Brown-fat-mediated tumour suppression by cold-altered global metabolism.

Glucose uptake is essential for cancer glycolysis and is involved in non-shivering thermogenesis of adipose tissues1-6. Most cancers use glycolysis to harness energy for their infinite growth, invasion and metastasis2,7,8. Activation of thermogenic metabolism in brown adipose tissue (BAT) by cold and drugs instigates blood glucose uptake in adipocytes4,5,9. However, the functional effects of the global metabolic changes associated with BAT activation on tumour growth are unclear. Here we show that exposure of tumour-bearing mice to cold conditions markedly inhibits the growth of various types of solid tumours, including clinically untreatable cancers such as pancreatic cancers. Mechanistically, cold-induced BAT activation substantially decreases blood glucose and impedes the glycolysis-based metabolism in cancer cells. The removal of BAT and feeding on a high-glucose diet under cold exposure restore tumour growth, and genetic deletion of Ucp1-the key mediator for BAT-thermogenesis-ablates the cold-triggered anticancer effect. In a pilot human study, mild cold exposure activates a substantial amount of BAT in both healthy humans and a patient with cancer with mitigated glucose uptake in the tumour tissue. These findings provide a previously undescribed concept and paradigm for cancer therapy that uses a simple and effective approach. We anticipate that cold exposure and activation of BAT through any other approach, such as drugs and devices either alone or in combination with other anticancer therapeutics, will provide a general approach for the effective treatment of various cancers.

Obesity-Associated GNAS Mutations and the Melanocortin Pathway.

BACKGROUND: GNAS encodes the Gαs (stimulatory G-protein alpha subunit) protein, which mediates G protein-coupled receptor (GPCR) signaling. GNAS mutations cause developmental delay, short stature, and skeletal abnormalities in a syndrome called Albright's hereditary osteodystrophy. Because of imprinting, mutations on the maternal allele also cause obesity and hormone resistance (pseudohypoparathyroidism). METHODS: We performed exome sequencing and targeted resequencing in 2548 children who presented with severe obesity, and we unexpectedly identified 22 GNAS mutation carriers. We investigated whether the effect of GNAS mutations on melanocortin 4 receptor (MC4R) signaling explains the obesity and whether the variable clinical spectrum in patients might be explained by the results of molecular assays. RESULTS: Almost all GNAS mutations impaired MC4R signaling. A total of 6 of 11 patients who were 12 to 18 years of age had reduced growth. In these patients, mutations disrupted growth hormone-releasing hormone receptor signaling, but growth was unaffected in carriers of mutations that did not affect this signaling pathway (mean standard-deviation score for height, -0.90 vs. 0.75, respectively; P = 0.02). Only 1 of 10 patients who reached final height before or during the study had short stature. GNAS mutations that impaired thyrotropin receptor signaling were associated with developmental delay and with higher thyrotropin levels (mean [±SD], 8.4±4.7 mIU per liter) than those in 340 severely obese children who did not have GNAS mutations (3.9±2.6 mIU per liter; P = 0.004). CONCLUSIONS: Because pathogenic mutations may manifest with obesity alone, screening of children with severe obesity for GNAS deficiency may allow early diagnosis, improving clinical outcomes, and melanocortin agonists may aid in weight loss. GNAS mutations that are identified by means of unbiased genetic testing differentially affect GPCR signaling pathways that contribute to clinical heterogeneity. Monogenic diseases are clinically more variable than their classic descriptions suggest. (Funded by Wellcome and others.).

Cosmetic preservative labeling in Philippine products in accordance with Philippine regulations.

