Gelsolin regulates receptor-mediated and fluid-phase endocytosis in platelets.

BACKGROUND AND OBJECTIVE: Endocytosis is the process by which platelets incorporate extracellular molecules into their secretory granules. Endocytosis is mediated by the actin cytoskeleton in nucleated cells, however, the endocytic mechanisms in platelets are undefined. To better understand platelet endocytosis, we studied gelsolin (Gsn), an actin-severing protein that promotes actin assembly. METHODS: Mouse platelets from gelsolin-null (Gsn-/-) and wild-type (WT) controls were used. The uptake of fluorescent cargo molecules was compared as a measure of their endocytic efficiency. Receptor-mediated endocytosis was measured by the uptake of fibrinogen and transferrin; fluid-phase endocytosis was monitored by the uptake of fluorescent dextrans. RESULTS: ADP-stimulated WT platelets readily internalized both receptor-mediated and fluid-phase cargo. In contrast, Gsn-/- platelets showed a severe defect in the endocytosis of both types of cargo. The treatment of WT platelets with the actin-disrupting drugs cytochalasin D and jasplankinolide also reduced endocytosis. Notably, the individual and combined effects of Gsn deletion and drug treatment were similar for both receptor-mediated and fluid-phase endocytosis, indicating that Gsn mediates endocytosis via its action on the actin cytoskeleton. CONCLUSION: Our study demonstrates that Gsn plays a key role in the uptake of bioactive mediators by platelets.

Effects of crosstalk between steroid hormones mediated thyroid hormone in zebrafish exposed to 4-tert-octylphenol: Estrogenic and anti-androgenic effects.

Alkylphenols, such as nonylphenol and 4-tert-octylphenol (OP), are byproducts of the biodegradation of alkylphenol ethoxylates and present substantial ecological and health risks in aquatic environments and higher life forms. In this context, our study aimed to explore the effect of OP on reproductive endocrine function in both female and male zebrafish. Over a period of 21 days, the zebrafish were subjected to varying concentrations of OP (0, 0.02, 0.1, and 0.5 µg/L), based on the lowest effective concentration (EC10 = 0.48 µg/L) identified for zebrafish embryos. OP exposure led to a pronounced increase in hepatic vitellogenin (vtg) mRNA expression and 17ß-estradiol biosynthesis in both sexes. Conversely, OP exhibits anti-androgenic properties, significantly diminishes gonadal androgen receptor (ar) mRNA expression, and reduces endogenous androgen (testosterone and 11-ketotestosterone) levels in male zebrafish. Notably, cortisol and thyroid hormone (TH) levels demonstrated concentration-dependent elevations in zebrafish, influencing the regulation of gonadal steroid hormones (GSHs). These findings suggest that prolonged OP exposure may result in sustained reproductive dysfunction in adult zebrafish, which is largely attributable to the intricate reciprocal relationship between hormone levels and the associated gene expression. Our comprehensive biological response analysis of adult zebrafish offers vital insights into the reproductive toxicological effects of OP, thereby enriching future ecological studies on aquatic systems.

Reconstructive Techniques in Pediatric Congenital Microtia: A Systematic Review and Meta-analysis.

Autografts and allografts are commonly used in microtia reconstruction. We aimed to systematically review and compare these reconstructive materials in pediatric congenital microtia reconstruction. A systematic review of the literature was performed. MEDLINE, Embase, PubMed, Web of Science, and CINAHL databases were searched for original studies on congenital microtia reconstruction in pediatric patients since database inception to 2021. Microtia grade was stratified as high or low. Meta-analysis of pooled proportions and continuous variables was performed using inverse variance weighting with a random effects model to compare between the autograft and allograft groups. Sixty-eight studies with a total of 5,546 patients used autografts (n = 5,382) or alloplastic implants (n = 164). Four other studies used prosthesis, cadaveric homografts, or tissue engineering. The allograft group was on average younger than the autograft group (8.4 vs. 11.1 years). There were no syndromic patients in the allograft group, compared to 43% in the autograft group. Patients treated with allografts had higher microtia grade than those treated with autograft (98 vs. 72%). Autografts were more commonly utilized by plastic surgeons and allografts by otolaryngologists (95 vs. 38%). No autografts and 41% of allografts were done concurrently with atresiaplasty or bone conduction implant. Satisfaction rates were similarly high (>90%) with similar complication rates (<10%). Microtia reconstruction using autografts and allografts had similar satisfaction and complication rates. Allografts were preferred for younger patients and concurrent hearing restoration. Further large-scale studies are required to evaluate the long-term efficacy of these reconstructive techniques.

