Uveal melanoma (UM) is the most common primary malignant intraocular tumor in adults. Although primary UM can be effectively controlled, a significant proportion of cases (40% or more) eventually ...develop distant metastases, commonly in the liver. Metastatic UM remains a lethal disease with limited treatment options. The initiation of UM is typically attributed to activating mutations in GNAQ or GNA11. The elucidation of the downstream pathways such as PKC/MAPK, PI3K/AKT/mTOR, and Hippo‐YAP have provided potential therapeutic targets. Concurrent mutations in BRCA1 associated protein 1 (BAP1) or splicing factor 3b subunit 1 (SF3B1) are considered crucial for the acquisition of malignant potential. Furthermore, in preclinical studies, actionable targets associated with BAP1 loss or oncogenic mutant SF3B1 have been identified, offering promising avenues for UM treatment. This review aims to summarize the emerging targeted and epigenetic therapeutic strategies for metastatic UM carrying specific driver mutations and the potential of combining these approaches with immunotherapy, with particular focus on those in upcoming or ongoing clinical trials.
In this review, we provide an overview of the emerging targeted and epigenetic therapeutic strategies for metastatic uveal melanoma harbouring specific driver mutations, which include GNAQ/11, BAP1 and SF3B1. Furthermore, we highlight the upcoming or ongoing clinical trials regarding these therapeutic strategies.
Uveal melanoma (UM) is the most common intraocular cancer in adults. UMs are usually initiated by a mutation in GNAQ or GNA11 (encoding Gq or G11, respectively), unlike cutaneous melanomas (CMs), ...which usually carry a BRAF or NRAS mutation. Currently, there are no clinically effective targeted therapies for UM carrying Gq/11 mutations. Here, we identified a causal link between Gq activating mutations and hypersensitivity to bromodomain and extra-terminal (BET) inhibitors. BET inhibitors transcriptionally repress YAP via BRD4 regardless of Gq mutation status, independently of Hippo core components LATS1/2. In contrast, YAP/TAZ downregulation reduces BRD4 transcription exclusively in Gq-mutant cells and LATS1/2 double knockout cells, both of which are featured by constitutively active YAP/TAZ. The transcriptional interdependency between BRD4 and YAP identified in Gq-mutated cells is responsible for the preferential inhibitory effect of BET inhibitors on the growth and dissemination of Gq-mutated UM cells compared to BRAF-mutated CM cells in both culture cells and animal models. Our findings suggest BRD4 as a viable therapeutic target for Gq-driven UMs that are addicted to unrestrained YAP function.
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To observe the therapeutic effect of parthenolide (PTL) on rabbit knee arthritis (KOA) and its effects on serum expression of interleukin-1beta (IL-1beta) and contents of tumor necrosis factor-alpha ...(TNF-alpha).
Eight rabbits were randomly selected from 40 healthy pure-bred New Zealand rabbits as the normal control group. The KOA model was established in the rest 32 rabbits by plaster cast fixation of the right hind limb extension position. After modeling they were randomly divided into 4 groups, i.e., the model control group, the high dose PTL group, the middle dose PTL group, and the low dose PTL group, 8 in each group. Serum contents of IL-1beta and TNF-alpha were detected using enzyme-linked immunosorbent assay.
Compared with the model group, IL-1beta and TNF-alpha concentration decreased in the 3 PTL groups (P < 0.01). The decrement was positively correlated with PTL concentrations (IL-1beta: r = 0.55, P < 0.01; TNF-alpha: r = 0.56, P < 0.01). The inhibition reached the peak when the PTL concentration ar
To investigate the mechanisms of cyclophosphamide sequential therapy for patients with primary Sjögren's syndrome-associated interstitial lung disease (PSS-ILD).
This was a retrospective review of 15 ...patients (2005 - 2008) with PSS-ILD who underwent cyclophosphamide sequential therapy. Peripheral blood and bronchoalveolar lavage (BALF) were obtain before and 3, 6, 12, 24 months after the treatment. The TNF-α and TGF-β(1)mRNA levels in peripheral blood were measured using reverse transcription-polymerase chain reaction (RT-PCR). Serum and BALF TNF-α, TGF-β(1)and MMP-9 levels were measured using sandwich enzyme-linked immunosorbent assay (ELISA).
