An immune cell map of human lung adenocarcinoma development reveals an anti-tumoral role of the Tfh-dependent tertiary lymphoid structure.

The immune responses during the initiation and invasion stages of human lung adenocarcinoma (LUAD) development are largely unknown. Here, we generated a single-cell RNA sequencing map to decipher the immune dynamics during human LUAD development. We found that T follicular helper (Tfh)-like cells, germinal center B cells, and dysfunctional CD8+ T cells increase during tumor initiation/invasion and form a tertiary lymphoid structure (TLS) inside the tumor. This TLS starts with an aggregation of CD4+ T cells and the generation of CXCL13-expressing Tfh-like cells, followed by an accumulation of B cells, and then forms a CD4+ T and B cell aggregate. TLS and its associated cells are correlated with better patient survival. Inhibiting TLS formation by Tfh or B cell depletion promotes tumor growth in mouse models. The anti-tumoral effect of the Tfh-dependent TLS is mediated through interleukin-21 (IL-21)-IL-21 receptor signaling. Our study establishes an anti-tumoral role of the Tfh-dependent TLS in the development of LUAD.

Immune-related long noncoding RNA zinc finger protein 710-AS1-201 promotes the metastasis and invasion of gastric cancer cells.

BACKGROUND: Gastric cancer (GC) is a prevalent malignant tumor of the gastrointestinal system. ZNF710 is a transcription factor (TF), and zinc finger protein 710 (ZNF710)-AS1-201 is an immune-related long noncoding RNA (lncRNA) that is upregulated in GC cells. AIM: To assess the correlation between ZNF710-AS1-201 and immune microenvironment features and to investigate the roles of ZNF710-AS1-201 in the invasion and metastasis processes of GC cells. METHODS: We obtained data from The Cancer Genome Atlas and Wujin Hospital. We assessed cell growth, migration, invasion, and programmed cell death using cell counting kit-8, EdU, scratch, Transwell, and flow cytometry assays. Quantitative real-time polymerase chain reaction (qRT-PCR) was used to identify the potential downstream targets of ZNF710-AS1-201. RESULTS: In GC tissues with low ZNF710-AS1-201 expression, immunoassays detected significant infiltration of various antitumor immune cells, such as memory CD8 T cells and activated CD4 T cells. In the low-expression group, the half-maximal inhibitory concentrations (IC50s) of 5-fluorouracil, cisplatin, gemcitabine, and trametinib were lower, whereas the IC50s of dasatinib and vorinostat were higher. The malignant degree of GC was higher and the stage was later in the high-expression group. Additionally, patients with high expression of ZNF710-AS1-201 had lower overall survival and disease-free survival rates. In vitro, the overexpression of ZNF710-AS1-201 greatly enhanced growth, metastasis, and infiltration while suppressing cell death in HGC-27 cells. In contrast, the reduced expression of ZNF710-AS1-201 greatly hindered cell growth, enhanced apoptosis, and suppressed the metastasis and invasion of MKN-45 cells. The expression changes in ZNF710 were significant, but the corresponding changes in isocitrate dehydrogenase-2, Semaphorin 4B, ARHGAP10, RGMB, hsa-miR-93-5p, and ZNF710-AS1-202 were not consistent or statistically significant after overexpression or knockdown of ZNF710-AS1-201, as determined by qRT-PCR. CONCLUSION: Immune-related lncRNA ZNF710-AS1-201 facilitates the metastasis and invasion of GC cells. It appears that ZNF710-AS1-201 and ZNF710 have potential as effective targets for therapeutic intervention in GC. Nevertheless, it is still necessary to determine the specific targets of the ZNF710 TF.

Prevalence and risk factors of fatigue and its association with quality of life among patients with chronic pancreatitis: A cross-sectional study.

