Gut microbiota and clinical response to immune checkpoint inhibitor therapy in patients with advanced cancer.

BACKGROUND: There is currently no well-accepted consensus on the association between gut microbiota and the response to treatment of immune checkpoint inhibitors (ICIs) in patients with advanced cancer. METHODS: Fecal samples were collected before ICI treatment. Gut microbiota was analyzed using 16 S ribosomal RNA sequencing. We investigated the relationship between the α-diversity of fecal microbiota and patients' clinical outcomes. Microbiota profiles from patients and healthy controls were determined. Pre-treatment serum was examined by cytokine array. RESULTS: We analyzed 74 patients, including 42 with melanoma, 8 with kidney cancer, 13 with lung cancer, and 11 with other cancers. Combination therapy of anti-PD1 and anti-CTLA-4 was used in 14 patients, and monotherapy in the rest. Clinical benefit was observed in 35 (47.3 %) cases, including 2 complete responses, 16 partial responses, and 17 stable diseases according to RECIST criteria. No significant difference in α-diversity was found between the benefiter and non-benefiter groups. However, patients with α-diversity within the range of our healthy control had a significantly longer median overall survival (18.9 months), compared to the abnormal group (8.2 months) (p = 0.041, hazard ratio = 0.546) for all patients. The microbiota composition of the benefiters was similar to that of healthy individuals. Furthermore, specific bacteria, such as Prevotella copri and Faecalibacterium prausnitzii, were associated with a favorable outcome. We also observed that serum IL-18 before treatment was significantly lower in the benefiters, compared to non-benefiters. CONCLUSIONS: The α-diversity of gut microbiota is positively correlated with more prolonged overall survival in cancer patients following ICI therapy.

Discovery of Biaryl Amide Derivatives as Potent, Selective, and Orally Bioavailable RORγt Agonists for Cancer Immunotherapy.

The master transcription factor receptor retinoic acid receptor-related orphan receptor γt (RORγt) regulates the differentiation of T-helper 17 (Th17) cells and the production of interleukin-17 (IL-17). Activation of RORγt+ T cells in the tumor microenvironment promotes immune infiltration to more effectively inhibit tumor growth. Therefore, RORγt agonists provide a reachable approach to cancer immunotherapy. Herein, a series of biaryl amide derivatives as novel RORγt agonists were designed, synthesized, and evaluated. Starting from the reported RORγt inverse agonist GSK805 (1), "functionality switching" and structure-based drug optimization led to the discovery of a promising RORγt agonist lead compound 14, which displayed potent and selective RORγt agonist activity and significantly improved metabolic stability. With excellent in vivo pharmacokinetic profiles, compound 14 demonstrated robust efficacy in preclinical tumor models of mouse B16F10 melanoma and LLC lung adenocarcinoma. Taken together, current studies indicate that 14 deserves further investigation as a potential lead RORγt agonist for cancer immunotherapy.

Blockade of de novo pyrimidine biosynthesis triggers autophagic degradation of oncoprotein FLT3-ITD in acute myeloid leukemia.

The internal tandem duplication of the FMS-like tyrosine kinase 3 (FLT3-ITD) is one of the most frequent genetic alterations in acute myeloid leukemia (AML). Limited and transient clinical benefit of FLT3 kinase inhibitors (FLT3i) emphasizes the need for alternative therapeutic options for this subset of myeloid malignancies. Herein, we showed that FLT3-ITD mutant (FLT3-ITD+) AML cells were susceptible toward inhibitors of DHODH, a rate-limiting enzyme of de novo pyrimidine biosynthesis. Genetic and pharmacological blockade of DHODH triggered downregulation of FLT3-ITD protein, subsequently suppressed activation of downstream ERK and STAT5, and promoted cell death of FLT3-ITD+ AML cells. Mechanistically, DHODH blockade triggered autophagy-mediated FLT3-ITD degradation via inactivating mTOR, a potent autophagy repressor. Notably, blockade of DHODH synergized with an FDA-approved FLT3i quizartinib in significantly impairing the growth of FLT3-ITD+ AML cells and improving tumor-bearing mice survival. We further demonstrated that DHODH blockade exhibited profound anti-proliferation effect on quizartinib-resistant cells in vitro and in vivo. In summary, this study demonstrates that the induction of degradation of FLT3-ITD protein by DHODH blockade may offer a promising therapeutic strategy for AML patients harboring FLT3-ITD mutation.

