Tixagevimab/cilgavimab (AZD7442/Evusheld) prevent from COVID19 in patients with hematologic malignancies under active chemotherapy.

Despite the efficacy of COVID-19 vaccines, patients with hematologic malignancy may still be fatal from COVID19. Therefore, we prospectively performed the analysis of administration of tixagevimab/cilgavimab in the real-world. In August 2022, 94 patients under active chemotherapy for lymphoma, multiple myeloma, or acute leukemia received a single dose AZD7442/Evusheld (two consecutive intramuscular injections of tixagevimab and cilgavimab, 300 mg each). Quantitative measurement of anti-SARS-CoV-2 spike protein (anti-S) and viral nucleocapsid (anti-N) titers were conducted before administration of tixagevimab/cilgavimab and at 1, 3, and 6 months after administration. Twenty-five patients (26.6%) had previously confirmed COVID-19 infection. Fifty-eight patients (61.7%) had previously received COVID-19 vaccinations, with a median of two doses (range, 1-5). The median anti-S Ab level increased from baseline (997.05 AU/mL) to 1 month (20,967.25 AU/mL), then decreased at 3 months (13,145.0 AU/mL), and 6 months (7123.0 AU/mL) (p < 0.001). There was no significant safety issue with tixagevimab/cilgavimab. With a median follow-up time of 6 months, thirteen patients (13.8%) had documented SARS-Cov-2 infection. A 20.2% rate of anti-N positivity was observed six months after the administration of tixagevimab/cilgavimab. The results of this study support the potential role of tixagevimab/cilgavimab for the prevention of symptomatic and severe COVID-19.Trial registration: KCT0007617; August 16, 2022.

AttSec: protein secondary structure prediction by capturing local patterns from attention map.

BACKGROUND: Protein secondary structures that link simple 1D sequences to complex 3D structures can be used as good features for describing the local properties of protein, but also can serve as key features for predicting the complex 3D structures of protein. Thus, it is very important to accurately predict the secondary structure of the protein, which contains a local structural property assigned by the pattern of hydrogen bonds formed between amino acids. In this study, we accurately predict protein secondary structure by capturing the local patterns of protein. For this objective, we present a novel prediction model, AttSec, based on transformer architecture. In particular, AttSec extracts self-attention maps corresponding to pairwise features between amino acid embeddings and passes them through 2D convolution blocks to capture local patterns. In addition, instead of using additional evolutionary information, it uses protein embedding as an input, which is generated by a language model. RESULTS: For the ProteinNet DSSP8 dataset, our model showed 11.8% better performance on the entire evaluation datasets compared with other no-evolutionary-information-based models. For the NetSurfP-2.0 DSSP8 dataset, it showed 1.2% better performance on average. There was an average performance improvement of 9.0% for the ProteinNet DSSP3 dataset and an average of 0.7% for the NetSurfP-2.0 DSSP3 dataset. CONCLUSION: We accurately predict protein secondary structure by capturing the local patterns of protein. For this objective, we present a novel prediction model, AttSec, based on transformer architecture. Although there was no dramatic accuracy improvement compared with other models, the improvement on DSSP8 was greater than that on DSSP3. This result implies that using our proposed pairwise feature could have a remarkable effect for several challenging tasks that require finely subdivided classification. Github package URL is https://github.com/youjin-DDAI/AttSec .

The inhibitory effect of Gremlin-2 on adipogenesis suppresses breast cancer cell growth and metastasis.

