Comparison of primary and metastatic site-related PD-L1 expression in predicting ORR in patients with advanced NSCLC who received ICB-based therapy.

BACKGROUND: Whether the value of PD-L1 expression from metastatic sites to predict the efficacy of immune checkpoint blockade (ICB)-based treatment is equivalent to that from a primary tumor is uncertain. This study aimed to compare the utility of PD-L1 TPS from a primary lung tumor and metastatic sites to predict the overall response rate (ORR) of first-line ICB-based treatment. METHODS: This study included 249 patients with advanced non-small cell lung cancer (NSCLC) who received first-line ICB-based treatment. All subjects underwent PD-L1 testing prior to ICB-based treatment and were divided into two cohorts corresponding to the different biopsy sites: lung primary site-sampled cohort (PT cohort, n = 167) and metastatic site-sampled cohort (MT cohort, n = 82). RESULTS: There was no statistical significance in PD-L1 TPS distribution between the two cohorts (p = 0.742). PD-L1 TPS ≥50% was also related to high ORR compared with PD-L1 < 50% in the PT cohort (34.3% vs. 14.1%, p = 0.004). In contrast, ICB-based therapy could bring comparable ORR (35.1% vs. 33.3%, p = 0.871) in the MT cohort regardless of PD-L1 TPS status (≥50%, or <50%). As supported, when the cutoff value of TPS was selected as 50%, it was suggested that PT-related PD-L1 was the independent predictor of ORR (OR 2.870, 95% CI: 1.231-6.694, p = 0.015) rather than MT-related PD-L1 (OR 0.689, 95% CI: 0.236-2.013, p = 0.495). Furthermore, ROC proved that PT-related PD-L1 expression manifested a better AUC of 0.621 (p = 0.026) than that of MT-related PD-L1 (AUC = 0.565, p = 0.362). CONCLUSION: Compared with PT-related PD-L1 expression, MT-related PD-L1 expression showed limited value in predicting ORR in patients with advanced NSCLC receiving ICB-based therapy. It was concluded that even patients with low MT-related PD-L1 expression could benefit from ICB-based therapy.

Top 100 cited articles in the thromboangiitis obliterans: a bibliometric analysis and visualized study.

OBJECTIVE: Thromboangiitis obliterans (TAO) is one of the most common types of peripheral arterial disease (PAD). This study aimed to explore the characteristics of the top 100 most cited articles in the TAO. METHODS: A bibliometric analysis based on the Web of Science (WOS) database was performed. Literature was retrieved and ranked by the citations. Listed below are the top 100 citations, including original articles, reviews, full-length proceeding papers, and case reports that were included for analysis. The type of literature, research areas, and languages were recorded. The trends of citations including the total citations, an analysis of publication and citation numbers were conducted each year. We analyzed citations from highly cited countries, authors, institutions, and journals. Research hotspots were gathered by a visualized analysis of author keywords. RESULTS: Most of the highly cited literature was original articles. A rising trend was observed in the number of citations per year. The peaks in the number of highly cited articles appeared in the year 1998 and 2006. The majority of the articles focused on the cardiovascular system and surgery. Journal of Vascular Surgery published most of the highly cited articles. The USA and Japan contributed nearly half the number of highly cited articles. Mayo Clinic and Nagoya University were highly cited institutions. Shionoya S and Olin JW were both the author with the largest number of citations and the most highly cited author in the reference. Articles that were highly cited most often addressed the following topics: "vasculitis", "autoimmune disease", and "critical limb ischemia". Keywords that were mostly used in recent years were "stem cell therapy", "progenitor therapy", and "immunoadsorption". The detection of bursts of author keywords showed the following: "permeability", "differentiation", and "critical limb ischemia" are recent keywords that have burst. CONCLUSIONS: In this study, the highly cited contributors in the field of TAO research were identified. Most cited articles in the top 100 focused on the cardiovascular system and surgery. Treatment and pathophysiology including stem cell therapy, progenitor therapy, genetics, autoimmunity, and inflammation are the hotspots of TAO.

Transanal total mesorectal excision versus laparoscopic intersphincteric resection for low rectal cancer: a propensity score matching analysis.

