Ligand-independent EphA2 contributes to chemoresistance in small-cell lung cancer by enhancing PRMT1-mediated SOX2 methylation.

Chemoresistance is the crux of clinical treatment failure of small-cell lung cancer (SCLC). Cancer stem cells play a critical role in therapeutic resistance of malignant tumors. Studies have shown that the role of erythropoietin-producing hepatocellular A2 (EphA2) in tumors is complex. This study aimed to test the hypothesis that ligand-independent activation of EphA2 modulates chemoresistance by enhancing stemness in SCLC. We verified that EphA2 was activated in chemoresistance sublines in a ligand-independent manner rather than a ligand-dependent manner. Ligand-independent EphA2 enhanced the expression of stemness-associated biomarkers (CD44, Myc, and SOX2), accelerated epithelial-mesenchymal transition (EMT) and reinforced self-renewal to drive the chemoresistance of SCLC, while the P817H mutant EphA2 neutralized intrinsic function. Co-immunoprecipitation (co-IP) and GST-pull down experiments were conducted to verify that EphA2 directly interacted with PRMT1. Moreover, EphA2 increased the expression and activity of PRMT1. Whereafter, PRMT1 interacted with and methylated SOX2 to induce stemness and chemoresistance in SCLC. Pharmacological inhibition of EphA2 showed a synergistic anti-tumor effect with chemotherapy in preclinical models, including patient-derived xenograft (PDX) models. These findings highlight, for the first time, that the EphA2/PRMT1/SOX2 pathway induces chemoresistance in SCLC by promoting stemness. EphA2 is a potential therapeutic target in SCLC treatment.

Hydrothermal Synthesis of a Technical Lignin-Based Nanotube for the Efficient and Selective Removal of Cr(VI) from Aqueous Solution.

Aminated lignin (AL) was obtained by modifying technical lignin (TL) with the Mannich reaction, and aminated lignin-based titanate nanotubes (AL-TiNTs) were successfully prepared based on the AL by a facile hydrothermal synthesis method. The characterization of AL-TiNTs showed that a Ti-O bond was introduced into the AL, and the layered and nanotubular structure was formed in the fabrication of the nanotubes. Results showed that the specific surface area increased significantly from 5.9 m2/g (TL) to 188.51 m2/g (AL-TiNTs), indicating the successful modification of TL. The AL-TiNTs quickly adsorbed 86.22% of Cr(VI) in 10 min, with 99.80% removal efficiency after equilibration. Under visible light, AL-TiNTs adsorbed and reduced Cr(VI) in one step, the Cr(III) production rate was 29.76%, and the amount of total chromium (Cr) removal by AL-TiNTs was 90.0 mg/g. AL-TiNTs showed excellent adsorption capacities of Zn2+ (63.78 mg/g), Cd2+ (59.20 mg/g), and Cu2+ (66.35 mg/g). After four cycles, the adsorption capacity of AL-TiNTs still exceeded 40 mg/g. AL-TiNTs showed a high Cr(VI) removal efficiency of 95.86% in simulated wastewater, suggesting a promising practical application in heavy metal removal from wastewater.

WITHDRAWN: lncRNA Linc00173 modulates glucose metabolism and multidrug chemoresistance in SCLC: Potential molecular panel for targeted therapy.

This article has been withdrawn at the request of the editor-in-chief. Following publication of this article, the editor-in-chief discovered evidence of image duplication in Figures 1I, 1J, 3F, S5B, and S6B. Given the duplication of several western blots representing several gene products, the editor-in-chief has lost faith in the findings presented in this article. The authors maintain that these image duplications were the result of errors in file management and do not affect the conclusions of the study. The full Elsevier Policy on Article Withdrawal can be found at https://www.elsevier.com/about/our-business/policies/article-withdrawal.

Inhibition of N-acetylglucosaminyltransferase V enhances the cetuximab-induced radiosensitivity of nasopharyngeal carcinoma cells likely through EGFR N-glycan alterations.