BACKGROUND: Gremlin-1 (GREM1) and Gremlin-2 (GREM2) are bone morphogenetic protein antagonists that play important roles in organogenesis, tissue differentiation, and tissue homeostasis. Although GREM1 has been reported to be involved in promoting various cancers, little has been reported about effects of GREM2 on cancer. Recently, it has been reported that GREM2 can inhibit adipogenesis in adipose-derived stromal/stem cells. However, as an inhibitor of adipogenesis, the role of GREM2 in cancer progression is not well understood yet. METHODS: Pre-adipocyte 3T3-L1 cells overexpressing mock or Grem2 were established using a lentiviral transduction system and differentiated into adipocytes-mock and adipocytes-Grem2, respectively. To investigate the effect of adipocyte-Grem2 on breast cancer cells, we analyzed the proliferative and invasion abilities of spheroids using a 3D co-culture system of breast cancer cells and adipocytes or conditioned medium (CM) of adipocytes. An orthotopic breast cancer mouse model was used to examine the role of adipocytes-Grem2 in breast cancer progression. RESULTS: Grem2 overexpression suppressed adipogenesis of 3T3-L1 cells. Proliferative and invasion abilities of spheroids formed by co-culturing MTV/TM-011 breast cancer cells and adipocytes-Grem2 were significantly reduced compared to those of spheroids formed by co-culturing MTV/TM-011 cells and adipocytes-mock. Compared to adipocytes-mock, adipocytes-Grem2 showed decreased mRNA expression of several adipokines, notably IL-6. The concentration of IL-6 in the CM of these cells was also decreased. Proliferative and invasive abilities of breast cancer cells reduced by adipocytes-Grem2 were restored by IL-6 treatment. Expression levels of vimentin, slug, and twist1 in breast cancer cells were decreased by treatment with CM of adipocytes-Grem2 but increased by IL-6 treatment. In orthotopic breast cancer mouse model, mice injected with both MTV/TM-011 cells and adipocytes-Grem2 showed smaller primary tumors and lower lung metastasis than controls. However, IL-6 administration increased both the size of primary tumor and the number of metastatic lung lesions, which were reduced by adipocytes-Grem2. CONCLUSIONS: Our study suggests that GREM2 overexpression in adipocytes can inhibit adipogenesis, reduce the expression and secretion of several adipokines, including IL-6, and ultimately inhibit breast cancer progression.

A Healthy Diet is Associated with a Lower Risk of Hepatic Fibrosis.

BACKGROUND: Higher diet quality is associated with a lower risk of NAFLD. OBJECTIVES: We examined the relationship between diet quality and hepatic fibrosis. METHODS: We analyzed cross-sectional associations between 3 a priori diet quality scores-the Dietary Approaches to Stop Hypertension (DASH) score, the Alternative Healthy Eating Index (AHEI), and a modified Mediterranean-style Diet Score (MDS)-and hepatic fat [controlled attenuation parameter (CAP)] and fibrosis [liver stiffness measurement (LSM)] measured by vibration-controlled transient elastography (VCTE) in 2532 Framingham Heart Study (FHS) participants and 3295 participants of the National Health and Nutrition Examination Survey (NHANES). RESULTS: Higher diet quality scores were associated with lower LSM in both FHS and NHANES after adjustment for demographic and lifestyle factors. Additional adjustment for CAP or BMI attenuated the observed associations. Association strength was similar across all 3 diet quality scores. Fixed-effect meta-analysis demonstrated that, under CAP-adjusted models, the LSM decreases associated with 1-SD increase of the DASH, AHEI, and MDS scores were 2% (95% CI: 0.7%, 3.3%; P = 0.002), 2% (95% CI: 0.7%, 3.3%; P = 0.003), and 1.7% (95% CI: 0.7%, 2.6%; P = 0.001), respectively, whereas in the meta-analysis of BMI-adjusted models, LSM reductions associated with 1-SD increase of the DASH, AHEI, and MDS scores were 2.2% (95% CI: -0.1%, 2.2%; P = 0.07), 1.5% (95% CI: 0.3%, 2.7%; P = 0.02), and 0.9 (95% CI: -0.1%, 1.9%; P = 0.07), respectively. CONCLUSIONS: We demonstrated associations of higher diet quality with favorable hepatic fat and fibrosis measures. Our data suggest that a healthy diet may reduce the likelihood of obesity and hepatic steatosis as well as the progression of steatosis to fibrosis.

Risk factors of menopause after allogeneic hematopoietic cell transplantation in premenopausal adult women.

