Risk of candidiasis associated with interleukin-17 inhibitors: Implications and management.

The application of interleukin-17 (IL-17) inhibitors, including secukinumab, ixekizumab, brodalumab, and bimekizumab, are associated with elevated risk of candidiasis. These medications interfere with the IL-17 pathway, which is essential for maintaining mucosal barriers and coordinating the immune response against Candida species. The observational data and clinical trials demonstrate the increased incidence of candidiasis in individuals treated with IL-17 inhibitors. Brodalumab and bimekizumab pose a greater risk than secukinumab in eliciting candidiasis, whereas the data regarding ixekizumab are equivocal. Higher doses and prolonged treatment duration of IL-17 inhibitors increase the risk of candidiasis by compromising the immune response against Candida species. Prior to prescribing IL-17 inhibitors, healthcare professionals should comprehensively evaluate patients' medical histories and assess their risk factors. Patients should be educated on the signs and symptoms of candidiasis to facilitate early detection and intervention. Future research should focus on identifying the risk factors associated with candidiasis in patients receiving IL-17 inhibitors. Prospective studies and long-term surveillance are required to explore the impact of specific inhibitors on the incidence and severity of candidiasis and to evaluate the effectiveness of combination therapies, such as concurrent use of IL-17 inhibitors and prophylactic antifungal agents.

Interleukin inhibitors and the associated risk of candidiasis.

Interleukins (ILs) are vital in regulating the immune system, enabling to combat fungal diseases like candidiasis effectively. Their inhibition may cause enhanced susceptibility to infection. IL inhibitors have been employed to control autoimmune diseases and inhibitors of IL-17 and IL-23, for example, have been associated with an elevated risk of Candida infection. Thus, applying IL inhibitors might impact an individual's susceptibility to Candida infections. Variations in the severity of Candida infections have been observed between individuals with different IL inhibitors, necessitating careful consideration of their specific risk profiles. IL-1 inhibitors (anakinra, canakinumab, and rilonacept), IL-2 inhibitors (daclizumab, and basiliximab), and IL-4 inhibitors (dupilumab) have rarely been associated with Candida infection. In contrast, tocilizumab, an inhibitor of IL-6, has demonstrated an elevated risk in the context of coronavirus disease 2019 (COVID-19) treatment, as evidenced by a 6.9% prevalence of candidemia among patients using the drug. Furthermore, the incidence of Candida infections appeared to be higher in patients exposed to IL-17 inhibitors than in those exposed to IL-23 inhibitors. Therefore, healthcare practitioners must maintain awareness of the risk of candidiasis associated with using of IL inhibitors before prescribing them. Future prospective studies need to exhaustively investigate candidiasis and its associated risk factors in patients receiving IL inhibitors. Implementing enduring surveillance methods is crucial to ensure IL inhibitors safe and efficient utilization of in clinical settings.

Constructing a Low-Cost Si-NSs@C/NG Composite by a Ball Milling-Catalytic Pyrolysis Method for Lithium Storage.

Silicon-based composites are promising candidates as the next-generation anode materials for high-performance lithium-ion batteries (LIBs) due to their high theoretical specific capacity, abundant reserves, and reliable security. However, expensive raw materials and complicated preparation processes give silicon carbon anode a high price and poor batch stability, which become a stumbling block to its large-scale practical application. In this work, a novel ball milling-catalytic pyrolysis method is developed to fabricate a silicon nanosheet@amorphous carbon/N-doped graphene (Si-NSs@C/NG) composite with cheap high-purity micron-size silica powder and melamine as raw materials. Through systematic characterizations such as XRD, Raman, SEM, TEM and XPS, the formation process of NG and a Si-NSs@C/NG composite is graphically demonstrated. Si-NSs@C is uniformly intercalated between NG nanosheets, and these two kinds of two-dimensional (2D) materials are combined in a surface-to-surface manner, which immensely buffers the stress changes caused by volume expansion and contraction of Si-NSs. Attributed to the excellent electrical conductivity of graphene layer and the coating layer, the initial reversible specific capacity of Si-NSs@C/NG is 807.9 mAh g-1 at 200 mA g-1, with a capacity retention rate of 81% in 120 cycles, exhibiting great potential for application as an anode material for LIBs. More importantly, the simple and effective process and cheap precursors could greatly reduce the production cost and promote the commercialization of silicon/carbon composites.

