Emerging therapeutic strategies for metastatic uveal melanoma: Targeting driver mutations.

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.

Reciprocal positive regulation between BRD4 and YAP in GNAQ-mutant uveal melanoma cells confers sensitivity to BET inhibitors.

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.

Development of γ-Al2O3 with oxygen vacancies induced by amorphous structures for photocatalytic reduction of CO2.

Inducing amorphous components into Al2O3 leads to elongation of the Al-O bond and the formation of oxygen vacancies, which makes Al2O3 an independent photocatalyst for CO2 adsorption and reduction. The generation rate of CO can reach 36.5 µmol g-1 h-1, which is 6.5 times that of P25 TiO2.

PTEN loss confers sensitivity to rapalogs in clear cell renal cell carcinoma.

Rapalogs (everolimus and temsirolimus) are allosteric mTORC1 inhibitors and approved agents for advanced clear cell renal cell carcinoma (ccRCC), although only a subset of patients derive clinical benefit. Progress in genomic characterization has made it possible to generate comprehensive profiles of genetic alterations in ccRCC; however, the correlations between recurrent somatic mutations and rapalog efficacy remain unclear. Here, we demonstrate by using multiple patient-derived ccRCC cell lines that compared to PTEN-proficient cells, PTEN-deficient cells exhibit hypersensitivity to rapalogs. Rapalogs inhibit cell proliferation by inducing G0/G1 arrest without inducing apoptosis in PTEN-deficient ccRCC cell lines. Using isogenic cell lines generated by CRISPR/Cas9, we validate the correlation between PTEN loss and rapalog hypersensitivity. In contrast, deletion of VHL or chromatin-modifying genes (PBRM1, SETD2, BAP1, or KDM5C) fails to influence the cellular response to rapalogs. Our mechanistic study shows that ectopic expression of an activating mTOR mutant (C1483F) antagonizes PTEN-induced cell growth inhibition, while introduction of a resistant mTOR mutant (A2034V) enables PTEN-deficient ccRCC cells to escape the growth inhibitory effect of rapalogs, suggesting that PTEN loss generates vulnerability to mTOR inhibition. PTEN-deficient ccRCC cells are more sensitive to the inhibitory effects of temsirolimus on cell migration and tumor growth in zebrafish and xenograft mice, respectively. Of note, PTEN protein loss as detected by immunohistochemistry is much more frequent than mutations in the PTEN gene in ccRCC patients. Our study suggests that PTEN loss correlates with rapalog sensitivity and could be used as a marker for ccRCC patient selection for rapalog therapy.

BAP1 loss augments sensitivity to BET inhibitors in cancer cells.

The tumor suppressor gene BAP1 encodes a widely expressed deubiquitinase for histone H2A. Both hereditary and acquired mutations are associated with multiple cancer types, including cutaneous melanoma (CM), uveal melanoma (UM), and clear cell renal cell carcinoma (ccRCC). However, there is no personalized therapy for BAP1-mutant cancers. Here, we describe an epigenetic drug library screening to identify small molecules that exert selective cytotoxicity against BAP1 knockout CM cells over their isogenic parental cells. Hit characterization reveals that BAP1 loss renders cells more vulnerable to bromodomain and extraterminal (BET) inhibitor-induced transcriptional alterations, G1/G0 cell cycle arrest and apoptosis. The association of BAP1 loss with sensitivity to BET inhibitors is observed in multiple BAP1-deficient cancer cell lines generated by gene editing or derived from patient tumors as well as immunodeficient xenograft and immunocompetent allograft murine models. We demonstrate that BAP1 deubiquitinase activity reduces sensitivity to BET inhibitors. Concordantly, ectopic expression of RING1A or RING1B (H2AK119 E3 ubiquitin ligases) enhances sensitivity to BET inhibitors. The mechanistic study shows that the BET inhibitor OTX015 exerts a more potent suppressive effect on the transcription of various proliferation-related genes, especially MYC, in BAP1 knockout cells than in their isogenic parental cells, primarily by targeting BRD4. Furthermore, ectopic expression of Myc rescues the BET inhibitor-sensitizing effect induced by BAP1 loss. Our study reveals new approaches to specifically suppress BAP1-deficient cancers, including CM, UM, and ccRCC.

Terahertz magneto-optical response of bismuth-gadolinium-substituted rare-earth garnet film.