The effect of health literacy, self-efficacy, social support and fear of disease progression on the health-related quality of life of patients with cancer in China: a structural equation model.

BACKGROUND: Health literacy (HL), self-efficacy (SE), social support (SS) and fear of disease progression (FOP) are all important factors affecting health-related quality of life (HRQoL) in cancer patients. However, their synergistic effects and underlying mechanisms on HRQoL in cancer patients remain unclear. Therefore, the purpose of this study was to construct a structural equation model (SEM) to explore the underlying mechanism of factors affecting HRQoL. It is hoped that this study will provide a theoretical basis for future interventions. METHODS: A cross-sectional design and convenience sampling method were used to investigate cancer inpatients in two general hospitals in Chongqing and Chengdu. Data were collected using structured scales, including HL, SE, SS, FOP and HRQoL. Finally, the SEM was constructed, and P ≤ 0.05 was considered significant. RESULTS: There were 1749 participants included in this study. Correlation analysis showed that all variables were significantly correlated with one another except for symptoms, physical health (PD) and social family (SF) (p < 0.01). The SEM of the HRQoL had a good overall fit (GFI = 0.943, AGFI = 0.917, NFI = 0.950, RFI = 0.936, CFI = 0.955, IFI = 0.955, RMSEA = 0.072). The model indicated that HL had the strongest correlation with HRQoL (ß = 0.398, p < 0.01), followed by FOP (ß = -0.364, p < 0.01), SE (ß = 0.347, p < 0.01) and SS (ß = 0.184, p < 0.01). CONCLUSIONS: The HRQoL of cancer patients is correlated with HL, SS, SE and FOP. HL can directly affect HRQoL and mediate HRQoL through SS and SE. Future programs should consider HL promotion, SE improvement and SS expansion as the breakthrough point when designing targeted intervention strategies. At the same time, the importance of the impact of FOP on the HRQoL of patients with cancer should not be ignored.

Broadband and Spectrally Selective Photothermal Conversion through Nanocluster Assembly of Disordered Plasmonic Metasurfaces.

Plasmonic metasurfaces have been realized for efficient light absorption, thereby leading to photothermal conversion through nonradiative decay of plasmonic modes. However, current plasmonic metasurfaces suffer from inaccessible spectral ranges, costly and time-consuming nanolithographic top-down techniques for fabrication, and difficulty of scale-up. Here, we demonstrate a new type of disordered metasurface created by densely packing plasmonic nanoclusters of ultrasmall size on a planar optical cavity. The system either operates as a broadband absorber or offers a reconfigurable absorption band right across the visible region, resulting in continuous wavelength-tunable photothermal conversion. We further present a method to measure the temperature of plasmonic metasurfaces via surface-enhanced Raman spectroscopy (SERS), by incorporating single-walled carbon nanotubes (SWCNTs) as an SERS probe within the metasurfaces. Our disordered plasmonic system, generated by a bottom-up process, offers excellent performance and compatibility with efficient photothermal conversion. Moreover, it also provides a novel platform for various hot-electron and energy-harvesting functionalities.

Discovery of novel triazine derivatives as potent retinoic acid receptor-related orphan receptor γt (RORγt) inverse agonists.

Retinoic Acid Receptor-Related Orphan Receptor γt (RORγt) has been exploited as a promising target for the new small molecule therapeutics to treat inflammatory and autoimmune diseases via modulating the interleukin-17 (IL-17) production by T helper 17 (Th17) cells. Herein, we reported a series of triazine-based derivatives as novel RORγt inverse agonists. By screening of our in-house compound library, the hit compound 1 was identified with weak RORγt inhibitory activity. Subsequently, we engineered detailed structural modifications to explore the structure-activity relationships (SARs) of triazines derivatives, which led to discovery of a number of potent RORγt inverse agonists with IC50 values in the range of 7 nM-50 nM in RORγt dual FRET assay. Among them, compound 14g displayed potent RORγt inverse agonistic activity with an IC50 value of 22.9 nM in dual FRET assay. In a cell-based reporter gene assay, compound 14g showed an IC50 value of 0.428 µM and maximum inhibition rate of 108.9%. Compound 14g also exhibited good metabolic stability and a decent pharmacokinetic profile with a low clearance (CL = 0.229 L/h/kg) and a reasonable oral exposure (AUC0-Last = 5058 ng/mL*h). Most importantly, 14g alleviated the severity of imiquimod-induced psoriasis in mice. Taken together, triazine-based derivatives represent a new chemical class of RORγt inverse agonists as potential therapeutic agents against autoimmune diseases.

