KCNK1 promotes proliferation and metastasis of breast cancer cells by activating lactate dehydrogenase A (LDHA) and up-regulating H3K18 lactylation.

Breast cancer is the most prevalent malignancy and the most significant contributor to mortality in female oncology patients. Potassium Two Pore Domain Channel Subfamily K Member 1 (KCNK1) is differentially expressed in a variety of tumors, but the mechanism of its function in breast cancer is unknown. In this study, we found for the first time that KCNK1 was significantly up-regulated in human breast cancer and was correlated with poor prognosis in breast cancer patients. KCNK1 promoted breast cancer proliferation, invasion, and metastasis in vitro and vivo. Further studies unexpectedly revealed that KCNK1 increased the glycolysis and lactate production in breast cancer cells by binding to and activating lactate dehydrogenase A (LDHA), which promoted histones lysine lactylation to induce the expression of a series of downstream genes and LDHA itself. Notably, increased expression of LDHA served as a vicious positive feedback to reduce tumor cell stiffness and adhesion, which eventually resulted in the proliferation, invasion, and metastasis of breast cancer. In conclusion, our results suggest that KCNK1 may serve as a potential breast cancer biomarker, and deeper insight into the cancer-promoting mechanism of KCNK1 may uncover a novel therapeutic target for breast cancer treatment.

High-Throughput Antigen Microarray Identifies Longitudinal Prognostic Autoantibody for Chemoimmunotherapy in Advanced Non-Small Cell Lung Cancer.

Chemoimmunotherapy has evolved as a standard treatment for advanced non-small cell lung cancer (aNSCLC). However, inevitable drug resistance has limited its efficacy, highlighting the urgent need for biomarkers of chemoimmunotherapy. A three-phase strategy to discover, verify, and validate longitudinal predictive autoantibodies (AAbs) for aNSCLC before and after chemoimmunotherapy was employed. A total of 528 plasma samples from 267 aNSCLC patients before and after anti-PD1 immunotherapy were collected, plus 30 independent formalin-fixed paraffin-embedded samples. Candidate AAbs were firstly selected using a HuProt high-density microarray containing 21,000 proteins in the discovery phase, followed by validation using an aNSCLC-focused microarray. Longitudinal predictive AAbs were chosen for ELISA based on responders versus non-responders comparison and progression-free survival (PFS) survival analysis. Prognostic markers were also validated using immunohistochemistry and publicly available immunotherapy datasets. We identified and validated a panel of two AAbs (MAX and DHX29) as pre-treatment biomarkers and another panel of two AAbs (MAX and TAPBP) as on-treatment predictive markers in aNSCLC patients undergoing chemoimmunotherapy. All three AAbs exhibited a positive correlation with early responses and PFS (p < 0.05). The kinetics of MAX AAb showed an increasing trend in responders (p < 0.05) and a tendency to initially increase and then decrease in non-responders (p < 0.05). Importantly, MAX protein and mRNA levels effectively discriminated PFS (p < 0.05) in aNSCLC patients treated with immunotherapy. Our results present a longitudinal analysis of changes in prognostic AAbs in aNSCLC patients undergoing chemoimmunotherapy.

Carbon-Carbon Bond Cleavage for Late-Stage Functionalization.

Late-stage functionalization (LSF) introduces functional group or structural modification at the final stage of the synthesis of natural products, drugs, and complex compounds. It is anticipated that late-stage functionalization would improve drug discovery's effectiveness and efficiency and hasten the creation of various chemical libraries. Consequently, late-stage functionalization of natural products is a productive technique to produce natural product derivatives, which significantly impacts chemical biology and drug development. Carbon-carbon bonds make up the fundamental framework of organic molecules. Compared with the carbon-carbon bond construction, the carbon-carbon bond activation can directly enable molecular editing (deletion, insertion, or modification of atoms or groups of atoms) and provide a more efficient and accurate synthetic strategy. However, the efficient and selective activation of unstrained carbon-carbon bonds is still one of the most challenging projects in organic synthesis. This review encompasses the strategies employed in recent years for carbon-carbon bond cleavage by explicitly focusing on their applicability in late-stage functionalization. This review expands the current discourse on carbon-carbon bond cleavage in late-stage functionalization reactions by providing a comprehensive overview of the selective cleavage of various types of carbon-carbon bonds. This includes C-C(sp), C-C(sp2), and C-C(sp3) single bonds; carbon-carbon double bonds; and carbon-carbon triple bonds, with a focus on catalysis by transition metals or organocatalysts. Additionally, specific topics, such as ring-opening processes involving carbon-carbon bond cleavage in three-, four-, five-, and six-membered rings, are discussed, and exemplar applications of these techniques are showcased in the context of complex bioactive molecules or drug discovery. This review aims to shed light on recent advancements in the field and propose potential avenues for future research in the realm of late-stage carbon-carbon bond functionalization.

