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The number of patients with Alzheimer’s disease (AD) and non-Alzheimer’s disease (non-AD) has drastically increased over recent decades. The amyloid cascade hypothesis attributes a vital role to amyloid-β protein (Aβ) in the pathogenesis of AD. As the main pathological hallmark of AD, amyloid plaques consist of merely the 42 and 40 amino acid variants of Aβ (Aβ42 and Aβ40). The cerebrospinal fluid (CSF) biomarker Aβ42/40 has been extensively investigated and eventually integrated into important diagnostic tools to support the clinical diagnosis of AD. With the development of highly sensitive assays and technologies, blood-based Aβ42/40, which was obtained using a minimally invasive and cost-effective method, has been proven to be abnormal in synchrony with CSF biomarker values. This paper presents the recent progress of the CSF Aβ42/40 ratio and plasma Aβ42/40 for AD as well as their potential clinical application as diagnostic markers or screening tools for dementia.

Alzheimer’s disease (AD) is the most common type of dementia in the elderly and causes neurodegeneration, leading to memory loss, behavioral disorder, and psychiatric impairment. One potential mechanism contributing to the pathogenesis of AD may be the imbalance in gut microbiota, local and systemic inflammation, and dysregulation of the microbiota–gut–brain axis (MGBA). Most of the AD drugs approved for clinical use today are symptomatic treatments that do not improve AD pathologic changes. As a result, researchers are exploring novel therapeutic modalities. Treatments involving the MGBA include antibiotics, probiotics, transplantation of fecal microbiota, botanical products, and others. However, single-treatment modalities are not as effective as expected, and a combination therapy is gaining momentum. The purpose of this review is to summarize recent advances in MGBA-related pathological mechanisms and treatment modalities in AD and to propose a new concept of combination therapy. “MGBA-based multitherapy” is an emerging view of treatment in which classic symptomatic treatments and MGBA-based therapeutic modalities are used in combination. Donepezil and memantine are two commonly used drugs in AD treatment. On the basis of the single/combined use of these two drugs, two/more additional drugs and treatment modalities that target the MGBA are chosen based on the characteristics of the patient’s condition as an adjuvant treatment, as well as the maintenance of good lifestyle habits. “MGBA-based multitherapy” offers new insights for the treatment of cognitive impairment in AD patients and is expected to show good therapeutic results.

Herein, we report that genetically programmable fusion cellular vesicles (Fus-CVs) displaying high-affinity SIRPα variants and PD-1 can activate potent antitumor immunity through both innate and adaptive immune effectors. Dual-blockade of CD47 and PD-L1 with Fus-CVs significantly increases the phagocytosis of cancer cells by macrophages, promotes antigen presentation, and activates antitumor T-cell immunity. Moreover, the bispecific targeting design of Fus-CVs ensures better targeting on tumor cells, but less on other cells, which reduces systemic side effects and enhances therapeutic efficacies. In malignant melanoma and mammary carcinoma models, we demonstrate that Fus-CVs significantly improve overall survival of model animals by inhibiting post-surgery tumor recurrence and metastasis. The Fus-CVs are suitable for protein display by genetic engineering. These advantages, integrated with other unique properties inherited from source cells, make Fus-CVs an attractive platform for multi-targeting immune checkpoint blockade therapy.

Hospital grassplot soil is an important repository of pathogenic fungi exposed to the hospital environment, and the diffusion of these fungi-containing soil particles in the air increases the risk of nosocomial fungal infections. In this study, from the perspective of soil microbes-plant holobiont, four medicinal plants Mirabilis jalapa, Artemisia argyi, Viola philippica, and Plantago depressa were used as materials, based on ITS high-throughput amplicon sequencing and simulated pot experiments to explore the effect of medicinal plants on the fungal community in hospital grassplot soil, in order to provide a new exploration for hospital grassplot soil remediation. The results showed that the fungal community ecological guilds in primary test soil was mainly pathogen, and the abundance of animal pathogen with potential threats to human reached 61.36%. After planting medicinal plants, the composition and function of soil fungal community changed significantly. Although this change varied with plant species and growth stages, all samples collected in the pot experiment showed that the pathogen abundance decreased and the saprotroph abundance increased. In addition, 45 of the 46 core fungal genera defined in all potted samples were present in primary test soil, and many of them were human potential pathogens. These findings imply that the idea of enhancing soil quality in hospital grassplot soil by planting specific plants is feasible. However, the initial fungal community of the hospital grassplot soil has a certain stability, and it is difficult to completely eliminate the threat of pathogenic fungi by planting medicinal plants.

