Prognosis and immunotherapy in melanoma based on selenoprotein k-related signature.

Selenium and selenoproteins are closely related to melanoma progression. However, it is unclear how SELENOK affects lipid metabolism, endoplasmic reticulum stress (ERS), immune cell infiltration, survival, and prognosis in melanoma patients. Transcriptome data from melanoma patients was used to investigate SELENOK levels and their effect on prognosis, followed by an investigation of SELENOK's effects on immune cell infiltration. Furthermore, a risk model based on ERS, lipid metabolism, and immune-related genes was constructed, and its utility in melanoma prognosis was evaluated. Finally, the drug sensitivity of the risk model was analyzed to provide a reference for melanoma therapy. The results showed that melanoma with a high SELENOK level had a greater degree of immune cell infiltration and a better prognosis. Additionally, SELENOK was found to regulate ERS, lipid metabolism, and immune cell infiltration in melanoma. The risk model based on SELENOK signature genes successfully predicted the prognosis of melanoma, and the low-risk group exhibited a favorable immunological microenvironment. Furthermore, high-risk patients with melanoma were candidates for chemotherapy with RAS pathway inhibitors, whereas low-risk patients were more susceptible to routinely used chemotherapy medicines. In summary, SELENOK was shown to regulate ERS, lipid metabolism, and immune cell infiltration in melanoma, and SELENOK was positively associated with the prognosis of melanoma. The risk model based on SELENOK signature genes was valuable for melanoma prognosis and therapy.

Cu-Catalyzed Amination of Base-Sensitive Aryl Bromides and the Chemoselective N- and O-Arylation of Amino Alcohols.

We report a general and functional-group-tolerant method for the Cu-catalyzed amination of base-sensitive aryl bromides including substrates possessing acidic functional groups and small five-membered heteroarenes. The results presented herein substantially expand the scope of Cu-catalyzed C-N coupling reactions. The combination of L8, an anionic N1,N2-diarylbenzene-1,2-diamine ligand, along with the mild base NaOTMS leads to the formation of a stable yet reactive catalyst that resists deactivation from coordination to heterocycles or charged intermediates. This system enables the use of low catalyst and ligand loadings. Exploiting the differences in nucleophile deprotonation in C-O and C-N coupling reactions catalyzed by Cu·L8 we developed a method to chemoselectively N- and O-arylate a variety of amino alcohol substrates. Employing NaOt-Bu as the base resulted exclusively in C-O coupling when the amino alcohols featured primary alcohols and more hindered amines or aniline groups. Utilizing NaOTMS enabled the ability to override the steric-based selectivity of these reactions completely and exclusively promoted C-N coupling regardless of the structure of the amino alcohol. The ability to invert the observed chemoselectivity is distinct from previously described methods that require protecting group manipulations or rely entirely on steric effects to control reactivity. These results substantially improve the scope of Cu-catalyzed C-N coupling reactions using N1,N2-diarylbenzene-1,2-diamine ligands and introduce a new chemoselective method to arylate amino alcohols.

Modulating endoplasmic reticulum stress attenuates mast cell degranulation.

OBJECTIVES: Degranulation of mast cells leads to direct allergic symptoms. The underlying mechanism needs to be explored further. Endoplasmic reticulum (ER) stress is involved in the pathogenesis of allergic conditions. The objective of this study is to gain a better understanding of the mechanism of mast cell degranulation. METHODS: Bone marrow derived mast cells and mast cells isolated from the airway tissues were prepared. The role of ER stress in mediating the release of mast cells was tested. RNA sequencing (RNAseq) was used to investigate the genetic activities of mast cells. RESULTS: Our observation showed that sensitization increased ER stress in mast cells. X-box-1 binding protein (XBP1) activity was linked to mast cell degranulation. Modulation of ER stress or XBP1 expression regulates the release of the mast cell mediator. XBP1 promoted the mediator release of mast cells by activating spleen tyrosine kinase (Syk). Activation of eukaryotic initiation factor 2a (eIF2a) inhibited XBP1 in mast cells. Semaphorin 3A was effective in preventing experimental allergic rhinitis (AR) due to its ability to suppress the release of mast cell mediators. CONCLUSIONS: ER stress is associated with the mast cell degranulation. By inhibiting XBP1, the crucial molecule of ER stress, mast cell degranulation can be suppressed and experimental AR can be mitigated.

