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Lung adenocarcinoma (LUAD) is a heterogeneous disease. Our study aimed to understand the unique molecular features of preinvasive to invasive LUAD subtypes. We retrospectively analyzed the clinical, histopathological, and molecular data of 3,254 Chinese patients with preinvasive lesions (n = 252), minimally invasive adenocarcinomas (n = 479), and invasive LUAD (n = 2,523). Molecular data were elucidated using a targeted 68-gene next-generation sequencing panel. Our findings revealed four preinvasive lesion-predominant gene mutations, including MAP2K1 insertion-deletions (indels), BRAF non-V600E kinase mutations, and exon 20 insertions (20ins) in both EGFR and ERBB2, which we referred to as mutations enriched in AIS (MEA). The detection rate of MEA in invasive tumors was relatively lower. MAP2K1 missense mutations, which were likely passenger mutations, co-occurred with oncogenic driver mutations, while small indels were mutually exclusive from other genes regardless of the invasion level. BRAF non-V600E kinase-mutant invasive adenocarcinomas (IAC) had significantly higher mutation rates in tumor suppressor genes but lower frequency of co-occurring oncogenic driver mutations than non-kinase-mutant IAC, suggesting the potential oncogenic activity of BRAF non-V600E kinase mutations albeit weaker than BRAF V600E. Moreover, similar to the extremely low frequency of MAP2K1 indels in IAC, BRAF non-V600E kinase domain mutations co-occurring with TSC1 mutations were exclusively found in preinvasive lesions. Compared with EGFR L858R and exon 19 deletion, patients with preinvasive lesions harboring 20ins in either EGFR or ERBB2 were significantly younger, while those with IAC had similar age. Furthermore, our study demonstrated distinct mutational features for subtypes of oncogene mutations favored by different invasion patterns in adenocarcinomas. In conclusion, our data demonstrate distinct mutational features between preinvasive lesions and invasive tumors with MEA, suggesting the involvement of MEA in the early stages of tumorigenesis. Further pre-clinical studies are required to establish the role of these genes in the malignant transformation of LUAD.

The aim of this study was to determine the optional extent of lymph node dissection of the squamous cell carcinoma (SCC) at the esophagogastric junction (EGJ) based on the incidence of metastasis in a retrospective single-center study. Patients with SCC involving and within 5 cm of the esophagogastric junction (EGJ) who underwent McKeown esophagectomy without preoperative treatment were reviewed in a prospectively maintained database at a single institution from 2015 to 2021. Lymph nodes stations was based on the definitions from the Japan Esophageal Society, and lymph nodes were further classified according to the metastatic incidence rate, as follows: Category-1 (strongly recommended for dissection), rate of more than 10%; Category-2 (weakly recommended for dissection), rate of from 5% to 10%; and Category-3 (not recommended for dissection), rate of less than 5%. Sixty-one patients were identified. T stage was pT1 (n = 9), pT2 (n = 11), pT3 (n = 40), and pT4 (n = 1). For all patients, category-1 nodes were predominantly abdominal stations (1, 2, 3, 7) and lower mediastinal stations (110); category-2 nodes were upper-middle mediastinal stations (105,106recR,107,108); station 106recL was category-3 with a metastasis rate of 4.92%. More nodal metastases were observed in cases with upper-margin exceeding EGJ >3 cm, and station 106recL was upgraded to category-2. For pT1 SCC, category-1 was focused on station 111, with no nodal metastasis in upper-middle mediastinal. For pT2 and pT3 SCC, cervical, thoracic, and abdominal lymph node metastases were found. Radical total mediastinal lymph node dissection is as important as abdominal dissection for SCC at EGJ, but lymph node dissection around the left recurrent laryngeal nerve appears to be exempt in T1 patients.

