Trident cold atmospheric plasma blocks three cancer survival pathways to overcome therapy resistance.

Therapy resistance is responsible for most cancer-related death and is mediated by the unique ability of cancer cells to leverage metabolic conditions, signaling molecules, redox status, and other pathways for their survival. Interestingly, many cancer survival pathways are susceptible to disturbances in cellular reactive oxygen species (ROS) and may therefore be disrupted by exogenous ROS. Here, we explore whether trident cold atmospheric plasma (Tri-CAP), a gas discharge with exceptionally low-level ROS, could inhibit multiple cancer survival pathways together in a murine cell line model of therapy-resistant chronic myeloid leukemia (CML). We show that Tri-CAP simultaneously disrupts three cancer survival pathways of redox deregulation, glycolysis, and proliferative AKT/mTOR/HIF-1α signaling in this cancer model. Significantly, Tri-CAP blockade induces a very high rate of apoptotic death in CML cell lines and in primary CD34+ hematopoietic stem and progenitor cells from CML patients, both harboring the therapy-resistant T315I mutation. In contrast, nonmalignant controls are minimally affected by Tri-CAP, suggesting it selectively targets resistant cancer cells. We further demonstrate that Tri-CAP elicits similar lethality in human melanoma, breast cancer, and CML cells with disparate, resistant mechanisms and that it both reduces tumor formation in two mouse models and improves survival of tumor-bearing mice. For use in patients, administration of Tri-CAP may be extracorporeal for hematopoietic stem cell transplantation therapy, transdermal, or through its activated solution for infusion therapy. Collectively, our results suggest that Tri-CAP represents a potent strategy for disrupting cancer survival pathways and overcoming therapy resistance in a variety of malignancies.

Sarcopenia risk and associated factors among Chinese community-dwelling older adults living alone.

Sarcopenia, defined as a progressive loss of muscle mass and reduced muscle strength and functional capacity, is common among older adults. This study aimed to assess the proportion of people at risk of sarcopenia and probable sarcopenia among Chinese community-dwelling older adults living alone and to identify the associated factors. A total of 390 older adults were included in this study. Sarcopenia and probable sarcopenia were defined according to the criteria of the Asian Working Group for Sarcopenia 2019. Data on socio-demographic characteristics, health status, health behaviours and lifestyle characteristics, nutritional status, physical activity level, and depressive symptoms were collected. The association between these characteristics and sarcopenia risk was analysed using a multivariate ordinal logistic regression. The proportion of subjects at risk of sarcopenia and probable sarcopenia was found to be 57.7% and 30%, respectively. Older age, being malnourished and being at risk of malnutrition were significantly associated with sarcopenia risk. Being educated to secondary level or above, being overweight or obese and higher physical activity level were associated with decreased sarcopenia risk. Our results showed that older adults living alone were at high risk of developing sarcopenia and probable sarcopenia. These results emphasise the urgent need to initiate aggressive screening and holistic lifestyle therapeutic intervention strategies for this high-risk population.

Economic Evaluation of Exercise-Based Fall Prevention Programs for People with Parkinson's Disease: A Systematic Review.