OBJECTIVES: Allogeneic hematopoietic stem-cell transplantation (HCT) is the only curative option for most hematologic malignancies. However, HSCT can cause early menopause and various complications in premenopausal women. Therefore, we aimed to investigate risk factors predicting early menopause and its clinical implications among survivors post HCT. METHODS: We retrospectively analyzed 30 adult women who had received HCT at premenopausal status between 2015 and 2018. We excluded patients who had received autologous stem cell transplantation, had relapsed, or died of any cause within 2 years of HCT. RESULTS: The median age at HCT was 41.6 years (range, 22-53). Post-HCT menopause was identified in 90% of myeloablative conditioning (MAC) HCT and 55% of reduced-intensity conditioning (RIC) HCT (p = .101). In the multivariate analysis, the post-HCT menopausal risk was 21 times higher in a MAC regimen containing 4 days of busulfan (p = .016) and 9.3 times higher in RIC regimens containing 2-3 days of busulfan (p = .033) than that of non-busulfan-based conditioning regimens. CONCLUSIONS: Higher busulfan dose in conditioning regimens is the most significant risk factor affecting post-HCT early menopause. Considering our data, we need to decide on conditioning regimens and individualized fertility counseling before HCT for premenopausal women.

Cyanobacteria control using Cu-based metal organic frameworks derived from waste PET bottles.

Copper sulfate (CuSO4) is actively used to control the proliferation of harmful algal blooms because of its fast and effective killing mechanism. However, its use unintentionally harms innocuous aquatic organisms. Therefore, there is a need to find non-toxic solutions for controlling algal blooms. In this study, Cu-based metal-organic framework (Cu-BDC MOF) chips (ca. 2 × 2 cm) were synthesized using waste polyethylene terephthalate (PET) bottles. The as-synthesized Cu-BDC MOF chips efficiently inhibited the cyanobacteria species Microcystis aeruginosa, which was comparable to the conventional dose of CuSO4 algaecide (1.00 mg L-1). Moreover, unlike the CuSO4 algaecide, Cu-BDC MOF chips did not cause any acute toxicity (48 h) to the water flea Daphnia magna. Both Cu-BDC MOF and Cu2O seemed to be responsible for the generation of reactive oxygen species, which resulted in the aggregation, photosynthesis disruption, and eventually growth inhibition of M. aeruginosa. This study suggests that the environmentally safe Cu-BDC MOF chip is a promising agent to sustainably control harmful algal blooms.

Tumor infiltrated immune cell types support distinct immune checkpoint inhibitor outcomes in patients with advanced non-small cell lung cancer.

The evaluation of PD-L1 expression alone has limitations in predicting clinical outcome in immune-checkpoint inhibitors (ICI). This study aimed to evaluate the predictive and prognostic effects of the presence of various immune cells in pretreatment tissue samples and to identify determinants associated with response in patients with advanced non-small cell lung cancer (NSCLC) treated with PD-1 blockade. Immune cell distribution was heterogeneous and the most dominant immune cell type was T cells. Patients with durable clinical benefit (DCB) showed significantly higher PD-L1 expression. The ratio of tumor/stroma region of T cell, B cell, and macrophage was significantly higher in patient with DCB. High intratumoral T- and B-cell density (≥median) was associated with DCB in the low PD-L1 expression (<50%) group. In univariate analyses, the overall survival (OS) benefit was shown according to intratumoral B-cell density (p = 0.0337). The incidence of hyperprogressive disease (HPD) was 13.0%. The Chi-square test revealed that HPD was significantly associated with intratumoral B-cell density but not T-cell or macrophage density. Our results demonstrate different predictive and prognostic values for infiltrating immune cells in tumor tissue, which may help in selecting patients for ICI.

The soluble VCAM-1 level is a potential biomarker predicting severe acute graft versus host disease after allogeneic hematopoietic cell transplantation.

