Long-term safety and influence on growth in patients receiving sirolimus: a pooled analysis.

BACKGROUND: Sirolimus is increasingly utilized in treating diseases associated with mTOR pathway overactivation. Despite its potential, the lack of evidence regarding its long-term safety across all age groups, particularly in pediatric patients, has limited its further application. This study aims to assess the long-term safety of sirolimus, with a specific focus on its impact on growth patterns in pediatric patients. METHODS: This pooled analysis inlcudes two prospective cohort studies spanning 10 years, including 1,738 participants (aged 5 days to 69 years) diagnosed with tuberous sclerosis and/or lymphangioleiomyomatosis. All participants were mTOR inhibitor-naive and received 1 mg/m²/day of sirolimus, with dose adjustments during a two-week titration period to maintain trough blood concentrations between 5 and 10 ng/ml (maximum dose 2 mg). Indicators of physical growth, hematopoietic, liver, renal function, and blood lipid levels were all primary outcomes and were analyzed. The adverse events and related management were also recorded. RESULTS: Sirolimus administration did not lead to deviations from normal growth ranges, but higher doses exhibited a positive association with Z-scores exceeding 2 SD in height, weight, and BMI. Transient elevations in red blood cell and white blood cell counts, along with hyperlipidemia, were primarily observed within the first year of treatment. Other measured parameters remained largely unchanged, displaying only weak correlations with drug use. Stomatitis is the most common adverse event (920/1738, 52.9%). In adult females, menstrual disorders were observed in 48.5% (112/217). CONCLUSIONS: Sirolimus's long-term administration is not associated with adverse effects on children's physical growth pattern, nor significant alterations in hematopoietic, liver, renal function, or lipid levels. A potential dose-dependent influence on growth merits further exploration. TRIAL REGISTRATION: Pediatric patients: Chinese clinical trial registry, No. ChiCTR-OOB-15,006,535. Adult patients: ClinicalTrials, No. NCT03193892.

Effects of exercise training on glucose metabolism indicators and inflammatory markers in obese children and adolescents: A meta-analysis.

BACKGROUND: Obesity in children and adolescents is a serious problem, and the efficacy of exercise therapy for these patients is controversial. AIM: To assess the efficacy of exercise training on overweight and obese children based on glucose metabolism indicators and inflammatory markers. METHODS: The PubMed, Web of Science, and Embase databases were searched for randomized controlled trials related to exercise training and obese children until October 2023. The meta-analysis was conducted using RevMan 5.3 software to evaluate the efficacy of exercise therapy on glucose metabolism indicators and inflammatory markers in obese children. RESULTS: In total, 1010 patients from 28 studies were included. Exercise therapy reduced the levels of fasting blood glucose (FBG) [standardized mean difference (SMD): -0.78; 95% confidence interval (CI): -1.24 to -0.32, P = 0.0008], fasting insulin (FINS) (SMD: -1.55; 95%CI: -2.12 to -0.98, P < 0.00001), homeostatic model assessment for insulin resistance (HOMA-IR) (SMD: -1.58; 95%CI: -2.20 to -0.97, P < 0.00001), interleukin-6 (IL-6) (SMD: -1.31; 95%CI: -2.07 to -0.55, P = 0.0007), C-reactive protein (CRP) (SMD: -0.64; 95%CI: -1.21 to -0.08, P = 0.03), and leptin (SMD: -3.43; 95%CI: -5.82 to -1.05, P = 0.005) in overweight and obese children. Exercise training increased adiponectin levels (SMD: 1.24; 95%CI: 0.30 to 2.18, P = 0.01) but did not improve tumor necrosis factor-alpha (TNF-α) levels (SMD: -0.80; 95%CI: -1.77 to 0.18, P = 0.11). CONCLUSION: In summary, exercise therapy improves glucose metabolism by reducing levels of FBG, FINS, HOMA-IR, as well as improves inflammatory status by reducing levels of IL-6, CRP, leptin, and increasing levels of adiponectin in overweight and obese children. There was no statistically significant effect between exercise training and levels of TNF-α. Additional long-term trials should be conducted to explore this therapeutic perspective and confirm these results.