N-acetylglucosaminyltransferase V (GnT-V), an enzyme that catalyzes the formation of the N-linked ß-1-6 branching of oligosaccharides, is related to the radiosensitivity of nasopharyngeal carcinoma (NPC). Cetuximab (C225) is an epidermal growth factor receptor (EGFR) inhibitor used as a radiosensitizer in the treatment of NPC. In this study, we used GnT-V as a molecular target to further sensitize cetuximab-treated NPC cells to radiation. The results from two NPC cell lines (CNE1 and CNE2) revealed that the silencing of GnT-V enhanced cetuximab-induced radiosensitivity by decreasing the ß-1-6 branching of oligosaccharides on the EGFR. GnT-V down-regulation combined with cetuximab decreased the survival fraction, healing rate and cell viability and increased the apoptosis rate. Concomitantly, the combination of cetuximab and irradiation did not change the EGFR mRNA and protein levels and decreased the ß-1-6 branching on the EGFR. Subsequently, we further explored the signaling downstream of EGF, particularly the PI3K/Akt signaling pathway, and discovered that treatment consisting of GnT-V down-regulation, irradiation and cetuximab was negatively correlated with phospho-Akt and phspho-PI3K. Finally, an in vivo experiment with radiotherapy revealed that the combination of GnT-V down-regulation and cetuximab decelerated tumor growth. In summary, our study demonstrated that the combination of decreased GnT-V activity and cetuximab enhanced NPC radiosensitivity, and the possible mechanism underlying this effect might involve the N-linked ß1-6 branching of the EGFR.

A long non-coding RNA HOTTIP expression is associated with disease progression and predicts outcome in small cell lung cancer patients.

BACKGROUND: Despite progress in treatment of small cell lung cancer (SCLC), the biology of the tumor still remains poorly understood. Recently, we globally investigated the contributions of lncRNA in SCLC with a special focus on sponge regulatory network. Here we report lncRNA HOTTIP, which is specifically amplified in SCLC, is associated with SCLC proliferation and poor prognosis of patients. METHODS: RT-qPCR was used to investigate the expression of HOTTIP in SCLC tissues and cell lines. The role of HOTTIP in SCLC cell proliferation was demonstrated by CCK8 assay, colony formation assay, flow cytometry analysis and in vivo SCLC xenograft model in nude mice through HOTTIP loss- and gain-of-function effects. Western blot assay was used to evaluate gene expression in cell lines at protein level. RNA pull-down, Mass spectrometry and RNA binding protein immunoprecipitation (RIP) were performed to confirm the molecular mechanism of HOTTIP involved in SCLC progression. RESULTS: We found that HOTTIP was overexpressed in SCLC tissues, and its expression was correlated with the clinical stage and the shorter survival time of SCLC patients. Moreover, HOTTIP knockdown could impair cell proliferation, affect the cell cycle and inhibit tumor growth of mice, while HOTTIP overexpression might enhance cell proliferation and cell cycle in vitro and in vivo. Mechanistic investigations showed that HOTTIP functions as an oncogene in SCLC progression by sponging miR-574-5p and affecting the expression of polycomb group protein EZH1. CONCLUSIONS: Overall, we identified that HOTTIP was involved in SCLC tumorigenesis through the ceRNA network "HOTTIP/miR-574-5p/EZH1". Our findings not only illuminate how HOTTIP confers an oncogenic function in SCLC pathogenesis, but also underscore a novel gene expression governing hallmarks in the disease.

TSPAN12 promotes chemoresistance and proliferation of SCLC under the regulation of miR-495.

Studies have shown that TSPAN12 serves as an oncogenic gene or tumor suppressor depending on the types of cancer. However, its role in the drug resistance of small cell lung cancer (SCLC) is still unknown. In this study, we investigated whether TSPAN12 regulates chemoresistance, proliferation and tumor growth of SCLC under the regulation of miR-495 using two drug resistant cell lines. The results showed that down-regulation of TSPAN12 inhibited cells chemoresistance, proliferation and tumor growth. Besides, TSPAN12 elevation in SCLC specimens correlated with poor pathologic stage and shorter survival time. In addition, the dual luciferase assay indicated that TSPAN12 was one of the directly targeted genes of miR-495. Our study revealed that TSPAN12 promoted chemoresistance of SCLC under the regulation of miR-495. TSPAN12 depletion is a promising strategy for inhibiting the chemoresistance in SCLC.

