Selenium Lessens Osteoarthritis by Protecting Articular Chondrocytes from Oxidative Damage through Nrf2 and NF-κB Pathways.

Osteoarthritis (OA) causes joint pain and disability due to the abnormal production of inflammatory cytokines and reactive oxygen species (ROS) in chondrocytes, leading to cell death and cartilage matrix destruction. Selenium (Se) intake can protect cells against oxidative damage. It is still unknown whether Se supplementation is beneficial for OA. This study investigated the effects of Se on sodium iodoacetate (MIA)-imitated OA progress in human chondrocyte cell line (SW1353 cells) and rats. The results showed that 0.3 µM of Se treatment could protect SW1353 cells from MIA-induced damage by the Nrf2 pathway by promoting the gene expression of glutathione-synthesis-related enzymes such as the glutamate-cysteine ligase catalytic subunit, the glutamate-cysteine ligase modifier subunit, and glutathione synthetase. In addition, glutathione, superoxide dismutase, glutathione peroxidase, and glutathione reductase expressions are also elevated to eliminate excessive ROS production. Moreover, Se could downregulate NF-κB, leading to a decrease in cytokines, matrix proteases, and glycosaminoglycans. In the rats, MIA-induced cartilage loss was lessened after 2 weeks of Se supplementation by oral gavage; meanwhile, glutathione synthesis was increased, and the expressions of pro-inflammatory cytokines were decreased. These results suggest that Se intake is beneficial for OA due to its effects of decreasing cartilage loss by enhancing antioxidant capacity and reducing inflammation.

[Inhibitory Effect of Metformin and Arsenic Trioxide on KG1a Cell Proliferation].

OBJECTIVE: To investigate the effect of metformin and arsenic trioxide on KG1a cells proliferation of acute myeloid leukemia and its possible mechanism. METHODS: CCK-8 method was used to detect the killing effect of metformin, arsenic trioxide and combined application on KG1a cells. Annexin V-FITC/PI Dual Stain Flow Cytometry was used to detect the effect of combined application on apoptosis of KG1a cells. Western blot was used to detect the expression of intracellular apoptosis-,autophagy-related protein. RESULTS: Metformin and arsenic trioxide alone or in combination could inhibit the proliferation of KG1a cells and induce apoptosis of KG1a cells, and the proliferation inhibition rate and apoptosis rate in the combined drug group were higher than those in the drug group alone(P <0.05). The combination of drugs induced upregulation of Caspase 8 protein and P62 protein expression and was higher than that in the drug group alone(P <0.05). CONCLUSION: Metformin can synergize with arsenic trioxide to kill KG1a cells, and its mechanism of action may be related to inducing apoptosis and enhancing autophagy.

Subfield-specific interneuron circuits govern the hippocampal response to novelty in male mice.

The hippocampus is the brain's center for episodic memories. Its subregions, the dentate gyrus and CA1-3, are differentially involved in memory encoding and recall. Hippocampal principal cells represent episodic features like movement, space, and context, but less is known about GABAergic interneurons. Here, we performed two-photon calcium imaging of parvalbumin- and somatostatin-expressing interneurons in the dentate gyrus and CA1-3 of male mice exploring virtual environments. Parvalbumin-interneurons increased activity with running-speed and reduced it in novel environments. Somatostatin-interneurons in CA1-3 behaved similar to parvalbumin-expressing cells, but their dentate gyrus counterparts increased activity during rest and in novel environments. Congruently, chemogenetic silencing of dentate parvalbumin-interneurons had prominent effects in familiar contexts, while silencing somatostatin-expressing cells increased similarity of granule cell representations between novel and familiar environments. Our data indicate unique roles for parvalbumin- and somatostatin-positive interneurons in the dentate gyrus that are distinct from those in CA1-3 and may support routing of novel information.

Association of geriatric measures and global frailty with cognitive decline after allogeneic hematopoietic cell transplantation in older adults.