A One-Size-Fits-All Approach to Pressure Ulcers: Whole-Buttock Fasciocutaneous Advancement Flap.

BACKGROUND: Buttock pressure injuries can be difficult to treat. There are many choices of flaps to reconstruct these wounds, but few are large, technically simple, and easily recycled. AIM AND OBJECTIVE: We are presenting our experience on surgical reconstruction of buttock pressure injuries using large whole-buttock fasciocutaneous flaps that are easily designed for ulcers regardless of location and size and are easily recycled for treatment of recurrences. MATERIAL AND METHODS: We conducted a retrospective review of all patients who received reconstruction with fasciocutaneous rotational flaps for buttock region pressure injuries from January 2013 to December 2018. The key steps of this one-size-fits-all flap include elevation of a large, oversized flap to achieve tension-free closure, avoiding fascial incisions over bony prominences, placing the V-Y type closure wound in the posteromedial thigh, and the use of closed incisional negative wound therapy postoperatively. RESULTS: Fifty patients underwent 54 flaps reconstruction for coverage of stage 4 gluteal pressure injuries between January 2013 and December 2018. Seventy-four percent healed without the need for further operation. The average size of the defect was 90 cm2 (maximum = 300 cm2). The average follow-up period was 31 months. Four of the 54 flaps were "recycled" flaps, 3 were performed for the coverage of recurrent ulcers and 1 flap was performed for treatment of a postoperative wound dehiscence. CONCLUSIONS: We recommend this simple, one-size-fits-all approach, whole-buttock fasciocutaneous flap when surgically treating gluteal pressure injuries for selected patients.

Gas phase fabrication of morphology-controlled ITO nanoparticles and their assembled conductive films.

ITO nanoparticles were generated in the gas phase with a magnetron plasma gas aggregation cluster source. Their morphologies were modified by modulating the discharging power of magnetron sputtering. The shape of the nanoparticles changed from rough spheroid formed with a higher discharging power to multi-branch formed with a lower discharging power. With a discharging power of 25 W, the ITO nanoparticles were enriched with tripod and tetrapod-shaped nanoparticles. The formation mechanism of multi-branch nanoparticles was attributed to the oriented attachment of the initially nucleated smaller nanocrystallites. Transparent conductive ITO nanoparticle films were fabricated by depositing the preformed nanoparticles with controlled thickness. The electron conduction in the film was dominated by electron tunnelling and/or hopping in the percolative channels comprised of closely spaced ITO nanoparticle assemblies and could be tuned from highly resistive nonmetal-like to highly conductive metal-like by changing the deposition thickness. The film also displayed a SPR band in the near-IR region. The conductivity of the multi-branch ITO nanoparticle film was significantly superior to that of the spheroidal nanoparticle film. For a 46 nm thick multi-branch ITO nanoparticle film, a surprisingly low specific resistance of 3.09 × 10-4 Ω cm, which is comparable to the top-class conductivity of bulk ITO films, was obtained after annealing at a mild temperature of 250 °C, with a transmittance larger than 85%.

Investigation of health literacy status and related influencing factors in military health providers of Chinese People's liberation Army, a cross-sectional study.

OBJECTIVE: The aim of this study was to investigate health literacy and analyze its influencing factors in military health providers of the Chinese People's Liberation Army (PLA Army). METHODS: From November to December 2018, cluster sampling was used to select 1512 military health providers from the Army Medical University. Health literacy was measured by using the Chinese Citizen Health Literacy Questionnaire (HLQ) (2015 edition). Influencing factors that may affect health literacy were assessed using the chi-square test and multivariate logistic regression models. RESULTS: The knowledge rate of health literacy was relatively low (21.6%). The knowledge rate of health-related skills (HRS, 18.7%) was the lowest of the three aspects of health literacy, and the knowledge rate of chronic diseases (CD, 19.6%) was the lowest of the six dimensions of health literacy. Participants who were older, were female, were of Han ethnicity, were the only child in their families, came from urban areas, never used tobacco, and had higher household income were likely to have higher health literacy. CONCLUSION: The health literacy levels of military health providers of the PLA Army are relatively low. Further research and health education are necessary to improve health literacy.