BACKGROUND: Preservatives are usually added to a wide array of consumer products to prevent growth of microbes and to prevent product destabilization and degradation. However, many of these preservatives are common skin sensitizers and may cause allergic contact dermatitis. The amount of preservatives may vary per country or region according to their respective legislation and may be reported in differences in prevalence rates of contact dermatitis. OBJECTIVE: To examine and identify preservatives in consumer products in accordance with Philippine legislation. To verify the accuracy of the list of ingredients of Philippine cosmetic products as legislated by the Philippine Bureau of Food and Drug Administration. METHODS: A total of 65 commonly used Philippine consumer products ranging from liquid facial and body washes, bar soaps, laundry detergents, feminine hygiene washes and wipes, shampoos and conditioners, sunblock, and moisturizers were selected. Ingredients noted on labels were documented. Products were subsequently investigated chemically for the presence of methylchloroisothiazolinone, methylisothiazolinone, or formaldehyde. RESULTS: The preservatives most commonly used in cosmetic products in the Philippine market are methylchloroisothiazolinone (MCI), methylisothiazolinone (MI), and/or formaldehyde. In accordance with Philippine legislation, almost all products provided a detailed ingredient list as printed on the packaging. Measurements of MCI/MI ranged from less than 1 ppm to 16 ppm, and MI ranged from only less than 1 ppm to 66 ppm, whereas formaldehyde was noted to range from less than 2.5 ppm to greater than 40 ppm in the products tested. Most products are manufactured by international brands, with a few products being manufactured locally. CONCLUSIONS: The preservatives found in cosmetic products were MCI, MI, and formaldehyde. Discrepancies were found in the preservatives and labeling of these products, with a majority of investigated Philippine products labeled inaccurately with varying concentrations of preservatives.

Pericyte-fibroblast transition promotes tumor growth and metastasis.

Vascular pericytes, an important cellular component in the tumor microenvironment, are often associated with tumor vasculatures, and their functions in cancer invasion and metastasis are poorly understood. Here we show that PDGF-BB induces pericyte-fibroblast transition (PFT), which significantly contributes to tumor invasion and metastasis. Gain- and loss-of-function experiments demonstrate that PDGF-BB-PDGFRß signaling promotes PFT both in vitro and in in vivo tumors. Genome-wide expression analysis indicates that PDGF-BB-activated pericytes acquire mesenchymal progenitor features. Pharmacological inhibition and genetic deletion of PDGFRß ablate the PDGF-BB-induced PFT. Genetic tracing of pericytes with two independent mouse strains, TN-AP-CreERT2:R26R-tdTomato and NG2-CreERT2:R26R-tdTomato, shows that PFT cells gain stromal fibroblast and myofibroblast markers in tumors. Importantly, coimplantation of PFT cells with less-invasive tumor cells in mice markedly promotes tumor dissemination and invasion, leading to an increased number of circulating tumor cells and metastasis. Our findings reveal a mechanism of vascular pericytes in PDGF-BB-promoted cancer invasion and metastasis by inducing PFT, and thus targeting PFT may offer a new treatment option of cancer metastasis.

VEGF-B promotes cancer metastasis through a VEGF-A-independent mechanism and serves as a marker of poor prognosis for cancer patients.

The biological functions of VEGF-B in cancer progression remain poorly understood. Here, we report that VEGF-B promotes cancer metastasis through the remodeling of tumor microvasculature. Knockdown of VEGF-B in tumors resulted in increased perivascular cell coverage and impaired pulmonary metastasis of human melanomas. In contrast, the gain of VEGF-B function in tumors led to pseudonormalized tumor vasculatures that were highly leaky and poorly perfused. Tumors expressing high levels of VEGF-B were more metastatic, although primary tumor growth was largely impaired. Similarly, VEGF-B in a VEGF-A-null tumor resulted in attenuated primary tumor growth but substantial pulmonary metastases. VEGF-B also led to highly metastatic phenotypes in Vegfr1 tk(-/-) mice and mice treated with anti-VEGF-A. These data indicate that VEGF-B promotes cancer metastasis through a VEGF-A-independent mechanism. High expression levels of VEGF-B in two large-cohort studies of human patients with lung squamous cell carcinoma and melanoma correlated with poor survival. Taken together, our findings demonstrate that VEGF-B is a vascular remodeling factor promoting cancer metastasis and that targeting VEGF-B may be an important therapeutic approach for cancer metastasis.

Modulation of age-related insulin sensitivity by VEGF-dependent vascular plasticity in adipose tissues.