BACKGROUND: Anus-preserving surgery for low rectal cancer has always been a serious difficulty for surgeons. Transanal total mesorectal excision (TaTME) and laparoscopic intersphincteric resection (ISR) are commonly used Anus-preserving surgeries for low rectal cancer. The aim of this study was to compare the clinical use of two surgical methods. METHODS: A total of 152 patients with low rectal cancer were treated with taTME in 75 cases and ISR in 77 cases. After propensity score matching, 46 patients in each group were included in the study. Perioperative outcomes, anal function scores (Wexner incontinence score) and quality of life scores (EORTC QLQ C30, EORTC QLQ CR38) at least 1 year after surgery were compared between the two groups. RESULTS: There were no significant differences between the two groups in terms of surgical outcomes, pathological examination of surgical specimens, postoperative recovery, and postoperative complications, except for patients in the taTME group who had their indwelling catheters removed later. Anal Wexner incontinence score was lower in taTME group than ISR group (P < 0.05). On the EORTC QLQ-C30 scale, the physical function and role function scores in the ISR group were lower than those in the taTME group (P < 0.05), while the fatigue, pain symptoms, and constipation scores in the ISR group were higher than those in the taTME group (P < 0.05). On the EORTC QLQ-CR38 scale, the scores of gastrointestinal symptoms and defecation problems in the ISR group were higher than those in the taTME group (P < 0.05). CONCLUSION: Compared with ISR surgery, taTME surgery is comparable in terms of surgical safety and short-term efficacy, and has better long-term anal function and quality of life. From the perspective of long-term anal function and quality of life, taTME surgery is a better surgical method for the treatment of low rectal cancer.

Anlotinib dramatically improved pulmonary hypertension and hypoxia caused by Pulmonary Tumor Thrombotic Microangiopathy (PTTM) associated with gastric carcinoma: a case report.

BACKGROUND: Pulmonary tumor thrombotic microangiopathy (PTTM) is a rare malignancy-related respiratory complication, demonstrating rapid progression of pulmonary hypertension (PH) and respiratory failure. Although a number of treatments have been attempted for patients diagnosed with or suspected of having PTTM, successful-treated cases of PTTM were mainly from imatinib therapy, which was a PDGF receptor inhibitor. Anlotinib was a novel tyrosine kinase inhibitor that targets VEGFR, FGFR, PDGFR, and c-kit. CASE PRESENTATION: We reported a patient of PTTM associated with gastric carcinoma, whom were treated with anlotinib, thereby exhibiting significant improvement of PH and respiratory dysfunction. CONCLUSION: Our case provides a new understanding of therapy to PTTM, with implications for defining anlotinib as candidate drug for PTTM. Clinical diagnosis and prompt initiation of anlotinib might be one of the strategies in patients with unstable PTTM.

A wide clinical spectrum of pulmonary affection in subjects with community-acquired Klebsiella pneumoniae liver abscess (CA-KPLA).

BACKGROUND: Klebsiella pneumoniae is a major pathogen of bacterial liver abscess in Asia. Particularly, patients with community-acquired Klebsiella pneumoniae liver abscess (CA-KPLA) tend to have a higher risk of invasive infection and pulmonary is a common invasive infectious site, making it a global clinical crisis. Therefore, considerable attention should be focused on the early prediction and active treatment strategies of such patients. METHODS: The clinical data of 127 CA-KPLA cases hospitalized from January 2017 to February 2022 were collected from a single center. Risk factors were analyzed by the use of univariable and multivariable analysis. Furthermore, independent risk factors of pulmonary affection were utilized to construct a predictive nomogram. RESULTS: The incidence of pulmonary affection in KPLA patients was 57.5% (73/127) and the majority manifested as nodular lesions with cavities and pleural effusion in chest CT images. Based on the predictive nomogram, the SOFA score (>2) was defined as the most dominant independent risk factor for the occurrence of pulmonary affection, followed by the maximum diameter of liver abscess (>3 cm), multiple liver abscesses, bacteremia, and badly-controlled diabetes sequentially. The validation of this nomogram also demonstrated good discriminative ability and satisfactory consistency. Finally, early drainage of liver abscess, initial combinational antibiotics, and early Carbapenem-including antibiotic usage were established as favorable factors for therapy in pulmonary affected CA-KPLA patients. CONCLUSION: This study provided an effective model for the early prediction of pulmonary affection in patients with CA-KPLA and some rational strategies for their early therapeutic remission.

Application of 24-h respiratory rate and oxygenation index variation to predict the outcome of high-flow nasal cannula therapy in patients with acute hypoxemic respiratory failure in a respiratory intensive care unit.