BACKGROUND: Fatigue is a debilitating symptom found in various chronic diseases and is associated with more severe symptoms and worse quality of life (QoL). However, this symptom has not been adequately addressed in chronic pancreatitis (CP), and there have been no studies on fatigue in patients with CP. METHODS: This cross-sectional study was conducted at the Changhai Hospital in Shanghai, China. Data on the patients' sociodemographic, disease, and therapeutic characteristics were collected. Fatigue was assessed using the Multidimensional Fatigue Inventory-20. QoL was assessed utilizing the European Organization for the Research and Treatment of Cancer of QoL questionnaire (EORTC-QLQ-C30). Sleep quality, anxiety and depression, and pain was assessed using Pittsburgh Sleep Quality Index, the Hospital Anxiety and Depression Scale, and the Brief Pain Inventory, respectively. RESULTS: The prevalence of fatigue among Chinese patients with CP was 35.51 % (87/245). Multivariate analysis showed that steatorrhea (OR = 2.638, 95 % CI: 1.117-6.234), history of smoking (OR = 4.627, 95 % CI: 1.202-17.802), history of endoscopic treatment (OR = 0.419, 95 % CI: 0.185-0.950), depression (OR = 5.924, 95 % CI: 2.462-14.255), and sleep disorder (OR = 6.184, 95 % CI: 2.543-15.034) were influencing factors for the presence of fatigue. The scores for global health and all functional dimensions in the EORTC-QLQ-C30 significantly decreased, whereas the scores for all symptom dimensions significantly increased in patients with fatigue. CONCLUSIONS: This study indicated that Fatigue is a common symptom and has a negative impact on the QoL of patients with CP. Steatorrhea, smoking history, endoscopic treatment, depression, and sleep disorders were associated with fatigue.

Plasma Metabonomics of Human Adenovirus-infected Patients with Pneumonia and Upper Respiratory Tract Infection.

OBJECTIVE: Human adenovirus (HAdV) infection is common and can develop to serious conditions with high mortality, yet the mechanism of HAdV infection remains unclear. In the present study, the serum metabolite profiles of HAdV-7-infected patients with pneumonia or upper respiratory tract infection (URTI) were explored. METHODS: In total, 35 patients were enrolled in the study following an outbreak of HAdV-7 in the army, of whom 14 had pneumonia and 21 had URTI. Blood samples were collected at the acute stage and at the recovery stage and were analyzed by untargeted metabolomics. RESULTS: Over 90% of the differential metabolites identified between the pneumonia patients and URTI patients were lipids and lipid-like molecules, including glycerophospholipids, fatty acyls, and sphingolipids. The metabolic pathways that were significantly enriched were primarily the lipid metabolism pathways, including sphingolipid metabolism, glycerophospholipid metabolism, and linoleic acid metabolism. The sphingolipid metabolism was identified as a significantly differential pathway between the pneumonia patients and URTI patients and between the acute and recovery stages for the pneumonia patients, but not between the acute and recovery stages for the URTI patients. Ceramide and lactosylceramide, involved in sphingolipid metabolism, were significantly higher in the pneumonia patients than in the URTI patients with good discrimination abilities [area under curve (AUC) 0.742 and 0.716, respectively; combination AUC 0.801]. CONCLUSION: Our results suggested that HAdV modulated lipid metabolism for both the patients with URTI and pneumonia, especially the sphingolipid metabolism involving ceramide and lactosylceramide, which might thus be a potential intervention target in the treatment of HAdV infection.

The transcription factor NAC102 confers cadmium tolerance by regulating WAKL11 expression and cell wall pectin metabolism in Arabidopsis.