Accelerated Course of Cerebral Adrenoleukodystrophy After Coronavirus Disease 2019 Infection.

BACKGROUND: Coronavirus disease 2019 (COVID-19) can not only infect the respiratory system but also affect the nervous system through the release of inflammatory factors. Our study aimed to investigate the effect of COVID-19 infection on cerebral adrenoleukodystrophy (ALD). METHODS: Changes in the neurological symptoms of cerebral ALD after infection with COVID-19 from January 2022 to February 2023 were retrospectively analyzed. The primary assessment indicator was the Neurologic Function Scale (NFS) score. RESULTS: A total of 17 male patients with cerebral ALD were enrolled, with a median age of 101 months (80 to 151 months). Among them, 11 (11 of 17, 64.7%) developed an exacerbation of neurological symptoms after COVID-19 infection. Two patients with NFS = 0 started presenting with neurological symptoms after infection. Fifteen patients were in the advanced stage (NFS >1 and/or Loes score >9), of which nine did not progress to major functional disabilities (MFDs). Seven of the nine patients (77.8%) experienced an increase in NFS scores, ranging from 1 to 9 points, within two weeks of COVID-19 infection, with four of them experiencing MFDs. For the other six patients who had progressed to MFDs, there was not much room for further degeneration, so the NFS score did not increase after COVID-19 infection. No deaths related to COVID-19 infection occurred. CONCLUSIONS: COVID-19 infection may aggravate neurological symptoms of cerebral ALD, particularly among patients who have not yet progressed to MFDs. Therefore, COVID-19 may accelerate the course of cerebral ALD, so protecting patients from infection is essential for maintaining the stability of the disease.

Case Report: Chronic inflammatory demyelinating polyradiculoneuropathy rather than hemophagocytic lymphohistiocytosis-the initial phenotype of PRF1 gene mutation.

Perforin is essentially involved in the granule-dependent killing activities of cytotoxic T lymphocytes and NK cells. Monoallelic PRF1 mutation increases the risk of autoimmune diseases, and biallelic PRF1 mutation causes familial hemophagocytic lymphohistiocytosis-2. Here, we report a case of a 12-year-old girl with chronic inflammatory demyelinating polyradiculoneuropathy (CIDP), followed by a rapidly progressive onset of hemophagocytic lymphohistiocytosis (HLH) 9 months later, alongside manifestations of demyelinating encephalopathy. Genetic sequencing revealed a heterozygous nonsense mutation in the PRF1 gene (c.984G>A; p.W328*) and a heterozygous missense mutation in the PRF1 gene (c.1349C>T; p.T450M). Eventually, she died because of no suitable allogeneic hematopoietic stem cell available in time. Our observations suggest that CIPD might represent the initial phenotype of biallelic PRF1 mutation and could serve as an early sign of subsequent HLH. A comprehensive understanding of this condition is paramount for timely diagnosis, treatment, and ultimately improved patient outcomes.

Sirolimus can promote the disappearance of renal angiomyolipoma associated with tuberous sclerosis complex: a prospective cohort study.

BACKGROUND: Renal angiomyolipoma (RAML) is the most common kidney lesion in patients with tuberous sclerosis complex (TSC), affecting about 80% of patients. It is a benign tumor that grows over time, usually bilaterally, and can easily lead to kidney complications such as acute hemorrhage. Herein, we investigated the efficacy and safety of sirolimus in children with TSC-associated RAML and explored the factors affecting tumor disappearance under sirolimus treatment through subgroup analysis. METHODS: A prospective cohort study was conducted. Sirolimus was initiated at 1 mg/(m2 × day), and dose adjustments were made by a 2-week titration period to attain a trough blood concentration of 5-10 ng/mL. The disappearance of RAML in children after sirolimus treatment was observed, and Cox regression was used to screen the factors affecting tumor disappearance. RESULTS: One hundred and twenty-six patients who met the criteria were analyzed. After 3 months, 6 months, 12 months, and 24 months of follow-up, tumors disappeared in 18 (14.3%), 30 (23.8%), 39 (31.0%), and 42 (33.3%) children, respectively. Tumors disappeared in 50 (39.7%) children by the last visit of each individual, and 30 (60%) of them occurred within 6 months. The multivariate Cox regression analysis showed that patients with a smaller maximum tumor diameter at baseline had a higher tumor disappearance rate. Thirty-six (29%) patients had stomatitis during the entire treatment period, and no serious adverse reactions were observed. CONCLUSIONS: Sirolimus could promote the disappearance of TSC-related RAML. The disappearance rate was correlated with the maximum diameter at baseline, and the smaller the tumor was, the higher the disappearance rate. It is well tolerated in the treatment of RAML associated with TSC.