Granzyme B promotes matrix metalloproteinase-1 (MMP-1) release from gingival fibroblasts in a PAR1- and Erk1/2-dependent manner: A novel role in periodontal inflammation.

OBJECTIVE: To gain insights into how proteases signal to connective tissues cells in the periodontium. BACKGROUND: The connective tissue degradation observed in periodontitis is largely due to matrix metalloproteinase (MMP) release by gingival fibroblasts. Granzyme B (GzmB) is a serine protease whose role in periodontitis is undefined. METHODS: Human gingival crevicular fluid (GCF) samples were obtained from sites with periodontal disease and healthy control sites. GzmB was quantified in the GCF ([GzmB]GCF ) by ELISA. Gingival fibroblasts (GF) were cultured in the presence or absence of recombinant GzmB. Culture supernatants were analyzed by ELISA to quantify GzmB-induced release of interstitial collagenase (MMP-1). In some experiments, cells were pre-treated with the inhibitor PD98059 to block MEK/ERK signaling. The protease-activated receptor-1 (PAR-1) was blocked with ATAP-2 neutralizing antibody prior to GzmB stimulation. Systemic MMP-1 levels were measured in plasma from wild-type (WT) and granzyme-B-knockout (GzmB-/- ) mice. RESULTS: The [GzmB]GCF in human samples was ~4-5 fold higher at sites of periodontal disease (gingivitis/periodontitis) compared to healthy control sites, suggesting an association between GzmB and localized matrix degradation. GzmB induced a ~4-5-fold increase in MMP-1 secretion by cultured fibroblasts. GzmB induced phosphorylation of Erk1/2, which was abrogated by PD98059. GzmB-induced upregulation of MMP-1 secretion was also reduced by PD98059. Blockade of PAR-1 function by ATAP-2 abrogated the increase in MMP-1 secretion by GF. Circulating MMP-1 was similar in WT and GzmB-/- mice, suggesting that GzmB's effects on MMP-1 release are not reflected systemically. CONCLUSION: These data point to a novel GzmB-driven signaling pathway in fibroblasts in which MMP-1 secretion is upregulated in a PAR1- and Erk1/2-dependent manner.

HPV-negative head and neck cancers with adverse pathological features carry specific molecular changes that are associated with survival.

BACKGROUND: Adverse pathological features following surgery in head and neck squamous cell carcinoma (HNSCC) are strongly associated with survival and guide adjuvant therapy. We investigated molecular changes associated with these features. METHODS: We downloaded data from the Cancer Genome Atlas and Cancer Proteome Atlas HNSCC cohorts. We compared tumors positive versus negative for perineural invasion (PNI), lymphovascular invasion (LVI), extracapsular spread (ECS), and positive margins (PSM), with multivariable analysis. RESULTS: All pathological features were associated with poor survival, as were the following molecular changes: low cyclin E1 (HR = 1.7) and high PKC-alpha (HR = 1.8) in tumors with PNI; six of 13 protein abundance changes with LVI; greater tumor hypoxia and high Raptor (HR = 2.0) and Rictor (HR = 1.6) with ECS; and low p38 (HR = 2.3), high fibronectin (HR = 1.6), low annexin A1 (HR = 3.1), and high caspase-9 (HR = 1.6) abundances with PSM. CONCLUSIONS: Pathological features in HNSCC carry specific molecular changes that may explain their poor prognostic associations.

