Application of ultrasound elastography for monitoring the effects of TβR1 shRNA therapy on hepatic fibrosis in a rat model

Background To investigate the application of ultrasound elastography in monitoring the effects of the transforming growth factor (TGF)-β1 signaling pathway-targeted combination therapy for hepatic fibrosis. Methods 1. Short hairpin RNA (shRNA) constructs targeted towards TβR1 were designed, synthesized, and packaged using an adeno-associated virus (AAV), and the effective target shRNA was selected based on transfection results. 2. Fifty rats were randomly allocated (n = 10 per group) to the (A) control group, (B) model group, (C) 0-week therapy group, (D) 4-week therapy group, and (E) combination therapy group. At weeks 2, 4, 6, 8, 10, and 12, acoustic radiation force impulse (ARFI) elastography was used to measure the liver stiffness, inner diameter of the portal vein diameter, and blood velocity; radio frequency ultrasound imaging was used to measure the abdominal aortic elasticity parameter and pulse wave velocity (PWV) of the rats. 3. At week 12, portal vein puncture was performed to measure the portal venous pressure, and rat liver specimens were obtained for the pathological measurement of the degree of hepatic fibrosis. Results 1. An shRNA interference sequence targeted towards TβR1 was successfully designed, screened, and packaged using an AAV, and small-animal imaging results indicated expression of the specific shRNA in the liver. 2. At week 12, the ultrasound elastography results were significantly different between the experimental groups and the control group (p < 0.01); among the experimental groups, differences were significant between the therapy groups and the model group (p < 0.01). For groups C and E, the therapeutic effects on hepatic fibrosis in rats were significant, with the pathological results indicating a significant reduction in the degree of hepatic fibrosis (p < 0.01). The therapeutic effectiveness of group D was less than that of group C (p < 0.05). Significant differences existed between the portal venous pressure of the experimental groups and of the control group (p < 0.01). For the abdominal aortic elasticity parameter measured by radio frequency ultrasound imaging, differences existed between the values obtained from the experimental groups and from that of the control group (p < 0.05), while statistically significant differences were not found among the various experimental groups. 3. Continuous ultrasound examination results indicated that the elasticity value of group A was significantly different from those of the other groups after 2 weeks of model establishment (p < 0.01); after 6 weeks, the elasticity values of groups C and E were significantly different compared with those of groups B and D (p < 0.01). For the abdominal aortic elasticity parameter and pulse wave velocity (PWV), there were no significant differences among the various groups (p > 0.05). Conclusion CCl4-induced hepatic fibrosis can be treated through shRNA silencing of TβR1. Ultrasound ARFI elastography is superior to external force-assisted elastography as it can reflect the degree of fibrosis in moderate to severe hepatic fibrosis and the variations in the degree of fibrosis after treatment. Portal venous pressure was positively correlated with the degree of fibrosis; with early combination therapy, both the degree of fibrosis and portal venous pressure could be effectively reduced.

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Application of ultrasound elastography for monitoring the effects of TβR1 shRNA therapy on hepatic fibrosis in a rat model

10.21203/rs.2.17000/v1 ◽

2019 ◽

Author(s):

Xiangzhou Shi ◽

Jing-Hua Li ◽

Ying-Bin Min ◽

Rui-Jing Yang ◽

Chun-Xiang He ◽

...

Keyword(s):