Background: An evaluation system is urgently needed to describe early predictors of the outcome of high-flow nasal cannula (HFNC) oxygen therapy in acute hypoxemic respiratory failure (AHRF) patients. Methods: All consecutive AHRF patients in a Respiratory Intensive Care Unit (RICU) receiving HFNC therapy between January 2019 and December 2021 were enrolled. Results: Of the 106 enrolled AHRF subjects, 57 (53.8%) succeeded in HFNC therapy and 49 (46.2%) failed. Being male (p = 0.006), initial respiratory rate oxygenation (ROX) index (p = 0.011), Acute Physiology and Chronic Health Evaluation II score (p = 0.007) and 24-h ROX index variation rate (p = 0.004) were independent factors of HFNC outcome; among these, 24-h ROX index variation rate (area under the curve = 0.825) was the best evaluation indicator. Conclusion: 24-h ROX index variation rate, introduced by our study, has shown the best potential to predict HFNC outcome in AHRF patients.

Nonylphenol regulates TL1A through the AhR/HDAC2/HNF4α pathway in endothelial cells to promote the angiogenesis of colorectal cancer.

BACKGROUND: Colorectal cancer (CRC) is one of the most malignant cancers worldwide. Nonylphenol (NP) is an endocrine-disruptor chemical and plays an important role in the development of cancers. However, the effects of NP on CRC remain unclear. In this study, we aimed to investigate the potential mechanisms of NP in the pathogenesis of CRC. METHODS: The levels of AhR, TL1A and HDAC2 in CRC tissues and endothelial cells were assessed by RT-qPCR or western blot. CHIP and dual luciferase reporter assays were used to confirm the interaction between AhR and HDAC2, or HNF4α and TL1A. The CCK8, would healing and tube formation assays were conducted to evaluate the proliferation, migration and angiogenesis of HUVECs. Western blot determined HNF4α protein and HNF4α acetylation levels. The secreted TL1A protein was detected by ELISA. The angiogenesis-related factor CD31 was tested by IHC. RESULTS: The expression level of AhR was significantly up-regulated in CRC tissues and endothelial cells. Moreover, NP activated the AhR pathway mediated colorectal endothelial cell angiogenesis and proliferation, while TL1A overexpression resisted these effects caused by NP. Besides, NP was found to modulate HNF4α deacetylation through AhR/HDAC2 to inhibit TL1A. Furthermore, in vivo experiments proved that NP regulated CRC growth and angiogenesis via AhR/HDAC2/HNF4α/TL1A axis. CONCLUSION: This study revealed that NP promoted CRC growth and angiogenesis through AhR/HDAC2/HNF4α/TL1A pathway and could be a new therapeutic target for CRC treatment.

AKT2 drives cancer progression and is negatively modulated by miR-124 in human lung adenocarcinoma.

BACKGROUND: AKT2 is highly expressed in many human cancers, including non-small cell lung cancer (NSCLC). Accumulating evidence has also revealed that AKT2 can promote NSCLC cell proliferation and metastasis. However, the involved mechanism remains unclear. Herein, our study mainly explored the function of AKT2 during cancer progression and uncovered a new post-transcriptional mechanism of AKT2 expression in lung adenocarcinoma (LUAD). METHODS: Quantitative real-time (qRT-PCR), western blot and immunohistochemistry (IHC) assays were performed to detect the expression of AKT2 and other proteins. Cell counting kit-8 (CCK-8), colony formation and EdU assays were performed to assess cell proliferation. Flow cytometry analysis was used to detect changes in the cell cycle and apoptosis. Transwell assays were used to evaluate cell migration and invasion. Additionally, a luciferase reporter assay and western blotting were employed to assess miR-124 targeting of AKT2. Xenograft mouse model was used to observe the role of miR-124/AKT2 axis on the occurrence and development of LUAD. RESULTS: We showed that AKT2 was highly expressed in NSCLC tissues and closely related to the poor prognosis of LUAD patients. Moreover, AKT2 affected LUAD cell proliferation, migration and invasion by regulating the cell cycle and promoting the occurrence of epithelial-mesenchymal transition (EMT) and the expression of matrix metalloproteinases (MMPs). In addition, we demonstrated that miR-124 overexpression downregulated AKT2 expression by binding to the 3'-untranslated region (3'- UTR) of AKT2 and thus inhibited the occurrence and development of LUAD in vivo and in vitro. CONCLUSIONS: Our results suggest that miR-124 overexpression can negatively regulate AKT2 and thus inhibit the progression of LUAD. Therefore, the miR-124/AKT2 axis may serve as a potential target for novel therapies for LUAD.

