Alteration of HER2 Status During Breast Cancer Progression: A Clinicopathological Analysis Focusing on HER2-Low Status.

Recent studies have shown that novel antibody-drug conjugates (ADCs) can improve clinical outcomes in patients with HER2-low breast cancers. This study aimed to investigate alteration of HER2 status during breast cancer progression with an emphasis on HER2-low status. Using 386 paired samples of primary and recurrent breast cancers, HER2 discordance rate between primary and matched recurrent samples, the relationships between HER2 discordance and clinicopathological characteristics and clinical outcomes of the patients were analyzed. HER2 discordance rate between primary breast cancer and first recurrence was 25.9% (κ = 0.586) with mostly zero-to-low (10.6%) or low-to-zero (9.3%) conversion. There was no significant difference in the discordant rates according to type or location of the recurrence. Of 70 cases with a second recurrence, HER2 discordance rate between the primary tumor and the second recurrence was 27.1% (κ = 0.554). HER2 discordance was associated with lower HER2 level, lymphovascular invasion, and progesterone receptor positivity of the primary tumor. In further analyses, HER2-zero-to-low conversion was associated with lymph node metastasis and hormone receptor (HR) positivity, whereas HER2-low-to-zero conversion was associated with HR negativity and triple-negative subtype. In survival analyses, HER2 discordance was associated with decreased overall survival of patients in the HR-positive group but not in the HR-negative group. Furthermore, patients with HER2-low-to-zero converted tumors showed worse overall survival compared with those with HER2-low concordant tumors. In conclusion, HER2 status changes during breast cancer progression in significant proportions, mostly between zero and low status. As HER2 instability increases during progression and affects clinical outcome, HER2 status needs to be reevaluated in recurrent settings.

Airborne transboundary microplastics-A Swirl around the globe.

Microplastics are persistent pollutants discovered and extensively researched in marine, freshwater, and terrestrial ecosystems but have yet to receive attention in an atmospheric context. Although recent reports stated the presence of microplastics in the air, their global existence and distribution are not critically discussed to date. This review aimed to investigate the current status of research on atmospheric microplastics through bibliometric analysis and by comparing and summarising published research on global distribution. The review also provides a summary of methods that have been used to collect samples, identify microplastics, quantify their occurrence, and determine their transport mechanisms. The bibliometric analysis revealed that atmospheric microplastic studies predominantly originated in China. Clothing, vehicle, and tire materials were the major primary sources while house furniture, construction materials, landfills, urban dust, plastic recycling processes, and agricultural sludge were precursor secondary sources. Polyethylene, polypropylene, and polyethylene terephthalate microfibres have most frequently found in indoor and outdoor atmospheres. Level of urbanization and temporal or spatial distributions governs the fate of airborne microplastics, however, the knowledge gap in the retention and circulation of microplastics through the atmosphere is still large. Many challenges and limitations were identified in the methods used, presentation of data, aerodynamic processes facilitating atmospheric transport, and scarcity of research in spatially and temporally diverse contexts. The review concluded that there was a greater need for globalization of research, methods and data standardization, and emphasizes the potential for future research with atmospheric transportation modelling and thermochemical analysis.

Kahweol Inhibits Pro-Inflammatory Cytokines and Chemokines in Tumor Necrosis Factor-α/Interferon-γ-Stimulated Human Keratinocyte HaCaT Cells.

Atopic dermatitis (AD), marked by intense itching and eczema-like lesions, is a globally increasing chronic skin inflammation. Kahweol, a diterpene that naturally occurs in coffee beans, boasts anti-inflammatory, antioxidative, and anti-cancer properties. This research explores the anti-inflammatory action of kahweol on HaCaT human keratinocytes stimulated by tumor necrosis factor-α (TNF-α) and interferon-γ (IFN-γ), focusing on key signal transduction pathways. Our results demonstrate that kahweol markedly reduces the production of IL-1ß, IL-6, C-X-C motif chemokine ligand 8, and macrophage-derived chemokine in TNF-α/IFN-γ-activated HaCaT cells. Furthermore, it curtails the phosphorylation of key proteins in the mitogen-activated protein kinase (MAPK) pathways, including c-Jun N-terminal kinase, extracellular signal-regulated kinase, and p38. Additionally, kahweol impedes the phosphorylation and nuclear translocation of the NF-κB p65 subunit and constrains its DNA-binding capability. It also hampers the phosphorylation, nuclear translocation, and DNA-binding activities of signal transducer and activator of transcription 1 (STAT1) and STAT3. Collectively, these findings suggest that kahweol hinders the generation of cytokines and chemokines in inflamed keratinocytes by inhibiting the MAPK, NF-κB, and STAT cascades. These insights position kahweol as a promising agent for dermatological interventions, especially in managing inflammatory skin conditions such as AD.

