Investigating the synergy of Shikonin and Valproic acid in inducing apoptosis of osteosarcoma cells via ROS-mediated EGR1 expression.

BACKGROUND: Osteosarcoma is the most prevalent malignant bone tumour with a poor prognosis. Shikonin (SHK) is derived from the traditional Chinese medicine Lithospermum that has been extensively studied for its notable anti-tumour effects, including for osteosarcoma. However, its application has certain limitations. Valproic acid (VPA) is a histone deacetylase inhibitor (HDACI) that has recently been employed as an adjunctive therapeutic agent that allows chromatin to assume a more relaxed state, thereby enhancing anti-tumour efficacy. PURPOSE: This study was aimed to investigate the synergistic anti-tumour efficacy of SHK in combination with VPA and elucidate its underlying mechanism. METHODS/STUDY DESIGN: CCK-8 assays were utilized to calculate the combination index. Additional assays, including colony formation, acridine orange/ethidium bromide double fluorescent staining, and flow cytometry, were employed to evaluate the effects on osteosarcoma cells. Wound healing and transwell assays were utilized to assess cell mobility. RNA sequencing, PCR, and Western blot analyses were conducted to uncover the underlying mechanism. Rescue experiments were performed to validate the mechanism of apoptotic induction. The impact of SHK and VPA combination treatment on primary osteosarcoma cells was also assessed. Finally, in vivo experiments were conducted to validate its anti-tumour effects and mechanism. RESULTS: The combination of SHK and VPA synergistically inhibited the proliferation and migration of osteosarcoma cells in vitro and induced apoptosis in these cells. Through a comprehensive analysis involving RNA sequencing, PCR, Western blot, and rescue experiments, we have substantiated our hypothesis that the combination of SHK and VPA induced apoptosis via the ROS-EGR1-Bax axis. Importantly, our in vivo experiments corroborated these findings, demonstrating the potential of the SHK and VPA combination as a promising therapeutic approach for osteosarcoma. CONCLUSION: The combination of SHK and VPA exerted an anti-tumour effect by inducing apoptosis through the ROS-EGR1-Bax pathway. Repurposing the old drug VPA demonstrated its effectiveness as an adjunctive therapeutic agent for SHK, enhancing its anti-tumour efficacy and revealing its potential value. Furthermore, our study expanded the application of natural compounds in the anti-tumour field and overcame some of their limitations through combination therapy. Finally, we enhanced the understanding of the mechanistic pathways linking reactive oxygen species (ROS) accumulation and apoptosis in osteosarcoma cells. Additionally, we elucidated the role of EGR1 in osteosarcoma cells, offering novel strategies and concepts for the treatment of osteosarcoma.

Efficacy of Danggui Buxue decoction on diabetic nephropathy-induced renal fibrosis in rats and possible mechanism.

OBJECTIVE: To observe the efficacy of Danggui Buxue decoction (, DBD) on diabetic nephropathy-induced renal fibrosis in rats, and to study the possible mechanism. METHODS: Sixty male Goto Kakizaki (GK) rats were randomly assigned to the model group, gliquidone group, astragaloside IV group, and high-, medium- and low-doses DBD groups. After 8 weeks, changes in body weight, blood glucose, serum creatinine, serum urea nitrogen, and total cholesterol were observed. Changes in transforming growth factor-ß1 (TGF-ß1), Smad3, and Smad5 pathways and the expression of the fibrosis-related proteins collagen IV (col IV), α-smooth muscle actin (α-SMA), and vimentin were assessed. The degree of renal fibrosis was observed by immunohistochemistry and Mason staining. The expression of interleukin 6 (IL-6), interleukin 10 (IL-10), tumor necrosis factor (TNF-α), and C-reactive protein (CRP) in the kidneys was assessed using enzyme linked immunosorbent assay. RESULTS: Our experiments showed that DBD effectively reduced blood glucose, blood urea nitrogen, and creatinine levels after 8 weeks of administration, improved renal function in diabetic rats, alleviated renal fibrosis, and reduced the renal tissue levels of IL-6, IL-10, TNF-α, and CRP. Furthermore, DBD decreased the expression of TGF-ß1, Smad3, col IV, α-SMA, and vimentin in renal tissues and increased the expression of Smad5. CONCLUSIONS: DBD ameliorates diabetic renal interstitial fibrosis by modulating the TGF-ß1/Smads pathway.

