The prognostic analysis and a machine-learning based disease-specific survival state model in pulmonary large-cell neuroendocrine carcinomas.

Background: Pulmonary large-cell neuroendocrine carcinoma (PLCNEC) is a rare and highly malignant lung cancer. Due to the paucity of data from clinical studies, its clinical characteristics and treatment remain controversial. The present study explored factors influencing the prognosis and survival outcomes of patients with PLCNEC and developed a dependable prognostic model using machine learning. Methods: The clinical data of PLCNEC patients were extracted from the Surveillance, Epidemiology, and End Results (SEER) database between 2010 and 2020. A total of 2,897 PLCNEC patients were enrolled and univariate and multivariate Cox regression analyses were performed to explore independent prognostic factors for disease-specific survival (DSS). Ten machine learning algorithms were utilized to predict the 2-year survival. The clinicopathological data collected from The First Affiliated Hospital of Sun Yat-sen University between 2010 and 2022 were used to test the trained machine. Results: Sex [hazard ratio (HR) 1.168, 95% confidence interval (CI): 1.063-1.284], age (HR 1.262, 95% CI: 1.144-1.391), surgery (HR 0.481, 95% CI: 0.413-0.559), chemotherapy (HR 0.450, 95% CI: 0.404-0.501), bone metastasis (HR 1.284, 95% CI: 1.124-1.466), brain metastasis (HR 1.167, 95% CI: 1.023-1.331), liver metastasis (HR 1.223, 95% CI: 1.069-1.399), American Joint Committee on Cancer-Node (AJCC-N), and tumor stage were independent prognostic factors. The gradient boosting decision tree (GBDT) performed better than other models, with an F1-score of 0.791 and an area under the curve of 0.831. Conclusions: Male, age ≥65 years, distant metastasis to the bone, liver, and brain are associated with a worse prognosis in PLCNEC patients, while surgery and chemotherapy are associated with improved prognosis. GBDT showed promising performance in predicting 2-year survival, which can serve as a valuable reference for clinical diagnosis and treatment of PLCNEC.

Thrombomodulin as a potential diagnostic marker of acute myocardial infarction and correlation with immune infiltration: Comprehensive analysis based on multiple machine learning.

BACKGROUND: Acute myocardial infarction (AMI) is a global health problem with high mortality. Early diagnosis can prevent the development of AMI and provide valuable information for subsequent treatment. Angiogenesis has been shown to be a critical factor in the development of infarction and targeting this process may be a potential protective strategy for preventing myocardial injury and improving the prognosis of AMI patients. This study aimed to screen and verify diagnostic markers related to angiogenesis in AMI and to investigate the molecular mechanisms of action associated with AMI in terms of immune cell infiltration. METHODS: The GSE66360 and the GSE60993 datasets were both downloaded from the GEO database and were used as the training cohort and the external validation cohort, respectively. Angiogenesis-related genes (ARGs) were downloaded from the MSigDB database. The hub ARGs were identified via LASSO, RF, and SVM-RFE algorithms. ROC curves were used to assess the accuracy of the hub ARGs. The potential mechanisms of the hub ARGs were analyzed by GSEA. The ssGSEA algorithm was used to determine differences in immune cell infiltration and immune function. The CIBERSORT algorithm was used for immune cell infiltration analysis. In addition, we constructed a ceRNA network map of differentially expressed ARGs. RESULTS: We identified the thrombomodulin (THBD) gene from ARGs as a potential diagnostic marker for AMI based on the LASSO, SVM-RFE, and RF algorithms. THBD was differentially expressed and had a potential diagnostic value (area under the curve [AUC] = 0.931 and 0.765 in the training and testing datasets, respectively). GSEA showed that the MAPK signaling pathway was more enriched in the high-expression group of THBD (P < 0.05). Immune cell infiltration analysis demonstrated that THBD was mainly positively correlated with monocytes (R = 0.48, P = 0.00055) and neutrophils (R = 0.36, P = 0.013). Finally, in the ceRNA regulatory network, THBD was closely associated with 9 miRNAs and 42 lncRNAs involved in AMI. CONCLUSION: THBD can be used as a potential diagnostic marker for AMI. This study provides new insights for future AMI diagnosis and molecular mechanism research. Moreover, immune cell infiltration plays an essential role in the occurrence and development of AMI.

