The capecitabine and temozolomide (CAPTEM) regimen is active in the treatment of metastatic pancreatic neuroendocrine tumors (pNETs), with response rates ranging from 30 to 70%. Small retrospective ...studies suggest that O(6)-methylguanine DNA methyltransferase (MGMT) deficiency predicts response to temozolomide. High tumor proliferative activity is also commonly perceived as a significant predictor of response to cytotoxic chemotherapy. It is unclear whether chromosomal instability (CIN), which correlates with alternative lengthening of telomeres (ALT), is a predictive factor. In this study, we evaluated 143 patients with advanced pNET who underwent treatment with CAPTEM for radiographic and biochemical response. MGMT expression (n=52), grade (n=128) and ALT activation (n=46) were investigated as potential predictive biomarkers. Treatment with CAPTEM was associated with an overall response rate (ORR) of 54% by RECIST 1.1. Response to CAPTEM was not influenced by MGMT expression, proliferative activity or ALT pathway activation. Based on these results, no biomarker-driven selection criteria for use of the CAPTEM regimen can be recommended at this time.
Primary prostate cancers are infiltrated with programmed death-1 (PD-1) expressing CD8+ T-cells. However, in early clinical trials, men with metastatic castrate-resistant prostate cancer did not ...respond to PD-1 blockade as a monotherapy. One explanation for this unresponsiveness could be that prostate tumors generally do not express programmed death ligand-1 (PD-L1), the primary ligand for PD-1. However, lack of PD-L1 expression in prostate cancer would be surprising, given that phosphatase and tensin homolog (PTEN) loss is relatively common in prostate cancer and several studies have shown that PTEN loss correlates with PD-L1 upregulation--constituting a mechanism of innate immune resistance. This study tested whether prostate cancer cells were capable of expressing PD-L1, and whether the rare PD-L1 expression that occurs in human specimens correlates with PTEN loss.
Human prostate cancer cell lines were evaluated for PD-L1 expression and loss of PTEN by flow cytometry and western blotting, respectively. Immunohistochemical (IHC) staining for PTEN was correlated with PD-L1 IHC using a series of resected human prostate cancer samples.
In vitro, many prostate cancer cell lines upregulated PD-L1 expression in response to inflammatory cytokines, consistent with adaptive immune resistance. In these cell lines, no association between PTEN loss and PD-L1 expression was apparent. In primary prostate tumors, PD-L1 expression was rare, and was not associated with PTEN loss.
These studies show that some prostate cancer cell lines are capable of expressing PD-L1. However, in human prostate cancer, PTEN loss is not associated with PD-L1 expression, arguing against innate immune resistance as a mechanism that mitigates antitumor immune responses in this disease.
Aims: Diabetes mellitus results from an absolute or relative deficiency of insulin-producing pancreatic β-cells. The turnover rate of adult human β-cells remains unknown. We employed two techniques ...to examine adult human islet β-cell turnover and longevity in vivo.
Methods: Subjects enrolled in National Institutes of Health clinical trials received thymidine analogs iododeoxyuridine (IdU) or bromodeoxyuridine (BrdU) 8 d to 4 yr prior to death. Archival autopsy samples from 10 patients (aged 17–74 yr) were employed to assess β-cell turnover by scoring nuclear analog labeling within insulin-staining cells. Human adult β-cell longevity was determined by estimating the cells’ genomic DNA integration of atmospheric 14C. DNA was purified from pancreatic islets isolated from cadaveric donors; whole islet prep DNA was obtained from a 15-yr-old donor, and purified β-cell DNA was obtained from two donors (ages 48 and 80 yr). 14C levels were then determined using accelerator mass spectrometry. Cellular “birth date” was determined by comparing the subject’s DNA 14C content relative to a well-established 14C atmospheric prevalence curve.
Results: In the two subjects less than 20 yr of age, 1–2% of the β-cell nuclei costained for BrdU/IdU. No β-cell nuclei costained in the eight patients more than 30 yr old. Consistent with the BrdU/IdU turnover data, β-cell DNA 14C content indicated that the “birth date” of cells occurred within the subject’s first 30 yr of life.
Conclusions: Under typical circumstances, human β-cells and their cellular precursors are established by young adulthood.
In vivo thymidine analog labeling and carbon-14 dating showed β-cell turnover in humans to be restricted to the first three decades of life.