Proteomics Identifies Circulating TIMP-1 as a Prognostic Biomarker for Diffuse Large B-Cell Lymphoma.

Diffuse large B-cell lymphoma (DLBCL) is a heterogeneous disease, although disease stratification using in-depth plasma proteomics has not been performed to date. By measuring more than 1000 proteins in the plasma of 147 DLBCL patients using data-independent acquisition mass spectrometry and antibody array, DLBCL patients were classified into four proteomic subtypes (PS-I-IV). Patients with the PS-IV subtype and worst prognosis had increased levels of proteins involved in inflammation, including a high expression of metalloproteinase inhibitor-1 (TIMP-1) that was associated with poor survival across two validation cohorts (n = 180). Notably, the combination of TIMP-1 with the international prognostic index (IPI) identified 64.00% to 88.24% of relapsed and 65.00% to 80.49% of deceased patients in the discovery and two validation cohorts, which represents a 24.00% to 41.67% and 20.00% to 31.70% improvement compared to the IPI score alone, respectively. Taken together, we demonstrate that DLBCL heterogeneity is reflected in the plasma proteome and that TIMP-1, together with the IPI, could improve the prognostic stratification of patients.

Identification of novel prognostic autoantibodies in diffuse large B-cell lymphoma treated with rituximab plus cyclophosphamide, doxorubicin, vincristine, and prednisone via a high-throughput antigen microarray.

BACKGROUND: R-CHOP (rituximab plus cyclophosphamide, doxorubicin, vincristine, and prednisone) is a standard first-line treatment for diffuse large B-cell lymphoma (DLBCL). However, 20%-40% of patients survive less than 5 years. Novel prognostic biomarkers remain in demand. METHODS: Baseline plasma autoantibodies (AAbs) were assessed in 336 DLBCLs. In the discovery phase (n = 20), a high-density antigen microarray (∼21,000 proteins) was used to expound AAb profiles. In the verification phase (n = 181), with a DLBCL-focused microarray, comparative results based on event-free survival at 24 months (EFS24) and lasso Cox regression models of progression-free survival (PFS) and overall survival (OS) were integrated to identify potential biomarkers. They were further validated by enzyme-linked immunosorbent assay in validation phase 1 (n = 135) and a dynamic cohort (n = 12). In validation phase 2, a two-AAb-based risk score was established. They were further validated in an immunohistochemistry cohort (n = 55) and four independent Gene Expression Omnibus datasets (n = 1598). RESULTS: Four AAbs (CREB1, N4BP1, UBAP2, and DEAF1) were identified that showed associations with EFS24 status (p < .05) and superior PFS and OS (p < .05). A novel risk score model based on CREB1 and N4BP1 AAbs was developed to predict PFS with areas under the curve of 0.72, 0.71, 0.76, and 0.82 at 1, 3, 5, and 7 years, respectively, in DLBCL treated with R-CHOP independent of the International Prognostic Index (IPI) and provided significant additional recurrence risk discrimination (p < .05) for the IPI. CREB1 and N4BP1 proteins and messenger RNAs were also associated with better PFS and OS (p < .05). CONCLUSIONS: This study identified a novel prognostic panel of CREB1, N4BP1, DEAF1, and UBAP2 AAbs that is independent of the IPI in DLBCL.

Longitudinal plasma proteomic analysis identifies biomarkers and combinational targets for anti-PD1-resistant cancer patients.

