Proteomic Stratification of Prognosis and Treatment Options for Small Cell Lung Cancer.

Small cell lung cancer (SCLC) is a highly malignant and heterogeneous cancer with limited therapeutic options and prognosis prediction models. Here, we analyzed formalin-fixed, paraffin-embedded (FFPE) samples of surgical resections by proteomic profiling, and stratified SCLC into three proteomic subtypes (S-I, S-II, and S-III) with distinct clinical outcomes and chemotherapy responses. The proteomic subtyping was an independent prognostic factor and performed better than current tumor-node-metastasis or Veterans Administration Lung Study Group staging methods. The subtyping results could be further validated using FFPE biopsy samples from an independent cohort, extending the analysis to both surgical and biopsy samples. The signatures of the S-II subtype in particular suggested potential benefits from immunotherapy. Differentially overexpressed proteins in S-III, the worst prognostic subtype, allowed us to nominate potential therapeutic targets, indicating that patient selection may bring new hope for previously failed clinical trials. Finally, analysis of an independent cohort of SCLC patients who had received immunotherapy validated the prediction that the S-II patients had better progression-free survival and overall survival after first-line immunotherapy. Collectively, our study provides the rationale for future clinical investigations to validate the current findings for more accurate prognosis prediction and precise treatments.

The effect of erythropoiesis­stimulating agents on lung cancer patients: a meta­analysis.

Previous studies have demonstrated that erythropoiesis-stimulating agents (ESAs) can reduce anemia and improve quality of life in cancer patients, but ESAs may increase mortality. Therefore, we conducted a meta-analysis of randomized controlled trials (RCT) comparing the effect and risk of ESAs about the prevention or treatment of anemia in cancer patients. Four databases including PubMed, Embase, Web of science and Cochrane Library were searched for published RCTS on ESAs in the treatment of anemia in lung cancer patients from 2000 to 2023. Endpoints including mortality, incidence of thrombotic vascular events, blood transfusion requirement, and incidence of adverse events. Our meta-analysis included 8 studies, with a sample size of 4240 patients, including 2548 patients in the ESAs group and 1692 patients in the control group. The risk of mortality was lower in patients using ESAs than control group (RR 0.96, 95% CI 0.92-0.99, P = 0.02). But there was no significant difference in the risk of mortality between the patients using ESAs and controls (RR 0.99, 95% CI 0.92-1.06, P = 0.69) after removing Pere 2020. Subgroup analysis found that patients diagnosed with small cell lung cancer (SCLC) (RR 1.00, 95% CI 0.92-1.08, P = 0.16) or non-small cell lung cancer (NSCLC) (RR 1.01, 95% CI 0.87-1.17, P = 0.13) were no significant difference in mortality rate. The thrombotic vascular events increase in patients using ESAs than control group (RR 1.40, 95% CI 1.13-1.72, P = 0.002). The blood transfusion requirement of ESAs group was lower than control group (RR 0.56, 95% CI 0.44-0.72, P < 0.00001). And the subgroups of Darbepoetin alfa (RR 0.57, 95% CI 0.41-0.79, P = 0.003) and Epoetin alfa (RR 0.68, 95% CI 0.47-0.99, P = 0.01) had lower transfusion requirements than the control group. In the SCLC subgroup (RR 0.51, 95% CI 0.40-0.65, P = 0.34), blood transfusion requirements were lower in the ESAs group, but there was no significant difference between the subgroup of patients with NSCLC (RR 0.61, 95% CI 0.36-1.04, P = 0.009). There was no statistically significant difference between the two groups in the incidence of adverse reactions (RR 0.98, 95% CI 0.95-1.00, P = 0.10). In conclusion, ESAs does not increase the mortality of lung cancer patients or may reduce the risk of death, and can reduce the need for blood transfusion, although ESA can increase the incidence of thrombotic vascular adverse events.Registration PROSPERO CRD42023463582.