Thyroid-gonadal hormonal interplay in zebrafish exposed to sodium perchlorate: Implications for reproductive health.

Perchlorate, a widespread environmental contaminant originating from various industrial applications, agricultural practices, and natural sources, poses potential risks to ecosystems and human health. While previous studies have highlighted its influence on the thyroid endocrine system and its impact on gonadal maturation, reproduction, and sex hormone synthesis, the specific interplay between thyroid and steroid hormones, in this context, remains largely unexplored. Therefore, this study was undertaken to investigate the adverse effects and underlying mechanisms triggered by exposure to sodium perchlorate (SP) on reproductive endocrine activity in zebrafish. For 21 d, the fish were exposed to test SP concentrations (0, 3, 30, 300 mg/L), which were determined based on the exposure concentrations that induced various toxic effects in the fish, considering naturally occurring concentrations. Exposure to SP, except at 3 mg/L in males, significantly decreased the production of thyroid hormone (TH) in both female and male zebrafish. Moreover, gonadal steroid levels were markedly reduced in both sexes. The expression of hepatic vitellogenin (VTG) mRNA in female zebrafish was significantly decreased, whereas aromatase activity in male zebrafish was significantly elevated in the SP exposure groups. The reduced levels of THs and gonadal steroid hormones were strongly correlated. Abnormal responses to SP exposure led to reduced reproductive success in the 300 mg/L SP exposure group. These findings indicate that prolonged and continuous exposure to a specific concentration of SP may lead to long-term reproductive problems in zebrafish, primarily through hormonal imbalances and suppression of hepatic VTG mRNA expression.

Genipin and pyrogallol: Two natural small molecules targeting the modulation of disordered proteins in Alzheimer's disease.

Alzheimer's disease (AD) is characterized by the aggregation of disordered proteins, such as amyloid beta (Aß) and tau, leading to neurotoxicity and disease progression. Despite numerous efforts, effective inhibitors of Aß and tau aggregates have not been developed. Thus, we aimed to screen natural small molecules from crude extracts that target various pathologies and are prescribed for patients with neurological diseases. In this study, we screened 162 natural small molecules prescribed for neurological diseases and identified genipin and pyrogallol as hit compounds capable of simultaneously regulating the aggregation of Aß and tau K18. Moreover, we confirmed the dual modulatory effects of these compounds on the reduction of amyloid-mediated neurotoxicity in vitro and the disassembly of preformed Aß42 and tau K18 fibrils. Furthermore, we observed the alleviatory effects of genipin and pyrogallol against AD-related pathologies in triple transgenic AD mice. Molecular dynamics and docking simulations revealed the molecular interaction dynamics of genipin and pyrogallol with Aß42 and tau K18, providing insights into their suppression of aggregation. Our findings suggest the therapeutic potential of genipin and pyrogallol as dual modulators for the treatment of AD by inhibiting aggregation or promoting dissociation of Aß and tau.

A novel association between platelet filamin A and soluble N-ethylmaleimide sensitive factor attachment proteins regulates granule secretion.

Background and Objective: The molecular mechanisms that underpin platelet granule secretion remain poorly defined. Filamin A (FLNA) is an actin-crosslinking and signaling scaffold protein whose role in granule exocytosis has not been explored despite evidence that FLNA gene mutations confer platelet defects in humans. Methods and Results: Using platelets from platelet-specific conditional Flna-knockout mice, we showed that the loss of FLNA confers a severe defect in alpha (α)- and dense (δ)-granule exocytosis, as measured based on the release of platelet factor 4 (aka CXCL4) and adenosine triphosphate (ATP), respectively. This defect was observed following activation of both immunoreceptor tyrosine-based activation motif (ITAM) signaling by collagen-related peptide (CRP) and G protein-coupled receptor (GPCR) signaling by thrombin and the thromboxane mimetic U46619. CRP-induced spikes in intracellular calcium [Ca2+]i were impaired in FLNA-null platelets relative to controls, confirming that FLNA regulates ITAM-driven proximal signaling. In contrast, GPCR-mediated spikes in [Ca2+]i in response to thrombin and U46619 were unaffected by FLNA. Normal platelet secretion requires complexing of the soluble N-ethylmaleimide-sensitive factor attachment protein receptor (SNARE) proteins synaptosomal-associated protein 23 (SNAP23) and syntaxin-11 (STX11). We determined that FLNA coimmunoprecipitates with both SNAP23 and STX11 upon platelet stimulation. Conclusion: FLNA regulates GPCR-driven platelet granule secretion and associates with SNAP23 and STX11 in an activation-dependent manner.