Combination Therapy ◽

Portal Vein ◽

Hepatic Fibrosis ◽

Therapy Group ◽

Venous Pressure ◽

Liver Stiffness ◽

Ultrasound Elastography ◽

Acoustic Radiation Force Impulse ◽

Invasive Technique ◽

Control Group

Abstract Background: To investigate the application of ultrasound elastography in monitoring the effects of the transforming growth factor (TGF)-β1 signaling pathway-targeted combination therapy for hepatic fibrosis. Methods: 1.Short hairpin RNA (shRNA) constructs targeted towards TβR1 were designed, synthesized, and packaged using an adeno-associated virus (AAV), and the effective target shRNA was selected based on transfection results. 2. Fifty rats were randomly allocated (n=10 per group) to the (A) control group, (B) model group, (C) 0-week therapy group, (D) 4-week therapy group, and (E) combination therapy group. At weeks 2, 4, 6, 8, 10, and 12, acoustic radiation force impulse (ARFI) elastography was used to measure the liver stiffness, inner diameter of the portal vein diameter, and blood velocity; radio frequency ultrasound imaging was used to measure the abdominal aortic elasticity parameter and pulse wave velocity (PWV) of the rats. 3. At week 12, portal vein puncture was performed to measure the portal venous pressure, and rat liver specimens were obtained for the pathological measurement of the degree of hepatic fibrosis. Conclusion: Ultrasound elastography can reflect the degree of fibrosis in moderate to severe hepatic fibrosis and the variations in the degree of fibrosis after treatment through shRNA silencing of TβR1 . Therefore, it is a potential non-invasive technique for monitoring the effects of anti-fibrosis therapy.

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IFN-α, IFN-γ, IL-2 combined with TNF-α for predicting efficacy of PD-1 inhibitors combination therapy in patients with solid cancers.

Journal of Clinical Oncology ◽

10.1200/jco.2021.39.15_suppl.2584 ◽

2021 ◽

Vol 39 (15_suppl) ◽

pp. 2584-2584

Author(s):

Penghui Xing ◽

Jinyan Zhang ◽

Rongfeng Liu ◽

Junyan Wang ◽

Ming Ma ◽

...

Keyword(s):

Combination Therapy ◽

Therapy Group ◽

Control Group ◽

Coincidence Rate ◽

Advanced Malignancies ◽

Tnf Α ◽

Significant Difference ◽

Group A ◽

Ifn Γ ◽

Group B

2584 Background: PD-1 inhibitors have transformed the treatment landscape for patients (pts) with many advanced malignancies. Combination therapy with PD-1 inhibitors for cancer is a trend. However, Biomarkers for the efficacy of combination therapy remains unknown. In order for the benefited population to be screened out, biomarkers need to be established. we will conduct the following study, to explore the IFN-α, IFN-γ, IL-2 combined with TNF-α for predicting efficacy of PD-1 inhibitors combination therapy. Methods: Using postoperative without lesions as control group (n=7). Pts with lesions as the experimental group (n=66). 27 of 66 pts received chemoradiotherapy (group A), 39 of 66 pts received PD-1 inhibitors combined with therapy (group B). IFN-α, IFN-γ, IL-2, TNF-α in peripheral blood of all pts were measured using flow cytometry. Results: 1) There was significant difference in proportion above normal concentrations (ANCs) of IFN-α between two groups (57.1% vs 43.5%, P<0.05), but there was no significant difference in IFN-γ, IL-2 and TNF-α between two groups (IFN-γ 57.1% vs 52.2%, IL-2 14.3% vs 5.8%, TNF-α 42.9% vs 43.5%, P>0.05). 2) The normal ratios of IFN-α, IFN-γ and TNF-α in group B was significantly higher than that in group A (IFN-α 64.1% vs 51.9%, IFN-γ 59% vs 37%, TNF-α 69.2% vs 44.4%, P<0.05). The proportion ANCs of IFN-α, IFN-γ, and TNF-α were lower in group A (IFN-α 35.9% vs 63%, P>0.05; IFN-γ 41% vs 63%, P<0.05; TNF-α 30.8% vs 55.6%, P<0.05). However, the proportion ANCs of IL-2 detection was lower (7.4% vs 5.1%). 3) In group B, 21 of 39 pts were evaluable. ORR was 52.4% (11/21) and DCR was 85.7% (18/21). The proportion ANCs of IFN-α, IFN-γ and TNF-α in the pts with PR was higher than that with SD (IFN-α 37.5% vs 28.6%, IFN-γ 37.5% vs 28.6%, TNF-α 50% vs 38.8%, P<0.05). 4) We found that the coincidence rate of IFN-α+ IFN-γ and IFN-α+ IFN-γ+TNF-α was higher in group B (Table). Conclusions: Our results suggest that the proportion ANCs of IFN-α, IFN-γ, and TNF-α in the pts with lesions were lower than that without lesions, it may be the decrease of immune function with lesions. There was positive correlation between proportion ANCs of IFN-α, IFN-γ and TNF-α and efficacy in these pts. IL-2 was not used as a routine detection indicator. The coincidence rate of IFN-α, IFN-γ combined with TNF-α was higher, it may help predict the outcome of PD-1 inhibitors combination therapy in pts with solid cancers, and helpful to screen the benefit population. Further study is needed.[Table: see text]