Phosphatidylserine promotes immunotherapy for airway allergy.

Type 1 regulatory T cells (Tr1 cells) play an important role in the maintenance of the immune homeostasis in the body. The induction of Tr1 cell is to be further investigated. The interaction of phosphatidylserine (PS) with TIM3 has immune regulation functions. The objective of this study is to elucidate the role of PS-TIM3 signals in inducing Tr1 cells. In this study, mice were treated using PS or specific immunotherapy by nasal instillation. A murine model of allergic rhinitis was developed using ovalbumin as a specific antigen. We found that PS-containing nasal instillation induced Tr1 cells in the airway tissues. PS promoted gene activities associated with IL-10 through activation of TIM3 in CD4+ T cells. TIM3 mediated the effects of PS on inducing Tr1 cells, in which the TIM3- PI3K-AKT pathway played a critical role. PS boosted allergen-specific immunotherapy by inducing specific antigen Tr1 cell generation. Concomitant administration of PS and SIT resulted in better therapeutic effects on AR. In conclusion, the data demonstrate that PS can promote the specific immunotherapy for AR through inducing antigen specific Tr1 cells in the airway tissues.

Cortisol synergizing with endoplasmic reticulum stress induces regulatory T-cell dysfunction.

The dysfunction of regulatory T cell (Treg) is associated with the pathogenesis of many immune diseases. The regiments used to re-establish Treg's function are currently unsatisfactory and need to be improved. The purpose of this study is to elucidate the synergistic effects of cortisol and endoplasmic reticulum (ER) stress on impairing regulatory T cell functions. In this study, blood samples were collected from patients with food allergy (FA). Immune cells were purified from blood specimens by flow cytometry. A mouse model of FA was established with ovalbumin as a specific antigen. We observed that serum cortisol levels of FA patients were negatively correlated with peripheral Treg counts. Overwhelmed ER stress status was detected in Tregs of FA patients. The antigen-specific immune response induced ER stress in Tregs, which was exacerbated by concurrent cortisol exposure. ER stress mediated the effects of cortisol on impairing the immune suppressive ability of Tregs. The expression of Rnf20 was observed in Tregs upon exposure to cortisol. Rnf20 reduced the expression of Foxp3 and transforming growth factor (TGF)-ß in Tregs. Rnf20 inhibition re-established the immunosuppressive functions of Tregs obtained in patients with FA. The experimental FA in mice was attenuated by inhibition of Rnf20 in Tregs. In summary, specific immune response in synergy with cortisol to induce the expression of Rnf20 in Tregs. Rnf20 reduces the levels of Foxp3 and TGF-ß to impair the immune suppressive function. Inhibition of Rnf20 can restore the immune suppressive ability of Tregs obtained from FA patients.

Endoplasmic reticulum stress impairs the immune regulation property of macrophages in asthmatic patients.

The current study aims to characterize the counteraction of M2 cells in response to Endoplasmic reticulum (ER) stress. ER stress was detected in bronchoalveolar lavage fluids (BALF) Mϕs, which was at unresolved state in asthma patients. A positive correlation was detected between ER stress in Mϕs and lung functions/allergic mediators/Th2 cytokines in BALF or specific IgE in the serum. Levels of immune regulatory mediator in the BALF were negatively correlated to ER stress in BALF Mϕs. The ER stress state influenced the immune regulatory property of BALF Mϕ. Exposure to environmental pollutant, 3-metheyl-4-nitrophenol, exacerbated ER stress in Mϕ, which affected the Mϕ phenotyping. Exacerbation of ER stress suppressed the expression of IL-10 and programmed cell death protein-1 (PD-1) in Mϕs by increasing the expression of the ring finger protein 20 (Rnf20). Conditional inhibition of Rnf20 in Mϕs attenuated experimental airway allergy.

