Arsenic (As) accumulation in different genotypes of indica rice (Oryza sativa L.) and health risk assessment based on inorganic As.

To reveal differences in arsenic (As) accumulation among indica rice cultivars and assess the human health risks arising from inorganic arsenic (iAs) intake via rice consumption, a total of 320 field indica rice samples and corresponding soil samples were collected from Fujian Province in China. The results showed that available soil As (0.03 to 3.83 mg/kg) showed a statistically significant positive correlation with total soil As (0.10 to 19.45 mg/kg). The inorganic As content in brown rice was between 0.001 and 0.316 mg/kg. Among the cultivars, ten brown rice samples (3.13%) exceeded the maximum contaminant level (MCL) of iAs in food of 0.2 mg/kg in China. The estimated daily intake (EDI) and calculated individual incremental lifetime cancer risk (ILCR) ranged from 0.337 µg/day to 106.60 µg/day and from 8.18 × 10-6 to 2.59 × 10-3, respectively. Surprisingly, the average EDI and the EDIs of 258 (80.63%) brown rice samples were higher than the maximum daily intake (MDI) of 10 µg/day in drinking water as set by the National Research Council. The mean ILCR associated with iAs was 54.3 per 100,000, which exceeds the acceptable upper limit (AUL) of 10 per 100,000 set by the USEPA. Notably, the cultivars Y-Liang-You 1 and Shi-Ji 137 exhibited significantly higher mean ILCRs compared to the AUL and other cultivars, indicating that they pose more serious cancer risks to the local population. Finally, this study demonstrated that the cultivars Yi-Xiang 2292 and Quan-Zhen 10 were the optimal cultivars to mitigate risks associated with iAs to human health from rice consumption.

A systematic review of endovenous ablation for the treatment of small saphenous varicose veins.

Insufficiency of the small saphenous vein causes 15% of varicose veins in the lower extremities. Endovenous ablation for the treatment of small saphenous vein varices has become a trend, and an increasing number of studies have reported the effects of different types of endovenous ablation in patients with small saphenous varicose veins. The purpose of this systematic review is to summarize the results of existing studies on endovenous ablation for the treatment of small saphenous varicose veins, compare its role and efficacy, and provide insights into the future development of endovenous ablation for treating small saphenous varicose veins. A systematic review of literature published from January 1, 2002 to January 1, 2022 was conducted from PubMed, Embase, and China Academic Journals full-text databases. The pre-determined inclusion criteria were clinical literature of endovenous ablation for treating small saphenous varicose veins. Keywords included "ablation", "small saphenous vein", "lesser saphenous vein", "short saphenous vein", "xiaoyinjingmai" and "xiaorong". Of the 506 articles screened, 33 articles were included in this review: 19 articles were related to endovenous laser ablation, five were related to mechanochemical ablation, seven were related to radiofrequency ablation, and two were related to both endovenous laser ablation and radiofrequency ablation. The anatomical success rate of endovenous laser ablation, radiofrequency ablation, and mechanochemical ablation were 94.3%, 96.0%, and 88.1%, respectively, and the heterogeneities were all moderate. Most of the current studies are of a low-quality level of research. Hence, long-term follow-up studies and large-scale randomized controlled trials are required to obtain high-quality evidence. Although the gold standard for the treatment of small saphenous vein insufficiency remains unclear, endovenous ablation is still the recommended method.

The germline HLA-A02B62 supertype is associated with a PD-L1-positive tumour immune microenvironment and poor prognosis in stage I lung cancer.

Background: Germline HLA class I molecule supertypes are shown to correlate with response to anti-PD-1 therapy. Here, we investigate the significance of germline HLA-A and HLA-B supertypes in tumour microenvironment of non-small-cell lung cancer. Methods: Totally 278 NSCLC patients were collected retrospectively. HLA genotyping was conducted using next-generation sequencing. The evaluation of tumour-infiltrating lymphocytes was performed by multiplex immunohistochemistry assay. Correlations among HLA supertypes, tumour infiltrating lymphocytes, and clinicopathological characteristics were assessed. Results: HLA-A03 and HLA-B62 were the supertypes with the highest proportions, at 69.1% and 52.2%, respectively. HLA-A02 or HLA-B62, but not HLA-A03, associated with higher PD-L1+ tumour and stromal cells levels, CD68+ cells, and CD68+PD-L1+ cells. Patients with both HLA-A02 and HLA-B62 supertypes displayed significantly higher PD-L1+ cells, CD68+ cells, and CD8+ cells levels than patients with other supertypes (P = 0.0301, P = 0.0479, P = 0.0192). These cells collectively constitute a hot but immunosuppressive tumour microenvironment. Accordingly, patients with both HLA-A02 and HLA-B62 supertypes had short progression-free survival after surgery (HR = 2.27, P = 0.0373). Conclusions: The HLA-A02B62 supertype could serve as a possible indicator of poor prognosis in early-stage lung cancer. However, it may also act as a favorable prognostic factor for immunotherapy, given its association with a PD-L1-positive tumour microenvironment.