Objectives: Falls are common in Parkinson's disease (PD). Exercise interventions can prevent falls. This review aims to (1) explore the existing evidence regarding the cost-effectiveness of exercise-based fall prevention programs for people with PD and (2) discuss the implications of the review findings for future research and clinical practice. Design: Databases AMED Allied and Complementary Medicine, CINAHL, CRD, EBSCO, EMBASE, MEDLINE, PubMed, Scopus, and Web of Science were searched from their inception until June 2019. Randomized and nonrandomized trials that included an economic evaluation of fall prevention programs for people with PD were considered. Quality of the economic evaluation was assessed using the Consensus on Health Economic Criteria list (CHEC-list), and the methodological quality was assessed using the Physiotherapy Evidence Database (PEDro) and Cochrane risk of bias tool. Results: Nine hundred and sixty-five studies were screened to include three studies involving 556 participants. Quality of economic evaluation assessed using CHEC-list was high. The methodological quality was high for two studies and low for one study. Tested interventions included Tai Ji Quan, physiotherapist-led, supervised, weekly and monthly balance, and strengthening exercises. The duration of the interventions ranged from 10 weeks to 6 months, while the intervention frequency ranged from two sessions per week to one session per month. Treatment sessions lasted for 60 min in all three studies. One high economic and methodological quality study comparing Tai Ji Quan with resistance and stretching exercises reported least cost resource use among Tai Ji Quan group (USD 80,441) and greater incremental number of falls prevented. All three tested interventions had an 80% probability of being cost-effective with the corresponding country-specific threshold incremental cost-effectiveness ratio values. Conclusions: The findings provide some evidence for exercise-based intervention as a cost-effective treatment option for preventing falls in PD; however, due to the limited number of available studies, heterogeneity of the interventions, and diversity of assessment settings, a firm conclusion cannot be established. Additional studies evaluating the cost-effectiveness of fall prevention programs involving larger samples and using different treatment parameters in various settings are warranted.

Malnutrition risks and their associated factors among home-living older Chinese adults in Hong Kong: hidden problems in an affluent Chinese community.

BACKGROUND: Although China is undergoing rapid economic development, it is facing an ageing population. No data exists on malnutrition risks of older adults in an affluent Chinese society. The aim of this study is to examine these risks and identify their associated factors among home-living older Chinese adults in Hong Kong. METHODS: This is a cross-sectional study, to which home-living subjects aged 60 or above were recruited, between May and September 2017, from a non-governmental community organisation located in three different districts of Hong Kong. Nutritional status was assessed by the Mini Nutritional Assessment (MNA), and its associated factors examined included socio-demographic characteristics, lifestyle, health status and diet. Multivariable logistic regression analysis was performed to identify factors associated with malnutrition risks (MNA < 24). RESULTS: Six hundred thirteen subjects (mean age: 78.5 ± 7.4; 54.0% females) completed the survey. Nearly 30% (n = 179) were at risk of malnutrition. By multivariable logistic regression, subjects (1) whose vision was only fair or unclear, (2) with poor usual appetite and (3) with main meal skipping behaviour had significantly higher malnutrition risk (all p < 0.05). CONCLUSIONS: In this affluent Chinese society, the malnutrition risk in older adults is close to the global average, which is a matter for much concern. Interventions are therefore warranted that target vulnerable groups with poor vision, appetite, and meal skipping behaviour. TRIAL REGISTRATION: Not applicable.

Detection of Osteoporosis from Percussion Responses Using an Electronic Stethoscope and Machine Learning.

Osteoporosis is an asymptomatic bone condition that affects a large proportion of the elderly population around the world, resulting in increased bone fragility and increased risk of fracture. Previous studies had shown that the vibroacoustic response of bone can indicate the quality of the bone condition. Therefore, the aim of the authors' project is to develop a new method to exploit this phenomenon to improve detection of osteoporosis in individuals. In this paper a method is described that uses a reflex hammer to exert testing stimuli on a patient's tibia and an electronic stethoscope to acquire the impulse responses. The signals are processed as mel frequency cepstrum coefficients and passed through an artificial neural network to determine the likelihood of osteoporosis from the tibia's impulse responses. Following some discussions of the mechanism and procedure, this paper details the signal acquisition using the stethoscope and the subsequent signal processing and the statistical machine learning algorithm. Pilot testing with 12 patients achieved over 80% sensitivity with a false positive rate below 30% and accuracies in the region of 70%. An extended dataset of 110 patients achieved an error rate of 30% with some room for improvement in the algorithm. By using common clinical apparatus and strategic machine learning, this method might be suitable as a large population screening test for the early diagnosis of osteoporosis, thus avoiding secondary complications.

Microphone Handling Noise: Measurements of Perceptual Threshold and Effects on Audio Quality.