BACKGROUND: Severe graft versus host disease (GVHD) is the main reason for non-relapse mortality following allogeneic hematopoietic cell transplantation (HCT). We investigated the serum protein profiles of patients who had undergone HCT to identify predictive biomarkers of severe acute GVHD (aGVHD). METHODS: Serum samples were collected for 30 patients from day - 7 to day + 14 of HCT. The serum levels of plasma beta2-microglobulin (ß2-MG), soluble vascular cell adhesion molecule-1 (sVCAM-1), platelet factor 4, and TNFSF-14 were measured by ELISA as potential biomarkers following 310 cytokine profiling array. RESULTS: The median age of the study patients was 53.5 years (range, 19-69). All grade and grade 2-4 aGVHD developed in 21 (70.0%) and 17 (56.7%) patients, respectively. Compared with their baseline levels on day - 7, ß2-MG and sVCAM-1 were significantly increased on day + 14 of the HCT procedure (P = 0.028 and P < 0.001, respectively). Patients with a grade 2-4 severe aGVHD showed a significantly higher sVCAM-1 level at baseline (day-7) and at day + 14, compared with the other group with a grade 1 aGVHD or no aGVHD (P = 0.028 and P = 0.035, respectively). CONCLUSION: Higher sVCAM- levels at baseline and on day + 14 in HCT patients could be a significant predictive biomarker of severe aGVHD.

Statistical modeling of health space based on metabolic stress and oxidative stress scores.

BACKGROUND: Health space (HS) is a statistical way of visualizing individual's health status in multi-dimensional space. In this study, we propose a novel HS in two-dimensional space based on scores of metabolic stress and of oxidative stress. METHODS: These scores were derived from three statistical models: logistic regression model, logistic mixed effect model, and proportional odds model. HSs were developed using Korea National Health And Nutrition Examination Survey data with 32,140 samples. To evaluate and compare the performance of the HSs, we also developed the Health Space Index (HSI) which is a quantitative performance measure based on the approximate 95% confidence ellipses of HS. RESULTS: Through simulation studies, we confirmed that HS from the proportional odds model showed highest power in discriminating health status of individual (subject). Further validation studies were conducted using two independent cohort datasets: a health examination dataset from Ewha-Boramae cohort with 862 samples and a population-based cohort from the Korea association resource project with 3,199 samples. CONCLUSIONS: These validation studies using two independent datasets successfully demonstrated the usefulness of the proposed HS.

Estimation of Number of Pigs Taking in Feed Using Posture Filtration.

Pork production is hugely impacted by the health and breeding of pigs. Analyzing the eating pattern of pigs helps in optimizing the supply chain management with a healthy breeding environment. Monitoring the feed intake of pigs in a barn provides information about their eating habits, behavioral patterns, and surrounding environment, which can be used for further analysis to monitor growth in pigs and eventually contribute to the quality and quantity of meat production. In this paper, we present a novel method to estimate the number of pigs taking in feed by considering the pig's posture. In order to solve problems arising from using the pig's posture, we propose an algorithm to match the pig's head and the corresponding pig's body using the major-and-minor axis of the pig detection box. In our experiment, we present the detection performance of the YOLOv5 model according to the anchor box, and then we demonstrate that the proposed method outperforms previous methods. We therefore measure the number of pigs taking in feed over a period of 24 h and the number of times pigs consume feed in a day over a period of 30 days, and observe the pig's feed intake pattern.

Improvement of Biological Effects of Root-Filling Materials for Primary Teeth by Incorporating Sodium Iodide.

Therapeutic iodoform (CHI3) is commonly used as a root-filling material for primary teeth; however, the side effects of iodoform-containing materials, including early root resorption, have been reported. To overcome this problem, a water-soluble iodide (NaI)-incorporated root-filling material was developed. Calcium hydroxide, silicone oil, and NaI were incorporated in different weight proportions (30:30:X), and the resulting material was denoted DX (D5~D30), indicating the NaI content. As a control, iodoform instead of NaI was incorporated at a ratio of 30:30:30, and the material was denoted I30. The physicochemical (flow, film thickness, radiopacity, viscosity, water absorption, solubility, and ion releases) and biological (cytotoxicity, TRAP, ARS, and analysis of osteoclastic markers) properties were determined. The amount of iodine, sodium, and calcium ion releases and the pH were higher in D30 than I30, and the highest level of unknown extracted molecules was detected in I30. In the cell viability test, all groups except 100% D30 showed no cytotoxicity. In the 50% nontoxic extract, D30 showed decreased osteoclast formation compared with I30. In summary, NaI-incorporated materials showed adequate physicochemical properties and low osteoclast formation compared to their iodoform-counterpart. Thus, NaI-incorporated materials may be used as a substitute for iodoform-counterparts in root-filling materials after further (pre)clinical investigation.

