Low-dose pegylated recombinant human granulocyte-colony stimulating factor as hematopoietic support for adjuvant chemotherapy in Chinese patients with breast cancer: An open-label, randomized, non-inferiority trial.

AIMS: The recommended dosage of pegylated recombinant human granulocyte-colony stimulating factor (PEG-rhG-CSF) for Western chemotherapy patients is 6 mg per cycle. However, for Eastern Asians, the optimal dose remains unknown. METHODS: This open-label, randomized, non-inferiority trial (NCT05283616) enrolled Chinese female breast cancer patients receiving adjuvant chemotherapy. Participants were randomized to receive either 3 or 6 mg of PEG-rhG-CSF per cycle, stratified by body weight (BW; ≤60 kg vs. >60 kg). The primary endpoint was timely absolute neutrophil count (ANC) recovery before the second cycle of chemotherapy. RESULTS: A total of 122 patients were randomized and 116 were included for efficacy analyses. The timely ANC recovery rate in the 3 mg arm was 89.8%, compared to 93.0% in the 6 mg arm (one-sided 95% confidence interval [CI] lower limit for difference: -11.7%), meeting the prespecified non-inferiority margin of 15%. The rate was 93.3% with PEG-rhG-CSF 3 mg and 96.6% with 6 mg in patients with BW ≤ 60 kg, and 86.2% and 89.3%, respectively, in those with BW > 60 kg. Although the incidence of severe neutropenia was similar across arms, the occurrence of excessively high ANC and white blood cell counts was higher in the 6 mg arm. No grade ≥3 adverse events related to PEG-rhG-CSF occurred. CONCLUSION: Three milligrams of PEG-rhG-CSF per cycle provided non-inferior neutrophil protection and attenuated neutrophil overshoot compared to 6 mg doses. This low-dose regimen could be a new supportive care option for Chinese breast cancer patients receiving anthracycline-based adjuvant chemotherapy.

The protective effect and mechanism of piperazine ferulate in rats with 5/6 nephrectomy-caused chronic kidney disease.

Chronic kidney disease (CKD) is a type of chronic disease in which multiple factors are responsible for the structural and functional disorders of the kidney. Piperazine ferulate (PF) has anti-platelet and anti-fibrotic effects, and its mechanism of action remains to be elucidated. This study aimed to investigate the protective effect of PF against CKD in rats and to determine its mechanism of action. Network pharmacology was used to predict potential PF action targets in the treatment of CKD and to further validate them. A rat model of CKD was established; blood was collected, etc., for the assessment of the renal function; renal pathologic damage was examined using hematoxylin and eosin (HE) staining and Masson staining; changes in the levels of TGF-ß1 and α-SMA were determined with ELISA; EPOR, FN, and COL I expression were detected utilizing immunohistochemistry; and HIF-1α, HIF-2α, and EPO protein molecules were analyzed deploying western blotting. PF reduces Scr, BUN, and 24 h UP levels; decreases FN and COL I expression; and attenuates renal injury. Additionally, PF inhibited TGF-ß1 and stimulated the production of HIF-1α and HIF-2α, which downregulated α-SMA and upregulated EPO. PF attenuated the progression of the CKD pathology, and the mechanism of its action is possibly associated with the promotion of HIF-1α/HIF-2α/EPO production and TGF-ß1 reduction.

Cadmium exposure dysregulates purine metabolism and homeostasis across the gut-liver axis in a mouse model.

Cadmium (Cd) exposure has been associated with the development of enterohepatic circulation disorders and hyperuricemia, but the possible contribution of chronic low-dose Cd exposure to disease progression is still need to be explored. A mouse model of wild-type mice (WT) and Uox-knockout mice (Uox-KO) to find out the toxic effects of chronic low-dose Cd exposure on liver purine metabolism by liquid chromatography-mass spectrometry (LC-MS) platform and associated intestinal flora. High throughput omics analysis including metabolomics and transcriptomics showed that Cd exposure can cause disruption of purine metabolism and energy metabolism. Cd changes several metabolites associated with purine metabolism (xanthine, hypoxanthine, adenosine, uridine, inosine) and related genes, which are associated with elevated urate levels. Microbiome analysis showed that Cd exposure altered the disturbance of homeostasis in the gut. Uox-KO mice were more susceptible to Cd than WT mice. Our findings extend the understanding of potential toxicological interactions between liver and gut microbiota and shed light on the progression of metabolic diseases caused by Cd exposure.