Mechanisms underlying age-related obesity and insulin resistance are generally unknown. Here, we report age-related adipose vascular changes markedly modulated fat mass, adipocyte functions, blood lipid composition, and insulin sensitivity. Notably, VEGF expression levels in various white adipose tissues (WATs) underwent changes uninterruptedly in different age populations. Anti-VEGF and anti- VEGF receptor 2 treatment in different age populations showed marked variations of vascular regression, with midaged mice exhibiting modest sensitivity. Interestingly, anti-VEGF treatment produced opposing effects on WAT adipocyte sizes in different age populations and affected vascular density and adipocyte sizes in brown adipose tissue. Consistent with changes of vasculatures and adipocyte sizes, anti-VEGF treatment increased insulin sensitivity in young and old mice but had no effects in the midaged group. Surprisingly, anti-VEGF treatment significantly improved insulin sensitivity in midaged obese mice fed a high-fat diet. Our findings demonstrate that adipose vasculatures show differential responses to anti-VEGF treatment in various age populations and have therapeutic implications for treatment of obesity and diabetes with anti-VEGF-based antiangiogenic drugs.

Vascular endothelial growth factor-dependent spatiotemporal dual roles of placental growth factor in modulation of angiogenesis and tumor growth.

Placental growth factor (PlGF) remodels tumor vasculatures toward a normalized phenotype, which affects tumor growth, invasion and drug responses. However, the coordinative and spatiotemporal relation between PlGF and VEGF in modulation of tumor angiogenesis and vascular remodeling is less understood. Here we report that PlGF positively and negatively modulate tumor growth, angiogenesis, and vascular remodeling through a VEGF-dependent mechanism. In two independent tumor models, we show that PlGF inhibited tumor growth and angiogenesis and displayed a marked vascular remodeling effect, leading to normalized microvessels with infrequent vascular branches and increased perivascular cell coverage. Surprisingly, elimination of VEGF gene (i.e., VEGF-null) in PlGF-expressing tumors resulted in (i) accelerated tumor growth rates and angiogenesis and (ii) complete attenuation of PlGF-induced vascular normalization. Thus, PlGF positively and negatively modulates tumor growth, angiogenesis, and vascular remodeling through VEGF-dependent spatiotemporal mechanisms. Our data uncover molecular mechanisms underlying the complex interplay between PlGF and VEGF in modulation of tumor growth and angiogenesis, and have conceptual implication for antiangiogenic cancer therapy.

Targeting of the MNK-eIF4E axis in blast crisis chronic myeloid leukemia inhibits leukemia stem cell function.

Chronic myeloid leukemia responds well to therapy targeting the oncogenic fusion protein BCR-ABL1 in chronic phase, but is resistant to treatment after it progresses to blast crisis (BC). BC is characterized by elevated ß-catenin signaling in granulocyte macrophage progenitors (GMPs), which enables this population to function as leukemia stem cells (LSCs) and act as a reservoir for resistance. Because normal hematopoietic stem cells (HSCs) and LSCs depend on ß-catenin signaling for self-renewal, strategies to specifically target BC will require identification of drugable factors capable of distinguishing between self-renewal in BC LSCs and normal HSCs. Here, we show that the MAP kinase interacting serine/threonine kinase (MNK)-eukaryotic translation initiation factor 4E (eIF4E) axis is overexpressed in BC GMPs but not normal HSCs, and that MNK kinase-dependent eIF4E phosphorylation at serine 209 activates ß-catenin signaling in BC GMPs. Mechanistically, eIF4E overexpression and phosphorylation leads to increased ß-catenin protein synthesis, whereas MNK-dependent eIF4E phosphorylation is required for nuclear translocation and activation of ß-catenin. Accordingly, we found that a panel of small molecule MNK kinase inhibitors prevented eIF4E phosphorylation, ß-catenin activation, and BC LSC function in vitro and in vivo. Our findings identify the MNK-eIF4E axis as a specific and critical regulator of BC self-renewal, and suggest that pharmacologic inhibition of the MNK kinases may be therapeutically useful in BC chronic myeloid leukemia.

Touch DNA-The prospect of DNA profiles from cables.

