Clinicopathological characteristics and prognosis of synchronous brain metastases from non-small cell lung cancer compared with metachronous brain metastases.

Purpose: Brain metastasis (BM) from non-small cell lung cancer (NSCLC) is a serious complication severely affecting patients' prognoses. We aimed to compare the clinicopathological features and prognosis of synchronous and metachronous BM from NSCLC. Methods: Clinical data of 461 patients with brain metastases from NSCLC who visited the Cancer Hospital of China Medical University from 2005 to 2017 were retrospectively collected. We analyzed the pathophysiological characteristics of synchronous and metachronous BM from NSCLC and survival rates of the patients. Propensity score matching analysis was used to reduce bias between groups. In addition, we used the Kaplan-Meier method for survival analysis, log-rank test to compare survival rates, and Cox proportional hazards regression model for multivariate prognosis analysis. Results: Among 461 patients with BM, the number of people who met the inclusion criteria was 400 cases, and after 1:2 propensity score matching,130 had synchronous BM and 260 had metachronous BM. The survival time was longer for metachronous BM in driver mutation-negative patients with squamous cell carcinoma than synchronous BM. Conversely, metachronous and synchronous BM with gene mutations and adenocarcinoma showed no differences in survival time. Multivariate analysis showed that metachronous BM was an independent prognostic factor for overall survival. Furthermore, the pathological type squamous cell carcinoma and Karnofsky Performance Status score <80 were independent risk factors affecting overall survival. Conclusion: BM status is an independent factor influencing patient outcome. Moreover, synchronous and metachronous BM from NSCLC differ in gene mutation profile, pathological type, and disease progression and hence require different treatments.

From intramuscular to nasal: unleashing the potential of nasal spray vaccines against coronavirus disease 2019.

Coronavirus disease 2019, caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), has affected 700 million people worldwide since its outbreak in 2019. The current pandemic strains, including Omicron and its large subvariant series, exhibit strong transmission and stealth. After entering the human body, the virus first infects nasal epithelial cells and invades host cells through the angiotensin-converting enzyme 2 receptor and transmembrane serine protease 2 on the host cell surface. The nasal cavity is an important body part that protects against the virus. Immunisation of the nasal mucosa produces immunoglobulin A antibodies that effectively neutralise viruses. Saline nasal irrigation, a type of physical therapy, can reduce the viral load in the nasal cavity and prevent viral infections to some extent. As a commonly used means to fight SARS-CoV-2, the intramuscular (IM) vaccine can induce the human body to produce a systemic immune response and immunoglobulin G antibody; however, the antibody is difficult to distribute to the nasal mucosa in time and cannot achieve a good preventive effect. Intranasal (IN) vaccines compensate for the shortcomings of IM vaccines, induce mucosal immune responses, and have a better effect in preventing infection. In this review, we discuss the nasal defence barrier, the harm caused by SARS-CoV-2, the mechanism of its invasion into host cells, nasal cleaning, IM vaccines and IN vaccines, and suggest increasing the development of IN vaccines, and use of IN vaccines as a supplement to IM vaccines.

Clinical factors and major pathological response after neoadjuvant chemoimmunotherapy in potentially resectable lung squamous cell carcinoma.

