Are quantum dots ready for in vivo imaging in human subjects?

Nanotechnology has the potential to profoundly transform the nature of cancer diagnosis and cancer patient management in the future. Over the past decade, quantum dots (QDs) have become one of the fastest growing areas of research in nanotechnology. QDs are fluorescent semiconductor nanoparticles suitable for multiplexed in vitro and in vivo imaging. Numerous studies on QDs have resulted in major advancements in QD surface modification, coating, biocompatibility, sensitivity, multiplexing, targeting specificity, as well as important findings regarding toxicity and applicability. For in vitro applications, QDs can be used in place of traditional organic fluorescent dyes in virtually any system, outperforming organic dyes in the majority of cases. In vivo targeted tumor imaging with biocompatible QDs has recently become possible in mouse models. With new advances in QD technology such as bioluminescence resonance energy transfer, synthesis of smaller size non-Cd based QDs, improved surface coating and conjugation, and multifunctional probes for multimodality imaging, it is likely that human applications of QDs will soon be possible in a clinical setting

GeV antiproton/gamma-ray excesses and the WW-boson mass anomaly: three faces of ∼60−70\sim 60-70 GeV dark matter particle?

For the newly discovered $W$-boson mass anomaly, one of the simplest dark matter (DM) models that can account for the anomaly without violating other astrophysical/experimental constraints is the inert two Higgs doublet model, in which the DM mass ($m_{S}$) is found to be within $\sim 54-74$ GeV. In this model, the annihilation of DM via $SS\to b\bar{b}$ and $SS\to WW^{*}$ would produce antiprotons and gamma rays, and may account for the excesses identified previously in both particles. Motivated by this, we re-analyze the AMS-02 antiproton and Fermi-LAT Galactic center gamma-ray data. For the antiproton analysis, the novel treatment is the inclusion of the charge-sign-dependent three-dimensional solar modulation model as constrained by the time-dependent proton data. We find that the excess of antiprotons is more distinct than previous results based on the force-field solar modulation model. The interpretation of this excess as the annihilation of $SS\to WW^{*}$ ($SS\to b\bar{b}$) requires a DM mass of $\sim 40-80$ ($40-60$) GeV and a velocity-averaged cross section of $O(10^{-26})~{\rm cm^3~s^{-1}}$. As for the $\gamma$-ray data analysis, rather than adopting the widely-used spatial template fitting, we employ an orthogonal approach with a data-driven spectral template analysis. The fitting to the GeV $\gamma$-ray excess yields DM model parameters overlapped with those to fit the antiproton excess via the $WW^{*}$ channel. The consistency of the DM particle properties required to account for the $W$-boson mass anomaly, the GeV antiproton excess, and the GeV $\gamma$-ray excess suggest a common origin of them.Comment: 8 page

Physiological Hypoxia Enhances Stemness Preservation, Proliferation, and Bidifferentiation of Induced Hepatic Stem Cells

Induced hepatic stem cells (iHepSCs) have great potential as donors for liver cell therapy due to their self-renewal and bipotential differentiation properties. However, the efficiency of bidifferentiation and repopulation efficiency of iHepSCs is relatively low. Recent evidence shows that physiological hypoxia, a vital factor within stem cell “niche” microenvironment, plays key roles in regulating tissue stem cell biological behaviors including proliferation and differentiation. In this study, we found that physiological hypoxia (10% O2) enhanced the stemness properties and promoted the proliferation ability of iHepSCs by accelerating G1/S transition via p53-p21 signaling pathway. In addition, short-term hypoxia preconditioning improved the efficiency of hepatic differentiation of iHepSCs, and long-term hypoxia promoted cholangiocytic differentiation but inhibited hepatic differentiation of iHepSCs. These results demonstrated the potential effects of hypoxia on stemness preservation, proliferation, and bidifferentiation of iHepSCs and promising perspective to explore appropriate culture conditions for therapeutic stem cells

The Natural Compound Myricetin Effectively Represses the Malignant Progression of Prostate Cancer by Inhibiting PIM1 and Disrupting the PIM1/CXCR4 Interaction

Background/Aims: Natural compounds are a promising resource for anti-tumor drugs. Myricetin, an abundant flavonoid found in the bark and leaves of bayberry, shows multiple promising anti-tumor functions in various cancers. Methods: The cytotoxic, pro-apoptotic, and anti-metastatic effects of myricetin on prostate cancer cells were investigated in both in vitro and in vivo studies. Short-hairpin RNA knockdown of the proviral integration site for Moloney murine leukemia virus-1 (PIM1), pull-down and co-immunoprecipitation assays, and an intracellular Ca2+ flux assay were used to investigate the potential underlying mechanism of myricetin. ONCOMINE database data mining and immunohistochemical analysis of prostate cancer tissues were used to evaluate the expression of PIM1 and CXCR4, as well as the correlation between PIM1 and CXCR4 expression and the clinicopathologic characteristics and prognoses of prostate cancer patients. Results: Myricetin exerted selective cytotoxic, pro-apoptotic, and anti-metastatic effects on prostate cancer cells by inhibiting PIM1 and disrupting the PIM1/CXCR4 interaction. Moreover, PIM1 and CXCR4 were coexpressed and associated with aggressive clinicopathologic traits and poor prognosis in prostate cancer patients. Conclusion: These results offer preclinical evidence for myricetin as a potential chemopreventive and therapeutic agent for precision medicine tailored to prostate cancer patients characterized by concomitant elevated expression of PIM1 and CXCR4