The study aimed to explore the bacterial community composition and the functions of core microbiota in Eucommia ulmoides bark. The bark samples of E. ulmoides were collected from Wangcang Sichuan Province, Cili Hunan Province, and Zunyi Guizhou Province, in China, respectively. Through the high-throughput sequencing methods and techniques, the community composition, core microbiota, and function of the bacteria were studied. The bacterial community of E. ulmoides bark consisted of 9 phyla, 11 classes, 22 orders, 28 families, 31 genera, and 37 OTUs. At the genus level, the dominant genus was the unclassified bacteria of Cyanobacteria, with a relative abundance of 97.01%. The bacterial communities of E. ulmoides bark from different areas have their unique units except for the common microbiota. The core microbiota of bacteria included an unclassified genus of Cyanobacteria, an unclassified genus of Mitochondria, Pseudomonas, Sphingobium, Rhizobium, Novosphingobium, Enterobacter, Rhodococcus, Curtobacterium, and Ralstonia. FAPROTAX function prediction suggested that the core microbiota has a substantial potential for photoautotrophy, phototrophy, aerobic chemoheterotrophy, chemoheterotrophy. Ten taxa composed the core microbiota, and the majority of them were related to the pharmacologically active ingredients of E. ulmoides bark. The research provides a scientific basis for the biological marker of genuineness and microbial technology for improving the content of medicinal ingredients of E. ulmoides.

High-dose radiation activates caspases in tumor cells to produce abundant DNA fragments for DNA sensing in antigen-presenting cells, but the intrinsic DNA sensing in tumor cells after radiation is rather limited. Here we demonstrate that irradiated tumor cells hijack caspase 9 signaling to suppress intrinsic DNA sensing. Instead of apoptotic genomic DNA, tumor-derived mitochondrial DNA triggers intrinsic DNA sensing. Specifically, loss of mitochondrial DNA sensing in Casp9-/- tumors abolishes the enhanced therapeutic effect of radiation. We demonstrated that combining emricasan, a pan-caspase inhibitor, with radiation generates synergistic therapeutic effects. Moreover, loss of CASP9 signaling in tumor cells led to adaptive resistance by upregulating programmed death-ligand 1 (PD-L1) and resulted in tumor relapse. Additional anti-PD-L1 blockade can further overcome this acquired immune resistance. Therefore, combining radiation with a caspase inhibitor and anti-PD-L1 can effectively control tumors by sequentially blocking both intrinsic and extrinsic inhibitory signaling.

Adult-onset leukoencephalopathy with axonal spheroids and pigmented glia (ALSP) is a rare autosomal dominant disorder caused by mutations in the colony-stimulating factor 1 receptor (CSF1R) gene. As of 2022, more than 100 different CSF1R mutations were reported in patients with CSF1R-related leukoencephalopathy. In this case report, we describe ALSP in a previously healthy 46-year-old woman who presented with memory impairment, poor interpersonal behavior, and decreased verbal fluency. Brain magnetic resonance imaging (MRI) showed confluent white matter changes and atrophy of the corpus callosum. Whole-exome sequencing identified a novel splice-site mutation (C.1858 + 5G A) in intron 13 of the CSF1R gene, resulting in an intron 12 retention and an exon 13 deletion of CSF1R mRNA.