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A combination of cognitive training and physical exercise for elderly with the mild cognitive impairment

Journal of Health Research ◽

10.1108/jhr-11-2018-0135 ◽

2019 ◽

Vol 33 (6) ◽

pp. 504-516 ◽

Cited By ~ 2

Author(s):

Ida Untari ◽

Achmad Arman Subijanto ◽

Dyah Kurnia Mirawati ◽

Ari Natalia Probandari ◽

Rossi Sanusi

Keyword(s):

Combination Therapy ◽

Physical Exercise ◽

Cognitive Training ◽

Therapy Group ◽

Meta Analysis ◽

Control Group ◽

Combination Therapy Group ◽

National Library ◽

Content Type ◽

Treatment Services

Purpose The purpose of this paper is to conduct systematic reviews on Indonesian papers, to examine the most recent evidence of the efficacy of the combination of cognitive training and physical exercise, and to make recommendations in order to improve prevention, care and treatment services in elderly patients with mild cognitive impairment (MCI). Design/methodology/approach The databases of Cochrane, Medline, NIH (US National Library Medicine), ProQuest, EbscoHost, Clinical Key, EMBASE, Medical Librarian (TWE) in Ovid, Science Direct, Scopus, The Lancet Global Health, PubMed, Emerald, Indonesian National Library, Google Scholar, Google Indonesia, and Garuda Portal were systematically searched using Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines to obtain empirical papers published between June 1976 and January 2018. Findings Out of the 3,293 articles collected, 10 were included in this analysis. The result of this combined meta-analysis compares the combination therapy group (cognitive therapy and physical exercise) with a control group. It shows that the control group was likely to experience MCI 1.65 times more often than the combination therapy group. According to the result acquired from the synthesized meta-analysis, the control group experienced MCI 1.65 times higher than the combination therapy. The finding is proven to be statistically significant (95% CI= 1.42–1.93). Research limitations/implications The research considers only English and Indonesian articles. Practical implications It is important to explore the most effective training characteristics in a special combined intervention differentiated by the duration, frequency, intervention, type and combination mode. There is a need for further investigation that focuses on the physiological mechanisms underlying the positive effects, by inserting a more comprehensive neuro-imaging measurement to assess specifically the domain that benefits in terms of cognitive functions and molecular markers. Finally, exploratory studies are definitely required, which will specifically examine maintenance and treatment effects as well as derive theoretical explanations related to the interventions and predictors. Social implications A combination of cognitive training and physical exercise intervention may improve the global health or cognitive functions. Originality/value A combination of cognitive training and physical exercise has been found to improve prevention, care and treatment services in elderly patients with MCI. There is an increase in value in comparison to the study of Karssemeijer, which considered five Indonesian articles.

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Effectiveness and Safety of Combination Therapy of Transarterial Chemoembolization and Apatinib for Unresectable Hepatocellular Carcinoma in the Chinese Population: A Meta-Analysis

Chemotherapy ◽

10.1159/000502510 ◽

2019 ◽

Vol 64 (2) ◽

pp. 94-104 ◽

Cited By ~ 1

Author(s):

Yan Wei ◽

Jianjun Liu ◽

Min Yan ◽

Shuguang Zhao ◽

Yong Long ◽

...

Keyword(s):