INTRODUCTION: Allogeneic hematopoietic cell transplantation (alloHCT) is increasingly offered to older adults, and its potential impact on cognition in this population is understudied. This work aims to evaluate the ability of cancer-specific geriatric assessments (cGA) and a global frailty index based on accumulation of deficits identified in the cGA to predict the risk of cognitive decline after alloHCT in older adults. MATERIALS AND METHODS: AlloHCT recipients aged 50 years or older completed a cGA, including a cognitive evaluation by the Blessed Orientation Memory Concentration (BOMC) test, at baseline prior to alloHCT and then at 3, 6, and 12 months after transplant. Baseline frailty was assessed using a deficit accumulation frailty index (DAFI) calculated from the cGA. A multinomial logit model was used to examine the association between predictors (individual cGA measures, DAFI) and the following three outcomes: alive with stable or improved cognition, alive with cognitive decline, and deceased. In post-hoc analyses, analysis of variance was used to compare BOMC scores at baseline, 3, 6, and 12 months across frailty categories. RESULTS: In total, 148 participants were included, with a median age of 62 (range 50-76). At baseline, 12% had cognitive impairment; at one year, 29% of survivors had improved BOMC scores, 33% had stable BOMC, and 37% had worse BOMC. Prior to transplant, 25% were pre-frail and 11% were frail. Individual baseline cGA measures were not associated with cognitive change at one year as assessed by BOMC. Adjusting for age, sex, and education, those who were frail at baseline were 7.4 times as likely to develop cognitive decline at one year than those who were non-frail, although this finding did not reach statistical significance (95% confidence interval [CI] 0.74-73.8, p = 0.09). The probability of being alive with stable/improved cognition at 12 months for the non-frail, pre-frail, and frail groups was 43%, 34%, and 8%, respectively. DISCUSSION: Baseline geriatric measures and frailty were not significantly associated with cognitive change as assessed by BOMC in adults aged 50 or older after alloHCT. However, the study was underpowered to detect clinically meaningful differences, and future work to elucidate potential associations between frailty and cognitive outcomes is warranted.

Patterns and Predictors of Functional Decline after Allogeneic Hematopoietic Cell Transplantation in Older Adults.

As allogeneic hematopoietic cell transplantation (alloHCT) is increasingly offered to older adults, geriatric assessment (GA) has been identified as a useful tool for predicting outcomes, particularly functional status. However, very few studies have examined the longitudinal change in GA measures in the post-alloHCT period. The objectives of this study were to describe the longitudinal change in GA and quality of life (QoL) measures after alloHCT and to identify predictors of greater functional decline post-transplantation. In this single-center prospective cohort study, patients age ≥50 years scheduled for alloHCT completed a cancer-specific GA and the Functional Assessment of Cancer Therapy-Bone Marrow Transplant (FACT-BMT) survey at baseline prior to alloHCT and then at 3, 6, and 12 months post-transplantation. Changes in GA and QoL measures at each post-transplantation time point (3, 6, and 12 months) compared to baseline were analyzed using paired t-tests. Exploration of potential predictors of greater post-transplantation functional decline, as measured by instrumental activities of daily living (IADL) and the Medical Outcomes Study Physical Health scale (MOS-PH), were examined using linear regression and the chi-square 2-sample test of proportions. Mean functional status generally exhibited a pattern of decline at 3 to 6 months post-alloHCT, with recovery to near baseline by 12 months. Mean mental health and emotional QoL were lowest at baseline and improved at all post-transplantation time points. Differences in baseline clinical characteristics were not associated with any differences in functional trajectories. Differences in baseline GA measures-patient-rated Karnofsky Performance Status, IADL, MOS-PH, Timed-Up-and-Go, Blessed Orientation-Memory-Concentration test, and Mental Health Inventory 5-also did not predict greater functional decline at 3 months. Patients whose IADL was improved or maintained at 3 months generally maintained their functional status at 6 and 12 months. Similarly, most patients who had an IADL decline at 3 months still had a functional decline at 6 months, although a proportion did have functional recovery by 12 months. Compared with patients who had improved/maintained IADL at 3 months, those with a decline in IADL at 3 months were significantly more likely to have persistent functional decline at 6 months (P < .0001) and 12 months (P = .02). In older alloHCT recipients, mean functional status declines short term after alloHCT with the possibility of recovery by 6 to 12 months, whereas mean mental and emotional health improve post-alloHCT. Functional decline at 3 months post-alloHCT is associated with persistent functional decline at 12 months.

Geriatric assessment in older adults with non-Hodgkin lymphoma: A Young International Society of Geriatric Oncology (YSIOG) review paper.

