A phase I study of pexidartinib, a colony-stimulating factor 1 receptor inhibitor, in Asian patients with advanced solid tumors.

Background Pexidartinib, a novel, orally administered small-molecule tyrosine kinase inhibitor, has strong selectivity against colony-stimulating factor 1 receptor. This phase I, nonrandomized, open-label multiple-dose study evaluated pexidartinib safety and efficacy in Asian patients with symptomatic, advanced solid tumors. Materials and Methods Patients received pexidartinib: cohort 1, 600 mg/d; cohort 2, 1000 mg/d for 2 weeks, then 800 mg/d. Primary objectives assessed pexidartinib safety and tolerability, and determined the recommended phase 2 dose; secondary objectives evaluated efficacy and pharmacokinetic profile. Results All 11 patients (6 males, 5 females; median age 64, range 23-82; cohort 1 n = 3; cohort 2 n = 8) experienced at least one treatment-emergent adverse event; 5 experienced at least one grade ≥ 3 adverse event, most commonly (18%) for each of the following: increased aspartate aminotransferase, blood alkaline phosphatase, gamma-glutamyl transferase, and anemia. Recommended phase 2 dose was 1000 mg/d for 2 weeks and 800 mg/d thereafter. Pexidartinib exposure, area under the plasma concentration-time curve from zero to 8 h (AUC0-8h), and maximum observed plasma concentration (Cmax) increased on days 1 and 15 with increasing pexidartinib doses, and time at Cmax (Tmax) was consistent throughout all doses. Pexidartinib exposure and plasma levels of adiponectin and colony-stimulating factor 1 increased following multiple daily pexidartinib administrations. One patient (13%) with tenosynovial giant cell tumor showed objective tumor response. Conclusions This was the first study to evaluate pexidartinib in Asian patients with advanced solid tumors. Pexidartinib was safe and tolerable in this population at the recommended phase 2 dose previously determined for Western patients (funded by Daiichi Sankyo; clinicaltrials.gov number, NCT02734433).

All-cause mortality of insulin plus dipeptidyl peptidase-4 inhibitors in persons with type 2 diabetes.

BACKGROUND: Dipeptidyl peptidase-4 (DPP-4) inhibitors could effectively reduce HbA1C and postprandial hyperglycemia and could incur only minimal danger of hypoglycemia. Patients with uncontrolled diabetes might be treated by the complementary action of insulin plus DPP-4 inhibitors. Here, we compared the all-cause mortality risk between DPP-4 inhibitor users and nonusers with underlying insulin therapy. METHODS: Using the population-based National Health Insurance Research Database of Taiwan, we conducted an 11-year retrospective cohort study. A total of 3120 patients undergoing insulin therapy for type 2 diabetes mellitus (T2DM) during 2000-2010 were enrolled. The overall incidence rates for all-cause mortality of 1560 DPP-4 inhibitor users and 1560 matched DPP-4 inhibitor nonusers were compared. RESULTS: No significant difference was found in the baseline demographic and clinical variables of the two groups of patients. Median follow-up period for the matched cohort was 1.67 years. All-cause mortality was observed in 93 (6.0%) of 1560 DPP-4 inhibitor nonusers and 36 (2.3%) of 1560 DPP-4 users. The incidence rate of mortality was 11.72 for DPP-4 inhibitor users and 38.16 per 1000 person-years for DPP-4 inhibitor nonusers. After multivariate adjustment, DPP-4 inhibitor users ran a reduced mortality risk (adjusted hazard ratio 0.32, 95% CI 0.22-0.47; p < 0.0001) than did the nonusers. CONCLUSION: Risk of all-cause mortality may be reduced when using insulin plus DPP-4 inhibitors than when using insulin plus non-DPP-4 inhibitors.

Neuronal Senescence in the Aged Brain.

Cellular senescence is a highly complicated cellular state that occurs throughout the lifespan of an organism. It has been well-defined in mitotic cells by various senescent features. Neurons are long-lived post-mitotic cells with special structures and functions. With age, neurons display morphological and functional changes, accompanying alterations in proteostasis, redox balance, and Ca2+ dynamics; however, it is ambiguous whether these neuronal changes belong to the features of neuronal senescence. In this review, we strive to identify and classify changes that are relatively specific to neurons in the aging brain and define them as features of neuronal senescence through comparisons with common senescent features. We also associate them with the functional decline of multiple cellular homeostasis systems, proposing the possibility that these systems are the main drivers of neuronal senescence. We hope this summary will serve as a steppingstone for further inputs on a comprehensive but relatively specific list of phenotypes for neuronal senescence and in particular their underlying molecular events during aging. This will in turn shine light on the association between neuronal senescence and neurodegeneration and lead to the development of strategies to perturb the processes.

