Lung cancer is the most commonly diagnosed cancer worldwide, and metastasis in lung cancer is the leading cause of cancer‐related deaths. Thus, understanding the mechanism of lung cancer metastasis ...will improve the diagnosis and treatment of lung cancer patients. Herein, we found that expression of cluster of differentiation 109 (CD109) was correlated with the invasive and metastatic capacities of lung adenocarcinoma cells. CD109 is upregulated in tumorous tissues, and CD109 overexpression was associated with tumor progression, distant metastasis, and a poor prognosis in patient with lung adenocarcinoma. Mechanistically, expression of CD109 regulates protein kinase B (AKT)/mammalian target of rapamycin (mTOR) signaling via its association with the epidermal growth factor receptor (EGFR). Inhibition of CD109 decreases EGFR phosphorylation, diminishes EGF‐elicited activation of AKT/mTOR, and sensitizes tumor cells to an EGFR inhibitor. Taken together, our results show that CD109 is a potential diagnostic and therapeutic target in lung cancer patients.
CD109 promotes lung cancer metastasis through promoting EGFR‐AKT‐mTOR signaling and CD109 is an independent prognostic marker for lung adenocarcinoma.
Aberrant activation of the epidermal growth factor receptor (EGFR/ERBB1) by erythroblastic leukemia viral oncogene homolog (ERBB) ligands contributes to various tumor malignancies, including lung ...cancer and colorectal cancer (CRC). Epiregulin (EREG) is one of the EGFR ligands and is low expressed in most normal tissues. Elevated EREG in various cancers mainly activates EGFR signaling pathways and promotes cancer progression. Notably, a higher EREG expression level in CRC with wild-type Kirsten rat sarcoma viral oncogene homolog (KRAS) is related to better efficacy of therapeutic treatment. By contrast, the resistance of anti-EGFR therapy in CRC was driven by low EREG expression, aberrant genetic mutation and signal pathway alterations. Additionally, EREG overexpression in non-small cell lung cancer (NSCLC) is anticipated to be a therapeutic target for EGFR-tyrosine kinase inhibitor (EGFR-TKI). However, recent findings indicate that EREG derived from macrophages promotes NSCLC cell resistance to EGFR-TKI treatment. The emerging events of EREG-mediated tumor promotion signals are generated by autocrine and paracrine loops that arise from tumor epithelial cells, fibroblasts, and macrophages in the tumor microenvironment (TME). The TME is a crucial element for the development of various cancer types and drug resistance. The regulation of EREG/EGFR pathways depends on distinct oncogenic driver mutations and cell contexts that allows specific pharmacological targeting alone or combinational treatment for tailored therapy. Novel strategies targeting EREG/EGFR, tumor-associated macrophages, and alternative activation oncoproteins are under development or undergoing clinical trials. In this review, we summarize the clinical outcomes of EREG expression and the interaction of this ligand in the TME. The EREG/EGFR pathway may be a potential target and may be combined with other driver mutation targets to combat specific cancers.
Neoadjuvant or adjuvant immunotherapy can improve outcomes in patients with resectable non-small-cell lung cancer (NSCLC). Perioperative regimens may combine benefits of both to improve long-term ...outcomes.
We randomly assigned patients with resectable NSCLC (stage II to IIIB N2 node stage according to the eighth edition of the
) to receive platinum-based chemotherapy plus durvalumab or placebo administered intravenously every 3 weeks for 4 cycles before surgery, followed by adjuvant durvalumab or placebo intravenously every 4 weeks for 12 cycles. Randomization was stratified according to disease stage (II or III) and programmed death ligand 1 (PD-L1) expression (≥1% or <1%). Primary end points were event-free survival (defined as the time to the earliest occurrence of progressive disease that precluded surgery or prevented completion of surgery, disease recurrence assessed in a blinded fashion by independent central review, or death from any cause) and pathological complete response (evaluated centrally).