Objective: Major pathological response (MPR) helps evaluate the prognosis of patients with lung squamous cell carcinoma (LUSC). However, the clinical factors that affect the achievement of MPR after neoadjuvant chemoimmunotherapy (NCIO) in patients with LUSC remain unclear. This study aimed to explore the clinical factors affecting the MPR after NCIO in patients with potentially resectable LUSC. Methods: This retrospective study included patients with stage IIB-IIIC LUSC who underwent surgical resection after receiving NCIO at a center between March 2020 and November 2022. In addition to the postoperative pathological remission rate, sex, age, body mass index (BMI), smoking history, TNM stage, hematological and imaging test results, and other indicators were examined before NCIO. According to the pathological response rate of the surgically removed tumor tissue, the patients were split into MPR and non-MPR groups. Results: In total, 91 LUSC patients who met the study's eligibility criteria were enrolled: 32 (35%) patients in the non-MPR group and 59 (65%) in the MPR group, which included 43 cases of pathological complete remission (pCR). Pre-treatment lymphocyte level (LY) (odds ratio [OR] =5.997), tumor burden (OR=0.958), N classification (OR=15.915), radiographic response (OR=11.590), pulmonary atelectasis (OR=5.413), and PD-L1 expression (OR=1.028) were independently associated with MPR (all P < 0.05). Based on these six independent predictors, we developed a nomogram model of prediction having an area under the curve (AUC) of 0.914 that is simple to apply clinically to predict the MPR. The MPR group showed greater disease-free survival (DFS) than the non-MPR group, according to the survival analysis (P < 0.001). Conclusion: The MPR rate of NCIO for potentially resectable LUSC was 65%. LY, tumor burden, N classification, radiographic response, pulmonary atelectasis, and PD-L1 expression in patients with LUSC before NCIO were the independent and ideal predictors of MPR. The developed nomogram demonstrated a good degree of accuracy and resilience in predicting the MPR following NCIO, indicating that it is a useful tool for assuring customized therapy for patients with possibly resectable LUSC.

RAMP1 Protects Hepatocytes against Ischemia-reperfusion Injury by Inhibiting the ERK/YAP Pathway.

Background and Aims: Hepatic ischemia-reperfusion injury (HIRI) is a prevalent complication of liver transplantation, partial hepatectomy, and severe infection, necessitating the development of more effective clinical strategies. Receptor activity-modifying protein 1 (RAMP1), a member of the G protein-coupled receptor adapter family, has been implicated in numerous physiological and pathological processes. The study aimed to investigate the pathogenesis of RAMP1 in HIRI. Methods: We established a 70% liver ischemia-reperfusion model in RAMP1 knockout (KO) and wild-type mice. Liver and blood samples were collected after 0, 6, and 24 h of hypoxia/reperfusion. Liver histological and serological analyses were performed to evaluate liver damage. We also conducted in-vitro and in-vivo experiments to explore the molecular mechanism underlying RAMP1 function. Results: Liver injury was exacerbated in RAMP1-KO mice compared with the sham group, as evidenced by increased cell death and elevated serum transaminase and inflammation levels. HIRI was promoted in RAMP1-KO mice via the induction of hepatocyte apoptosis and inhibition of proliferation. The absence of RAMP1 led to increased activation of the extracellular signal-regulated kinase (ERK)/mitogen-activated protein kinase (MAPK) pathway and yes-associated protein (YAP) phosphorylation, ultimately promoting apoptosis. SCH772984, an ERK/MAPK phosphorylation inhibitor, and PY-60, a YAP phosphorylation inhibitor, reduced apoptosis in in-vitro and in-vivo experiments. Conclusions: Our findings suggest that RAMP1 protects against HIRI by inhibiting ERK and YAP phosphorylation signal transduction, highlighting its potential as a therapeutic target for HIRI and providing a new avenue for intervention.

Nrf2 enhances the therapeutic efficiency of adipose-derived stem cells in the treatment of neurogenic erectile dysfunction in a rat model.

BACKGROUND: Erectile dysfunction (ED) caused by intraoperative nerve injury is a major complication of pelvic surgery. Adipose-derived stem cells (ADSCs) have presented therapeutic potential in a rat model of bilateral cavernous nerve injury (BCNI), while inadequate in vivo viability has largely limited their application. Nuclear factor-E2-related Factor (Nrf2) is a key transcription factor that regulates cellular anti-oxidative stress. In this work, we investigated the effect of Nrf2 expression regulation on the viability of ADSCs, and explore its repair potential in a BCNI rat model. RESULTS: The survival time of tert-Butylhydroquinone (tBHQ)-ADSCs in BCNI model increased obviously. In addition, the tBHQ-ADSCs group presented better restoration of major pelvic ganglion (MPG) nerve contents and fibers, better improvement of erectile function, and less penile fibrosis than the other groups. Moreover, the expression of Nrf2 and superoxide dismutase 1 (SOD1) were higher than those of other groups. CONCLUSION: Nrf2 could enhance the anti-oxidative stress ability of ADSCs, so as to improve the therapeutic effect of ADSCs on BCNI rat model.

