Transforming Growth Factor Beta and Alveolar Rhabdomyosarcoma: A Challenge of Tumor Differentiation and Chemotherapy Response.

Alveolar rhabdomyosarcoma (ARMS), an invasive subtype of rhabdomyosarcoma (RMS), is associated with chromosomal translocation events resulting in one of two oncogenic fusion genes, PAX3-FOXO1 or PAX7-FOXO1. ARMS patients exhibit an overexpression of the pleiotropic cytokine transforming growth factor beta (TGF-ß). This overexpression of TGF-ß1 causes an increased expression of a downstream transcription factor called SNAIL, which promotes epithelial to mesenchymal transition (EMT). Overexpression of TGF-ß also inhibits myogenic differentiation, making ARMS patients highly resistant to chemotherapy. In this review, we first describe different types of RMS and then focus on ARMS and the impact of TGF-ß in this tumor type. We next highlight current chemotherapy strategies, including a combination of the FDA-approved drugs vincristine, actinomycin D, and cyclophosphamide (VAC); cabozantinib; bortezomib; vinorelbine; AZD 1775; and cisplatin. Lastly, we discuss chemotherapy agents that target the differentiation of tumor cells in ARMS, which include all-trans retinoic acid (ATRA) and 5-Azacytidine. Improving our understanding of the role of signaling pathways, such as TGF-ß1, in the development of ARMS tumor cells differentiation will help inform more tailored drug administration in the future.

Rhabdomyosarcoma: Current Therapy, Challenges, and Future Approaches to Treatment Strategies.

Rhabdomyosarcoma is a rare cancer arising in skeletal muscle that typically impacts children and young adults. It is a worldwide challenge in child health as treatment outcomes for metastatic and recurrent disease still pose a major concern for both basic and clinical scientists. The treatment strategies for rhabdomyosarcoma include multi-agent chemotherapies after surgical resection with or without ionization radiotherapy. In this comprehensive review, we first provide a detailed clinical understanding of rhabdomyosarcoma including its classification and subtypes, diagnosis, and treatment strategies. Later, we focus on chemotherapy strategies for this childhood sarcoma and discuss the impact of three mechanisms that are involved in the chemotherapy response including apoptosis, macro-autophagy, and the unfolded protein response. Finally, we discuss in vivo mouse and zebrafish models and in vitro three-dimensional bioengineering models of rhabdomyosarcoma to screen future therapeutic approaches and promote muscle regeneration.

Nonlinear Absorption and Refraction of Highly Monodisperse and Luminescent ZnTe Quantum Dots and Their Self-Assembled Nanostructures: Implications for Optoelectronic Devices.

Zinc telluride (ZnTe) quantum dots (QDs) were synthesized by a unique supersaturation-controlled aqueous route. For a given pH, increasing the degree of initial supersaturation led to a decrease in the average diameter (d avg) of the QDs and increased monodispersity. Three samples of ZnTe QDs having average sizes of 0.8, 1.7, and 2.2 nm were synthesized (hence named ZnTe_0.8, ZnTe_1.7, and ZnTe_2.2). Nonlinear absorption (NLA) and nonlinear refraction (NLR) of these colloidal ZnTe QDs of different sizes were investigated by the Z-scan technique using a continuous He-Ne laser (632.8 nm, 15 mW). Isotropic assembly of ZnTe_2.2 leads to the formation of nanoballs (hence named ZnTe_NB). The NLA profile of smaller QDs, ZnTe_1.7 and ZnTe_0.8, was found to follow a three-photon absorption (3PA) model, while relatively bigger QDs, ZnTe_2.2, followed a two-photon absorption (2PA) model. On moving from ZnTe_0.8 to ZnTe_1.7, the three-photon absorption coefficient (γ) decreases by 26% (3.00 × 10-4 → 2.21 × 10-4 cm3/MW2). The two-photon absorption coefficient (ß) for ZnTe_2.2 is 0.3 cm/MW. For a 63% decrease in average diameter (2.2 → 0.8 nm), the refractive index (n 2) increases by 45% (2.48 × 10-2 → 3.6 × 10-2 cm2/MW). Overall, the NLR coefficient shows a decreasing trend with size. Upon isotropic self-assembly, ZnTe_NB, there is a significant increase in the NLR coefficient by 40% (2.48 × 10-2 → 3.48 × 10-2 cm2/MW) and a simultaneous decrease in the NLA coefficient by 45% (0.3 → 0.166 cm/MW). The figure of merit was also determined for all of the samples, and it was found that ZnTe_2.2 and ZnTe_0.8 were best suited for all-optical device applications. Further, the self-assembled nanostructures are promising for making optical waveguides for supercontinuum generation (SCG).

