Transcription factor KLF9 inhibits the proliferation, invasion, and migration of pancreatic cancer cells by repressing KIAA1522.

AIM: Pancreatic cancer (PC) has a poor prognosis and high mortality. Kruppel-like factor 9 (KLF9), a transcription factor, is aberrantly expressed in various neoplasms. The current study sought to analyze the functional role of KLF9 in the proliferation, invasion, and migration of PC cells. METHODS: The expression patterns of KLF9 and KIAA1522 in normal pancreatic cells (HPDE-C7) and PC cells (Panc 03.27, BxPc3, SW1990) were determined by real-time quantitative polymerase chain reaction and Western blot assay. After treatment of KLF9 overexpression, proliferation, invasion, and migration were evaluated by cell counting kit-8, 5-ethynyl-2'-deoxyuridine staining, and Transwell assays. The binding of KLF9 to the KIAA1522 promoter was analyzed by dual-luciferase assay and chromatin immunoprecipitation. The rescue experiment was conducted to analyze the role of KIAA1522. RESULTS: KLF9 was downregulated, while KIAA1522 was upregulated in PC cells. KLF9 overexpression mitigated the proliferation, invasion, and migration of PC cells. Enrichment of KLF9 led to inhibition of the KIAA1522 promoter and repressed KIAA1522 expression. KIAA1522 overexpression neutralized the inhibitory role of KLF9 in PC cell functions. CONCLUSION: KLF9 is enriched in the KIAA1522 promoter and negatively regulates KIAA1522 expression, thereby mitigating the proliferation, invasion, and migration of PC cells.

Suppression of hypoxia-induced CAV1 autophagic degradation enhances nanoalbumin-paclitaxel transcytosis and improves therapeutic activity in pancreatic cancer.

Nanoalbumin-paclitaxel (nab-paclitaxel) is a standard chemotherapy for pancreatic cancer but has shown limited efficacy. However, the mechanism through which circulating nab-paclitaxel passes through the tumour vascular endothelium has not been determined. In our study, a new nonradioactive and highly sensitive method for analysing nab-paclitaxel transcytosis was established. Based on these methods, we found that hypoxia significantly enhanced the autophagic degradation of CAV1 and therefore attenuated caveolae-mediated nab-paclitaxel transcytosis across endothelial cells (ECs). In a proof-of-concept experiment, higher levels of CAV1, accompanied by lower levels of LC3B, were observed in the vascular endothelium of pancreatic cancer tissues collected from patients who showed a good response to nab-paclitaxel compared with those from patients who showed a poor response to nab-paclitaxel. Furthermore, both in vivo and in vitro studies confirmed that suppressing the autophagic degradation of CAV1 via EC-specific ATG5 knockdown or hydroxychloroquine sulfate (HCQ) treatment significantly enhanced nab-paclitaxel translocation across the endothelial barrier into pancreatic cancer cells and amplified the inhibitory effect of nab-paclitaxel on pancreatic tumour growth. The stimulation of CAV1 expression by EC-specific overexpression of exogenous CAV1 or administration of gemcitabine hydrochloride (GE) had the same effect. These results demonstrated that suppressing CAV1 autophagic degradation is a novel translatable strategy for enhancing nab-paclitaxel chemotherapeutic activity in the treatment of pancreatic cancer.

Investigation on chain segment motions of various starch molecules under different glycerol-water system.