Long Intergenic Non-protein Coding RNA 511 in Cancers.

Background: Long intergenic non-protein coding RNA 511 (LINC00511) is upregulated in diverse cancers and involved in prognosis. This study aimed to evaluate the prognostic profile of LINC00511 in cancer patients. Methods: Published studies evaluating the prognosis of LINC00511 in patients with different cancers were identified from Medline, Embase, and Web of Science. Analysis of the association between LINC00511 and clinicopathological characteristics was conducted. GEPIA was used to validation and functional analysis and LnCeVar was used to get genomic variations. Results: We eventually included 9 studies, and the combined results showed LINC00511 was significantly associated with decreased OS (HR = 3.18, 95% CI = 2.29 ~ 4.42, P < 0.001) albeit with mild heterogeneity (I 2 = 58.1%, P h = 0.014), similarly in cancer type subgroups: breast cancer, digestive system cancer, and cervical cancer (all P < 0.001). There is no publication bias and meta-regression indicated follow-up time maybe heterogeneity of the results (P = 0.008). Additionally, LINC00511 appeared to be correlated with age, clinical stage, tumor size, and lymph node metastasis. Those findings were confirmed in GEPIA. Through LnCeVars, gene ontology and functional pathways were enriched, and dysregulated hallmarks and related ceRNA network of LINC00511 were disturbed. Conclusions: LINC00511 could be predictive of poor OS and lymph node metastasis in multiple cancers, in another word, LINC00511 serves as an unfavorable prognostic factor, and its mechanism is related to ceRNA.

Treatment of a case presenting as critical adenoviral ARDS using Cidofovir with early combinatorial prone ventilation and ECMO.

Here, we report a case of adenoviral pneumonia associated with critical ARDS treated with Cidofovir, prone ventilation and extracorporeal membrane oxygenation (ECMO). The patient responded well to therapy and recovered without further complications. Cidofovir, with early prone ventilation and ECMO support, may be a therapeutic option for patients with critical ARDS related to adenoviral pneumonia.

PD-L1 induced by IFN-γ from tumor-associated macrophages via the JAK/STAT3 and PI3K/AKT signaling pathways promoted progression of lung cancer.

BACKGROUND: Interferon-γ (IFN-γ) is conventionally regarded as an inflammatory cytokine that has a pivotal role in anti-infection and tumor immune surveillance. It has been used clinically to treat a variety of malignancies. However, increased evidence has suggested IFN-γ can act to induce tumor progression. The role of IFN-γ in regulating antitumor immunity appears to be complex and paradoxical. The mechanism underlying the dual aspects of IFN-γ function in antitumor immunity is not clear. METHODS: (1) Lung cancer cells (A549 cells) were cultured with pleural effusion or supernatant of tumor-associated macrophages (TAMs supernatant), and the expression levels of PD-L1 were detected by flow cytometer. The invasion capacity was measured in vitro using trans-well migration assays. (2) Pleural effusion mononuclear cells (PEMC) were separated by Ficoll Hypaque gradient. The expression of interleukin (IL)-6, IL-10, tumor necrosis factor (TNF)-α, and INF-γ in the tumor-associated macrophages was analyzed by flow cytometry. (3) A549 cells were stimulated with IL-6, IL-10, TNF-α, or IFN-γ and then the expression levels were detected by flow cytometry. (4) The expression levels of phospho-ERK (p-ERK), phospho-AKT (p-AKT), and phospho-Sat3 (p-Stat3) were analyzed with Western blot after stimulation with IFN-γ. (5) Cotreatment of the A549 cells with MAPK/ERK-specific inhibitor PD98059, PI3K/AKT-specific inhibitor LY294002, or JAK/STAT3-specific inhibitor AG490, respectively, blocked IFN-γ-induced PD-L1 expression, and then PD-L1 expression was detected by flow cytometry. RESULTS: We demonstrated that TAMs could induce the expression of PD-L1 by the secretion of IFN-γ through the Janus kinase/signal transducer and activator of transcription 3 (JAK/STAT3) signaling pathway and the phosphatidylinositol 3-kinase (PI3K)/AKT signaling pathway in A549 cells. Furthermore, the signal pathway blockers LY294002 or AG490 could block the induced expression of PD-L1 by IFN-γ. CONCLUSIONS: IFN-γ was not always successful as an antitumor agent. It also can promote tumor cells to evade immune surveillance. Researchers should be cautious in using IFN-γ as a therapeutic agent for cancer treatment.