TP53 or CDKN2A/B covariation in ALK/RET/ROS1-rearranged NSCLC is associated with a high TMB, tumor immunosuppressive microenvironment and poor prognosis.

INTRODUCTION: ALK-rearranged lung adenocarcinomas with TP53 mutations have more unstable genomic features, poorer ALK-TKI efficacy and a worse prognosis than ALK-rearranged lung adenocarcinomas with wild-type TP53. Here, we examine the gene variations that co-occur with ALK/RET/ROS1 rearrangements in NSCLC and the corresponding tumor immune microenvironment, as well as their association with prognosis. METHODS: A total of 155 patients with ALK/RET/ROS1 fusions were included retrospectively. Tumor genome mutation analysis was performed by next-generation sequencing. PD-L1 expression and tumor-infiltrating lymphocytes were assessed by multiplex immunohistochemistry. The correlations among gene covariation, the tumor immune microenvironment, and clinicopathological characteristics were analyzed. RESULTS: Among the 155 patients, concomitant TP53 mutation appeared most frequently (31%), followed by CDKN2A/B copy number loss (15%). The ALK/RET/ROS1 fusion and TP53 or CDKN2A/B covariation group had more males and patients with stage IV disease (p < 0.001, p = 0.0066). Patients with TP53 or CDKN2A/B co-occurrence had higher tumor mutation burdens and more neoantigens (p < 0.001, p = 0.0032). PD-L1 expression was higher in the tumor areas of the TP53 or CDKN2A/B co-occurring group (p = 0.00038). However, the levels of CD8+, CD8+PD1-, and CD8+PD-L1- TILs were lower in the tumor areas of this group (p = 0.043, p = 0.029, p = 0.025). In the TCGA NSCLC cohorts, the top 2 mutated genes were CDKN2A/B (24%) and TP53 (16%). The TP53 or CDKN2A/B co-occurring group had higher tumor mutation burdens and shorter OS (p < 0.001, p < 0.001). CONCLUSIONS: Patients with co-occurring TP53/CDKN2A/B variations and ALK/RET/ROS1 rearrangements are associated with high TMB, more neoantigens, an immunosuppressive microenvironment and a worse prognosis.

Pregnant woman with acute promyelocytic leukemia delivers healthy twins and is cured successfully: A case report.

Acute promyelocytic leukemia (APL) during pregnancy is rare and difficult to treat. To the best of our knowledge, there is little precedent for successful treatment with combined chemotherapeutic agents without affecting delivery. The present study reported the case of a 31-year-old woman pregnant with twins who presented to the antenatal service at 13-week gestational age with complaints of vaginal bleeding, lower abdominal pain, bleeding gums and skin ecchymosis, and was eventually diagnosed with APL. After treatment with all-trans-retinoic acid (ATRA) and arsenic trioxide (ATO)-based induction regimen, the patient achieved a complete remission (CR) and delivered two healthy male infants at 34 weeks of gestation. The use of ATRA and ATO for the treatment of APL is controversial due to teratogenic effects and lethal retinoic acid syndrome. However, the patient demonstrated that the chemotherapy regimen with ATRA and ATO during the second and third trimesters can result in a sustainable remission and successful pregnancy outcome.

Deletion of sphingosine kinase 2 attenuates cigarette smoke-mediated chronic obstructive pulmonary disease-like symptoms by reducing lung inflammation.