Patchy Colloidal Clusters with Broken Symmetry.

Colloidal clusters are prepared by assembling positively charged cross-linked polystyrene (PS) particles onto negatively charged liquid cores of swollen polymer particles. PS particles at the interface of the liquid core are closely packed around the core due to interfacial wetting. Then, by evaporating solvent in the liquid cores, polymers in the cores are solidified and the clusters are cemented. As the swelling ratio of PS cores increases, cores at the center of colloidal clusters are exposed, forming patchy colloidal clusters. Finally, by density gradient centrifugation, high-purity symmetric colloidal clusters are obtained. When silica-PS core-shell particles are swollen and serve as the liquid cores, hybrid colloidal clusters are obtained in which each silica nanoparticle is relocated to the liquid core interface during the swelling-deswelling process breaking symmetry in colloidal clusters as the silica nanoparticle in the core is comparable in size with the PS particle in the shell. The configuration of colloidal clusters is determined once the number of particles around the liquid core is given, which depends on the size ratio of the liquid core and shell particle. Since hybrid clusters are heavier than PS particles, they can be purified using centrifugation.

MDSC subtypes and CD39 expression on CD8+ T cells predict the efficacy of anti-PD-1 immunotherapy in patients with advanced NSCLC.

The major suppressive immune cells in tumor sites are myeloid derived suppressor cells (MDSCs), tumor-associated macrophages (TAMs), and Treg cells, and the major roles of these suppressive immune cells include hindering T-cell activities and supporting tumor progression and survival. In this study, we analyzed the pattern of circulating MDSC subtypes in patients with non-small cell lung cancer (NSCLC) whether those suppressive immune cells hinder T-cell activities leading to poor clinical outcomes. First, we verified PMN-MDSCs, monocytic-MDSCs (M-MDSCs), and Treg cells increased according to the stages of NSCLC, and MDSCs effectively suppressed T-cell activities and induced T-cell exhaustion. The analysis of NSCLC patients treated with anti-PD-1 immunotherapy demonstrated that low PMN-MDSCs, M-MDSCs, and CD39+ CD8+ T cells as an individual and all together were associated with longer progression free survival and overall survival, suggesting PMN-MDSCs, M-MDSCs, and CD39+ CD8+ T cells frequencies in peripheral blood might be useful as potential predictive and prognostic biomarkers.

Efficacy of intravenous iron treatment for chemotherapy-induced anemia: A prospective Phase II pilot clinical trial in South Korea.

BACKGROUND: Anemia is the most common and serious cancer-related complication. This study aimed to evaluate the efficacy of administration of ferric carboxymaltose without erythropoiesis-stimulating agents for treating anemia in cancer patients. Moreover, we identified the biomarkers of hemoglobin response to predict the need for iron therapy. METHODS AND FINDINGS: We enrolled patients with solid cancers who were treated at a single institute (Samsung Medical Center, South Korea), from April 2015 to July 2017, in this prospective single-arm Phase II clinical trial. Patients received intravenous ferric carboxymaltose (1,000 mg) infusion on the first day (visit 1) of treatment. The primary end point was the number of hemoglobin responders, defined as patients with an increase in hemoglobin level ≥ 1.0 g/dL from the baseline, a hemoglobin level ≥ 11.0 g/dL, or both, within an 8-week observation period (week 3, 6, or 8). Secondary end points included changes in transferrin saturation and levels of soluble transferrin receptors, hepcidin, erythropoietin, interleukin-6, and C-reactive protein (CRP) at each visit. Of the 103 recruited patients, 92 were eligible for analysis. The mean patient age was 57.3 ± 12.5 years, and 54.3% of the patients were women. The most common diagnoses were breast cancer (n = 23, 25.1%), lung cancer (n = 21, 22.9%), gastrointestinal cancer (n = 20, 20.9%), and lymphoma (n = 16, 17.7%). A hemoglobin response was observed in 36 (39.1%), 53 (57.6%), and 61 (66.3%) patients in the third, fifth, and eighth weeks, respectively. The mean increase in hemoglobin levels from the baseline to the end of treatment was 1.77 ± 1.30 g/dL. Baseline values of hepcidin (p = 0.008), total iron binding capacity (p = 0.014), ferritin (p = 0.048), and CRP (p = 0.044) were significantly different between the responder and nonresponder groups. Multiple logistic regression analysis for baseline anemia-related biochemical variable significantly associated with the hemoglobin response showed that only baseline hepcidin level was a significant factor for hemoglobin response (odds ratio = 0.95, 95% confidence interval 0.90-1.0, p = 0.045). Hemoglobin responders had significantly lower hepcidin levels than nonresponders (mean [±standard deviation], 13.45 [±14.71] versus 35.22 [±40.470 ng/ml]; p = 0.007). However, our analysis had some limitations such as the different patient characteristics in the studies that were included, institutional differences in the measurement of hepcidin level, and missing data on long-term safety. Therefore, our findings need further validation. CONCLUSIONS: Intravenous ferric carboxymaltose (1,000 mg) monotherapy increases hemoglobin levels without serious adverse events in patients with cancer. Hepcidin is a useful biomarker for predicting iron requirement in cancer patients. TRIAL REGISTRATION: Clinicaltrials.gov NCT02599012.