The molecular motion of starch at different glycerol concentrations (0, 20, 50, and 80 %) was investigated using Electron Paramagnetic Resonance (EPR) spectroscopy. Fourier-transform infrared (FTIR) spectroscopy and 1H nuclear magnetic resonance (1H NMR) spectroscopy confirmed that hydroxyl groups at the C2 and C3 positions of glucose units in corn starch (CS), waxy corn starch (WCS), and high amylose corn starch (HCS) were labeled with 4-amino-TEMPO. The crystallinities of CS, WCS, and HCS after spin-labeling decreased from 30.68 % to 3.21 %, 39.36 % to 1.65 %, and 28.54 % to 8.08 %, respectively. The pseudoplastic fluid properties of the spin-labeled starch remained shear-thin at different glycerol concentrations. EPR revealed the fast- and slow-motion components of the spin-labeled starch molecules dispersed in water. At a glycerol concentration of 20 %, the slow-motion component disappeared, indicating a faster rotational motion of the starch chain segments. As the glycerol concentration increased to 50 and 80 %, the rotational motion slowed because of high viscosity. In particular, the mobility of the spin-labeled WCS chains increased owing to easier access of glycerol and water to the branched structure. This study directly observed the dynamics of the molecular behavior of starch in glycerol-water systems.

The anti-digestibility mechanism of soy protein isolate hydrolysate on natural starches with different crystal types.

The effects of soy protein isolate hydrolysate (SPIH) on the physicochemical properties and digestive characteristics of three starch types (wheat, potato, and pea) were investigated. Fourier-transform infrared spectroscopy and molecular dynamics simulations showed that hydrogen bonds were the driving force of the interaction between SPIH and starch. Furthermore, the SPIH was predicted to preferentially bind to the terminal region of starch using molecular dynamics simulations. Compared to pure starch, adding 20 % SPIH to wheat starch, potato starch, and pea starch, the content of resistant starch increased by 39.71 %, 125.66 % and 37.83 %, respectively. Both the radial distribution function (RDF) and low field-nuclear magnetic resonance (LF-NMR) showed that SPIH reduced the flow of water molecules in starch, indicating that SPIH competed with starch for water molecules. Multiple characterization experiments and molecular dynamics simulations confirmed that the anti-digestibility mechanism of SPIH on natural starches with different crystal types could be attributed to the interaction between starch and SPIH, which decreased the catalytic efficiency of amylase. This study clarified the anti-digestibility mechanism of SPIH on natural starches, which provides new insights into the production of low-glycemic index foods for the diabetic population.

Pregnancy Benefit of Acupuncture on in vitro Fertilization: A Systematic Review and Meta-Analysis.

BACKGROUND: Currently, more and more infertility couples are opting for combined acupuncture to improve success rate of in vitro fertilization (IVF). However, evidence from acupuncture for improving IVF pregnancy outcomes remains a matter of debate. OBJECTIVE: To quantitatively summarized the evidence of the efficacy of acupuncture among women undergoing IVF by means of systematic review and meta-analysis. METHODS: Four English (PubMed, Web of Science, EMBASE, and Cochrane Register of Controlled Clinical Trials) and Four Chinese databases (Wanfang Databases, Chinese National Knowledge Infrastructure, Chinese Science and Technology Periodical Database, and SinoMed) were searched from database inception until July 2, 2023. Randomized controlled trials (RCTs) that evaluated the acupuncture's effects for women undergoing IVF were included. The subgroup analysis was conducted with respect to the age of participants, different acupuncture types, type of control, acupuncture timing, geographical origin of the study, whether or not repeated IVF failure, and acupuncture sessions. Sensitivity analyses were predefifined to explore the robustness of results. The primary outcomes were clinical pregnancy rate (CPR) and live birth rate (LBR), and the secondary outcomes were ongoing pregnancy rate and miscarriage rate. Random effects model with I2 statistics were used to quantify heterogeneity. Publication bias was estimated by funnel plots and Egger's tests. RESULTS: A total of 58 eligible RCTs representing 10,968 women undergoing IVF for pregnant success were identifified. Pooled CPR and LBR showed a signifificant difference between acupuncture and control groups [69 comparisons, relative risk (RR) 1.19, 95% confifidence intervals (CI) 1.12 to 1.25, I2=0], extremely low evidence; 23 comparisons, RR 1.11, 95%CI 1.02 to 1.21, I2=14.6, low evidence, respectively). Only transcutaneous electrical acupoint stimulation showed a positive effect on both CPR (16 comparisons, RR 1.17, 95%CI 1.06 to 1.29; I2=0, moderate evidence) and LBR (9 comparisons, RR 1.20, 95%CI 1.04 to 1.37; I2=8.5, extremely low evidence). Heterogeneity across studies was found and no studies were graded as high-quality evidence. CONCLUSION: Results showed that the convincing evidence levels on the associations between acupuncture and IVF pregnant outcomes were relatively low, and the varied methodological design and heterogeneity might inflfluence the fifindings. (Registration No. PROSPERO CRD42021232430).

