A single infusion of engineered long-lived and multifunctional T cells confers durable remission of asthma in mice.

Asthma, the most prevalent respiratory disease, affects more than 300 million people and causes more than 250,000 deaths annually. Type 2-high asthma is characterized by interleukin (IL)-5-driven eosinophilia, along with airway inflammation and remodeling caused by IL-4 and IL-13. Here we utilize IL-5 as the targeting domain and deplete BCOR and ZC3H12A to engineer long-lived chimeric antigen receptor (CAR) T cells that can eradicate eosinophils. We call these cells immortal-like and functional IL-5 CAR T cells (5TIF) cells. 5TIF cells were further modified to secrete an IL-4 mutein that blocks IL-4 and IL-13 signaling, designated as 5TIF4 cells. In asthma models, a single infusion of 5TIF4 cells in fully immunocompetent mice, without any conditioning regimen, led to sustained repression of lung inflammation and alleviation of asthmatic symptoms. These data show that asthma, a common chronic disease, can be pushed into long-term remission with a single dose of long-lived CAR T cells.

Specific multiplexed detection of mRNA splice variants based on size-coding DNA probes and universal PCR amplification.

Alternative messenger RNA (mRNA) splicing is a vital regulatory process during the gene expression of higher eukaryotes. The specific and sensitive quantification of disease-related mRNA splice variants in biological and clinical samples is becoming particularly important. Reverse transcription polymerase chain reaction (RT-PCR), the most classical strategy for the assay of mRNA splice variants, cannot avoid false positive signals, which poses a challenge to the specificity of mRNA splice variant detection. In this paper, by rationally designing two DNA probes with double recognition at the splice site and different lengths, different mRNA splice variants could generate amplification products of unique lengths. Combined with capillary electrophoresis (CE) separation, the product peak of the corresponding mRNA splice variant can be specifically detected, which can avoid false-positive signals caused by non-specific amplification of PCR, greatly improving the specificity of the mRNA splice variant assay. In addition, universal PCR amplification eliminates amplification bias caused by different primer sequences and improves quantitative accuracy. Furthermore, the proposed method can simultaneously detect multiple mRNA splice variants as low as 100 aM in a one-tube reaction and has been successfully applied to the assay of variants in cell samples, which will provide a new strategy for mRNA splice variant-based clinical diagnosis and research.

Specific recognition and sensitive quantification of mRNA splice variants via one-pot ligation-dependent loop-mediated isothermal amplification.

Specific recognition and sensitive quantification of mRNA alternative splice variants have been a necessity for exploring the regulatory mechanism of RNA splicing and revealing the association between pre-mRNA splicing and transcriptome function, as well as disease diagnosis. However, their wide abundance range and high sequence homology pose enormous challenges for high sensitivity and selectivity quantification of splice variants. Herein, taking advantage of the excellent specificity of ligation and the powerful nucleic acid replication feature of loop-mediated isothermal amplification (LAMP), we developed a one-pot method (termed one-pot ligation-LAMP) for specific recognition and sensitive quantification of mRNA splicing variants based on two splicing junction-specific stem-loop DNA probe ligation and the subsequently initiating LAMP. The one-pot ligation-LAMP can specifically detect as low as 100 aM mRNA splice variants without any nonspecific signals and quantify them with a wide dynamics range spanning at least six orders of magnitude. We have demonstrated that the one-pot ligation-LAMP is a versatile and practical strategy for accurately quantifying different splicing variants in complex biological samples with high sensitivity all in one tube within 90 min, thereby providing an attractive tool for mRNA splice variant-related studies.

Processing body (P-body) and its mediators in cancer.

