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The psychological and physiological indicators derived from studies of urban soundscapes have been suggested to explain the restoration effects of digital treatments using virtual reality (VR) environments. These experiences of virtual spaces that lead to emotional restoration are often related to natural environments such as waterfront and sites with vegetations. Perceptions of VR environments demonstrated that urban areas, including urban parks with traffic noise in the background were also considered as such spaces. VR technology used for experiencing spatial atmospheres creates a realistic audio and visual environment. Accordingly, subjects also respond to a survey on the audiovisual elements of the space. When verifying the restoration effect of soundscapes, physiological responses such as EEG and HRV are investigated along with questionnaire-based psychological responses. In this study, a statistical restoration model was constructed by interpreting psychophysiological responses and deriving the relationship between physical indicators for soundscapes based on such biological signals. However, various natural soundscape contents need to be further studied and produced to expect therapeutic effects.

Purpose: We evaluated whether Spatholobus suberectus extract (SSE) can be used as a means of preventing and treating osteoporosis by measuring its effect on osteoclast differentiation, gene expression, and bone resorption.Methods: SSE was used to examine the effect on RAW 264.7 cells stimulated with RANKL to induce bone resorption. The inhibitory effect of TRAP formation and the expression of the bone resorption factors TRAP, cathepsin K, and MMP-9 during differentiation were measured. The effects on the differentiation-related factors NFATc and TRAIL and on the expression of OC-STAMP, DC-STAMP, ATP6v0d2, MITF, c-Fos, and inflammation-related factors were also evaluated. The effect on bone resorption was evaluated by culturing RANKL-treated osteoclasts on artificial bone fragments and observing the resulting resorption traces. The effect on bone damage in experimental animals was also measured.Results: SSE inhibited the differentiation of RANKL-stimulated osteoclasts into osteoclasts and suppressed the expression of cathepsin K, TRAP, MMP-9, NFATc1, TRAIL, MITF, OC-STAMP, DC-STAMP, ATP6v0d2, and c-Fos genes. Bone pore formation due to osteoclast action was also inhibited, and LPS-induced bone loss was suppressed in animal experiments.Conclusions: SSE could be useful for the prevention or treatment of osteoporosis by inhibiting osteoclast differentiation and bone resorption and suppressing bone loss induced in experimental animals. However, studies of larger populations are required.

To determine the effects of multimodal rehabilitation initiated immediately after esophageal cancer surgery on physical recovery compared with conventional pulmonary rehabilitation.Retrospective study.Private quaternary care hospital.Fifty-nine inpatients (N=59) who participated in either conventional pulmonary rehabilitation (n=30) or in multimodal rehabilitation (n=29) after esophageal cancer surgery were included.Both groups performed pulmonary exercises, including deep breathing, chest expansion, inspiratory muscle training, coughing, and manual vibration. In the conventional pulmonary rehabilitation group, light-intensity mat exercise, stretching, and walking were performed. The multimodal rehabilitation group performed resistance exercises and moderate- to high-intensity aerobic interval exercises using a bicycle.The European Organization for Research and Treatment of Cancer Core Quality of Life Questionnaire C30 (EORTC QLQ-C30), pain, 6-minute walk test (6MWT), 30-second chair stand test, and grip strengths were assessed before and after the rehabilitation programs.Symptom scales of pain, dyspnea, and insomnia in the EORTC QLQ-C30 as well as 6MWT improved significantly after each program (P.05). 6MWT (73.1±52.6 vs 28.4±14.3, P.001, d=1.15), 30-second chair stand test (3.5±3.9 vs 0.35±2.0, P.001, d=1.06), and left grip strength (1.2±1.3 vs 0.0±1.5, P=.002, d=0.42) improved significantly in the multimodal rehabilitation group compared with the pulmonary rehabilitation group. While right grip strength also showed more improvement for those undergoing the multimodal program, the mean strength difference was not clinically meaningful.A multimodal inpatient rehabilitation program instituted early after esophageal cancer surgery improved endurance for walking more than conventional pulmonary rehabilitation as measured by the 6MWT and the 30-second chair stand test.