Enhancing Colonoscopy Preparation in Elderly Constipation Patients: A Personalized Approach with PEG and Exercise - A Case Study.

This study aimed to optimize bowel preparation efficacy for colonoscopy in elderly constipation patients. A 71-year-old patient with chronic constipation and a history of poor bowel preparation. To address these challenges, we implemented a personalized strategy combining of PEG administration and walking exercise. The PEG was administered according to a protocol, with intermittent exercise breaks of 10 minute. Bowel cleanliness was assessed using the Boston Bowel Preparation Scale (BBPS). Adverse reactions and tolerance were closely monitored throughout the intervention. The patient's BBPS score improved from 3 to 8 post-intervention. The exercise intervention was well-tolerated (rating I), and mild nausea was observed only after the first PEG dose. No severe adverse reactions occurred. Subsequent Follow-up revealed symptom relief. The personalized approach combining (PEG and exercise intervention) successfully improved bowel preparation quality in the elderly constipation patient undergoing colonoscopy. This approach considers age-related changes in gastrointestinal function and activity level, offering an effective strategy to improve patient tolerance and reduce adverse reactions during bowel preparation. The findings underscore the importance of tailoring interventions for elderly constipation patients to optimize the colonoscopy experience.

FHL2 promotes the aggressiveness of lung adenocarcinoma by inhibiting autophagy via activation of the PI3K/AKT/mTOR pathway.

BACKGROUND: Increasing evidence indicates that four and a half LIM domains 2 (FHL2) plays a crucial role in the progression of various cancers. However, the biological functions and molecular mechanism of FHL2 in lung adenocarcinoma (LUAD) remain unclear. METHODS: We evaluated the prognostic value of FHL2 in LUAD using public datasets and further confirmed its prognostic value with our clinical data. The biological functions of FHL2 in LUAD were evaluated by in vitro and in vivo experiments. Pathway analysis and rescue experiments were subsequently performed to explore the molecular mechanism by which FHL2 promoted the progression of LUAD. RESULTS: FHL2 was upregulated in LUAD tissues compared to adjacent normal lung tissues, and FHL2 overexpression was correlated with unfavorable outcomes in patients with LUAD. FHL2 knockdown significantly suppressed the proliferation, migration and invasion of LUAD cells, while FHL2 overexpression had the opposite effect. Mechanistically, FHL2 upregulated the PI3K/AKT/mTOR pathway and subsequently inhibited autophagy in LUAD cells. The effects FHL2 on the proliferation, migration and invasion of LUAD cells are dependent on the inhibition of autophagy, as of induction autophagy attenuated the aggressive phenotype induced by FHL2 overexpression. CONCLUSIONS: FHL2 promotes the progression of LUAD by activating the PI3K/AKT/mTOR pathway and subsequently inhibiting autophagy, which can be exploited as a potential therapeutic target for LUAD.

Relationship between hemoglobin and lung cancer: evidence from Mendelian randomization and National Health and Nutrition Examination Survey.

BACKGROUND: Lung cancer is the primary cause of cancer-related mortality worldwide. Hemoglobin (Hb) represents the most widely utilized test parameter in clinical settings. However, few articles have examined the causal relationship between Hb concentration and lung cancer incidence. METHODS: Mendelian randomization (MR) was first conducted to investigate the potential causality between Hb and lung cancer. Sensitivity analyses were applied to validate the reliability of MR results. Then, the National Health and Nutrition Examination Survey (NHANES) database was used to verify the effect of Hb on the prognosis of lung cancer. RESULTS: The MR analysis demonstrated that Hb was casually associated with the decreased risk of lung cancer in the European population (ORIVW 0.84, 95% CI 0.75-0.95, p = 0.006; ORWeighted-median 0.78, 95% CI 0.65-0.94, p = 0.008; ORMR-Egger 0.82, 95% CI 0.64-1.04, p = 0.11). The results from the NHANES database showed that a high value of Hb was associated with better outcomes for patients with lung cancer (HR 0.45, 95% CI 0.26-0.79, p = 1.6E-03). CONCLUSIONS: Our study provides further evidence for the relationship between Hb levels and lung cancer, highlighting the potential significance of Hb as a biomarker for predicting the risk and prognosis of lung cancer.