In recent years, processing bodies (P-bodies) formed by liquid-liquid phase separation, have attracted growing scientific attention due to their involvement in numerous cellular activities, including the regulation of mRNAs decay or storage. These cytoplasmic dynamic membraneless granules contain mRNA storage and decay components such as deadenylase and decapping factors. In addition, different mRNA metabolic regulators, including m6A readers and gene-mediated miRNA-silencing, are also associated with such P-bodies. Cancerous cells may profit from these mRNA decay shredders by up-regulating the expression level of oncogenes and down-regulating tumor suppressor genes. The main challenges of cancer treatment are drug resistance, metastasis, and cancer relapse likely associated with cancer stem cells, heterogeneity, and plasticity features of different tumors. The mRNA metabolic regulators based on P-bodies play a great role in cancer development and progression. The dysregulation of P-bodies mediators affects mRNA metabolism. However, less is known about the relationship between P-bodies mediators and cancerous behavior. The current review summarizes the recent studies on P-bodies mediators, their contribution to tumor development, and their potential in the clinical setting, particularly highlighting the P-bodies as potential drug-carriers such as exosomes to anticancer in the future.

Submucosal oesophageal squamous cell carcinoma with lymph node metastasis: a case report and literature review.

BACKGROUND: Submucosal oesophageal squamous cell carcinoma is a quite infrequent and special type of oesophageal cancer. Its endoscopic manifestations are similar to those of submucosal oesophageal lesions, so it is easily ignored or misdiagnosed. Thus, the exact and timely diagnosis of oesophageal subepithelial lesions (SELs) is crucial. Endoscopic submucosal dissection (ESD) improves the diagnosis rate of malignant SELs without specific endoscopic presentations. CASE PRESENTATION: We report a 63-year-old patient with submucosal lesions of the oesophagus under endoscopy, but CT suggested mediastinal lymphadenectasis. Thus, there was a contradiction between them. After multidisciplinary consultation, endoscopic submucosal dissection (ESD) resection was finally recommended. The lesion was completely resected by endoscopic submucosal dissection. Postoperative pathology reported poorly differentiated squamous cell carcinoma, and subsequent PET-CT examination provided clarity, revealing mediastinal lymph node metastasis. CONCLUSIONS: Not all oesophageal SELs are benign, and a small number of SELs can be malignant. Submucosal oesophageal squamous cell carcinoma is a rare disease that may be characterized by oesophageal subepithelial lesions (SELs). Therefore, the precise and timely diagnosis of SELs is essential. If it is necessary to obtain lesion tissue for a definite diagnosis, ESD with less invasiveness is an excellent choice.

Efficacy and safety of quinolones vs. other antimicrobials for the treatment of uncomplicated urinary tract infections in adults: a systematic review and meta-analysis.

INTRODUCTION AND HYPOTHESIS: In the present study, we aimed to compare the efficacy and safety of quinolones with trimethoprim-sulfamethoxazole (TMP/SMX), nitrofurantoin, fosfomycin, and ß-lactams for the treatment of uncomplicated urinary tract infections (UTIs) in adults. METHODS: All controlled clinical trials assessing quinolones for uncomplicated UTIs in adults were searched from PubMed, Embase, and Cochrane Library databases. Meta-analyses were used to evaluate the efficacy and safety in randomized controlled trials (RCTs). RESULTS: A total of 47 RCTs consisting of 8992 patients were included in the present analysis. The clinical and bacteriological remission rates of quinolones were significantly higher (P < 0.01) compared with ß-lactams and nitrofurantoin, while quinolones showed similar clinical and bacteriological remission rates compared with TMP/SMX and fosfomycin. Moreover, the bacterial resistance and relapse rates of quinolones were significantly lower (P < 0.01) compared with TMP/SMX, ß-lactams, and nitrofurantoin. Regarding the adverse drug reactions (ADRs), quinolones did not bring higher risks, while the incidence of ADRs in the quinolone group was also even significantly lower (P < 0.01) compared with the TMP/SMX and nitrofurantoin groups, including the most reported ADRs associated with the gastrointestinal tract. CONCLUSIONS: Compared with other anti-UTI drugs, quinolones exerted an excellent effect on clinical remission and bacteriological eradication, and the application of quinolones did not bring a higher risk of ADRs.

