Novel in-house knowledge-based automated planning system for lung cancer treated with intensity-modulated radiotherapy.

PURPOSE: The goal of this study was to propose a knowledge-based planning system which could automatically design plans for lung cancer patients treated with intensity-modulated radiotherapy (IMRT). METHODS AND MATERIALS: From May 2018 to June 2020, 612 IMRT treatment plans of lung cancer patients were retrospectively selected to construct a planning database. Knowledge-based planning (KBP) architecture named αDiar was proposed in this study. It consisted of two parts separated by a firewall. One was the in-hospital workstation, and the other was the search engine in the cloud. Based on our previous study, A­Net in the in-hospital workstation was used to generate predicted virtual dose images. A search engine including a three-dimensional convolutional neural network (3D CNN) was constructed to derive the feature vectors of dose images. By comparing the similarity of the features between virtual dose images and the clinical dose images in the database, the most similar feature was found. The optimization parameters (OPs) of the treatment plan corresponding to the most similar feature were assigned to the new plan, and the design of a new treatment plan was automatically completed. After αDiar was developed, we performed two studies. The first retrospective study was conducted to validate whether this architecture was qualified for clinical practice and involved 96 patients. The second comparative study was performed to investigate whether αDiar could assist dosimetrists in improving the quality of planning for the patients. Two dosimetrists were involved and designed plans for only one trial with and without αDiar; 26 patients were involved in this study. RESULTS: The first study showed that about 54% (52/96) of the automatically generated plans would achieve the dosimetric constraints of the Radiation Therapy Oncology Group (RTOG) and about 93% (89/96) of the automatically generated plans would achieve the dosimetric constraints of the National Comprehensive Cancer Network (NCCN). The second study showed that the quality of treatment planning designed by junior dosimetrists was improved with the help of αDiar. CONCLUSIONS: Our results showed that αDiar was an effective tool to improve planning quality. Over half of the patients' plans could be designed automatically. For the remaining patients, although the automatically designed plans did not fully meet the clinical requirements, their quality was also better than that of manual plans.

SIRT1-mediated deacetylation of NF-κB inhibits the MLCK/MLC2 pathway and the expression of ET-1, thus alleviating the development of coronary artery spasm.

Coronary artery spasm (CAS) is an intense vasoconstriction of coronary arteries that causes total or subtotal vessel occlusion. The cardioprotective effect of sirtuin-1 (SIRT1) has been extensively highlighted in coronary artery diseases. The aims within this study include the investigation of the molecular mechanism by which SIRT1 alleviates CAS. SIRT1 expression was first determined by reverse transcription-quantitative polymerase chain reaction (RT-qPCR) and Western blot analysis in an endothelin-1 (ET-1)-induced rat CAS model. Interaction among SIRT1, nuclear factor-kappaB (NF-κB), myosin light chain kinase/myosin light chain-2 (MLCK/MLC2), and ET-1 was analyzed using luciferase reporter assay, RT-qPCR, and Western blot analysis. After ectopic expression and depletion experiments in vascular smooth muscle cells (VSMCs), contraction and proliferation of VSMCs and expression of contraction-related proteins (α-SMA, calponin, and SM22α) were measured by collagen gel contraction, 5-ethynyl-2'-deoxyuridine (EdU) assay, RT-qPCR, and Western blot analysis. The obtained results showed that SIRT1 expression was reduced in rat CAS models. However, overexpression of SIRT1 inhibited the contraction and proliferation of VSMCs in vitro. Mechanistic investigation indicated that SIRT1 inhibited NF-κB expression through deacetylation. Moreover, NF-κB could activate the MLCK/MLC2 pathway and upregulate ET-1 expression by binding to their promoter regions, thus inducing VSMC contraction and proliferation in vitro. In vivo experimental results also revealed that SIRT1 alleviated CAS through regulation of the NF-κB/MLCK/MLC2/ET-1 signaling axis. Collectively, our data suggested that SIRT1 could mediate the deacetylation of NF-κB, disrupt the MLCK/MLC2 pathway, and inhibit the expression of ET-1 to relieve CAS, providing a theoretical basis for the prospect of CAS treatment and prevention.NEW & NOTEWORTHY Rat coronary artery spasm models exhibit reduced expression of SIRT1. Overexpression of SIRT1 inhibits contraction and proliferation of VSMCs. SIRT1 inhibits NF-κB through deacetylation to modulate VSMC contraction and proliferation. NF-κB activates the MLCK/MLC2 pathway. NF-κB upregulates ET-1 to modulate VSMC contraction and proliferation.