Background：Lymph node metastasis of lung cancer plays an important part in lung cancer diagnosis since its close relationship with patients’ prognosis and subsequent treatment, however, diagnosis of lymph node metastases often was tedious and takes too much time for pathologists. Automatized classification with few-shot learning algorithms is required for clinical situations that only unbalanced and small datasets can be collected. We developed a few-shot learning algorithms for automatized classification of lymphatic metastasis of lung carcinoma from Whole Slide Images (WSIs) through a deep convolutional neural network (DCNN).Material and methods: Lymph node slides of patients with lung cancer collected from July to December 2018 were reviewed and used for model development retrospectively. A total of 1701 lymph node slides from 453 lung cancer patients with different histological types were enrolled. Each slide could provide a different number of patches, in which 6, 8, 10, 20, and 30 positive patches and 12, 16, 20, 40, and 60 negative patches for training and validation, respectively. A total of 1577 WSIs were used. The receiver operating characteristic (ROC) analysis of the model was performed for estimating the performance and compared to the traditional deep learning approach Resnet34.Results: Deep learning methods, when trained with very few shots (6 positive/12 negative, 8 positive/16 negative, and 10 positive/20 negative patches), the traditional deep learning approach Resnet34 was outperformed by our Aitrox model. When the dataset was raised to 20 positive/40 negative patches, similar performance was achieved with AUC 0.5895 (95% CI, 0.5833-0.5910) for Resnet34 and 0.6124 (95% CI, 0.6077-0.6147) for our Aitrox model. Resnet34 over-performed our Aitrox model (AUC=0.6450 [95%CI, 0.6397-0.6470]) with an AUC of 0.7481 (95%CI, 0.7120-0.7485) when the training and validation dataset was raised to 30 positive/60 negative patches.Conclusions: This proposed few-shot method may address AI approaches to the diagnosis of lymphatic metastasis of lung carcinoma and other kinds of carcinoma in the future.

Rationale: Postmenopausal atherosclerosis (AS) has for decades been attributed to estrogen deficiency. Although the follicular stimulating hormone (FSH) levels rise sharply in parallel, the direct effect of FSH on AS has never been investigated. In this study, we explored the possible role of FSH in the development of AS. Methods: This was a prospective cohort study of 48 healthy premenopausal and 15 postmenopausal women. ApoE knockout mice were used as atherosclerosis model and human umbilical vascular endothelial cells (HUVECs) were cultured as cell model. Serum hormones and vascular cell adhesion molecule-1 (VCAM-1) levels were measured. Real-time PCR, histology for atherosclerotic lesions, immunofluorescence, luciferase assay, transfection experiments, flow chamber adhesion assay and western blot were performed. Results: In ApoE knockout mice, administration of FSH increased the atherosclerotic lesions and serum VCAM-1 concentration. Importantly, in blood samples of postmenopausal women, we detected significantly higher levels of FSH and VCAM-1 compared with those from premenopausal women, and there was a positive correlation between these two molecules. In cultured HUVECs, FSH receptor (FSHR) mRNA and protein expression were detected and FSH enhanced VCAM-1 expression. This effect was mediated by the activation of nuclear factor κB (NF-κB), which was sequentially enhanced by the activation of PI3K/Akt/mTOR cascade. FSH first enhanced GαS activity resulting in elevated cAMP level and PKA activity, which relayed the signals from FSHR to the PI3K/Akt/mTOR cascade. Furthermore, FSHR was detected in endothelial caveolae fraction and interacted with caveolin-1 and GαS. The disruption of caveolae or the silencing of caveolin-1 blocked FSH effects on signaling activation and VCAM-1 expression, suggesting the existence of a functional signaling module in membrane caveolae. Finally, FSH increased human monocyte adhesion to HUVECs which was reversed by the VCAM-1 neutralizing antibody. Conclusion: FSHR was located in the membrane caveolae of HUVECs and FSH promoted VCAM-1 expression via FSHR/GαS /cAMP/PKA and PI3K/Akt/mTOR/NF-κB pathway. This may contribute to the deleterious role of FSH in the development of AS in postmenopausal women.