Self-Aggregating Tau Fragments Recapitulate Pathologic Phenotypes and Neurotoxicity of Alzheimer's Disease in Mice.

In tauopathy conditions, such as Alzheimer's disease (AD), highly soluble and natively unfolded tau polymerizes into an insoluble filament; however, the mechanistic details of this process remain unclear. In the brains of AD patients, only a minor segment of tau forms ß-helix-stacked protofilaments, while its flanking regions form disordered fuzzy coats. Here, it is demonstrated that the tau AD nucleation core (tau-AC) sufficiently induced self-aggregation and recruited full-length tau to filaments. Unexpectedly, phospho-mimetic forms of tau-AC (at Ser324 or Ser356) show markedly reduced oligomerization and seeding propensities. Biophysical analysis reveal that the N-terminus of tau-AC facilitates the fibrillization kinetics as a nucleation motif, which becomes sterically shielded through phosphorylation-induced conformational changes in tau-AC. Tau-AC oligomers are efficiently internalized into cells via endocytosis and induced endogenous tau aggregation. In primary hippocampal neurons, tau-AC impaired axon initial segment plasticity upon chronic depolarization and is mislocalized to the somatodendritic compartments. Furthermore, it is observed significantly impaired memory retrieval in mice intrahippocampally injected with tau-AC fibrils, which corresponds to the neuropathological staining and neuronal loss in the brain. These findings identify tau-AC species as a key neuropathological driver in AD, suggesting novel strategies for therapeutic intervention.

Decoding the Roles of Amyloid-ß (1-42)'s Key Oligomerization Domains toward Designing Epitope-Specific Aggregation Inhibitors.

Fibrillar amyloid aggregates are the pathological hallmarks of multiple neurodegenerative diseases. The amyloid-ß (1-42) protein, in particular, is a major component of senile plaques in the brains of patients with Alzheimer's disease and a primary target for disease treatment. Determining the essential domains of amyloid-ß (1-42) that facilitate its oligomerization is critical for the development of aggregation inhibitors as potential therapeutic agents. In this study, we identified three key hydrophobic sites (17LVF19, 32IGL34, and 41IA42) on amyloid-ß (1-42) and investigated their involvement in the self-assembly process of the protein. Based on these findings, we designed candidate inhibitor peptides of amyloid-ß (1-42) aggregation. Using the designed peptides, we characterized the roles of the three hydrophobic regions during amyloid-ß (1-42) fibrillar aggregation and monitored the consequent effects on its aggregation property and structural conversion. Furthermore, we used an amyloid-ß (1-42) double point mutant (I41N/A42N) to examine the interactions between the two C-terminal end residues with the two hydrophobic regions and their roles in amyloid self-assembly. Our results indicate that interchain interactions in the central hydrophobic region (17LVF19) of amyloid-ß (1-42) are important for fibrillar aggregation, and its interaction with other domains is associated with the accessibility of the central hydrophobic region for initiating the oligomerization process. Our study provides mechanistic insights into the self-assembly of amyloid-ß (1-42) and highlights key structural domains that facilitate this process. Our results can be further applied toward improving the rational design of candidate amyloid-ß (1-42) aggregation inhibitors.

