Trehalose enhanced cold atmospheric plasma-mediated cancer treatment.

Cold atmospheric plasma (CAP) is a unique form of physical plasma that has shown great potential for cancer therapy. CAP uses ionized gas to induce lethal oxidative stress on cancer cells; however, the efficacy of CAP therapy continues to be improved. Here, we report an injectable hydrogel-mediated approach to enhance the anti-tumor efficacy of CAP by regulating the phosphorylation of eIF2α. We discovered that reactive oxygen and nitrogen species (ROS/RNS), two main anti-tumor components in CAP, can lead to lethal oxidative stress on tumor cells. Elevated oxidative stress subsequently induces eIF2α phosphorylation, a pathognomonic marker of immunogenic cell death (ICD). Trehalose, a natural disaccharide sugar, can further enhance CAP-induced ICD by elevating the phosphorylation of eIF2α. Moreover, injectable hydrogel-mediated delivery of CAP/trehalose treatment promoted dendritic cell (DC) maturation, initiating tumor-specific T-cell mediated anti-tumor immune responses. The combination therapy also supported the polarization of tumor-associated macrophages to an M1-like phenotype, reversing the immunosuppressive tumor microenvironment and promoting tumor antigen presentation to T cells. In combination with immune checkpoint inhibitors (i.e., anti-programmed cell death protein 1 antibody, aPD1), CAP/trehalose therapy further inhibited tumor growth. Importantly, our findings also indicated that this hydrogel-mediated local combination therapy engaged the host systemic innate and adaptive immune systems to impair the growth of distant tumors.

Ultrasensitive FET biosensor chip based on self-assembled organic nanoporous membrane for femtomolar detection of Amyloid-ß.

Early diagnosis of Alzheimer's disease (AD) is critical for preventing disease progression, however, the diagnosis of AD remains challenging for most patients due to limitations of current sensing technologies. A common pathological feature found in AD-affected brains is the accumulation of Amyloid-ß (Aß) polypeptides, which lead to neurofibrillary tangles and neuroinflammatory plaques. Here, we developed a portable ultrasensitive FET biosensor chip based on a self-assembled nanoporous membrane for ultrasensitive detection of Aß protein in complex environments. The microscale semiconductor channel was covered with a self-assembled organic nanoporous membrane modified by antibody molecules to pick up and amplify the Aß protein signal. The nanoporous structure helps protect the sensitive channel from non-target proteins and improves its stability since no chemical functionalization process involved, largely reduces background noise of the sensing platform. When a bio-gated target is captured, the doping state of the polymer bulk could be tuned and amplified the strength of the weak signal, achieving ultrasensitive detecting performance (enabling the device to detect target protein less than 1 fg/ml in 1 µl sample). Moreover, the device simplifies the circuit connection by integrating all the connections on a 2 cm × 2 cm chip, avoiding expensive and complex manufacturing processes, and makes it usable for portable prognosis. We believe that this ultrasensitive, portable, low-cost Aß sensor chip shows the great potential in the early diagnosis of AD and large-scale population screening applications.

Injectable cold atmospheric plasma-activated immunotherapeutic hydrogel for enhanced cancer treatment.

Despite the promise of immune checkpoint blockade (ICB) for cancer treatment, challenges associated with this therapy still exist, including low response rates and severe side effects in patients. Here, we report a hydrogel-mediated combination therapy for enhanced ICB therapy. Specifically, cold atmospheric plasma (CAP), an ionized gas consisting of therapeutically effective reactive oxygen species (ROS) and reactive nitrogen species (RNS), can effectively induce cancer immunogenic cell death, releasing tumor-associated antigens in situ and initiating anti-tumor immune responses, which, therefore, can synergistically augment the efficacy of immune checkpoint inhibitors. To minimize the systemic toxicity of immune checkpoint inhibitors and improve the tissue penetration of CAP, an injectable Pluronic hydrogel was employed as a delivery method. Our results show that major long-lived ROS and RNS in CAP can be effectively persevered in Pluronic hydrogel and remain efficacious in inducing cancer immunogenic cell death after intratumoral injection. Our findings suggest that local hydrogel-mediated combination of CAP and ICB treatment can evoke both strong innate and adaptive, local and systemic anti-tumor immune responses, thereby inhibiting both tumor growth and potential metastatic spread.

Additional health education and nutrition management cause more weight loss than concurrent training in overweight young females.