[Research on regularity of traditional Chinese medicine in treatment of Alzheimer's disease based on data mining].

To explore prescription medication regularity in the treatment of Alzheimer's disease with traditional Chinese medicine(TCM). With Alzheimer's disease or senile dementia as the subject, collecting and sorting out the journal papers in CNKI were collected as the data source to establish the literature research database of Alzheimer's disease prescriptions, and then the association rule analysis, factor analysis and systematic cluster analysis on the included TCM were conducted. Among the 113 prescriptions included in the standard, the single herb Acori Tatarinowii Rhizoma was the most common. The herbs were mainly warm and flat among four pro-perties, mainly sweet, bitter and spicy among five flavors. The drugs were mainly distributed in five internal organs, and the most commonly used drugs were deficiency tonifying drugs as well as blood activating and stasis removing drugs. In the association rule analysis, it was found that there were 6 drug pairs with the highest association strength. Eight common factors were extracted from the factor analysis, and they were classified into 6 categories in the systematic cluster analysis. The results have shown that the overall principles in treating Alzheimer's disease with modern Chinese medicine are tonifying deficiency, invigorating circulation, activating blood and dispelling phlegm.

Downregulation of microRNA-135b promotes atherosclerotic plaque stabilization in atherosclerotic mice by upregulating erythropoietin receptor.

Atherosclerotic plaque rupture is an important pathophysiologic mechanism of acute coronary syndrome. Emerging microRNAs (miRNAs) have been implicated in the atherosclerotic plaque formation and macrophage autophagy during the development of atherosclerosis (AS). Hence, this study was conducted to explore the role microRNA-135b (miR-135b) in macrophages and atherosclerotic plaque in mouse models of AS. The expression of miR-135b and erythropoietin receptor (EPOR) was altered in atherosclerotic mice to clarify their effect on inflammation, cell activities of aortic tissues, and macrophage autophagy. The obtained findings unraveled that miR-135b was upregulated and EPOR was downregulated in atherosclerotic mice. Upregulated miR-135b expression promoted cell apoptosis and inflammation, along with inhibited cell proliferation and decreased macrophage autophagy. Notably, miR-135 was validated to target EPOR and activate the PI3K/Akt signaling pathway. Moreover, miR-135b inhibition attenuated inflammation, atherosclerotic plaque development, and promoted macrophage autophagy. Besides, the effect of miR-135b inhibition was reversed in response to EPOR silencing. Taken conjointly, the study revealed that inhibition of miR-135b promoted macrophage autophagy and atherosclerotic plaque stabilization in atherosclerotic mice by inactivating the PI3K/Akt signaling pathway and upregulating EPOR.

Effects of velvet antler polypeptides on Alzheimer's disease cell model via miR-613 HDAC6 pathway.

To study the effect of velvet antler polypeptides (VAP) on Alzheimer's disease (AD) cell model, Aß25-35 was used to induce SK-N-SH cells to obtain AD cell model. The MDA, SOD, GSH-Px levels were determined using relevant kits. Flow cytometry was conducted to detect apoptosis, Western blot was employed to measure Bcl-2, Bax, HDAC6 protein expression, and qPCR was used to assay microRNA (miR)-613 and HDAC6 mRNA levels. Target Scan prediction combined with dual luciferase reporting experiments was conducted to analyze the targeting relationship between miR-613 and HDAC6. miR-613 was transfected in SK-N-SH cells; Alternatively, anti-miR-613 was transfected, followed by Aß25-35 and 80 mg/L of VAP. The AD model cells showed increased MDA content, apoptosis rate, Bax protein expression, HDAC6 mRNA and protein expression, but lower SOD, GSH-Px activities, Bcl-2 protein level, and miR-613 expression (p<0.05). VAP reduced MDA content, apoptosis rate, Bax protein expression, HDAC6 mRNA and protein expression, but enhanced SOD, GSH-Px activities, Bcl-2 protein level, and miR-613 expression (p<0.05). Over-expression of miR-613 increased SOD, GSH-Px activities, and Bcl-2 protein expression in AD model cells, but reduced HDAC6 protein levels, MDA content, apoptosis rate, and Bax protein levels (p<0.05). VAP may regulate Aß25-35-induced apoptosis so as to treat Alzheimer's disease.