The emerging role of xanthine oxidase inhibition for suppression of breast cancer cell migration and metastasis associated with hypercholesterolemia.

Hypercholesterolemia is reported to increase reactive oxygen species (ROS) and to promote breast cancer progression. ROS play an important role in tumor biology, and xanthine oxidase (XO) is an enzyme that generates ROS. The effects of febuxostat (FBX), an XO inhibitor, on breast cancer cell migration under LDL stimulation in vitro and metastasis of breast cancer associated with hypercholesterolemia in vivo were studied. In vitro, FBX significantly inhibited LDL-induced ROS production and cell migration. Treatment of small interfering RNA against XO was consistent with the findings of FBX treatment. In vivo, a significant increase of tumor growth and pulmonary metastasis was observed in a xenograft mouse model with 4T1 cells on a high cholesterol diet (HCD), both of which were markedly inhibited by FBX or allopurinol treatment. Moreover, ERK represented the main target-signaling pathway that was affected by FBX treatment in a xenograft mouse model on an HCD evaluated by NanoString nCounter analysis. Consistently, MEK/ERK inhibitors directly decreased the LDL-induced cell migration in vitro. In conclusion, FBX mitigates breast cancer cell migration and pulmonary metastasis in the hyperlipidemic condition, associated with decreased ROS generation and MAPK phosphorylation. The inhibition of ERK pathways is likely to underlie the XO inhibitor-mediated suppression of breast cancer cell migration.-Oh, S.-H., Choi, S.-Y., Choi, H.-J., Ryu, H.-M., Kim, Y.-J., Jung, H.-Y., Cho, J.-H., Kim, C.-D., Park, S.-H., Kwon, T.-H., Kim, Y.-L. The emerging role of xanthine oxidase inhibition for suppression of breast cancer cell migration and metastasis associated with hypercholesterolemia.

The Crucial Role of Xanthine Oxidase in CKD Progression Associated with Hypercholesterolemia.

In the present study, we investigated the effects of xanthine oxidase (XO) inhibition on cholesterol-induced renal dysfunction in chronic kidney disease (CKD) mice, and in low-density lipoprotein (LDL)-treated human kidney proximal tubule epithelial (HK-2) cells. ApoE knockout (KO) mice underwent uninephrectomy to induce CKD, and were fed a normal diet or high-cholesterol (HC) diet along with the XO inhibitor topiroxostat (1 mg/kg/day). HK-2 cells were treated with LDL (200 µg/mL) and topiroxostat (5 µM) or small interfering RNA against xanthine dehydrogenase (siXDH; 20 nM). In uninephrectomized ApoE KO mice, the HC diet increased cholesterol accumulation, oxidative stress, XO activity, and kidney damage, while topiroxostat attenuated the hypercholesterolemia-associated renal dysfunction. The HC diet induced cholesterol accumulation by regulating the expressions of genes involved in cholesterol efflux (Nr1h3 and Abca1) and synthesis (Srebf2 and Hmgcr), which was reversed by topiroxostat. Topiroxostat suppressed the expressions of genes related to hypercholesterolemia-associated inflammation and fibrosis in the unilateral kidney. LDL stimulation evoked changes in the cholesterol metabolism, nicotinamide adenine dinucleotide phosphate (NADPH) oxidase, and NF-κB pathways in HK-2 cells, which were mitigated by XO inhibition with topiroxostat or siXDH. These findings suggest that XO inhibition exerts renoprotective effects against hypercholesterolemia-associated kidney injury. XO could be a novel therapeutic target for hypercholesterolemia-associated kidney injury in uninephrectomized patients.