FOXQ1 promotes pancreatic cancer cell proliferation, tumor stemness, invasion and metastasis through regulation of LDHA-mediated aerobic glycolysis.

Pancreatic cancer (PC), a gastrointestinal tract malignant tumor, has a poor prognosis due to early metastasis and limited response to chemotherapy. Therefore, identifying novel therapeutic approaches for PC is critical. Epithelial-mesenchymal transition (EMT) is known as the vital progress in PC development, we constructed the EMT-related prognosis model to screen out that FOXQ1 probably involving in the EMT regulation. FOXQ1 has been linked to the malignant process in a number of cancers. However, its function in PC is unknown. In our work, the expression of FOXQ1 was elevated in PC tissues, and a high level of FOXQ1 in PC was linked to patients' poor prognosis. FOXQ1 overexpression promoted aerobic glycolysis and enhanced PC cell proliferation, tumor stemness, invasion, and metastasis. Whereas, FOXQ1 silencing showed the reverse effect. Furthermore, mechanistic studies indicated that FOXQ1 promotes LDHA transcription, and thus modulates aerobic glycolysis to enhance PC cell proliferation, tumor stemness, invasion, and metastasis by increasing LDHA expression. Therefore, these novel data suggest that FOXQ1 may be a possible therapeutic target in PC.

Placebo response in sham-acupuncture-controlled trials for migraine: A systematic review and meta-analysis.

AIM: To understand the placebo response of acupuncture and its effect on migraine and optimize the design of future acupuncture clinical trials on migraine treatment. METHODS: Randomized controlled trials with sham acupuncture as a control in migraine treatment were searched in four English databases from inception to September 1, 2022. The primary outcome was placebo response rate. Secondary outcomes were migraine symptoms, emotional condition, and quality of life. Factors associated with placebo response were also explored. Results were combined using risk difference (RD) or standardized mean difference (SMD) and 95% confidence interval (CI) with a random effects model. RESULTS: The final analysis included 21 studies involving 1177 patients. The pooled response rate of sham acupuncture was 0.34 (RD, 95% CI 0.23-0.45, I2 89.8%). The results (SMD [95% CI]) showed significant improvements in migraine symptoms (pain intensity -0.56 [-0.73 to -0.38], and episode conditions -0.55 [-0.75 to -0.35]); emotional condition (anxiety scale -0.49 [-0.90 to -0.08] and depression scale -0.21 [-0.40 to -0.03]); and quality of life on the Migraine-Specific Quality-of-Life Questionnaire (restrictive 0.78 [0.61-0.95]; preventive 0.52 [0.35-0.68]; and emotional 0.45 [0.28-0.62]) and on the Medical Outcomes Study Short-Form (physical 0.48 [0.34-0.62] and mental 0.21 [0.02-0.41]). Only acupuncture treatment frequency had a significant impact on the placebo response rate (RD 0.49 vs. 0.14; p = 0.00). CONCLUSIONS: The effect sizes for placebo response of sham acupuncture varied across migraine treatment trials. Further studies should routinely consider adjusting for a more complete set of treatment factors.

Lineage tracing of newly accrued nuclei in skeletal myofibers uncovers distinct transcripts and interplay between nuclear populations.