Clinical study on improving the strength and activity of lumbar spine with Qiang Jin exercises / 中国骨伤

OBJECTIVE@#To observe the effect of Qiang Jin exercises on the muscle strength and activity of lumbar spine in patients with lumbar disc herniation.@*METHODS@#From March 2016 to September 2017, at the Department of Orthopaedics, Shuguang Hospital, Shanghai University of Traditional Chinese Medicine, a total of 110 subjects were enrolled, and 98 eligible subjects were screened. The subjects were randomized by stratified randomization and divided into experimental group and control group, 49 cases in each group, 25 males and 24 females in the experimental group, 25 males and 24 females in the control group. The experimental group exercised with Qiang Jin exercises, one time each morning and evening, each time10 sets were made;the control group used classic rehabilitation training, training twice a week, and three months was a course of treatment. After 12 weeks of training, the muscle strength and activity of the lumbar spine were evaluated and compared with the muscle strength and activity of the lumbar spine before training.@*RESULTS@#The experimental group and the control group had different muscle strength and activity of the lumbar spine before and after treatment (@*CONCLUSION@#Qiang Jin exercises can effectively improve the muscle strength and activity of the lumbar spine and improve the daily living ability of patients.

Preventing Postpartum Depression With Mindful Self-Compassion Intervention: A Randomized Control Study.

Mindfulness and self-compassion are reported to have a preventive effects on depression and anxiety disorders. In the present study, we aimed to assess the effect of mindful self-compassion intervention on preventing postpartum depression in a group of symptomatic pregnant women. Participants were screened and assigned to the intervention and control groups randomly. A 6-week Internet-based Mindful Self-Compassion Program was used to train the participants. Multiple scales were used to assess depressive and anxiety symptoms, mindfulness, self-compassion, and mother and infant well-being. All assessments were performed at three time points: baseline, 3 months, and 1 year postpartum. Compared with the control group, the intervention group showed significant improvement in depressive and anxiety behaviors. In addition, the intervention group became more mindful and self-compassionate at 3 months and 1 year postpartum. More importantly, both mothers and infants experienced substantial improvement in well-being. Our findings indicate that mindful self-compassion intervention is effective in preventing postpartum depression and promoting mother and infant well-being.

Mechanisms and Components Identification of Naoxintong Intestinal Absorption Liquid Protecting Cardiac Injury Induced by H2O2 / 中国实验方剂学杂志

Objective: Intestinal absorption liquid as medicine carriers, one or more kinds of traditional Chinese medicine protecting cardiac injury in Naoxintong capsule will be found through separation and combination of prescription. This study also can expand protecting mechanisms of Naoxintong capsule. Method: Naoxintong intestinal absorption liquids of single, combination and total prescription were prepared. H9c2 cell line exposed to H2O2 was established. Cell survival rate was determined with methyl thiazolyl tetrazolium(MTT). Cell apoptosis rate was examined by Annexin Ⅴ-FITC/PI staining with a flow cytometer. Aquaporin1(AQP1) expression was detected by Western blot. One or more kinds of traditional Chinese medicine in Naoxintong capsule which exerted protective effect from cardiac injury were screened through separation and combination of prescription. Result: As compared with control group, the protein expression level of AQP1 was significantly increased(PPPPPPConclusion: Naoxintong capsule acts as a protective role in myocardial injury through decreasing AQP1 expression and inhibiting cell apoptosis. Salviae Miltiorrhizae Radix et Rhizoma, Pheretima, Scorpio are important components in Naoxintong capsule.

Identification of effective components from Naoxintong Capsules intestinal absorption liquid in inhibiting ADP-induced platelet aggregation / 中国中药杂志