Objectives: Acanthopanax senticosus is a tree used in traditional medicine for various diseases. In this study, we investigated the anti-cancer effects of a water extract of Acanthopanax senticocus fruit (ASF) on 2 human breast cancer cell lines (MCF-7 and MDA-MB-231).Methods: The MTT assay was used to assess cell proliferation. The expression of apoptosis-related genes was assessed by quantitative real-time PCR.Results: ASF treatment caused a dose-dependent inhibition of cell growth in both estrogen-independent MDA-MB-231 and estrogen-dependent MCF-7 breast cancer cells. ASF decreased mRNA expression of the apoptotic suppressor gene Bcl-xL, and increased mRNA expression of proapoptotic genes. ASF increased the mRNA expression of p21 and RIP-1 in both cell types. ASF decreased the mRNA expression of survivin in the MCF-7 cell line.Conclusions: ASF exhibits anti-cancer activity involving apoptotic cell death.

Supplementary Data from ASO-Based PKM Splice-Switching Therapy Inhibits Hepatocellular Carcinoma Growth

The M2 pyruvate kinase (PKM2) isoform is upregulated in most cancers and plays a crucial role in regulation of the Warburg effect, which is characterized by the preference for aerobic glycolysis over oxidative phosphorylation for energy metabolism. PKM2 is an alternative-splice isoform of the PKM gene and is a potential therapeutic target. Antisense oligonucleotides (ASO) that switch PKM splicing from the cancer-associated PKM2 to the PKM1 isoform have been shown to induce apoptosis in cultured glioblastoma cells when delivered by lipofection. Here, we explore the potential of ASO-based PKM splice switching as a targeted therapy for liver cancer. A more potent lead constrained-ethyl (cEt)/DNA ASO induced PKM splice switching and inhibited the growth of cultured hepatocellular carcinoma (HCC) cells. This PKM isoform switch increased pyruvate-kinase activity and altered glucose metabolism. In an orthotopic HCC xenograft mouse model, the lead ASO and a second ASO targeting a nonoverlapping site inhibited tumor growth. Finally, in a genetic HCC mouse model, a surrogate mouse-specific ASO induced Pkm splice switching and inhibited tumorigenesis, without observable toxicity. These results lay the groundwork for a potential ASO-based splicing therapy for HCC.Significance:Antisense oligonucleotides are used to induce a change in PKM isoform usage in hepatocellular carcinoma, reversing the Warburg effect and inhibiting tumorigenesis.

Primer sequences

Purpose: Cancer cells grow in an unfavorable metabolic milieu in the tumor microenvironment and are constantly exposed to metabolic stress such as chronic nutrient depletion. Cancer stem-like cells (CSC) are intrinsically resistant to metabolic stress, thereby surviving nutrient insufficiency and driving more malignant tumor progression. In this study, we aimed to demonstrate the potential mechanisms by which CSCs avoid Ca2+-dependent apoptosis during glucose deprivation.Experimental Design: We investigated cell viability and apoptosis under glucose deprivation, performed genome-wide transcriptional profiling of paired CSCs and parental cells, studied the effect of calcium/calmodulin-dependent protein kinase 2 alpha (CaMK2α) gene knockdown, and investigated the role of nuclear factor kappa B (NFκB) in CSCs during time-dependent Ca2+-mediated and glucose deprivation–induced apoptosis. We also observed the effect of combined treatment with 2-deoxy-d-glucose, a metabolic inhibitor that mimics glucose deprivation conditions in mouse xenograft models, and thapsigargin, a specific inhibitor of sarco/endoplasmic reticulum Ca2+-ATPase (SERCA).Results: We demonstrated the coordinated upregulation of SERCA in CSCs. SERCA, in turn, is transcriptionally regulated by CaMK2α via NFκB activation. Combined treatment with 2-deoxy-d-glucose and thapsigargin, a specific inhibitor of SERCA, significantly reduced tumor growth compared with that in untreated control animals or those treated with the metabolic inhibitor alone.Conclusions: The current study provides compelling evidence that CaMK2α acts as a key antiapoptosis regulator in metabolic stress-resistant CSCs by activating NFκB. The latter induces expression of SERCA, allowing survival in glucose-deprived conditions. Importantly, our combination therapeutic strategy provides a novel approach for the clinical application of CSC treatment. Clin Cancer Res; 24(7); 1677–90. ©2017 AACR.