Multinucleated skeletal muscle cells have an obligatory need to acquire additional nuclei through fusion with activated skeletal muscle stem cells when responding to both developmental and adaptive growth stimuli. A fundamental question in skeletal muscle biology has been the reason underlying this need for new nuclei in syncytial cells that already harbor hundreds of nuclei. To begin to answer this long-standing question, we utilized nuclear RNA-sequencing approaches and developed a lineage tracing strategy capable of defining the transcriptional state of recently fused nuclei and distinguishing this state from that of pre-existing nuclei. Our findings reveal the presence of conserved markers of newly fused nuclei both during development and after a hypertrophic stimulus in the adult. However, newly fused nuclei also exhibit divergent gene expression that is determined by the myogenic environment to which they fuse. Moreover, accrual of new nuclei through fusion is required for nuclei already resident in adult myofibers to mount a normal transcriptional response to a load-inducing stimulus. We propose a model of mutual regulation in the control of skeletal muscle development and adaptations, where newly fused and pre-existing myonuclear populations influence each other to maintain optimal functional growth.

Placebo response of sham acupuncture in patients with primary dysmenorrhea: A meta-analysis.

BACKGROUND: The placebo response of sham acupuncture in patients with primary dysmenorrhea is a substantial factor associated with analgesia. However, the magnitude of the placebo response is unclear. OBJECTIVE: This meta-analysis assessed the effects of sham acupuncture in patients with primary dysmenorrhea and the factors contributing to these effects. SEARCH STRATEGY: PubMed, Embase, Web of Science, and Cochrane CENTRAL databases were searched from inception up to August 20, 2022. INCLUSION CRITERIA: Randomized controlled trials (RCTs) using sham acupuncture as a control for female patients of reproductive age with primary dysmenorrhea were included. DATA EXTRACTION AND ANALYSIS: Pain intensity, retrospective symptom scale, and health-related quality of life were outcome measures used in these trials. Placebo response was defined as the change in the outcome of interest from baseline to endpoint. We used standardized mean difference (SMD) to estimate the effect size of the placebo response. RESULTS: Thirteen RCTs were included. The pooled placebo response size for pain intensity was the largest (SMD = -0.99; 95% confidence interval [CI], -1.31 to -0.68), followed by the retrospective symptom scale (Total frequency rating score: SMD = -0.20; 95% CI, -0.80 to -0.39. Average severity score: SMD = -0.35; 95% CI, -0.90 to -0.20) and physical component of SF-36 (SMD = 0.27; 95% CI, -0.17 to 0.72). Studies using blunt-tip needles, single-center trials, studies with a low risk of bias, studies in which patients had a longer disease course, studies in which clinicians had < 5 years of experience, and trials conducted outside Asia were more likely to have a lower placebo response. CONCLUSION: Strong placebo response and some relative factors were found in patients with primary dysmenorrhea. PROSPERO registration number: CRD42022304215. Please cite this article as: Sun CY, Xiong ZY, Sun CY, Ma PH, Liu XY, Sun CY, Xin ZY, Liu BY, Liu CZ, Yan SY. Placebo response of sham acupuncture in patients with primary dysmenorrhea: A meta-analysis. J Integr Med. 2023; 21(5): 455-463.

Placebo Response among Different Types of Sham Acupuncture for Low Back Pain: A Systematic Review and Meta-Analysis of Randomized Controlled Trials.