Intestinal absorption liquid was prepared by using everted intestinal sac method; meanwhile, its recipes were decomposed or restructured. Platelet aggregation activity was examined by biochemical tests and a microplate reader. One or more kinds of Chinese medicines which displayed inhibiting activity in Naoxintong Capsules were screened through separation and combination of prescription. The results showed that Naoxintong Capsules could inhibit ADP-induced platelet aggregation. Recipe decomposition and restructuring results showed that Salviae Miltiorrhizae Radix et Rhizoma, Paeoniae Radix Rubra, Cinnamomi Ramulus and Hirudo were the main effective medicines in inhibiting platelet aggregation. Furthermore, Cinnamomi Ramulus played a vital role in inhibiting activity among those four kinds of Chinese medicines. Coumarin derived from intestinal absorption liquid of Cinnamomi Ramulus had inhibiting activity in the range of 50-200 μmol·L⁻¹, and other ingredients such as cinnamyl alcohol and cinnamaldehyde also had inhibiting activities. In conclusion, Salviae Miltiorrhizae Radix et Rhizoma, Paeoniae Radix Rubra, Cinnamomi Ramulus and Hirudo are the main components for inhibiting ADP-induced platelet aggregation, and Cinnamomi Ramulus has the most strongest inhibiting activity in Naoxintong Capsules.

Complex network analysis of law on Chinese herbal drugs intervention on radiation induced lung injury / 中国中药杂志

To mainly analyze the prescription rules of Chinese herbal drugs for radiation induced lung injury, optimize the prescriptions, and provide a reference for the clinical treatment of radiation induced lung injury. The major Chinese databases CNKI, CBM and Wanfang data were searched to obtain the literature on Chinese herbal drugs for radiation induced lung injury. BICOMS 2 software was used to extract and collect all Chinese herbal drugs information and generate the co-occurrence matrix; NetDraw and Gcluto software were then used to make network map and visualization matrix for analysis. A total of 552 articles (19 types and 304 Chinese herbal drugs) were included. Ophiopogon japonicus had the highest frequency (229 times), followed by Astragalus membranaceus(181 times), Glycyrrhiza uralensis (166 times), and Scutellaria baicalensis (150 times). After the classification of efficacy, deficiency-supplementing medicinal (69 kinds of Chinese herbs), heat-clearing medicine (51 kinds of Chinese herbs) and phlegm cough medicine (42 kinds of Chinese herbs) accounted for 53.29% of all the Chinese herbs, acting in the main position. After the prescription analysis for the top 25 herbal prescriptions, six main structures of common prescriptions were found for the treatment of radiation induced lung injury. There are many kinds of Chinese herbal drugs for the treatment of radiation induced lung injury in clinical application. In the future, researchers can mainly focus on Ophiopogon japonicus etc. as the main drugs, combine with other high-frequency Chinese herbal drugs found in this study, or directly refer to the main structures of commonly used prescriptions found in this analysis.

Regulation of acupuncture on expression of AKT protein in lung tissues of asthma rats / 中国针灸

<p><b>OBJECTIVE</b>To explore the effects of acupuncture on the expression of protein kinase B (PKB/AKT) in lung tissues of asthma rats.</p><p><b>METHODS</b>Forty SPF male SD rats were randomly divided into a blank group, a model group, an acupuncture group and a blocker group, 10 rats in each one. The rat model of asthma was established by egg albumin stimulation in the model group, acupuncture group and blocker group. Since the establishment of rat model, the rats in the acupuncture group were treated with acupuncture at "Dazhui" (GV 14), "Feishu" (BL 13) and "Fengmen" (BL 12) before atomization; the rats in the blocker group were treated with intervention of blocker LY294002, once every two days, for 7 times. There was no treatment in the blank group and model group. HE staining was applied to observe the morphologic changes of lung tissues; the immunohistochemical method was applied to test the protein expression of AKT in lung tissue.</p><p><b>RESULTS</b>HE staining indicated the infiltration and aggregation of a variety of inflammatory cells around airways, as well as bronchial smooth muscle spasm and confined lumen in the model group; in the acupuncture group and blocker group the inflammatory cells were less and confined lumen was relieved. Compared with the blank group, the protein expression of AKT was higher in the model group (<0.05); compared with the model group, the protein expression of AKT in the acupuncture group and blocker group was reduced (both<0.05); the differences between the acupuncture group and blank group, blocker group were not significant (both>0.05).</p><p><b>CONCLUSIONS</b>Acupuncture could reduce the protein expression of AKT in lung tissue in asthma rats, leading to relieved inflammation reaction and airway remodeling.</p>