Exploratory study of autophagy inducer sirolimus for childhood cerebral adrenoleukodystrophy.

Objectives: X-linked adrenoleukodystrophy (ALD) is a peroxisomal disease caused by mutations in the ABCD1 gene. Childhood cerebral ALD (CCALD) is characterized by inflammatory demyelination, rapidly progressing, often fatal. Hematopoietic stem cell transplant only delays disease progression in patients with early-stage cerebral ALD. Based on emergency humanitarianism, this study aims to investigate the safety and efficacy of sirolimus in the treatment of patients with CCALD. Methods: This was a prospective, single-center, one-arm clinical trial. We enrolled patients with CCALD, and all enrolled patients received sirolimus treatment for three months. Adverse events were monitored and recorded to evaluate the safety. The efficacy was evaluated using the neurologic function scale (NFS), Loes score, and white matter hyperintensities. Results: A total of 12 patients were included and all presented with CCALD. Four patients dropped out and a total of eight patients in the advanced stage completed a 3-month follow-up. There were no serious adverse events, and the common adverse events were hypertonia and oral ulcers. After sirolimus treatment, three of the four patients with an initial NFS > 10 showed improvements in their clinical symptoms. Loes scores decreased by 0.5-1 point in two of eight patients and remained unchanged in one patient. Analysis of white matter hyperintensities revealed a significant decrease in signal intensity (n = 7, p = 0.0156). Conclusions: Our study suggested that autophagy inducer sirolimus is safe for CCALD. Sirolimus did not improve clinical symptoms of patients with advanced CCALD significantly. Further study with larger sample size and longer follow-up is needed to confirm the drug efficacy.Clinical Trial registration: https://www.chictr.org.cn/historyversionpuben.aspx, identifier ChiCTR1900021288.

A Study Against Colon Cancer Mechanism of Xanthium Sibiricum Herba Based on Computer Simulation and Bioinformatics.

INTRODUCTION: Cancer is one of the leading causes of death worldwide, accounting for nearly one in six deaths in 2020. As a folk medicine, Xanthium sibiricum Herba (XSH) has been used many times in clinical practice for the treatment of various diseases. With the increasing number of cancer patients, there is a clinical need to find effective anti-cancer drugs. AIM: This study aims to explores the bioactivity and the anti-cancer mechanism of XSH. METHODS: In this study, bioinformatics, network pharmacology, molecular docking, molecular dynamics simulation techniques, and apoptosis assay were used to explore the bioactivity and the anti-cancer mechanism of XSH. RESULTS: Finally, seven active ingredients in XSH after the screening were obtained, the two most active compounds were ß-sitosterol and aloe-emodin, and good anti-cancer activity of XSH was predicted. DISCUSSION: Four core targets were obtained from the PPI network map, namely Caspase-3 (CASP3), Transcription factor AP-1 (JUN), Myc proto-oncogene protein (MYC), and cellular tumor antigen p53 (TP53). GO and KEGG analyses showed that the mechanism of XSH anti-cancer is mainly related to the apoptosis process, and the main signaling pathways are enriched in the p53 signaling pathway, Apoptosis, and MAPK signaling. The molecular docking and molecular dynamics simulation results showed that CASP3, JUN, MYC, and TP53 had a high affinity with ß-sitosterol and aloe-emodin. Bioinformatics analyses demonstrated the importance of core targets. Apoptosis assay showed that XSH could significantly promote the apoptosis of cancer cells, and inhibit their proliferation and migration, especially colon cancer cells. CONCLUSION: This study uncovered the main active components, bioactivities, and potential targets of XSH, and further revealed the multi-component, multi-target, and multi-pathway mechanism of XSH for cancer treatment and promoting apoptosis.