Hepatocellular Carcinoma ◽

Combination Therapy ◽

Transarterial Chemoembolization ◽

Therapy Group ◽

Meta Analysis ◽

Cochrane Library ◽

Control Group ◽

Advanced Hepatocellular Carcinoma ◽

Combination Therapy Group ◽

Advanced Hcc

Background: The combination of transarterial chemoembolization (TACE) and apatinib has been used in the treatment of intermediate or advanced hepatocellular carcinoma (HCC). However, its effectiveness and safety are also argued. Methods: Eligible studies were collected from a computer search of literatures published from the database establishment to May 2019 in PubMed, Web of Science, EMBASE, Ovid, the Cochrane Library, Wanfang Database, China National Knowledge Infrastructure, and China Biology Medicine Disc. The objective response rate (ORR), the disease control rate (DCR), survival rate (SR), and the incidences of treatment-related adverse effects (AEs) were collected as the relevant outcomes. Data were analyzed through fixed/random effects of meta-analysis models with RevMan 5.3 software. Results: Eight randomized controlled clinical trials comprising 528 patients and 4 cohort studies comprising 226 patients were eventually included. Compared to the control group treated with TACE solely, combination therapy group, in which intermediate or advanced HCC patients were treated with TACE and apatinib, significantly enhanced ORR (relative risk [RR] 2.06, 95% CI 1.63–2.61, p < 0.001), DCR (RR 1.65, 95% CI 1.24–2.20, p < 0.001), and whole SRs of 6-month (RR 1.52, 95% CI 1.08–2.14, p = 0.02), 1-year (RR 1.52, 95% CI 1.25–1.84, p < 0.001), and 2-year (RR 1.84, 95% CI 1.34–2.54, p < 0.001). The incidence of hand foot syndrome, proteinuria, hypertension, and diarrhea was significantly increased in the combination therapy group compared with the control group (p < 0.05), and the incidence of nausea and vomiting, fever, and myelosuppression, respectively, was similar in 2 groups (p > 0.05). Conclusions: The combination therapy of TACE and apatinib can enhance the clinical effectiveness better than TACE solely in patients with intermediate or advanced HCC, while increase in the AEs is usually tolerable.

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Childhood Adversities are Associated with Diabetes Management in Working Age in Finland

International Journal of Family Medicine ◽

10.1155/2014/864572 ◽

2014 ◽

Vol 2014 ◽

pp. 1-7

Author(s):

Lauri Pisto ◽

Atte Vadén ◽

Lauri Sillanmäki ◽

Kari Mattila

Keyword(s):

Combination Therapy ◽

Social Insurance ◽

Diabetes Management ◽

Therapy Group ◽

Diabetes Type 2 ◽

Stressful Events ◽

Control Group ◽

Childhood And Adolescence ◽

Childhood Adversities ◽

Working Age

Backgrounds. Research findings suggest that the mind can cause physical disease. To plan the best quality of care, general practitioner needs to understand an individual's health problems in physical, social, and psychological dimensions. This study sought to establish whether adverse life events occurring in childhood and adolescence are associated with diabetes. Methods. The cohort was collected from the health and social support (HeSSup) study—a postal follow-up survey of randomized working-aged Finns initiated in 1998. The response rate was 40.0% and the final cohort size 24057. Data on reimbursed diabetes medication during the years 1998–2006 were obtained from the Social Insurance Institute of Finland registers. Subjects were divided into insulin, tablet, combination therapy, and drug-naive groups together with a control group without diabetes. The prevalence of childhood adversities was assessed based on answers to six survey questions. Results. Childhood adversities showed predominant linkage to diabetes type 2 groups, especially to the combination therapy group requiring combined insulin and tablet treatment. No connection was found between childhood adversities and insulin use. Cumulative adversities did not markedly increase the association. Conclusions. Stressful events in childhood are associated with diabetes combination therapy in working age. The meaning of the relationship remains unsolved.

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Effect of Udenafil on Portal Venous Pressure and Hepatic Fibrosis in Rats

Arzneimittelforschung ◽

10.1055/s-0031-1296453 ◽

2011 ◽

Vol 59 (12) ◽

pp. 641-646 ◽

Cited By ~ 5

Author(s):

Seul-Min Choi ◽

Jee-Hyun Shin ◽

Ju-Mi Kim ◽

Chan-Ho Lee ◽

Kyung-Koo Kang ◽

...

Keyword(s):

Hepatic Fibrosis ◽

Venous Pressure ◽

Portal Venous Pressure

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COMPARISON OF EFFECTS OF MASSAGE THERAPY ALONE AND IN COMBINATION WITH GREEN COCONUT WATER THERAPY ON Β-ENDORPHIN LEVEL IN TEENAGE GIRLS WITH DYSMENORRHEA

Belitung Nursing Journal ◽

10.33546/bnj.158 ◽

2017 ◽

Vol 3 (4) ◽

pp. 412-419

Author(s):

Fitria Hikmatul Ulya ◽

Agus Suwandono ◽

Ida Ariyanti ◽

Ari Suwondo ◽

Suryati Kumorowulan ◽

...