N, N'-methylene bisacrylamide/divinyl benzene based-highly cross-linked hybrid monolithic column: Production and its applications for powerful capture of four chlorophenols.

In this paper, the role of the halogen bond in capillary monolithic column microextraction was explored for the first time. Benzene-1,3,5-tricarbohydrazide (BTH) was synthesized as a functional monomer, N, N'-methylene bisacrylamide (MBA) and divinyl benzene (DVB) were used as cross-linking agents, the hybrid monolithic column of poly (BTH-co-DVB-co-MBA) was prepared using methanol and polyethylene glycol as pore-forming agents and azodiisobutyronitrile as the initiator. Due to the existence of BTH, a large number of nitrogen atoms (Lewis base) were introduced into the monolithic column, which could form a halogen bond with chlorine-containing organic pollutants and enhance its adsorption performance. Based on the monolithic column, a sensitive and environment-friendly solid-phase microextraction technology was studied. The monolithic column was integrated with high-performance liquid chromatography (HPLC) to extract and detect four kinds of chlorophenol in real water samples. Under best conditions, the method showed excellent extraction ability and linearity, with a linear correlation coefficient of 0.9958-0.9987, a low detection limit (LOD) of 0.04-0.23 µg L-1 (S/N = 3), and relative standard deviation (RSD) less than 3.09%. The recovery rate was kept between 87.30% and 123.00%, and the RSD was less than 3.83%, which indicated that the column had powerful capture performance, high precision, and strong anti-matrix interference ability in the real sample, and had potential application value in practical work.

Different Roles of the Insulin-like Growth Factor (IGF) Axis in Non-small Cell Lung Cancer.

Non-small cell lung cancer (NSCLC) remains one of the deadliest malignant diseases, with high incidence and mortality worldwide. The insulin-like growth factor (IGF) axis, consisting of IGF-1, IGF-2, related receptors (IGF-1R, -2R), and high-affinity binding proteins (IGFBP 1-6), is associated with promoting fetal development, tissue growth, and metabolism. Emerging studies have also identified the role of the IGF axis in NSCLC, including cancer growth, invasion, and metastasis. Upregulation of IGE-1 and IGF-2, overexpression of IGF-1R, and dysregulation of downstream signaling molecules involved in the PI-3K/Akt and MAPK pathways jointly increase the risk of cancer growth and migration in NSCLC. At the genetic level, some noncoding RNAs could influence the proliferation and differentiation of tumor cells through the IGF signaling pathway. The resistance to some promising drugs might be partially attributed to the IGF axis. Therapeutic strategies targeting the IGF axis have been evaluated, and some have shown promising efficacy. In this review, we summarize the biological roles of the IGF axis in NSCLC, including the expression and prognostic significance of the related components, noncoding RNA regulation, involvement in drug resistance, and therapeutic application. This review offers a comprehensive understanding of NSCLC and provides insightful ideas for future research.

Comparison of Affected-Vertebra Fixation of Cortical Bone Trajectory Screw and Pedicle Screw for Lumbar Tuberculosis: A Minimum 3-Year Follow-Up.