Extraction, purification, structural characteristics, biological activities, and application of the polysaccharides from Nelumbo nucifera Gaertn. (lotus): A review.

Nelumbo nucifera Gaertn. (lotus) is a widely distributed plant with a long history of cultivation and consumption. Almost all parts of the lotus can be used as foodstuff and nourishment, or as an herb. It is noteworthy that the polysaccharides obtained from lotus exhibit surprisingly and satisfying biological activities, which explains the various benefits of lotus to human health, including anti-diabetes, anti-osteoporosis, antioxidant, anti-inflammatory, anti-tumor, etc. Here, we systematically review the recent major studies on extraction and purification methods of polysaccharides from different parts (rhizome, seed, leaf, plumule, receptacle and stamen) of lotus, as well as the characterization of their chemical structure, biological activity and structure-activity relationship, and the applications of lotus polysaccharides in different fields. This article will give an updated and deeper understanding of lotus polysaccharides and provide theoretical basis for their further research and application in human health and manufacture development.

Diagnostic yield of a multi-strategy genetic testing procedure in a nationwide cohort of 728 patients with infantile spasms in China.

OBJECTIVE: Infantile spasms (IS) is a common epilepsy syndrome in infancy. Genetically based birth defects are among the many causes of infantile spasms. Genetic diagnosis can reveal the etiology of IS and guide treatment strategies and genetic counseling, but significant challenges surround the choice of appropriate genetic diagnostic strategies to improve the diagnostic yield in IS. METHODS: For a cohort of Chinese patients with IS, appropriate genetic testing methods were selected according to etiological classification. Methods included karyotyping, copy number variation detection, single-gene sequencing, targeted sequencing panel, and whole-exome sequencing. RESULTS: A total of 728 children with IS from fifteen provinces and municipalities in China from June 2015 to October 2020 were recruited in the study. Among them, 436 were males (59.9%). The median age was 9.46 months. The diagnostic yield of our study was 31.5% (185/587). The top five causative genes were TSC2 (n = 91), STXBP1 (n = 21), TSC1 (n = 15), SCN2A (n = 6), and CDKL5 (n = 6). The genetic diagnostic yield was 100% in Down syndrome (n = 1), neurofibromatosis (n = 2), and methylmalonic acidemia (n = 2), 83.5% in tuberous sclerosis complex (n = 127), and 16.7% in unsolved infantile spasms (n = 442). Different genetic testing methods for different etiologies show large differences in diagnostic yields. CONCLUSION: This study demonstrates that appropriate genetic testing procedures for different phenotypes can ensure a high diagnostic yield.

Safety of inactivated COVID-19 vaccine in tuberous sclerosis complex patients with epilepsy treated with rapamycin.

PURPOSE: To assess the safety of inactivated coronavirus 2019 disease (COVID-19) vaccine in tuberous sclerosis complex (TSC) patients with epilepsy. METHODS: All patients with epilepsy were selected from Efficacy and Safety of Sirolimus in Pediatric Patients with Tuberous Sclerosis (ESOSPIT) project and younger than 17 years old. The patients were treated with mTOR inhibitors (rapamycin). A total of 44 patients who completed the two-dose inactivated COVID-19 vaccine between July 7, 2021, and January 1, 2022, were enrolled. RESULTS: The median age of seizure onset was 23 months. About two-thirds of patients have focal seizures. Thirty-three patients use antiseizure medications. The mean duration of rapamycin treatment was 55.59 ± 18.42 months. Adverse reactions within 28 days after injection occurred in 11 patients (25%), all were under 12 years old. Injection site pain was the most reported event (20.45%), which was mild in severity and improved within one day. All patients had no seizure-related changes after vaccination. CONCLUSION: This study shows that the inactivated COVID-19 vaccine was well tolerated and safe in TSC patients with epilepsy, as well as for those treated with mTOR inhibitors.