Effects of microRNA-10a on synapse remodeling in hippocampal neurons and neuronal cell proliferation and apoptosis through the BDNF-TrkB signaling pathway in a rat model of Alzheimer's disease.

The aim of this study was to research the effects of microRNA-10a (miR-10a) on synapse remodeling and neuronal cells in rats with Alzheimer's disease (AD) through BDNF-TrkB signaling pathway. Rat models of AD were established. The neuronal cells were allocated into blank, negative control (NC), miR-10a mimics, miR-10a inhibitors, K252a, and miR-10a inhibitors + K252a groups. Expressions of miR-10a, p38, PSD95, BDNF, cAMP-response element-binding protein (CREB), and tropomyosin receptor kinase B (TrκB) were tested using RT-qPCR and Western blotting. Neuron cell proliferation, cycle, and apoptosis were observed using Cell counting kit-8 (CCK8) assay and flow cytometry. The ultrastructure was observed under a scanning electron microscope. The miR-10a expression of AD rats increased while p38, PSD95, BDNF, CREB, and TrκB expression decreased compared with the normal rats. Dual luciferase reporter gene assay testified miR-10a targeted BDNF. The expressions of p38, PSD95, BDNF, CREB, and TrκB decreased in the miR-10a mimics and K252a groups. Compared with the blank and NC group, the miR-10a mimics and K252a groups showed inhibited cell growth rate with cells mainly rest in the G1 satge, and increased spoptosis. The miR-10a inhibitors group presented an opposite trend to the miR-10a mimics and K252a groups. The synapse was complete and abundant in the miR-10a inhibitors group while disappeared in the miR-10a mimics and K252a groups. The results indicated that miR-10a restrains synapse remodeling and neuronal cell proliferation while promoting apoptosis in AD rats via inhibiting BDNF-TrkB signaling pathway.

A real-world analysis of stereotactic body radiotherapy combined with immunotherapy in advanced or recurrent non-small cell lung cancer (NSCLC): A single-center experience.

Background: We aimed to assess the value of stereotactic body radiotherapy (SBRT) delivered under the situation of controlled or progressed disease during ICI therapy in advanced or recurrent NSCLC. Methods: We retrospectively collected patients with advanced or recurrent NSCLC who received SBRT concurrently with ICI in our institution between January 2017 and December 2021. Patients were divided into two groups, including those for whom SBRT was delivered initially or to the residual tumors during the first- or later-line ICI treatment (Group 1), and those for whom SBRT was given to the progressed tumors irrespective of first- or later-line ICI treatment (Group 2). Results: A total of 144 patients were included. With median follow-up duration of 25.6 (range: 3.6 to 56.2) months, median progression-free survival (PFS) was 13.7 (95 % CI: 10.4 to 17.1) months and median overall survival (OS) was 52.8 [95 % CI: 30.6 to not available (NA)] months. In Group 1 (n = 78), median PFS was 17.9 (95 % CI: 14.5 to 29.8) months while median OS was not reached and 5-year OS rate was 61.2 %. In Group 2 (n = 66), median PFS was 8.0 (95 % CI: 6.0 to 13.1) months and median OS was 30.6 (95 % CI: 21.5 to NA) months. Conclusions: SBRT combined with ICI demonstrated favorable survival for advanced or recurrent NSCLC, delivered in a controlled-disease situation as well as to progressed diseases with salvage-intent. Future prospective studies are warranted to investigate the optimal SBRT dose regimen and appropriate combination strategy to synergize ICI.