Knowledge structure and emerging trends of cognitive impairment induced by sleep deprivation: A bibliometric analysis based on CiteSpace and VOSviewer from 2000 to 2022.

This paper implements a bibliometric approach to investigate the research hotspots and future research directions in the relevant field literature. It also offers research ideas and methods for preventing and treating cognitive impairment induced by sleep deprivation in the clinical setting. The evolution of various clusters in the field is summarized through Citespace's projection function for keywords in the literature. CiteSpace and Vosviewer are utilized to analyze and visualize the attributes of the articles, including number of publications, citation frequency, country/region, institution, journal, authors, keywords, and references, from the 2280 publications obtained. A total of 2280 publications were collected, with the number of papers and citations in the field continuously increasing year by year. The most influential country in this field is the United States, and the University of Washington is the most influential institution. The most authoritative journal in the field is identified as SLEEP. Sleep deprivation, prefrontal cortex, and performance are the current topics of interest. The article with the strongest citation burst, lasting from 2015 to 2018, is "Sleep Drives Metabolite Clearance from the Adult Brain." The most influential article and co-cited reference, "Neurocognitive Consequences of Sleep Deprivation," highlights that sleep deprivation from various causes may lead to cognitive impairment. Future research should investigate all forms of cognitive impairment resulting from sleep deprivation. The findings of this study will assist researchers in improving their knowledge structure, identifying research hotspots, and revealing future directions in the field.

A novel TPD52L2-ROS1 gene fusion expanding the molecular alterations in inflammatory myofibroblastic tumor: case report and literature review.

BACKGROUND: Inflammatory myofibroblastic tumor (IMT) is a distinctive tumor composed of spindle cells accompanied by mixed inflammatory cells, and immunohistochemical positivity for ALK (anaplastic lymphoma kinase protein) can be detected in half of IMTs. The diagnosis of ALK-negative IMT could be a challenge. Recently, the fusions of some kinase genes, such as RET, NTRK1, ROS1, etc., are revealed in ALK-negative IMT. CASE PRESENTATION: A 19-year-old woman presented with swelling of the left upper arm. Magnetic resonance imaging (MRI) scan revealed a tumor in the left postbrachium extended to the left axillary, serratus anterior muscle, and latissimus dorsi muscle. Histopathologically, the irregular-circumscribed tumor was composed of dense spindle-shaped cells with eosinophilic abundant cytoplasm and hyalinized mesenchyme in an inflammatory background. Immunohistochemically (IHC), tumor cells were positive for SMA, MDM2, and p16; the cells were negative for desmin, MyoD1, Myogenin, pan-cytokeratin, S100, SOX10, HMB45, Malen-A, CD34, CD31, CD99, and ALK. By RNA-based NGS, a novel fusion between TPD52L2 3' end of exon 1-4 and ROS1 5' end of exon 36-43 was revealed. ROS1 IHC staining was negative. The final diagnosis of IMT with TPD52L2-ROS1 fusion was made. Subsequently, the patient experienced a good clinical response to Crizotinib, and clinical follow-up showed stable disease after 9 months. CONCLUSION: This report expands the spectrum of ROS1 gene rearrangements in the IMT and highlights the importance of molecular analysis of IMT for getting a diagnostic clue and determining potential therapeutic strategies.

PU-Flow: A Point Cloud Upsampling Network With Normalizing Flows.

Point cloud upsampling aims to generate dense point clouds from given sparse ones, which is a challenging task due to the irregular and unordered nature of point sets. To address this issue, we present a novel deep learning-based model, called PU-Flow, which incorporates normalizing flows and weight prediction techniques to produce dense points uniformly distributed on the underlying surface. Specifically, we exploit the invertible characteristics of normalizing flows to transform points between euclidean and latent spaces and formulate the upsampling process as ensemble of neighbouring points in a latent space, where the ensemble weights are adaptively learned from local geometric context. Extensive experiments show that our method is competitive and, in most test cases, it outperforms state-of-the-art methods in terms of reconstruction quality, proximity-to-surface accuracy, and computation efficiency. The source code will be publicly available at https://github.com/unknownue/puflow.