Noninvasive prenatal diagnosis based on cell-free DNA for tuberous sclerosis: A pilot study.

BACKGROUND: Noninvasive prenatal diagnosis (NIPD) based on cell-free DNA (cfDNA) has been introduced into the clinical application for some monogenic disorders but not for tuberous sclerosis (TSC) yet, which is an autosomal dominant disease caused by various variations in TSC1 or TSC2 gene. We aimed to explore the feasibility of NIPD on TSC. METHODS: We recruited singleton pregnancies at risk of TSC from 14 families with a proband child. Definitive NIPD for TSC was performed using targeted next-generation sequencing of cfDNA in parallel with maternal white blood cell DNA (wbcDNA). The NIPD results were validated by amniocentesis or postnatal gene testing and follow-up of the born children. RESULTS: Missense mutations, nonsense mutations, frameshift mutations, and splice-site variants which were obtained through de-novo, maternal, or paternal inheritance were included. The mean and minimum gestational weeks of NIPD were 17.18 ± 5.83 and 8 weeks, respectively. The NIPD results were 100% consistent with the amniocentesis or postnatal gene testing and follow-up of the born children. CONCLUSION: This study demonstrates that NIPD based on cfDNA is feasible for TSC, but required to be confirmed with more samples. Studies on TSC can contribute to the application and promotion of NIPD for monogenic disorders.

Postnatal Cytomegalovirus Infection May Increase the Susceptibility of Tuberous Sclerosis Complex to Autism Spectrum Disorders.

Autism spectrum disorder (ASD), a highly hereditary and heterogeneous neurodevelopmental disorder, is influenced by genetic and environmental factors. Tuberous sclerosis complex (TSC) is a common syndrome associated with ASD. Cytomegalovirus (CMV) infection is an environmental risk factor for ASD. The similarities in pathological and mechanistic pathways of TSC and CMV intrigued us to investigate whether CMV and TSC interacted in ASD's occurrence. We detected CMV IgG seroprevalence of 308 TSC patients from our prospective cohort (September 2011 to March 2021) and 93 healthy children by magnetic particle indirect chemiluminescence immunoassay. A total of 206 TSC patients enrolled were divided into ASD and non-ASD groups, and the relationship between ASD and CMV seroprevalence was analyzed. Nested PCR and Western blot were used to detect CMV DNAs and proteins in cortical malformations of seven TSC patients with and without ASD. No difference was found in CMV seroprevalence between TSC patients and healthy children (74.0% versus 72.0%, P = 0.704). Univariate analysis showed the seroprevalence in TSC patients with ASD was higher than that in TSC patients without ASD (89.2% versus 75.1%, P = 0.063), and multifactorial analysis showed that CMV seroprevalence was a risk factor for ASD in TSC patients (OR = 3.976, 95% CI = 1.093 to 14.454). Moreover, CMV was more likely to be detected in the cortical malformations in TSC patients with ASD but not in those without ASD. The findings demonstrated that CMV may increase the susceptibility of TSC to ASD. IMPORTANCE CMV is an environmental risk factor for ASD, but its role in syndromic autism with known genetic etiology has been rarely studied. The pathogenesis of ASD is related to the interaction between environmental and genetic factors. This study demonstrated that CMV can contribute to the occurrence of ASD related to TSC, a common genetic syndrome associated with ASD. Our findings provided support for the theory of gene-environment interaction (G × E) in pathogenesis of ASD and a new perspective for the prevention and therapy for TSC related ASD.

Sirolimus treatment for tuberous sclerosis complex prior to epilepsy: Evidence from a registry-based real-world study.