RéSUMé: CONTEXTE: La dysfonction érectile (DE) causée par une lésion nerveuse peropératoire est une complication majeure de la chirurgie pelvienne. Les cellules souches dérivées du tissu adipeux (ADSC) ont constitué un potentiel thérapeutique dans un modèle de lésion bilatérale des nerfs caverneux (BCNI) chez le rat, mais une viabilité insuffisante in vivo a largement limité leur application. Nrf2 est un facteur de transcription clé qui régule le stress antioxydant cellulaire. Dans ce travail, nous avons étudié l'effet de la régulation de l'expression de Nrf2 sur la viabilité des ADSC, et exploré son potentiel de réparation dans un modèle de BCNI chez le rat. RéSULTATS: Le temps de survie des cellules tert-butylhydroquinone (tBHQ)-ADSC dans le modèle BCNI a significativement augmenté. De plus, le groupe tBHQ-ADSC a présenté une meilleure restauration du contenu et des fibres nerveuses des ganglions pelviens majeurs, une meilleure amélioration de la fonction érectile et une moindre fibrose pénienne que les autres groupes. Par ailleurs, l'expression de Nrf2 et de la superoxyde dismutase 1 était plus élevée dans ce groupe que dans les autres groupes. CONCLUSIONS: Nrf2 pourrait améliorer la capacité de stress anti-oxydatif des cellules ADSC, améliorant ainsi l'effet thérapeutique des ADSC sur le modèle de BCNI chez le rat.

Targeting CBX3 with a Dual BET/PLK1 Inhibitor Enhances the Antitumor Efficacy of CDK4/6 Inhibitors in Prostate Cancer.

The development of castration-resistant prostate cancer (CRPC) is a significant factor that reduces life expectancy among patients with prostate cancer. Previously, it is reported that CDK4/6 inhibitors can overcome the resistance of CRPC to BET inhibitors by destabilizing BRD4, suggesting that the combination of CDK4/6 inhibitors and BET inhibitors is a promising approach for treating CRPC. In this study, candidates that affect the combined antitumor effect of CDK4/6 inhibitors and BET inhibitors on CRPC is aimed to examine. The data demonstrates that CBX3 is abnormally upregulated in CDK4/6 inhibitors-resistant cells. CBX3 is almost positively correlated with the cell cycle in multiple malignancies and is downregulated by BET inhibitors. Mechanistically, it is showed that CBX3 is transcriptionally upregulated by BRD4 in CRPC cells. Moreover, it is demonstrated that CBX3 modulated the sensitivity of CRPC to CDK4/6 inhibitors by binding with RB1 to release E2F1. Furthermore, it is revealed that PLK1 phosphorylated CBX3 to enhance the interaction between RB1 and CBX3, and desensitize CRPC cells to CDK4/6 inhibitors. Given that BRD4 regulates CBX3 expression and PLK1 affects the binding between RB1 and CBX3, it is proposed that a dual BRD4/PLK1 inhibitor can increase the sensitivity of CRPC cells to CDK4/6 inhibitors partially through CBX3.

Melatonin synergistically enhances docetaxel induced endoplasmic reticulum stress to promote apoptosis by suppressing NF-κB activation in cervical cancer.

Cervical cancer is the fourth most common malignancy in women globally. Although chemotherapy significantly improves the survival of cervical cancer patients, the development of drug resistance is inevitable. In the present study, our study showed that melatonin suppressed the proliferation, cell survival, colony formation, and the ability of adhering to fibronectin in cervical cancer cells. Our data suggested that docetaxel insensitivity was caused by NF-κB pathway activation, and followed by reducing endoplasmic reticulum stress and apoptosis. We showed that melatonin functioned as an oncostatic agent via inhibition of NF-κB signaling in cervical cancer cells. Interestingly, melatonin not only reduced the basal and inducible NF-κB pathway activation, but also prevented docetaxel induced NF-κB pathway activation by stabilizing IκBα protein. Importantly, inhibition of NF-κB pathway activation by melatonin abrogated the protective effect of NF-κB activation on docetaxel provoked endoplasmic reticulum stress, and further enhanced endoplasmic reticulum stress and apoptosis to produce synergistic oncostatic effects in cervical cancer cells. In summary, we revealed that melatonin was a novel agent to enhance docetaxel sensitivity by abolishing NF-κB activation and aggravating endoplasmic reticulum stress. Our results might provide a rationale for the clinical application of melatonin to overcome docetaxel resistance in cervical cancer patients.