Non-Hodgkin lymphoma (NHL) is a disease of older adults, with a median age at diagnosis of 67 years. Treatment in older adults with NHL is challenging. The aging process is associated with a decline in functional reserve that varies among individuals, and results in an increasing risk of treatment-related toxicity and mortality. Chronological age and performance status fail to capture the multidimensional and heterogeneous nature of the aging process. A geriatric assessment (GA) screens multiple geriatric domains and provides a more accurate assessment of functional reserve. Several abbreviated GA tools have been developed for use in oncology clinics and help identify patients at high risk for chemotherapy-related toxicity and mortality. In this review, we explore GA tools validated for use in patients with NHL. We discuss the evidence behind GA-guided treatment in NHL and present a suggested approach to assessing frailty in this patient population.

Aggregation-induced emission (AIE)-guided dynamic assembly for disease imaging and therapy.

The phenomenon of aggregation-induced emission (AIE) is inseparable from molecular aggregation and self-assembly. Therefore, the combination of AIE and supramolecular self-assembly is well-matched. AIE-guided dynamic assembly (AGDA) could effectively respond to the endogenous stimuli (such as pH, enzymes, redox molecules) and exogenous stimuli (temperature, light, ultrasound) in the disease microenvironment, so as to achieve specific imaging and diagnosis of the disease lesions. Moreover, AGDA also dynamically adjust the intramolecular motions of AIE molecules, thereby adjusting the energy dissipation pathways and realizing the switch between photodynamic therapy and photothermal therapy for superior therapeutic effects. In this review, we aim to give an overview of the constructing strategies, stimuli-responsive imaging, regulation of intramolecular motion of AGDA in recent years, which is expected to grasp the research status and striving directions of AGDA for imaging and therapy.

Effectiveness of individual audio-visual coaching, respiratory modulated stereotactic body radiotherapy for localized hepatocellular carcinoma: Analysis of 29 cases from a single academic radiotherapy center.

OBJECTIVES: Recently, Stereotactic Body Radiotherapy (SBRT) has been suggested for managing hepatocellular carcinoma (HCC) curatively. Thus, we conducted this clinical study to evaluate retrospectively the effect of individualized audio-visual (AV) coaching, respiratory modulated SBRT. MATERIALS AND METHODS: Between 2014 and 2018, 29 patients with inoperable Barcelona Clinic Liver Cancer (BCLC) stage 0-B HCC received AV coaching, respiratory-modulated SBRT. We constructed a task-oriented multidisciplinary team to establish a standard operation process of respiratory modulation procedures and developed our AV coaching devices. In the training period, a goodness-of-fit test was applied individually. SBRT was delivered with a total dose of 40-54 Gy in 5-6 fractions individually. Freedom from local progression (FFLP) and overall survival (OS) were estimated using SPSS (version 17, SPSS Inc., Chicago, IL, USA) life tables. RESULTS: The patient characteristics were as follows: 32.7 ± 16 mm in maximum tumor diameter (range 11-94); BCLC stage 0: 3.4%, BCLC A: 48.3%, BCLC B: 48.3%; Child-Pugh classification A: 86.2%, Child-Pugh classification B: 13.8%, and a median of 2 prior liver-directed treatments (range 0-7). One-, 2-, and 3-year rates of FFLP of SBRT were 96.6%, 96.6%, and 96.6%, respectively. One-, 2-, and 3-year rates of OS were 81.5%, 72.4%, and 67.2%, respectively. No adverse event (AE) occurred in 41.4% of patients, 48.3% developed grade (G) 1-2 AE, 10.3% had G3 AE and none had G4-5 AE. CONCLUSION: Respiration-modulated SBRT is a promising noninvasive treatment option for patients with inoperable and localized HCC. Our data show that SBRT provides comparable tumor control to historical curative options like surgery and radiofrequency ablation of localized tumors. Thus, we are conducting a further prospective clinical trial with the intent to demarcate the clinical effectiveness of SBRT in a larger population of patients with HCC.

IRAK2, an IL1R/TLR Immune Mediator, Enhances Radiosensitivity via Modulating Caspase 8/3-Mediated Apoptosis in Oral Squamous Cell Carcinoma.

