose (0, 10, and 20 Gy), RT fields (flank, whole abdomen), and chemotherapy with dactinomycin and vincristine (2 drugs) vs. added doxorubicin (three drugs) on intra-abdominal tumor recurrence rates was analyzed by logistic regression in 450 patients.

A transdimensional Bayesian model for pattern recognition in DNA sequences.

Identification of transcription factor binding sites (TFBSs) is essential to elucidate gene regulatory networks. This article is focused on the recognition of overpresented short patterns, called "motifs", that may correspond to regulatory binding sites in the DNA sequences upstream of genes. An integrated Bayesian model is proposed to incorporate all unknown characteristics in motif discovery, including the number of motifs, motif widths, motif compositions, the number of motif sites, and locations of motif sites.

Wilcoxon-based group sequential designs for comparison of areas under two correlated ROC curves.

Clinical studies to evaluate the relative accuracies of two diagnostic modalities via their receiver operating characteristic (ROC) curves are currently conducted using fixed sample designs: cases are accrued until a predetermined sample size is achieved and, at that point, the areas under the ROC curves are computed and compared (Radiology 1982; 143:29-36; Radiology 1983; 148:839-843). In prospective ROC studies (Radiology 1990; 175:571-575), participants are recruited from a clinically defined cohort and diagnostic test information is obtained and interpreted in advance of ascertaining the definitive proof of diagnosis ('gold standard'). In retrospective studies, cases are selected from a set of patient records and their diagnostic tests are interpreted without knowledge of the 'gold standard'.

ITT analysis of randomized encouragement design studies with missing data.

In this paper, we considered a missing outcome problem in causal inferences for a randomized encouragement design study. We proposed both moment and maximum likelihood estimators for the marginal distributions of potential outcomes and the local complier average causal effect (CACE) parameter. We illustrated our methods in a randomized encouragement design study on the effectiveness of flu shots.

High telomerase RNA expression level is an adverse prognostic factor for favorable-histology Wilms' tumor.

Purpose: A primary objective of the fifth National Wilms Tumor Study (NWTS-5) was to identify prognostic indicators for patients with favorable-histology Wilms' tumor. The prognostic significance of telomerase expression level in primary tumor samples was assessed.

Patients And Methods: A case-cohort study was conducted involving 291 NWTS-5 registrants.

Cardiovascular fitness among U.S. adults: NHANES 1999-2000 and 2001-2002.

Purpose: To present information on cardiovascular fitness (estimated maximal oxygen uptake [VO2max] and cardiovascular fitness levels based on sex- and age-specific cut-points of estimated VO2max) among U.S. adults.

Age and kidney function are the primary correlates of fasting plasma total homocysteine levels in non-diabetic and diabetic adults. Results from the 1999-2002 National Health and Nutrition Examination Survey.

Background: Plasma total homocysteine (tHcy) is commonly elevated in persons with diabetes. This may be due to effects of insulin and/or glucose and/or metabolic control on the metabolism or plasma levels of tHcy. This study examined the effects of fasting plasma glucose status on fasting tHcy levels among adults without diabetes, and diabetes per se among adults with a self-report history of diabetes.

Prevalence and trends of a metabolic syndrome phenotype among u.s. Adolescents, 1999-2000.

Objective: To determine the prevalence of a metabolic syndrome phenotype among U.S. adolescents using the most recent national data and to examine trends in metabolic syndrome prevalence.

Influence of radiation therapy delay on abdominal tumor recurrence in patients with favorable histology Wilms' tumor treated on NWTS-3 and NWTS-4: a report from the National Wilms' Tumor Study Group.

Purpose: This study was undertaken to determine whether radiation therapy (RT) delay of >or=10 days had an adverse impact on abdominal tumor recurrence among children with favorable histology (FH) Wilms' tumor enrolled in National Wilms' Tumor Study (NWTS) 3 and 4.

Methods And Materials: A total of 1226 patients with Stage II-IV FH tumors who received flank or abdominal RT in NWTS-3 and NWTS-4 were included in this analysis. Recurrent disease in the operative bed was classified as flank recurrence.