9051 Background: Lung adenocarcinoma (LUAD) is further classified into several histological subtypes with adenocarcinoma in situ (AIS), minimally invasive adenocarcinoma (MIA), and invasive adenocarcinoma (IAC) as the three major subtypes according to the extent of invasion. AIS has been considered as a precursor of IAC. Considering the significantly higher mutation burden among IAC tumors than AIS tumors, it seems likely that AIS tumors undergo a process of accumulating various somatic mutations to gain invasive ability. To understand the gene mutations involved in this transformation, we compared the mutational features of AIS and IAC tumors. Methods: This retrospective study included 2,769 Chinese patients diagnosed with stage 0-IIIA LUAD. Targeted sequencing was performed on tissue DNA isolated from 246 AIS tumors and 2,523 IAC tumors using 68 lung cancer-related genes (Lung Core, Burning Rock Biotech). Results: Analysis of mutation profiles revealed that mutation count was significantly lower for AIS ( P< 0.01) as compared to IAC tumors. Moreover, AIS tumors had significantly higher mutation detection rates for ERBB2 exon 20 insertion (20ins) ( P≤0.05), EGFR 20ins ( P≤0.05), non-V600E BRAF mutations ( P≤0.05), and MAP2K1 small insertion-deletion variants ( P≤0.05). These 4 gene mutations were grouped and referred to as AIS-like mutations for further analysis. Detection rates of AIS-like mutations were 54.9% for AIS tumors and 7.8% for IAC tumors. Patients with AIS-like mutation-positive AIS tumors were significantly younger than those with AIS tumors without AIS-like mutations ( P =0.018), while age were similar for IAC tumors with or without AIS-like mutations. Mutation count was similar between AIS tumors with or without AIS-like mutations. Interestingly, IAC tumors harboring AIS-like mutations had a significantly higher mutation count than those harboring known oncogenic drivers ( P= 0.045). Further investigation of the molecular profiles of IAC tumors harboring AIS-like mutations (n = 198) revealed the presence of various concurrent mutations in 8 genes including TP53 (39.4%), EGFR (non-20ins) (16.7%), RB1 (7.1%), PIK3CA (6.6%), MET (5.1%), ROS1 (4.0%), FLT3 (4.0%), and PTEN (3.5%), which were absent among AIS tumors, particularly those that harbor AIS-like mutations. In addition to TP53 (35.8%), PIK3CA (4.5%), and RB1 (4.0%), IAC tumors without AIS-like mutations (n = 2,324) had additional concurrent mutations in 2 other genes CDK4 (5.7%) and STK11 (3.9%) as compared to AIS tumors. Conclusions: Our data suggest that AIS-like mutations could be involved in the early stages of tumorigenesis by initiating the accumulation of other gene mutations that are required for the transformation of AIS tumors into IAC tumors. Our study contributes to a deeper understanding of the distinct gene mutations between AIS and IAC tumors among Chinese LUAD patients.

Context: Endothelial microRNA 126 (miR-126) attenuates the development of atherosclerosis (AS). However, there is no evidence showing the role of miR-126 in estrogen’s antiatherogenic effects. Objective: We hypothesized that 17β-estradiol (E2) modulates miR-126 expression and thus may improve endothelial function and retard AS development. Design/Setting/Participants: This was a prospective cohort study of 12 healthy regularly menstruating female volunteers. ApoE−/− mice were used as the atherosclerosis model and human umbilical vascular endothelial cells (HUVECs) were cultured as the cell model. Main Outcome Measures: Serum hormones and miR-126-3p levels were measured up to 3 times for 1 cycle. Real-time polymerase chain reaction, histology for atherosclerotic lesions, immunofluorescence, luciferase assay, transfection experiments, cell proliferation, migration and tube formation assay, and western blot were performed. Results: Serum concentrations of miR-126-3p in cycling women were higher at the ovulatory and luteal phases than in the follicular phase, and they were positively correlated with E2 values. Administration of miR-126-3p mimics to ApoE−/− mice-attenuated atherogenesis, and antagomir-126-3p partially reversed the protective effect of E2 on atherogenesis. In HUVECs, E2 increased miR-126-3p expression via upregulation of Ets-1 (a transcription factor for miR-126). c-Src/Akt signaling was important for E2-mediated expression of Ets-1/miR-126. E2 decreased expression of miR-126-3p target Spred1 (a protein that inhibits mitogenic signaling). Overexpression of Spred1 partially blocked enhancement of endothelial cell proliferation, migration, and tube formation by E2. Additionally, E2 regulates miR-126-3p–mediated expression of vascular cell adhesion molecule-1 to inhibit monocyte adhesion into HUVECs. Conclusions: E2 protection against atherogenesis is possibly mediated by Ets-1/miR-126.

To recycle the sludge resource from sewage treatment plants and solve the problem of odor pollution, the sludge was converted into an adsorbent by carbonized pyrolysis and the process was optimized by orthogonal experiments. The capability for odor removal as well as the structure of the adsorbent was studied with H2S as a target pollutant. The results indicate that the main factor affecting the deodorization performance of the adsorbent is the activating time. The sludge adsorbent sample SAC1 prepared under optimum conditions exhibits the best deodorization performance with a H2S breakthrough time of 58 min and an iodine value nearly that of the coal activated carbon. The breakthrough time of H2S is much longer than that on the coal activated carbon. On the other hand, characterization results from X-ray diffractometer (XRD), X-ray photoelectron spectrometer (XPS) and scanning electron microscope (SEM) techniques show that SAC1 is composed of mainly graphite carbon with lower oxygen content on the surface. The bulk of SAC1 exhibits a honeycomb structure with well developed porosity and a high specific surface area of 120.47 m2·g−1, with the average pore diameter being about 5 nm. Such a structure is in favor of H2S adsorption. Moreover, SAC1 is detected to contain various metal elements such as Zn, Fe, Mg, etc., leading to a superior deodorization property to that of coal activated carbon.