PD-L1 expression and its correlation with clinicopathological and molecular characteristics in Chinese patients with non-small cell lung cancer.

Little is known about the relationship between programmed cell death-ligand 1 (PD-L1) expression and histologic and genetic features in real-world Chinese non-small cell lung cancer patients. From November 2017 to June 2019, tumor tissues were collected from 2674 non-small cell lung cancer patients. PD-L1 expression was detected with immunohistochemistry using the 22C3 and SP263 antibodies, and patients were stratified into subgroups based on a tumor proportion score of 1%, 1% to 49%, and ≥ 50%. Genetic alterations were profiled using targeted next-generation sequencing. In the total population, 50.5% had negative PD-L1 expression (tumor proportion score < 1%), 32.0% had low-positive expression (1%-49%), and 17.5% had high-positive expression (≥50%). The PD-L1 positive rate was 39.0% in squamous cell carcinomas and 53.6% in adenocarcinomas. PD-L1 expression was higher in squamous cell carcinomas (P < .001) and lower in adenocarcinomas (P < .001). Of the overall patient population, 11.2% had Kirsten rat sarcoma viral oncogene (KRAS) mutations, 44.9% had epidermal growth factor receptor (EGFR) mutations, 2.1% had BRAF V600E mutations, 0.3% had MET exon 14 skipping mutations, 5.4% had anaplastic lymphoma kinase translocations, and 0.9% had ROS proto-oncogene 1 translocations. Patients carrying ROS proto-oncogene 1 translocations (P = .006), KRAS (P < .001), and MET (P = .023) mutations had significantly elevated expression of PD-L1, while those harboring EGFR (P < .001) mutations had lower PD-L1 expression. In our study, PD-L1 expression was significantly higher in squamous cell carcinomas and lower in adenocarcinomas, and was positively associated with MET and KRAS mutations, as well as the wild-type EGFR gene state. Nonetheless, additional studies are needed to further validate those associations and determine the clinical significance for immune checkpoint inhibitors of these factors.

Transient-resting culture after activation enhances the generation of CD8+ stem cell-like memory T cells from peripheral blood mononuclear cells.

Adoptive cell therapy (ACT) has revolutionized the treatment of patients with cancer. The success of ACT depends largely on transferred T cell status, particularly their less-differentiated state with stem cell-like properties, which enhances ACT effectiveness. Stem cell-like memory T (TSCM) cells exhibit continuous self-renewal and multilineage differentiation similar to pluripotent stem cells. TSCM cells are promising candidates for cancer immunotherapies, whereas maintenance of a more stem-cell-like state before transfer is challenging. Here, we established a highly efficient protocol for generating CD8+ TSCM cells from peripheral blood mononuclear cells (PBMCs). The process involved activating PBMCs using anti-CD3 monoclonal antibody and RetroNectin, followed by a transient-resting culture period (24 h) and subsequent long-term expansion in vitro with interlukien-2. We report that this transient-resting culture after activation preserves CD8+ T cells in a stem memory phenotype (CD95+ CD45RA+ CCR7+) compared to the conventional culture method. Further, this approach reduces the expression of T cell immunoglobulin mucin-3, an exhaustion marker, and increases the expression of T cell factor-1, a master regulator of stemness even after long-term culture compared to the conventional culture method. In conclusion, our study presents a simplified and cost-effective method for generating and expanding CD8+ TSCM cells ex vivo. This approach streamlines the optimization of cancer immunotherapy using ACT.

Immunomodulatory Effects of Endodontic Sealers: A Systematic Review.