Epidemiology and clinicopathologic features of breast cancer in China and the United States.

Background: Breast cancer has kept increasing since the past decades and the incidence rate is the highest among all neoplasms nowadays. China, as well as other countries, faces severe burden from the increasing population with breast cancer. This study aimed to analyze the epidemiology and clinicopathologic features of breast cancer in China and the United States (US). Methods: Data of hospitalized patients diagnosed with primary breast cancer between 1 January 1999 and 31 December 2014 in the Cancer Hospital, Chinese Academy of Medical Sciences (CHCAMS) were reviewed. Clinical and demographic data were extracted from medical history systems, and the sixteen-year trends were analyzed. Meanwhile, retrieved data from the Surveillance, Epidemiology, and End Results (SEER) database from 1999 to 2014 were used for comparisons. Results: A total of 18,768 breast cancer patients were included from CHCAMS, China, with 18,685 female cases (99.57%) and 81 male cases (0.43%). A total of 762,954 breast cancer patients were included from the SEER database, US, with 757,357 female cases (99.27%) and 5,597 male cases (0.73%). The peak age of breast cancer was 45-49 years old from 1999 to 2014 in China, while the peak age was 55-59 years from 1999 to 2006 and 60-64 years from 2007 to 2014 in the US. There were more young (<35 years, 6.56% vs. 1.97%, P<0.001), less elderly (≥65 years, 9.99% vs. 40.88%, P<0.001), less stage I (24.93% vs. 48.84%, P<0.001) and more stage III (21.00% vs. 12.35%, P<0.001) breast cancer patients in China than in the US. Patients aged 30-49 years old had a decreased trend (P<0.001), while 55-64 years old patients had an increased trend (P<0.001) from 1999 to 2014 in China, the same trend was also observed in the US. Mucinous carcinoma and histological grade I breast cancer patients increased with age both in China and the US (P<0.001). Conclusions: The unique epidemiology and clinicopathologic features of breast cancer (earlier peak age, more younger patients, more advanced stage, etc.), as well as the typical trend in China, should be seriously recognized, so as to guide future prevention and management strategies.

Ginsenoside Rd, a natural production for attenuating fibrogenesis and inflammation in hepatic fibrosis by regulating the ERRα-mediated P2X7r pathway.

Ginseng, when used as a food and nutritional supplement, has the ability to regulate human immunity. Here, the potential anti-hepatic fibrosis effect of ginsenoside Rd (Rd), one of the protopanaxadiol types of ginsenoside, was investigated. We established a hepatic fibrosis model using intraperitoneal injection of thioacetamide (TAA) for five weeks in mice. In addition, an in vitro model was established by using TGF-ß to activate hepatic stellate cells (HSCs), treated with Rd and an estrogen-related receptor α (ERRα) inhibitor (XCT-790). The ERRα knockdown (shRNA-ERRα) of the primary mouse hepatocytes was used to establish hepatocyte injury by TGF-ß, and they were then incubated in Rd. The Rd significantly alleviated the histopathological changes, and reduced the serum alanine aminotransferase (ALT) and aspartate aminotransferase (AST) levels. The Rd could upregulate the ERRα and downregulate the fibrosis markers in the livers of mice. In TAA-induced mice, the Rd inhibited the purinergic ligand-gated ion channel 7 receptor (P2X7r)-mediated NLRP3 inflammasome activation, consequently reversing the liver inflammatory response. The Rd significantly increased the expression of ERRα and suppressed the extracellular matrix (ECM) in the HSCs or primary hepatocytes. The Rd significantly decreased the P2X7r-mediated NLRP3 inflammasome activation, consequently reversing the inflammatory response, including the production of IL-1ß, IL-23 in the activated HSCs and primary hepatocytes. The Rd could ameliorate the damage of the hepatocytes and further inhibit the entry of IL-1ß and IL-18 into the extracellular matrix. The Rd reduced the inflammatory reaction by regulating the ERRα-P2X7r signaling pathway while suppressing the fibrogenesis, which suggests that the Rd can serve as a novel dietary supplement approach to combat hepatic fibrosis.