BACKGROUND: Low back pain (LBP) is a prevalent and debilitating condition that poses a significant burden on healthcare systems. Acupuncture has been proposed as a promising intervention for LBP, but the evidence supporting its specific effect is insufficient, and the use of sham acupuncture as a control in clinical trials presents challenges due to variations in sham acupuncture techniques and the magnitude of the placebo effect. OBJECTIVE: To investigate the magnitude of the placebo response of sham acupuncture in trials of acupuncture for nonspecific LBP, and to assess whether different types of sham acupuncture are associated with different responses. METHODS: Four databases including PubMed, EMBASE, MEDLINE, and the Cochrane Library were searched through April 15, 2023, and randomized controlled trials (RCTs) were included if they randomized patients with LBP to receive acupuncture or sham acupuncture intervention. The main outcomes included the placebo response in pain intensity, back-specific function and quality of life. Placebo response was defined as the change in these outcome measures from baseline to the end of treatment. Random-effects models were used to synthesize the results, standardized mean differences (SMDs, Hedges'g) were applied to estimate the effect size. RESULTS: A total of 18 RCTs with 3,321 patients were included. Sham acupuncture showed a noteworthy pooled placebo response in pain intensity in patients with LBP [SMD -1.43, 95% confidence interval (CI) -1.95 to -0.91, I2=89%]. A significant placebo response was also shown in back-specific functional status (SMD -0.49, 95% CI -0.70 to -0.29, I2=73%), but not in quality of life (SMD 0.34, 95% CI -0.20 to 0.88, I2=84%). Trials in which the sham acupuncture penetrated the skin or performed with regular needles had a significantly higher placebo response in pain intensity reduction, but other factors such as the location of sham acupuncture did not have a significant impact on the placebo response. CONCLUSIONS: Sham acupuncture is associated with a large placebo response in pain intensity among patients with LBP. Researchers should also be aware that the types of sham acupuncture applied may potentially impact the evaluation of the efficacy of acupuncture. Nonetheless, considering the nature of placebo response, the effect of other contextual factors cannot be ruled out in this study. (PROSPERO registration No. CRD42022304416).

The Role of First Tarsometatarsal Joint Morphology and Instability in the Etiology of Hallux Valgus: A Case-Control Study.

BACKGROUND: The morphology of foot joints is widely accepted as a significant factor in the development of various foot disorders. Nevertheless, the role of the first tarsometatarsal joint (TMT1) morphology in hallux valgus (HV) remains unclear, and its impact on TMT1 instability has not been fully explored. This study aimed to investigate the TMT1 morphology and its potential correlation with HV and TMT1 instability. METHODS: Weightbearing computed tomography (WBCT) scans of 82 consecutive feet with HV and 79 controls were reviewed in this case-control study. Three-dimensional (3D) models of TMT1 were constructed using Mimics software and WBCT scans. The height of the TMT1 facet (FH) and the superior, middle, and inferior facet width (SFW, MFW, and IFW) were measured on anteroposterior view of the first metatarsal base. On the lateral view, the inferior lateral facet height and angle (ILFH and ILFA) were measured. TMT1 instability was evaluated using the TMT1 angle. RESULTS: Compared with the control group, the HV group had a significantly wider MFW (9.9 mm in HV, 8.7 mm in control), lower ILFH (1.7 mm in HV, 2.5 mm in control), smaller ILFA (16.3 degrees in HV, 24.5 degrees in control), and larger TMT1 angle (1.9 degrees in HV, 0.9 degrees in control) (all P < .05). No significant differences were found between the 2 groups in FH, SFW, and IFW (all P > .05). The study identified 4 types of TMT1 morphology: continuous-flat, separated-flat, continuous-protruded, and separated-protruded. The continuous-flat type possessed significantly larger HVA, IMA, and TMT1 angles compared with other types (all P < .001). CONCLUSION: This study indicates a potential association between TMT1 morphology and the severity of HV and identifies 4 TMT1 types. Notably, the continuous-flat type is found to be associated with more severe HV and TMT1 instability. LEVEL OF EVIDENCE: Level III, retrospective comparative study.

Tenogenic differentiation of human tendon-derived stem cells induced by long non-coding RNA LINCMD1 via miR-342-3p/EGR1 axis.