Gelsolin Modulates Platelet Dense Granule Secretion and Hemostasis via the Actin Cytoskeleton.

BACKGROUND AND OBJECTIVE: The mechanisms underlying platelet granule release are not fully understood. The actin cytoskeleton serves as the platelet's structural framework that is remodeled upon platelet activation. Gelsolin is a calcium-dependent protein that severs and caps existing actin filaments although its role in modulating platelet granule exocytosis is unknown. METHODS: The hemostatic function of wild-type (WT) and gelsolin null (Gsn-/- ) mice was measured ex vivo by rotational thromboelastometry analysis of whole blood. Platelets were purified from WT and Gsn-/- mouse blood and activated with thrombin. Platelet aggregation was assessed by light-transmission aggregometry. Clot retraction was measured to assess outside-in integrin signaling. Adenosine triphosphate (ATP) release and surface P-selectin were measured as markers of dense- and α-granule secretion, respectively. RESULTS: The kinetics of agonist-induced aggregation, clot retraction, and ATP release were accelerated in Gsn-/- platelets relative to WT. However, levels of surface P-selectin were diminished in Gsn-/- platelets. ATP release was also accelerated in WT platelets pretreated with the actin-depolymerizing drug cytochalasin D, thus mimicking the kinetics observed in Gsn-/- platelets. Conversely, ATP release kinetics were normalized in Gsn-/- platelets treated with the actin polymerization agonist jasplakinolide. Rab27b and Munc13-4 are vesicle-priming proteins known to promote dense granule secretion. Co-immunoprecipitation indicates that the association between Rab27b and Munc13-4 is enhanced in Gsn-/- platelets. CONCLUSIONS: Gelsolin regulates the kinetics of hemostasis by modulating the platelet's actin cytoskeleton and the protein machinery of dense granule exocytosis.

Platelet signaling at the nexus of innate immunity and rheumatoid arthritis.

Rheumatoid arthritis (RA) is a debilitating autoimmune disorder characterized by chronic inflammation of the synovial tissues and progressive destruction of bone and cartilage. The inflammatory response and subsequent tissue degradation are orchestrated by complex signaling networks between immune cells and their products in the blood, vascular endothelia and the connective tissue cells residing in the joints. Platelets are recognized as immune-competent cells with an important role in chronic inflammatory diseases such as RA. Here we review the specific aspects of platelet function relevant to arthritic disease, including current knowledge of the molecular crosstalk between platelets and other innate immune cells that modulate RA pathogenesis.

Platelet factor 4 (CXCL4/PF4) upregulates matrix metalloproteinase-2 (MMP-2) in gingival fibroblasts.

Periodontitis is a chronic inflammatory disease characterized by the release of matrix metalloproteinases (MMPs) from resident connective tissue cells in tooth-supporting tissues (periodontium). Platelet activation, and the attendant release of pro-inflammatory chemokines such as platelet factor 4 (CXCL4/PF4), are associated with periodontitis although the associated biochemical pathways remain undefined. Here we report that recombinant PF4 is internalized by cultured human gingival fibroblasts (hGFs), resulting in significant (p < 0.05) upregulation in both the production and release of MMP-2 (gelatinase A). This finding was corroborated by elevated circulating levels of MMP-2 (p < 0.05) in PF4-overexpressing transgenic mice, relative to controls. We also determined that PF4 induces the phosphorylation of NF-κB; notably, the suppression of NF-κB signaling by the inhibitor BAY 11-7082 abrogated PF4-induced MMP-2 upregulation. Moreover, the inhibition of surface glycosaminoglycans (GAGs) blocked both PF4 binding and NF-κB phosphorylation. Partial blockade of PF4 binding to the cells was achieved by treatment with either chondroitinase ABC or heparinase III, suggesting that both chondroitin sulfate and heparan sulfate mediate PF4 signaling. These results identify a novel pathway in which PF4 upregulates MMP-2 release from fibroblasts in an NF-κB- and GAG-dependent manner, and further our comprehension of the role of platelet signaling in periodontal tissue homeostasis.