Phonon polaritons, hybrid light-matter quasiparticles resulting from strong coupling of the electromagnetic field with the lattice vibrations of polar crystals are a promising platform for ...mid-infrared photonics but for the moment there has been no proposal allowing for their electrical pumping. Electrical currents in fact mainly generate longitudinal optical phonons, while only transverse ones participate in the creation of phonon polaritons. We demonstrate how to exploit long-cell polytypes of silicon carbide to achieve strong coupling between transverse phonon polaritons and zone-folded longitudinal optical phonons. We develop a microscopic theory predicting the existence of the resulting hybrid longitudinal-transverse excitations. We then provide an experimental observation by tuning the resonance of a nanopillar array through the folded longitudinal optical mode, obtaining a clear spectral anti-crossing. The hybridisation of phonon polaritons with longitudinal phonons could represent an important step toward the development of phonon polariton-based electrically pumped mid-infrared emitters.
Recent large-scale prospective studies suggest that long telomeres are associated with an increase cancer risk, counter to conventional wisdom.
To further clarify the association between leukocyte ...telomere length (LTL) and prostate cancer, and assess genetic variability in relation to both LTL and prostate cancer, we performed a nested case-control study (922 cases and 935 controls). The participants provided blood in 1993-1995 and were followed through August 2004 (prostate cancer incidence) or until 28 February 2013 (lethal or fatal prostate cancer). Relative LTL was measured by quantitative PCR and was calculated as the ratio of telomere repeat copy number to a single gene (36B4) copy number (T/S). Genotyping was performed using the TaqMan OpenArray SNP Genotyping Platform. Logistic regression was used to estimate odds ratios (ORs) and 95% confidence intervals (CIs) of all prostate cancer and subtypes defined by Gleason grade, stage and lethality (metastasis or death).
We observed a positive association between each s.d. increase in LTL and all (multivariable-adjusted OR 1.11, 95% CI: 1.01-1.22), low-grade (OR 1.13, 95% CI:1.01-1.27), and localised (OR 1.12, 95% CI:1.01-1.24) prostate cancer. Associations for other subtypes were similar, but did not reach statistical significance. In subgroup analyses, associations for high grade and advanced stage (OR=2.04, 95% CI 1.00-4.17; Pinteraction=0.06) or lethal disease (OR=2.37, 95% CI 1.19-4.72; Pinteraction=0.01) were stronger in men with a family history of the disease compared with those without. The minor allele of SNP, rs7726159, which has previously been shown to be positively associated with LTL, showed an inverse association with all prostate cancer risk after correction for multiple testing (P=0.0005).
In this prospective study, longer LTL was modestly associated with higher risk of prostate cancer. A stronger association for more aggressive cancer in men with a family history of the disease needs to be confirmed in larger studies.
Genetic loci containing variable numbers of tandem repeats (VNTR loci) form the basis for human gene mapping and identification, forensic analysis and paternity testing. The variability of bacterial ...tandem repeats has not been systematically studied. Eleven tandem repeat loci in the M. tuberculosis genome were analysed. Five major polymorphic tandem repeat (MPTR) loci contained 15-bp repeats with substantial sequence variation in adjacent copies. Six exact tandem repeat (ETR) loci contained large DNA repeats with identical sequences in adjacent repeats. These 11 loci were amplified in 48 strains to determine the number of tandem repeats at each locus. The strains analysed included 25 wild-type strains of M. tuberculosis, M. bovis, M. africanum and M. microti and 23 substrains of the attenuated M. bovis BCG vaccine. One of the five MPTR loci and all six ETR loci had length polymorphisms corresponding to insertions or deletions of tandem repeats. Most ETR loci were located in intergenic regions where copy number may influence expression of downstream genes. Each ETR locus had multiple alleles in the panel. Combined analysis identified 22 distinct allele profiles in 25 wild-type strains of the M. tuberculosis complex and five allele profiles in 23 M. bovis BCG substrains. Allele profiles were reproducible and stable, as demonstrated by analyses of multiple isolates of particular reference strains obtained from different laboratories. VNTR typing may be generally useful for strain differentiation and evolutionary studies in bacteria.
Globalization of clinical research has led to an increase in clinical trials conducted outside of the United States that are submitted to the US Food and Drug Administration (FDA) in new drug ...applications. This article discusses the FDA's experience with these submissions in specific therapeutic areas, including the extent of this practice, differences between the effectiveness and safety outcomes of studies conducted inside and outside the United States, and the FDA's approach to acceptance of these trials.