BACKGROUND: Tendon-derived stem cells (TDSCs) are proposed as a potential cell-seed for the treatment of tendon injury due to their tenogenic differentiation potential. In this work, we defined the action of long non-coding RNA (lncRNA) muscle differentiation 1 (LINCMD1) in tenogenic differentiation of human TDSCs (hTDSCs). METHODS: Quantitative real-time PCR (qRT-PCR) was used to assess the levels of LINCMD1, microRNA (miR)-342-3p, and early growth response-1 (EGR1) mRNA. Cell proliferation was detected by the XTT colorimetric assay. Protein expression was quantified by western blot. hTDSCs were grown in an osteogenic medium to induce osteogenic differentiation, and the extent of osteogenic differentiation was assessed by Alizarin Red Staining (ARS). The activity of alkaline phosphatase (ALP) was measured by the ALP Activity Assay Kit. Dual-luciferase reporter and RNA immunoprecipitation (RIP) assays were used to evaluate the direct relationship between miR-342-3p and LINCMD1 or EGR1. RESULTS: Our results showed that enforced expression of LINCMD1 or suppression of miR-342-3p accelerated the proliferation and tenogenic differentiation and reduced osteogenic differentiation of hTDSCs. LINCMD1 regulated miR-342-3p expression by binding to miR-342-3p. EGR1 was identified as a direct and functional target of miR-342-3p, and knockdown of EGR1 reversed the effects of miR-342-3p suppression on cell proliferation and tenogenic and osteogenic differentiation. Furthermore, the miR-342-3p/EGR1 axis mediated the regulation of LINCMD1 on hTDSC proliferation and tenogenic and osteogenic differentiation. CONCLUSION: Our study suggests the induction of LINCMD1 in tenogenic differentiation of hTDSCs through miR-342-3p/EGR1 axis.

[Pollution Characteristics and Risk Assessment of Antibiotics in Beiyun River Basin in Beijing].

To investigate the pollution characteristics and risk levels of antibiotics in water of the Beiyun River Basin in Beijing, the concentration of antibiotics was analyzed by using the solid-phase extraction and high-performance liquid chromatography-tandem mass spectrometry (SPE-HPLC-MS/MS) method. The results showed that seven types of four categories of antibiotics were detected in the samples from 12 sampling points; the total concentration of antibiotics including sulfapyridine, clarithromycin, azithromycin, roxithromycin, erythromycin, ofloxacin, and lincomycin ranged from 59.19 to 703.44 ng·L-1. Among these antibiotics, the detection rate of clarithromycin, azithromycin, roxithromycin, ofloxacin, and lincomycin was 100%; that of erythromycin was 41.67%; and that of sulfapyridine was 33.33%. Compared with that in some rivers in China, the Azithromycin, Erythromycin, and Clarithromycin in the Beiyun River Basin were at a relatively high level. The ecological risk assessment results showed that the most sensitive species was algae. The health risk quotients indicated that sulfapyridine, lincomycin, roxithromycin, azithromycin, and erythromycin presented no risk for every age group, whereas the health risk of clarithromycin was at a low level.

[Retracted] MicroRNA­526a targets p21­activated kinase 7 to inhibit tumorigenesis in hepatocellular carcinoma.

Following the publication of this paper, it was drawn to the Editors' attention by a concerned reader that certain of the data shown for the Transwell cell migration and invasion assays in Fig. 2C and D were strikingly similar to data appearing in different form in other articles by different authors. Owing to the fact that the contentious data in the above article had already been published elsewhere prior to its submission to Molecular Medicine Reports, the Editor has decided that this paper should be retracted from the Journal. The authors were asked for an explanation to account for these concerns, but the Editorial Office did not receive a reply. The Editor apologizes to the readership for any inconvenience caused. [Molecular Medicine Reports 16: 837­844, 2017; DOI: 10.3892/mmr.2017.6658].

Exosomal miR-125b-5p derived from cancer-associated fibroblasts promotes the growth, migration, and invasion of pancreatic cancer cells by decreasing adenomatous polyposis coli (APC) expression.