Efficacy and safety of triamcinolone acetonide in the prevention of esophageal stricture after endoscopic submucosal dissection: a meta-analysis.

AIM: The role of triamcinolone acetonide (TA) in the prevention of esophageal stricture is not well established. This meta-analysis aimed to evaluate its safety and efficacy for the prevention of esophageal stricture after endoscopic submucosal dissection (ESD). METHODS: A comprehensive search was performed in electronic databases including PubMed, the Cochrane Library, Embase for possible controlled studies. The primary outcomes were stenosis rate and endoscopic balloon dilatation (EBD) sessions required, and secondary outcome included complications. Random effects were used to calculate the pooled outcome. Sensitivity analysis and publication bias were conducted to verify the robustness and reliability of the results. Results: Ten studies containing 499 patients were obtained. In the pooled analysis, statistical significance was found in triamcinolone acetonide injection reduced the incidence of stenosis (OR = 0.29, 95% CI [0.11, 0.80], P < 0.05) and the number of endoscopic balloon dilation (MD = -3.33, 95% CI [-4.15, -2.50], P < 0.0001) compared with control. Triamcinolone acetonide injection therapy did not increase the risk of complications (OR = -0.77%, CI [-1.62, 0.09], P = 0.08). Subgroup analysis indicated that the single injection of triamcinolone acetonide after endoscopic submucosal dissection significantly reduced the incidence of stenosis compared with without any prophylaxis. Different concentrations and single session volume of triamcinolone acetonide reduced the incidence of stenosis. It also showed that the dose according to the size of the lesion was more effective than the fixed dose in preventing esophageal stricture. Conclusion: Triamcinolone acetonide injection can reduce the incidence of stricture formation as well as the need for EBD sessions without increasing complications.

Experimental Chemotherapy-Induced Mucositis: A Scoping Review Guiding the Design of Suitable Preclinical Models.

Mucositis is a common and most debilitating complication associated with the cytotoxicity of chemotherapy. The condition affects the entire alimentary canal from the mouth to the anus and has a significant clinical and economic impact. Although oral and intestinal mucositis can occur concurrently in the same individual, these conditions are often studied independently using organ-specific models that do not mimic human disease. Hence, the purpose of this scoping review was to provide a comprehensive yet systematic overview of the animal models that are utilised in the study of chemotherapy-induced mucositis. A search of PubMed/MEDLINE and Scopus databases was conducted to identify all relevant studies. Multiple phases of filtering were conducted, including deduplication, title/abstract screening, full-text screening, and data extraction. Studies were reported according to the updated Preferred Reporting Items for Systematic reviews and Meta-Analyses Extension for Scoping Reviews (PRISMA-ScR) guidelines. An inter-rater reliability test was conducted using Cohen's Kappa score. After title, abstract, and full-text screening, 251 articles met the inclusion criteria. Seven articles investigated both chemotherapy-induced intestinal and oral mucositis, 198 articles investigated chemotherapy-induced intestinal mucositis, and 46 studies investigated chemotherapy-induced oral mucositis. Among a total of 205 articles on chemotherapy-induced intestinal mucositis, 103 utilised 5-fluorouracil, 34 irinotecan, 16 platinum-based drugs, 33 methotrexate, and 32 other chemotherapeutic agents. Thirteen articles reported the use of a combination of 5-fluorouracil, irinotecan, platinum-based drugs, or methotrexate to induce intestinal mucositis. Among a total of 53 articles on chemotherapy-induced oral mucositis, 50 utilised 5-fluorouracil, 2 irinotecan, 2 methotrexate, 1 topotecan and 1 with other chemotherapeutic drugs. Three articles used a combination of these drugs to induce oral mucositis. Various animal models such as mice, rats, hamsters, piglets, rabbits, and zebrafish were used. The chemotherapeutic agents were introduced at various dosages via three routes of administration. Animals were mainly mice and rats. Unlike intestinal mucositis, most oral mucositis models combined mechanical or chemical irritation with chemotherapy. In conclusion, this extensive assessment of the literature revealed that there was a large variation among studies that reproduce oral and intestinal mucositis in animals. To assist with the design of a suitable preclinical model of chemotherapy-induced alimentary tract mucositis, animal types, routes of administration, dosages, and types of drugs were reported in this study. Further research is required to define an optimal protocol that improves the translatability of findings to humans.