Apoptosis in platelets is independent of the actin cytoskeleton.

Homeostasis between platelet production and clearance is essential for human health. A critical facet of the balance that facilitates platelet clearance from the circulation is apoptosis (programmed cell death). The precise cellular mechanisms that underpin platelet apoptosis are not defined. In nucleated cells, reorganization of the actin cytoskeleton is known to regulate platelet apoptosis. However, the role of the actin cytoskeleton in regulating apoptosis in platelets has not been extensively studied as they are anucleate and exhibit a distinctive physiology. Here, apoptosis was induced in washed human platelets using ABT-737, a BH3-mimetic drug. Mitochondrial depolarization was measured using the ratiometric dye JC-1; surface phosphatidylserine (PS) exposure was measured by annexin V binding; caspase-3 activation was measured by Western blotting. All three apoptotic markers were unaffected by the presence of either the actin depolymerizing drug cytochalasin D or the actin polymerizing drug jasplakinolide. Moreover, platelets were isolated from wild-type (WT) mice and mice deficient in gelsolin (Gsn), an actin-binding protein that is essential for normal cytoskeletal remodeling. In response to ABT-737, gelsolin-null (Gsn-/-) platelets initially showed accelerated PS exposure relative to WT platelets, however, both WT and Gsn-/- platelets exhibited similar levels of mitochondrial depolarization and caspase-3 activation in response to ABT-737. We conclude that ABT-737 induces established markers of platelet apoptosis in an actin-independent manner.

Filamin A regulates caspase-3 cleavage in platelets in a protein kinase C (PKC)-dependent manner.

Apoptosis is a critical process for the maintenance of cell populations, and involves mitochondrial depolarization, the sequential cleavage of caspase-9 and -3, followed by the externalization of phosphatidylserine (PS) on the plasma membrane. The actin cytoskeleton and its accessory proteins are known regulators of apoptotic signaling in nucleated cells but their roles in platelet apoptosis are undefined. Filamin A (FLNA) is a ubiquitously expressed actin-crosslinking protein that also serves as an intracellular signaling scaffold. Here we used platelets from mice with a platelet-specific FLNA deficiency (Flnafl/Y, Pf4-cre/+, termed platelet-specific knockout) to test the role of FLNA in platelet apoptosis. Treatment with the BH3-mimetic drug ABT-737 induced caspase-3 cleavage and PS exposure in platelets from floxed mice (Flnafl/Y, termed control) but these effects were essentially abrogated in FLNA-null platelets (platelet-specific knockout). Protein kinase C (PKC), a known FLNA ligand, was also activated by ABT-737, and PKC's phosphorylation of its downstream substrates was attenuated in FLNA-null platelets. The PKC inhibitor bisindolylmaleimide (BIM) also reduced caspase-3 cleavage, thus essentially phenocopying the FLNA-null platelets. Notably, the caspase-3 cleavage defect in FLNA-null platelets was rescued by the PKC-activating phorbol ester PMA, suggesting that FLNA and PKC share a common pathway in regulating platelet apoptosis. Mitochondrial depolarization and caspase-9 cleavage were unaffected by BIM treatment, suggesting that PKC specifically controls the downstream caspase-3 point of the pro-apoptotic signaling pathway. These data point to a novel role for FLNA in the regulation of platelet apoptosis, thus providing an improved understanding of how circulating platelet counts are maintained.

Direct observation of protein structural transitions through entire amyloid aggregation processes in water using 2D-IR spectroscopy.