Preparation of Highly Stable Polymer Microstructure with Enhanced Adhesion Strength by Pushpin-like Nano/Microstructure Array.

This polymer microstructure expands more available application, which is a milestone for the development of micro-electro-mechanical system devices towards intelligence and multifunction. Poor interface bonding between the polymer and Si or metal is a particular problem, which restricts the application and promotion of polymer materials. In this study, a transition strengthening layer is proposed to obtain a highly stable polymer microstructure by enhancing the interfacial adhesion strength. The transition strengthening layer is activated by a pushpin-like nano/microstructure array with micromachining technology. Given its good graphical qualities and compatibility, epoxy negative photoresist SU-8 is applied to evaluate the strengthened capabilities of the pushpin-like nano/microstructure array. The microstructure of SU-8 is prepared by the same processes, and then the adhesion strength between the SU-8 microstructure and various activated substrates is tested by the thrust tester. It was determined that SU-8 with an activated pushpin-like microstructure array possessed a highly stable adhesion ability, and its adhesion strength increased from 6.51 MPa to 15.42 MPa. With its ultrahigh stable adhesion ability, it has been applied in fabricating three typical microstructures (hollow square microstructure, gradually increasing adjacent periodic microstructure, and slender strip microstructures) and large-area SU-8 microstructures to evaluate the feasibility of the transition strengthening layer and repeatability and universality of the microfabrication processes. The drifting and gluing phenomenon are avoided by this method compared with the traditional design. The proposed pushpin-like nano/microstructure array is promising in enhancing the stability of polymer microstructures with a substrate.

Substance P promotes immunotherapy efficacy for airway allergy.

Background: Allergen-specific immunotherapy (AIT) has been employed in the treatment of allergic diseases for many years. However, the effectiveness of AIT requires improvement. Substance P (SP) can interact with immune cells, modulate immune cell activity, and regulate immune reaction. The purpose of this study is to use SP as an immune regulator to enhance the therapeutic efficacy of AIT. Methods: An established mouse model of the airway allergy disorder (AAD) was employed with ovalbumin as a specific antigen. The AAD response was evaluated through established procedures. AAD mice were treated with AIT employing SP as an immune regulator. Dendritic cells were isolated from the airway tissues by magnetic cell sorting, and were analyzed by RNA sequencing (RNAseq). Results: We observed that after sensitization with ovalbumin, mice exhibited AAD-like symptoms, serum specific IgE, and Th2 polarization. The presence of SP in the course of sensitization prevented the development of AAD. Treating mice with SP by nasal instillations induced IL-10, but not TGF-ß, in dendritic cells of the airway tissues. The most differentially expressed genes (DEG) in the dendritic cells were those related to the IL-10 expression, including Il10, Tac1r, and Mtor. The gene ontology analysis showed that these DEGs mainly mapped to the tachykinin-PI3K-AKT-mTOR pathway. The addition of SP substantially enhanced the therapeutic efficacy of AIT for AAD by inducing antigen specific type 1 regulatory T cells (Tr1 cells). Conclusion: Acting as an immune regulator, SP promotes the therapeutic efficacy for AAD by inducing antigen specific Tr1 cells in the airway tissues.

Dual-mode optical thermometer based on fluorescence intensity ratio of Eu3+/Mn4+ co-doping zinc titanate phosphors.