We report the magneto-optical Faraday response of bismuth-gadolinium-substituted rare-earth iron garnet at terahertz frequencies ranging from 100 GHz to 1.2 THz. The maximum transmittance of ±45° component is about 60% near the frequency point of 0.63 THz. When the external magnetic field change from -100 mT to +100 mT, the Faraday rotation angle is between -6° and +7.5°. The overall change of ellipticity is relatively small. The maximum value of the Verdet constant is about 260 °/mm/T at 0.1 THz and then gradually decreases to 80 °/mm/T at 1.2 THz. Within the considered frequency range, the thick film exhibits magnetically tunable, non-reciprocal characters and a strong magneto-optical effect within a small external magnetic field at room temperature, which will be widely used for the terahertz isolators, circulators, nonreciprocal phase shifters, and magneto-optical modulators.

Reverse construction of dominant/secondary facets in Bi24O31Br10 photocatalysts for boosting electronic transfer.

In this paper, it is found that the preferential growth of secondary {117} facets of Bi24O31Br10 into dominant facets would lead to higher photocatalytic activity, although the original main {213} facet has a stronger molecular oxygen adsorption ability, which illustrates that the charge separation efficiency induced by dominant/secondary facet control plays a more important role than that of O2 adsorptive performance in improving activity.

The simultaneous adsorption, activation and in situ reduction of carbon dioxide over Au-loading BiOCl with rich oxygen vacancies.

The main process of carbon dioxide (CO2) photoreduction is that excited electrons are transported to surface active sites to reduce adsorbed CO2 molecules. Obviously, electron transfer to the active site is one of the key steps in this process. However, current catalysts for CO2 adsorption, activation, and electron reduction occur in different locations, which greatly reduce the efficiency of photocatalysis. Herein, through a spontaneous chemical redox approach, the plasmonic photocatalysts of Au-BiOCl-OV with enhanced interfacial interaction were fabricated for visible light CO2 reduction through the simultaneous adsorption, activation and in situ reduction of CO2 without a sacrificial agent. By loading gold (Au) on the oxygen vacancy (OV), Au and BiOCl-OV formed a direct and tight interface contact, whose fine structure was confirmed by SEM, TEM, EPR and XPS, which not only effectively boosts the light utilization efficiency and the light carrier separation ability, but also can simultaneously adsorb, activate and in situ reduce carbon dioxide for highly efficient visible light photocatalysis. Thanks to the synergistic influence of Au and OV, Au-BiOCl-OV exhibits excellent photocatalytic performance without sacrificial agent and outstanding stability with a high CO and CH4 production yield, reaching 4.85 µmol g-1 h-1, which were 2.8 times higher than C-Au-BiOCl-OV (obtained by traditional NaBH4 reduction). This study proposes a new strategy for the production of high-performance collaborative catalysis in photocatalytic CO2 reduction.

Terahertz magneto-optical effect of wafer-scale La: yttrium iron garnet single-crystal film with low loss and high permittivity.

The wafer-scale La:YIG single crystal thick films were fabricated on a three-inch gadolinium gallium garnet (GGG) substrate by liquid phase epitaxy method. The terahertz (THz) optical and magneto-optical properties of La:YIG film were demonstrated by THz time domain spectroscopy (THz-TDS). The results show that a high refractive index of approximately 4.09 and a low absorption coefficient of 10-50 cm-1 from 0.1 to 1.6 THz for this La:YIG film. Moreover, the THz Faraday rotation effect of La:YIG film was measured by the orthogonal polarization detection method in THz-TDS system, which can be actively manipulated by a weak longitudinal magnetic field of up to 0.155 T. With 5 samples stacked together, the Faraday rotation angle varies linearly from -15° to 15°, and the Verdet constant of La:YIG is about 100 °/mm/T within the saturation magnetization. This magneto-optical single crystal thick film with large area shows low loss, high permittivity and strong magneto-optical effect in the THz regime, which will be widely used in magneto-optical polarization conversion, nonreciprocal phase shifter and isolator for THz waves.

Alterations of intestinal flora and the effects of probiotics in children with recurrent respiratory tract infection.

BACKGROUND: Recurrent respiratory tract infection (RRTI) is a disease occurred frequently in preschool children. METHODS: A total of 120 RRTI children were randomly divided into active group, remission group, intervention group and control group, meanwhile 30 healthy children were selected as the healthy group. Children in the intervention group were given oral Bifidobaeterium tetravaccine tablets (Live) for 2 months, while the control group received routine treatment. Stool sample were detected to analyze the bacterial strains. The occurrence of respiratory tract infection (RTI) was compared between different groups during 1 year follow-up. RESULTS: Compared with the healthy group, the number of Bifidobacteria and Lactobacilli in the active group, remission group, intervention group and control group was significantly decreased (P < 0.05). The number of Bifidobacteria and Lactobacilli in the intervention group was significantly higher compared to other RRTI groups (P < 0.05). During the follow-up period, the average annual frequency of different acute RTI and use of antibiotics were significantly reduced (P < 0.05), the average duration of cough, fever and use of antibiotics at each episode were also significantly shortened (P < 0.05) in the intervention group compared to the control group. CONCLUSIONS: Children with RRTI are susceptible to intestinal flora imbalance. Oral probiotics can effectively improve the RRTI intestinal microecological balance in children and reduce the frequency of RTI.