Maternal rodent exposure to di-(2-ethylhexyl) phthalate decreases muscle mass in the offspring by increasing myostatin.

BACKGROUND: Di-(2-ethylhexyl) phthalate (DEHP) and its metabolites can cross the placenta and may cause birth defects and developmental disorders. However, whether maternal DEHP exposure affects skeletal muscle development in the offspring and the pathways involved are unknown. This study investigated the effects of maternal DEHP exposure and the contribution of myostatin (MSTN) to skeletal muscle development in the offspring. METHODS: Pregnant wild-type and muscle-specific myostatin knockout (MSTN KO) C57BL/6 mice were randomized to receive vehicle (corn oil) or 250 mg/kg DEHP by gavage every other day until their pups were weaned (postnatal day 21 [PND21]). Body weights of the offspring mice were measured longitudinally, and their hindleg muscles were harvested at PD21. Also, C2C12 cells were treated with mono-2-ethylhexyl phthalate (MEHP), the primary metabolite of DEHP, and proteolysis, protein synthesis, and myogenesis markers were measured. The contribution of myostatin to maternal DEHP exposure-induced muscle wasting in the offspring was determined. RESULTS: Maternal DEHP exposure reduced body weight growth, myofibre size, and muscle mass in the offspring compared to controls (Quad: 2.70 ± 0.1 vs. 3.38 ± 0.23, Gastroc: 2.29 ± 0.09 vs. 2.81 ± 0.14, Tibialis: 1.01 ± 0.07 vs. 1.25 ± 0.11, mg/tibial length in mm, all P < 0.01, n = 35). Maternal DEHP exposure significantly increased Myostatin expression (2.45 ± 0.41 vs. 0.03 ± 0.00 DEHP vs. controls, P < 0.01, n = 5), Atrogin-1(2.68 ± 0.65 vs. 0.63 ± 0.01, P < 0.05, n = 5), MuRF1 (1.56 ± 0.51 vs. 0.31 ± 0.01, P < 0.05, n = 5), and Smad2/3 phosphorylation (4.12 ± 0.35 vs. 0.49 ± 0.18, P < 0.05), and decreased MyoD (0.27 ± 0.01 vs. 1.52 ± 0.01, P < 0.05, n = 5), Myogenin (0.25 ± 0.03 vs. 1.95 ± 0.56, P < 0.05, n = 5), and AKT phosphorylation (4.12 ± 0.35 vs. 1.00 ± 0.06, P < 0.05, n = 5), in skeletal muscle of the offspring in MSTNflox/flox , but not in MSTN KO mice. Maternal DEHP exposure resulted in up-regulation of CCAAT/enhancer-binding protein δ (C/EBPδ, 4.12 ± 0.35 vs. 1.00 ± 0.19, P < 0.05, n = 5) in skeletal muscle of the offspring in MSTNflox/flox and MSTN KO mice (4.12 ± 0.35 vs. 4.35 ± 0.28, P > 0.05, n = 5). In vitro, C/EBPδ silencing abrogated the MEHP-induced increases in Myostatin, MuRF-1, and Atrogin-1 and decreases in MyoD and Myogenin expression. CONCLUSIONS: Maternal DEHP exposure impairs skeletal muscle development in the offspring by enhancing the C/EBPδ-myostatin pathway in mice.

Microwave ablation versus laparoscopic resection as first-line therapy for solitary 3-5-cm HCC.

BACKGROUND AND AIMS: The study objective was to compare the effectiveness of microwave ablation (MWA) and laparoscopic liver resection (LLR) on solitary 3-5-cm HCC over time. APPROACH AND RESULTS: From 2008 to 2019, 1289 patients from 12 hospitals were enrolled in this retrospective study. Diagnosis of all lesions were based on histopathology. Propensity score matching was used to balance all baseline variables between the two groups in 2008-2019 (n = 335 in each group) and 2014-2019 (n = 257 in each group) cohorts, respectively. For cohort 2008-2019, during a median follow-up of 35.8 months, there were no differences in overall survival (OS) between MWA and LLR (HR: 0.88, 95% CI 0.65-1.19, p = 0.420), and MWA was inferior to LLR regarding disease-free survival (DFS) (HR 1.36, 95% CI 1.05-1.75, p = 0.017). For cohort 2014-2019, there was comparable OS (HR 0.85, 95% CI 0.56-1.30, p = 0.460) and approached statistical significance for DFS (HR 1.33, 95% CI 0.98-1.82, p = 0.071) between MWA and LLR. Subgroup analyses showed comparable OS in 3.1-4.0-cm HCCs (HR 0.88, 95% CI 0.53-1.47, p = 0.630) and 4.1-5.0-cm HCCs (HR 0.77, 95% CI 0.37-1.60, p = 0.483) between two modalities. For both cohorts, MWA shared comparable major complications (both p > 0.05), shorter hospitalization, and lower cost to LLR (all p < 0.001). CONCLUSIONS: MWA might be a first-line alternative to LLR for solitary 3-5-cm HCC in selected patients with technical advances, especially for patients unsuitable for LLR.

