Hyperfractionated Accelerated Radiotherapy Versus Stereotactic Body Radiotherapy in the Treatment of Limited-Stage Small Cell Lung Cancer: A Matched-Pair Analysis.

BACKGROUND: Concurrent chemoradiotherapy based on hyperfractionated accelerated radiotherapy (HART) is the first-line recommended regimen for the treatment of small-cell lung cancer (SCLC). However, Stereotactic Body Radiotherapy (SBRT) is also regarded as an effective treatment for limited-stage (LS) SCLC, and the efficacy and safety of HART versus SBRT stay controversial. METHODS: In this study, 188 LS-SCLC patients were retrospectively divided into two groups receiving chemotherapy combined with either HART or SBRT. In HART group, patients received 4500 cGy in 30 fractions, administered twice daily for 3 weeks. Whereas in the SBRT group, a total radiation dose of 4000-4500 cGy was delivered in 10 fractions over 2 weeks. Thirty-three pairs of patients were finally included for next analysis. RESULTS: The estimated objective response rates were 63.6 % (21/33) and 78.8 % (26/33) in HART group and SBRT group, respectively (P = 0.269). Furthermore, there was no significant difference between HART and SBRT groups in overall survival (26 months vs. 29 months, P = 0.362) and progression free survival (11 months vs. 15 months, P = 0.223). As for the adverse events, toxicity of both groups is similar and slight that no grade 4 event was observed. Grade 3 pneumonitis cases were all occurred in the HART group (9.1%, 3/33, P = 0.238), and grade 3 esophagitis cases were all occurred in the SBRT group (6.1%, 2/33, P = 0.492). CONCLUSION: Compared with HART, SBRT could be another effective treatment with satisfactory safety for the concurrent chemoradiotherapy in patients with LS-SCLC.

Diagnostic Value Analysis of Multi-Slice Helical Computed Tomography Reconstruction Parameters Combined with 3.0 T Magnetic Resonance in Clear Cell Renal Cell Carcinoma.

OBJECTIVE: The diagnostic value of multi-slice helical computed tomography (MSCT) reconstruction parameters combined with 3.0 T magnetic resonance (MR) in clear cell renal cell carcinoma (CCRCC) was analysed. METHODS: A total of 158 patients with renal tumours were selected in First Hospital in Zibo city from February 2018 to March 2023 for the retrospective study and divided into CCRCC and non-CCRCCs groups according to the final results of pathological diagnosis. MSCT detection and 3.0 T MR detection were performed in both groups for imaging manifestation analysis. The receiver operating characteristic (ROC) curve was used in analysing the clinical efficacy of each single and combined diagnosis. RESULTS: The results of pathological diagnosis showed 115 patients with CCRCC and 43 non-CCRCC patients, accounting for 72.78% and 27.22%, respectively. Patients with CCRCC had higher proportions of calcification, necrosis, cystic degeneration and more pseudocapsules than non-CCRCC patients (p < 0.05). Patients with CCRCC mainly showed peripheral and heterogeneous enhancement, whereas non-CCRCC patients mainly showed homogeneous enhancement, and the difference was significant (p < 0.05). The cortical phase, parenchymal phase and excretion stage had higher computed tomography (CT) values in the CCRCC group (p < 0.001), and no significant difference in the CT value of plain scan phase was found between the groups (p > 0.05). The CCRCC group had obviously higher apparent diffusion coefficient value and incidence of necrosis and cystic degeneration (p < 0.001), lower incidence of haemorrhage (p < 0.05) and distinctly higher cortical enhancement indexes in the cortical phase, parenchymal phase and delay period (p < 0.001). The ROC analysis showed that the area under the curve, specificity, sensitivity and 95% CI of combined detection were higher than those of each single detection. CONCLUSIONS: The combination of MSCT reconstruction parameters and 3.0 T MR has a certain diagnostic value for CCRCC. The combined diagnosis has higher area under the curve, specificity, sensitivity and 95% CI, which can provide effective reference for clinical diagnosis and treatment, with a certain clinical application value.

Distinct circulating cytokine/chemokine profiles correlate with clinical benefit of immune checkpoint inhibitor monotherapy and combination therapy in advanced non-small cell lung cancer.

