Human neutrophils have a vital role in host defense and inflammatory responses in innate immune systems. Growing evidence shows that the overproduction of reactive oxygen species and granular ...proteolytic enzymes from activated neutrophils is linked to the pathogenesis of acute inflammatory diseases. However, adequate therapeutic targets are still lacking to regulate neutrophil functions. Herein, we report that MVBR‐28, synthesized from the Mannich bases of heterocyclic chalcone, has anti‐neutrophilic inflammatory effects through regulation of intracellular pH. MVBR‐28 modulates neutrophil functions by attenuating respiratory burst, degranulation, and migration. Conversely, MVBR‐28 has no antioxidant effects and fails to alter elastase activity in cell‐free systems. The anti‐inflammatory effects of MVBR‐28 are not seen through cAMP pathways. Significantly, MVBR‐28 potently inhibits extracellular Ca2+ influx in N‐formyl‐methionyl‐leucyl‐phenylalanine (fMLF)‐ and thapsigargin‐activated human neutrophils. Notably, MVBR‐28 attenuates fMLF‐induced intracellular alkalization in a K+‐dependent manner, which is upstream of Ca2+ pathways. Collectively, these findings provide new insight into Mannich bases of heterocyclic chalcone regarding the regulation of neutrophil functions and the potential for the development of MVBR‐28 as a lead compound for treating neutrophilic inflammatory diseases.
Rosacea is a chronic inflammatory skin disorder. Inflammation and oxidative stress are involved in the etiopathogenesis of rosacea and chronic kidney disease (CKD). This study aimed to investigate ...the association between rosacea and CKD.
This population-based cohort study identified 277 patients with rosacea in the Taiwan National Health Insurance Research Database during 2001-2005. These patients were matched for age, sex, and comorbidities with 2216 patients without rosacea. All subjects were individually followed-up for 8-12 years to identify those who subsequently developed CKD.
The incidence rates of CKD per 1000 person-years were 16.02 in patients with rosacea and 10.63 in the non-rosacea reference population. After adjusting for other covariates and considering the competing risk of mortality, patients with rosacea remained at increased risk of CKD (adjusted sub-distribution hazard ratio (aSD-HR) 2.00; 95% confidence interval (CI) 1.05-3.82). The aSD-HRs (95% CI) for CKD were 1.82 (0.83-4.00) and 2.53 (1.11-5.75) for patients with mild and moderate-to-severe rosacea, respectively.
Rosacea is an independent risk factor for CKD. High rosacea severity and old age further increased CKD risk in patients with rosacea. Careful monitoring for CKD development should be included as part of integrated care for patients with rosacea.
HER3 mediates drug resistance against epidermal growth factor receptor (EGFR)-tyrosine kinase inhibitors (TKIs), resulting in tumor relapse in lung cancers. Previously, we demonstrated that EGFR ...induces HER3 overexpression, which facilitates the formation of cancer stem-like tumorspheres. However, the cellular mechanism through which EGFR regulates HER3 expression remains unclear. We hypothesized that EGFR downstream of STAT3 participates in HER3 expression because STAT3 contributes to cancer stemness and survival of EGFR-TKI resistant cancers.
First, RNAseq was used to uncover potential genes involved in the formation of lung cancer HCC827-derived stem-like tumorspheres. EGFR-positive lung cancer cell lines, including HCC827, A549, and H1975, were individually treated with a panel containing 172 therapeutic agents targeting stem cell-associated genes to search for potential agents that could be applied against EGFR-positive lung cancers. In addition, gene knockdown and RNAseq were used to investigate molecular mechanisms through which STAT3 regulates tumor progression and the survival in lung cancer.
BBI608, a STAT3 inhibitor, was a potential therapeutic agent that reduced the cell viability of EGFR-positive lung cancer cell lines. Notably, the inhibitory effects of BBI608 were similar with those associated with YM155, an ILF3 inhibitor. Both compounds reduced G9a-mediated HER3 expression. We also demonstrated that STAT3 upregulated G9a to silence miR-145-5p, which exacerbated HER3 expression in this study.
The present study revealed that BBI608 could eradicate EGFR-positive lung cancers and demonstrated that STAT3 enhanced the expression of HER3 through miR-145-5p repression by G9a, indicating that STAT3 is a reliable therapeutic target against EGFR-TKI-resistant lung cancers.