Independent risk evaluation associated with short-term black carbon exposure on mortality in two megacities of Yangtze River Delta, China.

The adverse health effects of PM2.5 have been well demonstrated by many studies. However, as a component of PM2.5, evidence on the mortality risk of black carbon (BC) is still limited. In this study, based on the data of daily mean PM2.5 concentration, BC concentration, meteorological factors, total non-accidental (all-cause) and cardiovascular mortality in Shanghai and Nanjing during 2015-2016, a semi-parameter generalized additive model (GAM) in the time series and the constituent residual approach were employed to explore the exposure-response relationship between BC and human mortality in these two megacities of Yangtze River Delta, China. The main objective was to separate the health effects of BC from total PM2.5, and compare the difference of mortality ER related to BC original concentration and adjusted concentration after controlling PM2.5. Results showed that there were all significantly associated with daily mortality for PM2.5 and BC. The percentage excess risk (ER) increases in all-cause and cardiovascular categories were 1.68 % (95 % s 1.28, 2.08) and 2.16 % (95 % CI: 1.54, 2.79) with 1 µg/m3 increment in original BC concentration in Shanghai. And the ER in Nanjing was smaller than that in Shanghai. After eliminating PM2.5 confounding effects by a constituent residual approach, the BC residual concentration still had a strong significant ER. The ER for BC residual in Shanghai got an obvious increase, and ER of the cardiovascular mortality for all, females and males increased by 0.55 %, 1.46 % and 0.62 %, respectively, while the ER in Nanjing decreased slightly. It also revealed that females were more sensitive to the health risk associated with short-term BC exposure than males. Our findings provide additional important evidence and ER for mortality related to independent BC exposure. Therefore, BC emission reduction should be paid more attention in air pollution control strategies to reduce BC-related health burdens.

Anti-hyperlipidemia on rats in vivo and new compounds from the seeds of Psoralea corylifolia.

In this study, it was confirmed at first time that the crude extracts of Psoralea corylifolia seeds (PCE34) can reduce serum lipids (AST, ALT, TG, TC, LDL, ALP, ACP and LDH), body weight and serum sugar, increase HDL and serum insulin in hyperlipidemic wistar rat induced by high-fat diet in vivo. Furthermore, eight new chalcones 1-8, one new flavanone 12, one new coumarin 14, three new meroterpenes 15-17 and one new bakuchiol 20 together with seven known compounds (9-11, 13, 18-19 and 21) were isolated from the PCE34. Their structures were elucidated based on analyses of their spectroscopic (UV, CD, NMR and HREIMS) data. All the isolates were evaluated for in vitro inhibitory activity against DGAT1/2, PTP1B and α-Glucosidase. Among them, compounds 1-3, 8-11, 14-17, 19 and 20 were found to exhibit selective inhibitory activity on DGAT1 with IC50 values ranging from 66.7 ± 1.2 to 87.2 ± 1.3 µM; 1, 8-12, 14 and 20 has the best inhibit active on PTP1B with IC50 values ranging from 13.8 ± 1.1 to 19.1 ± 1.6 µM; 1-12 and 14 displayed the significant inhibitory activities on α-Glucosidase with IC50 values ranging from 29.1 ± 1.2 to 79.4 ± 1.2 µM.