OBJECTIVE: This study aimed to compare the effect of concurrent training and the addition of health education and nutrition management on body composition and health-related outcomes. METHODS: Twenty-four healthy overweight females (20.42 ± 1.02 years, body mass index [BMI] 25.83 ± 3.63 kg∙m-2) were assigned to a concurrent training group (Exe, n = 12) or a concurrent training and health education group (Exe + Edu, n = 12). Both groups completed 8 weeks of concurrent training (6 days/week), whereas the Exe + Edu participants received additional health education and controlled daily energy intake within the basal metabolic rate. Body composition, serum glucose, lipids and related hormones were measured before and after intervention. RESULTS: After intervention, the Exe group lost 2.47 kg (±2.46) of body mass, 2.44 kg (±1.71) of total fat mass (FM), corresponding to a body fat percentage (BF%) of 2.25%. Losses of body mass, total FM and BF% in the Exe + Edu group were -5.19 ± 1.87 kg, -4.42 ± 1.83 kg and -4.33 ± 2.39%, respectively. The Exe + Edu participants had significantly greater reductions of body mass, total FM, and trunk and leg FM relative to the Exe participants (p < 0.05). Serum glucose, lipids, insulin and progesterone levels were improved in both groups without group difference. CONCLUSION: Concurrent training is an effective short-term training strategy for reducing FM and improving fasting glucose, blood lipids and related hormones. Furthermore, the combination of additional health education can achieve greater effects on weight loss and the reduction of total and regional FM, which may be a better obesity treatment method.

Stimuli-responsive nanoformulations for CRISPR-Cas9 genome editing.

The CRISPR-Cas9 technology has changed the landscape of genome editing and has demonstrated extraordinary potential for treating otherwise incurable diseases. Engineering strategies to enable efficient intracellular delivery of CRISPR-Cas9 components has been a central theme for broadening the impact of the CRISPR-Cas9 technology. Various non-viral delivery systems for CRISPR-Cas9 have been investigated given their favorable safety profiles over viral systems. Many recent efforts have been focused on the development of stimuli-responsive non-viral CRISPR-Cas9 delivery systems, with the goal of achieving efficient and precise genome editing. Stimuli-responsive nanoplatforms are capable of sensing and responding to particular triggers, such as innate biological cues and external stimuli, for controlled CRISPR-Cas9 genome editing. In this Review, we overview the recent advances in stimuli-responsive nanoformulations for CRISPR-Cas9 delivery, highlight the rationale of stimuli and formulation designs, and summarize their biomedical applications.

Advances in microneedles for non-transdermal applications.

INTRODUCTION: Microneedles (MNs) have emerged as a promising tool for various therapeutic and diagnostic applications. While MNs have been prominently used for transdermal applications, recent advances in materials science, microfabrication technologies, and clinical devices enable the expansion of MNs to diverse non-transdermal applications. AREAS COVERED: This review provides an overview of recent advances in the MN technology for non-transdermal applications. The classification of MNs and their applications to ocular, vascular, oral, mucosal, and cancer tissues are particularly highlighted. EXPERT OPINION: Recent efforts in MN designs have enabled and broadened MNs to many non-transdermal applications. It is anticipated to witness many new MN-mediated non-transdermal applications in the near future. By advancing MN systems with suitable properties for target tissues, it is possible to achieve high drug delivery efficiency that outperforms traditional drug delivery methods. Further endeavors in translation and commercialization of these novel technologies are equally critical.

Evaluation of Patient-Reported Outcome Measures in Intermittent Self-Catheterization Users: A Systematic Review.

OBJECTIVE: To identify patient-reported outcome measures (PROMs) for intermittent self-catheterization (ISC) users, critically assess and summarize the quality of the measurement properties, and describe the application scenarios on each instrument. DATA SOURCES: PubMed, EMBASE, Medline, PsycINFO, and relevant reference lists were systematically searched through December 2019 (updated May 2020). STUDY SELECTION: Two reviewers independently identified original English language publications that evaluated the psychometric properties of specific PROMs used in ISC patients. DATA EXTRACTION: The following data were obtained: author and publication year, content of domains and subscales, number of items, response options, constructs measured, language, and information on measurement properties. DATA SYNTHESIS: Eleven publications were deemed eligible, including 6 PROMs for measuring patients' ISC-related quality of life, self-confidence, satisfaction, difficulties, acceptance, and adherence to treatment. The Intermittent Self-Catheterization Questionnaire provided the most detail, and the Intermittent Catheterization Acceptance Test could be evaluated on the most consensus-based standards for the selection of health status measurement instrument properties. CONCLUSIONS: Several tools are available for ISC users, but at present there is no comprehensive, concise, and robust instrument with good psychometric properties. Further research on psychometric properties is needed to verify the remaining properties of existing scales and to develop novel tools for clinicians, researchers, and patients.