Cigarette smoke (CS) is the leading cause of chronic obstructive pulmonary disease (COPD), which is characterized by chronic bronchial inflammation and emphysema. Growing evidence supports the hypothesis that dysfunctional cystic fibrosis transmembrane conductance regulator (CFTR) is critically involved in the pathogenesis of CS-mediated COPD. However, the underlying mechanism remains unclear. Here, we report that supressed CFTR expression is strongly associated with abnormal phospholipid metabolism and increased pulmonary inflammation. In a CS-exposed mouse model with COPD-like symptoms, we found that pulmonary expression of sphingosine kinase 2 (SphK2) and sphingosine-1-phosphate (S1P) secretion were significantly upregulated. Therefore, we constructed a SphK2 gene knockout (SphK2-/-) mouse. After CS exposure for six months, histological lung section staining showed disorganized alveolar structure, increased pulmonary fibrosis, and emphysema-like symptoms in wild-type (WT) mice, which were less pronounced in SphK2-/- mice. Further, SphK2 deficiency also decreased CS-induced pulmonary inflammation, which was reflected by a remarkable reduction in pulmonary infiltration of CD45+CD11b+ neutrophils subpopulation and low levels of IL-6 and IL-33 in bronchial alveolar lavage fluid. However, treatment with S1P receptor agonist suppressed CFTR expression and increased Nf-κB-p65 expression and its nuclear translocation in CS-exposed SphK2-/-mice, which also aggravated small airways fibrosis and pulmonary inflammation. In contrast, inhibition of S1P signaling with the S1P receptor analogue FTY720 rescued CFTR expression, suppressed Nf-κB-p65 expression and nuclear translocation, and alleviated pulmonary fibrosis and inflammation after CS exposure. Our results demonstrate that SphK2-mediated S1P production plays a crucial role in the pathogenesis of CS-induced COPD-like disease by impairing CFTR activity and promoting pulmonary inflammation and fibrosis.

Superlattice-Stabilized WSe2 Cathode for Rechargeable Aluminum Batteries.

Rechargeable aluminum batteries (RABs), with abundant aluminum reserves, low cost, and high safety, give them outstanding advantages in the postlithium batteries era. However, the high charge density (364 C mm-3 ) and large binding energy of three-electron-charge aluminum ions (Al3+ ) de-intercalation usually lead to irreversible structural deterioration and decayed battery performance. Herein, to mitigate these inherent defects from Al3+ , an unexplored family of superlattice-type tungsten selenide-sodium dodecylbenzene sulfonate (SDBS) (S-WSe2 ) cathode in RABs with a stably crystal structure, expanded interlayer, and enhanced Al-ion diffusion kinetic process is proposed. Benefiting from the unique advantage of superlattice-type structure, the anionic surfactant SDBS in S-WSe2 can effectively tune the interlayer spacing of WSe2 with released crystal strain from high-charge-density Al3+ and achieve impressively long-term cycle stability (110 mAh g-1 over 1500 cycles at 2.0 A g-1 ). Meanwhile, the optimized S-WSe2 cathode with intrinsic negative attraction of SDBS significantly accelerates the Al3+ diffusion process with one of the best rate performances (165 mAh g-1 at 2.0 A g-1 ) in RABs. The findings of this study pave a new direction toward durable and high-performance electrode materials for RABs.

Optimized Properties in Multifunctional Polyphenylene Sulfide Composites via Graphene Nanosheets/Boron Nitride Nanosheets Dual Segregated Structure under High Pressure.

The practical application of polymer composites in the electronic and communications industries often requires multi-properties, such as high thermal conductivity (TC), efficient electromagnetic interference (EMI) shielding ability with low electrical conductivity, superior tribological performance, reliable thermal stability and excellent mechanical properties. However, the integration of these mutually exclusive properties is still a challenge, ascribed to their different requirement on the incorporated nanofillers, composite microstructure as well as processing process. Herein, a well-designed boron nitride nanosheet (BN)/graphene nanosheet (GNP)/polyphenylene sulfide (PPS) composite with a dual-segregated structure is fabricated via high-pressure molding. Rather than homogenous mixing of the hybrid fillers, GNP is first coated on PPS particles and followed by encapsulating the conductive GNP layers with insulating BN, forming a BN shell-GNP layer-PPS core composite particles. After hot-pressing, a dual segregated structure is constructed, in which GNP and BN are distinctly separated and arranged in the interfaces of PPS, which on the one hand gives rise to high thermal conductivity, and on the other hand, the aggregated BN layer can act as an "isolation belt" to effectively reduce the electronic transmission. Impressively, high-pressure is loaded and it has a more profound effect on the EMI shielding and thermal conductive properties of PPS composites with a segregated structure than that with homogenous mixed-structure composites. Intriguingly, the synergetic enhancement effect of BN and GNP on both thermal conductive performance and EMI shielding is stimulated by high pressure. Consequently, PPS composites with 30 wt% GNP and 10 wt% BN hot-pressed under 600 MPa present the most superior comprehensive properties with a high TC of 6.4 W/m/K, outstanding EMI SE as high as 70 dB, marvelous tribological performance, reliable thermal stability and satisfactory mechanical properties, which make it promising for application in miniaturized electronic devices in complex environments.