Acupuncture for TGF-β1 expression in lung tissues of asthma rats / 中国针灸

<p><b>OBJECTIVE</b>To explore the regulation of acupuncture for transforming growth factor β1 (TGF-β1) expression in the lung tissues of bronchial asthmatic rats.</p><p><b>METHODS</b>Forty SPF male SD rats were randomly divided into a blank group, a model group, an acupuncture group and a shallow fast acupuncture group, 10 rats in each group. Asthma model was established in the model, acupuncture, and shallow fast acupuncture groups, and no intervention was applied in the blank and model groups. Before atomization excitation, 20 min acupuncture was applied at "Dazhui" (GV 14) "Feishu" (BL 13) "Fengmen" (BL 12) in the acupuncture group. Acupuncture only into skin without needle retained at the above acupoints was used in the shallow fast acupuncture group before atomization excitation from the day of model established. All the treatment was given 7 times, once the other day. The pathological lunge tissues of rats were observed by HE staining; the protein expression of TGF-β1 in the lung tissues was examined by immunohistochemical staining and immunofluorescence staining. The TGF-β1 expressions in bronchoalveolar lavage fluid (BALF) and serum were showed by ELISA.</p><p><b>RESULTS</b>There were changes in the lung tissues in the model group, including mucus plug in the bronchial lumen, irregular bronchial epithelium, thick airway smooth muscle, local break, narrow lumen, a large number of inflammatory cell infiltration. The phenomena in the acupuncture group were improved and those in the shallow fast acupuncture group were not apparently changed compared with those in the model group. The IOD value of TGF-β1 expression in the model group increased compared with that in the blank group (<0.05); the positive expression in the acupuncture group was lower than those in the model and shallow fast acupuncture groups (both<0.05). The contents of TGF-β1 in BALF and serum of the acupuncture group were lower than those in the model and shallow fast acupuncture groups (all<0.05).</p><p><b>CONCLUSIONS</b>Acupuncture may improve airway inflammatory response and remolding of asthma by inhibiting TGF-β1 expression.</p>

Sinomenine prevents metastasis of human osteosarcoma cells via S phase arrest and suppression of tumor-related neovascularization and osteolysis through the CXCR4-STAT3 pathway.

Osteosarcoma is the most common primary malignant tumor of the bone. The long-term survivals continue to be unsatisfactory for patients with metastatic and recurrent disease. Metastasis is still a severe challenge in osteosarcoma treatment. Sinomenine, an alkaloid from traditional Chinese medicine, has been proved to possess potent antitumor and anti-invasion effect on various cancers. However, the effect of sinomenine on human osteosarcoma and the underlying mechanisms remains unknown. We report here that sinomenine inhibited proliferation by inducing S phase arrest and suppressing the clone formation. Significant inhibitory effects were found in invasion and metastasis in osteosarcoma, but little cytotoxicity was observed in tested concentrations. Exposure to sinomenine resulted in suppression of invasion and migration in osteosarcoma cells as well as tube formation ability in the human umbilical vein endothelial cells (HUVEC) and U2OS cells. Furthermore, it demonstrated that CXCR4 played a key role contributing to invasion in osteosarcoma which is considered to be a core target site in sinomenine treatment. Sinomenine inhibited invasion by suppressing CXCR4 and STAT3 phosphorylation then downregulating the expression of MMP-2, MMP-9, RANKL, VEGF downstream. In addition, then RANKL-mediated bone destruction stimulated by osteoclastogenesis and VEGF-related neovascularization were restrained. Importantly, in vivo, sinomenine suppressed proliferation, osteoclastogenesis and bone destruction. Through these various comprehensive means, sinomenine inhibits metastasis in osteosarcoma. Taken together, our results revealed that sinomenine caused S phase arrest, inhibited invasion and metastasis via suppressing the CXCR4-STAT3 pathway and then osteoclastogenesis-mediated bone destruction and neovascularization in osteosarcoma. Sinomenine is therefore a promising adjuvant agent for metastasis control in osteosarcoma.

