Effects of auricular acupressure on dysmenorrhea: A systematic review and meta-analysis of randomized controlled trials.

Background: Auricular acupressure (AA) is widely used in treatment of dysmenorrhea, but the safety and efficacy of auricular acupressure on dysmenorrhoea are still lack of evidence-based basis. Objective: The purpose of meta-analysis was to evaluate the effects of auricular acupressure on dysmenorrhea. Data sources: A systematic search was conducted in six electronic databases, including PubMed, Embase, Cochrane Central Register of Controlled Trials (CINAHL), Weipu (CQVIP), China National Knowledge Infrastructure (CNKI), and Wanfang databases, to retrieve studies published from the inception dates to June 10, 2022. Study selection: Randomized controlled trials (RCTs) that investigated the effectiveness of AA on dysmenorrhea were identified. Data extraction and synthesis: The data extraction and quality assessment of the included studies were performed by two reviewers independently. Outcomes were abstracted to determine the effect measure by using mean differences (MD), standardized mean differences (SMD), or odds ratio (OR) from a random effects model. Main outcomes and measures: Cure rate, total effective rate, and visual analogue scale (VAS) were described as primary outcomes; Short-form Menstrual Distress Questionnaire (MDQs), symptom scores, serum nitric oxide (NO) level, and adverse events were recorded as secondary outcomes. Results: Thirty-five RCTs involving 3960 participants were included in this study. Our findings indicated that, overall, AA was associated with a significant benefit in cured rate (OR = 1.95, 95%CI: [1.34, 2.83], P=0.0004, I2 = 75%), total effective rate (OR = 3.58, 95%CI: [2.92, 4.39], P<0.00001, I2 = 67%), VAS score (MD = -1.45, 95%CI: [-1.73, -1.17], P<0.00001, I2 = 67%), and symptom scores compared to the control group (SMD = -0.85, 95%CI: [-1.28, -0.43], P<0.0001, I2 = 91%). However, no difference in serum NO (SMD = 0.77, 95%CI: [-0.39, 1.92], P = 0.19, I2 = 89%) and MDQs (SMD = -0.58, 95%CI: [-1.26, 0.10], P = 0.10, I2 = 79%) was found between the two groups. Furthermore, subgroup analysis results indicated that AA showed significant superiorities in increasing cured rate and total effective rate, and reducing VAS score and symptom scores when compared to analgesics and non-intervention. Moreover, AA presented the same superiorities when used as an adjunctive strategy to other therapy. However, these benefits were not detected in AA used alone when compared to the therapies, including Chinese herbs, acupuncture, external application of Chineseherbal medicine, moxibustion, auricular needle, and health education. Conclusions: Overall, AA, as a potential safety therapy, is effective for the management of dysmenorrhea, such as increasing cured rate, total effective rate, VAS, and symptom scores. Nevertheless, AA showed no significant improvement in serum NO and MDQs. It is furtherly found that AA used alone is superior to analgesics and non-intervention regarding cured rate, total effective rate, VAS, and symptom scores. Furthermore, the same superiorities are observed when AA serves as an adjunctive strategy to other therapy. However, AA alone has little effect on them compared to other therapies, and there is no definite conclusion on the benefits of AA compared to placebo for patients with dysmenorrhea. Rigorous RCTs with blind method and placebo control are warranted to confirm these findings. Systematic review registration: https://www.crd.york.ac.uk/prospero/, identifier CRD42022338524.

Multi-organ metastasis as destination for breast cancer cells guided by biomechanical architecture.

A majority of breast cancer patients die of widespread aggressive multidrug-resistant tumors. Aspartate ß-hydroxylase (ASPH) is an α-ketoglutarate-dependent dioxygenase and oncofetal antigen involved in embryogenesis. To illustrate if ASPH could be targeted for metastatic breast cancer, embedded and on-top three-dimensional (3-D) cultures, 3-D invasion, mammosphere formation, immunofluorescence, immunohistochemistry, Western blot, co-IP and microarray were conducted. In vitro metastasis was developed to imitate how cancer cells invade basement membrane at the primary site, transendothelially migrate, consequently colonize and outgrow at distant sites. Orthotopic and experimental pulmonary metastatic (tail vein injection) murine models were established using stable breast cancer cell lines. Cox proportional hazards regression models and Kaplan-Meier plots were applied to assess clinical outcome of breast cancer patients. In adult non-cancerous breast tissue, ASPH is undetectable. Pathologically, ASPH expression re-emerged at ductal carcinoma in situ (DCIS), and enhanced with disease progression, from early-stage invasive ductal carcinoma (IDC) to late-stage carcinoma. ASPH at moderate to high levels contribute to aggressive molecular subtypes, early relapse or more frequent progression and metastases, whereas substantially shortened overall survival and disease-free survival of breast cancer patients. Through direct physical interactions with A disintegrin and metalloproteinase domain-containing protein (ADAM)-12/ADAM-15, ASPH could activate SRC cascade, thus upregulating downstream components attributed to multifaceted metastasis. ASPH-SRC axis initiated pro-invasive invadopodium formation causing breakdown/disorganization of extracellular matrix (ECM), simultaneously potentiated epithelial-mesenchymal transition (EMT), induced cancer stem cell markers (CD44 and EpCAM), enhanced mammosphere formation and intensified 3-dimentional invasion. Oncogenic SRC upregulated matrix metallopeptidases (MMPs) were assembled by invadopodia, acting as executive effectors for multi-step metastasis. ASPH-SRC signal guided multi-organ metastases (to lungs, liver, bone, spleen, lymph nodes, mesentery or colon) in immunocompromised mice. Malignant phenotypes induced by ASPH-SRC axis were reversed by the third-generation small molecule inhibitor (SMI) specifically against ß-hydroxylase activity of ASPH in pre-clinical models of metastatic breast cancer. Collectively, ASPH could activate ADAMs-SRC-MMPs cascades to promote breast cancer tumor progression and metastasis. ASPH could direct invadopodium construction as a biomechanical sensor and pro-metastatic outlet. ASPH-mediated cancer progression could be specifically/efficiently subverted by SMIs of ß-hydroxylase activity. Therefore, ASPH emerges as a therapeutic target for breast cancer.