The response rate of anti-PD1 therapy is limited, and the influence of anti-PD1 therapy on cancer patients is unclear. To address these challenges, we conducted a longitudinal analysis of plasma proteomic changes with anti-PD1 therapy in non-small cell lung cancer (NSCLC), alveolar soft part sarcoma (ASPS), and lymphoma patients. We included 339 plasma samples before and after anti-PD1 therapy from 193 patients with NSCLC, ASPS, or lymphoma. The plasma proteins were detected using data-independent acquisition-mass spectrometry and customable antibody microarrays. Differential proteomic characteristics in responders (R) and non-responders (NR) before and after anti-PD1 therapy were elucidated. A total of 1019 proteins were detected using our in-depth proteomics platform and distributed across 10-12 orders of abundance. By comparing the differential plasma proteome expression between R and NR groups, 50, 206, and 268 proteins were identified in NSCLC, ASPS, and lymphoma patients, respectively. Th17, IL-17, and JAK-STAT signal pathways were identified upregulated in NR group, while cellular senescence and transcriptional misregulation pathways were activated in R group. Longitudinal proteomics analysis revealed the IL-17 signaling pathway was downregulated after treatment. Consistently, many proteins were identified as potential combinatorial therapeutic targets (e.g., IL-17A and CD22). Five noninvasive biomarkers (FLT4, SFTPB, GNPTG, F5, and IL-17A) were further validated in an independent lymphoma cohort (n = 39), and another three noninvasive biomarkers (KIT, CCL3, and TNFSF1) were validated in NSCLC cohort (n = 76). Our results provide molecular insights into the anti-PD1 therapy in cancer patients and identify new therapeutic strategies for anti-PD1-resistant patients.

Mutational variant allele frequency profile as a biomarker of response to immune checkpoint blockade in non-small cell lung Cancer.

INTRODUCTION: Identifying new biomarkers for predicting immune checkpoint inhibitors (ICIs) response in non-small cell lung cancer (NSCLC) is crucial. We aimed to assess the variant allele frequency (VAF)-related profile as a novel biomarker for NSCLC personalized therapy. METHODS: We utilized genomic data of 915 NSCLC patients via cBioPortal and a local cohort of 23 patients for model construction and mutational analysis. Genomic, transcriptomic data from 952 TCGA NSCLC patients, and immunofluorescence (IF) assessment with the local cohort supported mechanism analysis. RESULTS: Utilizing the random forest algorithm, a 15-gene VAF-related model was established, differentiating patients with durable clinical benefit (DCB) from no durable benefit (NDB). The model demonstrated robust performance, with ROC-AUC values of 0.905, 0.737, and 0.711 across training (n = 313), internal validation (n = 133), and external validation (n = 157) cohorts. Stratification by the model into high- and low-score groups correlated significantly with both progression-free survival (PFS) (training: P < 0.0001, internal validation: P < 0.0001, external validation: P = 0.0066) and overall survival (OS) (n = 341) (P < 0.0001). Notably, the stratification system was independent of PD-L1 (P < 0.0001) and TMB (P < 0.0001). High-score patients exhibited an increased DCB ratio and longer PFS across both PD-L1 and TMB subgroups. Additionally, the high-score group appeared influenced by tobacco exposure, with activated DNA damage response pathways. Whereas, immune/inflammation-related pathways were enriched in the low-score group. Tumor immune microenvironment analyses revealed higher proportions of exhausted/effector memory CD8 + T cells in the high-score group. CONCLUSIONS: The mutational VAF profile is a promising biomarker for ICI therapy in NSCLC, with enhanced therapeutic stratification and management as a supplement to PD-L1 or TMB.

Development and validation of a novel risk stratification model and a survival rate calculator for diffuse large B-cell lymphoma in the rituximab era: a multi-institutional cohort study.

BACKGROUND: This study aimed to develop and validate a novel risk stratification model and a web-based survival rate calculator to improve discriminative and predictive accuracy for diffuse large B-cell lymphoma (DLBCL) in the rituximab era. METHODS: We retrospectively collected pre-treatment data from 873 primary DLBCL patients who received R-CHOP-based immunochemotherapy regimens at the Cancer Hospital, Chinese Academy of Medical Sciences, from January 1, 2005, to December 31, 2018. An independent cohort of 175 DLBCL patients from Fujian Cancer Hospital was used for external validation. FINDINGS: Age, ECOG PS, number of extranodal sites, Ann Arbor stage, bulky disease, and LDH levels were screened to develop the nomogram and web-based survival rate calculator. The C-index of the nomogram in the training, internal validation, and external validation cohorts was 0.761, 0.758, and 0.768, respectively. The risk stratification model generated based on the nomogram effectively stratified patients into three distinct risk groups. K-M survival curves demonstrated that the novel risk stratification model exhibited a superior level of predictive accuracy compared to IPI, R-IPI, and NCCN-IPI both in training and two validation cohorts. Additionally, the area under the curve (AUC) value of the novel model (0.763) for predicting 5-year overall survival rates was higher than those of IPI (0.749), R-IPI (0.725), and NCCN-IPI (0.727) in the training cohort. Similar results were observed in both internal and external validation cohort. CONCLUSIONS: In conclusion, we have successfully developed and validated a novel risk stratification model and a web-based survival rate calculator that demonstrated superior discriminative and predictive accuracy compared to IPI, R-IPI, and NCCN-IPI in the rituximab era.