Predicting and overcoming radioresistance are crucial in radiation oncology, including in managing oral squamous cell carcinoma (OSCC). First, we used RNA-sequence to compare expression profiles of parent OML1 and radioresistant OML1-R OSCC cells in order to select candidate genes responsible for radiation sensitivity. We identified IRAK2, a key immune mediator of the IL-1R/TLR signaling, as a potential target in investigating radiosensitivity. In four OSCC cell lines, we observed that intrinsically low IRAK2 expression demonstrated a radioresistant phenotype (i.e., OML1-R and SCC4), and vice versa (i.e., OML1 and SCC25). Next, we overexpressed IRAK2 in low IRAK2-expression OSCC cells and knocked it down in high IRAK2-expression cells to examine changes of irradiation response. After ionizing radiation (IR) exposure, IRAK2 overexpression enhanced the radiosensitivity of radioresistant cells and synergistically suppressed OSCC cell growth both in vitro and in vivo, and vice versa. We found that IRAK2 overexpression restored and enhanced radiosensitivity by enhancing IR-induced cell killing via caspase-8/3-dependent apoptosis. OSCC patients with high IRAK2 expression had better post-irradiation local control than those with low expression (i.e., 87.4% vs. 60.0% at five years, P = 0.055), showing that IRAK2 expression was associated with post-radiation recurrence. Multivariate analysis confirmed high IRAK2 expression as an independent predictor for local control (HR, 0.11; 95% CI, 0.016 - 0.760; P = 0.025). In conclusion, IRAK2 enhances radiosensitivity, via modulating caspase 8/3-medicated apoptosis, potentially playing double roles as a predictive biomarker and a novel therapeutic target in OSCC.

S-Equol Protects Chondrocytes against Sodium Nitroprusside-Caused Matrix Loss and Apoptosis through Activating PI3K/Akt Pathway.

Osteoarthritis (OA) is a common chronic disease with increasing prevalence in societies with more aging populations, therefore, it is causing more concern. S-Equol, a kind of isoflavones, was reported to be bioavailable and beneficial to humans in many aspects, such as improving menopausal symptoms, osteoporosis and prevention of cardiovascular disease. This study investigated the effects of S-Equol on OA progress in which rat primary chondrocytes were treated with sodium nitroprusside (SNP) to mimic OA progress with or without the co-addition of S-Equol for the evaluation of S-Equol's efficacy on OA. Results showed treatment of 0.8 mM SNP caused cell death, and increased oxidative stress (NO and H2O2), apoptosis, and proteoglycan loss. Furthermore, the expressions of MMPs of MMP-2, MMP-3, MMP-9, and MMP-13 and p53 were increased. The addition of 30 µM S-Equol could lessen those caused by SNP. Moreover, S-Equol activates the PI3K/Akt pathway, which is an upstream regulation of p53 and NO production and is associated with apoptosis and matrix degradation. As a pretreatment of phosphoinositide 3-kinases (PI3K) inhibitor, all S-Equol protective functions against SNP decrease or disappear. In conclusion, through PI3K/Akt activation, S-Equol can protect chondrocytes against SNP-induced matrix degradation and apoptosis, which are commonly found in OA, suggesting S-Equol is a potential for OA prevention.

Purification and Identification of Cholesterol Micelle Formation Inhibitory Peptides of Hydrolysate from High Hydrostatic Pressure-Assisted Protease Hydrolysis of Fermented Seabass Byproduct.

This research focuses on the proteolytic capacity of sea bass byproduct (SB) and their hypocholesterolemic activity via the cholesterol micelle formation (CMF) inhibition. SB was fermented with seven mixed lactic acid bacteria for 5 h at 42 °C. The lactic fermented SB was hydrolyzed with Protease N for 6 h under HHP to obtain the SB hydrolysates (HHP-assisted Protease N hydrolysis after fermentation, F-HHP-PN6). The supernatant was separated from the SB hydrolysate and freeze-dried. As the hydrolysis time extended to 6 h, soluble protein content increased from 187.1 to 565.8 mg/g, and peptide content increased from 112.8 to 421.9 mg/g, while inhibition of CMF increased from 75.0% to 88.4%. Decreasing the CMF inhibitory activity from 88.4% to 42.1% by simulated gastrointestinal digestion (FHHP-PN6 was further hydrolyzed by gastrointestinal enzymes, F-HHP-PN6-PP) reduced the CMF inhibitory activity of F-HHP-PN6. Using gel filtration chromatography, the F-HHP-PN6-PP was fractioned into six fractions. The molecular weight of the fifth fraction from F-HHP-PN6-PP was between 340 and 290 Da, and the highest inhibitory efficiency ratio (IER) on CMF was 238.9%/mg/mL. Further purification and identification of new peptides with CMF inhibitory activity presented the peptide sequences in Ser-Ala-Gln, Pro-Trp, and Val-Gly-Gly-Thr; the IERs were 361.7, 3230.0, and 302.9%/mg/mL, respectively.