A total of 802 patients were randomly assigned to receive durvalumab (400 patients) or placebo (402 patients). The duration of event-free survival was significantly longer with durvalumab than with placebo; the stratified hazard ratio for disease progression, recurrence, or death was 0.68 (95% confidence interval CI, 0.53 to 0.88; P = 0.004) at the first interim analysis. At the 12-month landmark analysis, event-free survival was observed in 73.4% of the patients who received durvalumab (95% CI, 67.9 to 78.1), as compared with 64.5% of the patients who received placebo (95% CI, 58.8 to 69.6). The incidence of pathological complete response was significantly greater with durvalumab than with placebo (17.2% vs. 4.3% at the final analysis; difference, 13.0 percentage points; 95% CI, 8.7 to 17.6; P<0.001 at interim analysis of data from 402 patients). Event-free survival and pathological complete response benefit were observed regardless of stage and PD-L1 expression. Adverse events of maximum grade 3 or 4 occurred in 42.4% of patients with durvalumab and in 43.2% with placebo. Data from 62 patients with documented
or
alterations were excluded from the efficacy analyses in the modified intention-to-treat population.
In patients with resectable NSCLC, perioperative durvalumab plus neoadjuvant chemotherapy was associated with significantly greater event-free survival and pathological complete response than neoadjuvant chemotherapy alone, with a safety profile that was consistent with the individual agents. (Funded by AstraZeneca; AEGEAN ClinicalTrials.gov number, NCT03800134.).
Recently, we demonstrated that
(PG2), the active ingredient in dried roots of
ameliorates cancer symptom clusters and improves quality of life (QoL) in patients with metastatic disease by modulating ...inflammatory cascade against the background roles of inflammatory cells, including macrophages, dendritic cells (DCs), and cytotoxic T lymphocytes (CTLs) in tumor initiation, metastasis, and progression. Nevertheless, the role of PG2 in the modulation of anticancer immunogenicity and therapeutic response remains relatively underexplored and unclear.
The present study investigates how and to what extent PG2 modulates cellular and biochemical components of the inflammatory cascade and enhances anticancer immunity, as well as the therapeutic implication of these bio-events in patients with lung cancer.
Herein, we demonstrated that PG2 significantly increased the M1/M2 macrophage polarization ratio in non-small cell carcinoma (NSCLC) H441 and H1299 cells. This PG2-induced preferential pharmacologic up-regulation of tumoral M1 population in vitro positively correlated with the downregulation of tumor-promoting IL-6 and IL-10 expression in NSCLC cell-conditioned medium, with concomitant marked inhibition of cell proliferation, clonogenicity, and tumorsphere formation. Our ex vivo results, using clinical sample from our NSCLC cohort, demonstrated that PG2 also promoted the functional maturation of DCs with consequent enhancement of T cell-mediated anticancer immune responses. Consistent with the in vitro and ex vivo results, our in vivo studies showed that treatment with PG2 elicited significant time-dependent depletion of the tumor-associated M2 population, synergistically enhanced the anti-M2-based anticancer effect of cisplatin, and inhibited xenograft tumor growth in the NSCLC mice models. Moreover, in the presence of PG2, cisplatin-associated dyscrasia and weight-loss was markedly suppressed.
These results do indicate a therapeutically-relevant role for PG2 in modulating the M1/M2 macrophage pool, facilitating DC maturation and synergistically enhancing the anticancer effect of conventional chemotherapeutic agent, cisplatin, thus laying the foundation for further exploration of the curative relevance of PG2 as surrogate immunotherapy and/or clinical feasibility of its use for maintenance therapy in patients with lung cancer.
•Previous research revealed that the breathing system is involved in diverse motor processes including running, orofacial movements, and even voluntary motor action.•In this study, we investigated ...whether the breathing system is associated with voluntary initiation of mental actions (i.e., motor and visual imagery) which are not accompanied by any overt movement.•We found that the breathing cycle is synchronized with the onset of self-initiated mental imagery performance which was preceded by the cortical readiness potential.•Our findings suggest breathing-action coupling is involved in more general action preparation processing, regardless of any subsequent motor process.
