Cannabidiol enhances Atezolizumab efficacy by upregulating PD-L1 expression via the cGAS-STING pathway in triple-negative breast cancer cells.

The treatment of patients with triple negative breast cancer (TNBC) relies on cytotoxic therapy. Currently, atezolizumab and chemotherapy can be combined in patients with TNBC. However, this approach is not effective for all patients with low reactivity to atezolizumab. As there is a lack of alternative treatment options, new anti-cancer drugs are urgently needed to enhance atezolizumab reactivity against TNBC. Recent strategies have focused on regulating the expression of programmed death-ligand 1 (PD-L1) or enhancing immune response activation by combining anti-cancer drugs with immune checkpoint inhibitors (ICIs). Cannabidiol (CBD), a cannabinoid component derived from the cannabis plant, has been reported to have anti-cancer therapeutic potential because of its capacity to induce apoptotic cell death in tumor cells while avoiding cytotoxicity in normal cells. Previous studies have demonstrated the effects of CBD on apoptosis in various cancer cell types. However, the potential role of CBD as an immune modulator in the regulation of PD-L1 expression and anti-cancer immune responses remains to be explored. In this study, we found that CBD stimulated PD-L1 expression in TNBC cells, which significantly induced the CBD-mediated cGAS-STING pathway activation. Taken together, we demonstrated that the combination of CBD and anti-PD-L1 antibody enhances the anti-cancer immune response in vitro and in vivo experiments. Our findings identified the mechanism of PD-L1 regulation by CBD in TNBC cells and suggested that CBD could be a potential candidate for the development of new combinatorial strategies with ICIs in TNBC patients.

Feasibility of deep learning algorithm in diagnosing lumbar central canal stenosis using abdominal CT.

OBJECTIVE: To develop a deep learning algorithm for diagnosing lumbar central canal stenosis (LCCS) using abdominal CT (ACT) and lumbar spine CT (LCT). MATERIALS AND METHODS: This retrospective study involved 109 patients undergoing LCTs and ACTs between January 2014 and July 2021. The dural sac on CT images was manually segmented and classified as normal or stenosed (dural sac cross-sectional area ≥ 100 mm2 or < 100 mm2, respectively). A deep learning model based on U-Net architecture was developed to automatically segment the dural sac and classify the central canal stenosis. The classification performance of the model was compared on a testing set (990 images from 9 patients). The accuracy, sensitivity, and specificity of automatic segmentation were quantitatively evaluated by comparing its Dice similarity coefficient (DSC) and intraclass correlation coefficient (ICC) with those of manual segmentation. RESULTS: In total, 990 CT images from nine patients (mean age ± standard deviation, 77 ± 7 years; six men) were evaluated. The algorithm achieved high segmentation performance with a DSC of 0.85 ± 0.10 and ICC of 0.82 (95% confidence interval [CI]: 0.80,0.85). The ICC between ACTs and LCTs on the deep learning algorithm was 0.89 (95%CI: 0.87,0.91). The accuracy of the algorithm in diagnosing LCCS with dichotomous classification was 84%(95%CI: 0.82,0.86). In dataset analysis, the accuracy of ACTs and LCTs was 85%(95%CI: 0.82,0.88) and 83%(95%CI: 0.79,0.86), respectively. The model showed better accuracy for ACT than LCT. CONCLUSION: The deep learning algorithm automatically diagnosed LCCS on LCTs and ACTs. ACT had a diagnostic performance for LCCS comparable to that of LCT.

An Innovative Inhibitor with a New Chemical Moiety Aimed at Biliverdin IXß Reductase for Thrombocytopenia and Resilient against Cellular Degradation.

Biliverdin IXß reductase (BLVRB) has emerged as a promising therapeutic target for thrombocytopenia due to its involvement in reactive oxygen species (ROS) mechanisms. During the pursuit of inhibitors targeting BLVRB, olsalazine (OSA) became apparent as one of the most potent candidates. However, the direct application of OSA as a BLVRB inhibitor faces challenges, as it is prone to degradation into 5-aminosalicylic acid through cleavage of the diazenyl bond by abundant azoreductase (AzoR) enzymes in gut microbiota and eukaryotic cells. To overcome this obstacle, we devised olsalkene (OSK), an inhibitor where the diazenyl bond in OSA has been substituted with an alkene bond. OSK not only matches the efficacy of OSA but also demonstrates improved stability against degradation by AzoR, presenting a promising solution to this limitation. Furthermore, we have found that both OSK and OSA inhibit BLVRB, regardless of the presence of nicotinamide adenine dinucleotide phosphate, unlike other known inhibitors. This discovery opens new avenues for investigating the roles of BLVRB in blood disorders, including thrombocytopenia.

Arteriovenous metabolomics in pigs reveals CFTR regulation of metabolism in multiple organs.