Laser-Induced Graphene Stretchable Strain Sensor with Vertical and Parallel Patterns.

In intelligent manufacturing and robotic technology, various sensors must be integrated with equipment. In addition to traditional sensors, stretchable sensors are particularly attractive for applications in robotics and wearable devices. In this study, a piezoresistive stretchable strain sensor based on laser-induced graphene (LIG) was proposed and developed. A three-dimensional, porous LIG structure fabricated from polyimide (PI) film using laser scanning was used as the sensing layer of the strain sensor. Two LIG pattern structures (parallel and vertical) were fabricated and integrated within the LIG strain sensors. Scanning electron microscopy, an X-ray energy dispersive spectrometer, and Raman scattering spectroscopy were used to examine the microstructure of the LIG sensing layer. The performance and strain sensing properties of the parallel and vertical stretchable LIG strain sensors were investigated in tensile tests. The relative resistance changes and the gauge factors of the parallel and vertical LIG strain sensors were quantified. The parallel strain sensor achieved a high gauge factor of 15.79 in the applied strain range of 10% to 20%. It also had high sensitivity, excellent repeatability, good durability, and fast response times during the tensile experiments. The developed LIG strain sensor can be used for the real-time monitoring of human motions such like finger bending, wrist bending, and throat swallowing.

Imaging dendritic spines: molecular organization and signaling for plasticity.

The structural plasticity of dendritic spines is considered to be essential for various forms of synaptic plasticity and, ultimately, learning and memory. The process is mediated by signaling pathways that promote the reorganization of the actin cytoskeleton and subsynaptic structures, which in turn cause structural and functional changes in dendritic spines. Recent advances in optical technologies have started to reveal the fine molecular structures and dynamic signaling occurring inside spines, providing significant insights into the molecular regulation of spines. Here, we highlight recent studies to resolve the molecular mechanisms underlying the spine actin cytoskeleton and plasticity with high spatiotemporal resolution. Moreover, we discuss new genome editing-based approaches in imaging the molecular structure and plasticity of dendritic spines.

Isolation and characterization of canine perivascular stem/stromal cells for bone tissue engineering.

For over 15 years, human subcutaneous adipose tissue has been recognized as a rich source of tissue resident mesenchymal stem/stromal cells (MSC). The isolation of perivascular progenitor cells from human adipose tissue by a cell sorting strategy was first published in 2008. Since this time, the interest in using pericytes and related perivascular stem/stromal cell (PSC) populations for tissue engineering has significantly increased. Here, we describe a set of experiments identifying, isolating and characterizing PSC from canine tissue (N = 12 canine adipose tissue samples). Results showed that the same antibodies used for human PSC identification and isolation are cross-reactive with canine tissue (CD45, CD146, CD34). Like their human correlate, canine PSC demonstrate characteristics of MSC including cell surface marker expression, colony forming unit-fibroblast (CFU-F) inclusion, and osteogenic differentiation potential. As well, canine PSC respond to osteoinductive signals in a similar fashion as do human PSC, such as the secreted differentiation factor NEL-Like Molecule-1 (NELL-1). Nevertheless, important differences exist between human and canine PSC, including differences in baseline osteogenic potential. In summary, canine PSC represent a multipotent mesenchymogenic cell source for future translational efforts in tissue engineering.

The pericyte antigen RGS5 in perivascular soft tissue tumors.