A psychoacoustic experiment was carried out to test the effects of microphone handling noise on perceived audio quality. Handling noise is a problem affecting both amateurs using their smartphones and cameras, as well as professionals using separate microphones and digital recorders. The noises used for the tests were measured from a variety of devices, including smartphones, laptops and handheld microphones. The signal features that characterise these noises are analysed and presented. The sounds include various types of transient, impact noises created by tapping or knocking devices, as well as more sustained sounds caused by rubbing. During the perceptual tests, listeners auditioned speech podcasts and were asked to rate the degradation of any unwanted sounds they heard. A representative design test methodology was developed that tried to encourage everyday rather than analytical listening. Signal-to-noise ratio (SNR) of the handling noise events was shown to be the best predictor of quality degradation. Other factors such as noise type or background noise in the listening environment did not significantly affect quality ratings. Podcast, microphone type and reproduction equipment were found to be significant but only to a small extent. A model allowing the prediction of degradation from the SNR is presented. The SNR threshold at which 50% of subjects noticed handling noise was found to be 4.2 ± 0.6 dBA. The results from this work are important for the understanding of our perception of impact sound and resonant noises in recordings, and will inform the future development of an automated predictor of quality for handling noise.

Nanosecond Pulse Electric Field Activated-Platelet Rich Plasma Enhances the Return of Blood Flow to Large and Ischemic Wounds in a Rabbit Model.

Platelet-rich plasma is a therapeutic strategy used for accelerating wound healing of a wide range of tissues through the release of platelet growth factors. Here, we describe a nonchemical, safe method for preparing platelet-rich plasma using nanosecond-pulsed electric fields (nsPEFs) and investigated the effect of this platelet-rich plasma on reperfusion of blood in large skin flap or ischemic hind limb wounds in New Zealand White rabbits. Laser Doppler images of blood flow to the dorsal surface of skin flap wounds or to ischemic hind limb wounds were obtained from wounds treated with 0.9% saline or nanosecond-pulsed electric field prepared platelet-rich plasma (nsPRP). Reperfusion in the skin flap wounds was greater in the nsPRP-treated wounds than in the wounds treated with saline on postoperative days 3 (P < 0.001) and 21 (P < 0.03). Reperfusion in the ischemic hind-limb treated with nsPRP was greater than in the saline-treated limb on post-operative Day 3 (P < 0.001), post-operative week 1 (P < 0.025) and post-operative week 4 (P < 0.015). In the hind limb ischemic tissue, the number of endothelial cells, collagen, and cells containing vascular endothelial growth factor (VEGF) was greater in the nsPRP-treated tissue. These results demonstrate that nsPRP improves blood flow in large surgical skin wounds and in ischemic wounds.

Perception and automatic detection of wind-induced microphone noise.

Wind can induce noise on microphones, causing problems for users of hearing aids and for those making recordings outdoors. Perceptual tests in the laboratory and via the Internet were carried out to understand what features of wind noise are important to the perceived audio quality of speech recordings. The average A-weighted sound pressure level of the wind noise was found to dominate the perceived degradation of quality, while gustiness was mostly unimportant. Large degradations in quality were observed when the signal to noise ratio was lower than about 15 dB. A model to allow an estimation of wind noise level was developed using an ensemble of decision trees. The model was designed to work with a single microphone in the presence of a variety of foreground sounds. The model outputted four classes of wind noise: none, low, medium, and high. Wind free examples were accurately identified in 79% of cases. For the three classes with noise present, on average 93% of samples were correctly assigned. A second ensemble of decision trees was used to estimate the signal to noise ratio and thereby infer the perceived degradation caused by wind noise.

Treatment of primary liver cancer using highly-conformal radiotherapy with kV-image guidance and respiratory control.