Concordance of HER2 status between core needle biopsy and surgical resection specimens of breast cancer: an analysis focusing on the HER2-low status.

BACKGROUND: Human epidermal growth factor receptor 2 (HER2)-low status has recently gained attention because of the potential therapeutic benefits of antibody-drug conjugates (ADCs) in breast cancer patients. We aimed to investigate the concordance of HER2 status between core needle biopsy (CNB) and subsequent surgical resection specimens focusing on the HER2-low status. METHODS: This retrospective study was conducted in 1,387 patients with invasive breast cancer whose HER2 status was evaluated in both CNB and surgical resection specimens. The discordance rates between CNB and surgical resection specimens and the clinicopathological features associated with HER2 status discordance were analyzed. RESULTS: The overall concordance rates of HER2 status between CNB and surgical resection specimens were 99.0% (κ = 0.925) for two-group classification (negative vs. positive) and 78.5% (κ = 0.587) for three-group classification (zero vs. low vs. positive). The largest discordance occurred in CNB-HER2-zero cases with 42.8% of them reclassified as HER2-low in surgical resection. HER2 discordance was associated with lower histologic grade, tumor multiplicity, and luminal A subtype. In multivariate analysis, tumor multiplicity and estrogen receptor (ER) positivity were independent predictive factors for HER2-zero to low conversion. CONCLUSIONS: Incorporation of HER2-low category in HER2 status interpretation reduces the concordance rate between CNB and surgical resection specimens. Tumor multiplicity and ER positivity are predictive factors for conversion from HER2-zero to HER2-low status. Therefore, HER2 status should be re-evaluated in resection specimens when considering ADCs in tumors exhibiting multiplicity and ER positivity.

Vitexicarpin Induces Apoptosis and Inhibits Metastatic Properties via the AKT-PRAS40 Pathway in Human Osteosarcoma.

Osteosarcoma, which has poor prognosis after metastasis, is the most common type of bone cancer in children and adolescents. Therefore, plant-derived bioactive compounds are being actively developed for cancer therapy. Artemisia apiacea Hance ex Walp. is a traditional medicinal plant native to Eastern Asia, including China, Japan, and Korea. Vitexicarpin (Vitex), derived from A. apiacea, has demonstrated analgesic, anti-inflammatory, antitumour, and immunoregulatory properties; however, there are no published studies on Vitex isolated from the aerial parts of A. apiacea. Thus, this study aimed to evaluate the antitumour activity of Vitex against human osteosarcoma cells. In the present study, Vitex (>99% purity) isolated from A. apiacea induced significant cell death in human osteosarcoma MG63 cells in a dose- and time-dependent manner; cell death was mediated by apoptosis, as evidenced by the appearance of cleaved-PARP, cleaved-caspase 3, anti-apoptotic proteins (Survivin and Bcl-2), pro-apoptotic proteins (Bax), and cell cycle-related proteins (Cyclin D1, Cdk4, and Cdk6). Additionally, a human phosphokinase array proteome profiler revealed that Vitex suppressed AKT-dependent downstream kinases. Further, Vitex reduced the phosphorylation of PRAS40, which is associated with autophagy and metastasis, induced autophagosome formation, and suppressed programmed cell death and necroptosis. Furthermore, Vitex induced antimetastatic activity by suppressing the migration and invasion of MMP13, which is the primary protease that degrades type I collagen for tumour-induced osteolysis in bone tissues and preferential metastasis sites. Taken together, our results suggest that Vitex is an attractive target for treating human osteosarcoma.

Quantitative and qualitative mutational impact of ionizing radiation on normal cells.

