The characteristics and prognosis of different disease patterns of multiple primary lung cancers categorized according to the 8th edition lung cancer staging system.

INTRODUCTION: The 8th edition lung cancer staging system was the first to describe the detailed diagnosis and staging of multiple primary lung cancers (MPLC). However, the characteristics and prognosis of MPLC categorized according to the new system have not been evaluated. METHOD: We retrospectively analyzed data from surgically treated MPLC patients in a single center from 2011 to 2013 and explored the characteristics and outcomes of different MPLC disease patterns. RESULTS: In total, 202 surgically treated MPLC patients were identified and classified into different groups according to disease categories and diagnostic time (multifocal ground glass/lepidic (GG/L) nodules: n = 139, second primary lung cancer (SPLC): n = 63, simultaneous MPLC (sMPLC): n = 171, and metachronous MPLC (mMPLC): n = 31). There were significant differences in clinical characteristics between SPLC and GG/L nodule patients and simultaneous and metachronous MPLC patients. The overall 1-, 3-, and 5-year lung cancer-specific survival rates of MPLC were 97.98%, 90.18%, and 82.81%, respectively. Five-year survival was better in patients with multiple GG/L nodules than in those with SPLC (87.94% vs. 71.29%, P < 0.05). Sex was an independent prognostic factor for sMPLC (5-year survival, female vs. male, 88.0% vs. 69.5%, P < 0.05), and in multiple tumors, the highest tumor stage was an independent prognostic factor for all categories of MPLC. CONCLUSIONS: The different disease patterns of MPLC have significantly different characteristics and prognoses. Clinicians should place treatment emphasis on the tumor with the highest stage as it is the main contributor to the prognosis of all categories of MPLC patients.

Pathological response and tumor stroma immunogenic features predict long-term survival in non-small cell lung cancer after neoadjuvant chemotherapy.

PURPOSE: Major pathological response (MPR) has become a surrogate endpoint for overall survival (OS) in non-small cell lung cancer (NSCLC) after neoadjuvant therapy, however, the prognostic histologic features and optimal N descriptor after neoadjuvant therapy are poorly defined. METHODS: We retrospectively analyzed data from 368 NSCLC patients who underwent surgery after neoadjuvant chemotherapy (NAC) from January 2010 to December 2020. The percentage of residual viable tumors in the primary tumor, lymph nodes (LN), and inflammation components within the tumor stroma were comprehensively reviewed. The primary endpoint was OS. RESULTS: Of the 368 enrolled patients, 12.0% (44/368) achieved MPR in the primary tumor, which was associated with significantly better OS (HR, 0.36 0.17-0.77, p = 0.008) and DFS (HR = 0.59, 0.36-0.92, p = 0.038). In patients who did not have an MPR, we identified an immune-activated phenotype in primary tumors, characterized by intense tumor-infiltrating lymphocyte or multinucleated giant cell infiltration, that was associated with similar OS and DFS as patients who had MPR. Neoadjuvant pathologic grade (NPG), consisting of MPR and immune-activated phenotype, identified 30.7% (113/368) patients that derived significant OS (HR 0.28, 0.17-0.46, p < 0.001) and DFS (HR 0.44, 0.31-0.61, p < 0.001) benefit from NAC. Moreover, the combination of NPG and the number of positive LN stations (nS) in the multivariate analysis had a higher C-index (0.711 vs. 0.663, p < 0.001) than the ypTNM Stage when examining OS. CONCLUSION: NPG integrated with nS can provide a simple, practical, and robust approach that may allow for better stratification of patients when evaluating neoadjuvant chemotherapy in clinical practice.

HER2 phosphorylation induced by TGF-ß promotes mammary morphogenesis and breast cancer progression.