Inflammation is a crucial step prior to healing, and the regulatory effects of endodontic materials on the immune response can influence tissue repair. This review aimed to answer whether endodontic sealers can modulate the immune cells and inflammation. An electronic search in Scopus, Web of Science, PubMed, and Google Scholar databases were performed. This systematic review was mainly based on PRISMA guidelines, and the risk of bias was evaluated by SYRCLEs and the Modified CONSORT checklist for in vivo and in vitro studies, respectively. In total, 28 articles: 22 in vitro studies, and six in vivo studies were included in this systematic review. AH Plus and AH 26 can down-regulate iNOS mRNA, while S-PRG sealers can down-regulate p65 of NF-κB pathways to inhibit the production of TNF-α, IL-1, and IL-6. In vitro and in vivo studies suggested that various endodontic sealers exhibited immunomodulatory impact in macrophages polarization and inflammatory cytokine production, which could promote healing, tissue repair, and inhibit inflammation. Since the paradigm change from immune inert biomaterials to bioactive materials, endodontic materials, particularly sealers, are required to have modulatory effects in clinical conditions. New generations of endodontic sealers could hamper detrimental inflammatory responses and maintain periodontal tissue, which represent a breakthrough in biocompatibility and functionality of endodontic biomaterials.

TIGIT-expressing zoledronate-specific γδ T cells display enhanced antitumor activity.

Human γδ T cells hold a pivotal role in tumor immunosurveillance through their prompt activation and cytokine secretion and have received much attention in adoptive immunotherapy of clear cell renal cell carcinoma (ccRCC). However, the therapeutic effects are limited in ccRCC. Therefore, it is now critical to improve therapeutic strategies based on γδ T cells, especially identification of functional γδ T cell subsets. In this study, we aimed to identify γδ T cells that might have enhanced responses against ccRCC. Bioinformatic analysis showed that ccRCC patients with high T cell immunoglobulin and immunoreceptor tyrosine-based inhibitory motif domain (TIGIT) expression had higher levels of effector molecules. Then, we examined the changes in the TIGIT+ γδ T cell percentages of 6 ccRCC patients and 14 healthy subjects through zoledronate (ZOL) stimulation. Results indicated that percentages of TIGIT+ γδ T cells were positively correlated with activated γδ T cells in early activation stage. Further study demonstrated that TIGIT+ γδ T cells exhibited enhanced activation, contained more terminally differentiated effector γδ T cells and produced higher cytokine compared with TIGIT- γδ T cells. Finally, we investigated the functions and found that TIGIT+ γδ T cells exhibited stronger tumor reactivities and higher cytotoxicity when challenged by tumor cells. Above results imply that TIGIT+ γδ T cells are the main effectors in ZOL recognition and tumor cells challenging. The results of the present study serve as basis for future functional studies on TIGIT+ γδ T cells and provide a promising approach of immunotherapy in ccRCC.

Sintilimab maintenance therapy post first-line cytokine-induced killer cells plus chemotherapy for extensive-stage small cell lung cancer.

Despite recent progress in treating advanced non-small cell lung cancer, clinical intervention in extensive-stage small-cell lung cancer (ES-SCLC) remains stagnant. The purpose of this study was to evaluate the clinical efficacy of cytokine-induced killer (CIK) cells combined with cytotoxic chemotherapy, followed by anti-programmed death 1 antibody (sintilimab) maintenance, in ES-SCLC patients. To explore a new method for safe treatment of ES-SCLC patients, thirteen ES-SCLC patients were enrolled between June 2019 and December 2021. All patients received first-line chemotherapy (etoposide plus platinum) combined with CIK cell therapy. Patients who reached a stable disease state or responded well to treatment received sintilimab maintenance treatment. The primary objective of this study was to determine the median overall survival (OS); the secondary objective was to assess the objective response rate (ORR), progression-free survival 1 and 2 (PFS1 was defined as the duration from the signing of informed consent to the date of tumor progression, or death, or the last follow-up. PFS2 was defined as the duration from the first day of sintilimab treatment to the date of tumor progression, death, or the last follow-up.), and adverse reactions. At a 24.1-month follow-up, the median OS was 11.8 (95% confidence interval [CI]: 10.6-13.0) months, median PFS1 was 5.5 (95% CI: 5.0-6.0) months, and the median PFS2 was 2.3 (95% CI: 0.5-4.1) months. The ORR was 76.9% (10/13), the disease control rate was 100% (13/13), and the 20-month survival rate was 41.7%. Eight participants exhibited grade 3 or 4 adverse events after combination therapy. During maintenance treatment with sintilimab, level 3 adverse events occurred in 1 patient (1/9). In conclusion, adding CIK cells to standard chemotherapy regimens, followed by maintenance therapy with sintilimab, may represent a new safe and effective treatment strategy. Clinical trial registration: ClinicalTrials.gov (NCT03983759).