Amyloid proteins that undergo self-assembly to form insoluble fibrillar aggregates have attracted much attention due to their role in biological and pathological significance in amyloidosis. This study aims to understand the amyloid aggregation dynamics of insulin (INS) in H2O using two-dimensional infrared (2D-IR) spectroscopy. Conventional IR studies have been performed in D2O to avoid spectral congestion despite distinct H-D isotope effects. We observed a slowdown of the INS fibrillation process in D2O compared to that in H2O. The 2D-IR results reveal that different quaternary structures of INS at the onset of the nucleation phase caused the distinct fibrillation pathways of INS in H2O and D2O. A few different biophysical analysis, including solution-phase small-angle X-ray scattering combined with molecular dynamics simulations and other spectroscopic techniques, support our 2D-IR investigation results, providing insight into mechanistic details of distinct structural transition dynamics of INS in water. We found the delayed structural transition in D2O is due to the kinetic isotope effect at an early stage of fibrillation of INS in D2O, i.e., enhanced dimer formation of INS in D2O. Our 2D-IR and biophysical analysis provide insight into mechanistic details of structural transition dynamics of INS in water. This study demonstrates an innovative 2D-IR approach for studying protein dynamics in H2O, which will open the way for observing protein dynamics under biological conditions without IR spectroscopic interference by water vibrations.

Lenvatinib in multimodal therapy for unresectable radioactive iodine-naïve differentiated thyroid cancer: A case report with literature review.

BACKGROUND: Patients with unresectable or metastatic differentiated thyroid carcinoma (DTC) are rare and require individualized therapy. This may require approaches not typically used in resectable disease. We report a patient treated with lenvatinib and external beam radiation therapy. CASE: An 87-year-old woman presented with cT4N1aM1 papillary thyroid carcinoma with tracheal invasion. She was not a candidate for surgery, radioactive-iodine, or radiation, so a trial of lenvatinib was offered. Her tumor showed clinical, biochemical, and radiological response after 5 months of lenvatinib, and she subsequently received external beam radiation. She enjoys good quality of life without evidence of cancer progression off therapy 21 months post-initiation of treatment. CONCLUSION: Lenvatinib may be effective in RAI-naïve advanced DTC patients as a component of individualized multimodal therapy when conventional options are not feasible.

Midwavelength Infrared Colloidal Nanowire Laser.

Realizing bright colloidal infrared emitters in the midwavelength infrared (or mid-IR), which can be used for low-power IR light-emitting diodes (LEDs), sensors, and deep-tissue imaging, has been a challenge for the last few decades. Here, we present colloidal tellurium nanowires with strong emission intensity at room temperature and even lasing at 3.6 µm (ω) under cryotemperature. Furthermore, the second-harmonic field at 1.8 µm (2ω) and the third-harmonic field at 1.2 µm (3ω) are successfully generated thanks to the intrinsic property of the tellurium nanowire. These unique optical features have never been reported for colloidal tellurium nanocrystals. With the colloidal midwavelength infrared (MWIR) Te nanowire laser, we demonstrate its potential in biomedical applications. MWIR lasing has been clearly observed from nanowires embedded in a human neuroblastoma cell, which could further realize deep-tissue imaging and thermotherapy in the near future.

Tumor molecular differences associated with outcome disparities of Black patients with head and neck cancer.

BACKGROUND: Numerous studies of head and neck squamous cell carcinoma (HNSCC) have demonstrated disparate outcomes by race and ethnicity. Beyond known associations with socioeconomic variables, whether these are also associated with differences in tumor molecular composition has thus far been poorly explored. METHODS: We downloaded clinical and multiplatform molecular data from The Cancer Genome Atlas and other published studies. These were compared between non-Hispanic Black (n = 43) and White (n = 354) patients with non-HPV-related tumors, using multivariable models. Publicly available validation cohorts were used. RESULTS: Black patients had poorer progression-free survival than White patients. Tumors of Black patients had greater copy number aberrations, and increased SFRP1 methylation and miRNA-mediated PRG4 silencing associated with poor survival. PI3K/AkT/mTOR pathway proteins were differentially expressed. CONCLUSIONS: There are molecular differences between tumors of Black and White patients that may partially account for differences in survival. These may inform targeted treatment decisions to achieve equitable outcomes.