Modulating the Graphitic Domains and Pore Structure of Corncob-Derived Hard Carbons by Pyrolysis to Improve Sodium Storage.

Biomass-derived hard carbon materials are considered as the most promising anode materials for sodium-ion batteries (SIBs) due to their abundant sources, environmental friendliness, and excellent electrochemical performance. Although much research exists on the effect of pyrolysis temperature on the microstructure of hard carbon materials, there are few reports that focus on the development of pore structure during the pyrolysis process. In this study, corncob is used as the raw material to synthesize hard carbon at a pyrolysis temperature of 1000~1600 °C, and their interrelationationship between pyrolysis temperature, microstructure and sodium storage properties are systematically studied. With the pyrolysis temperature increasing from 1000 °C to 1400 °C, the number of graphite microcrystal layers increases, the long-range order degree rises, and the pore structure shows a larger size and wide distribution. The specific capacity, the initial coulomb efficiency, and the rate performance of hard carbon materials improve simultaneously. However, as the pyrolysis temperature rises further to 1600 °C, the graphite-like layer begins to curl, and the number of graphite microcrystal layers reduces. In return, the electrochemical performance of the hard carbon material decreases. This model of pyrolysis temperatures-microstructure-sodium storage properties will provide a theoretical basis for the research and application of biomass hard carbon materials in SIBs.

Transcriptome analysis of the bivalve Placuna placenta mantle reveals potential biomineralization-related genes.

The shells of window pane oyster Placuna placenta are very thin and exhibit excellent optical transparency and mechanical robustness. However, little is known about the biomineralization-related proteins of the shells of P. placenta. In this work, we report the comprehensive transcriptome of the mantle tissue of P. placenta for the first time. The unigenes of the mantle tissue of P. placenta were annotated by using the public databases such as nr, GO, KOG, KEGG, and Pfam. 24,343 unigenes were annotated according to Pfam database, accounting for 21.48% of the total unigenes. We find that half of the annotated unigenes of the mantle tissue of P. placenta are consistent to the annotated unigenes from pacific oyster Crassostrea gigas according to nr database. The unigene sequence analysis from the mantle tissue of P. placenta indicates that 465,392 potential single nucleotide polymorphisms (SNPs) and 62,103 potential indel markers were identified from 60,371 unigenes. 178 unigenes of the mantle tissue of P. placenta are found to be homologous to those reported proteins related to the biomineralization process of molluscan shells, while 18 of them are highly expressed unigenes in the mantle tissue. It is proposed that four unigenes with the highest expression levels in the mantle tissue are very often related to the biomineralization process, while another three unigenes are potentially related to the biomineralization process according to the Quantitative Real-Time Polymerase Chain Reaction (qRT-PCR) analysis. In summary, the transcriptome analysis of the mantle tissue of P. Placenta shows the potential biomineralization-related proteins and this work may shed light for the shell formation mechanism of bivalves.

Lidocaine Ameliorates Psoriasis by Obstructing Pathogenic CGRP Signaling‒Mediated Sensory Neuron‒Dendritic Cell Communication.

Psoriasis is a chronic immune-mediated skin disorder with the nervous system contributing to its pathology. The neurogenic mediators of psoriasis are elusive, and whether the intervention of the cutaneous nervous system can treat psoriasis remains to be determined. In this study, we conducted a pilot study using an epidural injection of lidocaine to treat patients with psoriasis. Lidocaine treatment markedly reduced patients' clinical scores and improved an imiquimod-induced rat model of psoriasis as competent as systemic delivery of a TNF-α antibody. Imiquimod application elicited aberrant cutaneous nerve outgrowth and excessive generation of neuropeptide calcitonin gene-related peptide from dorsal root ganglion neurons, both of which were inhibited by epidural lidocaine treatment. Single-cell RNA sequencing unveiled the overrepresentation of calcitonin gene-related peptide receptors in dermal dendritic cell populations of patients with psoriasis. Through disturbing calcitonin gene-related peptide signaling, lidocaine inhibited IL-23 production by dendritic cells cocultured with dorsal root ganglion neurons. Thus, epidural nerve block with lidocaine demonstrates an effective therapy for psoriasis, which suppresses both inordinate sensory nerve growth in the inflamed skin and calcitonin gene-related peptide-mediated IL-23 production from psoriatic dendritic cells.