INSM1 Expression in Mesenchymal Tumors and Its Clinicopathological Significance.

Background: Insulinoma-associated protein 1 (INSM1) has been identified as a nuclear marker of neuroendocrine tumors. Although INSM1 appears to be a subtle and specific biomarker for neuroendocrine tumor, its expression and clinicopathological significance in mesenchymal tumors remain unclear. Methods: We analyzed INSM1 mRNA level in GEO database and conducted immunohistological staining to detect the expression of INSM1 on 576 mesenchymal tumors from pathology department of Tongji Hospital. Results: At transcription level, INSM1 expression in AITL (angioimmunoblastic T-cell lymphoma) was higher than their adjacent normal tissues as well as Hodgkin's lymphoma. Moreover, INSM1 expression in well-differentiated liposarcoma (WDLPS) was significantly higher than normal fat (P = 0.014) and dedifferentiated liposarcoma (DDLPS) (P = 0.0248). At protein level, the positive rate of INSM1 in AITL was 18/48 (47.4%), while in DDLPS was 9/20 (45%). INSM1 expression in AITL was significantly higher than Hodgkin's lymphoma (P = 0.008). And INSM1 expression in WDLPS was significantly lower than DDLPS (P = 0.015). Conclusion: The combination of GEO data and immunohistochemistry data indicated that the expression level of INSM1 was higher in AITL compared with normal control, suggesting that INSM1 may be involved in pathogenesis of AITL. The abnormal expression of INSM1 was found in WDLPS, and the positive rate of INSM1 was higher in DDLPS than in WDLPS. INSM1 may be involved in the regulation of liposarcoma development. There were significant differences in the expression of INSM1 between AITL and Hodgkin's lymphoma and WDLPS and DDLPS. These findings may assist in the differential diagnosis of these tumors when common markers are difficult to identify, enriching the diagnostic index system of mesenchymal tumors.

Inhibition of acylglycerol kinase sensitizes DLBCL to venetoclax via upregulation of FOXO1-mediated BCL-2 expression.

Background: Despite of the paradigm change on the treatments of acute myeloid leukemia (AML) and chronic lymphocytic leukemia (CLL) by venetoclax, it has been less successful in the treatment of diffuse large B-cell lymphoma (DLBCL). Here, we explored whether acylglycerol kinase regulates the sensitivity of DLBCLs to venetoclax and its mechanism in both cell lines and preclinical animal models. Methods: The expression of AGK and sensitivity to venetoclax of seven DLBCL cell lines were determined. Upon knockdown and overexpression of AGK by lentivirus in DLBCL cells, the venetoclax-induced apoptosis and PTEN-FOXO1-BCL-2 signaling axis were evaluated in vitro. The efficacy of venetoclax and PTEN-FOXO1-BCL-2 signaling axis were evaluated in immunodeficient NCG mice that were implanted with control or shAGK stably transduced SU-DHL4 cells. The expressions of AGK, BCL-2 and FOXO1 were evaluated in tumor tissues of DLBCL patients. Results: AGK expression was inversely correlated with sensitivity of DLBCL to venetoclax. Inhibition of AGK rendered the DLBCL cells more sensitive to venetoclax. Mechanistically, AGK phosphorylated and inactivated PTEN, which led to AKT activation and reduced FOXO1 nuclear translocation. Inhibition of AGK also led to enhanced efficacy of venetoclax for suppression of DLBCL tumor growth in vivo, which was dependent on FOXO1. In human DLBCL tumor tissues, the expression of AGK inversely correlated with BCL-2 expression, as well as the amounts of nuclear FOXO1. Conclusions: Our data demonstrated that AGK regulates venetoclax response in DLBCL via PTEN-FOXO1-BCL-2 signaling axis. Targeting AGK may enhance the efficacy of venetoclax for the treatment of DLBCL patients.