Assessment on the Efficacy and Safety of Aidi Injection Combined with Vinorelbine and Cisplatin for Treatment of Advanced Nonsmall Cell Lung Cancer / 中华医学杂志(英文版)

<p><b>BACKGROUND</b>The aim of this study was to assess the efficacy and safety of vinorelbine and cisplatin (NP chemotherapy) alone or in combination with Aidi injection for the treatment of advanced nonsmall cell lung cancer (NSCLC).</p><p><b>METHODS</b>Pertinent publications were identified in PubMed, EMBASE, Cochrane Library, CNKI, CQVIP, and Wanfang databases, up to December 8, 2015. After quality assessment of all included randomized controlled trials evaluating Aidi injection combined with NP chemotherapy for the treatment of advanced NSCLC, a meta-analysis was performed by Review Manager 5.2 and STATA 12.0 for statistical analyses.</p><p><b>RESULTS</b>Twelve studies including 509 and 503 cases in the experimental and control groups, respectively, were finally analyzed. The meta-analysis revealed that when cisplatin dose ranging from 20 to 40 mg/m 2 , combination of Aidi injection and NP chemotherapy was statistically different compared with NP chemotherapy alone in enhancing efficiency (relative risk [RR] = 1.24, 95% confidence interval [CI] [1.05-1.47], P = 0.010) and reducing the incidence of Grade II or above nausea and vomiting (RR = 0.49, 95% CI [0.30-0.80], P = 0.005). Meanwhile, with cisplatin ranging from 80 to 120 mg/m 2 , no significant differences in efficiency (RR = 1.11, 95% CI [0.87-1.42], P = 0.390) and Grade II or above nausea and vomiting (RR = 0.88, 95% CI [0.71-1.10], P = 0.260) were obtained. In addition, Aidi injection combined with NP chemotherapy was superior to NP chemotherapy alone in improving the quality of life, alleviating Grade II or above leukopenia and thrombocytopenia.</p><p><b>CONCLUSIONS</b>Aidi injection combined with NP chemotherapy can enhance efficiency, improve the quality of life, and decrease adverse effects in patients with advanced NSCLC.</p>

Effect of Aidi injection plus chemotherapy on gastric carcinoma: a Meta-analysis of randomized controlled trials.

OBJECTIVE: To conduct a Meta-analysis of studies on the effect of Aidi injection combined with chemotherapy versus chemotherapy alone in the treatment of gastric cancer (GC). METHODS: Nine electronic databases and six gray literature databases were comprehensively searched until April 20, 2013. Two reviewers independently selected and assessed included trials according to the inclusion and exclusion criteria. The risk of bias tool from the Cochrane Handbook version 5.1.0 was used to assess trial quality. All calculations were performed using Review Manager 5.0. RESULTS: Thirty-two studies including 1927 participants met the inclusion criteria, most of which were low quality. Compared with chemotherapy alone, Aidi injection plus the same chemotherapy significantly improved the effective rate [OR = 1.52, 95% CI (1.24, 1.86), P < 0.0001], clinical beneficial rate [OR = 1.77, 95% CI (1.33, 2.36), P < 0.0001], and quality of life [OR = 3.02, 95% CI (2.39, 3.82), P < 0.000 01]. There was a significant improvement in nausea and vomiting incidence [OR = 0.34, 95% CI (0.24, 0.47), P < 0.000 01], diarrhea [OR = 0.47, 95% CI (0.33, 0.69), P < 0.000 01], leukopenia (III-IV) [OR = 0.34, 95% CI (0.23, 0.51), P = 0.05], hemoglobin decrease (III-IV) [OR = 0.42, 95% CI (0.18-1.00), P = 0.05], thrombocytopenia (III-IV) [OR = 0.46, 95% CI (0.22, 0.96), P = 0.04], and damage to liver function [OR = 0.36, 95% CI (0.24, 0.54), P < 0.00001]. CONCLUSION: Aidi injection combined with chemotherapy significantly improved the clinical effect of chemotherapy, reducing the incidence of adverse events. Use of the CONSORT statement for randomized controlled trials is recommended for stricter reporting.

Brief introduction of research methods of commodity specification and grade of Chinese medicinal materials / 中国中药杂志

The commodity specification and grade of Chinese medicinal materials is a measure of the quality of traditional Chinese medicines (TCMs), which directly impacts on the safety and effectiveness of clinical medicines. It is an urgent problem to establish a set of standards which can both interpret the scientific connotation of the commodity specification and grade of Chinese medicinal materials and play a significant role on clinical medicines as well as markets. This paper reviews the research methods of the commodity specification and grade of Chinese medicinal materials such as sensory evaluation, chemical assessment, biological evaluation, and cited the applications of various methods for the classification of TCMs. It provides technical support for establishing standards of the commodity specification and grade of Chinese medicinal materials, and also constructs scientific basis for clinical rational drug use.