Supplementary Table from ASO-Based PKM Splice-Switching Therapy Inhibits Hepatocellular Carcinoma Growth

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As soundscapes have become increasingly important for human health recovery and comfort, studies have been performed on methodologies for evaluating soundscapes using physiological responses. This study proposes a method to evaluate visual attention using eye-tracking technology for objectively assessing soundscape perception. The visual elements of a spatial environment were divided into static and dynamic factors. The dynamic factors were perceived in real time using an object-detection algorithm. Virtual-reality evaluation environments of nine sites were realized. The identification of sound sources, visual elements, perceived affective quality, overall quality, and psychological restoration responses were examined using questionnaires for 60 subjects, and eye movement was measured. The visual identification responses for vehicles, sky, and vegetation deviated slightly from the questionnaire responses. However, the soundscape quality prediction model results indicated that the proposed methodology can complement the conventional questionnaire-based prediction models and is capable of deeper eventfulness relationship interpretation. Moreover, the proposed visual attention quantification technique complemented the restoration responses of the questionnaire-based methods by 1%–2%. These findings can guide future studies on soundscape evaluation via physiological measurements.

BackgroundNear-infrared fluorescence indocyanine green (NIRF-ICG) lymphangiography, a primary modality for detecting lymphedema, which is a disease due to lymphatic obstruction, enables real-time observations of lymphatic flow and reveals not only the spatial distribution of drainage (static analysis), but also information on the lymphatic contraction (dynamic analysis).MethodsWe have produced lymphatic obstruction models in upper limbs through the dissection of proximal lymph nodes (LNs) and radiation (dissection limbs). After the model formation during 1 week, the static and dynamic analysis using NIRF-ICG lymphangiography were performed for six weeks. The drainage pattern and leakage of lymph fluid were observed and time-domain signals of lymphatic contraction were measured in the distal lymph vessels. The obtained signals were converted to the frequency-domain spectrums using the signal processing.ResultsThe results of both static and dynamic analyses proved to be effective in accurately identify the extent of lymphatic disruption in the dissection limbs. The static analysis showed abnormal drainage patterns and an increased leakage of lymph fluid to the periphery of the vessels compared to the control limbs. Meanwhile, the waveforms were changed and the frequency of the contractile signals was increased by 58% in the dynamic analysis. Specifically, our findings revealed that regular lymphatic contractions, observed at a frequency range of 0.08 ∼ 0.13 Hz in the control limbs, were absent in the dissection limbs. The contractile regularity was not fully restored until the end of the follow-up, indicating a persistent lymphatic disruption in the dissected limbs.ConclusionThe dynamic analysis was consistent with the static analysis, and it could detect the abnormalities of lymphatic circulation by observing the characteristics of signals without the need for a control group. As NIRF-ICG lymphangiography is currently used in clinical practice, our findings may be useful for the early detection of the lymphatic circulation problem.

Background Petersen's hernia, which occurs after minimally invasive surgery for gastric cancer, can be reduced by defect closure. This study aimed to demonstrate the incidence of bowel obstruction above Clavien–Dindo classification grade III due to Petersen's hernia between the mesenteric fixation method(MEFIX) and the conventional methods during the 5-year follow-up period after laparoscopic gastric cancer surgery. Methods This prospective, single-blind, non-inferiority randomized controlled trial and multicenter study was conducted at hospitals in Korea. Patients with histologically diagnosed gastric cancer of clinical stage I, II, or III who underwent Roux-en-Y or B- II gastrojejunostomy anastomosis after laparoscopic gastrectomy were enrolled in this study. Patients who met the inclusion criteria were randomly assigned to two groups: a CLOSURE group that underwent Petersen's defect closure method and a MEFIX group that underwent the mesenteric fixation method. Discussion This trial is expected to provide high-level evidence showing that the MEFIX method can quickly and easily close Petersen's defect and reduce postoperative complications compared to the conventional method. It is also expected to be applicable not only after gastric cancer surgery but also after bariatric surgery. Trial registration The MEFIX study protocol was registered in htrp://register.clinicaltrials.gov as NCT05105360 (registration date: November 3, 2021)