Clinical Pharmacology & Therapeutics (2013); 94 2, 230–242. doi:10.1038/clpt.2013.70
The E26 transformation-specific (Ets-1) transcription factor is autoinhibited by a conformationally disordered serine-rich region (SRR) that transiently interacts with its DNA-binding ETS domain. In ...response to calcium signaling, autoinhibition is reinforced by calmodulin-dependent kinase II phosphorylation of serines within the SRR. Using mutagenesis and quantitative DNA-binding measurements, we demonstrate that phosphorylation-enhanced autoinhibition requires the presence of phenylalanine or tyrosine (ϕ) residues adjacent to the SRR phosphoacceptor serines. The introduction of additional phosphorylated Ser-ϕ-Asp, but not Ser-Ala-Asp, repeats within the SRR dramatically reinforces autoinhibition. NMR spectroscopic studies of phosphorylated and mutated SRR variants, both within their native context and as separate trans -acting peptides, confirmed that the aromatic residues and phosphoserines contribute to the formation of a dynamic complex with the ETS domain. Complementary NMR studies also identified the SRR-interacting surface of the ETS domain, which encompasses its positively charged DNA-recognition interface and an adjacent region of neutral polar and nonpolar residues. Collectively, these studies highlight the role of aromatic residues and their synergy with phosphoserines in an intrinsically disordered regulatory sequence that integrates cellular signaling and gene expression.
The growth, morphological, and electrical properties of thin-film Ge grown by molecular beam epitaxy on Si using a two-step growth process were investigated. High-resolution x-ray diffraction ...analysis demonstrated ∼0.10% tensile-strained Ge epilayer, owing to the thermal expansion coefficient mismatch between Ge and Si, and negligible epilayer lattice tilt. Micro-Raman spectroscopic analysis corroborated the strain-state of the Ge thin-film. Cross-sectional transmission electron microscopy revealed the formation of 90
°
Lomer dislocation network at Ge/Si heterointerface, suggesting the rapid and complete relaxation of Ge epilayer during growth. Atomic force micrographs exhibited smooth surface morphology with surface roughness < 2 nm. Temperature dependent Hall mobility measurements and the modelling thereof indicated that ionized impurity scattering limited carrier mobility in Ge layer. Capacitance- and conductance-voltage measurements were performed to determine the effect of epilayer dislocation density on interfacial defect states (D
it
) and their energy distribution. Finally, extracted D
it
values were benchmarked against published D
it
data for Ge MOS devices, as a function of threading dislocation density within the Ge layer. The results obtained were comparable with Ge MOS devices integrated on Si via alternative buffer schemes. This comprehensive study of directly-grown epitaxial Ge-on-Si provides a pathway for the development of Ge-based electronic devices on Si.
Variation in the land use environment (LUE) impacts the continuum of walkability to car dependency, which has been shown to have effects on health outcomes. Existing objective measures of the LUE do ...not consider whether the measurement of the construct varies across different types of communities along the rural/urban spectrum. To help meet the goals of the Diabetes Location, Environmental Attributes, and Disparities (LEAD) Network, we developed a national, census tract‐level LUE measure which evaluates the road network and land development. We tested for measurement invariance by LEAD community type (higher density urban, lower density urban, suburban/small town, and rural) using multiple group confirmatory factor analysis. We determined that metric invariance does not exist; thus, measurement of the LUE does vary across community type with average block length, average block size, and percent developed land driving most shared variability in rural tracts and with intersection density, street connectivity, household density, and commercial establishment density driving most shared variability in higher density urban tracts. As a result, epidemiologic studies need to consider community type when assessing the LUE to minimize place‐based confounding.
Plain Language Summary
A community's land use environment (LUE) describes its citizens ability to walk from place to place versus their reliance on vehicles for transportation. Some factors that might influence LUE include the street network, size of road blocks, density of walkable establishments (food stores, restaurants, schools, etc.), and the mixture of residential and commercial establishments. Existing objective measures of the LUE do not consider urbanicity, which can lead to differences due only to places being more or less rural. The Diabetes Location, Environmental Attributes, and Disparities (LEAD) Network created a national, census tract‐level LUE measure and assessed whether the LUE construct differed across LEAD community type groups (higher density urban, lower density urban, suburban/small town, and rural). We found that the LUE construct does vary across LEAD community type. Future epidemiologic studies examining the LUE need to consider urbanicity to account for these differences.
Key Points
Variation in the land use environment (LUE) impacts the continuum of walkability to car dependency, which has effects on health outcomes
We assessed measurement invariance of a land use construct across levels of urbanicity using multiple group confirmatory factor analysis
We determined that measurement of the LUE does vary across urbanicity which can lead to place‐based confounding
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