Organic/Inorganic Self-Assembled Hybrid Nano-Architectures for Cancer Therapy Applications.

Since the conceptualization of nanomedicine, numerous nanostructure-mediated drug formulations have progressed into clinical trials for treating cancer. However, recent clinical trial results indicate such kind of drug formulations has a limited improvement on the antitumor efficacy. This is due to the biological barriers associated with those formulations, for example, circulation stability, extravasation efficiency in tumor, tumor penetration ability, and developed multi-drug resistance. When employing for nanomedicine formulations, pristine organic-based and inorganic-based nanostructures have their own limitations. Accordingly, organic/inorganic (O/I) hybrids have been developed to integrate the merits of both, and to minimize their intrinsic drawbacks. In this context, the recent development in O/I hybrids resulting from a self-assembly strategy will be introduced. Through such a strategy, organic and inorganic building blocks can be self-assembled via either chemical covalent bonds or physical interactions. Based on the self-assemble procedure, the hybridization of four organic building blocks including liposomes, micelles, dendrimers, and polymeric nanocapsules with five functional inorganic nanoparticles comprising gold nanostructures, magnetic nanoparticles, carbon-based materials, quantum dots, and silica nanoparticles will be highlighted. The recent progress of these O/I hybrids in advanced modalities for combating cancer, such as, therapeutic agent delivery, photothermal therapy, photodynamic therapy, and immunotherapy will be systematically reviewed.

Two orders of magnitude extra SERS enhancement on silver nanoparticle-based substrate induced by laser irradiation in nitrogen ambient.

Photo-reduction of silver oxide and light-induced Ag nanoparticle (NP) generations have been applied for Surface-enhanced Raman spectroscopy (SERS) substrate fabricated for years. In this paper, we demonstrate a general method to enhance the SERS activity of conventional Ag NPs-based SERS substrates by performing Raman scattering measurement in a nitrogen ambient after a period of laser irradiation (photoactivation). The Raman characteristic peak intensity of carbonaceous impurities adsorbed on the surfaces of Ag NPs display an additional enhancement of 93 times after photoactivation in nitrogen ambient. A 3-fold extra Raman gain enhancement is also observed in the nitrogen-protected SERS measurement of R6G molecules. The extra SERS enhancement is attributed to the sub-nanometer scale near-field coupling between the Ag NPs and the photo-generated Ag clusters in the surface oxide layer of Ag NPs. This model is verified through the finite-difference time-domain (FDTD) simulations.

Discovery of Orally Available Retinoic Acid Receptor-Related Orphan Receptor γ-t/Dihydroorotate Dehydrogenase Dual Inhibitors for the Treatment of Refractory Inflammatory Bowel Disease.

Inflammatory bowel disease (IBD) is a multifactorial autoimmune disease, representing a major clinical challenge. Herein, a strategy of dual-targeting approach employing retinoic acid receptor-related orphan receptor γ-t (RORγt) and dihydroorotate dehydrogenase (DHODH) was proposed for the treatment of IBD. Dual RORγt/DHODH inhibitors are expected not only to reduce RORγt-driven Th17 cell differentiation but also to mitigate the expansion and activation of T cells, which may enhance anti-inflammatory effects. Starting from 2-aminobenzothiazole hit 1, a series of 2-aminotetrahydrobenzothiazoles were discovered as potent dual RORγt/DHODH inhibitors. Compound 14d stands out with IC50 values of 0.110 µM for RORγt and of 0.297 µM for DHODH. With acceptable mouse pharmacokinetic profiles, 14d exhibited remarkable in vivo anti-inflammatory activity and dose-dependently alleviated the severity of dextran sulfate sodium (DSS)-induced acute colitis in mice. Taken together, the present study provides a novel framework for the development of therapeutic agents for the treatment of IBD.