Black carp ATG16L1 negatively regulates STING-mediated antiviral innate immune response.

The precise control of interferon (IFN) production is indispensable for the host to eliminate invading viruses and maintain a homeostatic state. In mammals, stimulator of interferon genes (STING) is a prominent adaptor involved in antiviral immune signaling pathways. However, the regulatory mechanism of piscine STING has not been thoroughly investigated. Here, we report that autophagy related 16 like 1 (bcATG16L1) of black carp (Mylopharyngodon piceus) is a negative regulator in black carp STING (bcSTING)-mediated signaling pathway. Initially, we substantiated that knockdown of bcATG16L1 increased the transcription of IFN and ISGs and enhanced the antiviral activity of the host cells. Subsequently, we identified that bcATG16L1 inhibited the bcSTING-mediated IFN promoter activation and proved that bcATG16L1 suppressed bcSTING-mediated antiviral ability. Furthermore, we revealed that bcATG16L1 interacted with bcSTING and the two proteins shared a similar subcellular distribution. Mechanically, we found that bcATG16L1 attenuated the oligomerization of bcSTING, which was a key step for bcSTING activation. Taken together, our results indicate that bcATG16L1 interacts with bcSTING, dampens the oligomerization of bcSTING, and negatively regulates bcSTING-mediated antiviral activity.

Human umbilical cord mesenchymal stem cells improve uterine incision healing after cesarean delivery in rats by modulating the TGF-ß/Smad signaling pathway.

OBJECTIVE: Although human umbilical cord-derived mesenchymal stem cells (HU-MSCs) have attracted increasing attention because of their pivotal functions in the process of wound healing, the underlying molecular mechanisms have been poorly understood. It has been shown that the TGF-ß/Smad signaling pathway plays an important role in the process of scar formation. The present study focused on exploring whether HU-MSCs improve uterine incision healing after cesarean delivery in rats via the TGF-ß/Smad signaling pathway. STUDY DESIGN: Pregnant rats were randomly assigned to three groups, including the NP group, incision-injected group (HU-MSCs1 group), and tail vein-injected group (HU-MSCs2 group), and 30 days after cesarean section, sampling was carried out to further explore the specific mechanisms from tissue and protein levels. RESULTS: HU-MSCs secretion could inhibit the fibrosis of scar tissue. We observed that the TGF-ß induced expression of TGF-ß1, Smad2, and Smad3 was attenuated upon HU-MSCs treatment in scar tissue, while the decrease in TGF-ß3 expression was enhanced by HU-MSCs. Furthermore, HU-MSCs treatment accelerated wound healing and attenuated collagen deposition in a damaged uterine rat model, leading to the promoting of uterine incision scarring. In addition, the expression of alpha-smooth muscle actin (a-SMA) was enhanced by HU-MSCs treatment. CONCLUSION: HU-MSCs transplantation promotes rat cesarean section uterine incision scar healing by modulating the TGF-ß/Smad signaling pathway.

Differential regulation of autophagy on urine-concentrating capability through modulating the renal AQP2 expression and renin-angiotensin system in mice.

Autophagy, a cellular process of "self-eating," plays an essential role in renal pathophysiology. However, the effect of autophagy on urine-concentrating ability in physiological conditions is still unknown. This study aimed to determine the relevance and mechanisms of autophagy for maintaining urine-concentrating capability during antidiuresis. The extent of the autophagic response to water deprivation (WD) was different between the renal cortex and medulla in mice. Autophagy activity levels in the renal cortex were initially suppressed and then stimulated by WD in a time-dependent manner. During 48 h WD, the urine-concentrating capability of mice was impaired by rapamycin (Rapa) but not by 3-methyladenine (3-MA), accompanied by suppressed renal aquaporin 2 (AQP2), V2 receptor (V2R), renin, and angiotensin-converting enzyme (ACE) expression, and levels of prorenin/renin, angiotensin II (ANG II), and aldosterone in the plasma and urine. In contrast, 3-MA and chloroquine (CQ) suppressed the urine-concentrating capability in WD72 mice, accompanied by downregulation of AQP2 and V2R expression in the renal cortex. 3-MA and CQ further increased AQP2 and V2R expression in the renal medulla of WD72 mice. Compared with 3-MA and CQ, Rapa administration yielded completely opposite results on the above parameters in WD72 mice. In addition, 3-MA and CQ abolished the upregulation of prorenin/renin, ANG II, and aldosterone levels in the plasma and urine in WD72 mice. Taken together, our study demonstrated that autophagy regulated urine-concentrating capability through differential regulation of renal AQP2/V2R and ACE/ANG II signaling during WD.NEW & NOTEWORTHY Autophagy exhibits a double-edged effect on cell survival and plays an essential role in renal pathophysiology. We for the first time reported a novel function of autophagy that controls the urine-concentrating capability in physiological conditions. We found that water deprivation (WD) differentially regulated autophagy in the kidneys of mice in a time-dependent manner and autophagy regulates the urine-concentrating capability mainly by regulating AQP2/V2R and ACE/ANG II signaling in the renal cortex in WD mice.