Does sand mining affect the remobilization of copper and zinc in sediments? - A case study of the Jialing River (China).

It is generally accepted that the sand mining industry causes severe destruction in river basin environments. In this study, six sediment cores were collected, and sequential extraction was applied in conjunction with the diffusive gradients in the thin films (DGT) technique to explore the effect of sand mining on the remobilization of Cu and Zn in the sediments. The results showed that Cu and Zn were mainly bound in the residual fraction in the sediments. CDGT-Cu/Zn in the sediments presented obvious increasing trends at the bottom (-9 to -12 cm) at the four sites that experienced sand mining and a decreasing trend at the sites with no sand mining disturbance. Cu and Zn also tended to be transported from the sediments to the overlying water at the four sand mining sites. A correlation analysis found that F1 and F3 correlated well with CDGT-Cu/Zn, indicating that the water/exchangeable fraction and oxidized fraction were the main fractions that led to increases in DGT-labile Cu and Zn in the sediments. Further analysis found that the introduction of oxygen (O2) was the main reason for the simultaneous release of sulfur (S), Cu and Zn in the sediments, as indicated by the "dark area" of AgI gel appearing at the same position as the "hot spot area" of Chelex gel. Two main sand mining effects on the release of Cu and Zn were hypothesized: (1) intense sand disturbance leads to the transfer of the water/exchangeable fraction (F1) to the DGT-labile fraction and (2) O2 introduction promotes the reaction of stable sulfide (F3), thus transferring it to the DGT-labile fraction. The above results indicated that the sand mining industry should be paid much attention in the Jialing River, as it can obviously cause labile Cu and Zn release into the water.

Heat Transfer and Fluid Flow Characteristics of Microchannel with Oval-Shaped Micro Pin Fins.

A novel microchannel heat sink with oval-shaped micro pin fins (MOPF) is proposed and the characteristics of fluid flow and heat transfer are studied numerically for Reynolds number (Re) ranging from 157 to 668. In order to study the influence of geometry on flow and heat transfer characteristics, three non-dimensional variables are defined, such as the fin axial length ratio (α), width ratio (ß), and height ratio (γ). The thermal enhancement factor (η) is adopted as an evaluation criterion to evaluate the best comprehensive thermal-hydraulic performance of MOPF. Results indicate that the oval-shaped pin fins in the microchannel can effectively prevent the rise of heat surface temperature along the flow direction, which improves the temperature distribution uniformity. In addition, results show that for the studied Reynolds number range and microchannel geometries in this paper, the thermal enhancement factor η increases firstly and then decreases with the increase of α and ß. In addition, except for Re = 157, η decreases first and then increases with the increase of the fin height ratio γ. The thermal enhancement factor for MOPF with α = 4, ß = 0.3, and γ = 0.5 achieves 1.56 at Re = 668. The results can provide a theoretical basis for the design of a microchannel heat exchanger.

Visual Detection of Fusion Genes by Ligation-Triggered Isothermal Exponential Amplification: A Point-of-Care Testing Method for Highly Specific and Sensitive Quantitation of Fusion Genes with a Smartphone.

