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This clinical trial combined fulvestrant with the anti-androgen enzalutamide in women with metastatic ER+/HER2− breast cancer (BC). Eligible patients were women with ECOG 0–2, ER+/HER2− measurable or evaluable metastatic BC. Prior fulvestrant was allowed. Fulvestrant was administered at 500 mg IM on days 1, 15, 29, and every 4 weeks thereafter. Enzalutamide was given at 160 mg po daily. Fresh tumor biopsies were required at study entry and after 4 weeks of treatment. The primary efficacy endpoint of the trial was the clinical benefit rate at 24 weeks (CBR24). The median age was 61 years (46–87); PS 1 (0–1); median of 4 prior non-hormonal and 3 prior hormonal therapies for metastatic disease. Twelve had prior fulvestrant, and 91% had visceral disease. CBR24 was 25% (7/28 evaluable). Median progression-free survival (PFS) was 8 weeks (95% CI: 2–52). Adverse events were as expected for hormonal therapy. Significant (p PIK3CA and/or PTEN mutations. Baseline levels of phospho-proteins in the mTOR pathway were more highly expressed in biopsies of patients with shorter PFS. Fulvestrant plus enzalutamide had manageable side effects. The primary endpoint of CBR24 was 25% in heavily pretreated metastatic ER+/HER2− BC. Short PFS was associated with activation of the mTOR pathway, and PIK3CA and/or PTEN mutations were associated with an increased hazard of progression. Thus, a combination of fulvestrant or other SERD plus AKT/PI3K/mTOR inhibitor with or without AR inhibition warrants investigation in second-line endocrine therapy of metastatic ER+ BC.

To estimate how many boys with UDT must undergo orchiopexy to prevent one case of TC, one death from TC and one exposure to TC treatment beyond radical orchiectomy as compared to being treated at an older age. This retrospective study utilized data from a 2007 Swedish study of males who underwent orchiopexy for UDT (Pettersson et al.). TC incidence for boys undergoing orchiopexy for UDT was assessed based on the age at orchiopexy (0–6 years, 7–9 years, 10–12 years, 13–15 years). The incidence of TC in each age cohort was calculated and used to determine the number needed to treat (NNT) for each age group using assumptions based on published TC outcomes. For an index patient ≤ 6 years, 372 boys need to undergo orchiopexy to prevent a single case of TC, 1488 boys to prevent exposure to TC therapy beyond radical orchiectomy, and 5315 boys to prevent a single TC-related death compared to treatment at an older age. While there is evidence supporting benefits of early orchiopexy, the NNT to affect TC outcomes is very high. Even those with delayed orchiopexies have low risk for TC poor outcomes. This information can be used when counseling patients and families faced with UDT about the risks related to TC, especially with comorbidities.

Breast cancer is a global health threat and cases diagnosed in women during the years after childbirth, or postpartum breast cancers (PPBCs), have high risk for metastasis. In preclinical murine models, semaphorin 7a (SEMA7A) drives the metastatic potential of postpartum mammary tumors. Thus, we hypothesize that SEMA7A may drive metastasis of PPBC in women. We report that SEMA7A protein expression is increased in PPBCs compared to their nulliparous counterparts in our University of Colorado cohort. Additionally, tumors from PPBC patients with involved lymph nodes and lymphovascular invasion were higher on average suggesting a potential role for SEMA7A as a prognostic biomarker. Consistent with this hypothesis we identify a level of SEMA7A expression in tumors that can predict for recurrence. We propose SEMA7A as a potential biomarker and therapeutic target for PPBC patients, who currently lack strong predictors of outcome and unique targeted therapy options.

Germanium selenide is a promising material for electronic, photovoltaic, and thermoelectric applications; however, structural phase transitions of GeSe under pressure are controversial. Combining evolutionary algorithms, density functional theory, tight-binding method, and laser-heated diamond anvil cell experiments, pressure-induced phase transitions of GeSe are thoroughly investigated. Two novel intermediate phases are predicted to exist in between the well-known α-GeSe and the recently discovered β-GeSe under high pressure. α-GeSe is found to transform into a rhombohedral crystal structure with a space group of R3m at a low hydrostatic pressure. The R3m phase of GeSe exhibits robust ferroelectricity analogous to GeTe. By further increasing the pressure to approximately 6 GPa, the R3m phase is predicted to transform into a rock-salt structure, becoming a 3D topological crystalline insulator with an inverted band structure. The newly discovered GeSe high-pressure phases greatly enrich our knowledge of IV–VI compounds. The atoms in germanium selenide can adopt more configurations than previously thought according to a study by researchers in China. A phase change, the rearrangement of atoms in a solid from one crystal structure to another, can radically alter a material’s properties. Such a change in phase can be induced by exposing matter to high pressure. Kuo Li from the Center for High Pressure Science and Technology Advanced Research in Beijing, Yue Chen from The University of Hong Kong, and their co-workers have combined multiple computational and experimental techniques to identify the phases of germanium selenide, a material useful for energy conversion. Recently a high-pressure phase called β-GeSe was discovered in addition to the common low-pressure α-GeSe phase. The researchers predict two further phases at intermediate pressure, each with its own distinctive electrical properties. Pressure-induced phase transitions in GeSe are investigated from theory and experiment. Two new phases are predicted to exist in-between the well-known α-GeSe and the recently discovered β-GeSe under pressures. It is predicted that α-GeSe transforms into a rhombohedral structure with a space group of R3m and exhibits robust ferroelectricity at a low hydrostatic pressure. Laser-heated DAC experiments have been conducted to provide further evidence on the existence of the R3m phase. By increasing the hydrostatic pressure to approximately 6 GPa, the R3m phase is predicted to transform into a rock-salt crystal structure ( $$Fm\bar 3m$$ ) and become a topological crystalline insulator.

