ABSTRACT
Lung cancer is the main cause of cancer-related deaths worldwide. Due to lack of obvious clinical symptoms in the early stage of the lung cancer, it is hard to distinguish between malignancy and pulmonary nodules. Understanding the immune responses in the early stage of malignant lung cancer patients may provide new insights for diagnosis. Here, using high-through-put sequencing, we obtained the TCRß repertoires in the peripheral blood of 100 patients with Stage I lung cancer and 99 patients with benign pulmonary nodules. Our analysis revealed that the usage frequencies of TRBV, TRBJ genes, and V-J pairs and TCR diversities indicated by D50s, Shannon indexes, Simpson indexes, and the frequencies of the largest TCR clone in the malignant samples were significantly different from those in the benign samples. Furthermore, reduced TCR diversities were correlated with the size of pulmonary nodules. Moreover, we built a backpropagation neural network model with no clinical information to identify lung cancer cases from patients with pulmonary nodules using 15 characteristic TCR clones. Based on the model, we have created a web server named "Lung Cancer Prediction" (LCP), which can be accessed at http://i.uestc.edu.cn/LCP/index.html.
ABSTRACT
BACKGROUND AND PURPOSE: This phase Ib study was designed to assess the safety/tolerability and preliminary antitumor activity of neoadjuvant low-dose radiotherapy (LDRT) plus durvalumab and chemotherapy for potentially resectable stage III non-small-cell lung cancer (NSCLC). MATERIALS AND METHODS: Eligible patients received dose-escalated radiotherapy (10 Gy in 5 fractions [cohort 1], 20 Gy in 10 fractions [cohort 2], and 30 Gy in 15 fractions [cohort 3]) according to a 3 + 3 design, with concurrent durvalumab plus standard chemotherapy for two cycles. Primary objective was safety/tolerability. Secondary objectives included major pathological response (MPR), pathological complete response (pCR), event-free survival (EFS), and exploratory biomarker analysis. RESULTS: Nine patients were enrolled and completed the planned neoadjuvant therapy. No dose-limiting toxicity was recorded. Grade 3-4 treatment-related adverse events were observed in three (33.3 %) patients. Seven (77.8 %) patients successfully converted to resectable cases with R0 resection. No treatment-related surgical delay or death was reported. The MPR and pCR rates were both 33.3 % % (1/3) for cohort 1, 66.7 % (2/3) and 0.0 % for cohort 2, and 100.0 % (3/3), and 66.7 % (2/3) for cohort 3. At data cutoff, the 12 month-EFS rates were 33.3 %, 66.7 %, and 100 % for three cohorts, respectively. By biomarker analysis, TMB values were higher in either pathologically or radiologically responders than in others (all p > 0.05). CONCLUSION: Neoadjuvant LDRT plus durvalumab and chemotherapy was well-tolerated in potentially resectable stage III NSCLC. The preliminary efficacy supports this combined regimen's potential, the optimal radiotherapy dosage was determined to be 30 Gy in 15 fractions, warranting further clinical investigation.
Subject(s)
Antibodies, Monoclonal , Carcinoma, Non-Small-Cell Lung , Lung Neoplasms , Neoadjuvant Therapy , Humans , Carcinoma, Non-Small-Cell Lung/pathology , Carcinoma, Non-Small-Cell Lung/therapy , Carcinoma, Non-Small-Cell Lung/mortality , Male , Female , Middle Aged , Lung Neoplasms/pathology , Lung Neoplasms/therapy , Lung Neoplasms/mortality , Lung Neoplasms/drug therapy , Antibodies, Monoclonal/therapeutic use , Antibodies, Monoclonal/administration & dosage , Aged , Neoplasm Staging , Antineoplastic Combined Chemotherapy Protocols/therapeutic use , Chemoradiotherapy , Radiotherapy DosageABSTRACT
Advanced diffuse large B cell lymphoma (DLBCL) is a common malignant tumor with aggressive clinical features and poor prognosis. At present, there is lack of effective prognostic tool for patients with advanced (stage III/IV) DLBCL. The aim of this study is to identify prognostic indicators that affect survival and response and establish the first survival prediction nomogram for advanced DLBCL. A total of 402 patients with advanced DLBCL were enrolled in this study. COX multivariate analysis was used to obtain independent prognostic factors. The independent prognostic factors were included in the nomogram, and the nomogram to predict the performance of the model was established by R rms package, C-index (consistency index), AUC curve and calibration curve. The training and validation cohorts included 281 and 121 patients. In the training cohort, multivariate analysis showed that Ki-67 (70% (high expression) vs ≤ 70% (low expression), p < 0.001), LDH (lactate dehydrogenase) (elevated vs normal, p = 0.05), FER (ferritin) (elevated vs normal, p < 0.001), and ß2-microglobulin (elevated vs normal, p < 0.001) were independent predictors and the nomogram was constructed. The nomogram showed that there was a significant difference in OS among the low-risk, intermediate-risk and high-risk groups, with 5-year survival rates of 81.6%, 44% and 6%, respectively. The C-index of the nomogram in the training group was 0.76. The internal validation of the training group showed good consistency. In the internal validation cohort of the training group, the AUC was 0.828, and similar results were obtained in the validation group, with a C-index of 0.74 and an AUC of 0.803. The proposed nomogram provided a valuable individualized risk assessment of OS in advanced DLBCL patients.