Intracellular delivery of an anionic antisense oligonucleotide via receptor-mediated endocytosis

We describe the synthesis and characterization of a 5′ conjugate between a 2′-O-Me phosphorothioate antisense oligonucleotide and a bivalent RGD (arginine–glycine–aspartic acid) peptide that is a high-affinity ligand for the αvβ3 integrin. We used αvβ3-positive melanoma cells transfected with a reporter comprised of the firefly luciferase gene interrupted by an abnormally spliced intron. Intranuclear delivery of a specific antisense oligonucleotide (termed 623) corrects splicing and allows luciferase expression in these cells. The RGD–623 conjugate or a cationic lipid-623 complex produced significant increases in luciferase expression, while ‘free’ 623 did not. However, the kinetics of luciferase expression was distinct; the RGD–623 conjugate produced a gradual increase followed by a gradual decline, while the cationic lipid-623 complex caused a rapid increase followed by a monotonic decline. The subcellular distribution of the oligonucleotide delivered using cationic lipids included both cytoplasmic vesicles and the nucleus, while the RGD–623 conjugate was primarily found in cytoplasmic vesicles that partially co-localized with a marker for caveolae. Both the cellular uptake and the biological effect of the RGD–623 conjugate were blocked by excess RGD peptide. These observations suggest that the bivalent RGD peptide–oligonucleotide conjugate enters cells via a process of receptor-mediated endocytosis mediated by the αvβ3 integrin

Perturbed myoepithelial cell differentiation in BRCA mutation carriers and in ductal carcinoma in situ.

Myoepithelial cells play key roles in normal mammary gland development and in limiting pre-invasive to invasive breast tumor progression, yet their differentiation and perturbation in ductal carcinoma in situ (DCIS) are poorly understood. Here, we investigated myoepithelial cells in normal breast tissues of BRCA1 and BRCA2 germline mutation carriers and in non-carrier controls, and in sporadic DCIS. We found that in the normal breast of non-carriers, myoepithelial cells frequently co-express the p63 and TCF7 transcription factors and that p63 and TCF7 show overlapping chromatin peaks associated with differentiated myoepithelium-specific genes. In contrast, in normal breast tissues of BRCA1 mutation carriers the frequency of p63+TCF7+ myoepithelial cells is significantly decreased and p63 and TCF7 chromatin peaks do not overlap. These myoepithelial perturbations in normal breast tissues of BRCA1 germline mutation carriers may play a role in their higher risk of breast cancer. The fraction of p63+TCF7+ myoepithelial cells is also significantly decreased in DCIS, which may be associated with invasive progression

Giant magneto field effect in up-conversion amplified spontaneous emission via spatially extended states in organic-inorganic hybrid perovskites

Up-conversion lasing actions are normally difficult to realize in light-emitting materials due to small multi-photon absorption cross section and fast dephasing of excited states during multi-photon excitation. This paper reports an easily accessible up-conversion amplified spontaneous emission (ASE) in organic-inorganic hybrid perovskites (MAPbBr(3)) films by optically exciting broad gap states with sub-bandgap laser excitation. The broad absorption was optimized by adjusting the grain sizes in the MAPbBr3 films. At low sub-bandgap pumping intensities, directly exciting the gap states leads to 2-photon, 3-photon, and 4-photon up-conversion spontaneous emission, revealing a large optical cross section of multiphoton excitation occurring in such hybrid perovskite films. At moderate pumping intensity (1.19 mJ/cm(2)) of 700 nm laser excitation, a significant spectral narrowing phenomenon was observed with the full width at half maximum (FWHM) decreasing from 18 nm to 4 nm at the peak wavelength of 550 nm, simultaneously with a nonlinear increase on spectral peak intensity, showing an up-conversion ASE realized at low threshold pumping fluence. More interestingly, the up-conversion ASE demonstrated a giant magnetic field effect, leading to a magneto-ASE reaching 120%. In contrast, the upconversion photoluminescence (PL) showed a negligible magnetic field effect (&amp;lt; 1%). This observation provides an evidence to indicate that the light-emitting states responsible for up-conversion ASE are essentially formed as spatially extended states. The angular dependent spectrum results further verify the existence of spatially extended states which are polarized to develop coherent in-phase interaction. Clearly, using broad gap states with spatially extended light-emitting states presents a new approach to develop up-conversion ASE in organic-inorganic hybrid perovskites.Funding Agencies|973 ProgramNational Basic Research Program of China [2016YFA0301100, 2016YFA0302000, 2018YFA0306201]; China National Key Basic Research ProgramNational Basic Research Program of China [2016YFA0301100, 2016YFA0302000, 2018YFA0306201]; National Science Foundation of ChinaNational Natural Science Foundation of China (NSFC) [11774063, 11727811]; Science and Technology Commission of Shanghai MunicipalityScience &amp; Technology Commission of Shanghai Municipality (STCSM) [19XD1434600, 2019SHZDZX01, 19DZ2253000]; Air Force Office of Scientific Research (AFOSR)United States Department of DefenseAir Force Office of Scientific Research (AFOSR) [FA 9550-15-1-0064]; AOARD [FA2386-15-1-4104]; National Science FoundationNational Science Foundation (NSF) [NSF-1911659]</p