Mesenchymal Stem Cell-Mediated Mitochondrial Transfer: a Therapeutic Approach for Ischemic Stroke.

Stroke is the leading cause of death and adult disability worldwide. Mitochondrial dysfunction is one of the hallmarks of stroke-induced neuronal death, and maintaining mitochondrial function is essential in cell survival and neurological progress following ischemic stroke. Stem cell-mediated mitochondrial transfer represents an emerging therapeutic approach for ischemic stroke. Accumulating evidence suggests that mesenchymal stem cells (MSCs) can directly transfer healthy mitochondria to damaged cells, and rescue mitochondrial damage-provoked tissue degeneration. This review summarizes the research on MSCs-mediated mitochondrial transfer as a therapeutic strategy against ischemic stroke.

Effective Radiotherapy in Tracheobronchial Adenoid Cystic Carcinoma With Positive Surgical Margin.

BACKGROUND: The study aimed to evaluate the role of postoperative radiotherapy (PORT) in the treatment of trachea and main bronchus adenoid cystic carcinoma (ACC) with a positive surgical margin. METHODS: Patients with pathologically confirmed trachea or main bronchus ACC operated on at Shanghai Chest Hospital were enrolled. Survival, univariate, and multivariate analyses were performed. The χ2 test was applied to analyze the failure patterns among different groups (R0/0: negative margin resection without PORT; R1/0: positive margin resection without PORT; R1/1: positive margin resection with PORT). RESULTS: From January 2001 to December 2014, 77 patients were deemed eligible for the study. Pairwise comparisons showed that the overall survival rate of group R1/1 was comparable to that of group R0/0 (P = .438), and significantly longer than the rate of group R1/0 (P = .032). Additionally, the local disease-free survival rate of group R1/1 was much higher than that of group R0/0 (P = .023) and R1/0 (P = .001). Cox multivariate analysis identified the radiologic feature (P = .012) and PORT (P = .006) as significantly favorable prognostic factors for locoregional disease-free survival. By contrast, for overall survival, PORT (P = .032) was the only corresponding variable identified by univariate analysis. Furthermore, PORT significantly decreased the locoregional recurrence rate (P = .002) but not distant metastases (P > .999). CONCLUSIONS: PORT helped patients with tracheobronchial ACC and microscopic positive surgical margins to achieve a similar outcome as patients with complete resection. R0 resection may not be necessary for tracheobronchial ACC if it is difficult to be completely resected.

High Complete Response Rate in Patients With Metastatic Renal Cell Carcinoma Receiving Autologous Cytokine-Induced Killer Cell Therapy Plus Anti-Programmed Death-1 Agent: A Single-Center Study.

Background and Objective: The results of the CheckMate 025 trial established the status of nivolumab in the second-line treatment of metastatic renal cell carcinoma (mRCC), with an objective response rate (ORR) of 25% and a complete response (CR) rate of 1%. Thus, the efficacy of anti-programmed death (PD)-1 antibodies in the second-line treatment of mRCC requires improvement. The purpose of this study was to explore the clinical efficacy and safety of anti-PD-1 agents combined with cytokine-induced killer (CIK) cell therapy for refractory mRCC. Patients and Methods: Patients with mRCC refractory to previous targeted therapy were included in this study. All patients received anti-PD-1 plus CIK cell therapy. The ORR and CR rate, progression-free survival (PFS), overall survival (OS), and safety were assessed. Results: CR was observed in seven of the 29 patients, and partial response was observed in five patients. The ORR was 41.4% and the median PFS was 15.0 months. Up to the last follow-up, 15 patients died with an average survival time of 37 months. Among the patients who achieved a CR, one experienced cerebellar metastasis 18.8 months after discontinuation, but achieved CR again after localized gamma knife and 1-month axitinib treatment. This regimen was tolerated well and there was no treatment-related death. Conclusions: Combination therapy with anti-PD-1 and CIK cell therapy is safe and effective in patients with mRCC refractory to previous targeted therapy. The high CR rate and long disease-free survival even after long-term discontinued therapy suggest that this combination treatment may represent a potential curative regimen for this type of malignancy.