Clinical N3 is an independent risk factor of recurrence for breast cancer patients achieving pathological complete response and near-pathological complete response after neoadjuvant chemotherapy.

Background: Although achieving pathological complete response (pCR) and near-pathological complete response (near-pCR) after neoadjuvant chemotherapy (NAC) in breast cancer predicts a better outcome, some patients still experience recurrence. The aim of our study was to investigate the predictive factors of recurrence in the pCR and near-pCR population. Methods: We reviewed 1,209 breast cancer patients treated with NAC between January 2010 and April 2021 in the Cancer Hospital, Chinese Academy of Medical Sciences (CHCAMS). A total of 292 patients achieving pCR and near-pCR were included in our analysis. pCR was defined as ypT0N0/ypTisN0. Near-pCR was defined as ypT1mi/1a/1bN0 or ypT0/isN1mi. Clinical features and follow-up information were collected. Survival and predictive factors of recurrence were analyzed. Results: Of the 292 patients, 173 were pCR and 119 were near-pCR. The median age was 46 years (range, 23-75 years). The predominant tumor subtypes were human epidermal growth factor receptor type 2 (HER2)-positive breast cancer (49.0%) and triple-negative breast cancer (TNBC) (30.8%). The median duration of follow-up was 53 months (range, 9-138 months). A total of 25 (8.6%) patients developed recurrence, with 9 (5.2%) in the pCR group and 16 (13.4%) in the near-pCR group. The vast majority of recurrence occurred within 36 months from onset of NAC. The 5-year recurrence-free survival (RFS) rate of patients achieving pCR was significantly higher than that of patients achieving near-pCR (94.6% vs. 85.6%, p = 0.008). However, the 5-year overall survival (OS) rate between the two cohorts had no statistical difference (94.3% vs. 89.6%, p = 0.304). Clinical N3 (cN3) before NAC was an independent risk factor of recurrence in patients who achieved pCR (p = 0.003) and near-pCR (p = 0.036). Tumor size before NAC, subtypes of breast cancer, and chemotherapy regimens showed no significant association with RFS both for patients who achieved pCR and for those who achieved near-pCR (p > 0.05). Conclusions: cN3 before NAC was an independent risk factor of recurrence in patients who achieved pCR and near-pCR. It is worthwhile to closely monitor patients with cN3, especially in the first 3 years.

Chemotherapy Decision-Making and Survival Outcomes in Older Women With Early Triple-Negative Breast Cancer: Evidence From Real-World Practice.

Data regarding chemotherapy options and benefits in older women with early triple-negative breast cancer (TNBC) are limited. Our study aimed to assess the effects of adjuvant chemotherapy on recurrence-free survival (RFS), breast cancer-specific survival (BCSS), and overall survival (OS) rates in elderly TNBC patients. Patients aged ≥65 years diagnosed with stage I-III TNBC (except T1aN0) between 2010 and 2016 were retrospectively included. Multivariate Cox regression was performed to minimize bias. A total of 177 patients were included with a median age of 69 years (range, 65-86), almost all had a Charlson Comorbidity Index of 0-2, and 127 (71.8%) received chemotherapy. Patients who received chemotherapy were younger, had more advanced-stage disease and had better ECOG performance status (P<0.05). Among the 127 patients who were administered chemotherapy, 45 (35%) received taxane plus carboplatin, 36 (28%) received anthracycline-and-taxane-based regimens, and 23 (18%) received taxane-based regimens. The regimen options differed based on patient age and tumour stage (P<0.05). Nearly 80% of the patients completed ≥6 cycles of chemotherapy, and half had their dosage decreased. After adjustment for confounding factors, patients who received ≥6 cycles of chemotherapy were found to have improved RFS rates (hazard ratio [HR], 0.28; 95% confidence interval [CI], 0.09-0.87; P=0.027), and receipt of chemotherapy (≥1 cycle) was associated with better BCSS (HR, 0.19; 95% CI, 0.04-0.97; P=0.046) and OS (HR, 0.26; 95% CI, 0.08-0.87; P=0.029) rates. These results support the considering the risk for recurrence and performing individualized assessments when determining the appropriate chemotherapy approach for older women with early TNBC.