WW domain binding protein 5 induces multidrug resistance of small cell lung cancer under the regulation of miR-335 through the Hippo pathway.

BACKGROUND: Our previous study indicated that WW domain binding protein 5 (WBP5) expression was elevated significantly in a drug-resistant cell compared with its parental cell. Nevertheless, its functional role and underlying mechanisms remain unknown. METHODS: In this study, WBP5 was examined in 62 small cell lung cancer (SCLC) patient samples by immunohistochemical technique. Stable WBP5-overexpressed and WBP5-underexpressed cells were further established to assess the role of WBP5 in drug resistance, apoptosis and tumour growth. We also conducted western blot to detect the expression of MST2 and YAP1 and their phosphorylated protein. RESULTS: The results revealed that WBP5 expression was significantly associated with the shorter survival time in SCLC patients. Upregulation of WBP5 induced multidrug resistance (MDR) and decreased apoptosis, whereas downregulation of WBP5 enhanced drug sensitivity and increased apoptosis. We also found that miR-335 negatively regulated the MDR of WBP5 by targeting its 3'UTR. Furthermore, WBP5 can lower YAP1 phosphorylation at Serine 127 and induce nuclear accumulation of YAP1. Inhibition of YAP1 by Verteporfin could blunt the MDR phenotype of WBP5. CONCLUSIONS: WW domain binding protein 5 can modulate MDR through the Hippo pathway under the regulation of miR-335. WW domain binding protein 5 may be a prognostic predictor and a potential target for interfering with MDR in SCLC.

EPHA3 regulates the multidrug resistance of small cell lung cancer via the PI3K/BMX/STAT3 signaling pathway.

Multidrug resistance (MDR) is a major obstacle to the treatment of small cell lung cancer (SCLC). EPHA3 has been revealed to be the most frequently mutated Eph receptor gene in lung cancer with abnormal expression. Growing evidence indicates that the signaling proteins of EPHA3 downstream, including PI3K, BMX and STAT3, play crucial roles in tumorigenesis and cancer progression. To explore the possible role of EPHA3 in MDR, we assessed the influence of EPHA3 on chemoresistance, cell cycle, apoptosis, and tumor growth, as well as the relationship between EPHA3 and the expression of PI3K, BMX, and STAT3 in SCLC. We observed that overexpression of EPHA3 in SCLC cells decreased chemoresistance by increasing apoptosis and inducing G0/G1 arrest, accompanied by reduced phosphorylation of PI3K/BMX/STAT3 signaling pathway. Knockdown of EPHA3 expression generated a resistant phenotype of SCLC, as a result of decreased apoptosis and induced G2/M phase arrest. And re-expression of EPHA3 in these cells reversed the resistant phenotype. Meanwhile, increased phosphorylation of PI3K/BMX/STAT3 signaling pathway was observed in these cells with EPHA3 deficiency. Notably, both PI3K inhibitor (LY294002) and BMX inhibitor (LFM-A13) impaired the chemoresistance enhanced by EPHA3 deficiency in SCLC cell lines. Furthermore, EPHA3 inhibited growth of SCLC cells in vivo and was correlated with longer overall survival of SCLC patients. Thus, we first provide the evidences that EPHA3 is involved in regulating the MDR of SCLC via PI3K/BMX/STAT3 signaling and may be a new therapeutic target in SCLC.

Meta-analysis of the correlation between IL-6 -174 G/C polymorphism and polycystic ovarian syndrome.