BACKGROUND: An ever-increasing number of efforts are focused on identifying effective biomarkers for immune checkpoint inhibitors (ICIs). Cytokines and chemokines are critical to tumor growth, metastasis, tumor angiogenesis, and the immune response against tumor cells. In the study here, we determined the correlation between circulating cytokines/chemokines and the clinical benefit of ICIs for non-small cell lung cancer (NSCLC) patients. METHODS: Peripheral blood samples were collected before and during treatment (at 12th week). Plasma levels of cytokines/chemokines and specific stress response markers were measured using the Bio-Plex Pro Human Cytokines Grp I Panel (27-plex), an APEX1 detection kit, and a human LAP(TGF-ß1) immunoassay kit. A Mann-Whitney U-test or Wilcoxon signed-rank test and a Cox proportional hazards model were employed for statistical analysis. RESULTS: In the ICI monotherapy cohort, a high level of IL-6 at pretreatment or an elevation of IL-6, IL-8, FGF2, CXCL10, CCR1, PDFGB, TNF, and APEX1 posttreatment was associated with poor progress-free survival (PFS). A posttreatment elevation (defined herein as change rate) of CXCL10 was also associated with poor overall survival (OS). In the combinational therapy group, a high level of IL-12, IL-17A, FGF2, VEGF, and APEX1 at pretreatment and an elevation of CCL2 posttreatment were associated with poor PFS. A high level of IL-9, FGF2, PDFGB, CCL4, TFGB, and APEX1 at pretreatment and an elevation of IL-13, CSF2, and CCL2 at posttreatment were associated with poor OS of patients receiving combination therapy. CONCLUSIONS: The study here suggests that circulating cytokines/chemokines are feasible, noninvasive biomarkers for predicting clinical benefit of ICI treatment for NSCLC. Distinct circulating factor profiles were observed in individuals receiving ICI monotherapy or combination therapy.

Next generation sequencing targeted detection of somatic mutations in patients with mucinous adenocarcinoma of the appendix.

The aim of this study was to investigate the mutations in mucinous adenocarcinoma of the appendix (MAA). SNV was detected in 15 patients with MAA, Gene Ontology (GO), Kyoto Encyclopedia of Genes and Genomes (KEGG) and reactome pathway analyses were performed. Tumor mutational burden (TMB), mutant-allele tumor heterogeneity (MATH), microsatellite instability (MSI) was analysis. Finally, the human leukocyte antigen (HLA) typing of the samples was detected. The results showed that TP53 (27 %) and KRAS (20 %) were the highest mutation frequency in the sample, mainly occur in p53 pathway and RTK-RAS pathway. GO analysis reveals mutated genes are closely related to the regulation of GTPase activity, regulation of small GTPase mediated signal transduction and other BP, related to the CC and MF. Analysis of KEGG pathways indicated that the top canonical pathways associated with SNV was Wnt signaling pathway. Reactome pathway analysis further revealed that the mutant genes were closely related to muscle contraction. Only one patient had moderate TMB level and one patient with high MSI. In conclusion, the most common mutated genes and the signaling pathways closely related to MAA development were detected in this study, which will contribute to the development of immunotherapy for patients with MAA.

Toll-Like Receptor 4 Exacerbates Mycoplasma pneumoniaevia Promoting Transcription Factor EB-Mediated Autophagy.

Mycoplasma pneumoniae (M. pneumoniae) is the most common cause of community-acquired pneumonia. Toll-like receptors (TLRs) play an essential role in pneumonia. The purpose of this study was to investigate the roles of TLR4 in M. pneumoniae. Mice were administrated with 100 µl (1 × 107 ccu/ml) of M. pneumoniae. HE staining was applied for histological analysis. The protein expression was determined by western blot. The cytokine level was detected by ELISA. The results showed that TLR4-deficient mice were protected from M. pneumoniae. However, downregulation of TLR4 inhibited inflammatory response and autophagy. Moreover, transcription factor EB (TFEB) participated in M. pneumoniae-induced inflammatory response and autophagy, while knockdown of TLR4 downregulated TFEB and its nuclear translocation.

Estimating the prognosis of esophageal squamous cell carcinoma based on The Cancer Genome Atlas (TCGA) of m6A methylation-associated genes.