Evaluating the applicability of the ratio of PM2.5 and carbon monoxide as source signatures.

Air pollution is among the top risk faced by people around the world, and therefore combating it is among the top priorities. It begins with identifying the sources that contribute the most to local air pollution to prioritize their control. There are advanced methods for source identification and apportionment, but such methods are not available in many low-income countries and not everywhere in all high-income countries. We propose a simplified method by using source the signatures to help obtain information about the local source contribution if no other methods are available. Using low-cost monitors, particle mass (PM2.5) and carbon monoxide (CO) concentrations were measured and the ratio of CO/PM2.5 was determined. We investigated outdoor and indoor sources, including vehicular exhaust, combustion of biomass, incense and mosquito coil burning, and cigarette smoking. The results show that the ratios differed significantly between certain pollutant sources. Compressed natural gas (CNG) engines have a high ratio (mean value of 972 ± 419), which is attributed to relatively low PM2.5 emissions, while ship emissions and cigarette smoke recorded a relatively low ratio. Most traffic emissions recorded higher ratios than those of bushfire emissions, and ratios of most outdoor pollutant sources were much higher than those of indoor pollutant sources. There is a clear trend for ratios to decrease from high to low for CNG, petrol, diesel for buses, and fuel for ships. Our results suggest that the ratio of CO/PM2.5 can be used as an effective method to identify pollution sources.

Survival outcomes for dose-dense paclitaxel plus carboplatin neoadjuvant vs standard adjuvant chemotherapy in stage II to III triple-negative breast cancer: A prospective cohort study with propensity-matched analysis.

There is a scarcity of data exploring the long-term benefits of platinum-based (anthracycline-free) neoadjuvant chemotherapy (NACT) for triple-negative breast cancer (TNBC). The prospective cohort study was conducted at Cancer Hospital, Chinese Academy of Medical Sciences. Patients with TNBC in stage II-III were enrolled to receive NACT of dose-dense (dd) paclitaxel (175 mg/m2 ) plus carboplatin (AUC 4.0) biweekly (ddPCb) for 6 cycles, and matched patients during the same period who received standard adjuvant chemotherapy for survival comparison. From January 2014 to July 2021, 264 patients were included in the primary nonmatched analysis (neoadjuvant 99, adjuvant 165). Compared to those in the adjuvant group, patients receiving NACT had larger tumors, higher degrees of nodal burden and more advanced disease (P < .001). Almost all patients in the adjuvant group received epirubicin plus cyclophosphamide followed by paclitaxel. Within a median follow-up of 44.9 months, the 4-year recurrence-free survival (RFS, 82.6% vs 75.4%) and overall survival (OS, 86.6% vs 80.5%) were higher for patients in the neoadjuvant group without statistical difference. In the matched cohort of 134 patients (67 pairs), the 4-year RFS (84.9% vs 60.9%; hazard ratio [HR], 0.32; 95% confidence interval [CI], 0.15-0.69; P = .003) and OS (88.0% vs 65.9%, HR, 0.30, 95% CI, 0.12-0.75, P = .010) were significantly superior for platinum-based neoadjuvant than standard adjuvant chemotherapy. Compared to standard chemotherapy, ddPCb was related to less neutropenia and more thrombocytopenia. These results support the consideration of ddPCb as NACT for TNBC in stage II-III. Randomized data and predictive biomarkers for platinum-based chemotherapy are needed to be further investigated.

Identification of hub genes, miRNAs and regulatory factors relevant for Duchenne muscular dystrophy by bioinformatics analysis.