Long non-coding RNA RP11-342L8.2, derived from RNA sequencing and validated via RT-qPCR, is upregulated and correlates with disease severity in psoriasis patients.

OBJECTIVE: This study aimed to explore the dysregulated long non-coding RNA (lncRNA) expression profile in psoriatic tissue vs. normal skin tissue via RNA sequencing (RNA-seq), then further sort candidate lncRNAs to be validated by reverse transcription quantitative polymerase chain reaction (RT-qPCR), in order to investigate the comprehensive linkage of lncRNA with psoriasis. METHODS: Twenty-five psoriasis patients were consecutively enrolled, with their psoriatic and surrounding normal skin tissues obtained. Ten pairs of psoriatic and normal tissues were proposed to RNA-seq. Then, top 6 differentially expressed lncRNAs (DElncRNA) were sorted as candidate lncRNAs for validation by RT-qPCR in 25 pairs of samples. RESULTS: Principal component analysis (PCA) exhibited that lncRNA profile clearly distinguished psoriatic tissue from normal tissue, so did heatmap. Volcano plot disclosed 412 upregulated and 625 downregulated DElncRNAs in psoriatic tissue vs. normal tissue. Gene Ontology (GO) and Kyoko Encyclopedia of Genes and Genomes (KEGG) enrichment analyses exhibited that these DElncRNAs were mainly enriched in immune, inflammation, or proliferation-related biological processes and pathways such as neutrophil degranulation, regulation of immune response, positive regulation of cell proliferation, and MAPK signaling pathway. By RT-qPCR validation, lncRNAs RP11-22A3.2, RP11-342L8.2, and CTD-2006H14.2 were increased (all P < 0.001), while lncRNAs AP000442.4, CCDC144NL-AS1, and MIR663AHG were decreased (all P < 0.01) in psoriatic tissue vs. normal tissue. Interestingly, psoriatic lncRNA RP11-342L8.2 was also observed to positively correlated with psoriasis area and severity index (PASI) (r = 0.405, P = 0.045). CONCLUSION: Our present study exhibits some evidence for the landscape of lncRNAs implicated in psoriasis.

Investigation on the influence of additives on the oriented dissolution of calcite.

Similar to the crystal growth process, additives have a strong influence on the dissolution process of crystals. Studies on the dissolution process may shed light on understanding the biomineralization and bioinspired crystallization process. The influence of different kinds of additives including surfactants and polymers on the dissolution process of calcite {104} planes was investigated in detail in this work. The additives can be classified into three kinds according to their influence on the dissolution process of calcite under different concentration windows. The additives show three different kinds of dissolution behaviors with the increase of additive concentrations according to the tomographic variation of the calcite surface after the dissolution process. There are four dissolution modes of calcite while changing the additive concentrations in the solution. Rhombohedral etch pits with [4[combining macron]41] and [481[combining macron]] step edges are formed on the calcite {104} planes after the dissolution process at low additive concentrations (mode I). Calcite micropyramids begin to appear on the calcite surface and the densities of micropyramids increase with the increase of the additive concentrations until they cover the entire calcite surface after the dissolution process at medium additive concentrations (mode II). Instead of micropyramids, large pyramids with [481[combining macron]] and [4[combining macron]41] step edges and a size of about 50 µm form after the dissolution process at high additive concentrations (modes III and IV). We propose that the different anisotropic dissolution behaviors of calcite are strongly related to the concentrations and the adsorption features of the additives on the calcite surface. The additives may act as inhibitors of calcite dissolution, possibly through adsorption on calcite surfaces without preferred adsorption, or adsorption at specific kink sites or step edges. The influence of additives on the oriented dissolution of calcite is generally related to the adsorption density and homogeneity of additives on the calcite substrates.

Add-on effect of plum-blossom needling in alopecia areata: a qualitative evidence synthesis.