The mechanism exhausting CD8
+
T cells is not completely clear against tumors. Literature has demonstrated that cigarette smoking disables the immunological activity, so we propose nicotine is able ...to exhaust CD8
+
T cells. The CD8
+
T cells from healthy volunteers with and without cigarette smoking and the capacity of CD8
+
T cells against tumor cells were investigated. RNAseq was used to investigate the gene profiling expression in CD8
+
T cells. Meanwhile, small RNAseq was also used to search novel microRNAs involved in the exhaustion of CD8
+
T cells. The effect of nicotine exhausting CD8
+
T cells was investigated in vitro and in the humanized tumor xenografts in vivo. We found that CD8
+
T cells were able to reduce cell viability in lung cancer HCC827 and A549 cells, that secreted granzyme B, but CD8
+
T cells from the healthy cigarette smokers lost anti-HCC827 effect. Moreover, nicotine suppressed the anti-HCC827 effect of CD8
+
T cells. RNAseq revealed lower levels of IL2RB and GZMB in the exhausted CD8
+
T cells. We identified that miR-629-5p was increased by nicotine, that targeted IL2RB. Transfection of miR-629-5p mimic reduced IL2RB and GZMB levels. We further validated that nicotine reduced granzyme B levels using a nuclear imaging technique, and demonstrated that nicotine exhausted peripheral blood mononuclear cells against HCC827 growth in the humanized tumor xenografts. This study demonstrated that nicotine exhausted CD8
+
T cells against HCC827 cells through increasing miR-629-5p to suppress IL2RB.
This study aimed to identify vulnerable patients with head and neck cancer undergoing concurrent chemoradiation therapy (CCRT) who are susceptible to higher treatment-related adverse effects and have ...poorer treatment tolerance. This study also aimed to determine whether comprehensive geriatric assessment, developed in the geriatric population, can predict vulnerability to treatment-related adverse events and survival even in nongeriatric patients with head and neck cancer, as well as the prevalence of vulnerability and its effect on toxicities and survival among these patients.
This prospective cohort study examined 461 patients with primary head and neck cancer who underwent definitive CCRT during 2016 to 2017 at 3 medical centers across Taiwan. Vulnerability is defined as susceptibility to cancer- and treatment-related adverse events that result in poor treatment tolerance and unexpected emergent medical needs, such as hospitalization and emergency room visits. Vulnerability was assessed as impairment with ≥2 dimensions on comprehensive geriatric assessment, 7 days before CCRT. The association of vulnerability with treatment-related adverse events and survival was analyzed.
The prevalence of vulnerability was 22.2%, 27.3%, 30.2%, and 27.9% among patients aged 20 to 34, 35 to 49, 50 to 64, and >65 years, respectively. Survival was poorer in vulnerable patients than in nonvulnerable patients (hazard ratio, 1.97; 95% confidence interval, 1.26-3.07; P = .003). Vulnerable patients showed a higher tendency toward CCRT incompletion (19.5% vs 6.1%, P < .001), hospitalization (34.6% vs 23.5%, P = .020), need for tubal feeding (29.3% vs 11.8%, P < .001), and longer length of hospital stay (8.1 days vs 4.0 days, P = .004) than nonvulnerable patients. Hematologic and nonhematologic toxicities were more severe in vulnerable patients than in nonvulnerable patients.
Vulnerability, which is an urgent concern when it presents among patients with head and neck cancer, was independently associated with poorer survival and severe treatment-related complications. Vulnerability assessment should be routinely evaluated in all patients with primary head and neck cancer who are undergoing definitive CCRT, not only in such patients who are geriatric.
Cancer stem cells are capable of undergoing cell division after surviving cancer therapies, leading to tumor progression and recurrence. Inhibitory agents against cancer stem cells may be ...therapeutically used for efficiently eradicating tumors. Therefore, the aim of this study was to identify the relevant driver genes that maintain cancer stemness in epidermal growth factor receptor (EGFR)-positive colorectal cancer (CRC) cells and to discover effective therapeutic agents against these genes.
In this study, EGFR-positive cancer stem-like cells (CSLCs) derived from HCT116 and HT29 cells were used as study models for in vitro inductions. To identify the differential genes that maintain CSLCs, RNAseq analysis was conducted followed by bioinformatics analysis. Moreover, a panel containing 172 therapeutic agents targeting the various pathways of stem cells was used to identify effective therapeutics against CSLCs.
RNAseq analysis revealed that 654 and 840 genes were significantly upregulated and downregulated, respectively, in the HCT116 CSLCs. Among these genes, notably, platelet-derived growth factor A (PDGFA) and signal transducer and activator of transcription 3 (STAT3) were relevant according to the cancer pathway analyzed using NetworkAnalyst. Furthermore, therapeutic screening revealed that the agents targeting STAT3 and Wnt signaling pathways were efficient in reducing the cell viabilities of both HCT116 and HT29 cells. Consequently, we discovered that STAT3 inhibition using homoharringtonine and STAT3 knockdown significantly reduced the formation and survival of HT29-derived tumorspheres. We also observed that STAT3 phosphorylation was regulated by epidermal growth factor (EGF) to induce PDGFA and Wnt signaling cascades.
We identified the potential genes involved in tumorsphere formation and survival in selective EGFR-positive CRCs. The results reveal that the EGF-STAT3 signaling pathway promotes and maintains CRC stemness. In addition, a crosstalk between STAT3 and Wnt activates the Wnt/β-catenin signaling pathway, which is also responsible for cancer stemness. Thus, STAT3 is a putative therapeutic target for CRC treatment.