PURPOSE: Duchenne muscular dystrophy (DMD) is currently the most commonly diagnosed form of muscular dystrophy due to mutations in the dystrophin gene. However, its pathological process remains unknown and there is a lack of specific molecular biomarkers. The aim of our study is to explore key regulatory connections underlying the progression of DMD. MATERIALS AND METHODS: The gene expression profile dataset GSE38417 of DMD was obtained from the Gene Expression Omnibus (GEO) database. The differentially expressed genes (DEGs) between DMD patients and healthy controls were screened using geo2R, followed by Kyoto Encyclopedia of Genes and Genomes (KEGG) and Gene Ontology (GO) pathway enrichment analyses. Then a protein-protein interaction (PPI) network and sub-network of modules were constructed. To investigate the regulatory network underlying DMD, a global triple network including miRNAs, mRNAs and transcription factors (TFs) was constructed. RESULTS: A total of 1811 DEGs were found between the DMD and control groups, among which HERC5, SKP2 and FBXW5 were defined as hub genes with a degree of connectivity >35 in the PPI network. Furthermore, the five TFs ZNF362, ATAT1, SPI1, TCF12 and ABCF2, as well as the eight miRNAs miR-124a, miR-200b/200c/429, miR-19a/b, miR-23a/b, miR-182, miR-144, miR-498 and miR-18a/b were identified as playing crucial roles in the molecular pathogenesis of DMD. CONCLUSIONS: This paper provides a comprehensive perspective on the miRNA-TF-mRNA co-regulatory network underlying DMD, although the bioinformatic findings need further validation in future studies.

A phase 1 study of dalpiciclib, a cyclin-dependent kinase 4/6 inhibitor in Chinese patients with advanced breast cancer.

BACKGROUND: Dalpiciclib (SHR6390) is a novel inhibitor of cyclin-dependent kinase 4/6 which demonstrated promising anti-tumor potency in preclinical models. This first-in-human study was conducted to evaluate the tolerability, pharmacokinetics, safety, and preliminary antitumor activity of dalpiciclib in patients with advanced breast cancer (ABC). METHODS: In this open-label, phase 1 study, Chinese patients who had failed standard therapy were enrolled to receive oral dalpiciclib in 3 + 3 dose-escalation pattern at doses of 25-175 mg. Eligible patients were given a single-dose of dalpiciclib in week 1, followed by once daily continuous doses for 3 weeks, and 1 week off in 28-day cycles. Based on the tolerability, pharmacokinetics, and activity data revealed from the dose-escalation phase, three dose cohorts were selected to expand to 8-10 patients. The primary endpoints were maximum tolerated dose (MTD) and pharmacokinetics. RESULTS: Between Apr 15, 2016 and Dec 21, 2018, 40 patients were enrolled; all were diagnosed of hormone receptor-positive and HER2-negative ABC. Dalpiciclib 100 mg, 125 mg, and 150 mg cohorts were expanded to 10 patients. No dose-limiting toxicity was observed and the MTD was not reached. Adverse events (AEs) of grade 3 or 4 were observed in 22 (55.0%) of 40 patients, being neutropenia (52.5%), leukopenia (35.0%), thrombocytopenia (5.0%), and hypertension (2.5%). No serious AEs were reported. At the doses of 50-175 mg, steady state areas under the concentration-time curve and peak concentration increased almost proportionally with dose. The disease control rate (DCR) was 62.5% (25/40, 95% CI: 45.8-77.3). Two patients (5%; 125 mg and 150 mg cohorts) achieved partial response, with responses lasting 169 and 356+ days, respectively. Among the three expansion cohorts, the 150 mg cohort had the numerically highest DCR of 80.0% (95% CI: 44.4-97.5) and longest median progression-free survival of 8.4 months (95% CI: 2.1-not reached). CONCLUSIONS: Dalpiciclib showed acceptable safety profile and dose-dependent plasma exposure in Chinese patients with ABC. The recommended phase 2 dose was 150 mg. Preliminary evidence of clinical activity was observed, which warrants further validation. TRIAL REGISTRATION: ClinicalTrials.gov identifier: NCT02684266 . Registered Feb 17, 2016.