Zinc titanate phosphors containing Eu3+/ Mn4+ as active ions were synthesized by using the solid-state method. XRD patterns of the powders confirmed that the samples were a mixture of cubic Zn2TiO4 and hexagonal ZnTiO3 phases. The luminous intensity of ZTO: Eu3+phosphors and ZTO: Mn4+ phosphors both increased with the increase of doping concentration, reaching the maximum at 2 mol% Eu3+ and 0.3 mol% Mn4+, respectively. In the photoluminescence spectra of ZTO: Eu3+(2 mol%) phosphors with different Mn4+ doping amounts excited at 465 nm, the emission spectra revealed the characteristic peaks of Eu3+ with low Mn4+ content, and with the Mn4+ content increasing, the emission spectra contained both Mn4+ and Eu3+ luminescence peaks. In the variable temperature spectra, the relative sensitivity of the samples was improved with the concentration of Mn4+ increasing and achieved the maximum value of 3.2 %/K.

Engineered Switchable-Wettability Surfaces for Multi-Path Directional Transportation of Droplets and Subaqueous Bubbles.

Conventional engineered surfaces for fluid manipulation are hindered by the set wettability, and thus they can only achieve spontaneous transport of single-phase fluid, namely liquid or gas. Moreover, fluid transport systems that are robust to path defects have yet to be fully explored. Here, unprecedentedly, a universal wettability switching strategy is developed for achieving programmable directional transport of both droplets and subaqueous bubbles on a dumbbell-patterned functional surface (DPFS), featuring in strong robustness, high efficiency, and effective cost. By tuning the superwettability of DPFS through octadecyltrichlorosilane treatment and ultraviolet-C selective irradiation, the transport fluid can alternate between liquid and gas. The material's switchable superwettability regulates the fluid directed dynamics within the confined pattern, in which the sustaining fluid propelling relies on the surface energy difference between the starting and terminal sites. This enables the construction of multiple channels, which works synergistically with ultralow-volume-loss transport to impart the fluidic system with strong robustness against path defects. Underlying the completion of complex microfluidics tasks, spatially-selective cooling devices and subaqueous gas microreactors are successfully demonstrated. This energy-consumption-free fluid transport system opens a new avenue for on-chip programmable fluid manipulation, promoting innovative applications requiring rational control of two-phase fluid transport.

Semaphorin-3 Promotes Specific Immunotherapy Effects on Experimental Food Allergy.

Sustaining higher frequency of mast cells in the allergic lesion site has been recognized. Factors causing high numbers of mast cells in the local tissues are not fully understood yet. RAS signaling plays a role in sustaining certain cell activities. This study is aimed at elucidating the role of RAS activation in the apoptosis resistance induction in mast cells and at employing semaphorin 3A to regulate RAS activities in sensitized mast cells and alleviating the allergic response in the intestine. A food allergy (FA) mouse model was developed. Mast cells were isolated from FA mouse intestinal tissues by flow cytometry. Mast cell apoptosis was assessed by staining with annexin V and propidium iodide. We found that aberrantly higher p21-activated kinase-1 (Pak1) expression in FA mast cells was associated with mast cell aggregation in the intestine. Sensitization increased Pak1 expression and apoptosis resistance in intestinal mast cells. RAS and Pak1 mutually potentiated each other in sensitized mast cells. Semaphorin 3A (sema3A) suppressed the Pak1 expression and RAS activation in mast cells. sema3A restored the apoptosis sensitivity in sensitized mast cells. Administration of sema3A potentiated allergen-specific immunotherapy in experimental FA. In conclusion, mast cells of FA mice showed higher Pak1 expression and high RAS activation status that contributed to apoptosis resistance in mast cells. Administration of sema3A restored the sensitivity to apoptosis inducers and promoted the therapeutic effects of specific immunotherapy on experimental FA.

5-Bromo-2-chloro-4-fluoro-3-iodopyridine as a Halogen-rich Intermediate for the Synthesis of Pentasubstituted Pyridines.

The 60 individual halopyridine isomers that contain one bromine, chlorine, fluorine, iodine, and H are valuable potential building blocks in medicinal chemistry research, but surprisingly, there has been only one report on the synthesis of just two of them. Herein, we describe simple syntheses of the unique 5-bromo-2-chloro-4-fluoro-3-iodopyridine (10) and 3-bromo-6-chloro-4-fluoro-2-iodopyridine (32) using halogen dance reactions. C6 magnesiation of 10 and its 3-phenyl analogue 22 followed by trapping with electrophiles generated a variety of pentasubstituted pyridines with desired functionalities for further chemical manipulations.