Susceptibility of epithelial tumour cell lines to hyperthermia.

BACKGROUND: Human skin or mucosa exposes cells to both an internal and exogeneous thermal environment and the cells survive within a certain range of temperature. Exogeneous hyperthermia has been applied for the treatment of various types of cancers, fungal disease, and warts. OBJECTIVES: To determine whether different cellular components in the skin adapt to hyperthermic conditions differentially and further elucidate the mechanisms involved. MATERIALS & METHODS: Cell lines derived from normal and tumour epithelial cells were treated with hyperthermic conditions and tested for viability (using an MTS assay), apoptosis (using a FITC-conjugated annexin V apoptosis detection kit), and changes in intracellular calcium (using a calcium-sensitive fluorescent single-wavelength dye, Fluo-4 AM). RESULTS: Thermo-resistance of different cell types was different when cells were subjected to heat at 45̊C for 30 minutes. Stronger effects of hyperthermia were noted on cell viability and apoptosis in epidermal cells relative to their malignant counterparts, except for cell lines harbouring human papillomavirus (HPV). Hyperthermia had a much greater effect on cell viability and apoptosis in a HPV-negative cell line compared to HPV-positive cell lines. We further found that hyperthermia treatment resulted in a strong calcium influx which led to apoptotic cells. However, no obvious increase in apoptosis was observed in cells treated with the CRAC channel selective inhibitor, BTP2, before application of hyperthermia in all cell types, except three cervical cell lines harbouring HPV. CONCLUSION: We propose that hyperthermia results in a CRAC-related strong calcium influx which induces apoptosis, with the exception of HPV-positive cells.

Screening and identification of differentially expressed serum proteins in patients with vitiligo using two­dimensional gel electrophoresis coupled with mass spectrometry.

In the clinic, vitiligo is characterized by two stages: Stable and progressive. The pathogenesis of vitiligo is still not clear. Here, we identified serum markers of vitiligo by screening for differentially expressed proteins in patients with vitiligo compared to healthy individuals. Serum samples were collected from patients with vitiligo (n=10 for both the stable and progressive stages) and healthy individuals (n=10). Two­dimensional gel electrophoresis followed by matrix­assisted laser desorption/ionization time­of­flight mass spectrometry and western blotting were used to validate the differential expression of the proteins in the serum (n=20 each, at both stages for patients and healthy individuals). A total of 48 differentially expressed proteins were identified by gel image analysis. There were 28 differentially expressed proteins in patients with progressive vitiligo (PV) and 13 differentially expressed proteins in patients with stable vitiligo (SV) compared with that in healthy individuals. Additionally, 7 differentially expressed proteins were identified in patients with PV compared with those in patients with SV. The western blotting results showed that Peroxiredoxin­6, apolipoprotein L1, apolipoprotein E and mannose­binding protein were differentially expressed in patients with different stages of vitiligo. Our results showed that change serum levels of several proteins might be useful as biomarkers or in understanding the pathogenesis of vitiligo.

One-step synthesis, electronic structure, and photocatalytic activity of earth-abundant visible-light-driven FeAl2O4.

The development of inexpensive visible-light-driven photocatalysts is an important prerequisite for realizing the industrial application of photocatalysis technology. In this paper, an earth-abundant FeAl2O4 photocatalyst is prepared via facile solution combustion synthesis. Density functional theory and the scanning Kelvin probe technique are employed to ascertain the positions of the energy bands and the Fermi level. Phenol is taken as a model pollutant to evaluate the photocatalytic activity of FeAl2O4. The scavenger experiment results, ˙OH-trapping fluorescence technique, and electron spin resonance measurements confirm that the superoxide anion radical is the main active species generated in the photocatalytic process, which also further corroborates the proposed electronic structure of FeAl2O4. The degradation experiments and O2 temperature programmed desorption results over various samples verify that the crystallinity degree is a more important factor than the oxygen adsorption ability in determining photocatalytic activity.

Infrared-induced adult colloid milium treated with fractionated CO2 laser.