T Cells Expanded from PD-1+ Peripheral Blood Lymphocytes Share More Clones with Paired Tumor-Infiltrating Lymphocytes.

Both tumor-infiltrating lymphocytes (TIL) and PD-1+ peripheral blood lymphocytes (PBL) are enriched for tumor-reactive clones recognizing known and unknown tumor antigens. However, the relationship between the T-cell receptor-ß (TCRß) repertoires of the TILs and T cells expanded from paired PD-1+ PBLs, and whether T cells expanded from PD-1+ PBLs can be used to treat patients with cancer as TIL substitutes remain unclear. Here, we established a highly efficient protocol to prepare polyclonal T cells from PD-1+ PBLs. A functional T-cell assay and tetramer staining revealed that cells from PD-1+ PBLs were relatively enriched for tumor-reactive T cells. Furthermore, deep TCRß sequencing data revealed that an average of 11.29% (1.32%-29.06%; P = 0.015; n = 8) tumor-resident clonotypes were found in T cells expanded from paired PD-1+ PBLs, and the mean accumulated frequency of TIL clones found in T cells expanded from PD-1+ PBLs was 35.11% (7.23%-78.02%; P = 0.017; n = 8). Moreover, treatment of four patients, who failed multiline therapy and developed acquired resistance to anti-PD-1, with autologous T cells expanded from PD-1+ PBLs combined with anti-PD-1 antibody elicited objective responses from three of them. These results indicate that T cells expanded from PD-1+ PBLs share more clones with paired TILs and could be used to treat patients with cancer as TIL substitutes. SIGNIFICANCE: This study harnesses the tumor reactivity of PD-1+ PBLs, developing a method to expand T cells from these clones as a potential therapeutic strategy and TIL substitute in patients with cancer.See related commentary by Ladle, p. 1940.

Osteoblast-derived lipocalin-2 regulated by miRNA-96-5p/Foxo1 advances the progression of Alzheimer's disease.

Aim: Alzheimer's disease (AD) is the most frequent cause of dementia and characterized by the accumulation of ß-amyloid peptides in plaques and vessel walls. This study proposed a hypothesis of an inhibitory role of miR-96-5p in AD via regulating Foxo1. Methods & methods: AD mouse models were established by injecting with 1% pentobarbital. Results: Knockdown of miR-96-5p in the presence of naringin was shown to reduce the expression of Foxo1 and contents of superoxide dismutase, catalase and glutathione peroxidase, yet increase lipocalin-2 expression as well as hydroxyproline and malondialdehyde contents. Also, Foxo1-mediated lipocalin-2 inhibition attenuated AD. Conclusion: Our study shows downregulating miR-96-5p limited AD progression, highlighting miR-96-5p a potential therapeutic target in treating AD.

Epidermal Growth Factor Receptor (EGFR)-Tyrosine Kinase Inhibitors (TKIs) Combined with Chemotherapy Delay Brain Metastasis in Patients with EGFR-Mutant Lung Adenocarcinoma.