BACKGROUND: Alopecia areata (AA) is highly unpredictable, and therapeutic efficacy remains variable, which often prompts patients to seek alternative therapies. Plum-blossom needling has been widely used for thousands of years. The purpose of this meta-analysis was to critically evaluate the add-on effect of plum-blossom needling in AA and compared it with that of conventional treatment, which would provide guidance for AA therapy. METHODS: We searched PubMed, Embase, Chinese National Knowledge Infrastructure (CNKI), and WanFang database. We included randomized controlled trials that evaluated the add-on effect of plum-blossom needling treatment compared with conventional treatment alone group for AA. The risk of bias was assessed using the Cochrane Handbook for Systematic Reviews of Interventions. We also evaluated the relative risk (RR) and confidence interval (CIs) of response rate (any regrowth, major regrowth, and complete regrowth) between the plum-blossom needling add-on and the conventional control groups. RESULTS: Finally, eleven articles involving 1,192 patients were included in this meta-analysis (632 cases in the plum-blossom needling combination group and 560 in the conventional control group). The quality of these studies was medium or relatively low. The application of plum-blossom needling add-on therapy had consistent beneficial effects in any regrowth (RR 1.220; 95% CI: 1.108-1.343; P<0.01; Q=48.388, I2=79.334%), major regrowth (RR 1.403; 95% CI: 1.180-1.668; P<0.01; Q=68.359, I2=85.371%), and complete regrowth (RR 1.331; 95% CI: 1.104-1.606; P<0.01; Q=31.968, I2=68.718%). Subgroup analysis showed that plum-blossom needling add-on effect remained significant when topical treatment was used. Plum-blossom needling add-on therapy was generally well-tolerated, with no significantly increased risk of Adverse Events (RR 1.391; 95% CI: 0.475-4.073; P<0.01; Q=1.366, I2=0%). CONCLUSIONS: Our meta-analysis showed that the combinations of plum-blossom needling provided moderate positive add-one effects in AA patients. Further well-designed research is required to evaluate the optimal plum-blossom needling treatment procedure.

Efficacy of scopolamine plus propofol in the treatment of recalcitrant psoriasis: A pilot study.

Accumulating evidence suggests that botulinum neurotoxins (BoNTs), which inhibit acetylcholine release, can be used for treating plaque psoriasis. The therapeutic effects of scopolamine occur through antagonism of central muscarinic acetylcholine receptors. Thus, scopolamine has potential for the treatment of psoriasis. We aimed to evaluate the efficacy and safety of scopolamine plus propofol for the treatment of recalcitrant psoriasis. Twelve patients with recalcitrant psoriasis were enrolled. Patients received intravenous injection of scopolamine plus propofol for 5 consecutive days per month for a total of 3 months. Clinical efficacy was evaluated using a Psoriasis Area and Severity Index (PASI) score. Efficacy outcome was ≥75% reduction in PASI score (PASI75) from baseline. Two patients were lost to follow-up. At week 8, two of 10 patients (20%) achieved PASI75, and at week 12, seven of 10 (70%) achieved PASI75. Treatment was well tolerated, with no reported adverse events. Our study revealed the efficacy and safety of scopolamine plus propofol for the treatment of recalcitrant psoriasis. Scopolamine plus propofol therapy may be a new treatment for recalcitrant psoriasis.

Characterization and Comparison of Genetic Variation in Clinical Varicella-Zoster Virus Isolates Collected from Shanghai and Urumqi, China.

Varicella-zoster virus (VZV) is a ubiquitous human herpesvirus that causes chickenpox and zoster. Considering that VZV is a relatively and genetically stable virus, its global surveillance clades provide essential information for VZV evolution, immigration, and importation of different viral strains and recombination events. Eighty-eight VZV isolates from China (Shanghai and Urumqi) were genotyped using a scattered single-nucleotide polymorphism method in this prospective study. Our results were based on sequencing the open reading frames 1, 6, 12, 16, 17, 21, 22, 35, 37, 38, 50, 54, 55, 56, 60, and 66. We found that the majority of these 88 strains (81.8%) belonged to Clade 2 with significantly high homogeneity from Shanghai. However, in the Urumqi area, some strains were grouped to Clade 5, and some could not be attributed to any of the established VZV clades, although the majority of Urumqi strains belonged to Clade 2. Our results illustrated that due to geographical location, VZV could undergo genetic recombination, suggesting that VZV diversity is more complicated in certain areas and geographical separation contributes to VZV complexity.

Activation of Different Heterodimers of TLR2 Distinctly Mediates Pain and Itch.