OBJECTIVE: To evaluate whether sirolimus treatment could relieve the later burden of new-onset seizures in patients with tuberous sclerosis complex (TSC) prior to epilepsy. METHODS: A real-world matched case-control study was nested in another registry cohort study. Infants with TSC (<12 months old) without seizures whose parents agreed on sirolimus treatment for other symptoms were eligible for inclusion to the early sirolimus (ES) group. These patients were enrolled from 2015 to 2018. Controls in the late sirolimus (LS) group were matched from the registry cohort database for 2015-2018. Age and genotype were used as the initial stratifying criteria and other symptoms as the greedy matching criteria at a matching ratio of 1:4. None of the preventive drugs were introduced before seizure onset or before 2 years of age in the LS group. Both groups were followed up until June 2020. The primary objective was a comparison of the characteristics of the first seizure between the two groups. The secondary objective was the assessment of the final seizure status at the endpoint. RESULTS: There were 42 and 168 patients with TSC in the ES and LS groups, respectively. Early sirolimus treatment significantly reduced the seizure onset, especially in the patients aged <6 months. The mean onset-age was significantly delayed by sirolimus treatment (11.34±7.93 months vs. 6.94±6.03 months, P<0.001). The subtype of seizures that benefited the most was spastic (onset) seizures (all were infantile spasms) [5/42 (11.90%) vs. 73/168 (43.45%), P<0.001]; these seizures were either eliminated or alleviated. The sirolimus treatment addition prior to seizures was more effective than its addition after seizures in reducing drug-resistant epilepsy [10/42 (23.81%) vs. 70/147 (47.62%), P=0.004]. CONCLUSION: Early sirolimus treatment for TSC effectively modified the disease by preventing infantile spasms, delaying seizure onset, and relieving its severity. The anti-epileptogenic effect of sirolimus may be time- and dose-dependent.

Long-term administration of sirolimus does not affect the physical development of children with tuberous sclerosis complex.

PURPOSE: There was no evidence whether the mammalian/mechanistic target of rapamycin pathway hyperactivation and long-term use of mTOR inhibitors have any effects on the physical development of children. The aim was to evaluate these effects by comparing the physical development of children with TSC and normal children. METHODS: A total of 120 eligible children were enrolled. They were administered sirolimus and followed for at least 12 months. Height, weight, BMI and lipid metabolism index were collected during treatment. Pearson's chi-square and Fisher's exact test were used for comparison of proportions of patients exhibiting normal and abnormal physical growth before and after 1 year of treatment. Logistic regression was used to evaluate the influence of age, sex and abnormal lipid metabolism on the increased BMIs of TSC patients after treatment. RESULTS: Most of the enrolled TSC children were in the normal height, weight and BMI ranges at baseline (91.7%, 95.8% and 78.3%, respectively). Most remained in the normal height, weight and BMI ranges after 1 year of sirolimus treatment (94.2%, 95% and 76.7%, respectively). There was no significant difference in the proportion of physical development before and after treatment (p > 0.05). Thirty-eight (38/106, 35.8%) patients had increased BMIs after 1 year of treatment, but there was no significant correlation between age, sex and lipid metabolism and increased BMI. CONCLUSIONS: Overactivation of the mTOR pathway and long-term administration of sirolimus does not affect the physical development of children with TSC.

[Study on mechanism of Phytolaccae Radix and its split components based on network pharmacology].