Keyword(s):

Combination Therapy ◽

Rating Scale ◽

Therapy Group ◽

Massage Therapy ◽

Coconut Water ◽

Bivariate Analysis ◽

Enzyme Linked Immunosorbent Assay ◽

Control Group ◽

Menstrual Pain ◽

Teenage Girls

Background: Dysmenorrhea is pain during menstruation in lower abdomen, and is not due to other diseases. Effleurage massage and consuming green coconut water are considered able to reduce menstrual pain. However, little is known about the effect of the combination between the two interventions.Objective: To compare the effectiveness of effleurage massage and in combination with green coconut water on pain, anxiety, and ß-endorphin level in teenage girls with menstrual pain (dysmenorrhea).Design: A quasy experiment with pretest-posttest approach design with control group. There were 36 samples recruited in this study by purposive sampling, which were divided into a massage therapy group, the combination therapy group, and a control group. Menstrual pain was measured using Numeric Rating Scale, while anxiety was measured using Zung Self rating Anxiety Scale (ZSAS), and endorphin level using ELISA (Enzyme-Linked Immunosorbent Assay). One way anova test and repeated anova were performed as a bivariate analysis. Mancova and post hoc anova were used for multivariate analysis.Result: The combination of massage and green coconut water was more effective in reducing pain (p 0.013) and anxiety levels (p 0.000), and in increasing β-endorphin (p 0.029) with significant value of <0.05 compared to the massage therapy alone.Conclusion: The combination of effleurage massage and green coconut water had significant effect in decreasing anxiety and pain levels, and increasing β-endorphin levels in teenage girls with painful periods (dysmenorrhea); and more effective than performing effleurage massage only. It is suggested that this combination therapy could be used as an alternative therapy for women with dysmenrrohea.

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Contribution of changes in iron metabolism in pathogenesis of chronic diffuse liver diseases

Perm Medical Journal ◽

10.17816/pmj3765-12 ◽

2021 ◽

Vol 37 (6) ◽

pp. 5-12

Author(s):

A. P. Shchekotova ◽

I. A. Bulatova

Keyword(s):

Hepatic Fibrosis ◽

Iron Metabolism ◽

Liver Diseases ◽

Liver Lesion ◽

Ultrasound Elastography ◽

Control Group ◽

Biochemical Tests ◽

Ferritin Concentration ◽

Viral Hepatitis C ◽

Diffuse Liver Diseases

Objective. To assess the role of iron metabolism changes in the pathogenesis of chronic diffuse liver diseases (CDLD). Assessment of the hepatic fibrosis progression and the most significant factors, influencing it, is still an actual target of modern medicine. A certain interest from the point of view of complex approach to studying the mechanism of development and progression of fibrosis is the determination of serum markers of iron metabolism. Materials and methods. The study included 170 patients with CDLD: 150 with chronic viral hepatitis C and 20 with alcohol hepatic cirrhosis (AHC). Iron metabolism indices and functional hepatic biochemical tests were studied. Expression of hepatic fibrosis in hepatitis was estimated by means of the liver density index with the scale METAVIR using the data of ultrasound elastography (Fibroscan 502, Echosens, France); fibrosis development rate was calculated with T. Poynard method. The control group enclosed 100 persons. Results. There was revealed a significant elevation of the blood ferritin concentration among patients with chronic hepatitis up to 107.9 [31; 250] ng/ml compared with the control (22.0 [11; 33] ng/ml) and to 325.8 [209; 401] ng/ml in patients with AHC. Conclusions. Progression of fibrosis into cirrhosis in patients with CDLD is interconnected with iron metabolism disorders in the form of increased ferritin concentration, which correlates with the parameters of liver lesion severity that confirms a direct involvement of iron metabolism disorders in CDLD pathogenesis.

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Efficacy and Safety of Stem Cell Combination Therapy for Osteonecrosis of the Femoral Head: A Systematic Review and Meta-Analysis

Journal of Healthcare Engineering ◽

10.1155/2021/9313201 ◽

2021 ◽

Vol 2021 ◽

pp. 1-8

Author(s):

Junqiao Li ◽

Peng Su ◽

Jian Li ◽

Gang Chen ◽

Yan Xiong

Keyword(s):