Molecular mechanisms of tumor resistance to radiotherapy.

BACKGROUND: Cancer is the most prevalent cause of death globally, and radiotherapy is considered the standard of care for most solid tumors, including lung, breast, esophageal, and colorectal cancers and glioblastoma. Resistance to radiation can lead to local treatment failure and even cancer recurrence. MAIN BODY: In this review, we have extensively discussed several crucial aspects that cause resistance of cancer to radiation therapy, including radiation-induced DNA damage repair, cell cycle arrest, apoptosis escape, abundance of cancer stem cells, modification of cancer cells and their microenvironment, presence of exosomal and non-coding RNA, metabolic reprogramming, and ferroptosis. We aim to focus on the molecular mechanisms of cancer radiotherapy resistance in relation to these aspects and to discuss possible targets to improve treatment outcomes. CONCLUSIONS: Studying the molecular mechanisms responsible for radiotherapy resistance and its interactions with the tumor environment will help improve cancer responses to radiotherapy. Our review provides a foundation to identify and overcome the obstacles to effective radiotherapy.

Neutrophil elastase: From mechanisms to therapeutic potential.

Neutrophil elastase (NE), a major protease in the primary granules of neutrophils, is involved in microbicidal activity. NE is an important factor promoting inflammation, has bactericidal effects, and shortens the inflammatory process. NE also regulates tumor growth by promoting metastasis and tumor microenvironment remodeling. However, NE plays a role in killing tumors under certain conditions and promotes other diseases such as pulmonary ventilation dysfunction. Additionally, it plays a complex role in various physiological processes and mediates several diseases. Sivelestat, a specific NE inhibitor, has strong potential for clinical application, particularly in the treatment of coronavirus disease 2019 (COVID-19). This review discusses the pathophysiological processes associated with NE and the potential clinical applications of sivelestat.

Identification of LSM family members as potential chemoresistance predictive and therapeutic biomarkers for gastric cancer.

Introduction: The Like-Smith (LSM) family plays a critical role in the progression of several cancers. However, the function of LSMs in chemoresistance of gastric cancer (GC) is still elusive. Methods: The Cancer Genome Atlas (TCGA) database, Gene Expression Omnibus (GEO) database and Tumor Immune Estimation Resource Analysis (TIMER) were utilized to analyze the expression, prognostic value and immune infiltration of LSMs in GC patients. Moreover, qPCR and immunohistochemistry (IHC) experiment were conducted with clinical samples. Results: The expression of LSMs was upregulated in GC tissues and most of LSMs were negatively correlated with overall survival of GC patients with 5-fluorouracil (5-FU) treatment. We further revealed that LSM5, 7 and 8 were hub genes of GEO (GSE14210). Besides, the qPCR results demonstrated that a higher level of LSM5 and LSM8 was associated with 5-FU chemoresistance in GC. Moreover, both TIMER and IHC revealed that a lower expression of LSM5 and LSM8 was correlated with high infiltration of T cells, regulatory T cells, B cells, macrophages, and neutrophils. Discussion: Our study systematically investigated the expression pattern and biological features of LSM family members in GC, and identified LSM5 and LSM8 as potential biomarkers in GC with 5-FU chemotherapy.

Flexible Wearable Sensors in Medical Monitoring.

The popularity of health concepts and the wave of digitalization have driven the innovation of sensors in the medical field. Such continual development has made sensors progress in the direction of safety, flexibility, and intelligence for continuous monitoring of vital signs, which holds considerable promise for changing the way humans live and even treat diseases. To this end, flexible wearable devices with high performance, such as high sensitivity, high stability, and excellent biodegradability, have attracted strong interest from scientists. Herein, a review of flexible wearable sensors for temperature, heart rate, human motion, respiratory rate, glucose, and pH is highlighted. In addition, engineering issues are also presented, focusing on material selection, sensor fabrication, and power supply. Finally, potential challenges facing current technology and future directions of wearable sensors are also discussed.