BACKGROUND: Whether epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs) combined with chemotherapy can delay the occurrence of brain metastasis (BM) is unclear. OBJECTIVE: This retrospective study aimed to evaluate whether EGFR-TKIs combined with chemotherapy can delay BM and decrease the incidence of BM as initial progression. PATIENTS AND METHODS: The data of 100 patients with EGFR-mutant advanced lung adenocarcinoma were retrospectively reviewed. The patients had no BM at initial diagnosis, and BM occurred during the treatment. Patients received EGFR-TKI only or EGFR-TKI combined with chemotherapy. Intracranial progression-free survival (iPFS), systemic progression-free survival (PFS), and overall survival (OS) were evaluated. RESULTS: The overall median OS was 39 months (95% confidence interval (CI), 35.6-42.4 months). The median OS of EGFR-TKI combined with chemotherapy and EGFR-TKI only are 41 months (95% CI 35.5-46.5 months) and 39 months (95% CI 36.8-41.2 months), respectively. Patients in the combination treatment group had longer PFS (16 vs. 10 months; P = 0.030) and iPFS (21 vs. 14 months; P = 0.026). Further, as initial progression, fewer patients developed BM in the combined treatment group compared with the EGFR-TKI-only group (30.6% vs. 52.9%, P = 0.002) with a hazard ratio of 0.64 (95% CI 0.43-0.96). After controlling for significant covariables in a multivariable model, the different treatment strategies were independently associated with improved iPFS. CONCLUSIONS: In this retrospective analysis, EGFR-TKIs combined with chemotherapy could improve PFS. Further, the combined treatment could delay BM occurrence and decrease the incidence of BM as initial progression.

Upfront whole brain radiotherapy for multiple brain metastases in patients with EGFR-mutant lung adenocarcinoma.

Purpose: This study aimed to evaluate the efficacy of upfront whole-brain radiotherapy (WBRT) in EGFR-mutant lung adenocarcinoma patients with multiple brain metastases (BM). Methods: In this study, 195 patients with EGFR mutations who had multiple BM at preliminary diagnosis were included and retrospectively reviewed. Patients were admitted to receive the following treatments in a multi-disciplinary setting: upfront WBRT followed by EGFR-TKI, concurrent EGFR-TKI and WBRT and upfront EGFR-TKI followed by WBRT. A disease-specific graded prognostic assessment (DS-GPA) was performed for all the patients. The treatment response and overall survival (OS) were assessed as well. Results: The median OS of these patients was 27 months. Objective response rate (ORR) was significantly better in upfront WBRT group than other two groups (P=0.004). Moreover, patients who received upfront WBRT (n=67) had longer OS than the concomitant group (36 vs 25 months; P=0.006) and the upfront EGFR-TKI group (36 vs 25 months; P<0.0001). The prognosis of patients with different DS-GPA scores significantly differed (P<0.0001). In concomitant group and upfront EGFR-TKIs group, patients with higher DS-GPA scores of 2-3 had more favorable prognosis compared with those with lower DS-GPA scores of 0-1.5 (27 vs 25 months; P=0.023). Patients who received EGFR-TKIs concurrently with WBRT had longer OS than those received upfront EGFR-TKIs with high DS-GPA scores. (37 vs 17 months; P=0.023). Conclusion: The use of upfront WBRT for EGFR-mutated lung adenocarcinoma patients with multiple BM can improve ORR and OS. More importantly, patients with high DS-GPA scores are recommended to receive WBRT immediately after EGFR-TKIs therapy.

Correction to: Epidermal Growth Factor Receptor (EGFR)-Tyrosine Kinase Inhibitors (TKIs) Combined with Chemotherapy Delay Brain Metastasis in Patients with EGFR­Mutant Lung Adenocarcinoma.

The article Epidermal Growth Factor Receptor (EGFR)-Tyrosine Kinase Inhibitors (TKIs) Combined with Chemotherapy Delay Brain Metastasis in Patients with EGFR-Mutant Lung Adenocarcinom, written by Changhui Li, Bo Zhang, Jindong Guo, Fang Hu, Wei Nie, Xiaoxuan Zheng, Lixin Wang, Yuqing Lou, Yinchen Shen, Baohui Han, Xueyan Zhang, was originally published electronically on the publisher's internet portal (currently SpringerLink) on 03 July 2019 with open access. With the author(s)' decision to step back from Open Choice, the copyright of the article changed on 17 July 2019 to © Springer Nature Switzerland AG 2019 and the article is forthwith distributed under the terms of copyright.