Subject(s)
Lymphoma, Large B-Cell, Diffuse , Nomograms , Humans , Prognosis , Lymphoma, Large B-Cell, Diffuse/diagnosis , Lymphoma, Large B-Cell, Diffuse/pathology , Multivariate AnalysisABSTRACT
Cancer-induced bone pain (CIBP) stands out as one of the most challenging issues in clinical practice due to its intricate and not fully elucidated pathophysiological mechanisms. Existing evidence has pointed toward the significance of peroxisome proliferator-activated receptor γ coactivator-1α (PGC-1α) down-regulation in contributing to pain behaviors in various rodent models of neuropathic pain. In our current study, we aimed to investigate the role of PGC-1α in CIBP. Our results unveiled a reduction in PGC-1α expression within the spinal cord of CIBP rats, particularly in GABAergic interneurons. Notably, intrathecal administration of the PGC-1α activator ZLN005 suppressed the loss of spinal GABAergic interneurons. This suppression was achieved by inhibiting caspase-3-mediated apoptosis, ultimately leading to the alleviation of mechanical allodynia in CIBP rats. Further exploration into the mechanism revealed that PGC-1α activation played a pivotal role in mitigating ATP depletion and reactive oxygen species accumulation linked to mitochondrial dysfunction. This was achieved through the restoration of mitochondrial biogenesis and the activation of the SIRT3-SOD2 pathway. Impressively, the observed effects were prominently reversed upon the application of SR18292, a specific PGC-1α inhibitor. In conclusion, our findings strongly suggest that PGC-1α activation acts as a potent inhibitor of apoptosis in spinal GABAergic interneurons. This inhibition is mediated by the improvement of mitochondrial function, facilitated in part through the enhancement of mitochondrial biogenesis and the activation of the SIRT3-SOD2 pathway. The results of our study shed light on potential therapeutic avenues for addressing CIBP.
Subject(s)
Neoplasms , Sirtuin 3 , Rats , Animals , Sirtuin 3/metabolism , Apoptosis , Interneurons/metabolism , Pain/drug therapy , Pain/etiology , Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha/genetics , Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha/metabolismABSTRACT
Acute kidney injury (AKI) is a common complication following orthotopic liver transplantation (OLT) and is associated with increased morbidity and mortality.The aim of the current study was to determine the risk factors for AKI in patients undergoing OLT.A total of 103 patients who received OLT between January 2015 and May 2016 in Tongji Hospital,China,were retrospectively analyzed.Their demographic characteristics and perioperative parameters were collected,and AKI was diagnosed using 2012 Kidney Disease:Improving Global Outcomes (KDIGO) staging criteria.It was found that the incidence of AKI was 40.8% in this cohort and AKI was significantly associated with body mass index,urine volume,operation duration (especially > 480 min),and the postoperative use of vasopressors.It was concluded that relative low urine output,long operation duration,and the postoperative use of vasopressors are risk factors for AKI following OLT.