Impact of Polypharmacy Prior to Allogeneic Hematopoietic Stem Cell Transplantation in Older Adults.

Polypharmacy is common in older adults with cancer, but there is little evidence evaluating the impact of polypharmacy and other medication hazards on allogeneic hematopoietic cell transplantation (alloHCT) outcomes. A small number of prior studies have evaluated the impact of potentially inappropriate medication (PIM) use in the setting of alloHCT, with mixed results. We evaluated the effects of pre-alloHCT polypharmacy, PIM use, and drug-drug interactions (DDIs) on post-alloHCT outcomes, including overall survival (OS), progression-free survival (PFS), non-relapse mortality (NRM), hospital length of stay (LOS), number of non-hematologic grade ≥3 adverse events (AEs) within 100 days after alloHCT, and number of readmissions within the first 100 days after alloHCT. The study population was a single-center prospective cohort of 148 patients ≥ 50 years of age. Pre-alloHCT medication lists were retrospectively collected from the electronic medical record, including both scheduled and as-needed medications. PIMs were defined by a modified 2019 American Geriatrics Society Beers Criteria. DDIs were analyzed using Lexi-Interact. Polypharmacy was common in this population; the median number of medications was seven (range, 0 to 23). Fifty-two patients (35%) were prescribed nine or more medications, and 73 patients (49%) had at least one PIM prescribed. The median number of DDIs was three (range, 0 to 31), and the most common severity was major (48%). After adjusting for age and Hematopoietic Cell Transplant Comorbidity Index (HCTCI), both the number of all medications and number of scheduled medications were associated with inferior OS, with hazard ratios (HRs) of 1.07 (95% confidence interval [CI], 1.01 to 1.12; P = .02) and 1.08 (95% CI, 1.00 to 1.15; P = .04), respectively. Receipt of nine or more scheduled medications was associated with inferior OS (HR, 1.92; 95% CI, 1.11 to 3.32; P = .02). The number of PIMs was also significantly associated with OS (HR, 1.24; 95% CI, 1.00 to 1.54, P = .05). After adjusting for age, HCTCI, and total number of medications, a greater number of DDIs were significantly associated with longer hospital length of stay (difference, 0.74 days; 95% CI, 0.09 to 1.40, P = .03). In adjusted analyses, there were no significant polypharmacy-related predictors of NRM, LOS, or non-hematologic grade ≥3 AEs. These data demonstrate the utility of pre-alloHCT polypharmacy, PIM use, and DDIs as important prognostic factors and support routine pre-alloHCT medication review by physicians and pharmacists with a goal of appropriate de-prescribing where possible.

High incidence of fractures after R-CHOP-like chemotherapy for aggressive B-cell non-Hodgkin lymphomas.

PURPOSE: Patients with non-Hodgkin lymphoma (NHL) have a median age of 67, with 70% surviving over 5 years. Chemotherapy for aggressive NHL includes cyclophosphamide, anthracycline, and high doses of corticosteroids, which can impair bone health. By reviewing clinical characteristics and standard-of-care CT scans, we evaluate the prevalence and incidence of fractures and the clinical correlates of fractures in patients treated for aggressive B-cell NHL. METHODS: We retrospectively reviewed patients seen at the University of California San Francisco lymphoma clinic from January 1, 2016, to March 31, 2017 who had (1) aggressive B-cell NHL, (2) received first-line therapy with R-CHOP-like regimens, and had (3) CT scans pre- and post-treatment available for review. Associations between clinical variables and vertebral, rib, and pelvic fracture outcomes were assessed, and multivariate logistic regression models were used to identify predictors of prevalent and incident fractures. RESULTS: We identified 162 patients who met the inclusion criteria. Median age at diagnosis was 60 years. Of the 162 patients, 38 patients (28%) had prevalent fractures prior to receiving chemotherapy. Within 1 year after treatment, 16 patients (10%) developed new fractures. Having a prevalent fracture strongly predicted developing a new fracture after treatment, with incident fractures occurring in 12 of 38 patients with prevalent fractures versus 4 of 124 without prevalent fractures (odds ratio 10.45, p<0.0005). CONCLUSION: Our results suggest that patients with aggressive B-cell NHL who receive R-CHOP-like therapy should be screened for fractures prior to treatment and those with existing fractures should be considered for therapy to decrease risk of new fractures.