Abnormal global alternative RNA splicing in COVID-19 patients.

Viral infections can alter host transcriptomes by manipulating host splicing machinery. Despite intensive transcriptomic studies on SARS-CoV-2, a systematic analysis of alternative splicing (AS) in severe COVID-19 patients remains largely elusive. Here we integrated proteomic and transcriptomic sequencing data to study AS changes in COVID-19 patients. We discovered that RNA splicing is among the major down-regulated proteomic signatures in COVID-19 patients. The transcriptome analysis showed that SARS-CoV-2 infection induces widespread dysregulation of transcript usage and expression, affecting blood coagulation, neutrophil activation, and cytokine production. Notably, CD74 and LRRFIP1 had increased skipping of an exon in COVID-19 patients that disrupts a functional domain, which correlated with reduced antiviral immunity. Furthermore, the dysregulation of transcripts was strongly correlated with clinical severity of COVID-19, and splice-variants may contribute to unexpected therapeutic activity. In summary, our data highlight that a better understanding of the AS landscape may aid in COVID-19 diagnosis and therapy.

Diagnostic and Prognostic Values of KRAS Mutations on EUS-FNA Specimens and Circulating Tumor DNA in Patients With Pancreatic Cancer.

INTRODUCTION: The ability of carbohydrate antigen 19-9 (CA19-9) to differentiate pancreatic cancer from other benign pancreatic lesions is unsatisfactory. This study explored the diagnostic value of KRAS gene mutations and plasma circulating tumor DNA (ctDNA) in patients with pancreatic cancer. METHODS: The prospective cohort study comprised 149 consecutive patients with solid pancreatic lesions who underwent endoscopic ultrasound-guided fine-needle aspiration (EUS-FNA). KRAS subtype mutations were analyzed by digital droplet PCR (ddPCR) in EUS-FNA histopathology tissue samples, and blood samples were sent for plasma ctDNA analysis. The final diagnosis was based on surgical resection pathology or follow-up for at least 2 years. RESULTS: Adding KRAS mutation ddPCR increased the sensitivity and accuracy of EUS-FNA from 71.4% to 91.6% (P < 0.001) and 75.8% to 88.6% (P < 0.001), respectively. By comparison, the sensitivities of circulating biomarkers ctDNA and CA19-9 were only 35.2% and 71.2%. The area under the curve of the receiver operating characteristic curve (AUC) of EUS-FNA and KRAS ddPCR combination was >0.90 for distinguishing pancreatic cancer from benign lesions, whereas the AUC of EUS-FNA and CA19-9 combination was 0.83. The median survival time was significantly shorter in patients with G12D KRAS mutations than that in patients with other mutations (180 vs 240 days, P < 0.001). DISCUSSION: FNA tissue sample KRAS mutation analysis in tissues significantly improves the diagnostic accuracy of cyto/histopathological evaluation in EUS-FNA samples. The combination of EUS-FNA and tissue sample KRAS ddPCR provided a more accurate method for pancreatic cancer diagnosis, superior to the combination of EUS-FNA and CA19-9/ctDNA. G12D KRAS mutations in pancreatic cancer were independently associated with poor overall survival.

SOX11 is a sensitive and specific marker for pulmonary high-grade neuroendocrine tumors.