Purpose: The effects of inspiratory muscle training (IMT) with pulmonary rehabilitation (PR) on patients with non-small cell lung cancer (NSCLC) receiving radiotherapy (RT) have not been reported. This pilot study aimed to determine the effectiveness of IMT with PR on respiratory muscles and exercise capacity of NSCLC patients receiving RT. Methods: We retrospectively analyzed 20 patients who underwent RT for NSCLC. The rehabilitation included IMT, stretching, strengthening, and aerobic exercises three times a week for 4 weeks with concurrent RT. IMT training lasted 10 min, consisting of one cycle of 30 breaths using the Powerbreathe KH1 device (POWERbreathe KH1, HaB International Ltd, Southam, UK) in the hospital by a physical therapist. Patients underwent two IMT sessions at home daily at an intensity of approximately 30–50% of the participant’s maximum inspiratory muscle pressure (MIP) using the Threshold IMT tool. We analyzed results from the respiratory muscle strength test, pulmonary function test, 6-min walk test (6MWT), cardiopulmonary function test, cycle endurance test (CET), Inbody test, grip measurement, knee extensor/flexor strength measurement, Cancer Core Quality of Life Questionnaire (EORTCQ-C30), and NSCLC 13 (EORTC-LC13). Results: There were no adverse events during evaluation and IMT with PR. MIP (60.1±25.1 vs 72.5±31.9, p=0.005), 6MWT (439.2±97.1 vs 60.7±97.8, p=0.002), CET (181.39±193.12 vs 123.6±87.6, p=0.001), knee extensor (14.4±5.3 vs 17.4±5, p=0.012), and knee flexor (14.0±5.2 vs 16.9±5.5, p=0.004) significantly improved after IMT with PR. Conclusion: IMT with PR appears effective on respiratory muscles and exercise capacity without adverse events in NSCLC patients who underwent RT.

This review aimed to increase the understanding of oncologists and physiatrists about the necessity, efficacy, and safety of rehabilitation in advanced cancer patients with bone metastases and neural compromise.Recently, there are growing evidence supporting the safety and efficacy of rehabilitation in patients with bone metastases and neural compromise. Despite the potential benefits of rehabilitation, however, rehabilitative services are considerably underutilized in clinical practice. Many oncologists are not familiar with functional issues and have limited understanding of the available rehabilitative services. Moreover, medical professionals, even physiatrists, have uncertainties and concerns about skeletal complications and often regard rehabilitation as a contraindication in this patient group. This review aimed to raise awareness on the role of rehabilitation in the continuum of cancer treatment, to improve its use in clinical practice. A multidisciplinary team approach involving physiatrist may facilitate integration of relevant clinicians.

Objective: In this study, we investigated the protective effect of rhododendron mucronulatum extract (RME) on allergic reactions and inflammation.Methods: The effect of RME was determined using ELISA and RT-PCR in RBL-2H3 mast cells and RAW 264.7 macrophage cells. We determined cell viability, β-hexosaminidase release, and the synthesis of IL-4 and TNF-α in RBL-2H3 cells. In addition, we determined NO from RAW 264.7 and the gene expression of IL-1β, iNOS, IL-6, TNF-α, and IL-10.Results: RME inhibited β-hexosaminidase release and synthesis of IL-4 and TNF-α in RBL-2H3 by the anti-DNP IgE plus DNP-HSA stimulation. In addition, RME inhibited the production of NO and the gene expression of IL-1β, iNOS, IL-6, and TNF-α in LPS-stimulated RAW 264.7 cells.Conclusion: From these results, we concluded that RME possesses anti-allergic activity and anti-inflammatory activity due to the inhibition of mast cells and macrophage function.

The M2 pyruvate kinase (PKM2) isoform is upregulated in most cancers and plays a crucial role in regulation of the Warburg effect, which is characterized by the preference for aerobic glycolysis over oxidative phosphorylation for energy metabolism. PKM2 is an alternative-splice isoform of the PKM gene and is a potential therapeutic target. Antisense oligonucleotides (ASO) that switch PKM splicing from the cancer-associated PKM2 to the PKM1 isoform have been shown to induce apoptosis in cultured glioblastoma cells when delivered by lipofection. Here, we explore the potential of ASO-based PKM splice switching as a targeted therapy for liver cancer. A more potent lead constrained-ethyl (cEt)/DNA ASO induced PKM splice switching and inhibited the growth of cultured hepatocellular carcinoma (HCC) cells. This PKM isoform switch increased pyruvate-kinase activity and altered glucose metabolism. In an orthotopic HCC xenograft mouse model, the lead ASO and a second ASO targeting a nonoverlapping site inhibited tumor growth. Finally, in a genetic HCC mouse model, a surrogate mouse-specific ASO induced Pkm splice switching and inhibited tumorigenesis, without observable toxicity. These results lay the groundwork for a potential ASO-based splicing therapy for HCC. Significance: Antisense oligonucleotides are used to induce a change in PKM isoform usage in hepatocellular carcinoma, reversing the Warburg effect and inhibiting tumorigenesis.