Testosterone (T) deficiency is positively correlated with the increased incidence of cardiovascular disease. However, the effects of T on vascular endothelial cells remain obscure. Tube formation capacity is critical for vascular regeneration/repair and Smad1 plays an important role in these events. In this study, we investigated the effects of T on Smad1 activation and tube formation of cultured human umbilical endothelial cells (HUVECs). Our results showed that T rapidly increased endothelial Smad1 phosphorylation. This effect was mimicked by cell-impermeable T-BSA conjugates and was not altered by transcriptional inhibitor actinomycin D or translational inhibitor cycloheximide. T-induced Smad1 phosphorylation was blocked by ERK1/2 and c-Src inhibitors or their specific siRNAs, while it was reinforced by ERK1/2 or c-Src overexpression. Indeed, T rapidly activated ERK1/2 and c-Src signalings and c-Src was confirmed as the upstream of ERK1/2. Moreover, caveolae disruptor methyl-β-cyclodextrin (β-MCD) blocked Smad1 activation induced by T. The association of caveolin-1 with androgen receptor (AR) or c-Src was detected by immunoprecipitation and it was significantly increased by rapid T stimulation. Furthermore, fractional analysis showed that AR and c-Src were expressed in caveolae-enriched membrane fractions. T promoted tube formation of HUVECs, which was blocked by c-Src and ERK1/2 inhibitors or by the knockdown of Smad1. In conclusion, T increased tube formation of endothelial cells isolated from veins by stimulating Smad1 phosphorylation in a nongenomic manner, which was mediated by signals from AR/c-Src located in caveolae to ERK1/2 cascade. These findings may shed new light on the relevance of T to its vascular functions.

Pretilachlor used as one kind of acetanilide herbicides is potentially dangerous and biorefractory. In this work, electrochemical degradation of lab-synthetic pretilachlor wastewater was carried out with Sb doped Ti/SnO(2) electrode as anode and stainless steel as cathode. The effect of current density on pretilachlor degradation was investigated, and the degradation pathway of pretilachlor was inferred by analyzing its main degradation intermediates. The results showed that the removal of pretilachlor and TOC in treatment time of 60 min were 98.8% and 43.1% under the conditions of current density of 20 mA cm(-2), initial concentration of pretilachlor of 60 mg L(-1), Na(2)SO(4) dosage of 0.1 mol L(-1), pH of 7.2, respectively, while the energy consumption was 15.8 kWhm(-3). The main reactions for electrochemical degradation of pretilachlor included hydroxylation, oxidation, dechlorination, C-O bond and C-N bond cleavage, resulting in the formation of nine main intermediates.

OBJECTIVE To investigate the expressions of cyclooxygenase 2 (COX-2) and human epidermal growth factor receptor-2 (HER-2) in non-small cell lung cancer (NSCLC) and their clinical significance in identifying the progression and prognosis of the NSCLC patients. METHODS Immunohistochemical indirect method was used to detect the expressions of the COX-2 and HER-2 protein in 54 NSCLC specimens, 16 paraneoplastic specimens, and 10 normal tissue specimens. RESULTS The positive rates of COX-2 and HER-2 protein expressions were respectively 75.9% and 40.7% in the NSCLC specimens, 25% and 12.5% in the paraneoplastic specimens, and 0 in the normal tissue. The COX-2 protein expression in lung cancer (LC) was not only related to the smoking habit of the patients and histological grades of LC, but also to the TNM stages, and lymphatic metastasis ( P < 0.05). HER-2 protein expression closely correlated to the pathologic types, histological grades, TNM stages, and lymphatic metastasis ( P < 0.05). The result of univariate analysis showed that all the histological grades, TNM stages, lymphatic metastasis, and expressions of COX-2/HER-2 correlated to the prognosis of NSCLC patients (mean of P value < 0.01). The multivariate survival analysis indicated that there were significant differences in comparison of the survival time between the COX-2 (++/+++) /HER-2 (++/+++) and the COX-2 (-+)/HER-2 (-/+) groups ( P < 0.001), suggesting the COX-2/HER-2 was a negative prognostic factor. CONCLUSION COX-2 and HER-2 are valuable in identifying the progression of NSCLC and predicting the prognosis of NSCLC patients. COX-2 and HER-2 are useful for judging the NSCLC patient’s condition, and are of great value to the decision of NSCLC prognosis.