The comprehensive genomic impact of ionizing radiation (IR), a carcinogen, on healthy somatic cells remains unclear. Using large-scale whole-genome sequencing (WGS) of clones expanded from irradiated murine and human single cells, we revealed that IR induces a characteristic spectrum of short insertions or deletions (indels) and structural variations (SVs), including balanced inversions, translocations, composite SVs (deletion-insertion, deletion-inversion, and deletion-translocation composites), and complex genomic rearrangements (CGRs), including chromoplexy, chromothripsis, and SV by breakage-fusion-bridge cycles. Our findings suggest that 1 Gy IR exposure causes an average of 2.33 mutational events per Gb genome, comprising 2.15 indels, 0.17 SVs, and 0.01 CGRs, despite a high level of inter-cellular stochasticity. The mutational burden was dependent on total irradiation dose, regardless of dose rate or cell type. The findings were further validated in IR-induced secondary cancers and single cells without clonalization. Overall, our study highlights a comprehensive and clear picture of IR effects on normal mammalian genomes.

Genomic Landscape of Pulmonary Sarcomatoid Carcinoma.

PURPOSE: Pulmonary sarcomatoid carcinoma (PSC) is a rare aggressive subtype of non-small cell lung cancer (NSCLC) with limited therapeutic strategies. We attempted to elucidate the evolutionary trajectories of PSC using multiregional and longitudinal tumor samples. MATERIALS AND METHODS: A total of 31 patients were enrolled in this study and 11 longitudinal samples were available from them. Using whole exome sequencing data, we analyzed the mutational signatures in both carcinomatous and sarcomatous areas in primary tumors of the 31 patients and longitudinal samples obtained from 11 patients. Furthermore, digital droplet polymerase chain reaction (ddPCR), and programmed death-ligand 1 (PD-L1) immunohistochemistry using the Ventana SP263 assay were performed. RESULTS: TP53 was identified as the most frequently altered gene in the primary (74%) and metastatic (73%) samples. MET exon 14 skipping mutations, confirmed by ddPCR, and TP53 mutations were mutually exclusive; whereas, MET exon 14 skipping mutations frequently co-occurred with MDM2 amplification. Metastatic tumors showed dissimilar genetic profiles from either primary component. During metastasis, the signatures of APOBEC decreased in metastatic lesions compared with that in primary lesions. PSC showed higher MET and KEAP1 mutations and stronger PD-L1 protein expression compared with that recorded in other NSCLCs. CONCLUSION: Decreased APOBEC signatures and subclonal diversity were detected during malignant progression in PSC. Frequent MET mutations and strong PD-L1 expression distinguished PSC from other NSCLCs. The aggressiveness and therapeutic difficulties of PSC were possibly attributable to profound intratumoral and intertumoral genetic diversity. Next-generation sequencing could suggest the appropriate treatment strategy for PSC.

Extracts from Dendropanax morbifera leaves ameliorates cerebral ischemia-induced hippocampal damage by reducing oxidative damage in gerbil.

AIM: In this study, we investigated the effects of Dendropanax morbifera extract (DME) on neuroprotection against ischemic damage in gerbils. METHODS: DME (100 or 300 mg/kg) was orally administered to gerbils for three weeks, and 2 h after the last DME treatment, transient forebrain ischemia in the common carotid arteries was induced for 5 min. The forebrain ischemia-related cognitive impairments were assessed by spontaneous motor activity and passive avoidance test one and four days after ischemia, respectively. In addition, surviving and degenerating neurons were morphologically confirmed by neuronal nuclei immunohistochemical staining and Fluoro-Jade C staining, respectively, four days after ischemia. Changes of glial morphology were visualized by immunohistochemical staining for each marker such as glial fibrillary acidic protein and ionized calcium-binding protein. Oxidative stress was determined by measurements of dihydroethidium, O2· (formation of formazan) and malondialdehyde two days after ischemia. In addition, glutathione redox system such as reduced glutathione, oxidized glutathione levels, glutathione peroxidase, and glutathione reductase activities were measured two days after ischemia. RESULTS: Spontaneous motor activity monitoring and passive avoidance tests showed that treatment with 300 mg/kg DME, but not 100 mg/kg, significantly alleviated ischemia-induced memory impairments. In addition, approximately 67 % of mature neurons survived and 29.3 % neurons were degenerated in hippocampal CA1 region four days after ischemia, and ischemia-induced morphological changes in astrocytes and microglia were decreased in the CA1 region after 300 mg/kg DME treatment. Furthermore, treatment with 300 mg/kg DME significantly ameliorated ischemia-induced oxidative stress, such as superoxide formation and lipid peroxidation, two days after ischemia. In addition, ischemia-induced reduction of the glutathione redox system in the hippocampus, assessed two days after the ischemia, was ameliorated by treatment with 300 mg/kg DME. These suggest that DME can potentially reduce ischemia-induced neuronal damage through its antioxidant properties.