Cadmium (Cd) toxicity severely limits plant growth and development. Moreover, Cd accumulation in vegetables, fruits, and food crops poses health risks to animals and humans. Although the root cell wall has been implicated in Cd stress in plants, whether Cd binding by cell wall polysaccharides contributes to tolerance remains controversial, and the mechanism underlying transcriptional regulation of cell wall polysaccharide biosynthesis in response to Cd stress is unknown. Here, we functionally characterized an Arabidopsis thaliana NAC-type transcription factor, NAC102, revealing its role in Cd stress responses. Cd stress rapidly induced accumulation of NAC102.1, the major transcript encoding functional NAC102, especially in the root apex. Compared to wild type (WT) plants, a nac102 mutant exhibited enhanced Cd sensitivity, whereas NAC102.1-overexpressing plants displayed the opposite phenotype. Furthermore, NAC102 localizes to the nucleus, binds directly to the promoter of WALL-ASSOCIATED KINASE-LIKE PROTEIN11 (WAKL11), and induces transcription, thereby facilitating pectin degradation and decreasing Cd binding by pectin. Moreover, WAKL11 overexpression restored Cd tolerance in nac102 mutants to the WT levels, which was correlated with a lower pectin content and lower levels of pectin-bound Cd. Taken together, our work shows that the NAC102-WAKL11 module regulates cell wall pectin metabolism and Cd binding, thus conferring Cd tolerance in Arabidopsis.

Multiple stimulus-response berberine plus baicalin micelles with particle size-charge-release triple variable properties for breast cancer therapy.

OBJECTIVE: The aim was to develop a nanoscale drug delivery system with enzyme responsive and acid sensitive particle size and intelligent degradation aiming to research the inhibitory effect on breast cancer. SIGNIFICANCE: The delivery system addressed the problems of tissue targeting, cellular internalization, and slow drug release at the target site, which could improve the efficiency of drug delivery and provide a feasible therapeutic approach for breast cancer. METHODS: The acid sensitive functional material DSPE-PEG2000-dyn-PEG-R9 was synthesized by Michael addition reaction. Then, the berberine plus baicalin intelligent micelles were prepared by thin-film hydration. Subsequently, we characterized the physical and chemical properties of berberine plus baicalin intelligent micelles, evaluated its anti-tumor effects in vivo and in vitro. RESULTS: The target molecule was successfully synthesized, and the intelligent micelles showed excellent chemical and physical properties, delayed drug release and high encapsulation efficiency. In vitro and in vivo experiments also confirmed that the intelligent micelles could effectively target tumor sites, penetrate tumor tissues, enrich in tumor cells, inhibit tumor cell proliferation, inhibit tumor cell invasion and migration, and induce tumor cell apoptosis. CONCLUSION: Berberine plus baicalin intelligent micelles have excellent anti-tumor effects and no toxicity to normal tissues, which provides a new potential drug delivery strategy for the treatment of breast cancer.

[Intervention effect of injury control orthopedic strategy on fat embolism syndrome associated with long shaft fracture of lower limb].

OBJECTIVE: To observe the intervention effect of damage control orthopaedic(DCO) strategy on fat embolism syndrome(FES) associated with long shaft fracture of lower limbs. METHODS: Retrospective analysis was made on the clinical data of 163 patients with FES associated with lower limb long shaft fractures admitted from January 2015 to May 2021. They were divided into two groups based on the time point of implementing DCO strategy in January 2018. Total of 92 patients were admitted from January 2015 to December 2017 as the control group, and other 71 patients were admitted from January 2018 to May 2021 as the intervention group. The hospital mortality, arterial oxygen saturation (SaO2), arterial partial pressure of oxygen (PaO2) and oxygenation index (OI), hemoglobin (Hb), platelet count(PLT), Harris score of hip joint, HSS score of knee joint, AOFAS score of ankle joint, clinical efficacy and complications were observed and compared between two groups. RESULTS: Total of 163 patients were followed up for 12 to 18 months with an average of (16.91±1.22) months. The in-hospital mortality rate in the intervention group was 2.82% (2/71), and that in the control group was 16.30% (15/92), the difference between two groups was statistically significant(χ2=6.455, P<0.05). After the intervention, SaO2, PaO2 and OI in two groups were higher than those before the intervention(P<0.05), and after the intervention, SaO2, PaO2 and OI in two groups were statistically significant(P<0.05). Hb and PLT in two groups after intervention were higher than those before intervention (P<0.001), and there was statistically significant difference in Hb and PLT between two groups after intervention (P<0.05). The Harris score of hip joint, HSS score of knee joint and AOFAS score of ankle joint in both groups after 3 months of treatment were better than those before treatment (P<0.05). The total clinical effective rate of the intervention group was higher than that of the control group(χ2=4.194, P<0.05). The total incidence of complications in the intervention group was lower than that in the control group(χ2=4.747, P<0.05). CONCLUSION: DCO strategy is helpful to reduce the in-hospital mortality of patients with FES associated with long shaft fracture of lower extremities, eliminate FES symptoms and stabilize vital signs, gain time advantage for phase Ⅱ definitive surgery, and has significant clinical intervention effect, which is worth popularizing.