CPSF4 promotes tumor-initiating phenotype by enhancing VEGF/NRP2/TAZ signaling in lung cancer.

Lung cancer is the leading cause of malignant tumor-related deaths worldwide. The presence of tumor-initiating cells in lung cancer leads to tumor recurrence, metastasis, and resistance to conventional treatment. Cleavage and polyadenylation specificity factor 4 (CPSF4) activation in tumor cells contributes to the poor prognosis of lung cancer. However, the precise biological functions and molecular mechanisms of CPSF4 in the regulation of tumor-initiating cells remain unclear. We demonstrated that CPSF4 promotes tumor-initiating phenotype and confers chemoresistance to paclitaxel both in vitro and in vivo. Mechanistically, we showed that CPSF4 binds to the promoters of vascular endothelial growth factor (VEGF) and neuropilin-2 (NRP2) and activated their transcription. In addition, we showed that CPSF4/VEGF/NRP2-mediated tumor-initiating phenotype and chemoresistance through TAZ induction. Furthermore, analysis of clinical data revealed that lung cancer patients with high CPSF4 expression exhibit high expression levels of VEGF, NRP2, and TAZ and that expression of these proteins are positively correlated with poor prognosis. Importantly, selective inhibition of VEGF, NRP2, or TAZ markedly suppressed CPSF4-mediated tumor-initiating phenotype and chemoresistance. Our findings reveal the mechanism of CPSF4 modulating tumor-initiating phenotype and chemoresistance in lung cancer and indicate that the CPSF4-VEGF-NRP2-TAZ signaling pathway may be a prognosis marker and therapeutic target in lung cancer.

Thorax radiotherapy using 18F-positron emission tomography/computed tomography-guided precision radiotherapy is a prognostic factor for survival in patients with extracranial oligometastatic non-small cell lung cancer:A two-center propensity score-matched analysis.

Background: This retrospective study compared positron emission tomography (PET)/computed tomography (CT) and CT in the treatment of extracranial oligometastatic non-small-cell lung cancer (NSCLC) and explored the impact of thorax radiotherapy (TRT) on patient survival. Methods: We reviewed the medical records of Chinese patients with stage IV extracranial oligometastatic NSCLC who underwent PET/CT or CT at two centers. Propensity score matching (PSM) was used to control differences in patient characteristics between the maintenance chemotherapy alone and TRT plus maintenance chemotherapy groups. Results: We analyzed 192 eligible patients. The median survival time was better in patients who received PET/CT than in those who only received CT (n = 192, 16 months vs. 6 months, p<0.001). Subgroup analysis showed the median survival time was significantly longer in the TRT plus maintenance group than in the chemotherapy alone group in patients who underwent PET/CT examinations (n = 94, 25 months vs. 11 months, p<0.001). However, there was no statistical difference in survival between both groups in patients who underwent CT examinations (n = 98, 8 months vs. 5 months, p = 0.180). A multifactorial analysis revealed a more favorable prognosis in patients who underwent PET/CT evaluation (HR: 0.343, 95% CI: 0.250-0.471, p <0.001) and TRT (HR: 0.624, 95% CI: 0.464-0.840, p = 0.002), than in those who did not. PSM was consistent with these results. Conclusions: PET/CT-guided TRT is associated with improved clinical outcomes in patients with stage IV extracranial oligometastatic NSCLC.

In 18F-positron emission tomography/computed tomography-guided precision radiotherapy for centrally located non-small cell lung cancer, tumor related atelectasis is a prognostic factor of survival.