Background: N6-methyladenosine (m6A) mRNA modification is the most prevalent in certain tumors. However, its expression profile and prognostic value in human esophageal squamous cell carcinoma (ESCC) remains unknown. Methods: Herein, we performed an extensive investigation of the m6A-associated gene expression profile and determined its significance in the prognosis of ESCC. We received the RNA expression profiles of 81 ESCC tissues and one normal esophageal tissue from The Cancer Genome Atlas (TCGA) database. Kaplan-Meier (KM) survival analysis was used to assess the predictability of m6A methylation-associated gene expression in ESCC prognosis. In addition, univariate and multivariate Cox regression, as well as least absolute shrinkage and selection operator (LASSO) regression models were employed for the establishment of prognostic signatures. Lastly, KM survival analysis, proportional hazard models, and receiver operating characteristic (ROC) curves were used to verify the prognostic value. Moreover, we also investigated the associations among the m6A prognostic signature, immune cell infiltration, and programmed cell death-ligand 1 (PD-L1) expression. Results: We demonstrated that YTHDF3 [hazard ratio (HR): 0.910; 95% confidence interval (CI): 0.832-0.995; P=0.038], RBM15 (HR: 0.721; 95% CI: 0.549-0.948; P=0.019), KIAA1429 (HR: 0.801; 95% CI: 0.664-0.967; P=0.021), and ALKBH5 (HR: 0.948; 95% CI: 0.895-1.003; P=0.0.064) overexpression predicted better overall survival (OS) of ESCC patients. Furthermore, based on prognostic factors, the high-risk (H-R) cohort was found to have worse survival than the low-risk (L-R) cohort (P<0.001). Conclusions: We revealed three m6A methylation-associated genes that were closely correlated with enhanced survival in ESCC patients. In addition, we generated an independent prognostic signature based on the expression of YTHDF3, RBM15, KIAA1429, and ALKBH5 genes. The results revealed significantly higher proportions of CD8+ T cells and higher expression of PD-L1 in the H-R group.

Development of L-carnosine functionalized iron oxide nanoparticles loaded with dexamethasone for simultaneous therapeutic potential of blood brain barrier crossing and ischemic stroke treatment.

The development of suitable drug delivery carriers is significant in biomedical applications to improve the therapeutic efficiency. Recent progress in nanotechnological fields, paved the way for the formulation of variety of drug carriers. The brain disorders such as ischemic stroke, brain cancer, and CNS disorders were poorly treated due to the presence of blood brain barrier that hinders the passage of drugs to the brain. Hence, the formulated drugs should have the ability to cross the blood-brain barrier (BBB) for ischemic stroke treatment. In the present work, we have synthesized PLGA functionalized magnetic Fe3O4 nanoparticle (MNP) with L-carnosine peptide (LMNP) composite loaded with dexamethasone (dm@LMNP) and demonstrated as efficient drug delivery platform for simultaneous BBB crossing and treatment of ischemic stroke. The surface morphology, particles size and zeta potential of the prepared material was studied from SEM, PSD, PDI and TEM analyses. The drug loading of dexamethasone in LMNP (dm@LMNP) vesicles was found to be 95.6 ± 0.2%. The in vitro drug release kinetics displayed that prepared composited LMNP material provides controlled and sustainable releasing efficiency at pH 7.4 and 5.8 when compared to the PLGA NPs and free dexamethasone drug molecules. The cytotoxicity and the biocompatibility test results were found to be satisfactory. The L-carnosine loaded nano-formulation has been greatly leads to effective BBB crossing to access the brain tissues. These results showed that the Fe3O4 nanoparticles/PLGA polymer can be used as an effective drug carrier for the treatment of stroke and simultaneous blood brain barrier crossing.

Effects of liver-regulating herb compounds on testicular morphological and ultrastructural changes in varicocele rats through SCF/C-KIT pathway.

Liver-regulating herb compound (LRHC) has good effects on improving sperm quality and male fertility of varicocele (VC) patients. But the mechanism of LRHC on VC is still not clear. This study explored the effects of LRHC on histomorphological and ultrastructural changes and expression of stem cell factor (SCF) and C-KIT of VC rat testis. Twenty-four male rats were divided into three groups with eight rats in each group as sham, varicocele and LRHC groups. Testis specimens were collected for light microscopy and transmission electron microscopy respectively. The expression of SCF/C-KIT was detected with Western blot. Results showed that seminiferous tubules in VC rats were damaged and cell numbers were decreased. Ultrastructural alterations were observed, such as increased thickness of lamina propria, vacuolation in Sertoli cells, spermatocytes and spermatids, and abnormal head and mitochondria in spermatozoa. While in LRHC-treated rats, the architectures of seminiferous tubules were as organised and compact as that of sham animals, and ultrastructure of Sertoli, Leydig and germ cells developed well. LRHC ameliorated histological appearance and ultrastructure by VC. In addition, the abnormal expression of SCF and C-KIT were observed in testicular tissues from rats with VC, which were brought back to normal level by LRHC.

Impact of T-cell receptor and B-cell receptor repertoire on the recurrence of early stage lung adenocarcinoma.