Mutations in STK11/LKB1 in non-small cell lung cancer (NSCLC) are associated with poor patient responses to immune checkpoint blockade (ICB), and introduction of a Stk11/Lkb1 (L) mutation into murine lung adenocarcinomas driven by mutant Kras and Trp53 loss (KP) resulted in an ICB refractory syngeneic KPL tumor. Mechanistically this occurred because KPL mutant NSCLCs lacked TCF1-expressing CD8 T cells, a phenotype recapitulated in human STK11/LKB1 mutant NSCLCs. Systemic inhibition of Axl results in increased type I interferon secretion from dendritic cells that expanded tumor-associated TCF1+PD-1+CD8 T cells, restoring therapeutic response to PD-1 ICB in KPL tumors. This was observed in syngeneic immunocompetent mouse models and in humanized mice bearing STK11/LKB1 mutant NSCLC human tumor xenografts. NSCLC-affected individuals with identified STK11/LKB1 mutations receiving bemcentinib and pembrolizumab demonstrated objective clinical response to combination therapy. We conclude that AXL is a critical targetable driver of immune suppression in STK11/LKB1 mutant NSCLC. publishedVersion

Cantharellus cibarius is a widely distributed, popular, edible fungus with high nutritional and economic value. However, significant challenges persist in the microbial ecology and artificial cultivation of C. cibarius. Based on the 16S rRNA sequencing data, this study analyzed bacterial community structures and diversity of fruit bodies and rhizomorph parts of C. cibarius and mycosphere samples (collected in the Wudang District, Guiyang, Guizhou Province, China). It explored the composition and function of the core bacterial taxa. The analyzed results showed that the rhizomorph bacterial community structure was similar to mycosphere, but differed from the fruit bodies. Members of the Allorhizobium-Neorhizobium-Pararhizobium-Rhizobium complex had the highest abundance in the fruit bodies. However, they were either absent or low in abundance in the rhizomorphs and mycosphere. At the same time, members of the Burkholderia-Caballeronia-Paraburkholderia complex were abundant in the fruit bodies and rhizomorphs parts of C. cibarius, as well as mycosphere. Through functional annotation of core bacterial taxa, we found that there was an apparent trend of potential functional differentiation of related bacterial communities in the fruit body and rhizomorph: potential functional groups of core bacterial taxa in the fruit bodies centered on nitrogen fixation, nitrogen metabolism, and degradation of aromatic compounds, while those in rhizomorphs focused on aerobic chemoheterotrophy, chemoheterotrophy, defense against soil pathogens, decomposition of complex organic compounds, and uptake of insoluble inorganic compounds. The analysis of functional groups of bacteria with different structures is of great significance to understand that bacteria promote the growth and development of C. cibarius.

During a survey of rhizosphere soil fungi of Eucommia ulmoides in China, three Gongronella strains were isolated. Phylogenetic analysis showed that these strains grouped into a separate subclade, closely related to Gongronella sichuanensis. The new strains could be distinguished from G. sichuanensis by the smooth-walled, subglobose, or conical-cylindrical apophyses. Both phylogenetic analysis and morphological characteristics supported the three strains being a new species, named as Gongronella zunyiensis.

Mutations in

The core microbiome, as a unique group of microorganisms, is an emerging research hotspot that provides a new opportunity to improve growth and production of a host. However, the subjectivity associated with the concept of “core microbiome” means there is currently no uniform definition method for the core microbiome. In this study, the strengths and limitations of four commonly used definition methods for the core microbiome were explored from composition to function based on the 16S rRNA gene dataset of Eucommia ulmoides bark from 25 different biogeographical regions in China. There were differences in the composition of the core microbiomes defined by the different methods. The four definition methods of phylogeny, membership, composition, and network connection contained 274, 10, 5, and 5 core OTUs (operational taxonomic units), respectively. In contrast, the core microbiomes defined by different methods displayed similarities in function. In addition, different definition methods showed varying preferences for abundant taxa, intermediate taxa, and rare taxa. Some core taxa defined by the definition method of phylogeny were significantly associated with pharmacologically active ingredients of E. ulmoides bark. The findings of this study suggest that although the core microbiomes defined by different methods have preferences in composition and function, the term refers to a group of microbes that are particularly notable and important for host-associated microbiomes. Therefore, we propose: (I) The definition method of the core microbiome should be selected according to the ecological problems faced; (II) A combination of multiple methods may comprehensively reveal the core microbiome at different levels of the host, and may also facilitate understanding of the ecological and evolutionary processes that govern host-microbe interactions.

