Multivariate rational inattention

We study optimal control problems in the multivariate linear-quadratic-Gaussian framework under rational inattention and show that the multivariate attention allocation problem can be reduced to a dynamic tracking problem in information theory. We propose a general solution method to solve this problem by using rate distortion functions and semidefinite programming and derive the optimal form and dimension of signals without strong prior restrictions. We provide generalized reverse water-filling solutions for some special cases. Applying our method to solve three multivariate economic models, we obtain some results qualitatively different from the literature.First author draf

LDC7559 inhibits microglial activation and GSDMD-dependent pyroptosis after subarachnoid hemorrhage

Mounting evidence indicates that inhibition of microglial activation and neuronal pyroptosis plays important roles in brain function recovery after subarachnoid hemorrhage (SAH). LDC7559 is a newly discovered gasdermin D (GSDMD) inhibitor. Previous studies have demonstrated that LDC7559 could inhibit microglial proliferation and pyroptosis. However, the beneficial effects of LDC7559 on SAH remain obscure. Based on this background, we investigated the potential role and the mechanism of LDC7559 on SAH-induced brain damage both in vivo and in vitro. The findings revealed that microglial activation and neuronal pyroptosis were evidently increased after SAH, which could be markedly suppressed by LDC7559 both in vivo and in vitro. Meanwhile, LDC7559 treatment reduced neuronal apoptosis and improved behavior function. Mechanistically, LDC7559 decreased the levels of GSDMD and cleaved GSDMD after SAH. In contrast, nod-like receptor pyrin domain-containing 3 (NLRP3) inflammasome activation by nigericin increased GSDMD-mediated pyroptosis and abated the beneficial effects of LDC7559 on SAH-induced brain damage. However, LDC7559 treatment did not significantly affect the expression of NLRP3 after SAH. Taken together, LDC7559 might suppress neuronal pyroptosis and microglial activation after SAH by inhibiting GSDMD, thereby promoting brain functional recovery

EMT transcription factors snail and slug directly contribute to cisplatin resistance in ovarian cancer

<p>Abstract</p> <p>Background</p> <p>The epithelial to mesenchymal transition (EMT) is a molecular process through which an epithelial cell undergoes transdifferentiation into a mesenchymal phenotype. The role of EMT in embryogenesis is well-characterized and increasing evidence suggests that elements of the transition may be important in other processes, including metastasis and drug resistance in various different cancers.</p> <p>Methods</p> <p>Agilent 4 × 44 K whole human genome arrays and selected reaction monitoring mass spectrometry were used to investigate mRNA and protein expression in A2780 cisplatin sensitive and resistant cell lines. Invasion and migration were assessed using Boyden chamber assays. Gene knockdown of <it>snail </it>and <it>slug </it>was done using targeted siRNA. Clinical relevance of the EMT pathway was assessed in a cohort of primary ovarian tumours using data from Affymetrix GeneChip Human Genome U133 plus 2.0 arrays.</p> <p>Results</p> <p>Morphological and phenotypic hallmarks of EMT were identified in the chemoresistant cells. Subsequent gene expression profiling revealed upregulation of EMT-related transcription factors including <it>snail, slug, twist2 </it>and <it>zeb2</it>. Proteomic analysis demonstrated up regulation of Snail and Slug as well as the mesenchymal marker Vimentin, and down regulation of E-cadherin, an epithelial marker. By reducing expression of <it>snail </it>and <it>slug</it>, the mesenchymal phenotype was largely reversed and cells were resensitized to cisplatin. Finally, gene expression data from primary tumours mirrored the finding that an EMT-like pathway is activated in resistant tumours relative to sensitive tumours, suggesting that the involvement of this transition may not be limited to <it>in vitro </it>drug effects.</p> <p>Conclusions</p> <p>This work strongly suggests that genes associated with EMT may play a significant role in cisplatin resistance in ovarian cancer, therefore potentially leading to the development of predictive biomarkers of drug response or novel therapeutic strategies for overcoming drug resistance.</p

Timing of Brain Radiation Therapy Impacts Outcomes in Patients with Non-small Cell Lung Cancer Who Develop Brain Metastases