Fusion genes, playing a causal role in human tumorigenesis and developments, are deemed as gold standard molecular biomarkers in cancer diagnosis, therapy, and prognosis. A rapid, robust, and sensitive method of detection of fusion genes for point-of-care (POC) diagnosis is urgently needed. Here, taking the advantages of the superior specificity of the ligation reaction and the highly amplified efficiency of isothermal exponential amplification with a pH indicator, we developed a colorimetric method for visual detection of fusion genes with high sensitivity and specificity by the naked eye. More importantly, we first found that fusion genes can be accurately quantified in a wide dynamic range (2 zmol to 2 fmol) by an open-source app with a smartphone-assisted RGB (red, green, and blue value) reading mode. The proposed method for Visual detection of Fusion genes by Ligation-triggered Isothermal Exponential Amplification is termed Vis-Fusion LIEXA. We have demonstrated that the Vis-Fusion LIEXA is a practical and reliable method for accurate quantitative detection of the fusion gene in a complex biological sample at zmol level in 40 min only with a smartphone, thereby providing a user-friendly and point-of-care testing (POCT) tool for molecular diagnostics.

Molecular dynamics study on ions and water confined in the nanometer channel of Friedel's salt: structure, dynamics and interfacial interaction.

As a promising layered double hydroxide, Friedel's salt has gained popularity. The transport and adsorption behavior of ions and water molecules at the interface is the basis for investigating the durability of concrete, in marine environments in particular. In this paper, the transport behavior of water and ions in the nanopores of Friedel's salt and the adsorption mechanism of the ions were systematically investigated by molecular dynamics. The water molecules share a larger bulk density and good orientations at the interface while the adsorption rate of chloride ions climbs to 66.62%, owing to the desorption of the surface structural anions forming Ca-Clw ion clusters. The time correlation function was employed to examine the stability of the Ca-Clw bonds formed near the Friedel's salt interface. The Ca-Clw bonds were demonstrated to be very stable, implying that the aqueous chloride ion is difficult to desorb once it is adsorbed by the interface. The surface of the ordered Friedel's salt structure could form a hydrated shell to hinder the interaction between sodium ions and oxygen atoms. In addition, Friedel's salt exhibits a poor adsorption capacity for sodium ions since it provides few adsorption sites due to the limited amount of structural chloride ions. After all, the interaction between Friedel's salt and the external environment on the nano scale was explored for a better understanding of the inherent mechanism from a molecular simulation perspective.

A small-molecule Fenton reagent for self-augmented chemodynamic therapy by intelligently regulating intracellular acidosis.

A small-molecule Fenton reagent, integrating ferrocene with a carbonic anhydrase inhibitor, was designed to intelligently regulate intracellular acidosis for self-augmented chemodynamic therapy. Acidosis coupled with up-regulated ROS levels demonstrated potent cytotoxicity and effective tumor suppression.

Pan-cancer analysis of the prognostic and immunological role of GJB2: a potential target for survival and immunotherapy.

Background: GJB2 plays an essential role in the growth and progression of several cancers. However, asystematic pan-cancer analysis of GJB2 is lacking. Therefore, in this study, we performed a comprehensive pan-cancer analysis to determine the potential role of GJB2 in prognostic prediction and cancer immunotherapy response. Methods: The differential expression of GJB2 in the tumor and adjacent normal tissues of various cancer types was analyzed using the TIMER, GEPIA, and Sangerbox databases. GEPIA and Kaplan-Meier plotter databases were used to analyze the survival outcomes based on GJB2 expression levels in pan-cancer. Furthermore, the association of GJB2 expression with the immune checkpoint (ICP) genes, tumor mutational load (TMB), microsatellite instability (MSI), neoantigens, and tumor infiltration of immune cells was analyzed using via the Sangerbox database. The cBioPortal database was used to determine the characteristics of GJB2 gene alterations in the cancer tissues. The STRING database was used to identify the GJB2-binding proteins. GEPIA database was used to identify the GJB2 co-expressed genes. DAVID was used to perform the functional enrichment analysis of gene ontology (GO) terms and KEGG pathways associated with GJB2. Finally, the mechanistic role of GJB2 in pancreatic adenocarcinoma (PAAD) was analyzed using the LinkedOmics database. Results: The GJB2 gene was highly expressed in a variety of tumors. Furthermore, GJB2 expression levels showed significant positive or negative association with the survival outcomes in various cancers. GJB2 expression levels cor related with tumor mutational burden, microsatellite instability, neoantigens, and tumor infiltration of immune cells in multiple cancers. This suggested that GJB2 played a critical role in the tumor microenvironment. Functional enrichment analysis showed that the biological role of GJB2 in tumors included modulation of gap junction-mediated intercellular transport, regulation of cell communication by electrical coupling, ion transmembrane transport, autocrine signaling, apoptotic signaling pathway, NOD-like receptor signaling pathway, p53 signaling pathway, and PI3K-Akt signaling pathway. Conclusions: Our study demonstrated that GJB2 played a significant role in tumorigenesis and tumor immunity in multiple cancers. Furthermore, GJB2 is a potential prognostic biomarker and a promising therapeutic target in multiple types of cancers.