Toll-like receptors (TLRs) have been implicated in pain and itch regulation. TLR2, a TLR family member that detects microbial membrane components, has been implicated in pathologic pain. However, the role of TLR2 in pruritic and nociceptive responses has not been thoroughly investigated. In this study, we found that TLR2 was expressed in mouse dorsal root ganglia (DRG) and trigeminal ganglia (TG) neurons. Itch and pain behaviors, including histamine-dependent and histamine-independent acute itching, acetone/diethyl ether/water and 2,4-dinitrofluorobenzene-induced chronic itching and inflammatory pain, were largely attenuated in TLR2 knockout (KO) mice. The TLR2 agonist Pam3CSK4, which targets TLR2/1 heterodimers, evoked pain and itch behavior, whereas lipoteichoic acid (LTA) and zymosan, which recognize TLR2/6 heterodimers, produced only pain response. The TLR2 agonist-induced nociceptive and pruritic behaviors were largely diminished in transient receptor potential vanilloid 1 (TRPV1) and transient receptor potential ankyrin 1 (TRPA1) KO mice. Finally, Pam3Csk4 and zymosan increased the [Ca2+]i in DRG neurons from wild-type mice. However, the enhancement of [Ca2+]i was largely inhibited in the DRG neurons from TRPV1 and TRPA1 KO mice. Our results demonstrate that TLR2 is involved in different itch and pain behaviors through activating TLR1/TLR2 or TLR6/TLR2 heterodimers via TRPV1 and TRPA1 channels.

DDX5 Silencing Suppresses the Migration of Basal cell Carcinoma Cells by Downregulating JAK2/STAT3 Pathway.

Basal cell carcinoma is driven by the aberrant activation of hedgehog signaling. DEAD (Asp-Glu-Ala-Asp) box protein 5 is frequently overexpressed in human cancer cells and associated with the tumor growth and invasion. The purpose of this study was to investigate the role of DEAD (Asp-Glu-Ala-Asp) box protein 5 in the growth, migration, and invasion of basal cell carcinoma. The role of DEAD (Asp-Glu-Ala-Asp) box protein 5 was detected by quantitative real-time polymerase chain reaction, Western blot, and terminal deoxynucleotidyl transferase-mediated deoxyuridine triphosphate nick-end labeling assay in basal cell carcinoma cells. The associations between JAK2/STAT3 pathway and DEAD (Asp-Glu-Ala-Asp) box protein 5 were analyzed in basal cell carcinoma cells. Results showed that DEAD (Asp-Glu-Ala-Asp) box protein 5 is overexpressed in basal cell carcinoma cells. DEAD (Asp-Glu-Ala-Asp) box protein 5 knockdown inhibited the migration and invasion of basal cell carcinoma cells. DEAD (Asp-Glu-Ala-Asp) box protein 5 knockdown increased the apoptosis of basal cell carcinoma cells induced by tunicamycin. Results found that DEAD (Asp-Glu-Ala-Asp) box protein 5 knockdown increased JAK2 and STAT3 expression in basal cell carcinoma cells. JAK2 inhibitor decreased STAT3 expression and abolished the inhibitory effects of DEAD (Asp-Glu-Ala-Asp) box protein 5 silencing on migration and invasion in basal cell carcinoma cells. In conclusion, these results indicate that DEAD (Asp-Glu-Ala-Asp) box protein 5 is a potential target for inhibiting basal cell carcinoma cells growth, migration, and invasion by downregulating JAK2/STAT3 pathway.

Efficacy and Safety of Fire Needle Therapy for Nodular Prurigo: A Quantitative Study.