Simple and robust LC-MS/MS method for quantification of colistin methanesulfonate and colistin in human plasma for therapeutic drug monitoring.

A rapid, simple, and robust LC-MS/MS method was developed and validated for the quantitation of colistin and colistin methanesulfonate (CMS) in human plasma. The method also prevented overestimation of colistin concentration by establishing the stability of CMS under sample preparation conditions, including blood and plasma storage conditions. Polymyxin B1 was used as an internal standard, and positive-ion electrospray ionization in multiple reaction monitoring mode was used for quantification. Chromatographic separation was achieved using a Zorbax eclipse C18 column (3.5 µm, 2.1 mm i.d. × 100 mm), with a flow rate of 0.5 mL/min, 5 µL injection volume, and gradient elution with a mixture of acetonitrile-water (containing 0.1 % trifluoroacetic acid). The method had a quantifiable range of 0.043-8.61 and 0.057-11.39 µg/mL for colistin A and B in human plasma, respectively, under a total runtime of 6.0 min. Further, it demonstrated appropriate extraction efficiency, no significant interference from co-eluting endogenous compounds, and satisfactory intraday and interday precision and accuracy. The proposed procedure for sample preparation successfully addressed the issue of CMS instability, consequently diminishing the probability of overestimating the concentration of colistin. Therefore, this simple and robust LC-MS/MS method for CMS and colistin quantification in human plasma is a valuable tool for clinicians to accurately monitor colistin treatment in patients with infections caused by multidrug-resistant (MDR) Gram-negative bacteria.

Immunoassay Detects Salivary Anti-SSA/Ro-52 Autoantibodies in Seronegative Patients with Primary Sjögren's Syndrome.

The diagnostic work-up for Sjögren's syndrome is challenging and complex, including testing for serum autoantibodies to SSA/Ro and a labial salivary gland biopsy. Furthermore, the diagnosis is often delayed. In this study, we tested the hypothesis that anti-SSA/Ro autoantibodies are detectable in the saliva of patients with primary Sjögren's syndrome (pSS) because the disease affects the salivary glands, and these autoantibodies display greater discriminatory performance in saliva than in serum. SSA/Ro-52 Ags were used to develop what is, to our knowledge, a novel quantitative electrochemical-based immunoassay: the electric field-induced release and measurement (EFIRM) platform. The clinical utility was determined by measuring salivary anti-SSA/Ro-52 autoantibodies in patients with pSS and sicca (n = 34), patients without pSS with sicca (n = 35), and healthy subjects (n = 41). The statistical analysis of discrimination included the area under the receiver operating characteristic curve. Salivary anti-SSA/Ro-52 autoantibodies were measured in 94% (32 of 34) of patients with pSS with 85% (29 of 34) seropositivity. Four of the five seronegative patients with pSS had EFIRM-measurable anti-SSA/Ro-52 autoantibodies in saliva. Additionally, 60% (21 of 35) of the seronegative patients without pSS who had sicca had EFIRM-detectable SSA/Ro-52 autoantibodies in saliva, indicating the onset of autoimmune disease. Two of the 41 healthy control subjects had EFIRM-detectable SSA/Ro-52 autoantibodies in their saliva. Salivary SSA/Ro-52 autoantibodies significantly discriminated patients with pSS or patients with the initial stage of autoimmune disease from healthy subjects with an area under the receiver operating characteristic curve of 0.91. Our findings suggest that the proposed saliva SSA/Ro-52 immunoassay improves early and accurate diagnosis of seronegative patients with pSS and patients with early-onset autoimmune disease.

Erratum: Cedrol, a Sesquiterpene Isolated from Juniperus chinensis, Inhibits Human Colorectal Tumor Growth associated through Downregulation of Minichromosome Maintenance Proteins.

[This corrects the article on p. 221 in vol. 27, PMID: 36713942.].

Ethyl pyruvate prevents long-term stress-induced cognitive decline and modulates Akt/GSK-3ß signaling.