BACKGROUND: Synaptophysin (SYN), chromogranin A (CGA), CD56 and insulinoma-associated protein 1 (INSM1) are proposed neuroendocrine (NE) markers used for diagnosis of pulmonary NE tumors. These NE markers have been identified in subsets of non-NE tumors requiring differential diagnosis, thus we sought to explore new NE markers. METHODS: We evaluated the immunohistochemical expression of SOX11, a transcription factor involved in neurogenesis, in pulmonary NE tumors and large cell carcinomas (LCCs). RESULTS: We found that SOX11 showed a sensitivity similar to INSM1 and CGA, and less than SYN and CD56 in small cell lung carcinomas (SCLCs) and large cell neuroendocrine carcinomas (LCNECs). While SOX11 is more specific than the other four markers for diagnosis of high-grade neuroendocrine carcinomas (HG-NECs) because 1) None of LCCs (0/63), the most challenging non-NE tumor type for differential diagnosis due to overlapped morphology with LCNECs displayed SOX11 positivity. While expression of at least one of SYN, CGA, CD56 or INSM1 was identified in approximately 60% (18/30) of LCCs. 2) SOX11 was only expressed in 1 of 37 carcinoid tumors in contrast to diffuse expression of SYN, CGA, CD56 and INSM1. In HG-NECs, we noticed that SOX11 was a good complementary marker for SCLC diagnosis as it was positive in 7 of 18 SYN-/CGA-/CD56- SCLCs and 3 of 8 SYN-/CGA-/CD56-/INSM1- SCLCs, and SOX11 positivity in 4 of 6 SYN-/CGA-/CD56- cases previously diagnosed as LCCs with NE morphology provides additional evidence of NE differentiation for reclassification into LCNECs, which was further confirmed by electromicroscopical identification of neurosecretory granules. We also found SOX11 expression cannot predict the prognosis in patients with HG-NECs. CONCLUSIONS: Therefore, SOX11 is a useful complementary transcriptional NE marker for diagnosis and differential diagnosis of SCLC and LCNEC.

Prognostic value and non-neuroendocrine role of INSM1 in small cell lung cancer.

BACKGROUND: Small cell lung cancer (SCLC) is a malignant lung neuroendocrine tumor with early metastasis, rapid progression, and poor outcomes. Insulinoma-associated protein 1 (INSM1) has been an excellent marker for neuroendocrine (NE) differentiation and widely used in the diagnosis of NE neoplasms, including SCLC. However, its role beyond NE diagnostic marker remained little reported. METHODS: We examined immunohistochemical expression of INSM1 in 73 surgically resected SCLC, analyzed its prognostic value by Kaplan-Meier method, and investigated clinical-pathological features of INSM1 high SCLC. In vitro, We assessed INSM1 function on glucose intake, tumor migration, and Cisplatin resistance by 2-NBDG glucose uptake fluorescent assay, transwell assay, and ANNEXIN V/PI assay, respectively. In vivo, we evaluated the therapeutic value of metformin on reversing INSM1 induced chemoresistance by BALB/c nude mice xenograft tumor model. RESULTS: High INSM1 expression was correlated with lymph node metastasis (LNM) (p = 0.0005), later TNM stages (p = 0.0003), and predicted poor survival (Log-rank p = 0.038). Multivariate Cox analysis confirmed INSM1 as an independent prognostic factor in SCLC (p = 0.012, HR:3.195, 95%CI:1.288-7.927). Interestingly, LNM was correlated with worse prognosis only in patients received chemotherapy (Log-rank p = 0.027) rather than the others (Log-rank p = 0.40). In patients having LNM and treated with chemotherapy, high INSM1 was correlated with worse clinic outcome (Log-rank p = 0.009). In vitro, overexpression of INSM1 decreased AMPK-α expression as well as glucose intake, promoted tumor cell migration, and limited the apoptosis induced by Cisplatin, which all could be reversed by Metformin. In vivo, INSM1 overexpression also contributed to tumor growth beyond inducing Cisplatin resistance. CONCLUSION: Our finding suggested INSM1 played more role than a NE marker, partly through down-regulating AMPK signal. INSM1 may serve as a novel prognostic marker and therapeutic target in SCLC.

Serum semaphorin 4C as a diagnostic biomarker in breast cancer: A multicenter retrospective study.