Purpose: This study is aimed at comparing the clinical efficacy of cortical bone trajectory (CBT) screw fixation and pedicle screw (PS) fixation of the affected vertebrae in lumbar tuberculosis. Methods: We retrospectively analyzed the outcomes in 52 patients (27 cases in the CBT group, 25 cases in the PS group) with lumbar TB who underwent posterior affected-vertebra fixation combined with anterior debridement and bone grafting. The intraoperative blood loss, operative time, visual analog scale (VAS) scores for incision pain and leg pain, Japanese Orthopedic Association (JOA) score, bone grafting fusion, and complications were recorded. Results: All patients were followed up for 35-52 months and achieved good clinical outcomes. There were no differences between the two groups in the operative time, intraoperative blood loss, JOA score, bone grafting fusion, and complications. However, there was a significant difference between the two groups in VAS scores for incision pain on the 1st day and 3rd day after surgery. At the last follow-up, JOA scores were significantly improved in both groups compared to the preoperation. Conclusion: This retrospective study confirmed that both the affected-vertebra CBT screw fixation and PS fixation for lumbar TB via posterior and anterior approaches could achieve satisfactory outcomes, while the former resulted in better improvement for postoperative VAS scores.

Chemical peeling with 35% glycolic acid for the treatment of disseminated facial verruca plana: A randomized, split-face, evaluator-blinded trial.

Disseminated facial verruca plana is a chronic disorder that causes significant psychological distress. However, safe and effective treatment is lacking. This study aimed to explore the efficacy and safety of 35% glycolic acid (GA) for the treatment of disseminated facial verruca plana. A split-face clinical trial was conducted to explore the efficacy and safety of using chemical peeling with 35% GA for the treatment of disseminated facial verruca plana. One side of the face was applied with 35% GA once every fortnight for a total of three times. Adapalene gel was applied every night to the other side of the face as the control. The clearance rate of lesions was evaluated at different time points. Between June 2020 and December 2020, 30 patients with disseminated verruca plana who visited the Dermatology Hospital of Southern Medical University were enrolled. After three chemical peelings with 35% GA that was applied at 2-week intervals, 15 (50%) patients achieved >70% lesion reduction. The same effective rate in the adapalene gel-treated side of the face was documented in eight patients. Subgroup analysis showed a higher clearance rate in patients with a shorter disease duration. Moreover, concurrent improvements in facial roughness were observed in the 35% GA-treated group. Adverse effects including mild erythema and desquamation were observed during chemical peeling with 35% GA. In conclusion, chemical peeling with 35% GA could be a safe and effective option for treating disseminated facial verruca plana, especially for those who desire skin improvement.

PTEN loss correlates with T cell exclusion across human cancers.

BACKGROUND: Recent evidences had shown that loss in phosphatase and tensin homolog deleted on chromosome 10 (PTEN) was associated with immunotherapy resistance, which may be attributed to the non-T-cell-inflamed tumor microenvironment. The impact of PTEN loss on tumor microenvironment, especially regarding T cell infiltration across tumor types is not well understood. METHODS: Utilizing The Cancer Genome Atlas (TCGA) and publicly available dataset of immunotherapy, we explored the correlation of PTEN expressing level or genomic loss with tumor immune microenvironment and response to immunotherapy. We further investigated the involvement of PI3K-AKT-mTOR pathway activation, which is known to be the subsequent effect of PTEN loss, in the immune microenvironment modulation. RESULTS: We reveal that PTEN mRNA expression is significantly positively correlated with CD4/CD8A gene expression and T cells infiltration especially T helpers cells, central memory T cell and effector memory T cells in multiples tumor types. Genomic loss of PTEN is associated with reduced CD8+ T cells, type 1 T helper cells, and increased type 2 T helper cells, immunosuppressed genes (e.g. VEGFA) expression. Furthermore, T cell exclusive phenotype is also observed in tumor with PI3K pathway activation or genomic gain in PIK3CA or PIK3CB. PTEN loss and PI3K pathway activation correlate with immunosuppressive microenvironment, especially in terms of T cell exclusion. PTEN loss predict poor therapeutic response and worse survival outcome in patients receiving immunotherapy. CONCLUSION: These data brings insight into the role of PTEN loss in T cell exclusion and immunotherapy resistance, and inspires further research on immune modulating strategy to augment immunotherapy.

Pan-cancer analysis of genomic properties and clinical outcome associated with tumor tertiary lymphoid structure.