Stress is an inevitable part of life and, simultaneously, a stimulus that can trigger various neuropsychiatric disorders. Therefore, proper stress management is essential for maintaining a healthy life. In this study, we investigated the suppression of stress-induced cognitive deficit by controlling changes in synaptic plasticity caused by stress and confirmed that ethyl pyruvate (EP) has such an effect. Corticosterone, a stress hormone, suppresses long-term potentiation (LTP) in mouse acute hippocampal slices. EP blocked the LTP inhibitory effect of corticosterone by regulating GSK-3ß function. Restraint stress for 2 weeks increased the anxiety levels and caused the cognitive decline in the experimental animals. Administration of EP for 14 days did not affect the increase in anxiety caused by stress but improved cognitive decline caused by stress. In addition, the decrease in neurogenesis and synaptic function deficits in the hippocampus, which cause of cognitive decline due to stress, were improved by EP administration. These effects appear via regulation of Akt/GSK-3ß signaling, as in in vitro studies. These results suggest that EP prevents stress-induced cognitive decline through the modulation of Akt/GSK-3ß-mediated synaptic regulation.

Widespread somatic L1 retrotransposition in normal colorectal epithelium.

Throughout an individual's lifetime, genomic alterations accumulate in somatic cells1-11. However, the mutational landscape induced by retrotransposition of long interspersed nuclear element-1 (L1), a widespread mobile element in the human genome12-14, is poorly understood in normal cells. Here we explored the whole-genome sequences of 899 single-cell clones established from three different cell types collected from 28 individuals. We identified 1,708 somatic L1 retrotransposition events that were enriched in colorectal epithelium and showed a positive relationship with age. Fingerprinting of source elements showed 34 retrotransposition-competent L1s. Multidimensional analysis demonstrated that (1) somatic L1 retrotranspositions occur from early embryogenesis at a substantial rate, (2) epigenetic on/off of a source element is preferentially determined in the early organogenesis stage, (3) retrotransposition-competent L1s with a lower population allele frequency have higher retrotransposition activity and (4) only a small fraction of L1 transcripts in the cytoplasm are finally retrotransposed in somatic cells. Analysis of matched cancers further suggested that somatic L1 retrotransposition rate is substantially increased during colorectal tumourigenesis. In summary, this study illustrates L1 retrotransposition-induced somatic mosaicism in normal cells and provides insights into the genomic and epigenomic regulation of transposable elements over the human lifetime.

Purpurin ameliorates D-galactose-induced aging phenotypes in mouse hippocampus by reducing inflammatory responses.

Purpurin, an anthraquinone, has potent anti-oxidant and anti-inflammatory effects in various types of brain damage. In a previous study, we showed that purpurin exerts neuroprotective effects against oxidative and ischemic damage by reducing pro-inflammatory cytokines. In the present study, we investigated the effects of purpurin against D-galactose-induced aging phenotypes in mice. Exposure to 100 mM D-galactose significantly decreased cell viability in HT22 cells, and purpurin treatment significantly ameliorated the reduction of cell viability, formation of reactive oxygen species, and lipid peroxidation in a concentration-dependent manner. Treatment with 6 mg/kg purpurin significantly improved D-galactose-induced memory impairment in the Morris water maze test in C57BL/6 mice and alleviated the reduction of proliferating cells and neuroblasts in the subgranular zone of the dentate gyrus. In addition, purpurin treatment significantly mitigated D-galactose-induced changes of microglial morphology in the mouse hippocampus and the release of pro-inflammatory cytokines such as interleukin-1ß, interleukin-6, and tumor necrosis factor-α. In addition, purpurin treatment significantly ameliorated D-galactose-induced phosphorylation of c-Jun N-terminal kinase and cleavage of caspase-3 in HT22 cells. These results suggest that purpurin can delay aging by reducing the inflammatory cascade and phosphorylation of the c-Jun N-terminal in the hippocampus.

Genetic and immune microenvironment characterization of HER2-positive gastric cancer: Their association with response to trastuzumab-based treatment.