ABSTRACT
Ischemic stroke leads to high potentiality of mortality and disability.The current treatment for ischemic stroke is mainly focused on intravenous thrombolytic therapy.However,ischemia/reperfusion induces neuronal damage,which significantly influences the outcome of patients with ischemic stroke,and the exact mechanism implicated in ischemia/reperfusion injury remains unclear,although evidence shows that oxidative stress is likely to be involved.Betulinic acid is mainly known for its anti-tumor and anti-inflammatory activities.Our previous study showed that betulinic acid could decrease the reactive oxygen species (ROS) production by regulating the expression of NADPH oxidase.Thus,we hypothesized that betulinic acid may protect against brain ischemic injury in the animal model of stroke.Focal cerebral ischemia was achieved by using the standard intraluminal occlusion method and reperfusion enabled after 2 h ischemia.Neurological deficits were scored.Infarct size was determined with 2,3,5-triphenyltetrazolium chloride monohydrate (TTC) staining and the mRNA expression of NADPH oxidase 4 (NOX4) was determined by RT-PCR in infarct tissue.ROS generation and apoptosis in ischemic tissue were analyzed by measuring the oxidative conversion of cell permeable 2',7'-dichloro-fluorescein diacetate (DCF-DA) to fluorescent dichlorofluorescein (DCF) in fluorescence microplate reader and TUNEL assay,respectively.In Kunming mice,2 h of middle cerebral artery (MCA) occlusion followed by 24 or 72 h of reperfusion led to an enhanced NOX4 expression in the ischemic hemisphere.This was associated with elevated levels of ROS generation and neuronal apoptosis.Pre-treatment with betulinic acid (50 mg/kg/day for 7 days via gavage) prior to MCA occlusion prevented the ischemia/reperfusion-induced up-regulation of NOX4 and ROS production.In addition,treatment with betulinic acid could markedly blunt the ischemia/reperfusion-induced neuronal apoptosis.Finally,betulinic acid reduced infarct volume and ameliorated the neurological deficit in this stroke mouse model.Our results suggest that betulinic acid protects against cerebral ischemia/reperfusion injury in mice and the down-regulation of NOX4 may represent a mechanism contributing to this effect.
ABSTRACT
Descending nociceptive modulation from the supraspinal structures plays an important role in cancer-induced bone pain (CIBP).Rostral ventromedial medulla (RVM) is a critical component of descending nociceptive facilitation circuitry,but so far the mechanisms are poorly known.In this study,we investigated the role of RVM glial activation in the descending nociceptive facilitation circuitry in a CIBP rat model.CIBP rats showed significant activation of microglia and astrocytes,and also up-regulation of phosphorylated p38 mitogen-activated protein kinase (p38 MAPK) and pro-inflammatory mediators released by glial cells (IL-1β,IL-6,TNF-a and brain-derived neurotrophic factor) in the RVM.Stereotaxic microinjection of the glial inhibitors (minocycline and fluorocitrate) into CIBP rats' RVM could reverse the glial activation and significantly attenuate mechanical allodynia in a time-dependent manner.RVM microinjection of p38 MAPK inhibitor (SB203580) abolished the activation of microglia,reversed the associated up-regulation of pro-inflammatory mediators and significantly attenuated mechanical allodynia.Taken together,these results suggest that RVM glial activation is involved in the pathogenesis of CIBP.RVM microglial p38 MAPK signaling pathway is activated and leads to the release of downstream pro-inflammatory mediators,which contribute to the descending facilitation of CIBP.
ABSTRACT
This study examined the analgesic effect of diprospan in rats with trigeminal neuralgia.Rat model of trigeminal neuralgic pain was established by loosely ligating the left infraorbital branch of the trigeminal nerve.After allodynia developed,the rats were randomly divided into 2 groups (n=20 in each):diprospan group,in which the rats received diprospan (7 mg/mL,0.1 mL) injected to the left infraorbital foramen area; control group,in which saline (0.1 mL) was administered as the same manner as the diprospan group.The pain threshold (PT) in the left infraorbital area was measured before and 2,6,and 8 weeks after the administration.The expression of neuropeptides [substance P,preprotachykinin A (PPTA),calcitonin gene-related peptide (CGRP)] in the trigeminal nerve was detected at the same time points as the PT measurement by immunohistochemistry or in siru hybridization method.The results showed that in the diprospan group,the PT was 10.65± 1.26,10.77± 1.19 and 14.13± 1.34 g 2,6,and 8 weeks after the administration respectively,significantly higher than that before the administration (PT value:0.36±0.11) (P<0.05 for each).In the saline group,the PT was 0.37±0.13,0.66±0.09,4.45±1.29 and 13.72±1.72 g before and 2,6,and 8 weeks after the administration respectively with differences being significant between before and 6,8 weeks after the administration (P<0.01).No significant difference existed in the PT between the diprospan group and the saline group at pre-administration (P>0.05).The PT in the diprospan group was significantly greater than that in the saline group 2 and 6weeks post-administration (P<0.05).In the diprospan group,the expression levels of neuropeptides were significantly reduced as compared with those in the saline group 2 and 6 weeks post-administration (P<0.05).It was concluded that diprospan has an obvious analgesic effect on the trigeminal neuropathic pain partly by reducing the expression of neuropeptides in the trigeminal ganglia.