Identification of an antigen-presenting cells/T/NK cells-related gene signature to predict prognosis and CTSL to predict immunotherapeutic response for lung adenocarcinoma: an integrated analysis of bulk and single-cell RNA sequencing.

BACKGROUND: Antigen-presenting cells (APC)/T/NK cells are key immune cells that play crucial roles in fighting against malignancies including lung adenocarcinoma (LUAD). In this study, we aimed to identify an APC/T/NK cells-related gene signature (ATNKGS) and potential immune cell-related genes (IRGs) to realize risk stratification, prognosis, and immunotherapeutic response prediction for LUAD patients. METHODS: Based on the univariate Cox regression and the LASSO Cox regression results of 196 APC/T/NK cells-related genes collected from three pathways in the KEGG database, we determined the final genes and established the ATNKGS-related risk model. The single-cell RNA sequencing data were applied for key IRGs identification and investigate their value in immunotherapeutic response prediction. Several GEO datasets and an external immunotherapy cohort from Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, were applied for validation. RESULTS: In this study, nine independent public datasets including 1108 patients were enrolled. An ATNKGS containing 16 genes for predicting overall survival of LUAD patients was constructed with robust prognostic capability. The ATNKGS high risk group was related to significantly worse OS outcomes than those in the low-risk group, which were verified in TCGA and four GEO datatsets. A nomogram combining the ATNKGS risk score with clinical TNM stage achieved the optimal prediction performance. The single-cell RNA sequencing analysis revealed CTSL as an IRG of macrophage and monocyte. Moreover, though CTSL was an indicator for poor prognosis of LUAD patients, CTSL high expression group was associated with higher ESTIMATEScore, immune checkpoints expression, and lower TIDE score. Several immunotherapeutic cohorts have confirmed the response-predicting significance of CTSL in patients receiving immune checkpoint inhibitor (ICI) treatment. CONCLUSIONS: Our study provided an insight into the significant role of APC/T/NK cells-related genes in survival risk stratification and CTSL in response prediction of immunotherapy in patients with LUAD.

Immune checkpoint inhibitors combined with angiogenic inhibitors in the treatment of locally advanced or metastatic lung adenocarcinoma patients.

BACKGROUND: To report the efficacy and safety data of immunotherapy plus angiogenic inhibitors treatment in lung adenocarcinoma patients. METHODS: Eligible patients with pathological or cytological confirmed locally advanced or metastatic lung adenocarcinoma and treated with immune checkpoint inhibitors (ICI) plus angiogenic inhibitors were enrolled. The primary endpoints were progressive free survival (PFS). The secondary endpoints were objective response rate (ORR), disease control rate (DCR), overall survival (OS), and safety. RESULTS: A total of 46 consecutive enrolled patients received ICI plus angiogenic inhibitor, and the median follow-up was 9.6 months (range 1.5-32.5). The ORR and DCR were 8.7% (n = 4) and 50% (n = 23), respectively. Median PFS and OS were 2.9 months (95% CI 2.1-3.7) and 12.3 months (95% CI 7.6-17.0), respectively. Patients at stage IVB had an inferior PFS than stage IIIC or IVA (2.8 months vs 4.4 months, P = 0.003). The median PFS of patients who were treated with ICI plus bevacizumab was shorter than ICI plus anlotinib or apatinib (1.2 months vs 3.3 months, P = 0.005). The occurrence of hypertension during the combination treatment has been related to a tendency for prolonged PFS (5.5 months vs 2.6 months; P = 0.05). The overall incidence of treatment-related adverse events (TRAE) was 89.1% (n = 41), and grade 3-4 TRAE was occupied 21.4% (n = 10). CONCLUSION: This study objectively demonstrated that the treatment of ICI and antiangiogenic agents in lung adenocarcinoma could be a promising alternative therapeutic regimen, and the toxic effects were manageable. Subgroup analysis revealed that small molecular angiogenic inhibitors plus ICI and low tumor burden during treatment were better prognostic factors.