Perivascular soft tissue tumors are relatively uncommon neoplasms of unclear lineage of differentiation, although most are presumed to originate from or differentiate to pericytes or a modified perivascular cell. Among these, glomus tumor, myopericytoma, and angioleiomyoma share a spectrum of histologic findings and a perivascular growth pattern. In contrast, solitary fibrous tumor was once hypothesized to have pericytic differentiation--although little bona fide evidence of pericytic differentiation exists. Likewise the perivascular epithelioid cell tumor (PEComa) family shares a perivascular growth pattern, but with distinctive dual myoid-melanocytic differentiation. RGS5, regulator of G-protein signaling 5, is a novel pericyte antigen with increasing use in animal models. Here, we describe the immunohistochemical expression patterns of RGS5 across perivascular soft tissue tumors, including glomus tumor (n = 6), malignant glomus tumor (n = 4), myopericytoma (n = 3), angioleiomyoma (n = 9), myofibroma (n = 4), solitary fibrous tumor (n = 10), and PEComa (n = 19). Immunohistochemical staining and semi-quantification was performed, and compared to αSMA (smooth muscle actin) expression. Results showed that glomus tumor (including malignant glomus tumor), myopericytoma, and angioleiomyoma shared a similar diffuse immunoreactivity for RGS5 and αSMA across all tumors examined. In contrast, myofibroma, solitary fibrous tumor and PEComa showed predominantly focal to absent RGS5 immunoreactivity. These findings further support a common pericytic lineage of differentiation in glomus tumors, myopericytoma and angioleiomyoma. The pericyte marker RGS5 may be of future clinical utility for the evaluation of pericytic differentiation in soft tissue tumors.

Pericyte Antigens in Perivascular Soft Tissue Tumors.

INTRODUCTION: Perivascular soft tissue tumors are relatively uncommon neoplasms of unclear line of differentiation, although most are presumed to originate from pericytes or modified perivascular cells. Among these, glomus tumor, myopericytoma, and angioleiomyoma share a spectrum of histologic findings and a perivascular growth pattern. In contrast, solitary fibrous tumor (previously termed hemangiopericytoma) was once hypothesized to have pericytic differentiation. METHODS: Here, we systematically examine pericyte immunohistochemical markers among glomus tumor (including malignant glomus tumor), myopericytoma, angioleiomyoma, and solitary fibrous tumor. Immunohistochemical staining and semiquantification was performed using well-defined pericyte antigens, including αSMA, CD146, and PDGFRß. RESULTS: Glomus tumor and myopericytoma demonstrate diffuse staining for all pericyte markers, including immunohistochemical reactivity for αSMA, CD146, and PDGFRß. Malignant glomus tumors all showed some degree of pericyte marker immunoreactivity, although it was significantly reduced. Angioleiomyoma shared a similar αSMA + CD146 + PDGFRß+ immunophenotype; however, this was predominantly seen in the areas of perivascular tumor growth. Solitary fibrous tumors showed patchy PDGFRß immunoreactivity only. DISCUSSION: In summary, pericyte marker expression is a ubiquitous finding in glomus tumor, myopericytoma, and angioleiomyoma. Malignant glomus tumor shows a comparative reduction in pericyte marker expression, which may represent partial loss of pericytic differentiation. Pericyte markers are essentially not seen in solitary fibrous tumor. The combination of αSMA, CD146, and PDGFRß immunohistochemical stainings may be of utility for the evaluation of pericytic differentiation in soft tissue tumors.

Pericyte antigens in angiomyolipoma and PEComa family tumors.

Perivascular epithelioid cell tumors (PEComas) are an uncommon family of soft tissue tumors with dual myoid-melanocytic differentiation. Although PEComa family tumors commonly demonstrate a perivascular growth pattern, pericyte antigen expression has not yet been examined among this unique tumor group. Previously, we demonstrated that a subset of perivascular soft tissue tumors exhibit a striking pericytic immunophenotype, with diffuse expression of αSMA, CD146, and PDGFRß. Here, we describe the presence of pericyte antigens across a diverse group of PEComa family tumors (n = 19 specimens). Results showed that pericyte antigens differed extensively by histological appearance. Typical angiomyolipoma (AML) specimens showed variable expression of pericyte antigens among both perivascular and myoid-appearing cells. In contrast, AML specimens with a predominant spindled morphology showed diffuse expression of pericyte markers, including αSMA, CD146, and PDGFRß. AML samples with predominant epithelioid morphology showed a marked reduction in or the absence of immunoreactivity for pericyte markers. Lymphangiomyoma samples showed more variable and partial pericyte marker expression. In summary, pericyte antigen expression is variable among PEComa family tumors and largely varies by tumor morphology. Pericytic marker expression in PEComa may represent a true pericytic cell of origin, or alternatively aberrant pericyte marker adoption. Markers of pericytic differentiation may be of future diagnostic utility for the evaluation of mesenchymal tumors, or identify actionable signaling pathways for future therapeutic intervention.