BACKGROUND: We aimed to determine the molecular and immune microenvironment characteristics of HER2-positive gastric cancer (GC) related to the patient's response to first-line trastuzumab-based treatment. METHODS: Eighty-three cases of HER2-positive advanced gastric adenocarcinoma patients treated with trastuzumab were enrolled. Targeted deep sequencing and transcriptome analysis were performed on selected 21 cases (exploration cohort) along with two post-treatment samples. The results were compared between patients progressed before 6 months (Group 2) and others (Group 1), and were validated by FISH and immunohistochemistry in total cohort. Tumor-infiltrating immune cells were evaluated using RNA sequencing data and multiplex immunohistochemistry. Progression-free survival (PFS) analysis was performed. RESULTS: Group 1 showed frequent amplification of G1/S cell cycle checkpoint-related genes and upregulated KEGG pathways related to cell proliferation. In contrast, Group 2 had more frequent EGFR, HER3, and MET amplification and higher RNA expression in immune-related KEGG pathways than Group 1. In total cohort, significant predictors of better PFS were cell cycle-related including CCNE1 amplification, Cyclin A and PLK1 overexpression, and decreased Cyclin D3 and HER3 expression (p < 0.05), or immune-related including high density of CD3- CD57+ NK cells and PD-L1 combined positive score ≥5 (p < 0.05). The best prognostic predictors were a combination of Cyclin A, Cyclin E, p21, and HER3 (p < 0.001). CONCLUSION: HER2-positive GC with favorable response to trastuzumab were characterized by cell cycle-related gene alterations and increased CD3- CD57+ NK cell infiltration. These findings would be helpful to the fine modulation of therapeutic strategies for patients with HER2-positive GC.

Complications and Technical Consideration of Ultrasound-Guided Rectus Sheath Blocks: A Retrospective Analysis of 4033 Patients.

BACKGROUND: Although the ultrasound-guided rectus sheath block (RSB) is usually regarded as an easy and safe procedure in clinical settings, there is currently no report on complications incidence. Therefore, the present study investigated complications in a large cohort and described the technical considerations to minimize complications of real-time ultrasound-guided RSBs. METHODS: This was a retrospective cohort study of patients who underwent real-time ultrasound-guided RSBs for perioperative pain control in laparoscopic surgery with an umbilical port between February 1, 2017, and February 28, 2021, at the Asan Medical Center in South Korea. All RSBs were performed bilaterally using a 23-gauge Quincke needle, and a bilateral 2-block placement was regarded as 1 RSB. Patient data, including demographics, preoperative laboratory data, preoperative antiplatelet or anticoagulant medication with the duration of discontinuation, and type of surgery, were collected to show the study population characteristics and explore potential factors associated with adverse events such as hematoma. Ultrasound images of patients and adverse events of RSBs, including extrarectus sheath injections, vascular injuries, bowel injury, or local anesthetic systemic toxicity, were also analyzed accordingly. RESULTS: A total of 4033 procedures were analyzed. The mean body mass index of the patients was 24.1 (21.8-26.5) kg/m2. The preoperative laboratory data were within normal range in 4028 (99.9%) patients. Preoperative antiplatelets or anticoagulants were administered in 17.3% of the patients. Overall, 96 complications (2.4%) were observed. Among them, extrarectus sheath injection occurred in 88 cases (2.2%), which included preperitoneal injection (0.9%) and intraperitoneal injection (1.3%). Vascular injuries constituted 8 cases (0.2%) and all vascular injuries resulted in hematoma: 7 cases of inferior epigastric artery injury with rectus sheath hematoma and 1 of inferior mesenteric artery injury with retroperitoneal hematoma. Bowel injury or local anesthetic systemic toxicity was not reported. CONCLUSIONS: In this study of RSBs performed on 4033 patients using a 23-gauge Quincke needle in patients with low body mass index, there were 8 cases (0.2%) of vascular injury, all of which accompanied hematoma.

Protective effect of GK2 fused BLVRA protein against oxidative stress-induced dopaminergic neuronal cell damage.

It is well known that oxidative stress is highly associated with Parkinson's disease (PD), and biliverdin reductase A (BLVRA) is known to have antioxidant properties against oxidative stress. In this study, we developed a novel N-acetylgalactosamine kinase (GK2) protein transduction domain (PTD) derived from adenosine A2A and fused with BLVRA to determine whether the GK2-BLVRA fusion protein could protect dopaminergic neuronal cells (SH-SY5Y) from oxidative stress in vitro and in vivo using a PD animal model. GK2-BLVRA was transduced into various cells, including SH-SY5Y cells, without cytotoxic effects, and this fusion protein protected SH-SY5Y cells and reduced reactive oxygen species production and DNA damage after 1-methyl-4-phenylpyridinium (MPP+ ) exposure. GK2-BLVRA suppressed mitogen-activated protein kinase (MAPK) activation and modulated apoptosis-related protein (Bcl-2, Bax, cleaved Caspase-3 and -9) expression levels. In the PD animal model, GK2-BLVRA transduced into the substantia nigra crossed the blood-brain barrier and markedly reduced dopaminergic neuronal cell death in 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-induced animals. These results indicate that our novel PTD GK-2 is useful for the transduction of protein, and GK2-BLVRA exhibits a beneficial effect against dopaminergic neuronal cell death in vitro and in vivo, suggesting that BLVRA can be used as a therapeutic agent for PD.