Comprehensive Geriatric Assessment (CGA) is the gold standard for detecting frailty in elderly patients with cancer. Since CGA is time- and resource-consuming, many alternative frailty screening ...tools have been developed; however, it remains unknown whether these tools are suitable for older and adult patients with cancer. Therefore, we used the data collected for a large longitudinal study to compare the diagnostic performances of two frailty screening tools (Geriatric 8 G8 and Flemish version of the Triage Risk Screening Tool fTRST) to identify frailty risk profile among patients with cancer.
Patients aged ≥20 years with newly diagnosed cancer were enrolled. Frailty screening with G8, fTRST, and CGA were performed before anti-cancer treatment. Diagnostic characteristics obtained using G8 and fTRST were analyzed by C-index, and the validity of G8 and fTRST was also determined.
40.9% of the 755 patients with cancer displayed frailty on CGA. Both G8 and fTRST showed high sensitivity (80.6–88.4%) and negative predictive value (81.0–81.2%). The C-index of G8 was higher than that of fTRST (0.77 vs 0.71, p = .01). Moreover, the best G8 and fTRST cut-off points were ≤13 and ≥ 2, respectively. The validities of G8 and fTRST were also confirmed; however, frailty age differences were not observed in our study.
Frailty is a common problem for patients with cancer, and routine frailty screening is essential for both older and adult patients. G8 and fTRST are simple and useful frailty screening tools, while G8 is more suitable than fTRST for Taiwanese patients with cancer.
With the rapid growth of the elderly population and the increasing incidence of cancer, an increasing number of geriatric patients are receiving cancer treatment, making the selection of appropriate ...treatment an important issue. Increasing studies have confirmed that frailty can predict adverse outcomes in geriatric patients with cancer after treatment, but local data from Taiwan are lacking. Therefore, this study aimed to investigate the correlation between frailty and chemotherapy-related adverse outcomes in geriatric patients with cancer.
A total of 234 geriatric patients aged ≥65 years with cancer receiving chemotherapy were enrolled during the study period of September 2016 to November 2018. The collected data included: patients' basic demographics and Comprehensive Geriatric Assessment (CGA) before treatment, chemotherapy-related adverse outcomes, unexpected hospitalizations, and emergency department visits within 3 months of treatment. We investigated the association between frailty and chemotherapy-related adverse outcomes in geriatric patients with cancer using the chi-square test and logistic regression analysis.
The prevalence of frailty in geriatric patients with cancer was 58.1%. Age, marital status, main caregiver, cancer type, and Eastern Cooperative Oncology Group performance status, and physical fitness were factors associated with frailty. Frail geriatric patients with cancer were at higher risk of chemotherapy-related adverse outcomes, such as grades 3-4 thrombocytopenia (odds ratio OR = 11.13,
= 0.021) and grades 3-4 hyponatremia (OR = 12.03,
= 0.017), than non-frail patients, and they were at increased risk of unexpected hospitalizations (OR = 2.15,
= 0.025) and emergency department visits (OR = 1.99,
= 0.039).
Frailty is a common problem in geriatric patients with cancer and significantly impacts chemotherapy-related adverse outcomes. Our findings suggest that geriatric patients with cancer should undergo frail assessment prior to chemotherapy as a reference to guide future treatment decisions.
Data on long-term maternal outcomes in patients with systemic lupus erythematosus (SLE) are lacking. The study aimed to explore the relationships among SLE, pregnancy, outcomes of end-stage renal ...disease (ESRD), and overall mortality.
We established a retrospective cohort study consisting of four cohorts: pregnant (case cohort) and nonpregnant SLE patients, as well as pregnant and nonpregnant non-SLE patients. One case cohort and three comparison cohorts were matched by age at first pregnancy and index date of pregnancy by using the Taiwan National Health Insurance Research Dataset. All study subjects were selected based on the index date to the occurrence of ESRD or overall death. Cox proportional hazard regression models and Kaplan-Meier curves were used in the analysis.
SLE pregnant patients exhibited significantly increased risk of ESRD after adjusting for other important confounders, including immunosuppressant and parity (HR = 3.19, 95% CI: 1.35-7.52 for pregnant non-SLE; and HR = 2.77, 95% CI: 1.24-6.15 for nonpregnant non-SLE patients). No significant differences in ESRD incidence were observed in pregnant and nonpregnant SLE patients. Pregnant SLE patients exhibited better clinical condition at the baseline and a significantly lower risk of overall mortality than nonpregnant SLE patients.
Our data support current recommendations for SLE patients to avoid pregnancy until disease activity is quiescent. Multicenter recruitment and clinical information can be used to further examine the association of SLE and ESRD (or mortality) after pregnancy.
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