Cerium and nitrogen codoped TiO2 photocatalysts were successfully prepared by sol–gel method. The results showed that Ce doped in TiO2 could prevent phase transition of anatase to rutile and inhibit the growth of crystallite. In addition, Ce and N codoped in TiO2 enhanced the lattice distortion. N–Ti bond and N–Ti–O bond were formed in codoped titania, which narrowed the energy gap and extended the absorption edge to the visible light range, and the synergistic effects of the Ce and N codoped samples made the red shift more distinct. The results showed that the rate of hydrogen production was the best for the sample prepared under the conditions of the content of Ce doped for 0.6% (molar ratio) and calcination temperature of photocatalyst preparation at 500 °C. Cerium and nitrogen codoped TiO2 photocatalysts were successfully prepared by sol–gel method, and codoped TiO2 photocatalytic activity in the visible light is improved obviously.

OBJECTIVE Thus far there is no standard salvage regimen for patients with recurrent and refractory intermediate and high grade non-Hodgkin’s lymphoma (NHL). This study intends to investigate the therapeutic efficacy of the DICE (dexamethasone, isofosfamide, cisplatin and etoposide) regimen on the recurrent and refractory NHL, and to observe the related adverse effects. METHODS Clinical records of 22 patients with recurrent and refractory NHL, who failed to achieve a remission from the CHOP [cyclophosphamide, hydroxydaunomycin/doxorubicin (adriamycin), oncovin, prednisone] regimen within 2 to 6 cycles of treatment, were reviewed. DICE, as a salvage regimen with a median course of treatment of 4 cycles (ranging from 2 to 7 cycles), was now used, and evaluation of the therapeutic efficacy and adverse eff ect of DICE was conducted in all the patients. Of the 22 NHL cases, 8 were of T-cell origin and the other 14 B-cell origin. Salvage treatment was performed in the patients, with appraisal, prevention and treatment of the toxic reactions. RESULTS Following DICE treatment in the 22 patients, the total effective rate of the regimen was 63.6%, and the complete remission (CR) rate was 40.9%. The effective rates of DICE on the T and B-cell sourced NHL were 75.0% and 57.1%, and the CR rate were 37.5%, 42.9%, respectively ( P > 0.05). An increase of the lactate dehydrogenase (LDH) level accompanied by a giant lump was the short-term effect on patients with recurrence (mean P < 0.05) who were drug resistant. Myelosuppression, digestive system reaction and alopecia were the commonly-seen complications in the patients who received DICE regimen. All patients recovered after treatment, and no chemotherapy-related death occurred. CONCLUSION DICE regimen is effective in treating refractory and recurrent NHL.

Objective To investigate the correlation between polymorphism of the 5′-untranslated region (5′-UTR) of thymidylate synthase genes, as well as the lifestyle, and the susceptibility of gastric carcinoma.

Objective The aim of our study was to investigate the treatment of recurrent central nervous system lymphoma.

To evaluate the clinical significance of quantitative determination of serum lactic dehydrogenase (LDH) and beta 2-microglobulin (β2-MG) in patients with non-Hodgkin’s lymphoma (NHL). Date of the 65 patients from 2003 to 2004 were retrospectively analyzed, relationship between LDH and β2-MG activities and tumor phase, effect of treatment as well as prognosis were studied. The levels of LDH and β2-MG in the advanced stage, B group and bone marrow involvement were obviously higher than their comparison counterpart and the difference was significant (P < 0.05). There was no significant difference between the high LDH group and normal LDH group in the two-year survival rate. But the difference in the four-year survival rate was significance. The level of LDH and β2-MG are valuable for clinical stage, prognosis and evaluation of therapeutic response in patients with NHL.

The clomazone herbicide wastewater was treated using a combined technology composed of electrochemical catalytic oxidation and biological contact degradation. A new type of electrochemical reactor was fabricated and a Ti/SnO2 electrode was chosen as the anode in electrochemical-oxidation reactor and stainless steel as the cathode. Ceramic rings loaded with SnO2 were used as three-dimensional electrodes forming a packed bed. The operation parameters that might influence the degradation of organic contaminants in the clomazone wastewater were optimized. When the cell voltage was set at 30 V and the volume of particle electrodes was designed as two-thirds of the volume of the total reactor bed, the chemical oxygen demand (COD) removal rate could reach 82% after 120 min electrolysis, and the ratio of biochemical oxygen demand (BOD)/COD of wastewater increased from 0.12 to 0.38. After 12 h degradation with biological contact oxidation, the total COD removal rate of the combined technology reached 95%, and effluent COD was below 120 mg/L. The results demonstrated that this electrocatalytic oxidation method can be used as a pretreatment for refractory organic wastewater before biological treatment.