How the genomic landscape of a tumor shapes the formation of tertiary lymphoid structure (TLS) and how might TLS alter the clinical outcome or response to immunotherapy had not been systematically explored. Utilizing the genomic and transcriptome data of solid tumors on TCGA, we quantified TLS based on a previous identified 12-chemokine signature and evaluated its correlation with mutation/neoantigen burden, functional mutation of oncogenes and the presence of viral infection. Clinical data was integrated to decide the prognostic significance of TLS for different cancers after surgical treatment. Publicly available data (clinical and transcriptome data) of immunotherapy clinical trials involving melanoma and lung cancer were also collected to evaluate TLS's association with therapeutic outcome. Mutation burden and predicted neoantigen counts were positively correlated with TLS scoring in multiple cancer types. Mutation in tumor suppressor genes (KEAP1, PBRM1) and genes involved in extrinsic apoptosis (CASP8), antigen-presentation (HLA-A, HLA-B), immune regulation (SMAD4) or DNA repair (BRCA1, BRCA2, TP53BP1) correlated with TLS alteration in multiple tumor types, indicating the interaction between mutation landscape and TLS formation. Epstein-Barr virus (EBV) infection in gastric cancer and human papillomavirus (HPV) infection in Head and Neck squamous cell carcinoma were associated with increased TLS scoring. High TLS scoring predicted favorable prognosis in certain cancer after surgical treatment and improved response to immunotherapy in lung cancer and melanoma. Our findings unraveled the genomic properties associated with TLS formation in different solid tumors and highlighted the prognostic and predictive significance of TLS in surgical treatment and immunotherapy.

Nanotechnology Promotes Genetic and Functional Modifications of Therapeutic T Cells Against Cancer.

Growing experience with engineered chimeric antigen receptor (CAR)-T cells has revealed some of the challenges associated with developing patient-specific therapy. The promising clinical results obtained with CAR-T therapy nevertheless demonstrate the urgency of advancements to promote and expand its uses. There is indeed a need to devise novel methods to generate potent CARs, and to confer them and track their anti-tumor efficacy in CAR-T therapy. A potentially effective approach to improve the efficacy of CAR-T cell therapy would be to exploit the benefits of nanotechnology. This report highlights the current limitations of CAR-T immunotherapy and pinpoints potential opportunities and tremendous advantages of using nanotechnology to 1) introduce CAR transgene cassettes into primary T cells, 2) stimulate T cell expansion and persistence, 3) improve T cell trafficking, 4) stimulate the intrinsic T cell activity, 5) reprogram the immunosuppressive cellular and vascular microenvironments, and 6) monitor the therapeutic efficacy of CAR-T cell therapy. Therefore, genetic and functional modifications promoted by nanotechnology enable the generation of robust CAR-T cell therapy and offer precision treatments against cancer.

Evaluation of p16/Ki-67 Dual-Stained Cytology in Triaging HPV-Positive Women during Cervical Cancer Screening.

BACKGROUND: We aimed to evaluate the utility of p16/Ki-67 dual-stained cytology for triaging human papillomavirus (HPV)-positive women. METHODS: HPV-positive women ages ≥ 21 years were recruited in a multicenter prospective observational study between May 2016 and May 2017. The clinical performance of dual-stained cytology, with or without HPV16/18 genotyping, was evaluated for all HPV-positive women to detect cervical intraepithelial neoplasia grade 2 or worse (CIN2+). RESULTS: 846 HPV-positive women ages ≥ 21 years with valid cervical biopsies were enrolled for this study. For CIN2+ detection, dual-stained cytology showed statistically higher specificity (85.28%) than Pap cytology (80.00%, P < 0.001) and HPV16/18 genotyping (72.36%, P < 0.001), while the sensitivity of dual-stained cytology (63.49%) remained comparable with that of Pap cytology (61.90%, P = 0.832) and HPV16/18 genotyping (61.90%, P = 0.897). HPV16/18 genotyping in combination with dual-stained cytology was more specific (62.50% vs. 58.06%, P < 0.001), while it showed similar sensitivity (86.51% vs. 85.71%, P = 1.000), as compared with HPV16/18 genotyping in combination with Pap cytology. Similar patterns were also observed for CIN3+. CONCLUSIONS: p16/Ki-67 dual-stained cytology, either alone or in combination with HPV16/18 genotyping, showed a good stratification with high specificity and comparable sensitivity for HPV-positive women. IMPACT: This is one of the few studies that has evaluated the performance of dual-stained cytology for triaging HPV-positive women in China. The higher specificity and comparable sensitivity of dual-stained cytology in comparison with Pap cytology in the detection of CIN2+ or CIN3+ is of vital importance to developing countries, where Pap cytology faces many challenges.