BACKGROUND: To date, there is no approved blood-based biomarker for breast cancer detection. Herein, we aimed to assess semaphorin 4C (SEMA4C), a pivotal protein involved in breast cancer progression, as a serum diagnostic biomarker. METHODS: We included 6,213 consecutive inpatients from Tongji Hospital, Qilu Hospital, and Hubei Cancer Hospital. Training cohort and two validation cohorts were introduced for diagnostic exploration and validation. A pan-cancer cohort was used to independently explore the diagnostic potential of SEMA4C among solid tumors. Breast cancer patients who underwent mass excision prior to modified radical mastectomy were also analyzed. We hypothesized that increased pre-treatment serum SEMA4C levels, measured using optimized in-house enzyme-linked immunosorbent assay kits, could detect breast cancer. The endpoints were diagnostic performance, including area under the receiver operating characteristic curve (AUC), sensitivity, and specificity. Post-surgery pathological diagnosis was the reference standard and breast cancer staging followed the TNM classification. There was no restriction on disease stage for eligibilities. RESULTS: We included 2667 inpatients with breast lesions, 2378 patients with other solid tumors, and 1168 healthy participants. Specifically, 118 patients with breast cancer were diagnosed with stage 0 (5.71%), 620 with stage I (30.00%), 966 with stage II (46.73%), 217 with stage III (10.50%), and 8 with stage IV (0.39%). Patients with breast cancer had significantly higher serum SEMA4C levels than benign breast tumor patients and normal controls (P < 0.001). Elevated serum SEMA4C levels had AUC of 0.920 (95% confidence interval [CI]: 0.900-0.941) and 0.932 (95%CI: 0.911-0.953) for breast cancer detection in the two validation cohorts. The AUCs for detecting early-stage breast cancer (n = 366) and ductal carcinoma in situ (n = 85) were 0.931 (95%CI: 0.916-0.946) and 0.879 (95%CI: 0.832-0.925), respectively. Serum SEMA4C levels significantly decreased after surgery, and the reduction was more striking after modified radical mastectomy, compared with mass excision (P < 0.001). The positive rate of enhanced serum SEMA4C levels was 84.77% for breast cancer and below 20.75% for the other 14 solid tumors. CONCLUSIONS: Serum SEMA4C demonstrated promising potential as a candidate biomarker for breast cancer diagnosis. However, validation in prospective settings and by other study groups is warranted.

Bispecific antibody targeting TROP2xCD3 suppresses tumor growth of triple negative breast cancer.

BACKGROUND: Triple negative breast cancer (TNBC) is a subtype of breast cancers with poor prognosis and targeted drug therapies are limited. To develop novel and efficacious therapies for TNBC, we developed a bispecific antibody F7AK3 that recognizes both trophoblast cell surface antigen 2 (TROP2) and CD3 and evaluated its antitumor activities both in vitro and in vivo. METHODS: The binding affinities of F7AK3 to the two targets, TROP2 and CD3, were evaluated by surface plasmon resonance. Binding of F7AK3 to TNBC cells and T cells were evaluated by flow cytometry. Immunofluorescent staining was performed to demonstrate the interactions between T cells with TNBC cells. The cytotoxicity of T cells against TNBC cell lines and primary tumor cells mediated by F7AK3 were determined in vitro. In vivo antitumor activity of F7AK3 was investigated in a xenograft TNBC tumor model, using immunodeficient mice that were reconstituted with human peripheral blood mononuclear cells. RESULTS: We demonstrated that F7AK3 binds specifically to human TROP2 and CD3 antigens, as well as TNBC cell lines and primary tumor cells. Human T cells can only be activated by F7AK3 in the presence of target tumor cells. F7AK3 recruits T cells to TROP2+ tumor cells in vitro and into tumor tissues in vivo. Antitumor growth activity of F7AK3 is observed in a xenograft TNBC tumor model. CONCLUSION: This study showed the antitumor potential of an anti-TROP2xCD3 bispecific antibody F7AK3 to TNBC tumor cells both in vitro and in vivo. These data demonstrate that F7AK3 has the potential to treat TNBC patients, which warrants further preclinical and clinical evaluation of the F7AK3 in advanced or metastatic TNBC patients.