Isolated myeloid sarcoma with pericardial and pleural effusions as first manifestation: A case report.

RATIONALE: Myeloid sarcoma (MS) involves the proliferation of extramedullary blasts from 1 or more myeloid lineages, replacing the original tissue structures, and these neoplasias are called granulocytic sarcoma, chloroma, or extramedullary myeloid neoplasms. These tumors develop in lymphoid organs, bones, skin, soft tissues, various mucous membranes, organs, and the central nervous system. MS is rare in non-leukemic patients, while MS patient with effusion as the first manifestation is even rare. PATIENT CONCERNS: We report the case of 44-year-old woman with abdominal pain, diarrhea, and vomiting. DIAGNOSIS: Ultrasound examination and computed tomography of the chest revealed large pericardial effusions and bilateral pleural effusions. Cytomorphological examination of the pericardial and pleural effusion, flow cytometry, and immunohistochemical markers suggested myeloid tumor cells. However, concurrent peripheral blood and bone marrow examinations showed no evidence of acute myeloid leukemia. The patient was eventually diagnosed with isolated MS. INTERVENTIONS AND OUTCOMES: After chemotherapy with pirarubicin + cytarabine and high-dose cytarabine + etoposide, the pericardial effusion and pleural effusion were absorbed, and the mediastinal mass significantly shrunk. One year after patient gave up treatment, acute myeloid leukemia (AML) was confirmed by bone marrow examinations. CONCLUSION: The early manifestations of the patient lacked specificity and were highly susceptible to misdiagnosis. Cytomorphology and flow cytology indicated important directions for the diagnosis of the disease in the early stage. Administration of chemotherapy regimen containing cytarabine could prolong disease-free survival and time before progress to AML.

Naphthoquinones and triterpenoids from Arnebia euchroma (Royle) Johnst and their hypoglycemic and lipid-lowering effects.

A new pentacyclic triterpenoid, 2-hydroxy-1-ene-hydroxyhopanone (19), and a new benzoxepin-5-one, 3-(4-methyl-3-penten-1-yl)-6-hydroxy-9-methoxy-2H-1-benzoxepin-5-one (25), along with 26 known compounds (1-18, 20-24, 26-28), were isolated from the roots of Arnebia euchroma (Royle) Johnst. The structures of the new compounds were elucidated by extensive spectroscopic analyses. The absolute configurations of shikonofurans 9-13 were determined by quantum chemical ECD calculations and CD spectra comparison for the first time. Pharmacological study revealed that naphthoquinones 1-5, 7, and 8 had obvious cytotoxicity toward human lung adenocarcinoma A549 cell line. Meanwhile, the hypoglycemic and lipid-lowering effects of isolated compounds were assessed by checking their inhibitory effects on key enzymes regulating glucose and lipid metabolism. Results showed that compounds 1, 3, 5, 6, 8, 18, and 19 could inhibit the activity of ATP-citrate lyase (ACL); compound 7 could inhibit the activity of acetyl-CoA carboxylase (ACC1); while compounds 8 and 19 showed inhibitory effects on protein tyrosine phosphatase 1B (PTP1B). Among them, the naphthoquinone 6, steroid 18, and triterpenoid 19 showed moderate inhibitory effects on ACL and PTP1B, but didn't exhibit obvious cytotoxicity. This study demonstrated that compounds 6, 18, and 19 show great promising for the development of new agents for the treatment of metabolic diseases.

Macrophages-based immune-related risk score model for relapse prediction in stage I-III non-small cell lung cancer assessed by multiplex immunofluorescence.