PURPOSE: To implement a reliable, practical and reproducible treatment procedure, based on in-room kV-image guidance and respiratory control, for liver cancer patients treated with high dose conformal radiotherapy using a commercially available treatment system. MATERIALS AND METHODS: CT stimulation was conducted under voluntary breath hold or gating using the Varian Real-time Position Management™ (RPM) System. Treatments were delivered daily under kV image guidance to verify the diaphragmatic or lipiodol-defined tumor position. RESULTS: Thirty-three patients with liver confined hepatocellular carcinoma were treated between May 2006 and Dec 2009. After a median follow-up period of 16.5 months (range: 3.5-40.7), all but 2 patients demonstrated radiological tumor regression. Eight patients (24%) achieved complete remission. The median tumor shrinkage was 42% (27-100%). Subsequent in-field tumor progression was observed in only three patients (10%). For the 23 patients with abnormal alpha fetoprotein level, 22 of them showed biochemical response with a median AFP level drop of 78%. The treatment was well tolerated: Grade 3 toxicities occurred in 5 patients (1 leucopenia, 1 elevated liver enzyme and 3 elevated bilirubin level) but there was no grade 4 toxicity or treatment related death. The 1 year overall survival rate is 71.7% and median survival time is 17.2 months (3.5-40.7 months). CONCLUSIONS: Excellent treatment results with minimal toxicities could be achieved in a clinical environment with a commercially available highly sophisticated radiotherapy system.

Nanosecond pulse electric field activation of platelet-rich plasma reduces myocardial infarct size and improves left ventricular mechanical function in the rabbit heart.

In the current study, we used the novel, nonchemical method of nanosecond pulsed electric fields (nsPEF) to investigate the efficiency of a protocol involving the in vivo treatment of the ischemic and reperfused heart and heart cells in culture with platelet-rich plasma (PRP). Associated with the restoration of blood flow to the ischemic tissue is a phenomenon referred to as "ischemic reperfusion injury." Clinically a type of reperfusion injury occurs during coronary bypass surgery once blood perfusion to the heart is restarted. Although the restoration of oxygen to ischemic myocardial cells is critical for tissue survival, reperfusion causes myocardial oxidative stress, attributable in part to the increased production of reactive oxygen species (ROS). Enhanced ROS production is associated with mitochondrial damage. Adult female New Zealand white rabbits were anesthetized and a left thoracotomy performed to expose the heart. The distal segment of the left anterior descending coronary artery was occluded for 15 minutes and then released so reperfusion of the tissue could occur. PRP (.21 mg/heart) or saline was injected into the ischemic area of the myocardium. Mechanical function of the left ventricle was analyzed using a Millar catheter attached to a Micro-Med Analysis System. H9c2 cells in culture were treated with 1 mL of nsPEF activated PRP (1.05 mg/flask) for 24 hours before analysis for ROS production or mitochondrial depolarization damage). The left ventricle contracted and relaxed faster and infarct size was reduced in hearts treated with PRP compared with saline. ROS production and mitochondrial depolarization were reduced in H9c2 cells treated with PRP and stimulated with hydrogen peroxide. These results provide evidence that nsPEFs can successfully be used to prepare PRP and that the PRP is functional in heart protection possibly by reducing ROS generation and stabilizing the mitochondria of the ischemic/reperfused heart.

Real-time monitoring and control on deep inspiration breath-hold for lung cancer radiotherapy--combination of ABC and external marker tracking.