Metal theft in the railroad industry poses significant challenges to transport investigators. Cable sheaths left behind at crime scenes, if appropriately analysed, could provide valuable evidence in a forensic investigation, but attempts at recovering DNA are not routinely made. Experiments were set up to ascertain the success in DNA recovery from the surface of cable sheaths after deposition of (a) sweat, (b) extracted DNA and (c) fingermarks. Since investigators try to collect fingermarks and often treat the cables with cyanoacrylate fuming (CNA fuming) or wet powder suspensions (WPS) to enhance the marks this study investigated the recovery of DNA from fingermarks pre- and post-enhancement. The double-swab technique and mini-taping were compared as options to recover DNA from the cable sheaths. Results demonstrate that generally, there is no significant difference between using swabs or mini-tapes to recover the DNA from the non-porous cables (p>0.05). It was also illustrated that CNA fuming performed better than WPS in terms of subsequent recovery and profiling of DNA. CNA fuming resulted in an average increase in DNA recovered via swabbing and taping (more than 4× and 8×, respectively), as compared to no treatment, with 50% of the DNA recovered after CNA fuming generating full DNA profiles.

Hybrid Bilayer WSe2 -CH3 NH3 PbI3 Organolead Halide Perovskite as a High-Performance Photodetector.

A high-performance 2D photodetector based on a bilayer structure comprising a WSe2 monolayer and CH3 NH3 PbI3 organolead halide perovskite is reported. High performance is realized by modification of the WSe2 monolayer with laser healing and perovskite functionalization. After modification, the output of the device was three orders of magnitude better than the pristine device; the performance is superior to that of most of the 2D photodetectors based on transition-metal-dichalcogenides (TMDs). This result indicates that combinatory TMDs-halide perovskite hybrids can be promising building blocks in optoelectronics.

Antiangiogenic agents significantly improve survival in tumor-bearing mice by increasing tolerance to chemotherapy-induced toxicity.

Chemotherapy-induced broad toxicities are the leading cause of the drug-induced mortality in cancer patients. Antiangiogenic drugs (ADs) in combination with chemotherapy are widely used as front-line therapy for the treatment of various human cancers. However, the beneficial mechanisms underlying combination therapy are poorly understood. Here we show that, in several murine tumor models, administration of sunitinib markedly reduced chemotherapy-induced bone marrow toxicity. Intriguingly, in a sequential treatment regimen, delivery of ADs followed by chemotherapy demonstrated superior survival benefits compared with simultaneous administration of two drugs. In murine tumor models, we show that VEGF increased chemotoxicity by synergistically suppressing bone marrow hematopoiesis with cytostatic drugs. These findings shed light on molecular mechanisms by which ADs in combination with chemotherapy produce survival benefits in cancer patients and provide conceptual information guiding future designs of clinical trials, current practice, and optimization of ADs for the treatment of cancer.

Programmable Interfacial Band Configuration in WS2/Bi2O2Se Heterojunctions.

van der Waals heterojunctions based on transition-metal dichalcogenides (TMDs) offer advanced strategies for manipulating light-emitting and light-harvesting behaviors. A crucial factor determining the light-material interaction is in the band alignment at the heterojunction interface, particularly the distinctions between type-I and type-II alignments. However, altering the band alignment from one type to another without changing the constituent materials is exceptionally difficult. Here, utilizing Bi2O2Se with a thickness-dependent band gap as a bottom layer, we present an innovative strategy for engineering interfacial band configurations in WS2/Bi2O2Se heterojunctions. In particular, we achieve tuning of the band alignment from type-I (Bi2O2Se straddling WS2) to type-II and finally to type-I (WS2 straddling Bi2O2Se) by increasing the thickness of the Bi2O2Se bottom layer from monolayer to multilayer. We verified this band architecture conversion using steady-state and transient spectroscopy as well as density functional theory calculations. Using this material combination, we further design a sophisticated band architecture incorporating both type-I (WS2 straddles Bi2O2Se, fluorescence-quenched) and type-I (Bi2SeO5 straddles WS2, fluorescence-recovered) alignments in one sample through focused laser beam (FLB). By programming the FLB trajectory, we achieve a predesigned localized fluorescence micropattern on WS2 without changing its intrinsic atomic structure. This effective band architecture design strategy represents a significant leap forward in harnessing the potential of TMD heterojunctions for multifunctional photonic applications.

Upcycling fish scales through heating for steganography and Rhodamine B adsorption application.