Adult umbilical cord blood transplantation (CBT) has emerged as an important option for patients lacking matched related (MRD) and matched unrelated donors (MUD). We compared chronic GVHD (cGVHD) incidence, immunosuppression burden and late infections and hospitalizations in consecutive patients undergoing CBT (n=51) versus peripheral blood MUD transplant (n=57) at our center between June 2009 and April 2014. At 3 years post transplantation, the cumulative incidence (CI) of moderate to severe cGVHD was 44% following MUD versus 8% following CBT (P=0.0006) and CI of any cGVHD was 68% following MUD versus 32% following CBT (P=0.0017). Median time to being off immunosuppression among CB patients was 268 days versus not reached among MUD patients (P

Background To identify aberrant promoter methylation of genomic loci encoding microRNA (mgmiR) in head and neck squamous cell carcinoma (HNSCC) and to evaluate a biomarker panel of mgmiRs to improve the diagnostic accuracy of HNSCC in tissues and saliva. Methods Methylation of promoter regions of mgmiR candidates was initially screened using HNSCC and control cell lines and further selected using HNSCC and control tissues by quantitative methylation-specific PCR (qMS-PCR). We then examined a panel of seven mgmiRs for validation in an expanded cohort including 189 HNSCC and 92 non-HNSCC controls. Saliva from 86 pre-treatment HNSCC patients and 108 non-HNSCC controls was also examined using this panel of seven mgmiRs to assess the potentials of clinical utilization. Results Among the 315 screened mgmiRs, 12 mgmiRs were significantly increased in HNSCC cell lines compared to control cell lines. Seven out of the 12 mgmiRs, i.e., mgmiR9-1, mgmiR124-1, mgmiR124-2, mgmiR124-3, mgmiR129-2, mgmiR137, and mgmiR148a, were further found to significantly increase in HNSCC tumor tissues compared to control tissues. Using multivariable logistic regression with dichotomized variables, a combination of the seven mgmiRs had sensitivity and specificity of 92.6 and 92.4% in tissues and 76.7 and 86.1% in saliva, respectively. Area under the receiver operating curve for this panel was 0.97 in tissue and 0.93 in saliva. This model was validated by independent bootstrap validation and random forest analysis. Conclusions mgmiR biomarkers represent a novel and promising screening tool, and the seven-mgmiR panel is able to robustly detect HNSCC in both patient tissue and saliva. Electronic supplementary material The online version of this article (10.1186/s13148-018-0470-7) contains supplementary material, which is available to authorized users.

A major goal of immunotherapy for cancer is the activation of T cell responses against tumor-associated antigens (TAAs). One important strategy for improving antitumor immunity is vaccination with peptide variants of TAAs. Understanding the mechanisms underlying the expansion of T cells that respond to the native tumor antigen is an important step in developing effective peptide-variant vaccines. Using an immunogenic mouse colon cancer model, we compare the binding properties and the TCR genes expressed by T cells elicited by peptide variants that elicit variable antitumor immunity directly ex vivo. The steady-state affinity of the natural tumor antigen for the T cells responding to effective peptide vaccines was higher relative to ineffective peptides, consistent with their improved function. Ex vivo analysis showed that T cells responding to the effective peptides expressed a CDR3β motif, which was also shared by T cells responding to the natural antigen and not those responding to the less effective peptide vaccines. Importantly, these data demonstrate that peptide vaccines can expand T cells that naturally respond to tumor antigens, resulting in more effective antitumor immunity. Future immunotherapies may require similar stringent analysis of the responding T cells to select optimal peptides as vaccine candidates. Electronic supplementary material The online version of this article (doi:10.1007/s00262-012-1217-5) contains supplementary material, which is available to authorized users.

Chromatin immunoprecipitation followed by massively parallel next-generation sequencing (ChIP-seq) is a valuable experimental strategy for assaying protein-DNA interaction over the whole genome. Many computational tools have been designed to find the peaks of the signals corresponding to protein binding sites. In this paper, three computational methods, ChIP-seq processing pipeline (spp), PeakSeq and CisGenome, used in ChIP-seq data analysis are reviewed. There is also a comparison of how they agree and disagree on finding peaks using the publically available Signal Transducers and Activators of Transcription protein 1 (STAT1) and RNA polymerase II (PolII) datasets with corresponding negative controls.

High-throughput RNA sequencing is rapidly emerging as a favourite method for gene expression studies. We review three software packages -- edgeR, DEGseq and baySeq -- from Bioconductor http://bioconductor.org for analysing RNA-sequencing data. We focus on three aspects: normalisation, statistical models and the testing employed on these methods. We also discuss the advantages and limitations of these software packages.