Mutations in the cystic fibrosis transmembrane conductance regulator (CFTR) gene cause cystic fibrosis (CF), a multiorgan disease that is characterized by diverse metabolic defects. However, other than specific CFTR mutations, the factors that influence disease progression and severity remain poorly understood. Aberrant metabolite levels have been reported, but whether CFTR loss itself or secondary abnormalities (infection, inflammation, malnutrition, and various treatments) drive metabolic defects is uncertain. Here, we implemented comprehensive arteriovenous metabolomics in newborn CF pigs, and the results revealed CFTR as a bona fide regulator of metabolism. CFTR loss impaired metabolite exchange across organs, including disruption of lung uptake of fatty acids, yet enhancement of uptake of arachidonic acid, a precursor of proinflammatory cytokines. CFTR loss also impaired kidney reabsorption of amino acids and lactate and abolished renal glucose homeostasis. These and additional unexpected metabolic defects prior to disease manifestations reveal a fundamental role for CFTR in controlling multiorgan metabolism. Such discovery informs a basic understanding of CF, provides a foundation for future investigation, and has implications for developing therapies targeting only a single tissue.

Daunorubicin induces GLI1­dependent apoptosis in colorectal cancer cell lines.

Daunorubicin, also known as daunomycin, is a DNA­targeting anticancer drug that is used as chemotherapy, mainly for patients with leukemia. It has also been shown to have anticancer effects in monotherapy or combination therapy in solid tumors, but at present it has not been adequately studied in colorectal cancer (CRC). In the present study, from a screening using an FDA­approved drug library, it was found that daunorubicin suppresses GLI­dependent luciferase reporter activity. Daunorubicin also increased p53 levels, which contributed to both GLI1 suppression and apoptosis. The current detailed investigation showed that daunorubicin promoted the ß­TrCP­mediated ubiquitination and proteasomal degradation of GLI1. Moreover, a competition experiment using BODIPY­cyclopamine, a well­known Smo inhibitor, suggested that daunorubicin does not bind to Smo in HCT116 cells. Administration of daunorubicin (2 mg/kg, ip, qod, 15 days) into HCT116 xenograft mice profoundly suppressed tumor progress and the GLI1 level in tumor tissues. Taken together, the present results revealed that daunorubicin suppresses canonical Hedgehog pathways in CRC. Ultimately, the present study discloses a new mechanism of daunorubicin's anticancer effect and might provide a rationale for expanding the clinical application of daunorubicin.

Effect of modification methods on the physical properties and immunomodulatory activity of particulate ß-glucan.

ß-Glucan is an immunoenhancing agent whose biological activities are linked to molecular structure. On that basis, the polysaccharide can be physiochemically modified to produce valuable functional materials. This study investigated the physical properties and immunostimulatory activity of modified ß-glucan. Alkali-treated ß-glucan had a distinct shape and smaller particle size than untreated ß-glucan. The reduced particle size was conducive to the stability of the suspension because the ß-glucan appeared to be completely dissolved by this treatment, forming an amorphous mass. Furthermore, alkali treatment improved the immunostimulating activity of ß-glucan, whereas exposure of macrophages to heat-treated ß-glucan decreased their immune activity. ß-Glucan with reduced particle size by wet-grinding also displayed immunomodulatory activities. These results suggested that the particle size of ß-glucan is a key factor in ß-glucan-induced immune responses of macrophages. Thus, the modification of the ß-glucan particle size provides new opportunities for developing immunoenhancing nutraceuticals or pharmacological therapies in the future.

Check-all-that-apply (CATA)- and rate-all-that-apply (RATA)-based sensometric assessment of germinated-wheat beverages.

Sensometrics assesses sensory perspectives in consumer research using statistics and various methodologies. This study evaluated consumer responses to hot and cold germinated-wheat beverages in check-all-that-apply (CATA) and rate-all-that-apply (RATA) assessments using sensometric statistical approaches, including Cochran's Q test, penalty-lift analysis, and multiple factor analysis. Hot beverages (HB) were prepared by infusion using different amounts of germinated wheat (HB_1: 0.8 g/100 mL, HB_2: 2 g/100 mL, and HB_3: 4 g/100 mL), while cold beverages (CB) were made using cooled boiled germinated wheat with varying concentrations (CB_1: 25 g/L, CB_2: 50 g/L, and CB_3: 75 g/L). Results of the CATA study suggested that consumers preferred HB_1 and CB_1 because they expressed the sensory characteristics associated with liking, including "barley tea flavor", "neat taste", and "nutty taste", while "bitterish taste", "stuffy taste", and "astringent taste" were undesirable attributes. "Browning index", "barley tea odor", and "nutty taste" showed significant differences (p < 0.05) in both favorable and unfavorable rating scores. Overall, CB_1 elicited a clear taste and odor with fewer negative emotions. These findings demonstrate the usefulness of the sensometric approach combined with CATA and RATA analyses to obtain more easily interpretable results on the sensory perception of consumers to new food products. Supplementary Information: The online version contains supplementary material available at 10.1007/s13197-023-05884-z.