Incidence, survival comparison, and novel prognostic evaluation approaches for stage iii-iv pulmonary large cell neuroendocrine carcinoma and small cell lung cancer.

BACKGROUND: Pulmonary large cell neuroendocrine carcinoma (LCNEC) and small cell lung cancer (SCLC) are two types of high-grade neuroendocrine carcinomas of the lung with poor prognosis. LCNEC has not been thoroughly studied due to its rarity, data are also lacking regarding the survival comparison and prognosis analysis of patients with locally advanced or metastatic LCNEC and SCLC. METHODS: Data of patients with LCNEC, SCLC, and other NSCLC who were diagnosed from 1975 to 2019 were extracted from the Surveillance, Epidemiology and End Results (SEER) database to estimate incidence. Those in stage III-IV and being diagnosed from 2010 to 2015 were utilized further to investigate their clinical characteristics and prognosis. Propensity score matching (PSM) analyses at a ratio of 1:2 was used to compare their survival outcomes. Nomograms of LCNEC and SCLC were established with internal validation, and the nomogram of SCLC was externally validated by 349 patients diagnosed in Cancer hospital, Chinese Academy of Medical Sciences & Peking Union Medical College from January 1, 2012 to December 31, 2018. RESULTS: The incidence of LCNEC has been increasing in recent decades, meanwhile that of SCLC and other types of NSCLC were decreasing. A total of 91,635 lung cancer patients, including 785 with LCNEC, 15,776 with SCLC, and 75,074 with other NSCLC were enrolled for further analysis. The survival of stage III-IV LCNEC resembles that of SCLC, and significantly worse than other types of NSCLC before and after PSM analysis. In pretreatment prognostic analysis, age, T stage, N stage, M stage, bone metastasis, liver metastasis, and brain metastasis were found to be associated with the survival of both LCNEC and SCLC, besides sex, bilaterality, and lung metastasis were additional prognostic factors for SCLC. Two nomograms and convenient online tools respectively for LCNEC and SCLC were established accordingly with favorable predicting accuracy of < 1-year, < 2-year, < 3-year survival probabilities. In external validation of the SCLC nomogram with a Chinese cohort, the AUCs of 1-year, 2-year and 3-year ROC were 0.652, 0.669, and 0.750, respectively. All the results of 1-, 2-, 3- year variable-dependent ROC curves verified the superior prognostic value of our nomograms for LCNEC and SCLC over the traditional T/N/M staging system. CONCLUSIONS: Based on large sample-based cohort, we compared the epidemiological trends and survival outcomes between locally advanced or metastatic LCNEC, SCLC, and other NSCLC. Furthermore, two prognostic evaluation approaches respectively for LCNEC and SCLC might present as practical tools for clinicians to predict the survival outcome of these patients and facilitate risk stratification.

Tiliroside Protects against Lipopolysaccharide-Induced Acute Kidney Injury via Intrarenal Renin-Angiotensin System in Mice.

Tiliroside, a natural flavonoid, has various biological activities and improves several inflammatory diseases in rodents. However, the effect of Tiliroside on lipopolysaccharide (LPS)-induced acute kidney injury (AKI) and the underlying mechanisms are still unclear. This study aimed to evaluate the potential renoprotective effect of Tiliroside on LPS-induced AKI in mice. Male C57BL/6 mice were intraperitoneally injected with LPS (a single dose, 3 mg/kg) with or without Tiliroside (50 or 200 mg/kg/day for 8 days). Tiliroside administration protected against LPS-induced AKI, as reflected by ameliorated renal dysfunction and histological alterations. LPS-stimulated renal expression of inflammatory cytokines, fibrosis markers, and kidney injury markers in mice was significantly abolished by Tiliroside. This flavonoid also stimulated autophagy flux but inhibited oxidative stress and tubular cell apoptosis in kidneys from LPS-injected mice. Mechanistically, our study showed the regulation of Tiliroside on the intrarenal renin-angiotensin system in LPS-induced AKI mice. Tiliroside treatment suppressed intrarenal AGT, Renin, ACE, and Ang II, but upregulated intrarenal ACE2 and Ang1-7, without affecting plasma Ang II and Ang1-7 levels. Collectively, our data highlight the renoprotective action of Tiliroside on LPS-induced AKI by suppressing inflammation, oxidative stress, and tubular cell apoptosis and activating autophagy flux via the shift towards the intrarenal ACE2/Ang1-7 axis and away from the intrarenal ACE/Ang II axis.