IK1 Channel Agonist Zacopride Alleviates Cardiac Hypertrophy and Failure via Alterations in Calcium Dyshomeostasis and Electrical Remodeling in Rats.

Intracellular Ca2+ overload, prolongation of the action potential duration (APD), and downregulation of inward rectifier potassium (IK1) channel are hallmarks of electrical remodeling in cardiac hypertrophy and heart failure (HF). We hypothesized that enhancement of IK1 currents is a compensation for IK1 deficit and a novel modulation for cardiac Ca2+ homeostasis and pathological remodeling. In adult Sprague-Dawley (SD) rats in vivo, cardiac hypertrophy was induced by isoproterenol (Iso) injection (i.p., 3 mg/kg/d) for 3, 10, and 30 days. Neonatal rat ventricular myocytes (NRVMs) were isolated from 1 to 3 days SD rat pups and treated with 1 µmol/L Iso for 24 h in vitro. The effects of zacopride, a selective IK1/Kir2.1 channel agonist, on cardiac remodeling/hypertrophy were observed in the settings of 15 µg/kg in vivo and 1 µmol/L in vitro. After exposing to Iso for 3 days and 10 days, rat hearts showed distinct concentric hypertrophy and fibrosis and enhanced pumping function (P < 0.01 or P < 0.05), then progressed to dilatation and dysfunction post 30 days. Compared with the age-matched control, cardiomyocytes exhibited higher cytosolic Ca2+ (P < 0.01 or P < 0.05) and lower SR Ca2+ content (P < 0.01 or P < 0.05) all through 3, 10, and 30 days of Iso infusion. The expressions of Kir2.1 and SERCA2 were downregulated, while p-CaMKII, p-RyR2, and cleaved caspase-3 were upregulated. Iso-induced electrophysiological abnormalities were also manifested with resting potential (RP) depolarization (P < 0.01), APD prolongation (P < 0.01) in adult cardiomyocytes, and calcium overload in cultured NRVMs (P < 0.01). Zacopride treatment effectively retarded myocardial hypertrophy and fibrosis, preserved the expression of Kir2.1 and some key players in Ca2+ homeostasis, normalized the RP (P < 0.05), and abbreviated APD (P < 0.01), thus lowered cytosolic [Ca2 +]i (P < 0.01 or P < 0.05). IK1channel blocker BaCl2 or chloroquine largely reversed the cardioprotection of zacopride. We conclude that cardiac electrical remodeling is concurrent with structural remodeling. By enhancing cardiac IK1, zacopride prevents Iso-induced electrical remodeling around intracellular Ca2+ overload, thereby attenuates cardiac structural disorder and dysfunction. Early electrical interventions may provide protection on cardiac remodeling.

Association of breastfeeding and postmenopausal osteoporosis in Chinese women: a community-based retrospective study.

BACKGROUND: Postmenopausal osteoporosis (PMOP) has long been a pervasive public health concern. With the aging Chinese population, the prevention, assessment and management of postmenopausal osteoporosis were particularly important. During the breastfeeding, a large amount of Calcium loss from maternal bone for infants' growth. However, whether this loss is completely reversible remains controversial. As the relationship between breastfeeding and postmenopausal osteoporosis is different from society to society and is not clear from the literature, the purpose of this study was to determine whether breastfeeding was an independent factor for the development of PMOP based on Chinese postmenopausal population. METHODS: A retrospective cross-sectional investigation was conducted at Tianjin Xiaobailou health Community Healthcare Center between December 2017 and June 2018. Postmenopausal women over the age of 50 who underwent the annual health examination or visited the center to perform bone densitometry as a part of routine screening for disease were recruited. A trained community nurse administered a questionnaire to all participants by face-to-face interview. Participants were questioned about age, BMI, Vitamin D and calcium intake, the history of smoking, drinking and fracture, age of menarche, age of menopause, the number of pregnancy, parity, feeding pattern (breastfeeding, artificial feeding and mixed feeding) and overall breastfeeding duration. BMD measurements were carried out using quantitative ultrasound (QUS) at the bilateral radius. RESULTS: A total of 202 women who met the inclusive and exclusive criteria were enrolled. Univariate analysis revealed that overall breastfeeding more than 24 months increased the risk of osteoporosis (OR 39.00, 95%CI 2.40-634.65, p = 0.010). However, multivariate estimate of the risk of osteoporosis by overall breastfeeding duration suggested that when controlling for age, BMI, the number of pregnancy and parity, the overall breastfeeding duration was not an independent risk factor for postmenopausal osteoporosis (OR 5.22, 95%CI 0.18-147.76, p = 0.333). Additionally, age (OR 1.16, 95%CI 1.05-1.29, p = 0.003), BMI (OR 1.26, 95%CI 1.04-1.54, p = 0.021) and the number of pregnancy (OR 1.80, 95%CI 1.08-2.98, p = 0.024) were significant associated with postmenopausal osteoporosis. CONCLUSION: Breastfeeding was not associated with postmenopausal osteoporosis, while age, BMI and the number of pregnancy may contribute to increasing risk of postmenopausal osteoporosis in Chinese women.