AIM: The correlation between interleukin-6 (IL-6) gene polymorphism and polycystic ovary syndrome (PCOS) has been reported, but the conclusions are controversial. The present study was aimed to evaluate the association between IL-6 -174 G/C polymorphism and susceptibility of PCOS by meta-analysis. MATERIAL AND METHODS: A systematic search on Medline, Embase, CNKI, Wanfang Data and VIP databases containing Chinese and English studies was conducted electronically using specific eligibility criteria. Meta-analysis was performed using Review Manager 5.2 software after Hardy-Weinberg equilibrium test. Effect sizes of odds ratio and 95% confidence interval (CI) were calculated and combined appropriately. To verify the reliability of the results, subgroup analyses and sensitivity analyses were performed. RESULTS: Four selected studies containing 351 cases and 464 control participants were included. The pooled odds ratio between IL-6 -174 G/C polymorphism and susceptibility of PCOS under allele (C/G), dominant (CC+GC/GG) and recessive (CC/GG+GC) models were 0.63 (95%CI, 0.41-0.96), 0.53 (95%CI, 0.26-1.08) and 0.67 (95%CI, 0.39-1.16), respectively. The result under allele model was unstable in sensitivity analysis. Subgroup analysis showed that the correlation between IL-6 -174 G/C polymorphism and susceptibility of PCOS was not statistically significant in the studies that conformed to the Hardy-Weinberg equilibrium. CONCLUSION: IL-6 -174 G/C polymorphism may be not related to susceptibility of PCOS. Nevertheless, further studies with large samples and studies considering other single-nucleotide polymorphisms of the IL-6 gene are needed to confirm our findings.

Enhanced degradation of 2,4-dichlorophenol in groundwater by defective iron-based metal-organic frameworks: Role of SO3- and electron transfer.

The purposeful formation of crystal defects was regarded as an attractive strategy to enhance the catalytic activity of Fe-MOFs. In this study, the pyrolytic hydrochloric acid-modulated MIL-101-NH2 (P250HMN-2) was fabricated for the first time, and the important role of pyrolysis in the formation of crystal defects was confirmed. PDS was introduced as an enhancer for the P250HMN-2/Na2SO3 system. Without pH adjustment, 99.7 % of 2,4-DCP was removed by the P250HMN-2/Na2SO3/PDS system in 180 min. The catalytic performance of P250HMN-2 improved 2.5-fold than that of MIL-101-NH2. It was found that the high density of Fe-CUSs on P250HMN-2 were the major active sites, which could efficiently react with SO32- to generate ROS through electron transfer. The results of quenching experiments, probe tests, and EPR tests indicated that SO3-, SO4-, 1O2, OH, and SO5- were involved in the 2,4-DCP degradation process, with SO3-, SO4-, and 1O2 playing major roles. Moreover, P250HMN-2 could effectively degrade 2,4-DCP for 148 h in a fixed-bed reactor with excellent stability and reusability, indicating a promising catalyst for practical applications.

CDK4/6 Inhibitors Impede Chemoresistance and Inhibit Tumor Growth of Small Cell Lung Cancer.

Small cell lung cancer (SCLC) is characterized by rapid development of chemoresistance and poor outcomes. Cyclin-dependent kinase 4/6 inhibitors (CDK4/6is) are widely used in breast cancer and other cancer types. However, the molecular mechanisms of CDK4/6 in SCLC chemoresistance remain poorly understood. Here, Rb1flox/flox, Trp53flox/flox, Ptenflox/flox (RTP) and Rb1flox/flox, Trp53flox/flox, MycLSL/LSL (RPM) spontaneous SCLC mouse models, SCLC cell line-derived xenograft (CDX) models, and SCLC patient-derived xenograft (PDX) models are established to reveal the potential effects of CDK4/6is on SCLC chemoresistance. In this study, it is found that CDK4/6is palbociclib (PD) or ribociclib (LEE) combined with chemotherapeutic drugs significantly inhibit SCLC tumor growth. Mechanistically, CDK4/6is do not function through the classic Retionblastoma1 (RB) dependent axis in SCLC. CDK4/6is induce impair autophagy through the AMBRA1-lysosome signaling pathway. The upregulated AMBRA1 protein expression leads to CDK6 degradation via autophagy,  and the following TFEB and TFE3 nuclear translocation inhibition leading to the lysosome-related genes levels downregulation. Moreover, it is found that the expression of CDK6 is higher in SCLC tumors than in normal tissue and it is associated with the survival and prognosis of SCLC patients. Finally, these findings demonstrate that combining CDK4/6is with chemotherapy treatment may serve as a potential therapeutic option for SCLC patients.

Anemia status of infants and young children aged six to thirty-six months in Ma'anshan City: A retrospective study.