A clinical study on the nutritional status of patients with locally advanced rectal cancer during chemo-radiotherapy.

BACKGROUND: Rectal cancer is one of the most common gastrointestinal malignancies, and most cases include locally advanced cancers at the time of diagnosis (stage II/III). OBJECTIVES: The purpose of this study is to observe the dynamic changes in the nutritional status of patients with locally advanced rectal cancer during concurrent radiation therapy and chemotherapy and to evaluate the nutritional risk and incidence of malnutrition in these patients. METHODS: A total of 60 patients with locally advanced rectal cancer were enrolled in this study. The 2002 Nutritional Risk Screening and Patient-Generated Subjective Global Assessment Scales (PG-SGA) were used to assess nutritional risk and status. The European Organisation for Research and Treatment of Cancer Quality of Life Questionnaire (QLQ) - C30 and QLQ-CR38 scales were used for the quality of life evaluation. Toxicity was evaluated using the CTC 3.0 standard. RESULTS: The incidence of nutritional risk among these 60 patients was 38.33% (23 of 60) before and 53% (32 of 60) after concurrent chemo-radiotherapy. There were 28 patients in the well-nourished group, with a PG-SGA score of <2 points, and 17 patients in the nutrition-changed group, with a PG-SGA score of <2 points before and 2 points during and after chemo-radiotherapy. In the well-nourished group, the incidence of nausea, vomiting and diarrhea mentioned in the summary was lower and the expectations for the future (according to the QLQ-CR30 and QLQ-CR28 scales) were higher than in the undernourished group. The undernourished group required delayed treatment more often and experienced nausea, vomiting and diarrhea earlier and for longer than the well-nourished group. These results show that the quality of life of the well-nourished group was better. CONCLUSIONS: There is a degree of nutritional risk and deficiency in patients with locally advanced rectal cancer. Chemoradiotherapy increases the incidence of nutritional risk and deficiencies. KEY WORDS: Enteral nutrition, Colorectal neoplasms, Quality of life, Chemo-radiotherapy, EORTC.

Immune related biomarkers for cancer metastasis to the brain.

Brain metastasis accounts for a large number of cancer-related deaths. The host immune system, involved at each step of the metastatic cascade, plays an important role in both the initiation of the brain metastasis and their treatment responses to various modalities, through either local and or systemic effect. However, few reliable immune biomarkers have been identified in predicting the development and the treatment outcome in patients with cancer brain metastasis. Here, we provide a focused perspective of immune related biomarkers for cancer metastasis to the brain and a thorough discussion of the potential utilization of specific biomarkers such as tumor mutation burden (TMB), genetic markers, circulating and tumor-infiltrating immune cells, cytokines, in predicting the brain disease progression and regression after therapeutic intervention. We hope to inspire the field to extend the research and establish practical guidelines for developing and validating immune related biomarkers to provide personalized treatment and improve treatment outcomes in patients with metastatic brain cancers.

Pan-Cancer Analysis Identifies Tumor Cell Surface Targets for CAR-T Cell Therapies and Antibody Drug Conjugates.