Purpose: Tumor related atelectasis(TRA) is an essential factor affecting survival that can cause chest pain, cough, hemoptysis, chest tightness, dyspnea, and even death. In the current study, we explored the possible impact of TRA on survival in cancer patients and the guiding significance of 18F-positron emission tomography/computed(PET/CT) in radiotherapy for patients with atelectasis tumors. Methods: In this retrospective study, we analyzed the treatment model and survival of patients with centrally located non-small cell lung cancer(NSCLC) treated with radiotherapy at two medical centers between May 2005 and August 2019. We identified 152 eligible patients and used propensity score matching (1:1) to process the data to reduce confounding factors, data bias, and mal-distribution. Results: We used propensity scores created well-matched groups of 57 patients overall with or without TRA. The one-year survival rate of all patients was 71.9%, and the two-year survival rate was 33.3%. Compared to the atelectasis group, the overall survival (OS) of patients in the non-atelectasis group was significantly prolonged (25 months vs. 17 months, p = 0.004), as well as in the atelectasis recovery group (28 months vs. 14 months, p = 0.008). In multivariate analysis, non-atelectasis was closely correlated with favorable OS (HR, 1.804 (-2.840); 95% CI, 1.145-2.840; p = 0.011). Conclusion: PET/CT can accurately stage NSCLC and better guide the treatment of NSCLC complicated with atelectasis. Tumor-associated atelectasis in patients with centrally located NSCLC can lead to is a poor prognostic marker.

Research Progress in the Application of Exosomes in Immunotherapy.

Exosomes are nanoscale extracellular vesicles (EVs), which are present in all body fluids tested. They are secreted by a variety of cells including macrophages, dendritic cells, mast cells, granulocytes, lymphocytes, and tumor cells. Exosomes secreted by different cells have different biological components and functional characteristics and play an important role in many pathophysiological activities. Recent studies have revealed that exosomes can regulate the occurrence and development of inflammatory immune diseases and tumors by transmitting their unique proteins, lipids, and nucleic acids as signaling molecules to other cells. Exosomes serve as a novel class of diagnostic biomarkers and drug delivery systems with promising applications in immunotherapy, particularly because breakthroughs in nanotechnology have led to the development and exploration of engineered exosomes for immunotargeted therapies. Therefore, here we review the progress being made on the application of exosomes in immunotherapy and its multiple regulatory mechanisms and explore the potential application of exosomes in immunotherapy in the future.

Radiotherapy for head and neck tumours using an oral fixation and parameter acquisition device and TOMO technology: a randomised controlled study.

INTRODUCTION: Radiotherapy has become one of the main methods used for the treatment of malignant tumours of the head and neck. Spiral tomographic intensity-modulated radiotherapy has the many advantages of precision radiotherapy, which puts forward high requirements for postural reproducibility and accuracy. We will aim to ensure that the accurate positioning of the tumour will reduce the side effects of radiotherapy caused by positioning errors. We will design and implement this clinical trial using the patent of 'a radiotherapy oral fixation and parameter acquisition device (patent number: ZL201921877986.5)'. METHODS AND ANALYSIS: This will be a randomised, controlled, prospective study with 120 patients with head and neck tumours. Using the random number table method, a random number sequence will be generated, and the patients will be enrolled in the experimental group (oral fixation device) and the control group (conventional fixation) in a 2:1 ratio. The primary outcome will be the progression-free survival time after the treatment. Secondary outcomes will include the oral mucosal reaction and the quality of life. Follow-ups will be carried out according to the plan. This is V.1.0 of protocol on 1 April 2021. The recruitment process for this clinical trial commenced on 1 May 2021, and will end on 1 October 2022. ETHICS AND DISSEMINATION: The trial received ethical approval from Medical Ethics Committee of Liaoning Provincial Cancer Hospital (number 20210131X). The final results will be presented at a scientific conference and published in a peer-reviewed journal in accordance with the journal's guidelines. TRIAL REGISTRATION NUMBER: ChiCTR2100045096.

Association of Inflammation-Related Gene Polymorphisms With Susceptibility and Radiotherapy Sensitivity in Head and Neck Squamous Cell Carcinoma Patients in Northeast China.