Functional interaction between plasma phospholipid fatty acids and insulin resistance in leucocyte telomere length maintenance.

BACKGROUND: Previous evidence suggests that plasma phospholipid fatty acids (PPFAs) and HOMA insulin resistance (HOMA-IR) are independently related to leukocyte telomere length (LTL). However, there is limited evidence of regarding the effect of their interaction on relative LTL (RLTL). Therefore, here, we aimed to determine the effect of the interaction between PPFAs and HOMA-IR on RLTL. METHODS: We conducted a cross-sectional study, involving a total of 1246 subjects aged 25-74 years. PPFAs and RLTL were measured, and HOMA-IR was calculated. The effect of the interaction between PPFAs and HOMA-IR on RLTL was assessed by univariate analysis, adjusting for potential confounders. RESULTS: In age-adjusted analyses, multivariate linear regression revealed a significant association of the levels of elaidic acid, HOMA-IR, monounsaturated fatty acids (MUFA) and omega-6 (n-6) polyunsaturated fatty acid (PUFA) with RLTL. After adjustment of age and gender, race, smoking, drinking, tea, and exercise, elaidic acid, and omega-3 (n-3) PUFA were negatively associated with RLTL, and HOMA-IR and n-6 PUFA were positively associated with RLTL. These associations were not significantly altered upon further adjustment for anthropometric and biochemical indicators. Meanwhile, the effect of the interaction of elaidic acid and HOMA-IR on RLTL was significant, and remained unchanged even after adjusting for the aforementioned potential confounders. Interestingly, individuals who had the lowest HOMA-IR and the highest elaidic acid levels presented the shortest RLTL. CONCLUSIONS: Our findings indicated that shorter RLTL was associated with lower HOMA-IR and higher elaidic acid level. These findings might open a new avenue for exploring the potential role of the interaction between elaidic acid and HOMA-IR in maintaining RLTL.

Uniportal video-assisted thoracoscopic surgery for lung neoplasms with tracheal bronchus: a case report.

A 63-year-old woman came to our department complaint that an abnormal shadow was identified by chest computed tomography (CT). CT revealed a 21 mm × 18 mm solid nodule in the right upper lobe of lung, which was suspected to be lung cancer. We also found a bronchus directly arising from the trachea and running into the right upper lobe, which appeared to be tracheal bronchus (TB). Then she underwent the right upper lobectomy and mediastinal lymph node dissection using uniportal video-assisted thoracic surgery. During the surgery we found two bronchi which were posterior to the pulmonary hilum running into the right upper lobe. And one of them directly branched from the trachea and was thus confirmed to be TB. TB, which may be related to repeated lung infections, is a rare anomaly. The patient underwent surgery and the pathological diagnosis was lung invasive adenocarcinoma, pT1cN0M0 (stage IA3). Then the patient is being followed up outpatient. By doing chest CT before surgery, uniportal video-assisted thoracoscopic surgery (VATS) is safe for lung neoplasms with TB. To our knowledge, this is the first case report of uniportal VATS right upper lobectomy for lung neoplasms with TB.

Retrospective study on the efficacy of bisphosphonates in tyrosine kinase inhibitor-treated patients with non-small cell lung cancer exhibiting bone metastasis.