PurposeTo quantitatively assess the blood oxygen levels of the cerebral vein using quantitative susceptibility mapping (QSM), and to analyze the correlation between magnetic susceptibility value (MSV) and clinical laboratory indicators/cognitive scores in patients with Alzheimer’s disease (AD).Materials and MethodsFifty-nine patients (21 males and 38 females) with clinically confirmed AD (AD group) and 22 control subjects (12 males, 10 females; CON group) were recruited. Clinical data and laboratory examination indexes were collected. All patients underwent Mini-mental State Examination, Montreal Cognitive Assessment, Clock Drawing Task, and Activity of Daily Living Scale test, as well as a routine MRI and enhanced gradient echo T2 star weighted angiography (ESWAN).ResultsHigher cerebral venous MSV was observed in AD group compared to CON group, significant differences were observed for bilateral thalamus veins and left dentate nucleus veins. The MSV of bilateral thalamus veins, bilateral internal cerebral veins, and bilateral dentate nucleus veins had significant negative correlation with Mini-mental State Examination score; the MSV of bilateral thalamus veins, bilateral dentate nucleus veins, right septal vein had a significant negative correlation with Montreal Cognitive Assessment scores; a significant negative correlation between the MSV of bilateral thalamus veins, left dentate nucleus vein, right septal vein and the Clock Drawing Task score; the MSV of bilateral thalamus veins, left dentate nucleus vein had a significant negative correlation with Activity of Daily Living Scale score. The MSV of left dentate nucleus vein was positively correlated with the course of the disease, the MSV of bilateral septal vein were positively correlated with the total cholesterol, and the MSV of left septal vein had a positive correlation with LDL.ConclusionDecreasing cerebral venous oxygen level in AD patients may affect cognitive status, and associated with the deterioration of the disease in AD patients.

Background: Florbetapir (AV45) and fluorodeoxyglucose (FDG) PET imaging are valuable techniques to detect the amyloid-β (Aβ) load and brain glucose metabolism in patients with Alzheimer’s disease (AD). Objective: The purpose of this study is to access the characteristics of Aβ load and FDG metabolism in brain for further investigating their relationships with cognitive impairment in AD patients. Methods: Twenty-seven patients with AD (average 70.6 years old, N = 13 male, N = 14 female) were enrolled in this study. These AD patients underwent the standard clinical assessment and received detailed imaging examinations of the nervous system by using Mini-Mental State Examination (MMSE), Montreal Cognitive Assessment (MOCA), 18F-AV45, and 18F-FDG PET scans. Results: Of 27 AD patients, 22 patients (81.5%) showed significantly increases in Aβ load and 26 patients (96.3%) had significantly reductions in FDG metabolism. The moderate AD patients had more brain areas of reduced FDG metabolism and more severe reductions in some regions compared to mild AD patients, with no differences in Aβ load observed. Moreover, the range and degree of reduced FDG metabolism in several regions were positively correlated with the total score of MMSE or MOCA, whereas the range of Aβ load did not. No correlation was found between the range of Aβ load and the range of reduced FDG metabolism in this study. Conclusion: The reduction in FDG metabolisms captured by 18F-FDG imaging can be used as a potential biomarker for AD diagnosis in the future. 18F-AV45 imaging did not present valuable evidence for evaluating AD patient in this study.

Background The purpose of this study is to investigate the characteristics of amyloid beta (Aβ) load and fluorodeoxyglucose (FDG) metabolism and analyze their correlation with cognitive impairment in the cerebral cortex of Alzheimer's disease (AD) patients using 18F-florbetapir (18F-AV45) and 18F-FDG PET technology. Methods 27 patients with AD were enrolled. All AD patients underwent detailed clinical and imaging examinations of the nervous system, completed the Mini-Mental State Examination (MMSE) and Montreal Cognitive Assessment (MoCA) tests, and finished 18F-AV45 and 18F-FDG PET scans. NeuroQ software was used to analyze PET images. Results 81.48% (22 out of 27) AD patients had significantly increased Aβ load and 96.30% (26 out of 27) had significantly reduced FDG metabolism. Moderate AD patients had more brain areas of reduced FDG metabolism with more severe reduction in some brain regions compared with mild AD patients, despite there was no differences of Aβ load between these patients. The range of reduced FDG metabolism was negatively correlated with the total scores of MMSE and MoCA, and the degree of FDG metabolism in some brain regions was positively correlated with the total score of MMSE and MoCA. Conclusion Brain 18F-AV45 and 18F-FDG imaging may be potential biomarkers of AD, and 18F-FDG imaging is correlated with the degree of cognitive impairment in AD patients.