Background: Macrophages are critical players in regulating innate and adaptive immunity in the tumor microenvironment (TME). The prognostic value of macrophages and their heterogeneous phenotypes in non-small cell lung cancer (NSCLC) is still uncertain. Methods: Surgically-resected samples of 681 NSCLC cases were stained by multiplex immunofluorescence to examine macrophage phenotypes as well as the expression levels of program death-ligand 1 (PD-L1) on them in both tumor nest and tumor stroma, including pan-macrophage (CD68+), M1 (CD68+CD163-), and M2 macrophages (CD68+CD163+). Various other immune cell markers, including CD4, CD8, CD20, CD38, CD66B, FOXP3, and CD133, were also evaluated. Machine learning algorithm by Random Forest (RF) model was utilized to screen the robust prognostic markers and construct the CD68-based immune-related risk score (IRRS) for predicting disease-free survival (DFS). Results: The expression levels of CD68 were moderately correlated with the levels of PD-L1 (P<0.001), CD133 (P<0.001), and CD8 (P<0.001). Higher levels of CD68 (OR 1.03, 95% CI: 1.01-1.05, P<0.001) as well as M1 macrophage (OR 1.04, 95% CI: 1.01-1.06, P<0.001) indicated shorter DFS. Despite without statiscial significance, intratumoral M2 macrophage (OR 1.05, 95% CI: 0.99-1.10, P=0.081) was also associated with worse DFS. IRRS incorporating three intratumoral CD68-related markers and four intrastromal markers was constructed and validated to predict recurrence (high-risk group vs. low-risk group: OR 2.52, 95% CI: 1.89-3.38, P<0.001). The IRRS model showed good accuracy [area under the curve (AUC) =0.670, 0.709, 0.695, 0.718 for 1-, 3-, 5-year, and overall DFS survival, respectively] and the predictive performance was better than the single-marker model (area under the curve 0.718 vs. 0.500-0.654). A nomogram based on clinical characteristics and IRRS for relapse prediction was then established and exhibited better performance than the tumor-node-metastasis (TNM) classification and IRRS system (C-index 0.76 vs. 0.69 vs. 0.60, 0.74 vs. 0.67 vs. 0.60, 0.81 vs. 0.74 vs. 0.60 of the entire, training, testing cohort, respectively). Conclusions: Our study suggested close interactions between CD68 and other immune markers in TME, demonstrating the prognostic value of CD68 in relapse prediction in resectable NSCLC.

Systematic Review and Bioinformatic Analysis of microRNA Expression in Autism Spectrum Disorder Identifies Pathways Associated With Cancer, Metabolism, Cell Signaling, and Cell Adhesion.

Background: Previous studies have identified differentially expressed microRNAs in autism spectrum disorder (ASD), however, results are discrepant. We aimed to systematically review this topic and perform bioinformatic analysis to identify genes and pathways associated with ASD miRNAs. Methods: Following the Preferred Reporting Items for Systematic reviews and Meta-Analyses, we searched the Web of Science, PubMed, Embase, Scopus, and OVID databases to identify all studies comparing microRNA expressions between ASD persons and non-ASD controls on May 11, 2020. We obtained ASD miRNA targets validated by experimental assays from miRTarBase and performed pathway enrichment analysis using Metascape and DIANA-miRPath v3. 0. Results: Thirty-four studies were included in the systematic review. Among 285 altered miRNAs reported in these studies, 15 were consistently upregulated, 14 were consistently downregulated, and 39 were inconsistently dysregulated. The most frequently altered miRNAs including miR-23a-3p, miR-106b-5p, miR-146a-5p, miR-7-5p, miR-27a-3p, miR-181b-5p, miR-486-3p, and miR-451a. Subgroup analysis of tissues showed that miR-146a-5p, miR-155-5p, miR-1277-3p, miR-21-3p, miR-106b-5p, and miR-451a were consistently upregulated in brain tissues, while miR-4742-3p was consistently downregulated; miR-23b-3p, miR-483-5p, and miR-23a-3p were consistently upregulated in blood samples, while miR-15a-5p, miR-193a-5p, miR-20a-5p, miR-574-3p, miR-92a-3p, miR-3135a, and miR-103a-3p were consistently downregulated; miR-7-5p was consistently upregulated in saliva, miR-23a-3p and miR-32-5p were consistently downregulated. The altered ASD miRNAs identified in at least two independent studies were validated to target many autism risk genes. TNRC6B, PTEN, AGO1, SKI, and SMAD4 were the most frequent targets, and miR-92a-3p had the most target autism risk genes. Pathway enrichment analysis showed that ASD miRNAs are significantly involved in pathways associated with cancer, metabolism (notably Steroid biosynthesis, Fatty acid metabolism, Fatty acid biosynthesis, Lysine degradation, Biotin metabolism), cell cycle, cell signaling (especially Hippo, FoxO, TGF-beta, p53, Thyroid hormone, and Estrogen signaling pathway), adherens junction, extracellular matrix-receptor interaction, and Prion diseases. Conclusions: Altered miRNAs in ASD target autism risk genes and are involved in various ASD-related pathways, some of which are understudied and require further investigation.