Biocompatibility and Biological Effects of Surface-Modified Conjugated Polymer Nanoparticles.

Semiconductiong polymer nanoparticles (Pdots) have a wide range of applications in biomedical fields including biomolecular probes, tumor imaging, and therapy. However, there are few systematic studies on the biological effects and biocompatibility of Pdots in vitro and in vivo. The physicochemical properties of Pdots, such as surface modification, are very important in biomedical applications. Focusing on the central issue of the biological effects of Pdots, we systematically investigated the biological effects and biocompatibility of Pdots with different surface modifications and revealed the interactions between Pdots and organisms at the cellular and animal levels. The surfaces of Pdots were modified with different functional groups, including thiol, carboxyl, and amino groups, named Pdots@SH, Pdots@COOH, and Pdots@NH2, respectively. Extracellular studies showed that the modification of sulfhydryl, carboxyl, and amino groups had no significant effect on the physicochemical properties of Pdots, except that the amino modification affected the stability of Pdots to a certain extent. At the cellular level, Pdots@NH2 reduced cellular uptake capacity and increased cytotoxicity due to their instability in solution. At the in vivo level, the body circulation and metabolic clearance of Pdots@SH and Pdots@COOH were superior to those of Pdots@NH2. The four kinds of Pdots had no obvious effect on the blood indexes of mice and histopathological lesions in the main tissues and organs. This study provides important data for the biological effects and safety assessment of Pdots with different surface modifications, which pave the way for their potential biomedical applications.

Brain metastases and immune checkpoint inhibitors in non-small cell lung cancer: a systematic review and meta-analysis.

BACKGROUND: The use of immune checkpoint inhibitors (ICIs) for brain metastases (BMs) from non-small cell lung cancer (NSCLC) remains debatable. This study aimed to explore the efficacy of ICIs for NSCLC with BMs. We also evaluated the effect of BMs on outcomes of ICIs. METHODS: A systematic search of PubMed, Embase, Web of Science, and Cochrane databases was conducted to identify studies where the efficacy of ICIs against BMs from NSCLC, or the association between BMs and outcomes of ICIs were evaluated. Outcomes included intracranial objective response rate (icORR), intracranial disease control rate (icDCR), systemic ORR and DCR. RESULTS: Overall, 33 studies were included in this meta-analysis. The pooled icORR was 13% (95%CI 6-23%) and icDCR was 50% (95%CI 40-63%) for programmed cell death-ligand 1 (PD-L1) unselected patients with any BMs. For active BMs, pooled icORR was 15% (95%CI 6-28%) and icDCR was 47% (95% CI 36-57%). For PD-L1 ≥ 50% patients with any BMs, pooled icORR and icDCR were 68% (95%CI 57-80%) and 82% (95%CI 73-92%), respectively. Additionally, pooled systemic ORR and DCR for any BMs were 22% (95%CI 15-30%) and 41% (95%CI 18-67%), respectively. Patients with BMs had inferior progression-free survival (HR 1.19, 95%CI 1.07-1.33, P = 0.0016) and overall survival (HR 1.14, 95%CI 1.03-1.25, P = 0.011) when applying ICIs compared to those without BMs. However, no significant difference in systemic ORR between patients with and without BMs was observed (OR 0.94, 95%CI 0.72-1.20, P = 0.629). CONCLUSION: ICIs may be clinically active in NSCLC patients with BMs. More effective treatments for BMs from NSCLC are needed.

Anti-PD1/PDL1 IgG subclass distribution in ten cancer types and anti-PD1 IgG4 as biomarker for the long time survival in NSCLC with anti-PD1 therapy.

