Predicting immune checkpoint therapy response in three independent metastatic melanoma cohorts.

While Immune checkpoint inhibition (ICI) therapy shows significant efficacy in metastatic melanoma, only about 50% respond, lacking reliable predictive methods. We introduce a panel of six proteins aimed at predicting response to ICI therapy. Evaluating previously reported proteins in two untreated melanoma cohorts, we used a published predictive model (EaSIeR score) to identify potential proteins distinguishing responders and non-responders. Six proteins initially identified in the ICI cohort correlated with predicted response in the untreated cohort. Additionally, three proteins correlated with patient survival, both at the protein, and at the transcript levels, in an independent immunotherapy treated cohort. Our study identifies predictive biomarkers across three melanoma cohorts, suggesting their use in therapeutic decision-making.

One-shot dual gene editing for drug-resistant pancreatic cancer therapy.

It is challenging to diagnose patients with pancreatic ductal adenocarcinoma (PDAC) early on, and their treatment is often complex. Gemcitabine (GEM) is the first-line treatment for PDAC, but its efficacy is limited in most patients due to the GEM resistance from KRAS and P53 gene mutations. We describe the correction of a double gene mutation and therapeutic effect for the GEM resistant PDAC. Bio-available nanoliposomes (NL) possessing Cas9-ribonucleoproteins and adenine-base editors were developed to conduct KRAS and P53 mutation gene editing directly. NLs were conjugated with EGFR antibodies to tumor-specific delivery, and the anti-cancer effect was verified in vitro and in vivo Model. Our GEM-combinatorial therapeutic strategies using double gene editing systems with one-shot may be a potent therapy for PDAC, overcoming chemoresistance.

Amyloid Positivity in the Alzheimer/Subcortical-Vascular Spectrum.

OBJECTIVE: We investigated the frequency of ß-amyloid (Aß) positivity in 9 groups classified according to a combination of 3 different cognition states and 3 distinct levels of white matter hyperintensities (WMH) (minimal, moderate, and severe) and aimed to determine which factors were associated with Aß after controlling for WMH and vice versa. METHODS: A total of 1,047 individuals with subjective cognitive decline (SCD, n = 294), mild cognitive impairment (MCI, n = 237), or dementia (n = 516) who underwent Aß PET scans were recruited from the memory clinic at Samsung Medical Center in Seoul, Korea. We investigated the following: (1) Aß positivity in the 9 groups, (2) the relationship between Aß positivity and WMH severity, and (3) clinical and genetic factors independently associated with Aß or WMH. RESULTS: Aß positivity increased as the severity of cognitive impairment increased (SCD [15.7%], MCI [43.5%], and dementia [76.2%]), whereas it decreased as the severity of WMH increased (minimal [54.5%], moderate [53.9%], and severe [41.0%]) or the number of lacunes (0 [59.0%], 1-3 [42.0%], and >3 [23.4%]) increased. Aß positivity was associated with higher education, absence of diabetes, and presence of APOE ε4 after controlling for cognitive and WMH status. CONCLUSION: Our analysis of Aß positivity involving a large sample classified according to the stratified cognitive states and WMH severity indicates that Alzheimer and cerebral small vessel diseases lie on a continuum. Our results offer clinicians insightful information about the association among Aß, WMH, and cognition.

Endogenous expression mapping of malignant melanoma by mass spectrometry imaging.

BACKGROUND: Currently, only a limited number of molecular biomarkers for malignant melanoma exist. This is the case for both diagnosing the disease, staging, and efficiently measuring the response to therapy by tracing the progression of disease development and drug impact. There is a great need to identify novel landmarks of disease progression and alterations. METHODS: Matrix-assisted laser desorption ionisation mass spectrometry imaging (MALDI-MSI) has been developed within our group to study drug localisation within micro-environmental tissue compartments. Here, we expand further on this technology development and introduce for the first time melanoma tumour tissues to map metabolite localisation utilising high resolution mass spectrometry. MALDI-MSI can measure and localise the distribution pattern of a number of small molecule metabolites within tissue compartments of tumours isolated from melanoma patients. Data on direct measurements of metabolite identities attained at the local sites in tissue compartments has not been readily available as a measure of a clinical index for most cancer diseases. The current development on the mapping of endogenous molecular expression melanoma tumours by mass spectrometry imaging focuses on the establishment of a cancer tissue preparation process whereby a matrix crystal formation is homogenously built on the tissue surface, providing uniform molecular mapping. We apply this micro-preparation technology to disease presentation by mapping the molecular signatures from patient tumour sections. RESULTS: We have automated the process with a micro-technological dispensing platform. This provides the basis for thin film generation of the cancer patient tissues prior to imaging screening. Compartmentalisation of the tumour regions are displayed within the image analysis interfaced with histopathological grading and characterisation. CONCLUSIONS: This enables site localisation within the tumour with image mapping to disease target areas such as melanoma cells, macrophages, and lymphocytes.

Turmeric extract and its active compound, curcumin, protect against chronic CCl4-induced liver damage by enhancing antioxidation.