FDG metabolic parameter-based models for predicting recurrence after upfront surgery in synchronous colorectal cancer liver metastasis.

OBJECTIVE: This study aimed to develop and validate post- and preoperative models for predicting recurrence after curative-intent surgery using an FDG PET-CT metabolic parameter to improve the prognosis of patients with synchronous colorectal cancer liver metastasis (SCLM). METHODS: In this retrospective multicenter study, consecutive patients with resectable SCLM underwent upfront surgery between 2006 and 2015 (development cohort) and between 2006 and 2017 (validation cohort). In the development cohort, we developed and internally validated the post- and preoperative models using multivariable Cox regression with an FDG metabolic parameter (metastasis-to-primary-tumor uptake ratio [M/P ratio]) and clinicopathological variables as predictors. In the validation cohort, the models were externally validated for discrimination, calibration, and clinical usefulness. Model performance was compared with that of Fong's clinical risk score (FCRS). RESULTS: A total of 374 patients (59.1 ± 10.5 years, 254 men) belonged in the development cohort and 151 (60.3 ± 12.0 years, 94 men) in the validation cohort. The M/P ratio and nine clinicopathological predictors were included in the models. Both postoperative and preoperative models showed significantly higher discrimination than FCRS (p < .05) in the external validation (time-dependent AUC = 0.76 [95% CI 0.68-0.84] and 0.76 [0.68-0.84] vs. 0.65 [0.57-0.74], respectively). Calibration plots and decision curve analysis demonstrated that both models were well calibrated and clinically useful. The developed models are presented as a web-based calculator ( https://cpmodel.shinyapps.io/SCLM/ ) and nomograms. CONCLUSIONS: FDG metabolic parameter-based prognostic models are well-calibrated recurrence prediction models with good discriminative power. They can be used for accurate risk stratification in patients with SCLM. KEY POINTS: • In this multicenter study, we developed and validated prediction models for recurrence in patients with resectable synchronous colorectal cancer liver metastasis using a metabolic parameter from FDG PET-CT. • The developed models showed good predictive performance on external validation, significantly exceeding that of a pre-existing model. • The models may be utilized for accurate patient risk stratification, thereby aiding in therapeutic decision-making.

CHIP ameliorates neuronal damage in H2O2-induced oxidative stress in HT22 cells and gerbil ischemia.

Carboxyl terminus of Hsc70-interacting protein (CHIP) is highly conserved and is linked to the connection between molecular chaperones and proteasomes to degrade chaperone-bound proteins. In this study, we synthesized the transactivator of transcription (Tat)-CHIP fusion protein for effective delivery into the brain and examined the effects of CHIP against oxidative stress in HT22 cells induced by hydrogen peroxide (H2O2) treatment and ischemic damage in gerbils by 5 min of occlusion of both common carotid arteries, to elucidate the possibility of using Tat-CHIP as a therapeutic agent against ischemic damage. Tat-CHIP was effectively delivered to HT22 hippocampal cells in a concentration- and time-dependent manner, and protein degradation was confirmed in HT22 cells. In addition, Tat-CHIP significantly ameliorated the oxidative damage induced by 200 µM H2O2 and decreased DNA fragmentation and reactive oxygen species formation. In addition, Tat-CHIP showed neuroprotective effects against ischemic damage in a dose-dependent manner and significant ameliorative effects against ischemia-induced glial activation, oxidative stress (hydroperoxide and malondialdehyde), pro-inflammatory cytokines (interleukin-1ß, interleukin-6, and tumor necrosis factor-α) release, and glutathione and its redox enzymes (glutathione peroxidase and glutathione reductase) in the hippocampus. These results suggest that Tat-CHIP could be a therapeutic agent that can protect neurons from ischemic damage.