With increasing population and limited resources, a potential route for improving sustainability is increased reuse of waste materials. By re-looking at wastes, interesting properties and multifunctionalities can be discovered in materials previously explored. Despite years of research on bio-compatible fish scales, there is limited study on the fluorescence property of this abundant waste material. Controlled denaturation of collagen and introduction of defects can serve as a means to transform the fluorescence property of these fish scale wastes while providing more adsorption sites for pollutant removal, turning multifunctional fish scales into a natural steganographic material for transmitting text and images at both the macroscopic and microscopic levels and effectively removing Rhodamine B pollutants (91 % removal) within a short contact time (10 minutes). Our work offers a glimpse into the realm of engineering defects-induced fluorescence in natural material with potential as bio-compatible fluorescence probes while encouraging multidimensional applicability to be established in otherwise overlooked waste resources.

An essential role of the cysteine-rich domain of FZD4 in Norrin/Wnt signaling and familial exudative vitreoretinopathy.

The Wnt pathway plays important yet diverse roles in health and disease. Mutations in the Wnt receptor FZD4 gene have been confirmed to cause familial exudative vitreoretinopathy (FEVR). FEVR is characterized by incomplete vascularization of the peripheral retina, which can lead to vitreous bleeding, tractional retinal detachment, and blindness. We screened for mutations in the FZD4 gene in five families with FEVR and identified five mutations (C45Y, Y58C, W226X, C204R, and W496X), including three novel mutations (C45Y, Y58C, and W226X). In the retina, Norrin serves as a ligand and binds to FZD4 to activate the Wnt signaling pathway in normal angiogenesis and vascularization. The cysteine-rich domain (CRD) of FZD4 has been shown to play a critical role in Norrin-FZD4 binding. We investigated the effect of mutations in the FZD4 CRD in Norrin binding and signaling in vitro and in vivo. Wild-type and mutant FZD4 proteins were assayed for Norrin binding and Norrin-dependent activation of the canonical Wnt pathway by cell-surface and overlay binding assays and luciferase reporter assays. In HEK293 transfection studies, C45Y, Y58C, and C204R mutants did not bind to Norrin and failed to transduce FZD4-mediated Wnt/ß-catenin signaling. In vivo studies using Xenopus embryos showed that these FZD4 mutations disrupt Norrin/ß-catenin signaling as evidenced by decreased Siamois and Xnr3 expression. This study identified a new class of FZD4 gene mutations in human disease and demonstrates a critical role of the CRD in Norrin binding and activation of the ß-catenin pathway.

Nanopath-Beacons for Directed Silver Dendrites' Migration across Graphene Oxide Terrain.

With their special hierarchical fractal and highly symmetric formation, silver dendrites have a large surface area and plentiful active sites at edges, which have allowed them to exhibit unique properties ranging from superhydrophobic surfaces to biosensors. Yet, many suggested synthesis processes either require a long reaction time or risk contamination from sacrificial elements. Limited research in directing while enhancing the growth of these silver dendrites also hinders the application of these unique microstructures as site-selective hydrophobicity of surfaces and location-dependent SERS (surface-enhanced Raman spectroscopy). A possible solution to this is to utilize WO3 nanocubes as beacons to accelerate and conduct the growth of these silver dendrites through the electrochemical migration process. These nanocubes effortlessly altered the applied electric field distributed between the electrodes, depending on their orientations and positions. As the silver dendrites branched from the nanocubes, the dendrites themselves further concentrated the electric field to encourage the growth of more loose fractal silver dendrites. The combinatory effect successfully directs the growth of silver dendrites along the concentrated electric field paths. Both changes to the electric field and directed growth of silver dendrites are underscored using Multiphysics COMSOL simulations and time-lapse microscopy. This work provided insight into the possibility of designing microstructures to direct and accelerate the growth of silver dendrites.

Identification of New Prognostic Markers and Therapeutic Targets for Non-Muscle Invasive Bladder Cancer: HER2 as a Potential Target Antigen.