Impact of 23-valent pneumococcal polysaccharide vaccination on the frequency of pneumonia-related hospitalization and survival in elderly patients with prostate cancer: A seven-year nationwide matched cohort study.

BACKGROUND: The 23-valent pneumococcal polysaccharide vaccine (PPSV23) is indicated for adults who have a high risk of pneumonia; however, its effectiveness in patients with prostate cancer who are at a risk of pneumonia because of age and cancer treatments, including androgen-deprivation therapy, is unknown. METHODS: Between 2000 and 2010, 38,735 patients with prostate cancer were diagnosed in Taiwan. After exclusions and exact matching for age, previous pneumonia, and influenza vaccination, 2188 vaccinated patients and 2188 unvaccinated patients were recruited. The incidence density of all-cause bacterial pneumonia hospitalizations was analyzed. RESULTS: Over 7 years of follow-up, patients who received the PPSV23 had a significantly lower incidence density, with 142.8 per 1000 person-years versus 162.0 per 1000 person-years for unvaccinated patients. More patients in the vaccinated cohort were never hospitalized for pneumonia compared with those in the unvaccinated cohort (64.2% vs 62.2%, respectively). After adjusting for the Charlson comorbidity index, cancer treatment modalities, and socioeconomic levels, the risk of pneumonia-related hospitalization in the PPSV23 vaccination cohort was 0.48 times lower than that in the unvaccinated cohort (adjusted incidence rate ratio, 0.48; P = .046). For patients who received the influenza vaccination, subgroup analysis demonstrated that PPSV23 vaccination significantly decreased the risk (adjusted incidence rate ratio, 0.45; P < .001). Compared with unvaccinated controls, PPSV23-vaccinated patients had a lower cumulative incidence for the first occurrence of pneumonia-related hospitalization (34.49% vs 36.36%; P = .178) and higher overall survival (47.5% and 42.3%, respectively; P < .001). CONCLUSIONS: Vaccination of elderly patients who have prostate cancer with the relatively common and inexpensive PPSV23 can decrease the risk of pneumonia and prolong survival.

Cardiac Screening for High Risk Sudden Cardiac Death in School-Aged Children.

BACKGROUND: Sudden cardiac death (SCD) is an uncommon but significant cause of death in the young. Citywide cardiac screening of school-aged children has been performed in Taipei since 1989. In this study, we investigate the efficacy of this screening method for identifying those at high risk of SCD. METHODS: This study analyzed the data from the results of cardiac screening for school-aged children in Taipei from 2003 to 2014. The cardiac screening included: Stage I, questionnaire surveys, simplified phonocardiography test and simplified electrocardiography (ECG) test; Stage II, physical examination and auscultation by a pediatric cardiologist for all children who had abnormal findings in stage I screening; Stage III, referral to a pediatric cardiologist for further examinations. Logistic regression and decision tree analyses were performed. RESULTS: A total of 566,447 students were screened, of whom 685 were identified as being at high risk of SCD. The most common causes of being at high risk of SCD included Wolff-Parkinson-White syndrome, long QT syndrome, cardiomyopathy and Marfan's syndrome. Using logistic regression analysis, the simplified ECG test was identified as being the most effective tool (odds ratio = 16.4, p < 0.001) and past history as the second most crucial factor (odds ratio = 3.95, p < 0.001) for detecting a high risk of SCD. Decision tree analysis showed that serial studies with a past history and the simplified ECG test could accurately identify those at high risk of SCD. CONCLUSIONS: Questionnaire survey and simplified electrocardiography test-based cardiovascular screening in school-aged children can identify those at high risk of SCD.