Transforming growth factor ß (TGF-ß) and HER2 signaling collaborate to promote breast cancer progression. However, their molecular interplay is largely unclear. TGF-ß can activate mitogen-activated protein kinase (MAPK) and AKT, but the underlying mechanism is not fully understood. In this study, we report that TGF-ß enhances HER2 activation, leading to the activation of MAPK and AKT. This process depends on the TGF-ß type I receptor TßRI kinase activity. TßRI phosphorylates HER2 at Ser779, promoting Y1248 phosphorylation and HER2 activation. Mice with HER2 S779A mutation display impaired mammary morphogenesis, reduced ductal elongation, and branching. Furthermore, wild-type HER2, but not S779A mutant, promotes TGF-ß-induced epithelial-mesenchymal transition, cell migration, and lung metastasis of breast cells. Increased HER2 S779 phosphorylation is observed in human breast cancers and positively correlated with the activation of HER2, MAPK, and AKT. Our findings demonstrate the crucial role of TGF-ß-induced S779 phosphorylation in HER2 activation, mammary gland development, and the pro-oncogenic function of TGF-ß in breast cancer progression.

Turning Threat to Therapy: A Nanozyme-Patch in Surgical Bed for Convenient Tumor Vaccination by Sustained In Situ Catalysis.

Complete surgical resection of tumor is difficult as the invasiveness of cancer, making the residual tumor a lethal threat to patients. The situation is deteriorated by the immune suppression state after surgery, which further nourishes tumor recurrence and metastasis. Immunotherapy is promising to combat tumor metastasis, but is limited by severe toxicity of traditional immunostimulants and complexity of multiple functional units. Here, it is reported that the simple "trans-surgical bed" delivery of Cu2- x Se nanozyme (CSN) by a microneedle-patch can turn the threat to therapy by efficient in situ vaccination. The biocompatible CSN exhibits both peroxidase and glutathione oxidase-like activities, efficiently exhausting glutathione, boosting free radical generation, and inducing immunogenic cell death. The once-for-all inserting of the patch on surgical bed facilitates sustained catalytic action, leading to drastic decrease of recurrence rate and complete suppression of tumor-rechallenge in cured mice. In vivo mechanism interrogation reveals elevated cytotoxic T cell infiltration, re-educated macrophages, increased dendritic cell maturation, and memory T cells formation. Importantly, preliminary metabolism and safety evaluation validated that the metal accumulation is marginable, and the important biochemical indexes are in normal range during therapy. This study has provided a simple, safe, and robust tumor vaccination approach for postsurgical metastasis control.

PRMT blockade induces defective DNA replication stress response and synergizes with PARP inhibition.

Multiple cancers exhibit aberrant protein arginine methylation by both type I arginine methyltransferases, predominately protein arginine methyltransferase 1 (PRMT1) and to a lesser extent PRMT4, and by type II PRMTs, predominately PRMT5. Here, we perform targeted proteomics following inhibition of PRMT1, PRMT4, and PRMT5 across 12 cancer cell lines. We find that inhibition of type I and II PRMTs suppresses phosphorylated and total ATR in cancer cells. Loss of ATR from PRMT inhibition results in defective DNA replication stress response activation, including from PARP inhibitors. Inhibition of type I and II PRMTs is synergistic with PARP inhibition regardless of homologous recombination function, but type I PRMT inhibition is more toxic to non-malignant cells. Finally, we demonstrate that the combination of PARP and PRMT5 inhibition improves survival in both BRCA-mutant and wild-type patient-derived xenografts without toxicity. Taken together, these results demonstrate that PRMT5 inhibition may be a well-tolerated approach to sensitize tumors to PARP inhibition.

ICT-based fluorescent probes for intracellular pH and biological species detection.

Fluorescent probes, typically based on the intramolecular charge transfer (ICT) mechanism, have received considerable research attention in cell detection due to their non-invasiveness, fast response, easy regulation, high sensitivity, and low damage tolerance for in vivo bio-samples. Generally, intracellular pH and biological species such as various gases, metal ions, and anions constitute the foundation of cells and participate in the basic physiological processes, whose abnormal level can lead to poisoning, cardiovascular disease, and cancer in living organisms. Therefore, monitoring of their quantity plays an essential role in understanding the status of organisms and preventing, diagnosing, and treating diseases. In the last decades, remarkable progress has been made in developing ICT probes for the detection of biological elements. In this review, we highlight the recent ICT probes focusing primarily on the detection of intracellular pH, various gases (H2S, CO, H2O2, and NO), metal ions (Cu2+, Hg2+, Pb2+, Zn2+, and Al3+), and anions (ClO-, CN-, SO3 2-, and F-). In addition, we discuss the issues and limitations of ICT-based fluorescent probes for in vivo detection and explore the clinical translational potential and challenges of these materials, providing valuable guidance and insights for the design of fluorescent materials.