BACKGROUND: Inflammation-related gene polymorphisms are some of the most important determinants for cancer susceptibility, clinical phenotype diversity, and the response to radiotherapy and chemotherapy. However, the relationship between these polymorphisms and head and neck squamous cell carcinoma (HNSCC) remains unclear. The aim of this study was to investigate the role of inflammation-related gene polymorphisms in the developmental risk and radiotherapy sensitivity of HNSCC. METHODS: The Matrix-Assisted Laser Desorption Ionization Time of Flight (MALDI-TOF) genotyping system was used to genotype 612 individuals from a Chinese population for 28 inflammation-related gene polymorphisms. RESULTS: The protein kinase B (AKT1) rs1130233 TT, dominance model (CT+TT vs. CC), recessive model (TT vs. CT+CC), and rs2494732 CC genotypes were associated with reduced risk of HNSCC (P=0.014; P=0.041; P=0.043). The polymeric immunoglobulin receptor (PIGR) rs291097 GA, dominance model (GA+AA vs. GG), and rs291102 dominance model (GA+AA vs. GG) were associated with increased risk of HNSCC (P=0.025; P=0.025; P=0.040). The interleukin-4 receptor-α (IL-4RA) rs1801275 AA genotype was significantly correlated with increased radiotherapy sensitivity of HNSCC patients (P=0.030). In addition, age ≤ 60 years, non-smoker status, and normal levels of squamous cell carcinoma antigen (SCC) were found to be associated with increased radiotherapy sensitivity of HNSCC patients (P=0.033; P=0.033; P=0.030). CONCLUSION: The AKT1 rs1130233, AKT1 rs2494732, PIGR rs291097, and PIGR rs291102 polymorphisms were significantly related to the risk of HNSCC. The IL-4RA rs1801275 polymorphism, age ≤ 60 years, non-smoker status, and normal levels of SCC were significantly associated with increased radiotherapy sensitivity of HNSCC.

Downregulation of RIG-I mediated by ITGB3/c-SRC/STAT3 signaling confers resistance to interferon-α-induced apoptosis in tumor-repopulating cells of melanoma.

BACKGROUND: Interferon-α (IFN-α) plays a pivotal role in host antitumor immunity, and the evasion of IFN-α signaling pathway can lead to IFN-α resistance during the treatment of cancer. Although the interplay between IFN-α and tumor cells has been extensively investigated in differentiated tumor cells, much less attention has been directed to tumor-repopulating cells (TRCs). METHODS: Three-dimentional soft fibrin matrix was used to select and grow highly malignant and tumorigenic melanoma TRCs. The regulation of integrin ß3 (ITGB3)-c-SRC-STAT signaling pathway in melanoma TRCs was investigated both in vitro and in vivo. The relevant mRNA and protein expression levels were analyzed by qRT-PCR and western blot analysis. Immunoprecipitation and chromatin immunoprecipitation (ChIP) followed by qPCR (ChIP-qPCR) assays were performed to detect protein-protein and protein-DNA interactions. The clinical impacts of retinoic acid inducible gene-I (RIG-I) were assessed in melanoma datasets obtained from The Cancer Genome Atlas and Gene Expression Omnibus profiles. RESULTS: IFN-α-induced apoptosis was decreased in melanoma TRCs. Compared with conventional flask-cultured cells, IFN-α-mediated STAT1 activation was diminished in melanoma TRCs. Decreased expression of RIG-I in melanoma TRCs led to diminished activation of STAT1 via enhancing the interaction between Src homology region 2 domain-containing phosphatase-1 and STAT1. In addition, low expression levels of RIG-I correlated with poor prognosis in patients with melanoma. STAT3 was highly phosphorylated in TRCs and knockdown of STAT3 reversed the downregulation of RIG-I in TRCs. Knockdown of STAT3 resulted in STAT1 activation and increased expression of the pro-apoptosis genes in IFN-α-treated TRCs. Combined treatment of STAT3 inhibitor and IFN-α increased the apoptosis rate of TRCs. Disruption of ITGB3/c-SRC/STAT3 signaling pathway significantly elevated the efficiency of IFN-α-induced apoptosis of TRCs. CONCLUSIONS: In melanoma TRCs, ITGB3-c-SRC-STAT3 pathway caused RIG-I repression and then affect STAT1 activation to cause resistance to IFN-α-induced apoptosis. RIG-I is a prognostic marker in patients with melanoma. Combination of STAT3 inhibitor and IFN-α could enhance the efficacy of melanoma treatment. Our findings may provide a new concept of combinatorial treatment for future immunotherapy.