Background and objective Radiotherapy combined with chemotherapy or molecular targeted therapy remains the standard of treatment for brain metastases from non-small cell lung cancer (NSCLC). The aim of this study is to determine if the deferral of brain radiotherapy impacts patient outcomes. Methods Between May 2003 and December 2015, a total of 198 patients with brain metastases from NSCLC who received both brain radiotherapy and systemic therapy (chemotherapy or targeted therapy) were identified. The rate of grade 3-4 adverse reactions related to chemotherapy and radiotherapy had no significant difference between two groups. 127 patients received concurrent brain radiotherapy and systemic therapy, and 71 patients received deferred brain radiotherapy after at least two cycles of chemotherapy or targeted therapy. Disease specific-graded prognostic assessment was similar in early radiotherapy group and deferred radiotherapy group. Results Median overall survival (OS) was longer in early radiotherapy group compared to deferred radiotherapy group (17.9 months vs 12.6 months; P=0.038). Progression free survival (PFS) was also improved in patients receiving early radiotherapy compared to those receiving deferred radiotherapy (4.0 months vs 3.0 months; P<0.01). Receiving tyrosine kinase inhibitor (TKI) therapy after the diagnosis of brain metastases as any line therapy improved the OS (20.0 months vs 10.7 months; P<0.01), whereas receiving TKI as first line therapy did not (17.9 months vs 15.2 months; P=0.289). Conclusion Our study suggests that the use of deferred brain radiotherapy may resulted in inferior OS in patients with NSCLC who develop brain metastases. A prospective multi-central randomized study is imminently needed

Effects of Local Radiation Combined with Chemotherapy in the treatment of Patients with Extensive-stage Small Cell Lung Cancer

Background and objective Chemotherapy is a highly efficient primary treatment for extensive-stage small cell lung cancer (ES-SCLC). However, patients receiving such treatment are prone to develop drug resistance. Local treatment is palliative and thus can alleviate the local symptoms and improve quality of life, but limited evidence is available for prolonging survival. Hence, this study evaluated the role of local treatment in chemotherapy of patients with ES-SCLC. Methods A total of 302 ES-SCLC cases were enrolled in this retrospective study. Prognostic factors were analyzed by Kaplan-Meier and Cox multivariate proportional hazards model. Results Median progression-free survival (PFS) and median survival time (MST) of the patients were 4.4 and 10.4 months, respectively. 1-, 2-, and 3-year survival rates were 37.8%, 10.2% and 4.4%, correspondingly. The MST of the primary tumor radiotherapy plus chemotherapy group was 14.3 months, whereas that of the chemotherapy group was 8.2 months (P<0.01). The MSTs of multiple-site, single-site, and non-metastasis local treatments were 18.7, 12.3 and 8.9 months, respectively (P<0.01). The MSTs of initiative, passive, and non-metastasis local treatments were 16.0, 10.9 and 9.4 months, correspondingly (P<0.01). The MSTs of patients with prophylactic cranial irradiation (PCI) and those without PCI were 19.8 and 9.9 months, respectively (P<0.01). Primary tumor radiotherapy, metastasis local treatment, and PCI were independent prognostic factors for ES-SCLC. Conclusion Primary tumor radiotherapy, metastasis local treatment, and PCI can significantly improve survival in patients with ES-SCLC

Construction of an endoplasmic reticulum stress-related signature in lung adenocarcinoma by comprehensive bioinformatics analysis

Abstract Background Lung Adenocarcinoma (LUAD) is a major component of lung cancer. Endoplasmic reticulum stress (ERS) has emerged as a new target for some tumor treatments. Methods The expression and clinical data of LUAD samples were downloaded from The Cancer Genome Atlas (TCGA) and The Gene Expression Omnibus (GEO) database, followed by acquiring ERS-related genes (ERSGs) from the GeneCards database. Differentially expressed endoplasmic reticulum stress-related genes (DE-ERSGs) were screened and used to construct a risk model by Cox regression analysis. Kaplan–Meier (K-M) curves and receiver operating characteristic (ROC) curves were plotted to determine the risk validity of the model. Moreover, enrichment analysis of differentially expressed genes (DEGs) between the high- and low- risk groups was conducted to investigate the functions related to the risk model. Furthermore, the differences in ERS status, vascular-related genes, tumor mutation burden (TMB), immunotherapy response, chemotherapy drug sensitivity and other indicators between the high- and low- risk groups were studied. Finally, quantitative real-time polymerase chain reaction (qRT-PCR) was used to validate the mRNA expression levels of prognostic model genes. Results A total of 81 DE-ERSGs were identified in the TCGA-LUAD dataset, and a risk model, including HSPD1, PCSK9, GRIA1, MAOB, COL1A1, and CAV1, was constructed by Cox regression analysis. K-M and ROC analyses showed that the high-risk group had a low survival, and the Area Under Curve (AUC) of ROC curves of 1-, 3- and 5-years overall survival was all greater than 0.6. In addition, functional enrichment analysis suggested that the risk model was related to collagen and extracellular matrix. Furthermore, differential analysis showed vascular-related genes FLT1, TMB, neoantigen, PD-L1 protein (CD274), Tumor Immune Dysfunction and Exclusion (TIDE), and T cell exclusion score were significantly different between the high- and low-risk groups. Finally, qRT-PCR results showed that the mRNA expression levels of 6 prognostic genes were consistent with the analysis. Conclusion A novel ERS-related risk model, including HSPD1, PCSK9, GRIA1, MAOB, COL1A1, and CAV1, was developed and validated, which provided a theoretical basis and reference value for ERS-related fields in the study and treatment of LUAD