Stem Cell ◽

Combination Therapy ◽

Cell Therapy ◽

Stem Cell Therapy ◽

Therapy Group ◽

Core Decompression ◽

Control Group ◽

Efficacy And Safety ◽

Porous Tantalum

Background. The treatment results of core decompression (CD) and biomechanical support are not always satisfactory in osteonecrosis of the femoral head (ONFH). Stem cell therapy has been incorporated into traditional treatment in order to promote bone regeneration. The efficacy and safety of stem cell therapy combined with CD or biomechanical support on advanced and long-term patients with ONFH were unknown. The aim of this study was to assess whether stem cell combination therapy is superior to single CD or porous tantalum rod implantation treatment in ONFH. Methods. A systematic search of the literature was performed to evaluate all included randomized controlled trials (RCTs) on stem cell combination therapy for patients with ONFH in PubMed, Cochrane Library, Web of Science, and Embase sites. We assessed the quality and risk of bias for the included studies. And the outcomes of Harris hip score (HHS), visual analogue scale (VAS), and adverse events were statistically analyzed. Results. We included 10 randomized controlled trials, containing a total of 498 patients with 719 hips. Stem cell therapy combined with CD versus CD alone for HHS of ONFH was different (MD = 8.87, 95% CI = [5.53, 12.22], P < 0.00001 ). The combination of stem cell therapy and CD can effectively improve HHS. Similarly, the VAS of the stem cell combination therapy group also differed compared with the control group (MD = −14.07, 95% CI = [−18.32, −9.82], P < 0.00001 ). The result showed that stem cell combination therapy can relieve the pain of patients with ONFH. There was no significant difference in adverse response outcome events between the combination therapy group and the control group (RR = 1.57, 95% CI = [0.62, 3.97], P = 0.34 ). Conclusions. Stem cell therapy combined with core decompression is an effective and feasible method with few complications in the clinical treatment of early-stage ONFH. Even in the combination of porous tantalum rod implantation and peripheral blood stem cells, stem cell combination therapy is superior to single biomechanical support treatment. But high-quality, large-sample, multicenter, and long-term follow-up RCTs are still needed to corroborate the efficacy and safety of stem cell combination therapy in ONFH treatment.

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THE USE OF IONTOPHORESIS WITH HYALURONIC ACID ASSOCIATED WITH GOLD NANOPARTICLES ACCELERATES WOUND HEALING IN RATS

10.22541/au.164141365.55966776/v1 ◽

2022 ◽

Author(s):

Carolini Mendes ◽

Rubya Zaccaron ◽

LIVIA HERUNDINA DE VASCONCELOS ◽

Ligia Venturini ◽

Laura Casagrande Casagrande ◽

...

Keyword(s):

Combination Therapy ◽

Inflammatory Cytokines ◽

Therapy Group ◽

Combined Therapy ◽

Repair Process ◽

Control Group ◽

Combination Therapy Group ◽

Wound Area ◽

Treatment Application ◽

Epithelial Lesion

This study aimed to investigate the effects of iontophoresis with HA associated to GNPs solution in an epithelial lesion model. Fifty Wistar rats (n=10/group) were randomly assigned to the following groups: epithelial lesion (EL); (EL+MIC); (EL+MIC+HA); (EL+MIC+GNPs); (EL+MIC+HA-GNPs). The animals induced to an epithelial lesion and treatment started 24 hours after injury with microcurrents (300µA) containing gel with HA (0.9%) and/or GNPs (30mg/Kg) in the electrodes (1mL) for seven days. The animals were sacrificed 12 hours after the last treatment application. Results demonstrated a reduction in the levels of pro-inflammatory cytokines (IFNϒ, IL-1β, TNFα, IL6) in the group in which the therapies were combined; an increase in the levels of anti-inflammatory cytokines (IL-4, IL-10) and growth factors (FGF, TGFβ) in EL+MIC+HA and EL+MIC+HA-GNPs groups. As for dichlorofluorescein (DCF) and nitrite levels, decreased in the combined therapy group when compared to the control group, as well as the oxidative damage (carbonyl and sulfhydryl). In antioxidant defense, there was an increase in glutathione (GSH) and a decrease in superoxide dismutase (SOD) in the combination therapy group. Histological analysis showed a reduction in the inflammatory infiltrate in groups treated with MIC and in the combination therapy group. An increase in contraction of the wound area was obtained in all treated groups when compared to the control group, proving that the proposed therapies are effective in the process of epithelial healing. The results of this study demonstrated that the associated therapies favor the tissue repair process more significantly compared to the isolated therapies.

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