Therapeutic Observation of Fire Needling plus Chinese Herbal Medicine for Alopecia Areata / 上海针灸杂志

Objective To observe the clinical efficacy of fire needling plus Chinese herbal medicine in treating alopecia areata. Method Fifty patients with alopecia areata were randomized into a treatment group of 35 cases and a control group of 15 cases. The treatment group was intervened by fire needling plus Chinese herbal medicine, while the control group was by oral administration of Chinese herbal medicine alone. The clinical efficacies were compared after 3-month treatment.Result The total effective rate was 97.1% in the treatment group versus 73.3% in the control group, and the difference was statistically significant (P<0.05).Conclusion Fire needling plus Chinese herbal medicine is an effective method in treating alopecia areata.

The research progress of treating cervical spondylosis of nerve root type with traditional Chinese medicine / 国际中医中药杂志

200 papers on nerve root type cervical spondylosis treated with Chinese medicine were retrieved and 38 papers with complete diagnostic criteria and medical statistics were included for study. The results showed acupuncture, massage, and herbal therapy were three common methods and have their own advantage, but systemic, standardized and normative treatment program was lack. In the meantime of treating nerve root type cervical spondylosis, prevention should also be paid attention. The treatment, prevention and exercise on the whole therapeutic idea should be established, which has far-reaching significance.

[Awareness of occupational low back pain: a survey of 244 midwives].

OBJECTIVE: To investigate the awareness of occupational low back pain and knowledge of related prevention and healthcare measures among midwives, and to determine the incidence of low back pain among them. METHODS: A questionnaire survey was carried out with the use of Roland-Morris Disability Questionnaire (Chinese version) (CRMDQ) among 244 midwives from second- and third-class hospitals in Tianjin, China. Related indices were statistically analyzed. RESULTS: Among 244 midwives who participated in the survey, only 18.4% knew the definition of occupational low back pain, 28.3% knew the pathogenic mechanism, and 54.1% knew its harm. About 9.4%∼85.2% of midwives mastered at least one method for prevention and health care against occupational low back pain. Proper or improper use of human body mechanics was closely related to the development of occupational low back pain (P < 0.01). There was a high proportion of midwives with a demand for application of human body mechanics principle in operation, and the proportion was as high as 99.2%. All the 24 items in CRMDQ were scored, with the lowest score of 1, the highest score of 24, and an average score of 8.5 ± 7.2. CONCLUSION: The awareness rate of occupational low back pain was low among the 244 midwives in this study. The incidence of low back pain, which had influenced the health status and occupational practice, was high among them.

Chemical constituents from seeds of Brassica campestris / 中国中药杂志

Fourteen compounds were isolated by column chromatography from the ethyl acetate extract of the seeds of Brassica campestris. Their structures were elucidated by physicochemical properties and spectroscopic data analysis. The isolated compounds were respectively identified as (5Z,7E)-4, 4-dimethyl-5-acetyl-5, 7-nonadienoic acid (1), indole-3-carboxaldehyde (2), blumenol A (3), vinylsyringol (4), sinapinic acid (5), sinapic acid ethyl ester (6), protocatechuic acid (7), crinosterol (8), campesterol (9), 7-oxo-stigmasterol (10), kaempferol (11), 2,5-dihydroxybenzoic acid (12), syringic acid (13) and daucosterol (14). Compound 1 was a new compound and the other compounds were isolated from this plant for the first time except for compounds 4, 5 and 13.

On-site quality control of acupuncture randomized controlled trial: design of content and checklist of quality control based on PICOST / 中国针灸

To effectively guarantee quality of randomized controlld trial (RCT) of acupuncture and develop reasonable content and checklist of on-site quality control, influencing factors on quality of acupuncture RCT are analyzed and scientificity of quality control content and feasibility of on-site manipulation are put into overall consideration. Based on content and checklist of on-site quality control in National 11th Five-Year Plan Project Optimization of Comprehensive Treatment Plan for TCM in Prevention and Treatment of Serious Disease and Clinical Assessment on Generic Technology and Quality Control Research, it is proposed that on-site quality control of acupuncture RCT should be conducted with PICOST (patient, intervention, comparison, out come, site and time) as core, especially on quality control of interveners' skills and outcome assessment of blinding, and checklist of on-site quality control is developed to provide references for undertaking groups of the project.