Introduction It has been reported that environmental factors such as hypoxia could contribute to the pathogenesis of Alzheimer's disease (AD). Therapeutics like hyperbaric oxygen treatment, which improves tissue oxygen supply and ameliorates hypoxic conditions in the brain, may be an alternative therapy for AD and amnestic mild cognitive impairment (aMCI). The present work aims to investigate the potential therapeutic effect of hyperbaric oxygen treatment for AD and aMCI. Methods We recruited 42 AD, 11 aMCI, and 30 control AD patients in this study. AD and aMCI patients were treated with 40 minutes of hyperbaric oxygen once a day for 20 days and assessed by neuropsychiatric assessments including Mini‐Mental State Examination (MMSE), Montreal Cognitive Assessment (MoCA), and Activities of Daily Living (ADL) scale before and at 1‐, 3‐, and 6‐month follow‐up after treatment. Control AD patients who were not given hyperbaric oxygen treatment had similar clinical profile as hyperbaric oxygen treated AD. We examined 10 of the AD/aMCI patients with fluorodeoxyglucose positron emission tomography. Results In self‐comparison study, one course of hyperbaric oxygen treatment significantly improved the cognitive function assessed by MMSE and MoCA in AD patients after 1‐month follow‐up; such treatment also significantly improved MMSE score at 3‐month follow‐up and MoCA score at 1‐ and 3‐month follow‐up in aMCI patients. The ADL scale was significantly improved in AD patients after 1‐ and 3‐month follow‐up. Compared to the control AD patients, the MMSE and MoCA in hyperbaric oxygen treated AD patients were significantly improved after 1‐month follow‐up. Hyperbaric oxygen treatment also ameliorated the reduced brain glucose metabolism in some of the AD and aMCI patients. Conclusion Based on previous studies and our recent findings, we propose that hyperbaric oxygen treatment may be a promising alternative therapy for AD and aMCI.