In this quantitative study, we evaluated the effectiveness and safety of fire needle therapy for nodular prurigo. We systematically searched several databases, including EMBASE, PubMed, the Cochrane Library, the Web of Science, the China Network Knowledge Infrastructure, the Wanfang Data Knowledge Service Platform, and the China Science and Technology Journal Database, and retrieved randomized controlled trials comparing conventional therapies (control group) with fire needle therapy alone or in combination with conventional therapies. Revman 5.2 software was used to calculate risk ratios (RR) with 95% confidence intervals (CI). In total, 14 trials with 1176 participants were included. Our quantitative study showed that the effectiveness rate of fire needle therapy combined with conventional therapies was significantly higher than that of conventional therapies alone (fire needle + traditional Chinese medicine [TCM] vs. TCM: RR, 1.11; 95% CI, 1.04 to 1.18; fire needle + oral thalidomide + topical glucocorticoid [TGC] vs. thalidomide + TGC: RR, 1.41; 95% CI, 1.17 to 1.70; fire needle + TGC vs. TGC only: RR, 1.18; 95% CI, 1.07 to 1.31). Similar results were obtained for the Symptom Score Reducing Index (fire needle + TCM vs. TCM: mean difference [MD], -3.39; 95% CI: -5.39 to -1.39), visual analog scale scores for itching severity (fire needle vs. halometasone cream: MD, -0.93; 95% CI, -1.29 to -0.58; fire needle + TCM vs. TCM: MD, -1.18; 95% CI, -1.78 to -0.58), and Dermatology Life Quality Index (fire needle vs. halometasone cream: MD, -3.03; 95% CI, -3.43 to -2.63; fire needle + TCM vs. TCM: MD, -2.53; 95% CI, -3.12 to -1.94). Adverse event and recurrence rates were comparable between groups. Thus, fire needle therapy alone or combined with conventional treatments may be effective for nodular prurigo, without any additional side effects.

The In-Situ Synthesis of a 3D SnS/N-Doped Graphene Composite with Enhanced Electrochemical Performance as a Low-Cost Anode Material in Sodium Ion Batteries.

SnS/N-doped graphene (SnS/NG) composites are promising anode materials for sodium ion batteries. Generally, SnS is synthesized from SnCl2·2H2O. However, SnCl2·2H2O is not suitable for large-scale production due to its high price. Compared with SnCl2·2H2O, SnCl4·5H2O has a lower price, more stable chemical properties and better water solubility. Until now, there have been no related reports on the synthesis of SnS from SnCl4·5H2O. In this work, the fabrication of SnS/NG in a facile, two-step process, which combines a hot water bath and thermal annealing and uses SnCl4·5H2O as a precursor, is described. The mechanism of phase transformation in the direct synthesis of SnS from Sn4+ is also discussed in detail. Applying our methodology, SnS nanoparticles were grown in-situ on graphene sheets and wrapped by N-doped graphene sheets to form a 3D SnS/NG composite. With 35.35% content of graphene in the SnS/NG composite, the reversible specific capacity remained at 417.8 mAh/g at 1000 mA/g after 100 cycles, exhibiting a high specific capacity and good cycling stability. In addition, the composite also had an excellent rate performance, with a specific capacity of 366.9 mAh/g obtained even at 5000 mA/g. Meanwhile, the fast sodium storage kinetics of SnS/NG were also analyzed, providing some theoretical support for further study.

Klotho Protein Protects Human Keratinocytes from UVB-Induced Damage Possibly by Reducing Expression and Nuclear Translocation of NF-κB.

BACKGROUND UV-related skin disease such as actinic keratosis is a major concern in public health. In view of the cell injury induced by UVB, Klotho protein it is an ideal therapy to eliminate UVB-induced cell damages and the associated signaling pathways. MATERIAL AND METHODS To gain insights into the potential role of Klotho and the underlying molecular mechanism, we constructed a Klotho-overexpress HaCaT cell line and assessed the protection against UVB insults. The effects of exposure to UVB radiation on the human keratinocyte HaCaT cells, including cell growth, apoptosis, and changes of selected biomarkers, were measured by CCK-8, flow cytometry, Quantitative real-time PCR, and Western blot analysis. RESULTS We found that enhanced NF-κB activity was accompanied by decreased expression of the anti-aging protein Klotho upon UVB stimulation, which was further confirmed with in vivo experiments. Overexpression of Klotho was able to considerably alleviate the UVB-induced damages to cells and reversed the UVB-caused biomarker changes to a great extent, which was comparable to the effects of administration of NF-κB inhibitor PDTC, suggesting the inhibition of nuclear translocation and DNA-binding activity of NF-κB. Furthermore, Klotho overexpression was proved to decrease the nuclear expression of NF-κB as much as the treatment with PDTC, which provides support for the direct regulation of NF-κB by Klotho. CONCLUSIONS Collectively, our work provides new insight into the potential role of Klotho in the context of UVB-induced injuries in human keratinocytes, as well as providing the basis for future study of new therapies against UV-related skin disease.