Surgical resection is the only curative treatment for patients with early stage non-small cell lung cancer. However, approximately 33% of non-small cell lung cancer patients recur with the stage I disease, which may be attributed to a deficiency in antitumor immunity. In the present study, for early stage lung adenocarcinoma patients with early recurrence and early non-recurrence, we investigated the quantity of tumor-infiltrating T and B cells by immunohistochemistry, as well as the genes in the complementarity determining region 3 of the T-cell receptor ß chain and the B-cell receptor immunoglobulin heavy chain. A decreased number of tumor-infiltrating lymphocytes cells (CD3+, CD4+, CD8+ and CD20+) was present in early recurrence patients. A significant increase in oligoclones and a reduction in T-cell receptor diversity were observed in the early recurrence group. Furthermore, there was a preference for V, J gene, and VJ gene combinations in patients with early recurrence versus non-recurrence, suggesting that this may be a new biomarker for the recurrence of early stage lung adenocarcinoma. These data indicate that T and B cell receptor repertoires influence the depth of human adaptive immune responses, and in addition to the quantity of tumor infiltrating T and B cells, may contribute to the prevention of early stage lung adenocarcinoma recurrence after surgical resection. Our study illustrates the potential value of the immune repertoire for predicting clinical efficacy and patient outcomes.

The regulatory role of APE1 in epithelial-to-mesenchymal transition and in determining EGFR-TKI responsiveness in non-small-cell lung cancer.

BACKGROUND: Epithelial-to-mesenchymal transition (EMT) plays a pivotal role in resistance to EGFR tyrosine kinase inhibitors (TKIs) in non-small-cell lung cancer (NSCLC). Our previous study revealed that in osteosarcoma, human apurinic/apyrimidinic endonuclease 1 (APE1) regulates transforming growth factor-ß (TGF-ß), an important player in EMT. We therefore hypothesized a link between APE1 and EGFR-TKI responsiveness in NSCLC. METHODS: The protein levels of APE1 were analyzed in tumors of NSCLC patients receiving EGFR-TKI treatment. The correlation between APE1 expression and progression-free survival (PFS), overall survival (OS), or response rate were analyzed. The impact of APE1 on the response to EGFR-TKIs was measured by exogenous manipulation of APE1 in EGFR-TKI-sensitive and EGFR-TKI-resistant cells. RESULTS: We indicate that low expression of APE1 in tumors is associated with a significantly longer PFS (20.8 months vs 8.4 months, P = 0.008) and a preferential OS (39.0 months vs 17.0 months, P = 0.001), with no difference in initial response rate to EGFR-TKIs. We observed that APE1 protein level was significantly increased in EGFR-TKI-resistant cells and was associated with downregulated E-cadherin and upregulated vimentin. The EMT phenotype, as well as the levels of TGF-ß, was suppressed in APE1 knockdown HCC827/IR and PC-9/ER cells, while the EMT phenotype was promoted in APE1-overexpressed HCC827 and PC-9 cells. Furthermore, a specific APE1 redox inhibitor (ie, E3330) effectively reversed the EMT phenotype and further sensitized the cells to EGFR-TKIs. CONCLUSION: This study revealed a significant role of APE1 in EGFR-TKI resistance via novel regulatory effects on the EMT phenotype in NSCLC.

APE1 deficiency promotes cellular senescence and premature aging features.

Base excision repair (BER) handles many forms of endogenous DNA damage, and apurinic/apyrimidinic endonuclease 1 (APE1) is central to this process. Deletion of both alleles of APE1 (a.k.a. Apex1) in mice leads to embryonic lethality, and deficiency in cells can promote cell death. Unlike most other BER proteins, APE1 expression is inversely correlated with cellular senescence in primary human fibroblasts. Depletion of APE1 via shRNA induced senescence in normal human BJ fibroblasts, a phenotype that was not seen in counterpart cells expressing telomerase. APE1 knock-down in primary fibroblasts resulted in global DNA damage accumulation, and the induction of p16INK4a and p21WAF1 stress response pathways; the DNA damage response, as assessed by γ-H2AX, was particularly pronounced at telomeres. Conditional knock-out of Apex1 in mice at post-natal day 7/12 resulted in impaired growth, reduced organ size, and increased cellular senescence. The effect of Apex1 deletion at post-natal week 6 was less obvious, other than cellular senescence, until ∼8-months of age, when premature aging characteristics, such as hair loss and impaired wound healing, were seen. Low APE1 expression in patient cancer tissue also correlated with increased senescence. Our results point to a key role for APE1 in regulating cellular senescence and aging features, with telomere status apparently affecting the outcome.