Association of serum microcystin levels with neurobehavior of school-age children in rural area of Southwest China: A cross-sectional study.

To investigate whether microcystin-LR (MC-LR) influences children's cognitive function and memory ability, we measured serum MC-LR and whole blood lead levels in 697 primary students, and collected their academic and neurobehavioral test scores. The median of serum MC-LR levels was 0.80 µg/L (the value below the limit of detection to 1.67 µg/L). The shapes of the associations of serum MC-LR levels (cut-point: 0.95 µg/L) with scores on academic achievements, digit symbol substitution test and long-term memory test were parabolic curves. Logistic regression analysis showed that MC-LR at concentrations of 0.80-0.95 µg/L was associated with the increased probability of higher achievements on academic achievements [odds ratio (OR) = 2.20, 95% confidence interval (CI): 1.28-3.79], and also with scores on digit symbol substitution test (OR = 1.73, 95% CI: 1.05-2.86), overall memory quotient (OR = 2.27, 95% CI: 1.21-4.26), long-term memory (OR = 1.85, 95% CI: 1.01-3.38) and short-term memory (OR = 2.13, 95% CI: 1.14-3.98) after adjustment for confounding factors. Antagonism of MC-LR and lead on long-term memory was observed (synergism index = 0.15, 95% CI: 0.03-0.74). In conclusion, serum MC-LR at concentrations of 0.80-0.95 µg/L was positively associated with higher scores on cognitive and neurobehavioral tests, and antagonism between MC-LR at concentrations of 0.80-1.67 µg/L and lead exposure was obviously observed on long-term memory in children. Concerning that MC-LR is a neurotoxin at high doses, our observation is interesting and need further investigation.

Realizing the enhanced cyclability of a cactus-like NiCo2O4 nanocrystal anode fabricated by molecular layer deposition.

Lithium-ion batteries with conversion-type anode electrodes have attracted increasing interest in providing higher energy storage density than those with commercial intercalation-type electrodes. However, conversion-type materials exhibit severe structural instability and capacity fade during cycling. In this work, a molecular layer deposition (MLD)-derived conductive Al2O3/carbon layer was employed to stabilize the structure of the cactus-like NiCo2O4 nanocrystal (NC) anode. The conductive Al2O3/carbon network and cactus-like NiCo2O4 NCs are beneficial for fast Li+/e- transport. Moreover, the Al2O3/carbon buffer-layer can prevent the NiCo2O4 NCs from agglomeration and form a steady solid electrolyte interphase (SEI), thus hampering the penetration of the electrolyte. Owing to these advantages, the assembled NiCo2O4@Al2O3/carbon half battery shows a high reversible capacity (931.2 mA h g-1 at 2 A g-1) and long-term stability of 290 mA h g-1 at 5 A g-1 over 500 cycles. Quantitative analyses further reveal the fast kinetics and the capacitance-battery dual model mechanism in the 3D core-shell structures. The design and introduction of MLD-derived hybrid coating may open a new way to conversion-type and alloy-type anode materials beyond NiCo2O4 to achieve high cyclability.

Involvement of Aquaporins in the Intense Pulsed Light-Enhanced Wound Healing in Diabetic Rats.

BACKGROUND AND OBJECTIVES: We previously demonstrated that intense pulsed light (IPL) irradiation prior to wounding improved the wound healing in rats with diabetes mellitus (DM). Also, we found that IPL upregulated the expression of aquaporin 3 (AQP3), a protein that is crucial for wound healing, in normal rats. This present study aimed to examine the involvement of AQPs in the IPL-enhanced wound healing in diabetic rats. STUDY DESIGN/MATERIALS AND METHODS: Streptozotocin was used to induce diabetes in Sprague-Dawley rats. Animals were divided into four groups: normal group, DM only group, DM rats with IPL treatment 2 weeks before wounding (DM + IPL-Pre group), and DM rats with concurrent IPL irradiation and wounding (DM + IPL-Con group). Wounds were created on the dorsal skin of rats. The expressions of AQP1, 3, 4, 7, and 9 in the pre-injured skin, periwound, and wound were determined. RESULTS: Among all the AQPs analyzed, only the expressions of AQP3 and AQP7 were significantly altered. Unirradiated diabetic rats showed much higher expression level of AQP3 in the regenerating skin compared with normal rats. IPL pretreatment, but not concurrent treatment, attenuated the expression toward the level detected in the normal wounds. In contrast, a lower expression level of AQP7 was noted in the regenerating skin of DM only rats and IPL pretreatment upregulated the expression to a level similar to that in the normal rats. CONCLUSION: The beneficial effect of IPL pretreatment on the wound healing in diabetic rats might involve a mechanism by which the expression of AQPs is regulated. Lasers Surg. Med. © 2020 Wiley Periodicals LLC.