Small molecule inhibitors reveal allosteric regulation of USP14 via steric blockade.

The ubiquitin system is important for drug discovery, and the discovery of selective small-molecule inhibitors of deubiquitinating enzymes (DUBs) remains an active yet extremely challenging task. With a few exceptions, previously developed inhibitors have been found to bind the evolutionarily conserved catalytic centers of DUBs, resulting in poor selectivity. The small molecule IU1 was the first-ever specific inhibitor identified and exhibited surprisingly excellent selectivity for USP14 over other DUBs. However, the molecular mechanism for this selectivity was elusive. Herein, we report the high-resolution co-crystal structures of the catalytic domain of USP14 bound to IU1 and three IU1 derivatives. All the structures of these complexes indicate that IU1 and its analogs bind to a previously unknown steric binding site in USP14, thus blocking the access of the C-terminus of ubiquitin to the active site of USP14 and abrogating USP14 activity. Importantly, this steric site in USP14 is very unique, as suggested by structural alignments of USP14 with several known DUB X-ray structures. These results, in conjunction with biochemical characterization, indicate a coherent steric blockade mechanism for USP14 inhibition by compounds of the IU series. In light of the recent report of steric blockade of USP7 by FT671, this work suggests a potential generally applicable allosteric mechanism for the regulation of DUBs via steric blockade, as showcased by our discovery of IU1-248 which is 10-fold more potent than IU1.

Risk factors and negative consequences of patient's delay for penile carcinoma.

BACKGROUND: Delayed first medical consultation (patient's delay) is quite common in cases of penile carcinoma (PC), but its reasons and impacts remain unclear. We conducted this study to ascertain risk factors resulting in delayed treatment seeking and evaluate its influence on prognosis. METHODS: From 2004 to 2010 at 4 centers, 254 patients were enrolled into this study from 262 consecutive PC cases. Patients' sexual performance was investigated using the International Index of Erectile Function (IIEF)-15 at the sixth-month end after treatment. Data for prognostic analyses was obtained via a 5-year follow-up. RESULTS: A multivariate model ascertained 4 risk factors (single, living in rural areas, heavy drinking alcohol, and aspecific initial symptoms) and 1 protective factor (history of condyloma) significantly associated with patient's delay. Delay >3 months led to significant risks for adverse clinical characteristics, low penis-sparing rate, and poor sexual function restoration. Although patient's delay was not found to impact on postoperative relapses and 5-year overall survival (OS), patients with delay >6 months had significantly inferior 2-year OS. CONCLUSIONS: Single, living in rural areas, heavy drinking alcohol, and aspecific initial symptoms are significant risk factors of PC associated with patient's delay. Delay >3 months will lead to significantly inferior clinical consequences. Minimizing patient's delay is the key to avoid amputation and retain superior sexual potency. Improving patient education on initial symptoms of PC is necessary in men of >40 years old.

Benzo(a)pyrene induces interleukin (IL)-6 production and reduces lipid synthesis in human SZ95 sebocytes via the aryl hydrocarbon receptor signaling pathway.

In this study, we determined the effects of benzo(a)pyrene (BaP) on the expression of aryl hydrocarbon receptor (AhR) and cytochrome P450 1A1 (CYP1A1), and assessed the action of BaP on inflammatory cytokine expression and lipid synthesis in SZ95 sebocytes in vitro. BaP (10(-8), 10(-7), 10(-6) and 10(-5)M) was not cytotoxic for SZ95 sebocytes after 24h exposure. Expression of AhR was promoted in mRNA lever, while was inhibited in protein lever after BaP (10(-5)M) exposure. CYP1A1 expression was up-regulated in both mRNA and protein levels. BaP (10(-5)M) exerted a stimulatory action on interleukin (IL)-6 secretion, while a dose-dependently inhibitory effect on lipid synthesis from 10(-8)M to 10(-5)M in SZ95 sebocytes. Both actions were partly antagonized in AhR-knockdowned SZ95 sebocytes. This study demonstrates that BaP can activate AhR signaling pathway, and exhibits pro-inflammatory effects and inhibitory effects on sebum production in human sebocytes.