Adult colloid milium is a rare cutaneous deposition disorder that frequently involves areas of chronic sun exposure. The most common clinical presentation exhibits multiple, firm, and amber-colored papules that cluster to form large plaques. Histologically, there are masses of amorphous, eosinophilic material expanding the papillary dermis, and at times extending into the mid-dermis, with adjacent solar elastosis. When this disorder affects the face, disfiguring is of great concern and treatment is often sought. Attempts to safely remove colloid milium are generally unsuccessful. Dermabrasion has been reported to be effective. The present authors present a case with extensive facial colloid milium successfully ablated by the fractionated CO2 laser.

Synthesis and biological evaluation of dehydroepiandrosterone-fused thiazole, imidazo[2,1-b]thiazole, pyridine steroidal analogues.

A series of steroidal[17,16-d]thiazole, steroidal[1,2-b]pyridine and steroidal[17,16-d]thiazole[2,1-b]imidazo products were synthesized through a convenient and productive method. Anti-proliferation activity against EC109 (human esophageal carcinoma), EC9706 (human esophageal carcinoma) and MGC-803 (human gastric carcinoma) cell lines was examined in vitro. Among the screened compounds, several highly potential compounds were located.

[Mechanism of E1A-mediated escape from ras-induced senescence in human fibraoblasts].

OBJECTIVE: To study the effect of binding activities of the NH(2) terminus of E1A to the proteins regulating cell growth on ras-induced cell senescence and explore the mechanism of E1A-mediated escape from ras-induced senescence by E1A in human fibroblast. METHODS: In primary human fibroblasts, the proteins regulating cell growth in association with E1A NH(2) terminus, including the Rb family proteins, p300/CBP, and p400, were inactivated or interfered. The effect of alterations in the binding activities of these proteins on cell senescence bypass mediated by E1A was evaluated by cell growth curve. RESULTS: The Inactivation of Rb family proteins alone was not sufficient to rescue ras-induced cell senescence, whereas inactivation of both the Rb proteins and p300/CBP blocked ras-induced senescence of human fibroblasts. CONCLUSION: Rb and p300/CBP binding activities are both required for E1A to bypass ras-induced senescence in human fibroblasts.

[Cisplatin induces drug resistance in human esophageal squamous carcinoma cell line EC109 by decreasing CTR1 protein expression].

OBJECTIVE: To investigate the mechanism of the development of cisplatin resistance in a human esophageal squamous carcinoma cell line. METHODS: The cytotoxicity of cisplatin in the cisplatin-resistant resistant cell line EC109/CDDP and its parental cell line EC109 was measured by MTT assay. Whole-cell cisplatin accumulation and Pt-DNA adduct formation were determined by inductively coupled plasma mass spectrometry (ICP-MS). Western blotting was used to investigate the protein expression of full length PARP, cleaved PARP, and copper transporter 1 (CTR1). RESULTS: EC109/CDDP cells was more resistant to cisplatin-induced cytotoxicity and apoptosis than EC109 cells. Compared with EC109 cells, EC109/CDDP cells exhibited less cisplatin accumulation and Pt-DNA adduct formation with also decreased CTR1 protein expression. CONCLUSION: Cisplatin induces drug resistant phenotype by decreasing the protein level of CTR1, which controls cell accumulation and cytotoxic effect of cisplatin.

Therapeutic effects of melatonin on heatstroke-induced multiple organ dysfunction syndrome in rats.

Melatonin reportedly exerts beneficial effects to attenuate multiple organ dysfunction syndrome (MODS) in septic shock. Heatstroke resembles septic shock in many aspects. Thus, this study was performed on the anesthetized rats by using heat exposure to induce heatstroke-associated MODS. We evaluated the effect of melatonin, a versatile molecule synthesized in the pineal gland and in many organs, in heatstroke rats and showed that melatonin (0.2-5.0 mg/kg of body weight, i.v., immediately after the start of heat stress) significantly (i) attenuated hyperthermia, hypotension and hypothalamic ischemia and hypoxia, (ii) reduced plasma index of the toxic oxidizing radicals like nitric oxide metabolites and hydroxyl radicals, (iii) diminished plasma index of hepatic and renal dysfunction like creatinine, blood urea nitrogen, alanine aminotransferase, aspartate aminotransferase, alkaline phosphatase, and lactate dehydrogenase, (iv) attenuated plasma systemic inflammation response molecules like soluble intercellular and lesion molecule-1, E-selectin, tumor necrosis factor-alpha, interleukin (IL)-1ß, and IL-6, (v) promoted plasma levels of an anti-inflammatory cytokine IL-10, (vi) reduced an index of infiltration of polymorphonuclear neutrophils in the lung like myeloperoxidase activity, and (vii) promoted the survival time to fourfold compared with the heatstroke alone group. Thus, melatonin could be a novel agent for the treatment of heatstroke animals or patients in the early stage.