BACKGROUND: Anemia in infants and young children can have long-term effects on cognitive and physical development. In Ma'anshan City, China, there has been growing concern about the prevalence of anemia among children aged 6 to 36 mo. Understanding the factors influencing this condition is crucial for targeted interventions and improving overall child health in the region. AIM: To analyze the anemia status and influencing factors of infants and young children aged 6 to 36 mo in Ma'anshan City, China. Providing scientific evidence for reducing the incidence of anemia and improving the health level of children in this age group. METHODS: The study encompassed 37698 infants and young children, aged from 6 to 36 mo, who underwent health examinations at the Ma'anshan Maternal and Child Health Hospital from January 2018 to October 2022 were included in the study. Basic information, physical examination, and hemoglobin detection data were collected. Descriptive analysis was used to analyze the prevalence of anemia in children in the region, and univariate analysis was used to analyze the influencing factors of anemia. RESULTS: The mean hemoglobin level of infants and young children aged 9 to 36 mo increased with age, and the anemia detection rate decreased with age. The anemia detection rate in rural infants aged 6, 9, and 12 mo was higher than that in urban infants. Although the anemia detection rate was higher in 6-mo-old boys than girls, it was higher in 24-mo-old girls than boys. There were statistically significant differences in the anemia detection rates among 9-mo-old and 12-mo-old infants with different nutritional statuses (emaciation, overweight, obese, and normal). Moreover, there were no statistically significant differences in anemia detection rates among infants and young children with different nutritional statuses at other ages. Besides, the anemia detection rates in obese infants aged 9 and 12 mo were higher than those in normal and overweight infants, with statistically significant differences. Finally, there were no statistically significant differences in the anemia detection rates between emaciation infants and those with other nutritional statuses. CONCLUSION: The anemia situation among infants and young children aged 6 to 36 mo in Ma'anshan City, China, is relatively prominent and influenced by various factors. Our result shown that attention should be paid to the anemic infant and young child population, with strengthened education and targeted prevention and dietary guidance to help them establish good living habits, improve nutritional status, and reduce the occurrence of anemia to improve children's health levels.

Identifying CDC7 as a synergistic target of chemotherapy in resistant small-cell lung cancer via CRISPR/Cas9 screening.

There is currently a lack of efficacious treatments for patients with chemo-resistant small-cell lung cancer (SCLC), leading to poor prognoses. We examined a chemo-resistant SCLC cell line using genome-wide CRISPR/Cas9 screening and identified serine/threonine kinase cell division cycle 7 (CDC7) as a potential synergistic target. Silencing CDC7 in chemo-resistant SCLC cells decreased the IC50 and improved the efficacy of chemotherapy. Based on the highest single agent model, the CDC7 inhibitor XL413 had a synergistic effect with both cisplatin and etoposide in chemo-resistant SCLC cells, but had no such effect in chemo-sensitive SCLC cells; the combination of XL413 and chemotherapy significantly inhibited cell growth. Western blot and flow cytometry showed that the combined treatments increased apoptosis, whereas XL413 alone had little effect on apoptosis. An analysis of cell cycle and cyclin protein levels indicated that the combination of XL413 and chemotherapy-induced G1/S phase arrest and DNA damage in chemo-resistant SCLC cells. Xenografted tumor and histoculture drug response assays using patient-derived xenografts showed that XL413 improved the efficacy of chemotherapy in vivo and with SCLC tissues. These results suggest that XL413 exerts a synergistic effect with chemotherapy on chemo-resistant SCLC.

Study on ionic association behavior in sodium nitrate solution.

Raman spectroscopy combined with component analysis and molecular dynamics simulation were used to study chemical species and their transformation in aqueous sodium solutions. Study shows that the characteristic vibrational frequency of nitrate ions (ν1-NO3-) blue-shifted from 1043.9 to 1046.9 cm-1, and the full width at half maximum increased from 6.8 to 10.8 cm-1 as the concentration increasing. When water/salt molar ratio (WSR) > 30, the relative concentration (RC) of free hydrated ions and solvent shared ion pair accounts for the vast majority, and there is almost no contact ion pair in solution. When WSR less than 30, due to the continuous reduction of the number of water molecules, the hydrated water molecules around the sodium ions and nitrate ions begin to decrease, and solvent shared ion pair or contact ion pair gradually forms. Sodium ions and nitrate ions mainly exist in a monodentate coordination. When WSR > 160, both the relative concentration of contact ion pair and complex structure is close to 0. This work proves that a lower RC of complex structure in solution, a smaller supersaturation of the solution is achieved, meaning aqueous sodium nitrate solution is easier to nucleate crystals.