Light Scattering Technology-Combined Ligation-Dependent Loop-Mediated Isothermal Amplification (LL-LAMP) for Sensitive Detection of RNA.

Loop-mediated isothermal amplification (LAMP) has been widely used in nucleic acid assay because of its high specificity, sensitivity, and isothermal property. However, the complexity of amplification product detection is still a major challenge for its wide applications. Herein, we developed a light scattering technology-assisted, low-cost, and simple detection manner of LAMP products without expensive reagents and complicated instruments. Only needing to add a kind of strong acid to the amplification products, the amplification products can aggregate into large particles in a strongly acidic medium, and large particles can produce strong light scattering, which shows a good proportional relationship with the number of amplification products in a wide range. The proposed method shows excellent sensitivity and high specificity that can quantify RNA as low as 100 aM with a single-base resolution.

Ultrasensitive quantification of multiplexed mRNA variants via splice-junction anchored DNA probes and SplintR ligase-initiated PCR.

A method based on mRNA-templated ligation of splice-junction anchored DNA probes followed by PCR amplification of the ligated product has been developed for multiplexed detection of mRNA splice variants with high sensitivity and specificity. The proposed assay can detect as low as 10 aM mRNA splicing variants and has been successfully applied to detect real samples.

Characterization of lamin B receptor of Sf9 cells and its fate during Autographa californica nucleopolyhedrovirus infection.

Baculovirus nucleocapsids egress from the nuclear membrane during infection. However, details of alternation of nuclear membrane structure during baculovirus egress are unknown. In this study, we examined the changes of lamin B receptor (LBR), a main inner nuclear membrane component, during Autographa californica nucleopolyhedrovirus (AcMNPV) infection. Firstly, the open reading frame (Orf) of Sf9 lbr was cloned by reverse transcription PCR, and the distribution of LBR in Sf9 cells were observed by fusing LBR with the red fluorescence protein mcherry. Besides, the amount of endogenous LBR during AcMNPV infection was detected by western blotting. Moreover, the distribution of LBR after AcMNPV infection was observed under the confocal fluorescence microscopy. Furthermore, the effects of protein kinase C (PKC) inhibitor on stability of LBR and release of budded virus (BVs) were determined. The results showed that Sf9 lbr contains an Orf of 2040 nucleotides (NTs), which encodes a predicted protein of 679 amino acids (AAs). Fluorescence microscopy showed that LBR is localized to the nuclear membrane. Western blotting result showed that the amount of endogenous LBR is significantly reduced after AcMNPV infection. Transfection and infection assay demonstrated that the fluorescence of LBR nearly completely disappeared after viral infection. PKC inhibitor can suppress the degradation of LBR induced by AcMNPV, resulting in the reduction of viral titer of progeny viruses. The electron microscopy analysis demonstrated that PKC inhibitor did not influence virion entry, uncoating, and assembly, but may partially protect the nuclear membrane from disruption by AcMNPV. Taken together, AcMNPV infection can distort the expression of LBR, which may promote the egress of nucleocapsids.

One-pot detection of telomerase activity with high sensitivity and specificity via RNA FRET probes and RNase H-assisted signal cycling amplification.