Efficacy and safety of acupuncture in postoperative ileus after gynecological surgery: A protocol for system review and meta-analysis of randomized controlled trials.

BACKGROUND: Acupuncture is widely used in treatment of postoperative ileus (POI), but the safety and efficacy of acupuncture in POI after gynecological surgery still lack of evidence-based basis. METHODS: PubMed, CINAHL, EMBASE, Web of science, Google Scholar, Wangfang database, Chinese Biomedical Literature Database (SinoMed), Chinese Science and Technology Periodical Database, and China National Knowledge Infrastructure database will be searched until December 31, 2020. Two independent investigators will screen the relevant randomized controlled trials from Data one by one by using prespecified criteria. The relevant data from included studies will be extracted and analyzed by using RevMan V.5.3 software. Quality of the included studies will be estimated by using the Cochrane Collaboration risk of bias tool, and publication bias will be assessed by using Egger test and Begg test. In addition, quality of evidence will be evaluated by using Grading of Recommendations Assessment, Development, and Evaluation. RESULTS: We will analyze the effect of acupuncture on time to first flatus and time to bowel sound recovery as the primary outcomes of this review. Meanwhile, frequency of bowel sounds, time to defecation, time of hospital stay, biochemical indicators related to gastrointestinal motility, inflammation factors, responder rate, and adverse events for patients receiving gynecological surgery. CONCLUSION: Our findings will benefit researchers and provide reference for the treatment and prevention of POI for the patients undergoing gynecological surgery.

ASPH-notch Axis guided Exosomal delivery of Prometastatic Secretome renders breast Cancer multi-organ metastasis.

BACKGROUND: Aspartate ß-hydroxylase (ASPH) is silent in normal adult tissues only to re-emerge during oncogenesis where its function is required for generation and maintenance of malignant phenotypes. Exosomes enable prooncogenic secretome delivering and trafficking for long-distance cell-to-cell communication. This study aims to explore molecular mechanisms underlying how ASPH network regulates designated exosomes to program development and progression of breast cancer. METHODS: Stable cell lines overexpressing or knocking-out of ASPH were established using lentivirus transfection or CRISPR-CAS9 systems. Western blot, MTT, immunofluorescence, luciferase reporter, co-immunoprecipitation, 2D/3-D invasion, tube formation, mammosphere formation, immunohistochemistry and newly developed in vitro metastasis were applied. RESULTS: Through physical interactions with Notch receptors, ligands (JAGs) and regulators (ADAM10/17), ASPH activates Notch cascade to provide raw materials (especially MMPs/ADAMs) for synthesis/release of pro-metastatic exosomes. Exosomes orchestrate EMT, 2-D/3-D invasion, stemness, angiogenesis, and premetastatic niche formation. Small molecule inhibitors (SMIs) of ASPH's ß-hydroxylase specifically/efficiently abrogated in vitro metastasis, which mimics basement membrane invasion at primary site, intravasation/extravasation (transendothelial migration), and colonization/outgrowth at distant sites. Multiple organ-metastases in orthotopic and tail vein injection murine models were substantially blocked by a specific SMI. ASPH is silenced in normal adult breast, upregulated from in situ malignancies to highly expressed in invasive/advanced ductal carcinoma. Moderate-high expression of ASPH confers more aggressive molecular subtypes (TNBC or Her2 amplified), early recurrence/progression and devastating outcome (reduced overall/disease-free survival) of breast cancer. Expression profiling of Notch signaling components positively correlates with ASPH expression in breast cancer patients, confirming that ASPH-Notch axis acts functionally in breast tumorigenesis. CONCLUSIONS: ASPH-Notch axis guides particularly selective exosomes to potentiate multifaceted metastasis. ASPH's pro-oncogenic/pro-metastatic properties are essential for breast cancer development/progression, revealing a potential target for therapy.