Profiling Tumor Immune Microenvironment of Non-Small Cell Lung Cancer Using Multiplex Immunofluorescence.

This study attempted to profile the tumor immune microenvironment (TIME) of non-small cell lung cancer (NSCLC) by multiplex immunofluorescence of 681 NSCLC cases. The number, density, and proportion of 26 types of immune cells in tumor nest and tumor stroma were evaluated, revealing some close interactions particularly between intrastromal neutrophils and intratumoral regulatory T cells (Treg) (r2 = 0.439, P < 0.001), intrastromal CD4+CD38+ T cells and CD20-positive B cells (r2 = 0.539, P < 0.001), and intratumoral CD8-positive T cells and M2 macrophages expressing PD-L1 (r2 = 0.339, P < 0.001). Three immune subtypes correlated with distinct immune characteristics were identified using the unsupervised consensus clustering approach. The immune-activated subtype had the longest disease-free survival (DFS) and demonstrated the highest infiltration of CD4-positive T cells, CD8-positive T cells, and CD20-positive B cells. The immune-defected subtype was rich in cancer stem cells and macrophages, and these patients had the worst prognosis. The immune-exempted subtype had the highest levels of neutrophils and Tregs. Intratumoral CD68-positive macrophages, M1 macrophages, and intrastromal CD4+ cells, CD4+FOXP3- cells, CD8+ cells, and PD-L1+ cells were further found to be the most robust prognostic biomarkers for DFS, which were used to construct and validate the immune-related risk score for risk stratification (high vs. median vs. low) and the prediction of 5-year DFS rates (23.2% vs. 37.9% vs. 43.1%, P < 0.001). In conclusion, the intricate and intrinsic structure of TIME in NSCLC was demonstrated, showing potency in subtyping and prognostication.

Comparison of therapy with ß-lactam/ß-lactamase inhibitor combinations or carbapenems for bacteraemia of nonurinary source caused by ESBL-producing Escherichia coli or Klebsiella pneumoniae.

BACKGROUND: Extended-spectrum ß-lactamase (ESBL)-producing Enterobacteriaceae has become a public health concern. This study aimed to compare the clinical outcomes of patients with nonurinary source bacteraemia caused by ESBL-producing Escherichia coli (E. coli) or Klebsiella pneumoniae (ESBL-producing EK) receiving ß-lactam/ß-lactamase inhibitor combinations (BLICs) versus carbapenem treatment and assess the risk factors of mortality with these two drugs. METHODS: We conducted a retrospective single-centre study of adult hospitalised patients with ESBL-producing EK bloodstream infection (BSI) from nonurinary source at our centre over a 4-year period. One hundred and eighty patients who received BLICs or carbapenems were included in the analysis. The outcome variables were 14-day treatment failure and 30-day mortality. For more reliable results, propensity score analysis was performed to compare the efficacy of the two drugs and analyse their risk factors for 30-day mortality. RESULTS: Out of 180 patients, 114 received BLICs, and 66 received carbapenem therapy. Compared to carbapenem-treated patients, those treated with BLICs were older and had higher age-adjusted Charlson comorbidity index, but they had shorter stay in the hospital. Additionally, their Pitt bacteraemia score, SOFA score, rate of leukaemia, and immune compromise were lower. After propensity score matching (PSM), the baseline characteristics of patients in the two treatment groups were balanced. BLICs were associated with a higher 14-day treatment failure rate (20.6%, 13/63) than carbapenems (16.3%, 7/43), although the difference was not significant in either univariate analysis (P = 0.429) or multivariate analysis (P = 0.122). And the 30-day mortality rate in BTG (11.1%, 7/63) and CTG (11.6%, 5/43) did not significantly differ (univariate analysis, P = 0.926; multivariate analysis, P = 0.420). In the multivariate analysis, after PSM, leukaemia was the only independent predictor of mortality in both BTG and CTG. CONCLUSIONS: Our study showed that BLICs had higher 14-day treatment failure rate compared with carbapenems, although there were no statistically significant differences because of the small number of patients, therefore, further evaluation of the efficacy of BLICs is needed.