BACKGROUND: Curcumin, a major active component of turmeric, has previously been reported to alleviate liver damage. Here, we investigated the mechanism by which turmeric and curcumin protect the liver against carbon tetrachloride (CCl4)-induced injury in rats. We hypothesized that turmeric extract and curcumin protect the liver from CCl4-induced liver injury by reducing oxidative stress, inhibiting lipid peroxidation, and increasing glutathione peroxidase activation. METHODS: Chronic hepatic stress was induced by a single intraperitoneal injection of CCl4 (0.1 ml/kg body weight) into rats. Turmeric extracts and curcumin were administered once a day for 4 weeks at three dose levels (100, 200, and 300 mg/kg/day). We performed ALT and AST also measured of total lipid, triglyceride, cholesterol levels, and lipid peroxidation. RESULT: We found that turmeric extract and curcumin significantly protect against liver injury by decreasing the activities of serum aspartate aminotransferase and alanine aminotransferase and by improving the hepatic glutathione content, leading to a reduced level of lipid peroxidase. CONCLUSIONS: Our data suggest that turmeric extract and curcumin protect the liver from chronic CCl4-induced injury in rats by suppressing hepatic oxidative stress. Therefore, turmeric extract and curcumin are potential therapeutic antioxidant agents for the treatment of hepatic disease.

The effect of xanthorrhizol on the expression of matrix metalloproteinase-1 and type-I procollagen in ultraviolet-irradiated human skin fibroblasts.

Matrix metalloproteinases (MMPs) are key regulators of the skin photoaging process that is set in motion by exposure to ultraviolet (UV) irradiation. This skin damage results from UV-induced generation of reactive oxygen species, which are associated with upregulation of MMPs and decreased collagen synthesis. We investigated the effects of xanthorrhizol, isolated from Curcuma xanthorrhiza, on the expression of MMP-1 and type-I procollagen in UV-irradiated human skin fibroblasts. Fibroblasts cultured in the presence or absence of purified xanthorrhizol or C. xanthorrhiza extract were irradiated with UV (20 mJ/cm(2)), and MMP-1 and type-I procollagen levels were measured using Western blot analysis. Xanthorrhizol (0.001-0.1 microM) and C. xanthorrhiza extract (0.01-0.5 microg/mL) induced a significant, dose-dependent decrease in the expression of MMP-1 protein, and increased the expression of type-1 procollagen. At a concentration of 0.1 microM, xanthorrhizol nearly completely abrogated MMP-1 expression. The MMP-1-suppressing and type-1 procollagen-inducing effects of xanthorrhizol treatment were greater than those of epigallocatechin 3-O-gallate (EGCG), which is known to be a natural anti-aging agent. These results suggest that xanthorrhizol is a potential candidate for the prevention and treatment of skin aging.

4-O-Methylgallic acid suppresses inflammation-associated gene expression by inhibition of redox-based NF-kappaB activation.

4-O-methylgallic acid (4-OMGA) is an in vivo major metabolite of gallic acid which is abundant in red wine, tea, legumes and fruit. We examined the in vitro and in vivo effects of 4-OMGA on the production and expression of nitric oxide (NO) and prostaglandin E(2) (PGE(2)) as well as the expression of inducible NO synthase (iNOS), cyclooxygenase-2 (COX-2), tumor necrosis factor-alpha (TNF-alpha), and interleukin-1beta (IL-1beta). 4-OMGA inhibited the expression and production of these inflammatory genes and mediators in RAW264.7 cells and primary macrophages stimulated with lipopolysaccharide (LPS). This compound also reduced the serum levels of these inflammatory mediators in endotoxemic mice. 4-OMGA inhibited iNOS promoter activity and NF-kappaB activation in LPS-treated RAW264.7 cells. 4-OMGA inhibited the LPS-mediated increase in reactive oxygen species production and exogenous H(2)O(2)-induced NF-kappaB activation. Moreover, this compound blocked IkappaBalpha phosphorylation and degradation and nuclear translocation of the cytosolic NF-kappaB p65 subunit, which highly correlated with its inhibitory effect on IkappaB kinase activity and inflammatory mediator production. These results suggest that 4-OMGA suppresses inflammation-associated gene expression by blocking NF-kappaB activation through the inhibition of redox-sensitive IkappaB kinase activity, suggesting that this compound may be beneficial for treating endotoxemia.

Downregulation of gelsolin and retinoic acid receptor beta expression in gastric cancer tissues through histone deacetylase 1.

BACKGROUND AND AIM: Overexpression of histone deacetylase (HDAC)1, which controls the expression of genes related to cell cycle and apoptosis, has recently been reported in gastric cancer (GC) tissues. In the present study, the pattern of gelsolin and retinoic acid receptor (RAR)beta expression in GC tissues showing HDAC1 overexpression was investigated. METHODS: Expression profiles of HDAC1, gelsolin, and RARbeta were evaluated and compared using reverse transcription-polymerase chain reaction, immunoblotting, and immunohistochemical analyses with 22 paired primary human GC tissues and corresponding normal tissues. RESULTS: Compared with normal gastric tissue, increased expression of HDAC1 mRNA and protein was detected in 17 (77.3%) of 22 GC tissues, while decreased expressions of gelsolin mRNA and protein were shown in 15 (68.1%) samples. Concomitantly, expressions of RARbeta mRNA and protein were decreased in 16 (72.7%) and 17 (77.3%), respectively. Among 17 GC tissues with increased HDAC1 expression, the expressions of gelsolin and RARbeta were simultaneously decreased in 14 (82.4%) and 15 (88.2%) GC tissues, which indicates a strong inverse correlation between HDAC1 and gelsolin/RARbeta expressions. Correlation between HDAC1 and gelsolin/RARbeta was also confirmed by immunohistochemistry. CONCLUSIONS: Taken together, the results of the present study reveal that silencing of gelsolin and RARbeta occurs in GC tissues probably through HDAC1 overexpression and might play some role in gastric carcinogenesis.