NOX1 Inhibition Attenuates Kidney Ischemia-Reperfusion Injury via Inhibition of ROS-Mediated ERK Signaling.

The protective effects of nicotinamide adenine dinucleotide phosphate (NADPH) oxidase (NOX) 1 inhibition against kidney ischemia-reperfusion injury (IRI) remain uncertain. The bilateral kidney pedicles of C57BL/6 mice were clamped for 30 min to induce IRI. Madin-Darby Canine Kidney (MDCK) cells were incubated with H2O2 (1.4 mM) for 1 h to induce oxidative stress. ML171, a selective NOX1 inhibitor, and siRNA against NOX1 were treated to inhibit NOX1. NOX expression, oxidative stress, apoptosis assay, and mitogen-activated protein kinase (MAPK) pathway were evaluated. The kidney function deteriorated and the production of reactive oxygen species (ROS), including intracellular H2O2 production, increased due to IRI, whereas IRI-mediated kidney dysfunction and ROS generation were significantly attenuated by ML171. H2O2 evoked the changes in oxidative stress enzymes such as SOD2 and GPX in MDCK cells, which was mitigated by ML171. Treatment with ML171 and transfection with siRNA against NOX1 decreased the upregulation of NOX1 and NOX4 induced by H2O2 in MDCK cells. ML171 decreased caspase-3 activity, the Bcl-2/Bax ratio, and TUNEL-positive tubule cells in IRI mice and H2O2-treated MDCK cells. Among the MAPK pathways, ML171 affected ERK signaling by ERK phosphorylation in kidney tissues and tubular cells. NOX1-selective inhibition attenuated kidney IRI via inhibition of ROS-mediated ERK signaling.

A retrospective feasibility study of biweekly docetaxel in patients with high-risk metastatic castration-naïve prostate cancer.

BACKGROUND: Results from randomized phase III trials have shown that thrice-weekly docetaxel added to androgen-deprivation therapy (ADT) has a significant impact on the survival of patients with metastatic castration-naïve prostate cancer (mCNPC) and established early chemotherapy as part of the standard of care for high-risk disease. Controversy remains, however, because some patients experience critical toxicities related to docetaxel. The purpose of the current study was to evaluate the feasibility and adverse events of biweekly-administered docetaxel in patients with previously-untreated, high-risk mCNPC. METHODS: The study included 35 consecutive patients with high-risk mCNPC who received ADT plus docetaxel 40 mg/m2. Oral prednisone 5 mg twice daily was also given. Treatment was repeated every two weeks for up to 12 cycles or until disease progression or unacceptable toxicity occurred. High-risk was defined as bone metastases beyond axial skeleton and/or visceral disease. RESULTS: The included patients' median age was 68 years (range: 31-86 years) and 17 (49%) had visceral metastases. Biweekly docetaxel was generally well-tolerated; the most commonly observed adverse events, considering those of all grades, included alopecia (74%), nail changes (42%), and constipation (31%). Hematologic adverse events were infrequent, and no patient received hematopoietic growth factors. One patient died after the fourth cycle due to respiratory failure, which occurred as a complication of pneumonia. Among the 35 patients, 28 completed the planned 12 cycles of biweekly docetaxel. Prostate-specific antigen response (> 50% decrease from baseline) was recorded in 33 patients (94%), and the radiologic response rate was 49%. Median progression-free survival was 13.6 months (95% confidence interval: 6.7-20.4). CONCLUSION: ADT plus biweekly-administered docetaxel appeared to be tolerated and effective in patients with high-risk mCNPC.