Tumor cells can be recognized through tumor surface antigens by immune cells and antibodies, which therefore can be used as drug targets for chimeric antigen receptor-T (CAR-T) therapies and antibody drug conjugates (ADCs). In this study, we aimed to identify novel tumor-specific antigens as targets for more effective and safer CAR-T cell therapies and ADCs. Here, we performed differential expression analysis of pan-cancer data obtained from the Cancer Genome Atlas (TCGA), and then performed a series of conditional screenings including Cox regression analysis, Pearson correlation analysis, and risk-score calculation to find tumor-specific cell membrane genes. A tumor tissue-specific and highly expressed gene set containing 3919 genes from 17 cancer types was obtained. Moreover, the prognostic roles of these genes and the functions of these highly expressed membrane proteins were assessed. Notably, 427, 584, 431 and 578 genes were identified as risk factors for LIHC, KIRC, UCEC, and KIRP, respectively. Functional enrichment analysis indicated that these tumor-specific surface proteins might confer tumor cells the ability to invade and metastasize. Furthermore, correlation analysis displayed that most overexpressed membrane proteins were positively correlated to each other. In addition, 371 target membrane protein-coding genes were sifted out by excluding proteins expressed in normal tissues. Apart from the identification of well-validated genes such as GPC3, MSLN and EGFR in the literature, we further confirmed the differential protein expression of 23 proteins: ADD2, DEF6, DOK3, ENO2, FMNL1, MICALL2, PARVG, PSTPIP1, FERMT1, PLEK2, CD109, GNG4, MAPT, OSBPL3, PLXNA1, ROBO1, SLC16A3, SLC26A6, SRGAP2, and TMEM65 in four types of tumors. In summary, our findings reveal novel tumor-specific antigens, which could be potentially used for next-generation CAR-T cell therapies and ADC discovery.

What is responsible for acute myocardial infarction in combination with aplastic anemia? A case report and literature review.

BACKGROUND: Aplastic anemia (AA) complicated with myocardial infarction (MI) is rare and associated with poor prognosis. Here, we present a case of AA with recurrent acute MI (AMI) in a patient treated with cyclosporine A (CsA) and stanozolol. In this patient, we suspect the long-term use of medication linked to platelets hyperfunction. CASE SUMMARY: In 2017, a 45-year-old man was rushed to the emergency department of China-Japan Union Hospital due to precordial pain for 5 h. Based on his symptoms, medical history, blood tests, and findings from coronary angiography (CAG), the patient was diagnosed with acute anterior wall, ST-segment elevated MI, Killip II grade, AA, and dyslipidemia. In 2021, the patient was readmitted to the hospital for 2 h due to chest pain. Because the patient's platelet count was 30 × 109/L and he had severe thrombocytopenia, we performed CAG following platelet transfusion. Optical coherence tomography revealed lipid plaque and thrombus mass in his right coronary artery. The antithrombotic approach was adjusted to employ only anticoagulants (factor Xa inhibitors) and adenosine diphosphate inhibitors (clopidogrel) after assessing the risk of bleeding/thrombotic events. Long-term follow-up revealed that the patient had made a good recovery. CONCLUSION: Patients with AA should be closely monitored for the risk of thrombosis and cardiovascular events, particularly when taking stanozolol or CsA for an extended period of time.

Correction to "Genome-wide CRISPR-Cas9 screening identifies that hypoxia-inducible factor-1a-induced CBX8 transcription promotes pancreatic cancer progression via IRS1/AKT axis".

[This corrects the article on p. 1709 in vol. 13, PMID: 34853645.].

Vitamin D intake as well as circulating 25-hydroxyvitamin D level and risk for the incidence and recurrence of colorectal cancer precursors: A meta-analysis.