Prediction of the World Health Organization Grade of rectal neuroendocrine tumors based on CT histogram analysis.

OBJECTIVES: To investigate the diagnostic value of contrast-enhanced computed tomography (CECT) histogram analysis in predicting the World Health Organization (WHO) grade of rectal neuroendocrine tumors (R-NETs). MATERIALS AND METHODS: A total of 61 (35 G1, 12 G2, 10 G3, and 4 NECs) patients who underwent preoperative CECT and treated with surgery to be confirmed as R-NETs were included in this study from January 2014 to May 2019. We depicted ROIs and measured the CECT texture parameters (mean, median, 10th, 25th, 75th, 90th percentiles, skewness, kurtosis, and entropy) from arterial phase (AP) and venous phase (VP) images by two radiologists. We calculated intraclass correlation coefficient (ICC) and compared the histogram parameters between low-grade (G1) and higher grade (HG) (G2/G3/NECs) by applying appropriate statistical method. We obtained the optimal parameters to identify G1 from HG using receiver operating characteristic (ROC) curves. RESULTS: The capability of AP and VP histogram parameters for differentiating G1 from HG was similar in several histogram parameters (mean, median, 10th, 25th, 75th, and 90th percentiles) (all p < 0.001). Skewness, kurtosis, and entropy on AP images showed no significant differences between G1 and HG (p = 0.853, 0.512, 0.557, respectively). Entropy on VP images was significantly different (p = 0.017) between G1 and HG, however, skewness and kurtosis showed no significant differences (p = 0.654, 0.172, respectively). ROC analysis showed a good predictive performance between G1 and HG, and the 75th (AP) generated the highest area under the curve (AUC = 0.871), followed by the 25th (AP), mean (VP), and median (VP) (AUC = 0.864). Combined the size of tumor and the 75th (AP) generated the highest AUC. CONCLUSIONS: CECT histogram parameters, including arterial and venous phases, can be used as excellent indicators for predicting G1 and HG of rectal neuroendocrine tumors, and the size of the tumor is also an important independent predictor.

CCL7 recruits cDC1 to promote antitumor immunity and facilitate checkpoint immunotherapy to non-small cell lung cancer.

The efficacy of checkpoint immunotherapy to non-small cell lung cancer (NSCLC) largely depends on the tumor microenvironment (TME). Here, we demonstrate that CCL7 facilitates anti-PD-1 therapy for the KrasLSL-G12D/+Tp53fl/fl (KP) and the KrasLSL-G12D/+Lkb1fl/fl (KL) NSCLC mouse models by recruiting conventional DC 1 (cDC1) into the TME to promote T cell expansion. CCL7 exhibits high expression in NSCLC tumor tissues and is positively correlated with the infiltration of cDC1 in the TME and the overall survival of NSCLC patients. CCL7 deficiency impairs the infiltration of cDC1 in the TME and the subsequent expansion of CD8+ and CD4+ T cells in bronchial draining lymph nodes and TME, thereby promoting tumor development in the KP mouse model. Administration of CCL7 into lungs alone or in combination with anti-PD-1 significantly inhibits tumor development and prolongs the survival of KP and KL mice. These findings suggest that CCL7 potentially serves as a biomarker and adjuvant for checkpoint immunotherapy of NSCLC.

Transcriptional and proteomic insights into the host response in fatal COVID-19 cases.

Coronavirus disease 2019 (COVID-19), the global pandemic caused by SARS-CoV-2, has resulted thus far in greater than 933,000 deaths worldwide; yet disease pathogenesis remains unclear. Clinical and immunological features of patients with COVID-19 have highlighted a potential role for changes in immune activity in regulating disease severity. However, little is known about the responses in human lung tissue, the primary site of infection. Here we show that pathways related to neutrophil activation and pulmonary fibrosis are among the major up-regulated transcriptional signatures in lung tissue obtained from patients who died of COVID-19 in Wuhan, China. Strikingly, the viral burden was low in all samples, which suggests that the patient deaths may be related to the host response rather than an active fulminant infection. Examination of the colonic transcriptome of these patients suggested that SARS-CoV-2 impacted host responses even at a site with no obvious pathogenesis. Further proteomics analysis validated our transcriptome findings and identified several key proteins, such as the SARS-CoV-2 entry-associated protease cathepsins B and L and the inflammatory response modulator S100A8/A9, that are highly expressed in fatal cases, revealing potential drug targets for COVID-19.