Massive PD-L1 and CD8 double positive TILs characterize an immunosuppressive microenvironment with high mutational burden in lung cancer.

BACKGROUND: Programmed cell death ligand 1 (PD-L1) expressed on tumor and immune cells are both associated with the response to programmed cell death 1 (PD-1) pathway blockade therapy. Here, we examine the role of CD8+PD-L1+ tumor-infiltrating lymphocyte (Tils) in the tumor microenvironment of non-small cell lung cancer (NSCLC). METHODS: Tumor tissue samples of a total of 378 patients from two NSCLC cohorts were collected retrospectively. Tumor genetic variations were measured by targeted next-generation sequencing of 543 oncogenes. Tils were assessed by multiplex immunohistochemistry assay. Correlations among Tils, tumor genetic variations, and clinicopathological characteristics were analyzed. RESULTS: The levels of CD8+PD-L1+ Tils varied in NSCLC tumor tissues. Tumor samples with high CD8+PD-L1+ Tils had higher levels of CD8+ Tils, CD68+ macrophages, PD-L1+ tumor cells, PD-1+ Tils, and CD163+ M2-type macrophages, and also had a higher tumor mutation burden, all of which collectively constituted a typically hot but immunosuppressive tumor microenvironment. Therefore, in a non-immunotherapy cohort, we observed that the higher the CD8+PD-L1+ Tils level in the tumor tissue, the worse the prognosis (progression-free survival; cohort A, stage I-II tumor; p=0.005). Contrarily, in an immunotherapy cohort, where the immune suppression was blocked by anti-PD-1 treatment, the higher the CD8+PD-L1+ Tils level, the better the response to the anti-PD-1 treatment (complete response/partial response vs stable disease/progressive disease; cohort B; p=0.0337). CONCLUSIONS: CD8+PD-L1+ Tils may be an indicator of the hot but immunosuppressive tumor microenvironment which is related to a high tumor mutation burden. PD-1 pathway blockade therapy can help to mitigate this immunosuppression and obtain better curative effects.

Effect of Nano-Tracer on Identification of Sentinel Lymph Nodes in Pelvic Cavity and Postoperative Complications in Patients with Cervical Cancer.

Cervical cancer is the most common malignant tumor of the female reproductive system. Its incidence rate ranks first among female malignant tumors in China and has been increasing in recent years. However, pelvic lymph node metastasis is an important factor affecting the prognosis of cervical cancer, because pelvic lymph node metastasis determines the scope of surgery, it is also an important basis for postoperative adjuvant treatment. Therefore, an accurate and effective method is needed to detect the presence of lymphatic metastases in time to guide the need for systematic pelvic lymph node dissection. This article explores the clinical application of nano-tracer in the surgical treatment of cervical cancer patients and the impact of postoperative complications on patients with pelvic sentinel lymph nodes. The results show that the success rate of sentinel lymph node tracing in cervical cancer surgery is high, and it is a safe and efficient lymph tracer, which can provide an effective way to study cervical micro metastasis and lymphatic chemotherapy.

The CD68+ macrophages to CD8+ T-cell ratio is associated with clinical outcomes in hepatitis B virus (HBV)-related hepatocellular carcinoma.

BACKGROUND: Tumor microenvironment plays an essential role during the progression of hepatocellular carcinoma (HCC). Tumor infiltrating immune cells (TILs) was an important component of tumor microenvironment. However, whether TIL features are correlated with the prognosis of HCC patients remains unclear. METHODS: Cancer tissue and paired paracancerous tissues from 220 stage II∼III HBV-related HCC patients were collected. TILs were analyzed using a tyramide signal amplification system combined with immunohistochemistry. Kaplan-Meier survival analysis was conducted to investigate the associations between the prognosis and the infiltrating pattern of TILs. RESULTS: The patients were classified into three distinct subgroups (Clusters (C)1-3) with different overall survival (OS) and disease-free survival (DFS) according to the distribution pattern of TILs. The CD68/CD8 ratio in the cancer SA was correlated with the prognosis. Patients with a higher CD68/CD8 ratio exhibited poorer OS and DFS than those with a lower ratio. The CD68/CD8 ratio in the cancer SA was an independent factor for OS prediction but not DFS. CONCLUSION: CD68+ macrophages and CD8+ T-cells are essential immunological determinants for HBV-related HCC prognosis, and the CD68/CD8 ratio in cancer SA is a novel, prognostic factor for OS prediction in HBV-related HCC patients.