Objective: Vitamin D consumption and circulating 25(OH)D level are associated with decreased risk of colorectal cancer (CRC) and colorectal adenoma (CRA), but few studies have assessed their relationship with the incidence and recurrence of CRC precursors. Therefore, we performed this meta-analysis to further evaluate the association. Methods: We searched PubMed, Web of Science, Scopus and Embase databases in English until August 2021. Studies evaluating the association of vitamin D intake and circulating 25(OH)D level with risk of CRC precursors were included. A random-effects model was used to pool the risk estimates. Results: A total of 48 studies were selected for inclusion. The CRC precursors incidence was negatively correlated with total vitamin D intake (RR = 0.84 95%CI: 0.80-0.88) and circulating 25(OH)D level (RR = 0.79 95%CI: 0.67-0.92). However, vitamin D intake and circulating 25(OH)D level did not show significant effects on the risk of CRC precursors recurrence. For dose-response analysis, evidence of a linear association was found between CRC precursors incidence and circulating 25(OH)D level, and the risk decreased by 14% per 10 ng/ml increment of circulating 25(OH)D level (RR = 0.86 95% CI: 0.75-0.99). Conclusion: Vitamin D intake and circulating 25(OH)D level can play an effective role in reducing the risk of incidence of CRC precursors. However, they have not prevented the recurrence of CRC precursors.

Alterations in bile acids as metabolic signatures in the patients with human adenovirus type 7 infection.

Objectives: The changes in metabolism by human adenovirus (HAdV) infection was unclear. The potential mechanism of HAdV-7 causing acute respiratory tract infection was explored. Methods: Totally 35 patients with HAdV-7 infection, 32 asymptomatic cases with HAdV-7 and 14 healthy controls were enrolled from an outbreak of HAdV-7 in the army. The serum samples were analyzed by untargeted and targeted metabolomics. The effects of differential metabolites were verified on HAdV-7 replication in an A549 cell line. Results: The untargeted metabolomics analysis revealed more significant changes in the classes of sphingolipids, polyketides, glycerolipids, fatty acyls, and carboxylic acids and their derivatives in the patients with HAdV-7 than in healthy controls. Two key metabolic pathways of secondary and primary bile acid biosynthesis were noted from pathway enrichment analysis. Targeted metabolomics analysis showed that the levels of unconjugated bile acids in the patients were significantly lower, while the levels of glyco- and tauro- conjugated bile acids in patients and asymptomatic cases were higher than those in the healthy controls. The profiles of cytokines and peripheral lymphocyte subsets obviously varied at different levels of bile acids, with significant differences after HAdV-7 infection. A cell verification test demonstrated that the replication of HAdV-7 significantly reduced when GCDCA and TCA were added. Conclusion: Bile acids inhibited HAdV-7 replication in vitro. Alterations in bile acids was metabolic signatures of HAdV-7 infected subjects, and our results suggested bile acids might play protective roles against HAdV-7 infection.

ITCH facilitates proteasomal degradation of TXNIP in hypoxia- induced lung cancer cells.

BACKGROUND: Lung cancer (LC) is one of the most common cancers and a leading cause of cancer-related deaths worldwide. In many pathological conditions, particularly in the tumor microenvironment, cells and tissues frequently exist in a hypoxic state. Here, we evaluated Itchy E3 ubiquitin protein ligase (ITCH) expression in LC cells following hypoxia treatment. METHODS: LC cell lines were treated with hypoxic condition. Cell migration, invasion, inflammation, reactive oxygen species (ROS) production, and apoptosis of LC cells were determined by wound healing assay, Transwell invasive assay, ELISA, DCFH-DA staining, and flow cytometry, respectively. qPCR and WB were used to determine the expression of ITCH and TXNIP. Co-IP was performed to assess the interaction between ITCH and TXNIP. RESULTS: ITCH expression was downregulated in LC cells under hypoxic conditions. Next, LC cells were subjected to hypoxic conditions and changes in cell viability and metastasis were determined. Hypoxic conditions resulted in increased migration and invasion abilities of LC cells. Intracellular reactive oxygen species (ROS) production, inflammation, and apoptosis were also promoted by hypoxia. We found that ITCH overexpression led to the proteasomal degradation of thioredoxin-interacting protein (TXNIP), whereas the expression of the ITCH C830A mutant did not affect TXNIP levels in LC cells. The gain-of-function experiment demonstrated that migration, invasion, ROS generation, inflammation, and apoptosis of hypoxia-conditioned LC cells were ameliorated by ITCH overexpression, whereas the ITCH C830A mutant did not cause any changes in these phenotypes. Furthermore, the contribution of TXNIP knockdown and ITCH overexpression to the hypoxia-induced features in LC cells with ITCH C830A was found to be similar. CONCLUSION: Our results suggest a novel mechanism underlying the changes in ITCH-mediated malignant phenotypes of hypoxia-conditioned LC cells via TXNIP.