BACKGROUND: Antibodies targeting programmed cell death-1(PD1) and its ligand (PDL1) have revolutionized cancer therapy. However, little is known about the preexisted anti-PD1/PDL1 autoantibodies (AAbs) distribution in multiple cancer types, nor is their potential biomarker role for anti-PD1 therapy. METHOD: Plasma anti-PD1/PDL1 AAb IgG and subclasses (IgG1-4) were detected by enzyme-linked immune sorbent assay (ELISA) in 190 cancer patients, covering 10 cancer types (lung, breast, esophageal, colorectal, liver, prostatic, cervical, ovarian, gastric cancers and lymphoma), the comprehensive correlation of AAbs with multiple clinical parameters was analyzed. We further tested these AAbs in 76 non-small cell lung cancer (NSCLC) samples receiving anti-PD1 therapy, the association of AAbs level with survival was analyzed and validated in an independent cohort (n = 32). RESULTS: Anti-PD1/PDL1 AAb IgG were globally detected in 10 types of cancer patients. IgG1 and IgG2 were the major subtypes for anti-PD1/PDL1 AAbs. Correlation analysis revealed a distinct landscape between various cancer types. The random forest model indicated that IgG4 subtype was mostly associated with cancer. In discovery cohort of 76 NSCLC patients, high anti-PD1 IgG4 was associated with a reduced overall survival (OS, p = 0.019), not progression-free survival (PFS, p = 0.088). The negative association of anti-PD1 IgG4 with OS was validated in 32 NSCLC patients (p = 0.032). CONCLUSION: This study reports for the first time the distribution of preexisted anti-PD1/PDL1 AAb IgG and subclasses across 10 cancer types. Moreover, the anti-PD1 AAb IgG4 subclass was identified to associate with OS, which may serve as a potential biomarker for anti-PD1 therapeutic survival benefit in NSCLC patients.

Toxicity profile of anaplastic lymphoma kinase tyrosine kinase inhibitors for patients with non-small cell lung cancer: A systematic review and meta-analysis.

Anaplastic lymphoma kinase (ALK) inhibitors are commonly used for patients harboring ALK-positive non-small cell lung cancer (NSCLC). This meta-analysis was conducted to evaluate the toxicity profile of ALK inhibitors. Pubmed, Web of Science, Embase, and the Cochrane Central Register of Controlled Trials databases were systematically searched for clinical trials conducted in advanced NSCLC treated with ALK inhibitors. The incidences of pooled adverse events (AEs) were conducted using the random effects model. We included 30 studies in the meta-analysis. Almost all patients receiving ALK inhibitor monotherapy occurred at least one AE. The pooled incidences of grade ≥ 3 AEs were 71.3% for ceritinib 750 mg, 44.6% for crizotinib, 37.4% for alectinib, and 35.3% for ensartinib. Only one study each reported the incidence of grade ≥ 3 AEs for brgatinib (72.8%), lorlatinib (72.4%), and ceritinib 450 mg (64.8%), respectively. The rates of dose reduction due to AEs ranking from high to low were ceritinib 750 mg, brigatinib, ceritinib 450 mg, lorlatinib, crizotinib, ensartinib, and alectinib. The rates of treatment discontinuation due to AEs were low, ranging from 3.8% to 10.5%. Gastrointestinal AEs were most common for ceritinib 750 mg. Hepatic transaminases elevation was mostly observed in ceritinib and brigatinib. Rash frequently occurred for ensartinib. Lorlatinib had a high incidence of hypertriglyceridemia and hypercholesterolemia, which were rarely reported in other ALK inhibitors. The incidences of grade ≥ 3 AEs for individual ALK inhibitor were moderately high yet manageable. Different toxicity spectrums were found in each ALK inhibitor.

Metabolic crosstalk in the tumor microenvironment regulates antitumor immunosuppression and immunotherapy resisitance.

The successful treatment of human cancers by immunotherapy has been made possible by breakthroughs in the discovery of immune checkpoint regulators, including CTLA-4 and PD-1/PD-L1. However, the immunosuppressive effect of the tumor microenvironment still represents an important bottleneck that limits the success of immunotherapeutic approaches. The tumor microenvironment influences the metabolic crosstalk between tumor cells and tumor-infiltrating immune cells, creating competition for the utilization of nutrients and promoting immunosuppression. In addition, tumor-derived metabolites regulate the activation and effector function of immune cells through a variety of mechanisms; in turn, the metabolites and other factors secreted by immune cells can also become accomplices to cancer development. Immune-metabolic checkpoint regulation is an emerging concept that is being studied with the aim of restoring the immune response in the tumor microenvironment. In this review, we summarize the metabolic reprogramming of various cell types present in the tumor microenvironment, with a focus on the interaction between the metabolic pathways of these cells and antitumor immunosuppression. We also discuss the main metabolic checkpoints that could provide new means of enhancing antitumor immunotherapy.