Controllable Fabrication of Percolative Metal Nanoparticle Arrays Applied for Quantum Conductance-Based Strain Sensors.

We use gas phase deposition of well-defined nanoparticles (NPs) to fabricate closely-spaced Pd NP arrays on flexible membranes prepatterned with interdigital electrodes (IDEs). The evolution of the morphology and electron conductance of the NP arrays during deposition is analyzed. The growth of two-dimensional percolation clusters of interconnected NPs, which correlate with the percolation pathway for electron conduction in the NP deposits, is demonstrated. The percolative nature of the NP arrays permits us to finely control the percolation geometries and conductance of the NP film by controlling the NP deposition time so as to realize a precise and reproducible fabrication of sensing materials. Electron transport measurements reveal that the electrical conductance of the NP films is dominated by electron tunneling or hopping across the NP percolating networks. Based on the percolative and quantum tunneling nature, the closely-spaced Pd NP films on PET membranes are used as flexible strain sensors. The sensor demonstrates an excellent response ability to distinguish tiny deformations down to 5×10-4 strain and a high sensitivity with a large gauge factor of 200 up to 4% applied strain.

Ghrelin ameliorates tumor-induced adipose tissue atrophy and inflammation via Ghrelin receptor-dependent and -independent pathways.

Adipose tissue (AT) atrophy is a hallmark of cancer cachexia contributing to increased morbidity/mortality. Ghrelin has been proposed as a treatment for cancer cachexia partly by preventing AT atrophy. However, the mechanisms mediating ghrelin's effects are incompletely understood, including the extent to which its only known receptor, GHSR-1a, is required for these effects. This study characterizes the pathways involved in AT atrophy in the Lewis Lung Carcinoma (LLC)-induced cachexia model and those mediating the effects of ghrelin in Ghsr +/+ and Ghsr -/- mice. We show that LLC causes AT atrophy by inducing anorexia, and increasing lipolysis, AT inflammation, thermogenesis and energy expenditure. These changes were greater in Ghsr -/-. Ghrelin administration prevented LLC-induced anorexia only in Ghsr +/+, but prevented WAT lipolysis, inflammation and atrophy in both genotypes, although its effects were greater in Ghsr +/+. LLC-induced increases in BAT inflammation, WAT and BAT thermogenesis, and energy expenditure were not affected by ghrelin. In conclusion, ghrelin ameliorates WAT inflammation, fat atrophy and anorexia in LLC-induced cachexia. GHSR-1a is required for ghrelin's orexigenic effect but not for its anti-inflammatory or fat-sparing effects.

In Vivo Imaging of Senescent Vascular Cells in Atherosclerotic Mice Using a ß-Galactosidase-Activatable Nanoprobe.

Senescence-associated diseases have severely diminished the quality of life and health of patients. However, a sensitive assay of these diseases remains limited due to a lack of straightforward methods. Considering that senescence-associated ß-galactosidase (SA-ß-Gal) is overexpressed in senescent cells, the detection of SA-ß-Gal in senescent cells and tissues might be a feasible strategy for the early diagnosis of SA diseases. In this study, a ß-galactosidase-activatable nanoprobe BOD-L-ßGal-NPs was developed for the imaging of senescent cells and vasculature in atherosclerotic mice via real-time monitoring of ß-Gal. BOD-L-ßGal-NPs was fabricated by encapsulating a newly designed NIR ratiometric probe BOD-L-ßGal within a poly(lactic-co-glycolic) acid (PLGA) core. Nanoprobe BOD-L-ßGal-NPs showed good accumulation in arteries, thus successfully visualizing senescent cells and vasculature in atherosclerotic mice by tail vein injection. Our findings indicated that nanoprobe BOD-L-ßGal-NPs holds great potential for the early diagnosis and therapy of atherosclerosis and other aging-associated diseases.