The Role of BiP and the IRE1α-XBP1 Axis in Rhabdomyosarcoma Pathology.

BACKGROUND: Rhabdomyosarcoma (RMS) is the most common soft-tissue sarcoma in children, and is associated with a poor prognosis in patients presenting with recurrent or metastatic disease. The unfolded protein response (UPR) plays pivotal roles in tumor development and resistance to therapy, including RMS. METHODS: In this study, we used immunohistochemistry and a tissue microarray (TMA) on human RMS and normal skeletal muscle to evaluate the expression of key UPR proteins (GRP78/BiP, IRE1α and cytosolic/nuclear XBP1 (spliced XBP1-sXBP1)) in the four main RMS subtypes: alveolar (ARMS), embryonal (ERMS), pleomorphic (PRMS) and sclerosing/spindle cell (SRMS) RMS. We also investigated the correlation of these proteins with the risk of RMS and several clinicopathological indices, such as lymph node involvement, distant metastasis, tumor stage and tumor scores. RESULTS: Our results revealed that the expression of BiP, sXBP1, and IRE1α, but not cytosolic XBP1, are significantly associated with RMS (BiP and sXBP1 p-value = 0.0001, IRE1 p-value = 0.001) in all of the studied types of RMS tumors (n = 192) compared to normal skeletal muscle tissues (n = 16). In addition, significant correlations of BiP with the lymph node score (p = 0.05), and of IRE1α (p value = 0.004), cytosolic XBP1 (p = 0.001) and sXBP1 (p value = 0.001) with the stage score were observed. At the subtype level, BiP and sXBP1 expression were significantly associated with all subtypes of RMS, whereas IRE1α was associated with ARMS, PRMS and ERMS, and cytosolic XBP1 expression was associated with ARMS and SRMS. Importantly, the expression levels of IRE1α and sXBP1 were more pronounced in ARMS than in any of the other subtypes. The results also showed correlations of BiP with the lymph node score in ARMS (p value = 0.05), and of sXBP1 with the tumor score in PRMS (p value = 0.002). CONCLUSIONS: In summary, this study demonstrates that the overall UPR is upregulated and, more specifically, that the IRE1/sXBP1 axis is active in RMS. The subtype and stage-specific dependency on the UPR machinery in RMS may open new avenues for the development of novel targeted therapeutic strategies and the identification of specific tumor markers in this rare but deadly childhood and young-adult disease.

Synergistic antibacterial effects of analgesics and antibiotics against Staphylococcus aureus.

The local use of analgesics and antibiotics is common during the treatment of periprosthetic joint infection (PJI). The effect of nonantimicrobial drugs on antibacterial activity is underappreciated in clinical practice. This study focuses on the novel assessment of the combined antibacterial effects of commonly used analgesics and antibiotics against methicillin-sensitive Staphylococcus aureus (MSSA)-pathogen associated with most PJIs. We identified that bupivacaine/lidocaine and ketorolac/gentamicin combinations yielded fractional inhibitory concentration indices below 0.4, indicative of synergistic antibacterial effect. Time-kill curves were used for in-depth characterization of the synergy, and the obtained results demonstrated pronounced synergistic effects of bupivacaine/lidocaine and ketorolac/gentamicin combinations against MSSA.

Hollow Silver Nanostructures: The Role of Capping Agents in Tailoring the Shape, Structure, and Plasmonic Properties.

The shape- and structure-directing ability of capping agents, namely, acetic acid (AA) and folic acid (FA), has been analyzed in the synthesis of hollow plasmonic nanostructures via the nanoscale Kirkendall effect. FA was found to possess both shape-directing and structure-directing abilities when spherical solid Ag2O nanoparticles were transformed into hollow silver nanocubes (HAgNCs). In contrast, AA acted only as a structure-directing agent in the transformation from solid Ag2O nanospheres to hollow Ag nanospheres (HAgNSs). FA capping leads to enhanced plasmon tunability range from 535 to 640 nm in the hollow silver nanostructures. The size and shape of nanostructures were analyzed by high-resolution transmission electron microscopy (HRTEM). HRTEM revealed that the outer diameter of AA-capped HAgNSs is 50 ± 10 nm while edge-length for FA-capped HAgNCs is 100 ± 15 nm. The diameter of inner void space was found to be 30 ± 5 and 43 ± 5 nm for HAgNSs and HAgNCs, respectively. The phase purity of the hollow nanostructures was confirmed by X-ray diffraction and energy dispersive X-ray measurements. Due to unique structural and plasmonic features, FA-capped HAgNCs are well-suited for biomedical applications.