(1) The average levels of serum TNF-α (0.39 ± 0.22) and TGF-β(1) (0.31 ± 0.18) mRNA in patients with PSS-ILD were higher compared with that in patients with PSS without ILD. TNF-α level (0.23 ± 0.19) was significantly decreased 3 months after cyclophosphamide treatment (t = 2.533, P < 0.05), and TGF-β(1) (0.31 ± 0.18) level markedly decreased after 6 months of treatmen
Background：Human immunodeficiency virus （HIV） is spreading rapidly among men who have sex with men （MSM） in China.Anonymous questionnaires or direct interviews have been frequently used to study ...their behavior.The aim of the study was to describe the behavioral risk profile of the MSM in Beijing using the randomized response techniques （RRTs）.Methods：A cross-sectional survey of sexual behavior among a sample of MSM was conducted in two HIV counseling and testing clinics in Beijing.The survey was carried out with an anonymous questionnaire containing sensitive questions on sexual behavior.To obtain the honest responses to the sensitive questions,three distinctive RRTs were used in the questionnaire：（1） Additive randomized response model for quantitative questions,（2） randomized response model for multiple choice questions,and （3） Simmons randomized response model for binomial questions.Formulae for the point estimate,variance,and confidence interval （CI） were provided for each specific model.Results：Using RRTs in a sample of 659 participants,the mean age at first homosexual encounter was estimated to be 21.7 years （95% CI：21.2-22.2）,and each had sex with about three （2.9,95% CI：2.4-3.4） male partners on average in the past month.The estimated rate for consistent condom use was 56.4% （95% CI：50.1-62.8%）.In addition,condom was estimated to be used among 80.0% （95% CI：74.1-85.9%） of the population during last anal sex with a male partner.Conclusions：Our study employed RRTs in a survey containing questions on sexual behavior among MSM,and the results showed that RRT might be a useful tool to obtain truthful feedback on sensitive information such as sexual behavior from the respondents,especially in traditional Chinese cultural settings.
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•Extracts of Dioscorea septemloba were characterized.•The extracts acted as mixed-type corrosion inhibitors•Surface analysis confirmed the presence of the extracts on the metal ...surface.•The adsorption properties were discussed by computational studies.
The adsorption and corrosion inhibition performance of the water phase and organic phase extracts from Dioscorea septemloba on carbon steel have been carried out in 1 M HCl solutions. Extracts characterization was accomplished by NMR spectroscopy and the generic carbohydrate test. Electrochemical techniques and gravimetry were utilized for the evaluation of corrosion inhibition behaviors. 3D surface measurement instrument, SEM, and FT-IR were used to examine the surface properties of carbon steel coupons after full immersion in 1 M HCl solutions without and with the extracts. Quantum chemical calculation (QCC) and molecular dynamics simulation (MDS) were used to predict and describe the electronic and adsorption properties of some characterized compounds in the extracts. Both extracts exhibited similar corrosion inhibition behaviors acting as mixed-type inhibitors and having their efficiencies dependent on concentration and temperature. Time-dependent corrosion evaluation showed that the inhibition efficiencies of the extracts were improved with time. Low surface roughness data were recorded for the extracts by 3D surface measurements and the results were consistent with the observations from SEM micrographs and FT-IR spectra. Computational parameters obtained from QCC and MDS were used to predict the adsorption behavior of some characterized compounds from the extracts.
Neuropathic pain is among the most debilitating forms of chronic pain. Studies have suggested that chronic pain pathogenesis involves neuroimmune interactions and blood-spinal cord barrier (BSCB) ...disruption. However, the underlying mechanisms are poorly understood. We modeled neuropathic pain in rats by inducing chronic constriction injury (CCI) of the sciatic nerve and analyzed the effects on C-X-C motif chemokine 10 (CXCL10)/CXCR3 activation, BSCB permeability, and immune cell migration from the circulation into the spinal cord. We detected CXCR3 expression in spinal neurons and observed that CCI induced CXCL10/CXCR3 activation, BSCB disruption, and mechanical hyperalgesia. CCI-induced BSCB disruption enabled circulating T cells to migrate into the spinal parenchyma. Intrathecal administration of an anti-CXCL10 antibody not only attenuated CCI-induced hyperalgesia, but also reduced BSCB permeability, suggesting that CXCL10 acts as a key regulator of BSCB integrity. Moreover, T cell migration may play a critical role in the neuroimmune interactions involved in the pathogenesis of CCI-induced neuropathic pain. Our results highlight CXCL10 as a new potential drug target for the treatment of nerve injury-induced neuropathic pain.