The prognostic impact of decreased pretreatment haemoglobin level on the survival of patients with lung cancer: a systematic review and meta-analysis.

BACKGROUND: Many studies have reported the prognostic value of haemoglobin level for cancers. Whereas the prognostic impact of decreased pretreatment haemoglobin level on the survival of patients with lung cancer remains controversial, herein, a systematic review and meta-analysis were conducted to investigate whether a decreased haemoglobin level before treatment is a significant predictor of survival in patients with lung cancer. METHODS: We performed a systematic review and meta-analysis of observational studies to evaluate the prognostic impact of a decreased haemoglobin level on the survival of patients with lung cancer. Relevant studies were retrieved from databases including PubMed, Embase, Web of Science and the Cochrane Library. Reference lists were hand-searched for potentially eligible studies. The Newcastle-Ottawa scale was used to assess the quality of included studies. Observational studies were included if they provided sufficient information for the extraction of the pooled hazard ratios (HR) and 95% confidence intervals (95% CI) for overall survival, disease-free survival, relapse-free survival, progression-free survival, event-free survival and time to progression. Subgroup analysis, meta-regression and sensitivity analyses were applied to explain the heterogeneity. RESULTS: Fifty-five articles involving a total of 22,719 patients were obtained to evaluate the correlation between haemoglobin level and survival. The results indicated that decreased haemoglobin level was significantly associated with poor overall survival of patients with lung cancer (HR 1.51, 95% CI 1.42-1.61), both in non-small cell lung cancer (HR 1.57, 95% CI 1.44-1.72) and in small cell lung cancer (HR 1.56, 95% CI 1.21-2.02). We also found that the lower the haemoglobin level, the shorter was the overall survival of patients with lung cancer (HR 1.11, 95% CI 1.06-1.16). However, the relationship between decreased haemoglobin and relapse-free survival was not significant (HR 1.37, 95% CI 0.91-2.05). CONCLUSION: A decreased pretreatment haemoglobin level among patients with lung cancer is a prognostic factor of poor survival that can serve as an important indicator in survival prediction, risk stratification and treatment selection. In clinical practice, more attention should be paid to monitoring pretreatment haemoglobin levels among patients with lung cancer.

Analysis of the status of Chinese clinical practice guidelines development.

BACKGROUND: The work of developing clinical practice guidelines began just a little more than ten years ago in China. Up to now, there have been few studies about them. OBJECTIVES: To review and analyze the status of Chinese clinical practice guidelines in 1997-2007. METHODS: All Chinese guidelines from 1997-2007 were collected, and made a regression analysis, and a citation analysis for evaluating the impact of guidelines. To analyze the developing quality, the most influential guidelines were evaluated with AGREE instrument, and each guideline was evaluated to check for any updating. In order to analyze the objective and target population, all guidelines were classified and counted separately according to disease/symptom center, and whether towards specialists or general practitioners. RESULTS: 143 guidelines were collected. An exponential function equation was established for the trend in the number of guidelines. The immediacy index in every year was very low while the average citation rate was not. Both the percentages of highly cited and never cited were high. For the evaluation with AGREE, only the average score of clarity and presentation was high (89.9%); the remaining were much lower. Editorial independence scored 0. Only 27 (18.9%) of 143 guidelines, were found to be evidence-based. Only a few had ever been updated, with an average updating interval of 5.2 years. Only 2.1% were symptom-centered, and only 4.2% were aimed at general practitioners. CONCLUSION: Much progress has been obtained for Chinese guidelines development. However, there were still defects, and greater efforts should be made in the future.