BackgroundMutations in tumor suppressor STK11/LKB1 are associated with negative predictive and prognostic impact in NSCLC patients receiving immune checkpoint inhibitors (CPI) in several published cohorts, although there have been some conflicting reports on the association of such mutations with patient outcomes in this setting [1–9]. STK11/LKB1 tumors are characterized by a suppressive tumor micro-environment devoid of cytotoxic T cells, and we hypothesized that targeting the receptor tyrosine kinase AXL, a known driver of an innate immune suppressive microenvironment, would restore sensitivity to PD-1 in syngeneic pre-clinical models as well as in patients harboring STK11/LKB1 mutated NSCLC.MethodsStk11/Lkb1 (L) mutation was introduced by CRISPR technology into murine lung adenocarcinomas driven by mutant Kras and Trp53 loss (KP). Sensitivity towards anti-PD-1 was evaluated in the absence and presence of the small molecule AXL inhibitor bemcentinib in the KPL model and in a human NSCLC xenograft model carrying a STK11/LKB1 mutation. The immune tumor landscape was mapped following introduction of the Stk11/Lkb1 mutation and therapeutic intervention with anti-PD-1/pembrolizumab and bemcentinib. FFPE fine-needle aspirate biopsies of target lesions were acquired from patients at screening immediately prior to enrollment in BGBC008, a PhII single-arm, 2-stage study with bemcentinib (200mg/d) and pembrolizumab (200 mg/q3wk) for previously-treated stage IV lung adenocarcinoma patients who were CPI naïve or CPI refractory. Patients were assessed for response according to RECIST1.1 criteria at scheduled scan intervals.ResultsIntroduction of a STK11/LKB1 mutation into murine lung adenocarcinomas driven by mutant Kras and Trp53 loss resulted in a PD-1 refractory syngeneic KPL tumor. Mechanistically this occurred because KPL mutant NSCLCs lacked TCF1-expressing CD8 T cells, a phenotype that was recapitulated in human STK11/LKB1 mutant NSCLCs. Systemic inhibition of AXL with bemcentinib resulted in increased type I interferon secretion from dendritic cells resulting in expansion of tumor-associated TCF1+PD-1+CD8 T cells and restored therapeutic response to PD-1. This effect was observed in a syngeneic immunocompetent mouse model and in humanized mice bearing STK11/LKB1 mutant NSCLC human tumor xenografts.In an ongoing clinical trial (NCT03184571), 3 evaluable NSCLC patients with identified STK11/LKB1 mutations demonstrated objective clinical response/clinical benefit to the combination of AXL inhibitor bemcentinib and pembrolizumabConclusionsIn these models, AXL is a critical targetable driver of immune suppression in STK11/LKB1 mutant NSCLC contributing to CPI resistance. Our results show that inhibition of AXL rescues this deficit and represents a new clinical strategy in combination with anti-PD-1 therapy in NSCLC patients carrying a STK11/LKB1 mutationAcknowledgementsThe authors would like to thank all patients and their caretakers for participating in this trial.Trial RegistrationPatients treated with bemcentinib and pembrolizumab combination therapy were enrolled in the BGBC008 clinical trial (BerGenBio ASA and Merck & Co., Inc., Kenilworth NJ, USA, NCT03184571)ReferencesGu M, Xu T, Chang P. KRAS/LKB1 and KRAS/TP53 co-mutations create divergent immune signatures in lung adenocarcinomas. Ther Adv Med Oncol. 2021;13:17588359211006950.Cho BC, Lopes G, Kowalski DM. Relationship between STK11 and KEAP1 mutational status and efficacy in KEYNOTE-042: pembrolizumab monotherapy as first-line therapy for PD-L1 positive advanced NSCLC. Cancer Res. 2020;80(16 Supplement):CT084.Aredo JV, Padda SK, Kunder CA. Impact of KRAS mutation subtype and concurrent pathogenic mutations on non-small cell lung cancer outcomes. Lung Cancer. 2019;133:144–150.Kwack WG, Shin SY, Lee SH. Primary Resistance to Immune Checkpoint Blockade in an STK11/TP53/KRAS-Mutant Lung Adenocarcinoma with High PD-L1 Expression. Oncol Targets Ther. 2020;13:8901–8905.Shire NJ, Klein AB, Golozar A. STK11 (LKB1) mutations in metastatic NSCLC: Prognostic value in the real world. PLoS One. 2020;15(9):e0238358. 6. Skoulidis F, Goldberg ME, Greenawalt DM. STK11/LKB1 Mutations and PD-1 Inhibitor Resistance in KRAS-Mutant Lung Adenocarcinoma. Cancer Discov. 2018;8(7):822–835. 7. Wang H, Guo J, Shang X. Less immune cell infiltration and worse prognosis after immunotherapy for patients with lung adenocarcinoma who harbored STK11 mutation. Int. Immunopharmacol. 2020;84:106574. 8. Kitajima S, Ivanova E, Gou S. Suppression of STING Associated with LKB1 Loss in KRAS-Driven Lung Cancer. Cancer Discov. 2019;9(1):34–45. 9. Mograbi B, Heeke S, Hofman P. The Importance of STK11/LKB1 Assessment in Non-Small Cell Lung Carcinomas. Diagnostics (Basel). 2021;11(2):196.Ethics ApprovalThis study was approved by the following ethical committees: Use of human cord blood: UT Southwestern (UTSW) Parkland Hospital, STU 112010-047Animal studies: UTSW Medical Center, Institutional Animal Care and Use Committee, APN 2015-100921Clinical study: London Bridge Research Ethics Committee (UK): 17/LO/0418; REC-South East (Norway): 2017/473; Drug Research Ethics Committee of the University Hospital Clinic of Barcelona (Spain): BGBC008/MK-3475_PN-531; Medical College of Wisconsin Institutional Review Board #4 (USA): PRO00029453