[The optimization and assessment of the method for inducing hyperuricemia in rats].

Objective: To explore an effective method for inducing a rat model with hyperuricemia in a short period and assess the effects of the model. Methods: Sprague-Dawley rats were adopted as donors and randomly divided into control group (CT group, n=6) and 5 model groups (M1-M5 groups, n=8 in each group). M1 group (gavage with 10 g/kg yeast extracts and 100 mg/kg adenine, twice per day, 300 mg/kg oxonic acid potassium by intraperitoneal injection, in the 7th day of model inducing), M2 group (gavage with 10 g/kg yeast extracts and 100 mg/kg adenine, twice per day, 300 mg/kg oxonic acid potassium by intraperitoneal injection, in the 1st, 3rd and 7th day of model inducing),M3 group (gavage with 10 g/kg yeast extracts and 100 mg/kg adenine, twice per day, 300 mg/kg oxonic acid potassium by intraperitoneal injection, once per day during the model inducing), M4 group (gavage with 20 g/kg yeast extracts and 100 mg/kg adenine, twice per day, 300 mg/kg oxonic acid potassium by intraperitoneal injection, once per day during the model inducing), M5 group (gavage with 30 g/kg yeast extracts and 100 mg/kg adenine, twice per day, 300 mg/kg oxonic acid potassium by intraperitoneal injection, once per day during the model inducing), and group CT (gavaged with equal volume sterilized water and intraperitoneal injected with normal saline according to the weight and at the same frequency as the model groups). The model inducing lasted for 7 days. After the inducing was finished, blood and 24-hour urine were sampled for uric acid and creatinine determination. Then rats were maintained for 2 weeks and blood and 24-hour urine samples were collected, the concentration of uric acid and creatinine were detected. The kidney and stomach were weighed,morphological changes in kidney were observed. Results: After model inducing, the body weight of rats in all model groups was lower than that of the control group (P＜0.01). Deaths occurred in all the rats with model treatments except M2. M4 and M5 groups were failed to be analyzed because of the high mortality, model 1 and 3 groups had 4 and 2 deaths, respectively. The uric acid levels in blood and urine of the model groups were significantly elevated (P＜ 0.01) at the end of model inducing. The model 2 group's blood uric acid was highest among the model groups (P＜0.05). It sustained a higher concentration than CT group in the three model groups after 2 weeks feeding (P＜0.05). The kidneys in model groups obviously swelling and were heavier than CT group (P＜0.01). The inflammation and structural damages were observed in kidneys of all model groups.Conclusion: The yeast extract (10 g/kg), adenine (100 mg/kg) gavage combined with intraperitoneal injections(the 1st, 3rd, 7th day during inducing) of potassium oxonate can be an rapid and effective method for inducing the rat model with hyperuricemia, which can be suggested to the related research.

Geriatric assessment in older alloHCT recipients: association of functional and cognitive impairment with outcomes.

Use of allogeneic hematopoietic cell transplantation (alloHCT) is increasing in older patients with hematologic malignancies. Studies suggest that geriatric assessment (GA), incorporating functional measures such as instrumental activities of daily living (IADL), delineates subtle age-related impairments that enhance risk-stratification. The objective of this multi-institutional retrospective study was to evaluate the prognostic utility of GA metrics collected pre-alloHCT. Eligibility criteria included age ≥50 and pre-alloHCT GA inclusive of at least IADL. Beyond IADL, additional geriatric metrics were collected where available and included Medical Outcomes Study Physical Health score (MOS-PH), Timed Up and Go (TUG), and cognition by Blessed Orientation Memory Concentration (BOMC). Three hundred thirty subjects were included, with a median age of 63 (range 50 to 77). Impairments were frequent: 36% had at least 1 IADL impairment; 14% had TUG ≥13.5 seconds; and 17% had cognitive impairment (BOMC ≥ 7). Median MOS-PH score was 80. IADL and age were not significantly associated with nonrelapse mortality (NRM) or overall survival (OS). In multivariate analysis, only impaired cognition and Hematopoietic Cell Transplant-Comorbidity Index score ≥3 showed an independent association with 1-year NRM (subdistribution hazard ratio [SHR], 2.36; P = .01; and SHR, 2.19; P = .009, respectively). Cognitive impairment independently conferred inferior 1-year OS (hazard ratio, 1.94; P = .01). In a preplanned subgroup analysis in 224 patients aged ≥60 years, cognitive impairment remained the sole GA metric predictive of NRM (2-year NRM: SHR, 2.72; P = .007). These data suggest that cognitive impairment elevates risk of post-alloHCT NRM in older patients.