Rho-kinase inhibition by Fasudil promotes tumor maturation and apoptosis in small-cell lung cancer.

Small-cell lung cancer (SCLC) is a poorly differentiated neuroendocrine neoplasm with inadequate therapeutic options. Fasudil is a Rho-associated protein kinase 1 and 2 (ROCK1/2) inhibitor whose clinical indications remain limited in cardiocerebrovascular diseases. This study aimed to report a possible implication of Fasudil for SCLC. The expression and prognostic value of ROCK1/2 were investigated immunohistochemically in surgical specimens. The positive rates of ROCK1 (77/113, 68.1%) and ROCK2 (94/113, 83.2%) were distinctly higher in SCLC than in other lung neuroendocrine tumors. The high expression level of ROCK1 was related to the poor long-term survival of patients, especially in the classic SCLC subtype. In vitro, SCLC cell line treated with Fasudil exhibited synapse-like morphologic change, accompanied by a reduction in the expression levels of c-myc and cyclin D1. Cell cycle arrest was further demonstrated, accompanied by sensitivity to starvation-induced apoptosis, indicating tumor maturation. In addition, RNA-seq identified hundreds of differentially expressed genes involved in the positive regulation of neuron differentiation, stem cell differentiation, cell development, and nervous system development. Finally, Fasudil inhibited SCLC growth, promoted structural maturity, and induced apoptosis in BALB/c nude mice xenograft model. In conclusion, these results indicated a potential and novel application of Fasudil for SCLC treatment.

Clinicopathological Features and Outcomes of Acute Kidney Injury in Critically Ill COVID-19 with Prolonged Disease Course: A Retrospective Cohort.

BACKGROUND: The incidence, severity, and outcomes of AKI in COVID-19 varied in different reports. In patients critically ill with COVID-19, the clinicopathologic characteristics of AKI have not been described in detail. METHODS: This is a retrospective cohort study of 81 patients critically ill with COVID-19 in an intensive care unit. The incidence, etiologies, and outcomes of AKI were analyzed. Pathologic studies were performed in kidney tissues from ten deceased patients with AKI. RESULTS: A total of 41 (50.6%) patients experienced AKI in this study. The median time from illness to AKI was 21.0 (IQR, 9.5-26.0) days. The proportion of Kidney Disease Improving Global Outcomes (KDIGO) stage 1, stage 2, and stage 3 AKI were 26.8%, 31.7%, and 41.5%, respectively. The leading causes of AKI included septic shock (25 of 41, 61.0%), volume insufficiency (eight of 41, 19.5%), and adverse drug effects (five of 41, 12.2%). The risk factors for AKI included age (per 10 years) (HR, 1.83; 95% CI, 1.24 to 2.69; P=0.002) and serum IL-6 level (HR, 1.83; 95% CI, 1.23 to 2.73; P=0.003). KDIGO stage 3 AKI predicted death. Other potential risk factors for death included male sex, elevated D-dimer, serum IL-6 level, and higher Sequential Organ Failure Assessment score. The predominant pathologic finding was acute tubular injury. Nucleic acid tests and immunohistochemistry failed to detect the virus in kidney tissues. CONCLUSIONS: AKI was a common and multifactorial complication in patients critically ill with COVID-19 at the late stage of the disease course. The predominant pathologic finding was acute tubular injury. Older age and higher serum IL-6 level were risk factors of AKI, and KDIGO stage 3 AKI independently predicted death.