Erratum: Author correction to "Coordinated regulation of BACH1 and mitochondrial metabolism through tumor targeted self-assembled nanoparticles for effective triple negative breast cancer combination therapy" [Acta Pharmaceutica Sinica B 12 (2022) 3934-3951].

[This corrects the article DOI: 10.1016/j.apsb.2022.06.009.].

Stromal BMP signaling regulates mucin production in the large intestine via interleukin-1/17.

Bone morphogenic protein (BMP) signaling is critical for intestinal development, homeostasis, and function performance. Although the function of BMP signaling in the intestinal epithelium is well appreciated, the direct effect of BMP on intestinal stromal cells is poorly understood. Here, we show that disruption of BMP signaling by genetic ablation of Alk3 or Smad4 expands the stromal cell pool, the mucosa tumefaction, and colonic polyposis in the large intestine. Interleukin (IL) secretion by stromal cells is notably increased, including IL-1, IL-11, and IL-17. Specifically, IL-1 and IL-17a hyperactivate the mucin production by goblet cells through nuclear factor κB signaling, and abnormal mucin accumulation results in the morphological changes, epithelial barrier destruction, and polyposis development. Together, our results provide an insight into the role of BMP signaling in intestinal stromal cells to regulate epithelium function. This study further highlights the role of mucin-producing goblet cells in intestinal homeostasis and colitis development.

Loss of the methylarginine reader function of SND1 confers resistance to hepatocellular carcinoma.

Staphylococcal nuclease Tudor domain containing 1 (SND1) protein is an oncogene that 'reads' methylarginine marks through its Tudor domain. Specifically, it recognizes methylation marks deposited by protein arginine methyltransferase 5 (PRMT5), which is also known to promote tumorigenesis. Although SND1 can drive hepatocellular carcinoma (HCC), it is unclear whether the SND1 Tudor domain is needed to promote HCC. We sought to identify the biological role of the SND1 Tudor domain in normal and tumorigenic settings by developing two genetically engineered SND1 mouse models, an Snd1 knockout (Snd1 KO) and an Snd1 Tudor domain-mutated (Snd1 KI) mouse, whose mutant SND1 can no longer recognize PRMT5-catalyzed methylarginine marks. Quantitative PCR analysis of normal, KO, and KI liver samples revealed a role for the SND1 Tudor domain in regulating the expression of genes encoding major acute phase proteins, which could provide mechanistic insight into SND1 function in a tumor setting. Prior studies indicated that ectopic overexpression of SND1 in the mouse liver dramatically accelerates the development of diethylnitrosamine (DEN)-induced HCC. Thus, we tested the combined effects of DEN and SND1 loss or mutation on the development of HCC. We found that both Snd1 KO and Snd1 KI mice were partially protected against malignant tumor development following exposure to DEN. These results support the development of small molecule inhibitors that target the SND1 Tudor domain or the use of upstream PRMT5 inhibitors, as novel treatments for HCC.

The cyclooxygenase-expressing mesenchyme resists intestinal epithelial injury by paracrine signaling.

Paracrine signals play pivotal roles in organ homeostasis. Mesenchymal stromal cells (MSCs) play a key role in regulating epithelium homeostasis in the intestine while their paracrine effects are poorly characterized. Here, we identified prostaglandin E2 (PGE2) secreted by cyclooxygenase (COX)-expressing MSCs as a vital factor to maintain the intestinal mucosal barrier. We found that MSCs-induced organoid swelling through paracrine effect in vitro, a process due to enhanced water adsorption and is mediated by the COX-PGE2-EP4 axis. To further explore the regulatory effect of this axis on the intestinal epithelial barrier in vivo, we established the conditional knockout mouse model to specifically delete COX in MSCs and found that PGE2 reduction downregulated the gene Muc2 and induced a gastric metaplasia-like phenotype. Moreover, PGE2 defects increased the susceptibility of intestinal epithelium to colitis. Our study uncovers the paracrine signaling of COX-expressing MSCs in intestinal mucosal barrier maintenance, providing a basis for understanding the role of mesenchymal cells in the pathophysiological function of the intestine.

Recent Progress of Activity-Based Fluorescent Probes for Imaging Leucine Aminopeptidase.