Background: A significant desmoplastic response, particularly in the fibroblasts, is a characteristic of pancreatic ductal adenocarcinoma (PDAC). Increasing evidence has shown that cancer-associated fibroblasts (CAFs) assist tumor development, invasion, and metastasis in PDAC. However, CAFs-derived molecular determinants that regulate the molecular mechanisms of PDAC have not been fully characterized. Methods: The expression of microRNA 125b-5p (miR-125b-5p) in Pancreas Cancer (PC) tissue and para-cancerous normal tissue was examined using Polymerase Chain Reaction (PCR). Cell counting kit-8 (CCK8), wound healing, and transwell experiments were utilized to assess the effect of miR-125b-5p. Using a cell luciferase activity test and bioinformatics, it was demonstrated that miR-125b-5p may bind to the 3'-untranslated region (3'-UTR) of the adenomatous polyposis coli (APC), thereby limiting the progression of pancreatic cancer. Results: PDAC cells are prompted to proliferate, undergo the epithelial-mesenchymal transition (EMT), and spread. Importantly, CAFs release exosomes into PDAC cells, which significantly increase the level of miR-125b-5p in those cells. Meanwhile, pancreatic cancer cell lines and PDAC tissues have considerably higher miR-125b-5p expression. MiR-125b-5p's elevated expression mechanically suppresses the expression of APC and accelerates the spread of pancreatic cancer. Conclusions: Exosomes released by CAFs promote PDAC growth, invasion, and metastasis. Exosomal miR-125b-5p inhibition offers an alternate strategy for combating the basic malady of PDAC.

[ASPIRE guidelines and their enlightenment on application of sham acupuncture in clinical researches].

Reasonable and standard application of sham acupuncture control is the key to determine the quality of acupuncture clinical trials, and is also a difficult problem faced by acupuncture clinical research. The UK National Institute for Health Research and the Medical Research Council jointly published the Applying Surgical Placebo in Randomised Evaluation (ASPIRE) guidelines on the application of placebo surgical operation in randomized evaluation, which includes 4 parts: rationale and ethics, design, conduct, and interpretation and translation, providing comprehensive guidance for the application of placebo controls in surgical trials. As an operational intervention, acupuncture is similar to surgery, so, ASPIRE guidelines can also provide certain guidance for the application of sham acupuncture. In the present paper, we introduce the ASPIRE guidelines, and put forward its enlightenment and reference to the application of sham acupuncture control in combination with retrospecting the current situations of sham acupuncture research. We hold that future studies should strengthen the consideration of the rationality and ethics of sham acupuncture, standardize the design of sham acupuncture control, and convey the information related to sham acupuncture to patients with appropriate descriptions.

Expression of Myomaker and Myomerger in myofibers causes muscle pathology.

BACKGROUND: Skeletal muscle development and regeneration depend on cellular fusion of myogenic progenitors to generate multinucleated myofibers. These progenitors utilize two muscle-specific fusogens, Myomaker and Myomerger, which function by remodeling cell membranes to fuse to each other or to existing myofibers. Myomaker and Myomerger expression is restricted to differentiating progenitor cells as they are not detected in adult myofibers. However, Myomaker remains expressed in myofibers from mice with muscular dystrophy. Ablation of Myomaker from dystrophic myofibers results in reduced membrane damage, leading to a model where persistent fusogen expression in myofibers, in contrast to myoblasts, is harmful. METHODS: Dox-inducible transgenic mice were developed to ectopically express Myomaker or Myomerger in the myofiber compartment of skeletal muscle. We quantified indices of myofiber membrane damage, such as serum creatine kinase and IgM+ myofibers, and assessed general muscle histology, including central nucleation, myofiber size, and fibrosis. RESULTS: Myomaker or Myomerger expression in myofibers independently caused membrane damage at acute time points. This damage led to muscle pathology, manifesting with centrally nucleated myofibers and muscle atrophy. Dual expression of both Myomaker and Myomerger in myofibers exacerbated several aspects of muscle pathology compared to expression of either fusogen by itself. CONCLUSIONS: These data reveal that while myofibers can tolerate some level of Myomaker and Myomerger, expression of a single fusogen above a threshold or co-expression of both fusogens is damaging to myofibers. These results explain the paradigm that their expression in myofibers can have deleterious consequences in muscle pathologies and highlight the need for their highly restricted expression during myogenesis and fusion.