A Retrospective Analysis of Risk Factors and Patient Outcomes of Bloodstream Infection with Extended-Spectrum ß-Lactamase-Producing Escherichia coli in a Chinese Tertiary Hospital.

OBJECTIVE: The present study assessed risk factors and patient outcomes of bloodstream infection (BSI) caused by extended-spectrum ß-lactamase (ESBL)-producing Escherichia coli (E. coli). METHODS: A retrospective study was performed to analyze risk factors and patient outcomes of BSI caused by extended-spectrum ß-lactamase-producing Escherichia coli (ESBL-EC) in one Chinese tertiary hospital over a 7.5-year period. The clinical characteristics of patients infected with ESBL-producing and non-ESBL-producing E. coli were compared. Predictors of 30-day mortality in patients with E. coli BSI were also identified in our study. RESULTS: The results of drug sensitivity showed that quinolones, aminoglycosides, ß-lactam/ß-lactamase inhibitor combinations (BLICs) and trimethoprim/sulfamethoxazole exhibited significant differences between the ESBL and non-ESBL groups. Of the 963 patients with E. coli BSI, 57.6% developed ESBL-EC. Multivariate analysis showed that biliary tract infection (BTI) [P<0.001,OR (95% CI):1.798 (1.334-2.425)], urinary tract obstructive disease [P=0.001,OR (95% CI):2.106 (1.366-3.248)], surgery within 3 months [P=0.002,OR (95% CI):1.591 (1.178-2.147)], hospitalization within 3 months [P<0.001,OR (95% CI):2.075 (1.579-2.725)], ICU admission [P=0.011,OR (95% CI):1.684 (1.124-2.522)] and history of cephalosporin use [P=0.006,OR (95% CI):3.097 (1.392-6.891)] were statistically significant. In mortality analysis, aCCI>2 [P=0.016,OR (95% CI): 2.453 (1.179-5.103)], gastrointestinal catheterization [P=0.004, OR (95% CI): 2.525 (1.333-4.782)] were significantly associated with 30-day mortality. According to Kaplan-Meier survival analysis, we found that in SOFA<2 group and SOFA≥2 group, the mortality rate of patients treated with BLICs were lower than that of carbapenems(P<0.05). CONCLUSION: This study showed that BTI, urinary tract obstructive disease, surgery within 3 months, hospitalization within 3 months, ICU admission and cephalosporin exposure were independent risk factors for the emergence of ESBL-EC BSI. Analysis of risk factors for 30-day mortality revealed that the factors independently associated with a higher risk of mortality were aCCI>2, gastrointestinal catheterization. Compared to carbapenems, the BLICs had preferable effect to treat patients with ESBL-EC BSI. Notably, patients with severe illness were inlcined to use carbapenems, which affected the analysis results. Therefore, we suggest that BLICs could be recommended to treat mild patients with ESBL-EC bacteremia.

The mutation profiles of cell-free DNA in patients with oesophageal squamous cell carcinoma who were responsive and non-responsive to neoadjuvant chemotherapy.

BACKGROUND: The aim of this study was to evaluate the clinical value of plasma cell-free DNA (cfDNA) mutation profiles in patients with oesophageal squamous cell carcinoma (OSCC) who received neoadjuvant chemotherapy. METHODS: Twenty-two OSCC patients received neoadjuvant chemotherapy and were divided into two groups according to their response to the therapy. Fifteen patients were in the responsive group, and seven patients were in the non-responsive group. The blood samples were collected, and the plasma cfDNA mutation profiles were sequenced by a cancer gene-targeted next-generation sequencing (NGS) panel. RESULTS: The driver gene molecular mutation burden (MMB) was significantly higher in the non-responsive group compared with the responsive group. Furthermore, we found that the differential MMB included the DNA damage response, Wnt, PI3K, Hippo, RTK/RAS, p53, and AHR pathway. The MMB yielded an area under the receiver operation characteristic (ROC) curve of 0.89 for predicting the response to neoadjuvant chemotherapy. The cfDNA copy number variations (CNVs) yielded an area under ROC curve of 1.0 for predicting the response to neoadjuvant chemotherapy. CONCLUSIONS: The driver gene MMB and CNVs in plasma cfDNA may be potential biomarkers for predicting the response to neoadjuvant chemotherapy in patients with OSCC.