PURPOSE: In this article, the breath-hold and gating concepts were combined for application of lung cancer radiation treatment. The tumor movement was immobilized based on deep inspiration breath hold (DIBH), in which the breath-hold consistency and stability were monitored by infrared (IR) tracking and controlled by gating with a predefined threshold. The authors' goal is to derive the benefits from both techniques, namely, the minimized treatment margin and the known advantages of deep inspiration. The efficacy of the technique in terms of tumor immobility and treatment setup accuracy was evaluated in the study. METHODS: Fourteen patients who were diagnosed with non small cell lung cancer were included in this study. The control of tumor immobility was investigated interfractionally and intrafractionally. The intrabreath-hold tumor motion was devised based on the external marker movement, in which the tumor-marker correlation was studied. The margin of the planning target volume (PTV) was evaluated based on two factors: (1) The treatment setup error accounts for the patient setup and interbreath-hold variations and (2) the intrabreath-hold tumor motion in which the residual tumor motion during irradiation was studied. RESULTS: As the result of the study, the group systematic error and group random error of treatment setup measured at the isocenter were 0.2(R) +/- 1.6, 1.0(A) +/- 2.0, and 0.3(S) +/- 1.5 mm in the left-right (LR), anterior-posterior (AP), and caudal-cranial (CC) directions, respectively. The Pearson correlation coefficient were 0.81 (LR), 0.76 (AP), and 0.85 (CC) mm and suggest tendency in linear correlation of tumor and marker movement. The intrabreath-hold tumor was small in all directions. The group PTV margins of 3.8 (LR), 4.6 (AP), and 4.8 (CC) mm were evaluated to account for both setup errors and residual tumor motion during irradiation. CONCLUSIONS: The study applies the DIBH technique in conjunction with IR positional tracking for tumor immobilization and treatment setup localization. The technique not only proved to be reliable in terms of good tumor immobility and accurate treatment positioning but also to be potentially useful for dose escalation treatment as regarding of the substantially reduced PTV margin and minimizing radiation toxicity from the fully expanded lung volume.

Chronic hepatitis C genotype 6 responds better to pegylated interferon and ribavirin combination therapy than genotype 1.

BACKGROUND AND AIMS: Chronic hepatitis C genotype 6 is common in Hong Kong, especially among i.v. drug abusers. Responses of these patients to combination of pegylated interferon and ribavirin treatment were inconsistent and the numbers of patients involved in previous studies were small. We performed a retrospective study to compare the therapeutic responses of this regimen in patients infected with genotype 6 and genotype 1. METHODS: Seventy patients with either genotype 6 or genotype 1 were recruited. Both groups received 800-1200 mg of ribavirin daily plus either 180 mg of pegylated alpha-interferon-2a or 1.5 mg/kg pegylated alpha-interferon-2b weekly for 48 weeks. Their responses to treatments were compared. RESULTS: The early virological response to combination therapy of patients with genotype 6 was significantly better than that of genotype 1 (88.6% vs 74.3%, P = 0.03). Significant difference was also identified in the end of treatment response of the two genotypes (60% vs 81.4% for genotype 1 and 6, respectively; P = 0.005). The sustained virological response (SVR) to treatment in patients with genotype 6 was also significantly superior to that of patients with genotype 1 (75.7% vs 57.1%, P = 0.02). Multiple logistic regression analysis demonstrated that age of 55 years or less, genotypes of hepatitis C virus, liver biopsy staging and baseline hepatitis C virus RNA of 200,000 IU/mL or less were independent predictors for better SVR in this cohort. CONCLUSION: Patients with chronic hepatitis C genotype 6 respond better to pegylated interferon and ribavirin combination treatment than patients with genotype 1.

Monaural room acoustic parameters from music and speech.

This paper compares two methods for extracting room acoustic parameters from reverberated speech and music. An approach which uses statistical machine learning, previously developed for speech, is extended to work with music. For speech, reverberation time estimations are within a perceptual difference limen of the true value. For music, virtually all early decay time estimations are within a difference limen of the true value. The estimation accuracy is not good enough in other cases due to differences between the simulated data set used to develop the empirical model and real rooms. The second method carries out a maximum likelihood estimation on decay phases at the end of notes or speech utterances. This paper extends the method to estimate parameters relating to the balance of early and late energies in the impulse response. For reverberation time and speech, the method provides estimations which are within the perceptual difference limen of the true value. For other parameters such as clarity, the estimations are not sufficiently accurate due to the natural reverberance of the excitation signals. Speech is a better test signal than music because of the greater periods of silence in the signal, although music is needed for low frequency measurement.