Transient receptor potential vanilloid type 4 (TRPV4) promotes tumorigenesis via NFAT4 activation in nasopharyngeal carcinoma.

Transient receptor potential vanilloid type 4 (TRPV4) can function as an oncogene or tumor suppressor depending on the tumor types. However, little is known regarding the effect of TRPV4 in nasopharyngeal carcinoma (NPC), a highly prevalent malignancy in Southern China and Southeast Asia. We found that TRPV4 mRNA and protein levels were significantly upregulated in NPC tissues. In addition, activation of TRPV4 in NPC cell lines using GSK1016790A (100 nM) induced a Ca2+ influx, whereas pharmacological inhibition or gene knockdown of TRPV4 reduced the proliferation rates of NPC cells. TRPV4 knockdown also decreased the growth of tumor xenografts in vivo. Mechanistically, TRPV4-mediated tumorigenesis is dependent on the activation of Ca2+/calcineurin/calcineurin-nuclear factor of activated T cell 4 (NFAT4) signaling. Furthermore, NFAT4 protein level was overexpressed in NPC tissues and correlated positively with TRPV4. Taken together, TRPV4 promotes the malignant potential of NPC cells by activating NFAT4 signaling. Our findings highlight TRPV4-NFAT4 axis as a potential therapeutic target in NPC.

Geminal Diheteroatomic Motifs: Some Applications of Acetals, Ketals, and Their Sulfur and Nitrogen Homologues in Medicinal Chemistry and Drug Design.

Acetals and ketals and their nitrogen and sulfur homologues are often considered to be unconventional and potentially problematic scaffolding elements or pharmacophores for the design of orally bioavailable drugs. This opinion is largely a function of the perception that such motifs might be chemically unstable under the acidic conditions of the stomach and upper gastrointestinal tract. However, even simple acetals and ketals, including acyclic molecules, can be sufficiently robust under acidic conditions to be fashioned into orally bioavailable drugs, and these structural elements are embedded in many effective therapeutic agents. The chemical stability of molecules incorporating geminal diheteroatomic motifs can be modulated by physicochemical design principles that include the judicious deployment of proximal electron-withdrawing substituents and conformational restriction. In this Perspective, we exemplify geminal diheteroatomic motifs that have been utilized in the discovery of orally bioavailable drugs or drug candidates against the backdrop of understanding their potential for chemical lability.

Synthesis of functionalized derivatives of the gamma-secretase modulator BMS-932481 and identification of its major metabolite.

In an effort to improve physical properties by introducing polar functionality into the bicyclic pyrimidine gamma-secretase modulator (GSM) clinical candidate BMS-932481, we prepared several oxidative products of BMS-932481. Among the analogs that were prepared, the C-5 alcohol 3 was identified as the predominant metabolite of BMS-932481 found in rat and human liver microsomes. Alcohol 3 was determined to be chemically unstable, leading to the hypothesis that 3 may lead to the production of reactive species both in vitro and in vivo.

[Three-dimension CT assisted treatment of nasal fracture].