Mitochondrial uncoupling proteins protect human airway epithelial ciliated cells from oxidative damage.

Apical cilia on epithelial cells defend the lung by propelling pathogens and particulates out of the respiratory airways. Ciliated cells produce ATP that powers cilia beating by densely grouping mitochondria just beneath the apical membrane. However, this efficient localization comes at a cost because electrons leaked during oxidative phosphorylation react with molecular oxygen to form superoxide, and thus, the cluster of mitochondria creates a hotspot for oxidant production. The relatively high oxygen concentration overlying airway epithelia further intensifies the risk of generating superoxide. Thus, airway ciliated cells face a unique challenge of producing harmful levels of oxidants. However, surprisingly, highly ciliated epithelia produce less reactive oxygen species (ROS) than epithelia with few ciliated cells. Compared to other airway cell types, ciliated cells express high levels of mitochondrial uncoupling proteins, UCP2 and UCP5. These proteins decrease mitochondrial protonmotive force and thereby reduce production of ROS. As a result, lipid peroxidation, a marker of oxidant injury, decreases. However, mitochondrial uncoupling proteins exact a price for decreasing oxidant production; they decrease the fraction of mitochondrial respiration that generates ATP. These findings indicate that ciliated cells sacrifice mitochondrial efficiency in exchange for safety from damaging oxidation. Employing uncoupling proteins to prevent oxidant production, instead of relying solely on antioxidants to decrease postproduction oxidant levels, may offer an advantage for targeting a local area of intense ROS generation.

Neuroimaging Approach: Effects of Hot and Cold Germinated Wheat Beverages on Electroencephalographic (EEG) Activity of the Human Brain.

Neuroimaging studies using electroencephalography (EEG) have been crucial in uncovering brain activity in sensory perception, emotion regulation, and decision-making. Despite tea's global popularity, its temperature-related neural basis remains underexplored. This study investigated the effect of hot and cold germinated wheat beverages (HB and CB) in changes of brain waves using EEG. Four distinct approaches and topographical assessments were performed to gain deeper insights into the impact of EEG signals in the human brain. The four approaches showed different impacts of HB and CB intake, as all EEG spectral powers increased after drinking HB and decreased after consumption of CB. Significant increases in delta and theta waves were observed as a result of drinking HB, but significant decreases in alpha and beta waves were observed after drinking CB. The topographic maps illustrate the significant effects of HB more prominently than those of CB, displaying greater changes in delta, theta, and beta. These findings suggest the intake of HB is probably related to relaxation, calmness, mindfulness and concentration, while the intake of CB is related to alertness, attention, and working memory. Ultimately, the neuroscientific approaches provided in this study could advance consumer-based research on beverage consumption.

The Multi-dimensional Assessment of Suicide Risk in Chronic illness-20 (MASC-20): Development and validation.

BACKGROUND: We developed and tested the psychometric properties of the Multi-dimensional assessment of suicide risk in chronic illness-20 (MASC-20), which assess suicidal behavior (SB), and its associated distress in chronic physical illness (CPI). METHODS: Items were developed by incorporating inputs from patient interviews, a review of existing instruments, and expert consultations. Pilot testing with 109 patients and field testing with 367 patients with renal, cardiovascular, and cerebrovascular diseases were conducted. We analyzed Time (T) 1 data to select items and T2 data to examine psychometric properties. RESULTS: Forty preliminary items were selected through pilot testing; 20 were finalized from field testing. Optimal internal consistency (α = 0.94) and test-retest reliability (Intra class correlation coefficient = 0.92) of the MASC-20 supported reliability. Good fit of the four-factor model (physical distress, psychological distress, social distress, and SB) from exploratory structural equation modeling demonstrated factorial validity. Its correlations with MINI suicidality (r = 0.59) and the Schedule of Attitudes Toward Hastened Death-abbreviated scores (r = 0.62) indicated convergent validity. Higher MASC-20 scores in patients with clinical levels of depression and anxiety and low health status demonstrated known-group validity. The MASC-20 distress score predicted SB beyond known SB risk factors, supporting incremental validity. A cutoff score of 16 was optimal for identifying suicide risk. The area under the curve was within a moderately accurate range. The sum of sensitivity and specificity (1.66) indicated diagnostic utility. LIMITATIONS: MASC-20's applicability to other patient populations and its sensitivity to change requires testing. CONCLUSIONS: The MASC-20 appears to be a reliable and valid tool for assessing SB in CPI.