This paper aimed to explore the mechanism of the split components of Phytolaccae Radix by means of network pharmaco-logy. Based on the theoretical hypothesis of the nature and taste of traditional Chinese medicine, the chemical components of the separated components of Phytolaccae Radix were selected by using Traditional Chinese Medicine Systems Pharmacology Database(TCMSP) and Traditional Chinese Medicines IntegratedDatabase(TCMID) databases in combination with related literatures. Relevant target analysis was carried out based on PubChem and SwissTargetPrediction databases. Targets corresponding to disease were excavated based on GeneCards for each split component, corresponding potential targets were obtained through mapping the target set of target compounds to disease targets. GO biological process analysis and KEGG pathway enrichment analysis were performed on the mapped targets with the help of DAVID database. Based on Cytoscape software and the corresponding efficacy, the network diagram of "medicinal material-split components-compound-target-pathway" was constructed to explore the mechanism of different efficacy of the separated components of Cytoscape. And the target purgation and diuretic mapping was used as the target of the traditional efficacy of smoothening secretion for the first time. The study explored esculentoside component, fatty oil component and phenolic acid component, a total of 30 target compounds and 301 corresponding targets, involving 44 potential targets for "anti-inflammatory", 50 potential targets for "immunoregulation", 52 potential targets for "smoothening secretion", 28 potential targets for "antibacterial activity", 28 potential targets for "antiviral effect", and 29 potential targets for "antitumor effect". Topological analysis revealed 14 key gene targets such as MAPK8, MAPK14, EGFR and PTGS2. A total of 684 GO entries and 235 KEGG pathways were obtained through bioinformatics enrichment analysis, mainly involving TNF signaling pathway, NF-kappaB signaling pathway and MAPK signaling pathway. This study revealed the multi-component, multi-target, and multi-channel action mechanism of the split components of Phytolaccae Radix, which provided certain basis for the next step to clarify the split components of Phytolaccae Radix through the method of system biology, and injected new content and significance into the study of properties and flavors theory.

Clinical application and mechanism of traditional Chinese medicine in treatment of lung cancer.

ABSTRACT: Lung cancer is a malignant tumor characterized by a rapid proliferation rate, less survivability, high mortality, and metastatic potential. This review focuses on updated research about the clinical application of traditional Chinese medicine (TCM) as an adjuvant therapy to lung cancer treatment and the mechanisms of TCM effect on lung cancer in vitro and in vivo. We summarized the recent 5 years of different research progress on clinical applications and antitumor mechanisms of TCM in the treatment of lung cancer. As a potent adjuvant therapy, TCM could enhance conventional treatments (chemotherapy, radiation therapy, and epidermal growth factor receptors [EGFRs] tyrosine kinase inhibitors [TKIs]) effects as well as provide synergistic effects, enhance chemotherapy drugs chemosensitivity, reverse drug resistance, reduce adverse reactions and toxicity, relieve patients' pain and improve quality of life (QOL). After treating with TCM, lung cancer cells will induce apoptosis and/or autophagy, suppress metastasis, impact immune reaction, and therapeutic effect of EGFR-TKIs. Therefore, TCM is a promisingly potent adjuvant therapy in the treatment of lung cancer and its multiple mechanisms are worthy of an in-depth study.

Juvenile xanthogranuloma as a new type of skin lesions in tuberous sclerosis complex.

OBJECTIVE: Tuberous sclerosis complex (TSC) is a rare autosomal dominant genetic disease with many manifestations, and it involves any organ. In this study, we report a TSC patient with new type skin lesions. METHODS: A 7-month-old TSC boy with multiple cutaneous nodules was admitted in our hospital. We collected the clinical data of the patient. We performed biopsy of cutaneous nodules and whole-exome sequencing in both paraffin block tissue and blood samples. RESULTS: The patient presented with a 2 month history of gradual growth multiple cutaneous nodules. He had cardiac rhabdomyoma, subependymal giant cell astrocytoma (SEGA) and hypomelanotic macules. The pathological finding of cutaneous nodules was consistent with juvenile xanthogranuloma (JXG). After 3 months of sirolimus treatment, the multiple nodules disappeared. The whole-exome sequencing identified TSC1 (c.2356C > T, p.R786*) mutation in both paraffin block tissue and blood samples. We overturned the original pathological diagnosis and finally identified JXG as a new type of skin lesions in TSC. CONCLUSION: This is the first report on the occurrence of JXG skin lesions in TSC patient. Genetic testing is necessary in JXG. These findings expand the phenotype of skin in patients with TSC and contribute to the elucidation of JXG pathogenesis and treatment.

Sirolimus improves seizure control in pediatric patients with tuberous sclerosis: A prospective cohort study.