Previous research has suggested that bodily signals from internal organs are associated with diverse cortical and subcortical processes involved in sensory-motor functions, beyond homeostatic reflexes. For instance, a recent study demonstrated that the preparation and execution of voluntary actions, as well as its underlying neural activity, are coupled with the breathing cycle. In the current study, we investigated whether such breathing-action coupling is limited to voluntary motor action or whether it is also present for mental actions not involving any overt bodily movement. To answer this question, we recorded electroencephalography (EEG), electromyography (EMG), and respiratory signals while participants were conducting a voluntary action paradigm including self-initiated motor execution (ME), motor imagery (MI), and visual imagery (VI) tasks. We observed that the voluntary initiation of ME, MI, and VI are similarly coupled with the respiration phase. In addition, EEG analysis revealed the existence of readiness potential (RP) waveforms in all three tasks (i.e., ME, MI, VI), as well as a coupling between the RP amplitude and the respiratory phase. Our findings show that the voluntary initiation of both imagined and overt action is coupled with respiration, and further suggest that the breathing system is involved in preparatory processes of voluntary action by contributing to the temporal decision of when to initiate the action plan, regardless of whether this culminates in overt movements.
As a complex phenomenon, sleep quality is difficult to objectively define and measure, and multiple factors related to sleep quality, such as age, lifestyle, physical activity, and physical fitness, ...feature prominently in older adult populations. The aim of the present study was to evaluate subjective sleep quality using the Pittsburgh Sleep Quality Index (PSQI) and to associate sleep quality with health-related physical fitness factors, depressive symptoms, and the number of chronic diseases in the middle-aged and elderly.
We enrolled a total of 283 middle-aged and elderly participants from a rehabilitation clinic or health examination department. The PSQI was used to evaluate sleep quality. The health-related fitness assessment included anthropometric and physical fitness parameters. Depressive symptoms were measured with the Center for Epidemiologic Studies Depression Scale (CES-D) short form. Data were analyzed with SPSS 18.0, and descriptive statistics and logistic regression analysis were used for the analyses.
Overall, 27.9% of participants in this study demonstrated bad sleepers (with a PSQI score of > 5), 10.2% of study participants frequently used sleep medication to help them fall asleep, and 6.0% reported having significant depressive symptoms (with a CES-D score of ≥10). There are two major findings: (1) depression symptoms, the number of chronic diseases, self-rated health, and arthritis were significantly associated with a poor sleep quality, and (2) the 2-min step test was associated with longer sleep latency. These results confirmed that the 2-min step was associated with a longer sleep latency among the health-related physical fitness items.
Our study found that depressive syndrome, chronic disease numbers, a poor self-rated health status, and arthritis were the main risk factors that influenced subjective sleep quality.
Cancer metastasis leading to the dysfunction of invaded organs is the main cause of the reduced survival rates in lung cancer patients. However, the molecular mechanism for lung cancer metastasis ...remains unclear. Recently, the increased activity of inflammasome appeared to correlate with the metastatic progression and immunosuppressive ability of various cancer types. Our results showed that the mRNA levels of absence in melanoma 2 (AIM2), one of the inflammasome members, are extensively upregulated in primary tumors compared with normal tissues derived from the TCGA lung adenocarcinoma (LUAD) database. Moreover, Kaplan‐Meier analysis demonstrated that a higher mRNA level of AIM2 refers to a poor prognosis in LUAD patients. Particularly, AIM2 upregulation is closely correlated with smoking history and the absence of EGFR/KRAS/ALK mutations in LUAD. We further showed that the endogenous mRNA levels of AIM2 are causally associated with the metastatic potentials of the tested LUAD cell lines. AIM2 knockdown suppressed but overexpression promoted the migration ability and lung colony–forming ability of tested LUAD cells. In addition, we found that AIM2 upregulation is closely associated with an increased level of immune checkpoint gene set, as well as programmed cell death‐ligand 1 (PD‐L1) transcript, in TCGA LUAD samples. AIM2 knockdown predominantly repressed but overexpression enhanced PD‐L1 expression via altering the activity of PD‐L1 transcriptional regulators NF‐κB/STAT1 in LUAD cells. Our results not only provide a possible mechanism underlying the AIM2‐promoted metastatic progression and immune evasion of LUAD but also offer a new strategy for combating metastatic/immunosuppressive LUAD via targeting AIM2 activity.
The illustration of a possible mechanism for the AIM2‐fostered EMT progression and PD‐L1 expression in the metastatic/immunosuppressive lung adenocarcinoma. AIM2 increases PD‐L1 expression via activating its transcriptional regulators NF‐kB/STAT1.