Leucine aminopeptidase (LAP) is an important protease that can specifically hydrolyze Leucine residues. LAP occurs in microorganisms, plants, animals, and humans and is involved in a variety of physiological processes in the human body. In the physiological system, abnormal levels of LAP are associated with a variety of diseases and pathological processes, such as cancer and drug-induced liver injury; thus, LAP was chosen as the early biochemical marker for many physiological processes, including cancer. Considering the importance of LAP in physiological and pathological processes, it is critical that high-efficiency and dependable technology be developed to monitor LAP levels. Herein, we summarize the organic small molecule fluorescence/chemiluminescence probes used for LAP detection in recent years, which can image LAP in cancer, drug-induced liver injury (DILI), and bacteria. It can also reveal the role of LAP in tumors and differentiate the serum of cirrhotic, drug-induced liver injury and normal models.

Transforming Growth Factor Beta Promotes Inflammation and Tumorigenesis in Smad4-Deficient Intestinal Epithelium in a YAP-Dependent Manner.

Transforming growth factor beta (TGF-ß), a multifunctional cytokine, plays critical roles in immune responses. However, the precise role of TGF-ß in colitis and colitis-associated cancer remains poorly defined. Here, it is demonstrated that TGF-ß promotes the colonic inflammation and related tumorigenesis in the absence of Smad family member 4 (Smad4). Smad4 loss in intestinal epithelium aggravates colitis and colitis-associated neoplasia induced by dextran sulfate sodium (DSS) and azoxymethane/dextran sulfate sodium (AOM/DSS), leading to over-activated immune responses and increased TGF-ß1 levels. In Smad4-deficient organoids, TGF-ß1 stimulates spheroid formation and impairs intestinal stem cell proliferation and lineage specification. YAP, whose expression is directly upregulated by TGF-ß1 after Smad4 deletion, mediates the effect of TGF-ß1 by interacting with Smad2/3. Attenuation of YAP/TAZ prevents TGF-ß1-induced spheroid formation in Smad4-/- organoids and alleviates colitis and colitis-associated cancer in Smad4-deficient mice. Collectively, these results highlight an integral role of the TGF-ß/Smad4 axis in restraining intestinal inflammation and tumorigenesis and suggest TGF-ß or YAP signaling as therapeutic targets for these gastrointestinal diseases intervention.

Standard: Human intestinal cancer organoids.

Intestinal cancer is one of the most frequent and lethal types of cancer. Modeling intestinal cancer using organoids has emerged in the last decade. Human intestinal cancer organoids are physiologically relevant in vitro models, which provides an unprecedented opportunity for fundamental and applied research in colorectal cancer. "Human intestinal cancer organoids" is the first set of guidelines on human intestinal organoids in China, jointly drafted and agreed by the experts from the Chinese Society for Cell Biology and its branch society: the Chinese Society for Stem Cell Research. This standard specifies terms and definitions, technical requirements, test methods for human intestinal cancer organoids, which apply to the production and quality control during the process of manufacturing and testing of human intestinal cancer organoids. It was released by the Chinese Society for Cell Biology on 24 September 2022. We hope that the publication of this standard will guide institutional establishment, acceptance and execution of proper practocal protocols, and accelerate the international standardization of human intestinal cancer organoids for clinical development and therapeutic applications.

CDK5-PRMT1-WDR24 signaling cascade promotes mTORC1 signaling and tumor growth.

The mammalian target of rapamycin complex1 (mTORC1) is a central regulator of metabolism and cell growth by sensing diverse environmental signals, including amino acids. The GATOR2 complex is a key component linking amino acid signals to mTORC1. Here, we identify protein arginine methyltransferase 1 (PRMT1) as a critical regulator of GATOR2. In response to amino acids, cyclin-dependent kinase 5 (CDK5) phosphorylates PRMT1 at S307 to promote PRMT1 translocation from nucleus to cytoplasm and lysosome, which in turn methylates WDR24, an essential component of GATOR2, to activate the mTORC1 pathway. Disruption of the CDK5-PRMT1-WDR24 axis suppresses hepatocellular carcinoma (HCC) cell proliferation and xenograft tumor growth. High PRMT1 protein expression is associated with elevated mTORC1 signaling in patients with HCC. Thus, our study dissects a phosphorylation- and arginine methylation-dependent regulatory mechanism of mTORC1 activation and tumor growth and provides a molecular basis to target this pathway for cancer therapy.