PURPOSE: This study aimed to analyze the therapeutic effect of sirolimus on seizures in pediatric patients with tuberous sclerosis. METHODS: We first compared the efficacy of controlling seizures in all patients after they had taken sirolimus for one year, and then we performed a subgroup analysis based on whether the administered antiepileptic drugs were changed to determine whether the efficacy was associated with changes of antiepileptic drugs. RESULTS: A total of 91 eligible children were enrolled. The response rate was 78.0 % (71/91), and 47.2 % (43/91) of all patients were became seizure-free. The improvement in seizure control before and after treatment with sirolimus was significant (p < 0.001). In the AEDs unaltered group, 34 were responders (34/45, 75.6 %, 95 % CI 17.4-88.3), of which 24 were seizure-free (24/34, 70.6 %). In the AEDs-altered group, 37 were responders (37/46, 80.4 %, 95 % CI 56.7-88.1), of which 19 were seizure-free (19/37, 51.4 %). There was no significant difference between the two groups for reductions in rate of seizure frequency (p = 0.308). In the patients with refractory epilepsy, treatment with sirolimus was also effective (p = 0.01). Logistic regression analysis showed that age was an important factor affecting outcome of epilepsy (p = 0.003, 95 % CI 2.05-38.31). No Grade 3 or 4 adverse events were noted during the follow-up. CONCLUSIONS: Sirolimus has a significant effect on seizures associated with tuberous sclerosis complex (TSC), with no or only moderate adverse events after long-term administration. Sirolimus could be used as the first-line medication for pediatric patients with TSC-associated epilepsy.

Targeting and Specific Activation of Antigen-Presenting Cells by Endogenous Antigen-Loaded Nanoparticles Elicits Tumor-Specific Immunity.

Immunotherapy has shown tremendous promise for improving cancer treatment. Unfortunately, antigen-presenting cells (APCs) in cancer patients cannot effectively recognize and process tumor antigens to activate host immune responses. In this study, an approach is developed to improve cancer immunotherapy that utilizes endogenous antigen-carrying nanoparticles (EAC-NPs), which encompasses a set of antigens isolated from solid tumors and adjuvants. The EAC-NPs specifically target APCs and subsequently result in enhanced T cell responses and improved antitumor efficacy. Mechanistic studies reveal that the EAC-NPs enhance and prolong the presence of immune compounds in APCs, which ensure persistent antigen loading and stimulation, induce a rapid proliferation of CD4+ and CD8+ T cells, and significantly increase the ratios of intratumoral CD4+ T/Treg and CD8+ T/Treg. The work using nanotechnology provides a promising strategy in improving antitumor immunity by enhancing the immunogenicity and presentation of tumor self-antigens for cancer immunotherapy.

Confocal laser endomicroscopy distinguishing benign and malignant gallbladder polyps during choledochoscopic gallbladder-preserving polypectomy: A case report.

BACKGROUND: In the last decade, confocal laser endomicroscopy (CLE) has emerged as a new endoscopic imaging modality for real-time in vivo histological examination at the microscopic level. CLE has been shown to be useful for distinguishing benign and malignant lesions and has been widely used in many digestive diseases. In our study, we used CLE for the first time to examine the morphology of cholesterol polyps as well as the different parts of normal gallbladder mucosa. CASE SUMMARY: A 57-year-old woman was diagnosed by ultrasound with a polyp of 21 mm in the gallbladder wall. She consented to polyp removal by laparoscopic choledo-choscopy. During laparoscopic cholecystectomy combined with choledochoscopic polyp resection, CLE was used to observe the morphology of the polyp surface cells. The appearance of the mucosa and microvessels in various parts of the gallbladder were also observed under CLE. Through comparison between postoperative pathology and intraoperative CLE diagnosis, the reliability of intraoperative CLE diagnosis was confirmed. CLE is a reliable method to examine living cell pathology during cholecystectomy. Based on our practice, CLE should be prioritized in the diagnosis of gallbladder polyps. CONCLUSION: Compared with traditional histological examination, CLE has several advantages. We believe that CLE has great potential in this field.