Soluble Receptor for Advanced Glycation End Product Is Involved in the Inflammatory Response of Human Adenovirus-Infected Patients.

Human adenovirus (HAdV) infection causes excessive inflammation associated with severe tissue injury, such as pneumonia. The molecules involved in the underlying inflammatory mechanisms remain to be elucidated. Receptor for advanced glycation end product (RAGE) is mainly expressed on immune cells and lung tissues, and it is a key factor in the initiation and development of inflammation. RAGE can be cleaved by metalloprotease 9 (MMP9) to release the extracellular segment, which is named soluble RAGE (sRAGE), into the intercellular space, where it can bind to RAGE ligands and block RAGE activation and subsequent inflammation. In our study, we enrolled HAdV-infected patients and their contacts to examine the relationship between sRAGE and inflammation induced by HAdV infection. The results showed that HAdV infection stimulated inflammatory cytokine secretion, increased such as high mobility group box 1 (HMGB1) levels, and suppressed sRAGE expression. sRAGE levels were significantly different between patients with or without pneumonia. We also found that MMP9 was significantly lower in patients with pneumonia, and it was positively correlated with sRAGE levels over 7 days after disease onset. The mitogen-activated protein kinase (MAPK) pathway is an important immune activation signaling pathway that is regulated by RAGE. We observed the activation of the MAPK pathway in the peripheral blood mononuclear cells (PBMCs) of patients. Negative correlations between sRAGE and phosphorylated JNK and p38 were observed. These results suggest that sRAGE is involved in HAdV-induced inflammatory responses, and might be a potential therapeutic target to alleviate the HAdV-induced excessive inflammation.

Targeting cancer stemness mediated by BMI1 and MCL1 for non-small cell lung cancer treatment.

Lung cancer is the leading cause of cancer-associated death, with a global 5-year survival rate <20%. Early metastasis and recurrence remain major challenges for lung cancer treatment. The stemness property of cancer cells has been suggested to play a key role in cancer plasticity, metastasis and drug-resistance, and is a potential target for drug development. In this study, we found that in non-small cell lung cancer (NSCLC), BMI1 and MCL1 play crucial roles of cancer stemness including invasion, chemo-resistance and tumour initiation. JNK signalling serves as a link between oncogenic pathway or genotoxicity to cancer stemness. The activation of JNK, either by mutant EGFR or chemotherapy agent, stabilized BMI1 and MCL1 proteins through suppressing the expression of E3-ubiquitin ligase HUWE1. In lung cancer patient samples, high level of BMI1 is correlated with poor survival, and the expression of BMI1 is positively correlated with MCL1. A novel small-molecule, BI-44, was developed, which effectively suppressed BMI1/MCL1 expressions and inhibited tumour formation and progression in preclinical models. Targeting cancer stemness mediated by BMI1/MCL1 with BI-44 provides the basis for a new therapeutic approach in NSCLC treatment.

The Tomato Transcription Factor SlNAC063 Is Required for Aluminum Tolerance by Regulating SlAAE3-1 Expression.