Diacylglycerol acyltransferase inhibitory new meroterpenes from the seeds of Psoralea corylifolia, and their structure-activity relationship study.

Five new meroterpenes, 12α-Psoracorylifol F (1), 7ß,8α-hydroxy-12ß-Psoracorylifol F (2), 8-ketone-Cyclobakuchiol C (3), 7α,8ß-hydroxy-12ß-Cyclobakuchiol C (4) and 8α-hydroxy-Cyclobakuchiol C (5) together with six known compounds (6-11) were isolated from seeds of Psoralea corylifolia, and their structures were elucidated on the basis of spectroscopic and physicochemical analyses. All the isolates were evaluated for in vitro inhibitory activity against DGAT1/2. Among them, compounds 1-6 were found to exhibit selective inhibitory activity on DGAT1 with IC50 values ranging from 61.5 ± 1.1 to 89.1 ± 1.2 µM.

Two new sesquiterpenes from the stems of Tripterygium wilfordii.

Two new ß-dihydroagarofuran-type sesquiterpenes 1ß,2α,6α,8ß,15- pentaacetoxy- 9α-benzoyloxy- ß-dihydroagarofuran (1) and 1ß,2ß,6α,15-tetraacetoxy-9ß-benzoyloxy- ß-dihydroagarofuran (2), together with five known abietane diterpenoids (3-7) were isolated from ethyl acetate extract of stems of Tripterygium wilfordii. Their structures were elucidated on the basis of detailed spectroscopic and physico-chemical analyses. All the isolates were evaluated for in vitro inhibitory activity against A549, HOS and MCF-7. Among them, compounds 4 and 5 exhibited manifest inhibition on A549, HOS and MCF-7 cancer cell lines.

Investigation of hub genes and immune status in heart transplant rejection using endomyocardial biopsies.

T cell-mediated rejection (TCMR) and antibody-mediated rejection (ABMR) are severe post-transplantation complications for heart transplantation (HTx), whose molecular and immunological pathogenesis remains unclear. In the present study, the mRNA microarray data set GSE124897 containing 645 stable, 52 TCMR and 144 ABMR endomyocardial biopsies was obtained to screen for differentially expressed genes (DEGs) between rejected and stable HTx samples and to investigate immune cell infiltration. Functional enrichment analyses indicated roles of the DEGs primarily in immune-related mechanisms. Protein-protein interaction networks were then constructed, and ICAM1, CD44, HLA-A and HLA-B were identified as hub genes using the maximal clique centrality method. Immune cell infiltration analysis revealed differences in adaptive and innate immune cell populations between TCMR, ABMR and stable HTx samples. Additionally, hub gene expression levels significantly correlated with the degree and composition of immune cell infiltration in HTx rejection samples. Furthermore, drug-gene interactions were constructed, and 12 FDA-approved drugs were predicted to target hub genes. Finally, an external GSE2596 data set was used to validate the expression of the hub genes, and ROC curves indicated all four hub genes had promising diagnostic value for HTx rejection. This study provides a comprehensive perspective of molecular and immunological regulatory mechanisms underlying HTx rejection.

Identifying Hub Genes, Key Pathways and Immune Cell Infiltration Characteristics in Pediatric and Adult Ulcerative Colitis by Integrated Bioinformatic Analysis.