Bark represents a unique microbial habitat. Revealing the interactions among bark-associated microbes is important for understanding their diversity, stability, and function, and how core microbiome influences the health and production of the host plant. We used amplicon sequencing of bark from the medicinal plant Eucommia ulmoides collected across nine distinct biogeographical regions in China, and comprehensively analyzed the diversity, rare biosphere and core taxa of bark fungi. The co-occurrence network results showed significant differences in the compositions of core mycobiota in E. ulmoides bark between the nine regions. Ecological factors (e.g., temperature and rainfall) were crucial determinants of differences in the unique core mycobiota of E. ulmoides from different regions. The metacommunity-scale network indicated that Cladosporium, Alternaria, and Teratosphaeria were core fungal taxa of E. ulmoides bark. Moreover, some core fungal taxa included rare taxa in particular local communities which, despite their relatively low abundance, may play a significant role in the community structure of E. ulmoides bark.

The study aimed to explore the bacterial community composition and the functions of core microbiota in Eucommia ulmoides bark. The bark samples of E. ulmoides were collected from Wangcang Sichuan Province, Cili Hunan Province, and Zunyi Guizhou Province, in China, respectively. Through the high-throughput sequencing methods and techniques, the community composition, core microbiota, and function of the bacteria were studied. The bacterial community of E. ulmoides bark consisted of 9 phyla, 11 classes, 22 orders, 28 families, 31 genera, and 37 OTUs. At the genus level, the dominant genus was the unclassified bacteria of Cyanobacteria, with a relative abundance of 97.01%. The bacterial communities of E. ulmoides bark from different areas have their unique units except for the common microbiota. The core microbiota of bacteria included an unclassified genus of Cyanobacteria, an unclassified genus of Mitochondria, Pseudomonas, Sphingobium, Rhizobium, Novosphingobium, Enterobacter, Rhodococcus, Curtobacterium, and Ralstonia. FAPROTAX function prediction suggested that the core microbiota has a substantial potential for photoautotrophy, phototrophy, aerobic chemoheterotrophy, chemoheterotrophy. Ten taxa composed the core microbiota, and the majority of them were related to the pharmacologically active ingredients of E. ulmoides bark. The research provides a scientific basis for the biological marker of genuineness and microbial technology for improving the content of medicinal ingredients of E. ulmoides.

The lack of sufficient functional tumor-infiltrating lymphocytes in the tumor microenvironment (TME) is one of the primary indications for the poor prognosis of patients with cancer. In this study, we developed an Erbitux-based IL-21 tumor-targeting fusion protein (Erb-IL21) to prolong the half-life and improve the antitumor efficacy of IL-21. Compared with Erb-IL2, Erb-IL21 demonstrated much lower toxicity in vivo. Mechanistically, Erb-IL21 selectively expanded functional cytotoxic T lymphocytes but not dysfunctional CD8(+) T cells in the TME. We observed that the IL-21–mediated antitumor effect largely depended on the existing intratumoral CD8(+) T cells, instead of newly migrated CD8(+) T cells. Furthermore, Erb-IL21 overcame checkpoint blockade resistance in mice with advanced tumors. Our study reveals that Erb-IL21 can target IL-21 to tumors and maximize the antitumor potential of checkpoint blockade by expending a subset of tumor antigen–specific CD8(+) T cells to achieve effective tumor control.

Solid cancers are able to escape immune surveillance and are resistant to current treatment in immunotherapy. Recent evidence indicates the critical role of the stimulator of interferon genes (STING) pathway in antitumor immunity. STING-targeted activation is extensively investigated as a new strategy for cancer therapy. Previously, we reported a safe and efficacious STING-activating nanovaccine to boost systemic tumor-specific T cell responses in multiple tumor models. Local radiotherapy has been reported to not only reduce tumor burden but also enhance local antitumor immunity in a STING-dependent manner. In this study, we demonstrate that combination of these two modalities leads to a synergistic response with long-term regression of large established tumors in two mouse tumor models. The percentage of CD8+ T cells increased significantly in primary tumors after combination therapy. Mechanistically, the augmented T cell responses of radiotherapy and nanovaccine is STING pathway dependent. Furthermore, nanovaccine synergizes with radiotherapy to achieve a better therapeutic effect in distal tumors. These findings suggest that combination of local radiotherapy with systemic PC7A nanovaccine offers a useful strategy to improve the therapeutic outcome of late stage solid cancers.