Pollution of greenhouse soils and crops by heavy metals as a result of annual application of large amounts of pesticides and fertilizers is of great concerns. We investigated the effect of biochar ...(BC) as a potential immobilizing medium for cadmium (Cd) by assessing Cd bioavailability, fractions, and uptake of metals by lettuce plants in metal-contaminated greenhouse soils. Experiments were conducted in two typical vegetable greenhouses displaying different levels of heavy metal pollution (GH1, lightly heavy-metal-polluted greenhouse; GH2, heavily heavy-metal-polluted greenhouse), in Wuhan City suburbs, Hubei Province, China. For each greenhouse site three replicates of each of three levels of BC (B0, 0tha−1; B10, 10tha−1; B20, 20tha−1) were arranged in a randomized complete block design. The application of BC increased soil pH and soil organic matter and changed Cd fractions in the soil. The exchangeable Cd fraction decreased and there was an increase in the oxide- and organic-bound and residual fractions with the application of BC, implying that BC application could immobilize the Cd in greenhouse soil. The rates of Cd immobilization in soil increased with the amount of BC applied. The exchangeable Cd fractions in soils amended with B10 decreased by 45–62% and in soils amended with B20 by 66–89% compared to the control. The addition of BC reduced the concentration of Cd in lettuce shoots in the lightly heavy-metal-polluted soils, but in the heavily heavy-metal-contaminated soils it had either no effect, or promoted Cd absorption by lettuce shoots. Total Cd measured in lettuce tissues did not decrease with the addition of BC when compared to the control, as there was increased accumulations of lettuce biomass with biochar application.
Biochar, a cost-effective amendment, has been reported to play pivotal roles in improving soil fertility and immobilizing soil pollutants due to its well-developed porous structure and tunable ...functionality. However, the properties of biochar and soils can vary inconsistently after field application. This may affect the remediation of biochar on heavy metal (HM)-contaminated soil being altered. Therefore, we selected lettuce as a model crop to determine the effects of short-term, long-term, and reapplication of biochar on soil physicochemical properties, microbial community, HM bioavailability, and plant toxicity. Our investigation revealed that the long-term application of biochar remarkably improved soil fertility, increased the relative abundance of the phylum Proteobacteria which was highly resistant to HMs, and reduced the abundance of phylum Acidobacteria. These changes in soil properties decreased the accumulation of Cd and Pb in lettuce tissues. The short- and long-term applications of biochar had no substantial effects on biomass, quality, and photosynthesis of lettuce. Moreover, the short-term and reapplication of biochar had no significant effects on soil bacterial communities but decreased the accumulation of Cd and Pb in lettuce tissues. It showed that the changes in the physical, chemical, and biological properties of soil after long-term application of biochar promoted the remediation of HM-contaminated soil. Furthermore, microbial community compositions varied with metal stress and biochar application, while the relative abundance of the phylum Actinobacteria in HM-contaminated soil with long-term biochar application was markedly higher than in HM-contaminated soil without biochar application.
•Different biochar application had different remediation effects on the soil.•Long-term application of biochar can change the microbial community composition of the soil.•Long-term and reapplication of biochar can effectively decrease the bioaccumulation of HMs in soil.•Long-term and reapplication of biochar decrease the accumulation of HMs in lettuce.•Biochar application had no effects on photosynthesis and chlorophyll fluorescence parameters of lettuce.
Composite-polymer-electrolytes (CPEs) embedded with advanced filler materials offer great promise for fast and preferential Li
conduction. The filler surface chemistry determines the interaction with ...electrolyte molecules and thus critically regulates the Li
behaviors at the interfaces. Herein, we probe into the role of electrolyte/filler interfaces (EFI) in CPEs and promote Li
conduction by introducing an unsaturated coordination Prussian blue analog (UCPBA) filler. Combining scanning transmission X-ray microscope stack imaging studies and first-principle calculations, fast Li
conduction is revealed only achievable at a chemically stable EFI, which can be established by the unsaturated Co-O coordination in UCPBA to circumvent the side reactions. Moreover, the as-exposed Lewis-acid metal centers in UCPBA efficiently attract the Lewis-base anions of Li salts, which facilitates the Li
disassociation and enhances its transference number (t
). Attributed to these superiorities, the obtained CPEs realize high room-temperature ionic conductivity up to 0.36 mS cm
and t
of 0.6, enabling an excellent cyclability of lithium metal electrodes over 4,000 h as well as remarkable capacity retention of 97.6% over 180 cycles at 0.5 C for solid-state lithium-sulfur batteries. This work highlights the crucial role of EFI chemistry in developing highly conductive CPEs and high-performance solid-state batteries.
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