A Randomized, Double-Blind, Controlled Phase III Clinical Trial to Evaluate the Immunogenicity and Safety of a Lyophilized Human Rabies Vaccine (Vero Cells) in Healthy Participants Aged 10–60 Years Following Essen and Zagreb Vaccination Procedures

Objective: In this paper, we aim to show that the immunogenicity of the lyophilized human rabies vaccine (Vero cells) (investigational vaccine) developed by Dalian Aleph Biomedical Co., Ltd. in healthy participants aged 10–60 years old is non-inferior to the lyophilized PVRV (positive control) manufactured by Liaoning Chengda Biotechnology Co., Ltd. (Shenyang, China), and that its safety is clinically acceptable. Method: A total of 2776 participants were enrolled in this study and divided into four groups: a five-dose test group, a five-dose control group, a four-dose test group, and a four-dose control group. The patients in the four-dose groups (Zagreb) were vaccinated on Days 0 (two doses), 7 (one dose), and 21 (one dose), and those in the five-dose groups (Essen) were vaccinated on Days 0, 3, 7, 14, and 28 (one dose each). The rabies-virus-neutralizing antibody assay with the RFFIT was used to assess the immunogenicity, and the adverse events (AEs) and serious adverse events (SAEs) were identified and collated. Results: The positive seroconversion rate was up to 100% on Days 14 and 35/42 after vaccination following any procedures in pre-immunization antibody-negative participants, and the positive seroconversion rate and geometric mean concentration (GMC) of the test groups (Zagreb and Essen vaccination procedures) was not inferior to that of the control groups. On Day 7 after vaccination, the immunogenicity of the Zagreb procedure with two doses of the vaccine on Day 0 was superior to the Essen procedure with one dose of vaccine, that is, the former had a higher seroconversion rate and RVNA titer. The non-inferiority criterion of immunogenicity was met for the whole population, the population aged 10–18 years and ≥18 years, and the pre-immunization antibody-positive population. The incidences of all AEs, solicited AEs, and unsolicited AEs in both groups were not statistically significant, and no vaccination-related SAEs were observed. Conclusion: The investigated vaccine is safe, its immunogenicity is non-inferior to that of the control vaccine, and the efficacy of the Zagreb procedure is superior to that of the Essen procedure 7 days after the first dose

Real-world data on the first-line immune checkpoint inhibitors or in combination with chemotherapy in older patients (aged ≥ 75 years) with advanced non-small cell lung cancer

Purpose: The purpose of this study is to investigate the efficacy and safety of immune checkpoint inhibitors (ICIs) or plus with chemotherapy in older patients. Methods: We enrolled 110 older patients with non-small cell lung cancer (NSCLC ≥75 years) who received either chemotherapy alone (chemo), ICI plus chemotherapy (ICI + chemo), or ICI alone and ICI plus other therapies, which included anti-angiogenesis drugs or other novel ICI (ICIs). Patient characteristics, treatment response, survival, and toxicity were evaluated. Results: In total population, the ICIs group has the highest disease control rate (DCR 75%). There were no significant differences in progression-free survival (PFS) and overall survival (OS) among older patients between ICI + chemo and ICIs groups (PFS: 5.3 months vs. 5.5 months, p = 0.70, OS: 10.7 months vs. 20.3 months, p = 0.995). Meanwhile, we observed ICIs had a longer PFS and OS than chemo group (PFS: 3.9 months vs. 5.5 months, p = 0.01, OS: 10.9 months vs. 20.3 months, p = 0.05). Subgroup analysis showed that patients with programmed death ligand-1 (PD-L1) ≥ 1% had a distinct longer trend toward OS in ICIs group compared to ICI + chemo group (22.4 months vs. 10.7 months, p = 0.605), even though there was no significant difference. In terms of safety, ICIs was more tolerable and had a lower discontinuation rate than ICI + chemo group. Conclusion: In the real world, ICI + chemo is more likely to be discontinued due to adverse effects and does not significantly improve patient survival compared with ICIs treatment in total population and subgroup. Therefore, ICI alone or ICIs plus other therapies, such as anti-angiogenesis drugs or other novel ICI (ICIs) could be recommended for older cases with PD-L1 positive NSCLC