Bacillus Calmette-Guérin (BCG) is the gold standard adjuvant treatment for non-muscle-invasive bladder cancer (NMIBC). However, given the current global shortage of BCG, new treatments are needed. We evaluated tumor microenvironment markers as potential BCG alternatives for NMIBC treatment. Programmed death-ligand 1, human epidermal growth factor receptor-2 (HER2), programmed cell death-1 (PD1), CD8, and Ki67 levels were measured in treatment-naïve NMIBC and MIBC patients (pTa, pT1, and pT2 stages). Univariate and multivariate Cox proportional hazard models were used to determine the impact of these markers and other clinicopathological factors on survival, recurrence, and progression. EP263, IM142, PD1, and Ki67 levels were the highest in the T2 stage, followed by the T1 and Ta stages. HER2 and IM263 expressions were higher in the T1 and T2 stages than in the Ta stage. In NMIBC, the significant prognostic factors for recurrence-free survival were adjuvant therapy, tumor grade, and HER2 positivity, whereas those for progression-free survival included age, T-stage, and IM263. Age, T-stage, EP263, PD1, CD8, and Ki67 levels were significant factors associated with overall survival. IM263 and HER2 are potential biomarkers for progression and recurrence, respectively. Therefore, we propose HER2 as a potential target antigen for intravesical therapeutics as a BCG alternative.

Dynamic Tuning of Moiré Superlattice Morphology by Laser Modification.

In artificial van der Waals (vdW) layered devices, twisting the stacking angle has emerged as an effective strategy to regulate the electronic phases and optical properties of these systems. Along with the twist registry, the lattice reconstruction arising from vdW interlayer interaction has also inspired significant research interests. The control of twist angles is significantly important because the moiré periodicity determines the electron propagation length on the lattice and the interlayer electron-electron interactions. However, the moiré periodicity is hard to be modified after the device has been fabricated. In this work, we have demonstrated that the moiré periodicity can be precisely modulated with a localized laser annealing technique. This is achieved with regulating the interlayer lattice mismatch by the mismatched lattice constant, which originates from the variable density of sulfur vacancy generated during laser modification. The existence of sulfur vacancy is further verified by excitonic emission energy and lifetime in photoluminescence measurements. Furthermore, we also discover that the mismatched lattice constant has the equivalent contribution as the twist angle for determining the lattice mismatch. Theoretical modeling elaborates the moiré-wavelength-dependent energy variations at the interface and mimics the evolution of moiré morphology.

2D Electrolytes: Theory, Modeling, Synthesis, and Characterization.

A class of compounds sharing the properties of 2D materials and electrolytes, namely 2D electrolytes is described theoretically and demonstrated experimentally. 2D electrolytes dissociate in different solvents, such as water, and become electrically charged. The chemical and physical properties of these compounds can be controlled by external factors, such as pH, temperature, electric permittivity of the medium, and ionic concentration. 2D electrolytes, in analogy with polyelectrolytes, present reversible morphological transitions from 2D to 1D, as a function of pH, due to the interplay of the elastic and Coulomb energies. Since these materials show stimuli-responsive behavior to the environmental conditions, 2D electrolytes can be considered as a novel class of smart materials that expand the functionalities of 2D materials and are promising for applications that require stimuli-responsive demeanor, such as drug delivery, artificial muscles, and energy storage.

Performance Improvement by Ozone Treatment of 2D PdSe2.

Atomic-scale defects in two-dimensional transition metal dichalcogenides (TMDs) often dominate their physical and chemical properties. Introducing defects in a controllable manner can tailor properties of TMDs. For example, chalcogen atom defects in TMDs were reported to trigger phase transition, induce ferromagnetism, and drive superconductivity. However, reported strategies to induce chalcogen atom defects including postgrowth annealing, laser irradiation, or plasma usually require high temperature (such as 500 °C) or cause unwanted structural damage. Here, we demonstrate low-temperature (60 °C) partial surface oxidation in 2D PdSe2 with low disorder and good stability. The combination of scanning tunneling microscopy, X-ray photoelectron spectroscopy, and density functional theory calculations provide evidence of atomic-scale partial oxidation with both atomic resolution and chemical sensitivity. We also experimentally demonstrate that this controllable oxygen incorporation effectively tailors the electronic, optoelectronic, and catalytic activity of PdSe2. This work provides a pathway toward fine-tuning the physical and chemical properties of 2D TMDs and their applications in nanoelectronics, optoelectronics, and electrocatalysis.