Human telomerase is a universal cancer biomarker and a promising anticancer therapeutic target. Sensitive and specific detection of telomerase activity is of great significance for cancer diagnosis and treatment. Up to now, many methods have been established to detect the activity of telomerase, but most of these methods require complex probe design and tedious experimental steps generally including telomere extension reaction, amplification of the extended products and signal detection. Herein, we propose a one-pot method to detect the telomerase activity via RNA FRET probes and RNase H-assisted signal cycling amplification, and the proposed assay can integrate the telomere extension reaction, signal amplification and readout in one step without requirement of amplification of the extended products, which greatly simplifies the experimental design and operation steps. Additionally, the proposed one-pot method has high sensitivity and can unequivocally detect the telomerase activity in as few as 5 cancer cells, which holds great potential in telomerase-related fundamental and clinical studies.

A label-free aptamer-based biosensor for microRNA detection by the RNA-regulated fluorescence of malachite green.

MicroRNAs (miRNAs) have been considered as promising molecular biomarkers for disease diagnosis, prognosis, as well as drug development. Herein, we wish to report a low background and label-free aptamer-based biosensor for miRNA assay by RNA-regulated fluorescence of malachite green (MG). In this biosensor-based strategy, target miRNA can specifically hybridize with the DNA extension template to form the T7 in vitro transcription system. Then the following transcription amplification produces a large number of MG RNA aptamers (MGAs) which light up the fluorescence of the MG, achieving significant fluorescence enhancement for miRNA quantitative analysis. The aptamer-based biosensor exhibits high sensitivity with a quite low detection limit of 10 amol target miRNA and high specificity to clearly discriminate very similar miRNA family members, even only one base difference. Furthermore, we have demonstrated that the biosensor is practical and reliable for the quantitative detection of miRNA in complex real samples.

Pidotimod, an immunostimulant in pediatric recurrent respiratory tract infections: A meta-analysis of randomized controlled trials.

OBJECTIVES: Recurrent respiratory tract infections (RRTIs) remain a great challenge to pediatricians, because they can increase the risk of various complications and there is no confirmed effective treatment. In the present study, we aimed to assess the effectiveness and safety of pidotimod (PDT), an immunostimulant, in treatment of RRTIs in children aged 14 years and under. METHODS: PubMed, EMBASE, Web of Science, Cochrane Library, ClinicalTrials.gov, CBM and CNKI were searched from their inception up to February 2018. All randomized controlled trials (RCTs) using PDT with various treatment durations and enrolling participants <14 years of age were included in the present review. The interventions were PDT plus conventional treatment (e.g. anti-bacterial and antiviral therapy) or PDT alone versus the conventional treatment plus placebo or conventional treatment alone. RESULTS: A total of 29 RCTs consisting of 4344 pediatric patients were included in this meta-analysis. Ten RCTs were published from Italy, Russia or Greece, and 19 RCTs were published by Chinese groups. However, appropriate randomization methods were only used in 15 trials. Only one study had explicit allocation concealment. Since only eight RCTs were double-blind and placebo controlled, the evidence was not assessed as high quality. The meta-analysis indicates that treatment with PDT resulted in a significant increase in the proportion of participants who had lower RTIs (RR 1.59; 95% CI 1.45-1.74, p < 0.00001) compared with the conventional treatment. PDT could significantly decrease the duration of cough and fever. The number of patients in using antibiotics was also remarkably decreased in the PDT treatment group. Moreover, PDT administration improved the levels of serum immunoglobulin (IgG, IgA, or IgM) and T-lymphocyte subtypes (CD3+, CD4+). Besides, PDT administration did not increase the risk of adverse events of any cause (RR = 1.05, 95% CI 0.72-1.54, p = 0.80). CONCLUSIONS: PDT showed a good efficacy and safety in treatment of pediatric RRTIs. Further high-quality and large-scale RCTs are still required to provide confirmatory evidence. TRIAL REGISTRATION: The protocol of this study can be found at PROSPERO with the registration number of CRD42018093541.