BACKGROUND AND AIMS: In the present study, we investigated the differentially expressed genes (DEGs), pathways and immune cell infiltration characteristics of pediatric and adult ulcerative colitis (UC). METHODS: We conducted DEG analysis using the microarray dataset GSE87473 containing 19 pediatric and 87 adult UC samples downloaded from the Gene Expression Omnibus. Gene ontology and pathway enrichment analyses were conducted using Metascape. We constructed the protein-protein interaction (PPI) network and the drug-target interaction network of DEGs and identified hub modules and genes using Cytoscape and analyzed immune cell infiltration in pediatric and adult UC using CIBERSORT. RESULTS: In total, 1700 DEGs were screened from the dataset. These genes were enriched mainly in inter-cellular items relating to cell junctions, cell adhesion, actin cytoskeleton and transmembrane receptor signaling pathways and intra-cellular items relating to the splicing, metabolism and localization of RNA. CDC42, POLR2A, RAC1, PIK3R1, MAPK1 and SRC were identified as hub DEGs. Immune cell infiltration analysis revealed higher proportions of naive B cells, resting memory T helper cells, regulatory T cells, monocytes, M0 macrophages and activated mast cells in pediatric UC, along with lower proportions of memory B cells, follicular helper T cells, γδ T cells, M2 macrophages, and activated dendritic cells. CONCLUSIONS: Our study suggested that hub genes CDC42, POLR2A, RAC1, PIK3R1, MAPK1 and SRC and immune cells including B cells, T cells, monocytes, macrophages and mast cells play vital roles in the pathological differences between pediatric and adult UC and may serve as potential biomarkers in the diagnosis and treatment of UC.

Screening and identification of key regulatory connections and immune cell infiltration characteristics for lung transplant rejection using mucosal biopsies.

This study aimed to explore key regulatory connections underlying lung transplant rejection. The differentially expressed genes (DEGs) between rejection and stable lung transplantation (LTx) samples were screened using R package limma, followed by functional enrichment analysis and protein-protein interaction network construction. Subsequently, a global triple network, including miRNAs, mRNAs, and transcription factors (TFs), was constructed. Furthermore, immune cell infiltration characteristics were analyzed to investigate the molecular immunology of lung transplant rejection. Finally, potential drug-target interactions were generated. In brief, 739 DEGs were found between rejection and stable LTx samples. PTPRC, IL-6, ITGAM, CD86, TLR8, TYROBP, CXCL10, ITGB2, and CCR5 were defined as hub genes. Eight TFs, including STAT1, SPIB, NFKB1, SPI1, STAT5A, RUNX1, VENTX, and BATF, and five miRNAs, including miR-335-5p, miR-26b-5p, miR-124-3p, miR-1-3p, and miR-155-5p, were involved in regulating hub genes. The immune cell infiltration analysis revealed higher proportions of activated memory CD4 T cells, follicular helper T cells, γδ T cells, monocytes, M1 and M2 macrophages, and eosinophils in rejection samples, besides lower proportions of resting memory CD4 T cells, regulatory T cells, activated NK cells, M0 macrophages, and resting mast cells. This study provided a comprehensive perspective of the molecular co-regulatory network underlying lung transplant rejection.

The oncogenic role of Jagged1/Notch signaling in cancer.

Aberrant activation of Notch signaling plays an oncogenic role in cancer development. Jagged1 (JAG1) is an important Notch ligand that triggers Notch signaling through cell-cell interactions. JAG1 overexpression has been reported in many different types of cancer and correlates with a poor clinical prognosis. JAG1/Notch signaling controls oncogenic processes in different cell types and cellular contexts. Furthermore, JAG1/Notch signaling cascades activate a number of oncogenic factors that regulate cellular functions such as proliferation, metastasis, drug-resistance, and angiogenesis. To suppress the severe toxicity of pan-Notch inhibitors, JAG1 is attracting increasing attention as a source of therapeutic targets for cancers. In this review, the oncogenic role of JAG1/Notch signaling in cancer is discussed, as well as implications of strategies to inhibit JAG1/Notch signaling activity.

The Role of DLLs in Cancer: A Novel Therapeutic Target.

Delta-like ligands (DLLs) control Notch signaling. DLL1, DLL3 and DLL4 are frequently deregulated in cancer and influence tumor growth, the tumor vasculature and tumor immunity, which play different roles in cancer progression. DLLs have attracted intense research interest as anti-cancer therapeutics. In this review, we discuss the role of DLLs in cancer and summarize the emerging DLL-relevant targeting methods to aid future studies.