Alanine aminotransferase influencing performances of routine available tests detecting hepatitis B-related cirrhosis.

The performances of routine tests such as FIB-4 and APRI in detecting cirrhosis and significant fibrosis in chronic hepatitis B (CHB) have been shown to be discrepant between studies. Novel tests such as red cell distribution width-platelet ratio (RPR), γ-glutamyl transpeptidase to platelet ratio (GPR) and easy liver fibrosis test (eLIFT) are introduced recently. To evaluate the aminotransferase influence on the performance of these routine tests, a total of 1005 CHB patients who underwent liver biopsies and routine tests were retrospectively analysed. The diagnostic cut-offs referring to likelihood ratio were determined for excluding or including cirrhosis diagnosis and also for ruling in significant fibrosis diagnosis. The performances of RPR, FIB-4, eLIFT and APRI in detecting cirrhosis seemed improved at higher ALT levels, while GPR was conversely impaired. The likelihood ratio was âˆ for APRI cut-off 2 diagnosing cirrhosis in ALT < 2 upper limit of normal (ULN), 14.6 for APRI cut-off 1.5 determining significant fibrosis in ALT ≤ 5ULN and 20.6 for FIB-4 cut-off 3.2 diagnosing ≥ F3 in the total cohort, respectively. The optimal cut-offs for cirrhosis diagnosis were increased with higher ALTs by tests which included aminotransferase, but not for RPR. The proportions of patients classified as having cirrhosis or no cirrhosis stratified by ALT level cut-offs were superior. Stepwise applying RPR, GPR and eLIFT would determine 60% of patients as having cirrhosis or no cirrhosis with an accuracy of 93.0%. In conclusion, the performance of aminotransferase comprising tests in detecting cirrhosis in CHB were influenced by ALT levels. Thus, ALT stratified cut-offs may be a preferred alternative. In resource-limited settings, stepwise applying routine tests could be recommended as a preferred measurement for cirrhosis detection.

Emerging Challenges of Radiation-Associated Cardiovascular Dysfunction (RACVD) in Modern Radiation Oncology: Clinical Practice, Bench Investigation, and Multidisciplinary Care.

Radiotherapy (RT) is a crucial treatment modality in managing cancer patients. However, irradiation dose sprinkling to tumor-adjacent normal tissues is unavoidable, generating treatment toxicities, such as radiation-associated cardiovascular dysfunction (RACVD), particularly for those patients with combined therapies or pre-existing adverse features/comorbidities. Radiation oncologists implement several efforts to decrease heart dose for reducing the risk of RACVD. Even applying the deep-inspiration breath-hold (DIBH) technique, the risk of RACVD is though reduced but still substantial. Besides, available clinical methods are limited for early detecting and managing RACVD. The present study reviewed emerging challenges of RACVD in modern radiation oncology, in terms of clinical practice, bench investigation, and multidisciplinary care. Several molecules are potential for serving as biomarkers and therapeutic targets. Of these, miRNAs, endogenous small non-coding RNAs that function in regulating gene expression, are of particular interest because low-dose irradiation, i.e., 200 mGy (one-tenth of conventional RT daily dose) induces early changes of pro-RACVD miRNA expression. Moreover, several miRNAs, e.g., miR-15b and miR21, involve in the development of RACVD, further demonstrating the potential bio-application in RACVD. Remarkably, many RACVDs are late RT sequelae, characterizing highly irreversible and progressively worse. Thus, multidisciplinary care from oncologists and cardiologists is crucial. Combined managements with commodities control (such as hypertension, hypercholesterolemia, and diabetes), smoking cessation, and close monitoring are recommended. Some agents show abilities for preventing and managing RACVD, such as statins and angiotensin-converting enzyme inhibitors (ACEIs); however, their real roles should be confirmed by further prospective trials.