METTL3 promotes chemoresistance in small cell lung cancer by inducing mitophagy.

BACKGROUND: Small cell lung cancer (SCLC) is the most aggressive subtype of lung cancer. Although most patients are initially sensitive to first-line combination chemotherapy with cisplatin and etoposide, chemotherapy drug resistance easily develops and quickly leads to tumour progression. Therefore, understanding the mechanisms of chemotherapy drug resistance and how to reverse it is key to improving the prognosis of patients with SCLC. Moreover, N6-methyladenosine (m6A) is the most abundant mRNA modification and is catalysed by the methyltransferase complex, in which methyltransferase-like 3 (METTL3) is the sole catalytic subunit. METHODS: The effects of METTL3 on chemoresistance in SCLC cells were determined using qRT-PCR, Western blotting, immunohistochemistry, cell counting kit (CCK-8) assays, flow cytometry, and tumorigenicity experiments. Methylated RNA immunoprecipitation sequencing (MeRIP-seq), MeRIP qPCR, immunofluorescence, and drug inhibitor experiments were performed to confirm the molecular mechanism of Decapping Protein 2 (DCP2), which is involved in the chemoresistance of SCLC. RESULTS: In the present study, we found that METTL3 is a marker for poor SCLC prognosis, and it is highly expressed in chemoresistant SCLC cells. METTL3 promotes SCLC chemoresistance by positively regulating mitophagy. METTL3 induces m6A methylation of DCP2 and causes the degradation of DCP2, which promotes mitochondrial autophagy through the Pink1-Parkin pathway, leading to chemotherapy resistance. We also found that STM2457, a novel METTL3 inhibitor, can reverse SCLC chemoresistance. CONCLUSIONS: The m6A methyltransferase METTL3 regulates Pink1-Parkin pathway-mediated mitophagy and mitochondrial damage in SCLC cells by targeting DCP2, thereby promoting chemotherapy resistance in patients with SCLC.

Prognostic value of circulating tumor DNA using target next-generation sequencing in extensive-stage small-cell lung cancer.

BACKGROUND: Chemotherapy remains the mainstay of treatment for small-cell lung cancer (SCLC). Liquid biopsies provide a convenient and non-invasive detection method for monitoring disease progression in patients with SCLC. METHODS: We performed next-generation sequencing of 159 plasma samples from 69 patients with extensive-stage (ES)-SCLC. Circulating tumor (ct)DNA levels were quantified in haploid genome equivalents per mL (hGE/mL). MuTect2 was used to detect single nucleotide variants and short insertions/deletions. The "enrichKEGG" function in the "clusterProfiler" R package was used to enrich the mutated genes that only appeared during disease progression. RESULTS: In our cohort, 66 of 69 (95.7%) plasma samples at the time of diagnosis had detectable somatic mutations; TP53 (89%) and RB1(56%) were the most frequent mutations, as well as copy number variations in some common SCLC-related genes such as RB1. Combination ctDNA and tissue testing improved the overall detection rate of actionable mutations from 19.4% to 26.9% compared with that of tissue detection alone. In addition, ctDNA levels changed dynamically during the course of treatment and were significantly associated with decreased progression-free survival. Notably, actionable mutations were detected at the time of diagnosis and during disease progression. CONCLUSIONS: Our study revealed a dynamic somatic mutation profile through continuous ctDNA detection and confirmed that ctDNA levels can reflect tumor burden and predict PFS in patients with extensive stage-SCLC. Furthermore, we demonstrated that plasma ctDNA assays can provide real-time information on somatic mutations for potential targeted therapies for SCLC.

Cell plasticity in patients with NSCLC: The controversial origins of transformed SCLC.