Serum APE1 autoantibodies: a novel potential tumor marker and predictor of chemotherapeutic efficacy in non-small cell lung cancer.

Apurinic/apyrimidinic endonuclease 1 (APE1), which has the dual functions of both DNA repair and redox activity, has been reported to be highly expressed in non-small cell lung cancer (NSCLC), and this appears to be a characteristic related to chemotherapy resistance. In this study, we identified serum APE1 autoantibodies (APE1-AAbs) in NSCLC patients and healthy controls by immunoblotting and investigated the expression of APE1-AAbs by indirect ELISA from the serum of 292 NSCLC patients and 300 healthy controls. In addition, serum APE1-AAbs level alterations of 91 patients were monitored before and after chemotherapy. Our results showed that serum APE1-AAbs can be detected in both NSCLC patients and healthy controls. Serum APE1-AAbs were significantly higher than those of healthy controls and closely related to APE1 antigen levels both in tumor tissues and the peripheral blood. Moreover, the change in levels of serum APE1-AAbs in NSCLC is closely associated with the response to chemotherapy. These results suggest that APE1-AAbs is a potential tumor marker and predictor of therapeutic efficacy in NSCLC.

[Evaluation of serum cytokines in small cell lung cancer and its clinical significance].

BACKGROUND AND OBJECTIVE: It has been proven that serum cytokines could be changed in the early stage of patients with small cell lung cancer (SCLC). The current research investigates the different changes of cytockines and searches for potential biomarkers to improve the situation of the early diagnosis of SCLC. METHODS: The differential expression cytokines were detected using Reybiotech G6/G7 analysis of microarrays in the serum of 4 SCLC patients, 4 normal controls, and 4 phlegmonosis controls. The differential cytokines were confirmed by enzyme-linked immunosorbentassay (ELISA) in 197 SCLC patients, 180 normal controls, and 97 phlegmonosis controls. RESULTS: The levels of the 4 most valuable biomarkers in SCLC, including Leptin, MSP-α, uPAR, and MIP-1ß, were significantly higher than that in the other groups with microaaray screening (P<0.05). The ELISA results showed that the uPAR are much higher in SCLC patients than that in the controls, in which the diagnostic sensitivity and specificity were 52.93% and 83.36%, respectively. The Leptin level was significantly higher in SCLC patients who do not have obvious body weight lost, whereas no difference were found in the SCLC who have obvious body weight lost compared with control groups. The diagnostic sensitivity and specificity of Leptin are 50.11% and 86.77%. The MSP-α and MIP-1ß level have no significant difference among the three groups. CONCLUSION: The uPAR elevated level is significant in indicating SCLC diagnoses. The Leptin may be associated with SCLC in patients who do not have a change in weight.

[meta-analysis of serum tumor markers in lung cancer].

BACKGROUND AND OBJECTIVE: the detection of serum tumor markers is of great value for early diagnosis of lung cancer. The aim of this study is to summarize the clinic significance characteristics of serum markers contributing to the detection of lung cancer. METHODS: references about serum markers of lung cancer were estimated using meta-analysis method. 712 references which included more than 20 cases, 20 controls, the serum markers of 52 832 patients with malignancies and 32 037 patients as controls were evaluated. RESULTS: overall the detection of 13 markers play a significant part in lung cancer diagnosis. The sensitivity of CEA, CA125, CYFRA21-1, TPA, SCCAg, DKK1, NSE, ProGRP in the patients' serum with lung cancer were 47.50%, 50.11%, 57.00%, 50.93%, 49.00%, 69.50%, 39.73%, 51.48% and the specificity were 92.34%, 80.19%, 90.16%, 88.41%, 91.07%, 92.20%, 89.11%, 94.89%. In the combined analysis of tumor markers: the sensitivity, specificity of NSE+ProGRP were 88.90% and 72.82% in diagnosis of small cell lung cancer, respectively. In diagnosis of squamous corcinoma, the sensitivity and specificity of TSGF+SCCAg+CYFRA21-1 were 95.30% and 74.20%. The the sensitivity and specificity of CA153+Ferrtin+CEA were 91.90% and 44.00% in diagnosis of lung cancer. CONCLUSIONS: although the assay of tumor markers in serum is useful for diagnosis of early lung cancer, the sensitivity and specificity are low. Combined detection of these tumor markers could increase sensitivity and specificity.