Genetic trajectory and clonal evolution of multiple primary lung cancer with lymph node metastasis.

Multiple primary lung cancer (MPLC) with lymph node metastasis (LNM) is a rare phenomenon of multifocal lung cancer. The genomic landscapes of MPLC and the clonal evolution pattern between primary lung lesions and lymph node metastasis haven't been fully illustrated. We performed whole-exome sequencing (WES) on 52 FFPE (Formalin-fixed Paraffin-Embedded) samples from 11 patients diagnosed with MPLC with LNM. Genomic profiling and phylogenetic analysis were conducted to infer the evolutional trajectory within each patient. The top 5 most frequently mutated genes in our study were TTN (76.74%), MUC16 (62.79%), MUC19 (55.81%), FRG1 (46.51%), and NBPF20 (46.51%). For most patients in our study, a substantial of genetic alterations were mutually exclusive among the multiple pulmonary tumors of the same patient, suggesting their heterogenous origins. Individually, the genetic profile of lymph node metastatic lesions overlapped with that of multiple lung cancers in different degrees but are more genetically related to specific pulmonary lesions. SETD2 was a potential metastasis biomarker of MPLC. The mean putative neo-antigen number of the primary tumor (646.5) is higher than that of lymph node metastases (300, p = 0.2416). Primary lung tumors and lymph node metastases are highly heterogenous in immune repertoires. Our findings portrayed the comprehensive genomic landscape of MPLC with LNM. We characterized the genomic heterogeneity among different tumors. We offered novel clues to the clonal evolution between MPLC and their lymphatic metastases, thus advancing the treatment strategies and preventions of MPLC with LNM.

Coordinated regulation of BACH1 and mitochondrial metabolism through tumor-targeted self-assembled nanoparticles for effective triple negative breast cancer combination therapy.

The poor prognosis of triple negative breast cancer (TNBC) results from a lack of approved targeted therapies coupled with aggressive proliferation and metastasis, which is associated with high recurrence and short overall survival. Here we developed a strategy by employing tumor-targeted self-assembled nanoparticles to coordinately regulate BACH1 (BTB domain and CNC homology 1) and mitochondrial metabolism. The BACH1 inhibitor hemin and mitochondria function inhibitor berberine derivative (BD) were used to prepare nanoparticles (BH NPs) followed by the modification of chondroitin sulfate (CS) on the surface of BH NPs to achieve tumor targeting (CS/BH NPs). CS/BH NPs were found to be able to inhibit tumor migration and invasion by significantly decreasing the amounts of tumor cell metabolites, glycolysis and metastasis-associated proteins, which were related to the inhibition of BACH1 function. Meanwhile, decreased mitochondrial membrane potential, activated caspase 3/9 and increased ROS production demonstrated coordinated regulation of BACH1 and mitochondrial metabolism. In a xenograft mice model of breast cancer, CS/BH NPs significantly inhibited tumor growth and metastasis due to the synergetic effect of hemin and BD without showing obvious toxicities for major organs. In sum, the results of efficacy and safety experiments suggest potential clinical significance of the prepared self-assembled CS/BH nanoparticles for the treatment of TNBC.

Effect of dexmedetomidine on postoperative systemic inflammation and recovery in patients undergoing digest tract cancer surgery: A meta-analysis of randomized controlled trials.