Bisphosphonates (Bps) inhibit the maturation of osteoclasts and suppress the adhesion of cancer cells to the bone matrix. They are recommended as the standard treatment for tumors exhibiting bone metastasis (BM). However, whether Bps can improve the prognosis of patients with tyrosine kinase inhibitor (TKI)-treated non-small cell lung cancer (NSCLC) exhibiting BM remains unclear. A total of 129 patients with NSCLC initially diagnosed with BM at The First Affiliated Hospital of Sun Yat-Sen University (Guangzhou, China) between January 2005 and December 2017 were analyzed in the present retrospective study. Median progression free survival (mPFS) time, median bone metastasis overall survival (mBM-OS) time and bone-associated progression-free survival were analyzed. Among the 129 patients, patients treated with Bps experienced significantly prolonged PFS time [mPFS: 7.1 vs. 5.1 months; hazard ratio (HR), 0.51; confidence interval (CI), 0.30-0.87; P=0.0114] in comparison with patients not treated with Bps. Of the 49 patients treated with frontline TKIs (EGFR TKIs or ALK TKI), 32 received Bps at the same time, while 17 patients received TKIs alone. The results revealed that mPFS time was significantly greater in the TKIs plus Bps group than in the TKIs alone group (mPFS: 11.2 vs. 6.9 months; HR, 0.13; CI, 0.05-0.35; P<0.0001). Significantly prolonged BM-OS time was also observed in the combination group in comparison with the TKIs alone group (mBM-OS: 31 vs. 22 months; HR, 0.31; CI, 0.10-0.96; P=0.0413). The present study demonstrated that among the patients who received TKIs (EGFR TKIs or ALK TKIs), those who also received Bps experienced significantly longer PFS time and tended to exhibit significantly improved BM-OS time, which indicated that Bps should be added to the treatment regimen of patients with NSCLC exhibiting genetic mutations and bone metastasis who have been prescribed TKIs (EGFR TKIs or ALK TKIs).

Deciphering Microenvironment of NSCLC based on CD8+ TIL Density and PD-1/PD-L1 Expression.

Purpose: To determine whether distinct tissue immune microenvironments differentially impact on clinical outcome in non-small cell lung cancer (NSCLC), an extended analysis of PD-1/PD-L1 and Tumor Infiltrating Lymphocytes (TILs) was performed. Materials and Methods: 1016 NSCLC mRNA-sequence samples from The Genome Data Analysis Center (TCGA) and 275 NSCLC mRNA-microarray samples from Gene Expression Omnibus (GEO) were included as testing cohort and validation cohort respectively. Enrichment scores of CD8+ T cells' metagene were used for quantifying its infiltrating density. Based on the median values of CD8+ T cell density and PD-1/PD-L1 mRNA expression, the samples were classified into four Tumor Immune Microenvironment types (TIMTs). Overall survival, as well as clinicopathological features, mutational profiles, mismatch repair score etc. were compared across the four types. Results: Neither PD-1 expression nor PD-L1 expression was associated with outcome in the overall NSCLC. Classification of TIMT based on PD-1/PD-L1 and CD8+ TIL could efficiently classify patients of different survival in ADC but not SCC, with the best overall survival achieved in TIMT3 (high CD8+ TIL and low PD-1/PD-L1), whereas TIMT2 (low CD8+ TIL and high PD-1/PD-L1) manifested the worst outcome. TIMT classification based on PD-1/ CD8+ TIL could better stratify patient of different prognosis than PD-L1/ CD8+ TIL based classification. EGFR wide type and IFNγ overexpression were associated with TIMT4 (high PD-1/PD-L1 and high CD8+ TIL), whereas tumor mutational burden (TMB) manifested no significant difference across four TIMTs. Conclusion: The classification of tumors into four microenvironment subtypes based on PD-1/PD-L1 status and CD8+ TIL is an appropriate approach to stratify patients of different clinical outcome and better guide the practical use of immunotherapy.

Supramolecular hydrogels based on poly (ethylene glycol)-poly (lactic acid) block copolymer micelles and α-cyclodextrin for potential injectable drug delivery system.