In recent years, the application of targeted therapy has greatly improved the survival of NSCLC patients with known tumor mutations. However, the plasticity of tumor cells can drive them to transform into a phenotypic state that is no longer targeted by drugs. One of the mechanisms by which drug resistance occurs is the transformation from NSCLC to SCLC. This seems to occur because of the selection pressure exerted by the drugs. However, the transformation has also been observed in non-targeted patients, which challenges the origin of transformed SCLC. In the present study, the current clinical understanding of transformed SCLC is summarized along with the current understanding of its genome status and cloning history in cancer progression. This was done to explore the origins of transformed SCLC, find key molecular markers to predict the occurrence of the transformation, and permit timely adjustment of patients' treatment plans. Besides, the current clinical trials on transformed SCLC are discussed. Finally, recommendations are made on the problems that need to be solved to improve the diagnosis and treatment of patients with transformed SCLC.

Intermittent Theta Burst Stimulation vs. High-Frequency Repetitive Transcranial Magnetic Stimulation in the Treatment of Methamphetamine Patients.

Background and Aims: In this brief report, we compare the effectiveness and safety of intermittent theta burst stimulation (iTBS) and conventional 10 Hz repetitive transcranial magnetic stimulation (rTMS) in patients with methamphetamine use disorder (MAUD). Our study suggests that iTBS would also reduce drug craving in patients with MAUD just as the 10 Hz; thus, there may be no difference in treatment effects between these two methods. Methods: In total twenty male methamphetamine (MA) addicts were randomly assigned to iTBS (n = 10) or 10 Hz (n = 10) groups for 12 treatments. Cue-evoked cravings, anxiety, depression, and withdrawal symptoms were measured at baseline before the first treatment, and post-tests after days 10, 15, and 20. Results: The results showed that iTBS and 10 Hz treatment had similar effectiveness in reducing cue-induced craving in male addicts for MA. Both 10 Hz and iTBS improved withdrawal symptoms of patients with MAUD. Conclusions: Intermittent theta burst stimulation may be similar in effectiveness as 10 Hz in treating patients with MAUD. The clinical usefulness of rTMS could be improved substantially because of the increase in its capacity, cost, and accessibility. Importantly, the effectiveness of rTMS in the treatment of patients with MAUD is not yet proven, and should be tested in the large double-blind sham-controlled studies.

MHC-II Signature Correlates With Anti-Tumor Immunity and Predicts anti-PD-L1 Response of Bladder Cancer.

A large proportion of anti-tumor immunity research is focused on major histocompatibility complex class I (MHC-I) molecules and CD8+ T cells. Despite mounting evidence has shown that CD4+ T cells play a major role in anti-tumor immunity, the role of the MHC-II molecules in tumor immunotherapy has not been thoroughly researched and reported. In this study, we defined a MHC-II signature for the first time by calculating the enrichment score of MHC-II protein binding pathway with a single sample gene set enrichment analysis (ssGSEA) algorithm. To evaluate and validate the predictive value of the MHC class II (MHC-II) signature, we collected the transcriptome, mutation data and matched clinical data of bladder cancer patients from IMvigor210, The Cancer Genome Atlas (TCGA) databases and Gene Expression Omnibus (GEO) databases. Comprehensive analyses of immunome, transcriptome, metabolome, genome and drugome were performed in order to determine the association of MHC-II signature and tumor immunotherapy. We identified that MHC-II signature is an independent and favorable predictor of immune response and the prognosis of bladder cancer treated with immune checkpoint inhibitors (ICIs), one that may be superior to tumor mutation burden. MHC-II signature was significantly associated with increased immune cell infiltration and levels of immune-related gene expression signatures. Additionally, transcriptomic analysis showed immune activation in the high-MHC-II signature subgroup, whereas it showed fatty acid metabolism and glucuronidation in the low-MHC-II signature subgroup. Moreover, exploration of corresponding genomic profiles highlighted the significance of tumor protein p53 (TP53) and fibroblast growth factor receptor 3 (FGFR3) alterations. Our results also allowed for the identification of candidate compounds for combined immunotherapy treatment that may be beneficial for patients with bladder cancer and a high MHC-II signature. In conclusion, this study provides a new perspective on MHC-II signature, as an independent and favorable predictor of immune response and prognosis of bladder cancer treated with ICIs.