Determination of the microscopic acid dissociation constant of piperacillin and identification of dissociated molecular forms.

For amphoteric ß-lactam antibiotics, the acid dissociation constant (pK a) is a fundamental parameter to characterize physicochemical and biochemical properties of antibiotics and to predict persistence and removal of drugs. pK a of piperacillin (PIP) is determined by potentiometric titration with a glass electrode. Electrospray ionization mass spectrometry (ESI-MS) is creatively applied to verify the reasonable pK a value at every dissociation step. Two microscopic pK a values (3.37 ± 0.06 and 8.96 ± 0.10) are identified and attributed to the direct dissociation of the carboxylic acid functional group and one secondary amide group, respectively. Different from other ß-lactam antibiotics, PIP presents a dissociation pattern where direct dissociation is involved instead of protonation dissociation. Moreover, the degradation tendency of PIP in an alkaline solution may alter the dissociation pattern or dismiss the corresponding pK a of the amphoteric ß-lactam antibiotics. This work offers a reliable determination of the acid dissociation constant of PIP and a clear interpretation of the effect of stability of antibiotics on the dissociation process.

Safety and efficacy of intra-articular injection of platelet-rich plasma for the treatment of ankle osteoarthritis: a systematic review and meta-analysis.

PURPOSE: To evaluate the safety and efficacy of platelet-rich plasma (PRP) intra-articular injective treatments for ankle osteoarthritis (OA). METHODS: A systematic literature search was conducted following the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines in PubMed, Scopus, Embase, Google Scholar, and the Cochrane library until May 2022. Both randomized and non-randomized studies were included with the assessment of the risk of bias. We recorded the participant's age, gender, type of PRP, injection volume, the kit used, and activating agent. We subsequently assessed the short-term and long-term efficacy of PRP using the functional scores and visual analog scale (VAS). RESULTS: We included four studies with a total of 127 patients, with a mean age of 56.1 years. 47.2% were male (60/127), according to eligibility criteria. There were three cohort studies and one randomized controlled trial (RCT) study, and no study reported severe adverse events. All included studies used the Leukocyte-poor PRP. Short-term follow-up results suggested significant improvement of the American Orthopaedic Foot and Ankle Society (AOFAS) score in the PRP injection group compared to the control group (n = 87 patients; MD: 6.94 [95% CI: 3.59, 10.29]; P < 0.01). Consistently, there was a statistical difference in AOFAS score between PRP injection and control groups in the final follow-up (≥ 6 months) (n = 87 patients; MD: 9.63 [95% CI: 6.31, 12.94]; P < 0.01). Furthermore, we found a significant reduction in VAS scores in the PRP groups at both the short-term follow-up (n = 59 patients; MD, - 1.90 [95% CI, - 2.54, - 1.26]; P < 0.01) and the ≥ six months follow-up (n = 79 patients; MD, - 3.07 [95% CI, - 5.08, - 1.05]; P < 0.01). The improvement of AOFAS and VAS scores at ≥ six months follow-up reached the minimal clinically important difference (MCID). Nevertheless, the treatment effect of AOFAS and VAS scores offered by PRP at short-term follow-up did not exceed the MCID. Substantial heterogeneity was reported at the ≥ six months follow-up in VAS scores (I2: 93%, P < 0.01). CONCLUSION: This meta-analysis supports the safety of PRP intra-articular injection for ankle OA. The improvements of AOFAS and VAS scores in the PRP group at short-term follow-up do not exceed the MCID to be clinically significant. PRP injection provides significant improvement of AOFAS score and reduced pain at ≥ six months follow-up. The efficacy of PRP should be interpreted with caution regarding the high heterogeneity and the scarcity of available literature, which urges large-scale RCTs with longer follow-up to confirm the potential efficacy of PRP injection for ankle OA.