Current practices of cytoreductive surgery and hyperthermic intraperitoneal chemotherapy in the treatment of peritoneal surface malignancies: an international survey of oncologic surgeons.

BACKGROUND: The goal of the study was to investigate the current clinical practices among oncologic surgeons regarding cytoreductive surgery (CRS) with intraoperative hyperthermic intraperitoneal chemotherapy (HIPEC). METHODS: From September to October 2016, an online questionnaire surveyed the oncologic surgeons by email. The questionnaire included 20 multiple-choice questions of the following: eligibility for the CRS with HIPEC procedure, perioperative staging and surgery skill, assessment of residual tumors, and method used for intraperitoneal HIPEC. RESULTS: The response rate was 16% (34/217). The majority of respondents (68%) worked at a university hospital. All respondents indicated that mesenteric invasion is the most crucial factor affecting treatment decision. Most surgeons (79%) used the Sugarbaker's staging system to intraoperatively measure the extent of peritoneal invasion. The methods used to measure the extent of miliary pattern of residual tumor spread, and the amount of residual tumor after electrocauterization varied among the surgeons. Most responders (65%) used the closed system of HIPEC. CONCLUSIONS: Despite the fact that CRS HIPEC is the standard treatment for PSM, the clinical practices are very different according to each clinical situation. Nevertheless, mesenteric invasion was found to be the most important factor impacting the treatment decision-making by the majority of responders.

Clinical trial of nintedanib in patients with recurrent or metastatic salivary gland cancer of the head and neck: A multicenter phase 2 study (Korean Cancer Study Group HN14-01).

BACKGROUND: Salivary gland cancers (SGCs) are uncommon and account for less than 5% of all head and neck cancers, but they are histologically heterogeneous. No specific therapy, including targeted agents, has consistently improved clinical outcomes in recurrent/metastatic SGC. Recent studies suggest that vascular endothelial growth factor receptor (VEGFR) and platelet-derived growth factor receptor (PDGFR) play important roles in SGC. Nintedanib is a potent small-molecule, triple-receptor tyrosine kinase inhibitor (VEGFR1, VEGFR2, and VEGFR3; fibroblast growth factor receptor 1 [FGFR1], FGFR2, and FGFR3; and PDGFRα and PDGFRß). This study sought to determine the antitumor activity of nintedanib in patients with recurrent or metastatic SGC. METHODS: This open-label, multicenter, phase 2, single-arm study was conducted at 11 hospitals in South Korea. Patients with pathologically confirmed recurrent and/or metastatic SGC for whom at least 1 line of systemic chemotherapy had failed were enrolled. Nintedanib was given orally at 200 mg twice a day until disease progression or unacceptable toxicity. The primary endpoint was the response rate. The secondary endpoints were progression-free survival, overall survival, toxicity, and the disease-control rate. The Simon 2-stage minimax design was used. RESULTS: The median age of the patients was 54 years, 60% were female, and 95% had an Eastern Cooperative Oncology Group performance status of 0 or 1. The majority of the patients had adenoid cystic carcinoma (65%), and 40% received at least 2 prior rounds of chemotherapy. After 20 patients were enrolled, the study was stopped because no responders were observed at stage I. There were no partial responses, but the disease-control rate was 75% (15 of 20). The median duration of stable disease was 8.2 months (range, 1.76-12.36 months). At the time of the data cutoff, with a median follow-up of 9.5 months, the median overall survival had not been reached, and the progression-free survival rate at 6 months was 60% (95% confidence interval, 0.34-0.79). Grade 3 adverse events included liver enzyme elevation (25%) and nausea/vomiting (5%). Four patients who required a dose reduction because of a grade 3 liver enzyme elevation showed no further grade 3 events. CONCLUSIONS: Single-agent nintedanib did not yield a partial response but did achieve a 75% disease-control rate with long-term stabilization in SGC patients. Because of the high rate and long duration of disease control with a good safety profile, further investigation is warranted. Cancer 2017;123:1958-1964. © 2017 American Cancer Society.