Objective:To investigate the diagnosis and evaluation methods of nasal bone fractures after nasal trauma, and the guiding significance of three-dimensional CT imaging technology for its treatment. Method:A total of 255 patients with nasal bone fractures were randomly selected from our hospital. All patients underwent CT scan of the nasal bones and reconstructed on a computer system. The reconstructed CT images were observed, measured and evaluated. Analyze the morphological characteristics of nasal bone fractures and evaluate the involvement of other facial structures. Result:Among 255 patients with nasal trauma, there were traumatic nasal bone fractures, including 71 cases（27.8%） with simple nasal bone fractures, 143 cases（56.1%） with traumatic nasal septum deviation, and 41 cases（16.1%） with other fractures. External nasal fracture classification: type Ⅰ（unilateral nasal bone or maxillary frontal fracture） 91 cases（35.7%）， type Ⅱ（bilateral nasal bone or fracture） 21 cases（8.2%），type Ⅲ（with trauma Nasal septum deviation） 143 cases（56.1%）. A total of 214 patients（83.9%） underwent surgical treatment, and underwent nasal endoscopic reduction of nasal bone fractures under local anesthesia, and 77 patients（30.2%） underwent nasal septum surgery. Conclusion:CT three-dimensional imaging technology can clearly display the location of the nasal bone fracture, the shape of the fracture line, the number of fragments formed by the fracture, and quantitative analysis of the deformity caused by it, which plays an important role in its diagnosis and treatment.

[Functional nasolacrimal duct decompression for chronic dacryocystitis].

Objective:To investigate the feasibility of endoscopic nasolacrimal decompression for chronic dacryocystitis. Method:22 patients with chronic dacryocystitis hospitalized at Longgang ENT hospital were participated in this study. An injection of 30% iohexol was administered to conduct lacrimal sac angiography. The injection was stopped when the agent reflux from the lacrimal duct, and a computed tomography（CT） scan of the lacrimal duct was performed immediately. Sinuses Trachea Isoftware was used to reconstruct a three-dimensional（3D） view of the lacrimal passage and its surrounding structures. The software was used to simulate the "cutting" of the lacrimal sac and nasolacrimal duct; the lacrimal sac and nasal lacrimal duct were removed after 1/2-3/4 circumferences to decompress the passage and expose the membranous nasolacrimal duct. CT scans were performed on ten adult frozen cadaveric heads, and the nasolacrimal duct decompression operation was simulated. Then, the bone of the nasolacrimal duct was removed, membranous nasolacrimal duct was exposed, and the capsular nasolacrimal duct was dilated. Result:①The lacrimal angiography study revealed that lacrimal duct obstruction occurred in the nasolacrimal duct segment, accounting for 72.7%（16/22） of the study cases. ② The anatomical examination showed that the outer sidewall of the nasolacrimal duct was composed of the tear groove of the maxilla, and the inner wall was composed of the descending process of the lacrimal bone. ③ In cadaveric heads, decompression of the osseous nasolacrimal duct was performed, exposing the membranous nasolacrimal duct. ④ A balloon catheter could dilate the membranous nasolacrimal duct and allow the lacrimal passage to be flushed. Conclusion:Endoscopic nasolacrimal decompression preserves the integrity of the lacrimal duct, allows drainage of the lacrimal duct, and avoids obstruction of the lacrimal duct by preventing lacrimal granulation.

Soluble CD83 alleviates experimental allergic rhinitis through modulating antigen-specific Th2 cell property.

Background and aims: Dysfunction of the immune regulatory system plays a role in the pathogenesis of allergic rhinitis (AR). The underlying mechanism needs to be further investigated. Published data indicate that soluble CD83 (sCD83) has immune regulatory activities. This study aims to investigate the role of sCD83 in the alleviation of experimental AR. Methods: Peripheral blood samples were obtained from AR patients. Serum levels of sCD83 were determined by enzyme-linked immunosorbent assay. A murine AR model was developed to test the effects of sCD83 on suppressing experimental AR. Results: We found that serum levels of sCD83 in the AR group were lower than that in the healthy control group. A negative correlation was identified between the serum sCD83 levels and the frequency of T helper-2 (Th2) cells. The low serum sCD83 levels were also associated with the Bcl2L12 expression in antigen-specific Th2 cells. Exposure to sCD83 enhanced the responsiveness of antigen-specific Th2 cells to apoptosis inducers via suppressing the Bcl2L12 expression. Administration of sCD83 efficiently suppressed experimental AR. Conclusions: sCD83 contributes to immune homeostasis by regulating CD4+ T cell activities. Administration of sCD83 may have translational potential for the treatment of AR or other allergic diseases.