Impaired lung function is associated with morbidity and mortality in the elderly. However, there is a paucity of data regarding the long-term effects of particulate matter (PM) on lung function among ...the elderly. This study evaluated the exposure-response relationship between ambient PM and different lung function indices among the elderly in Taiwan. A cross-sectional survey of individuals aged ≥65 years was conducted in Taiwan from October 2015 to September 2016. Those who attended the annual health examination for the elderly in five hospitals of varying background PM concentrations were enrolled. The long-term (2015 annual mean concentration) exposure to air pollution was estimated by the Kriging method at the residence of each subject. The association between ambient PM exposure and lung function was evaluated by linear regression modeling, with adjustments for age, sex, height, weight, educational attainment, presence of asthma or chronic obstructive pulmonary disease, smoking status, season, and co-pollutants. There were 1241 subjects (mean age, 70.5 years). The mean residential PM
and PM
in 2015 was 26.02 and 18.01 μg/m
, respectively. After adjustments for confounders and co-pollutants, the FVC decrease was best associated with fine particles (PM
), whereas the FEV
, FEF
, FEF
and FEF
decreases were best associated with coarse particles (PM
). An IQR (10 μg/m
) increase in PM
decreased FVC by 106.38 ml (4.47%), while an IQR (7.29 μg/m
) increase in PM
decreased FEV
and FEF
by 91.23 ml (4.85%) and 104.44 ml/s (5.58%), respectively. Among the Taiwanese elderly, long-term PM
exposure mainly decreases the vital capacity of lung function. Moreover, PM
has a stronger negative effect on the function of conductive airways than PM
.
The coronavirus disease 2019 (COVID-19) pandemic, caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), has become a public health emergency. The most common symptoms of COVID-19 ...are fever, cough, and fatigue. While most patients with COVID-19 present with mild illness, some patients develop pneumonia, an important risk factor for mortality, at early stage of viral infection, putting these patients at increased risk of death. So far, little has been known about differences in the T cell repertoires between COVID-19 patients with and without pneumonia during SARS-CoV-2 infection. Herein, we aimed to investigate T cell receptor (TCR) repertoire profiles and patient-specific SARS-CoV-2-associated TCR clusters between COVID-19 patients with mild disease (no sign of pneumonia) and pneumonia. The TCR sequencing was conducted to characterize the peripheral TCR repertoire profile and diversity. The TCR clustering and CDR3 annotation were exploited to further discover groups of patient-specific TCR clonotypes with potential SARS-CoV-2 antigen specificities. Our study indicated a slight decrease in the TCR repertoire diversity and a skewed CDR3 length usage in patients with pneumonia compared to those with mild disease. The SARS-CoV-2-associated TCR clusters enriched in patients with mild disease exhibited significantly higher TCR generation probabilities and most of which were highly shared among patients, compared with those from pneumonia patients. Importantly, using similarity network-based clustering followed by the sequence conservation analysis, we found different patterns of CDR3 sequence motifs between mild disease- and pneumonia-specific SARS-CoV-2-associated public TCR clusters. Our results showed that characteristics of overall TCR repertoire and SARS-CoV-2-associated TCR clusters/clonotypes were divergent between COVID-19 patients with mild disease and patients with pneumonia. These findings provide important insights into the correlation between the TCR repertoire and disease severity in COVID-19 patients.
Immune checkpoint inhibitors, including anti‐programmed death 1 and anti‐programmed death ligand 1, have become prominent treatment options for various types of cancers. However, immune checkpoint ...inhibitors are associated with various cutaneous adverse events, one of which is psoriasiform drug eruption. Some cases of psoriasiform drug eruption can only be controlled through the cessation of immune checkpoint inhibitors and administration of systemic immunosuppressants, such as corticosteroids and methotrexate. However, no clear guideline is available on the management of this specific rash, and the use of systemic immunosuppressants is contraindicated in selected conditions. In this article, we report a case of annular psoriasiform drug eruption induced by an anti‐programmed death ligand 1 monoclonal antibody, durvalumab. The patient responded well to the combination of phototherapy and topical treatment, which allowed continuation of durvalumab treatment without concomitant systemic immunosuppressants in a 2‐year follow up.
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