Aluminum (Al) toxicity constitutes one of the major limiting factors of plant growth and development on acid soils, which comprises approximately 50% of potentially arable lands worldwide. When suffering Al toxicity, plants reprogram the transcription of genes, which activates physiological and metabolic pathways to deal with the toxicity. Here, we report the role of a NAM, ATAF1, 2 and CUC2 (NAC) transcription factor (TF) in tomato Al tolerance. Among 53 NAC TFs in tomatoes, SlNAC063 was most abundantly expressed in root apex and significantly induced by Al stress. Furthermore, the expression of SlNAC063 was not induced by other metals. Meanwhile, the SlNAC063 protein was localized at the nucleus and has transcriptional activation potentials in yeast. By constructing CRISPR/Cas9 knockout mutants, we found that slnac063 mutants displayed increased sensitivity to Al compared to wild-type plants. However, the mutants accumulated even less Al than wild-type (WT) plants, suggesting that internal tolerance mechanisms but not external exclusion mechanisms are implicated in SlNAC063-mediated Al tolerance in tomatoes. Further comparative RNA-sequencing analysis revealed that only 45 Al-responsive genes were positively regulated by SlNAC063, although the expression of thousands of genes (1,557 upregulated and 636 downregulated) was found to be affected in slnac063 mutants in the absence of Al stress. The kyoto encyclopedia of genes and genomes (KEGG) pathway analysis revealed that SlNAC063-mediated Al-responsive genes were enriched in "phenylpropanoid metabolism," "fatty acid metabolism," and "dicarboxylate metabolism," indicating that SlNAC063 regulates metabolisms in response to Al stress. Quantitative real-time (RT)-PCR analysis showed that the expression of SlAAE3-1 was repressed by SlNAC063 in the absence of Al. However, the expression of SlAAE3-1 was dependent on SlNAC063 in the presence of Al stress. Taken together, our results demonstrate that a NAC TF SlNAC063 is involved in tomato Al tolerance by regulating the expression of genes involved in metabolism, and SlNAC063 is required for Al-induced expression of SlAAE3-1.

The number of cycles of adjuvant chemotherapy in stage III and high-risk stage II rectal cancer: a nomogram and recursive partitioning analysis.

OBJECTIVE: The prognostic role of the number of cycles of adjuvant chemotherapy (ACT) after total mesorectal excision in stage III and high-risk stage II rectal cancer is unknown. As a result of this, our study was designed to assess the effect of the number of cycles of ACT on the prediction of cancer-specific survival. METHODS: Four hundred patients that were diagnosed as stage III and high-risk stage II rectal cancer from January 2012 to January 2018 and who had received total mesorectal excision were enrolled in this study. A nomogram incorporating the number of cycles of ACT was also developed in this study. For internal validation, the bootstrap method was used and the consistency index was used to evaluate the accuracy of the model. The patients were stratified into risk groups according to their tumor characteristics by recursive partitioning analysis. RESULTS: We found that the risk of death was decreased by 26% (HR = 0.74, 95% CI: 0.61-0.89, P = 0.0016) with each increasing ACT cycle. The N stage, positive lymph node ratio (PLNR), carcinoembryonic antigen, neutrophil-to-lymphocyte ratio, and the number of cycles of ACT were chosen and entered into the nomogram model. Recursive partitioning analysis-based risk stratification revealed a significant difference in the prognosis in rectal cancer patients with high-risk, intermediate-risk, and low-risk (3-year cancer-specific survival: 0.246 vs. 0.795 vs. 0.968, P < 0.0001). Seven or more cycles of ACT yielded better survival in patients with PLNR ≥ 0.28 but not in patients with PLNR < 0.28. CONCLUSION: In conclusion, the nomogram prognosis model based on the number of cycles of ACT predicted individual prognosis in rectal cancer patients who had undergone total mesorectal excision. These findings further showed that in patients with PLNR ≥ 0.28, no fewer than 7 cycles of ACT are needed to significantly reduce the patient's risk of death.