Variant SNPs at the microRNA complementary site in the B7­H1 3'­untranslated region increase the risk of non­small cell lung cancer.

Single nucleotide polymorphisms (SNPs) in microRNA­binding sites located in the 3'­untranslated region (UTR) of target genes can have an effect on the interaction of microRNA­mediated regulation, which results in changes in the expression levels of target genes ultimately associated with cancer risk and patient prognosis. However, the role of SNPs at the 3'­UTR of B7­H1 in the susceptibility of non­small cell lung cancer (NSCLC) remains to be fully elucidated. In the present study, SNPs with a minor allele frequency >10%, which were located at the microRNA complementary site in the PD­L1 3'­UTR, were selected via bioinformatic prediction using Ensembl and miRanda 2010. A total of three SNPs were selected, s2297136, rs4143815 and rs4742098, in the 3'­UTR of B7­H1. The rs2297136 and rs4742098 SNPs exhibited significant differences between 320 patients with NSCLC and 199 healthy individuals, respectively (P<0.001 and P=0.007). For the rs2297136 SNP, the AG genotype was significantly associated with evaluation of the risk of NSCLC, compared the AA genotype [odds ratio (OR)=2.287; 95% confidence interval (95% CI)=1.558­3.358]. Similarly, for the rs4742098 SNP, the AG genotype differed from the AA genotype on eva-luation of the risk of NSCLC (OR=1.599; 95% CI=1.027­2.488). Dual­luciferase reporter assays showed that rs2297136 and rs4742098 in the B7­H1 3'­UTR contributed to the occurrence of NSCLC through disrupting the interaction between miR­296­5p, miR­138 and B7­H1 mRNA. These results indicated that genetic polymorphisms affecting the expression of B7­H1 modified cancer susceptibility.

Exon 19 L747P mutation presented as a primary resistance to EGFR-TKI: a case report.

Active mutations of the EGFR gene have been proved to predict the activity of EGFR-TKI. The most common mutations are the exon 19 deletion and exon 21 point mutation, both of which are sensitive to EGFR-TKI. However, rare EGFR mutations or complex mutations still exist, and data of which are scarce and controversial. Their response to EGFR-TKI remains uncertain. We presented a patient diagnosed with stage IV lung adenocarcinoma who was found to have the EGFR mutation in exon 19 (L747P) before any treatment. The disease progressed 2 months after the chemotherapy containing cisplatin and pemetrexed, and erlotinib was administered, but there was no response found. This EGFR-TKI naïve patient failed to achieve the desired effect with the therapy of EGFR-TKI. L747P may be associated with primary resistance to EGFR-TKI in this case.

Fragment-based design of novel quinazolinon derivatives as human acrosin inhibitors.

Human acrosin is a promising target for the male contraceptives. On the basis of the active site of human acrosin, a series of novel quinazolinon compounds were designed by a fragment docking and growing strategy. In vitro anti-acrosin assay revealed that all the compounds showed potent human acrosin inhibitory activities. In particular, compounds 5c and 5g are more active than the known inhibitors. Molecular docking studies revealed that the quinazolinon inhibitors interacted with human acrosin mainly through hydrogen bonding and hydrophobic interactions. The binding mode was also consistent with the structure-activity relationships. The quinazolinon derivatives in this study can serve as new lead structure for the development of novel male contraceptives.

[Nandeshi: a powerful inhibitor of human acrosin activity].

OBJECTIVE: To evaluate the inhibitory effect of Nandeshi, an acrosin inhibitor, on human acrosin activity. METHODS: We collected sperm samples from 10 healthy fertile men and cultured them with Nandeshi at 30 degrees C for 5 minutes at the concentrations of 0. 100, 0.120, 0.144, 0.173, 0.207, 0.249, 0.299, 0.358 and 0.430 mmol/L, with the controls treated with a well-known acrosin inhibitor N-alpha-p-tosyl-L-lysine chloromethylketone (TLCK) at 150.0, 189.8, 213.6, 240.3, 270.3, 304.1 and 342.1 mmol/L. Then we determined the residual activity of human acrosin by improved Kennedy assay. RESULTS: The residual activity of acrosin was negatively correlated with the Nandeshi concentration, and Nandeshi exhibited an inhibition rate about 800 times that of TLCK. CONCLUSION: Nandeshi has a powerful inhibitory effect on human acrosin, and improved Kennedy assay is a simple, practical and highly sensitive technique for the detection of human acrosin activity.