Perioperative immune function, postoperative cognitive function and prognosis are momentous issues for patients undergoing digestive tract cancer surgery. Studies have investigated the efficacy of dexmedetomidine (DEX) administration on these issues, but the results are inconsistent. Therefore, this meta-analysis aimed to summarize all the existing evidence and draw a conclusion more accurately on these associations. Trials were located through electronic searches of the PubMed, Embase, the Cochrane Library and Web of Science databases sources (from the establishment date of databases to April 2022). Bibliographies of the retrieved articles were checked. A total of 17 RCTs involving 1619 patients were included. The results showed that DEX decreased the level of C-reactive protein (SMD = -4.26, 95%CI: -6.16, -2.36), TNF-α (SMD = -4.22, 95%CI: -5.91, -2.54) and IL-6 (SMD = -2.71, 95%CI: -4.46, -0.97), and increased the level of IL-10 (SMD = 1.74, 95%CI: 0.25, 3.24). DEX also increased CD4+ T cells (SMD = 0.55, 95%CI: 0.29, 0.82) and CD4+/CD8+ ratio (SMD = 0.62, 95%CI: 0.24, 1.01). Thus, DEX was associated with alleviation of postoperative systemic inflammatory response and immune dysfunction. Furthermore, DEX increased mini-mental state examination scores at 12h (SMD = 1.10, 95%CI: 0.74,1.45), 24h (SMD = 0.85, 95%CI: 0.59, 1.11), 48h (SMD = 0.89, 95%CI: 0.50, 1.28) and 72h (SMD = 0.75, 95%CI: 0.38, 1.11) after surgery. DEX decreased the occurrence of postoperative cognitive dysfunction (POCD) at 24h (OR = 0.22, 95%CI: 0.11, 0.46) and 72h (OR = 0.39, 95%CI: 0.22, 0.68) after surgery. DEX decreased first flatus time (SMD = -1.55, 95%CI: -2.82, -0.27) and hospital stay (SMD = -1.23, 95%CI: -1.88, -0.59). Therefore, based on perioperative immune dysfunction alleviation, DEX attenuated POCD and potential neuroinflammation, improved postoperative recovery and clinical prognosis of patients undergoing digest tract cancer surgery. Further studies are necessary to elucidate the clinical application of DEX from an immunological perspective.

Intestinal cellular heterogeneity and disease development revealed by single-cell technology.

The intestinal epithelium is responsible for food digestion and nutrient absorption and plays a critical role in hormone secretion, microorganism defense, and immune response. These functions depend on the integral single-layered intestinal epithelium, which shows diversified cell constitution and rapid self-renewal and presents powerful regeneration plasticity after injury. Derailment of homeostasis of the intestine epithelium leads to the development of diseases, most commonly including enteritis and colorectal cancer. Therefore, it is important to understand the cellular characterization of the intestinal epithelium at the molecular level and the mechanisms underlying its homeostatic maintenance. Single-cell technologies allow us to gain molecular insights at the single-cell level. In this review, we summarize the single-cell RNA sequencing applications to understand intestinal cell characteristics, spatiotemporal evolution, and intestinal disease development.

Clinical characteristics, surgical treatments, prognosis, and prognostic factors of primary tracheal cancer patients: 20-year data of the National Cancer Center, China.

Background: Tracheal cancer is a rare malignancy of which previous reports are mostly case reports or small series. Herein, we sought to evaluate the clinical characteristics, surgical treatments, and prognosis of surgically treated primary tracheal cancer patients. Methods: Patients with primary tracheal cancer who had received surgery in our center between January 2000 and December 2020 were enrolled. Clinical and surgical features were collected by retrospective review of medical records and follow-up was done by telephone interview. The statistical tests were two-sided. Results: A total of 128 patients were included in the study, 49.2% of whom were male, and the average age was 49.4±13.6 years. The most common histological subtype was adenoid cystic carcinoma (ACC; 78/128, 60.9%) followed by squamous cell carcinoma (SCC; 24/128, 18.8%). The percentage of tumors located in the cervical trachea, thoracic trachea, and carina were 50%, 41.4%, and 8.6%, respectively. Among those analyzed, 32.0% of the primary tumors had invaded adjacent organs (E2 disease) and 7.8% of patients had lymph node involvement. Tracheal resection plus reconstruction (with or without thyroidectomy) was the predominant surgical procedure, followed by carinal resection with neocarina. Radical resection (R0) was performed on 61.7% of patients and 63 (49.2%) patients received adjuvant therapy. Compared to ACC, SCC patients had significantly higher risk of tumor of the carina, nodal metastasis, and complications. The 5-year overall survival (OS) for the entire cohort was 84.5% and factors associated with poor prognosis included carinal tumor [hazard ratio (HR) =10.206; P<0.001], E2 disease (HR =8.870; P=0.001), lymph node metastasis (HR =15.197; P<0.001), and postoperative complications (HR =12.497; P=0.001). Conclusions: The two major subtypes of tracheal cancer are ACC and SCC. Tumor location, extension, lymph node metastasis and complication are survival related factors for surgically treated patients.