Treatment patterns and survival after 18F-fluorodeoxyglucose positron emission tomography/computed tomography-guided local consolidation therapy for oligometastatic non-small cell lung cancer: a two-center propensity score-matched analysis.

PURPOSE: In this retrospective study, we evaluated the treatment patterns and survival after positron emission tomography-computed tomography (PET/CT)-guided local consolidation therapy (LCT) for oligometastatic non-small cell lung cancer (NSCLC). METHODS: We reviewed the medical records of Chinese patients with oligometastatic stage IV non-small cell lung cancer (≤ 5 metastases) who had undergone PET/CT and were eligible for systemic therapy at two centers between May 2005 and August 2019. Propensity score matching (1:1) was used to reduce selection bias and imbalanced distribution of confounding factors. RESULTS: We identified 84 eligible patients and used propensity scores to create well-matched groups of 35 patients who did or did not undergo LCT. Among all patients, the 1-year overall survival (OS) rate was 47.6% and the 2-year OS rate was 22.6%. Relative to the group that did not receive LCT, the LCT group had a significantly higher OS rate (13 months vs. 7 months, p = 0.002). The two groups had similar incidences and classifications of LCT-related side effects. In multivariable analysis, LCT was found to be strongly associated with a favorable OS (hazard ratio: 0.508, 95% confidence interval: 0.311-0.828, p = 0.001). CONCLUSION: We concluded that LCT was significantly associated with improved clinical outcomes among the Chinese patients with oligometastatic NSCLC who were eligible for systemic treatment and could undergo PET/CT evaluation.

Variations of MRI-assessed peristaltic motions during radiation therapy.

PURPOSE: Understanding complex abdominal organ motion is essential for motion management in radiation therapy (RT) of abdominal tumors. This study investigates abdominal motion induced by respiration and peristalsis, during various time durations relevant to RT, using various CT and MRI techniques acquired under free breathing (FB) and breath hold (BH). METHODS: A series of CT and MRI images acquired with various techniques under free breathing and/or breath hold from 37 randomly-selected pancreatic or liver cancer patients were analyzed to assess the motion in various time frames. These data include FB 4DCT from 15 patients (for motion in time duration of 5 sec), FB 2D cine-MRI from 4 patients (time duration of 1.7 min, 1 second acquisition time per slice), FB cine-MRI acquired using MR-Linac from 6 patients in various fractions (acquisition time is less than 0.6 seconds per slice), FB 4DMRI from 2 patients (time duration of 2 min), respiration-gated T2 with gating at the end expiration (time duration of 3-5 min), and BH T1 with multiphase dynamic contrast in acquisition times of 17 seconds for each of five phases (pre-contrast, arterial, venous, portal venous and delayed post-contrast) from 10 patients. Motions of various organs including gallbladder (GB) and liver were measured based on these MRI data. The GB motion includes both respiration and peristalsis, while liver motion is primarily respiration. By subtracting liver motion (respiration) from GB motion (respiration and peristalsis), the peristaltic motion, along with small residual motion, was obtained. RESULTS: From cine-MRI, the residual motion beyond the respiratory motion was found to be up to 0.6 cm in superior-inferior (SI) and 0.55 cm in anterior-posterior (AP) directions. From 2D cine-MRI acquired by the MR-Linac, different peristaltic motions were found from different fractions for each patient. The peristaltic motion was found to vary between 0.3-1 cm. From BH T1 phase images, the average motions that were primarily due to peristalsis movements were found to be 1.2 cm in SI, 0.7 cm in AP, and 0.9 cm in left-right (LR) directions. The average motions assessed from 4DCT were 1.0 cm in SI and 0.3 cm in AP directions, which were generally smaller than the motions assessed from cine-MRI, i.e., 1.8 cm in SI and 0.6 cm in AP directions, for the same patients. However, average motions from 4DMRI, which are coming from respiratory were measured to be 1.5, 0.5, and 0.4 cm in SI, AP, and LR directions, respectively. CONCLUSION: The abdominal motion due to peristalsis can be similar in magnitude to respiratory motion as assessed. These motions can be irregular and persistent throughout the imaging and RT delivery procedures, and should be considered together with respiratory motion during RT for abdominal tumors.