A supramolecular hydrogel system was prepared by the host-guest interaction between the α-cyclodextrin (α-CD) and poly (ethylene glycol) (PEG) chains of the poly (ethylene glycol)-block-poly (lactic acid) (PEG-b-PLA) micelles. The formation of inclusion complex (IC) crystals between α-CD and the PEG chains of the micelles was verified by different techniques. Rheological studies indicated that the gelation kinetics and the mechanical strength of the hydrogels could be modulated by the α-CD concentration. Also, the shear-thinning and self-healing properties of the hydrogels were confirmed. Doxorubicin (DOX) could be encapsulated into the hydrogels via the micelles and be released from the hydrogels sustainably, with the release rate dependent on the α-CD concentration. The released DOX showed higher inhibition efficacy against HeLa cells compared with the free drug. These attractive features, together with the superior biocompatibility, make the present hydrogels an potential injectable drug delivery system for tumour treatment.

Value of combining serum carcinoembryonic antigen and PET/CT in predicting EGFR mutation in non-small cell lung cancer.

BACKGROUND: We sought to investigate the associations between pretreatment serum Carcinoembryonic antigen (CEA) level, 18F-Fluoro-2-deoxyglucose (18F-FDG) uptake value of primary tumor and epidermal growth factor receptor (EGFR) mutation status in non-small cell lung cancer (NSCLC). METHODS: We retrospectively reviewed medical records of 210 NSCLC patients who underwent EGFR mutation test and 18F-FDG positron emission tomography/computed tomography (PET/CT) scan before anti-tumor therapy. The associations between EGFR mutations and patients' characteristics, serum CEA, PET/CT imaging characteristics maximal standard uptake value (SUVmax) of the primary tumor were analyzed. Receiver-operating characteristic (ROC) curve was used to assess the predictive value of these factors. RESULTS: EGFR mutations were found in 70 patients (33.3%). EGFR mutations were more common in high CEA group (CEA ≥7.0 ng/mL) than in low CEA group (CEA <7.0 ng/mL) (40.4% vs. 27.6%; P=0.05). Females (P<0.001), non-smokers (P<0.001), patients with adenocarcinoma (P<0.001) and SUVmax <9.0 (P=0.001) were more likely to be EGFR mutation-positive. Multivariate analysis revealed that gender, tumor histology, pretreatment serum CEA level, and SUVmax were the most significant predictors for EGFR mutations. The ROC curve revealed that combining these four factors yielded a higher calculated AUC (0.80). CONCLUSIONS: Gender, histology, pretreatment serum CEA level and SUVmax are significant predictors for EGFR mutations in NSCLC. Combining these factors in predicting EGFR mutations has a moderate diagnostic accuracy, and is helpful in guiding anti-tumor treatment.

Restoration of KLF4 Inhibits Invasion and Metastases of Lung Adenocarcinoma through Suppressing MMP2.

BACKGROUND: KLF4 is a zin-finger transcription factor that plays roles in differentiation, development, and proliferation. Recent studies show that KLF4 is involved in tumorigenesis and somatic cells reprogramming. Metastasis is the primary cause of death in patients with lung cancer, and its biological mechanisms are poorly understood. GOALS: In this study, we aim to explore the expression pattern and biological function of KLF4 in lung adenocarcinoma. METHODS: We determined KLF4 in lung adenocarcinoma tissue and cell lines, using immunohistochemistry and western blotting. And we further analyzed the correlation between KLF4 expression and clinicopathologic parameters. We restored KLF4 expression and studied its effect on lung adenocarcinoma cells in vivo and in vitro. Luciferase assay was used to study impact of KLF4 on activity of MMP2 promoter. RESULTS: KLF4 is dramatically down-regulated in lung adenocarcinoma tissue and cell lines. Promoter methylation contributes to the down-regulation of KLF4. Down-regulation of KLF4 in lung adenocarcinoma tissue is significantly associated with reduced survival time. Restoration of KLF4 inhibits migration and invasion of lung adenocarcinoma cells in vitro. Metastases to lungs significantly decrease in mice intravenously injected with tumor cells overexpressing KLF4. KLF4 inhibits invasion and metastasis via suppressing MMP2 promoter activity. CONCLUSION: The ability of KLF4 to inhibit migration, invasion, and metastasis of lung tumor cells indicates a potential role of KLF4 as therapeutic target in lung adenocarcinoma. KLF4 might be utilized as a favorable biomarker for prognosis of lung adenocarcinoma patients.