Shape and size dependent nonlinear refraction and absorption in citrate-stabilized, near-IR plasmonic silver nanopyramids.

Using a combination of a mild stabilizer and a mild reductant, sodium citrate and hydrazine hydrate, anisotropic silver nanocrystals (NCs) were synthesized with tunable plasmon peaks at 550 nm, 700 nm, 800 nm, 900 nm and 1010 nm (the samples are named Ag-550, Ag-700, Ag-800, Ag-900 and Ag-1010, respectively). TEM investigations revealed that Ag-550 NCs were pentagonal nanoplates while the other four samples were nanopyramids with a pentagonal base with the edge length varying between 15 and 30 nm. The non-linear optical (NLO) properties of these NCs were studied by the Z-scan technique using the CW He-Ne laser (632.8 nm, 15 mW). The shape change from 2D nanoplates (Ag-550) to 3D nanopyramids (Ag-700) resulted in sign reversal of the non-linear refractive index, n2, from a negative (-3.164 × 10-8 cm2 W-1) to a positive one (1.195 × 10-8 cm2 W-1). This corresponds to a change from a self-defocussing effect to a self-focussing one. Besides shape, the size effect is also prominently observed. Amongst nanopyramids, as the edge length increases, n2 increases linearly and reaches a maximum of 3.124 × 10-8 cm2 W-1. Doubling the edge length from 15 nm to 30 nm resulted in 162% increase in n2. On moving from Ag-550 to Ag-900 NCs, with the increasing plasmon wavelength, the non-linear absorption (NLA) coefficient increased exponentially to a high value of 8.52 × 10-4 cm W-1. However, Ag-1010 showed 29% decrease in NLA which is attributed to twinning present in the crystal structure as seen in the HR-TEM images. Due to the tunable NLO properties, these anisotropic Ag NCs hold great potential for applications in optical limiting, switching and data storage.

Water-soluble, luminescent ZnTe quantum dots: supersaturation-controlled synthesis and self-assembly into nanoballs, nanonecklaces and nanowires.

A supersaturation-controlled aqueous synthesis route has been developed for ZnTe quantum dots (QDs) with high monodispersity, size tunability, stability, band-edge luminescence (full-width at half-maximum (FWHM) 10-12 nm) and negligibly small Stokes' shift (2-4 nm). The degree of supersaturation of the initial reaction mixture was varied by increasing the reagent concentration, but keeping the molar ratio Zn(2+) : thioglycolic acid : Te(2-) constant at 1 : 2.5 : 0.5. For a 10× increase in supersaturation, the photoluminescence (PL) peak underwent a 50 nm blue shift from 330 to 280 nm at pH 6. The effect was more pronounced at pH 12, where the PL peak blue-shifted by 100 nm from 327 to 227 nm. Concomitantly, the FWHM was also reduced to a low value of 10 nm, indicating high monodispersity. For a 10× change in supersaturation, the particle size decreased by 63% (from 2.2 to 0.8 nm) at pH 12, whereas it changed by 19% (from 2.1 to 1.7 nm) at pH 6. High-resolution transmission electron microscopy and selected area electron diffraction data further revealed that the QDs synthesized at higher supersaturation had a better crystallinity. These QDs exhibited the unique property of undergoing isotropic and anisotropic self-assembly, which resulted in a blue shift and a red shift in the absorption and PL spectra, respectively. Isotropic assembly into spherical nanoballs (100 nm diameter, 1 nm inter-QD separation) occurred when the QDs were stored at pH 12 for 3 weeks at room temperature. The nanoballs further self-assembled into a 'pearl necklace' arrangement. On the partial removal of the capping agents, the QDs self-organized anisotropically into nanowires (1.3 µm long and 4.6 nm in diameter). The self-assembled nanostructures showed exciton-exciton coupling and excellent PL properties, which may be useful in enhanced optoelectronics, photovoltaics and biochemical sensing.