Increasing evidence demonstrates that interleukin-10 (IL-10), known as an immunosuppressive cytokine, induces antitumor effects depending on CD8

Epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs) are a first-line therapy for rapidly killing tumors such as those associated with non-small cell lung cancer by blocking oncogenic receptor signaling, but tumor relapse often occurs. Here, we have observed that hypofractionated EGFR TKI treatment (HypoTKI) is more potent than standard hyperfractionated EGFR TKI treatment (HyperTKI), and its antitumor effect associated with preventing tumor relapse depends on T cells. HypoTKI triggers greater innate sensing for type I IFN and CXCL10 production through the Myd88 signaling pathway to enhance tumor-specific T cell infiltration and reactivation. We also demonstrate that timely programmed cell death ligand-1 (PD-L1) blockade can synergize with HypoTKI to control advanced large tumors and effectively limit tumor relapse without severe side effects. Our study provides evidence for exploring the potential of a proper combination of EGFR TKIs and immunotherapy as a first-line treatment for treating EGFR-driven tumors.

Summary Increasing evidence demonstrates that interleukin-10 (IL-10), known as an immunosuppressive cytokine, induces antitumor effects depending on CD8+ T cells. However, it remains elusive how immunosuppressive effects of IL-10 contribute to CD8+ T cell-mediated antitumor immunity. We generated Cetuximab-based IL-10 fusion protein (CmAb-(IL10)2) to prolong its half-life and allow tumor-targeted delivery of IL-10. Our results demonstrated potent antitumor effects of CmAb-(IL10)2 with reduced toxicity. Moreover, we revealed a mechanism of CmAb-(IL10)2 preventing dendritic cell (DC)-mediated CD8+ tumor-infiltrating lymphocyte apoptosis through regulating IFN-γ production. When combined with immune checkpoint blockade, CmAb-(IL10)2 significantly improves antitumor effects in mice with advanced tumors. Our findings reveal a DC-regulating role of IL-10 to potentiate CD8+ T cell-mediated antitumor immunity and provide a potential strategy to improve cancer immunotherapy.

EGFR tyrosine kinase inhibitors (TKIs) have been clinically considered as the first line therapy for EGFR-driven tumor patients. Although the initial outcome of patients has significantly improved, almost all patients eventually relapse. Fully understanding the mechanisms of the anti-tumor effect of EGFR TKIs will help promote the clinical development of more efficient therapeutic strategies. The traditional view of the main mechanism is that the inhibitors can directly inhibit EGFR downstream signaling pathways to induce tumor cell death. Whether and how EGFR TKIs affect the host immune system is largely unknown. In current study, we have established syngeneic murine tumor models that are sensitive to EGFR TKIs treatment. To our surprise, we revealed that EGFR TKI treatment could control tumor growth and limit tumor relapse in T cells dependent manner. Mechanistically, EGFR TKI triggers type I IFN and its stimulation gene CXCL10 production through the Myd88 signaling pathway to enhance tumor specific T cells infiltration and activation. However, EGFR TKI cannot efficiently limit tumor relapse in advanced tumor models because of PD-L1 upregulation in the tumor microenvironment after treatment. We have observed that anti-PDL1 blockade can synergize with EGFR TKI to control advanced tumors. Our study will challenge the current regimen of EGFR TKI in clinic and provide new efficient therapeutic strategies for EGFR dependent cancer patients. Citation Format: Zhida Liu, Chuanhui Han, Aijun Shen, Chunbo Dong, Jian Qiao, Yang-Xin Fu. EGFR tyrosine kinase inhibitor limits tumor relapse through enhancing anti-tumor T cell responses [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 2752.

Entorhinal cortex (EC), thought to be the location of the earliest lesions in Alzheimer’s disease (AD), has been widely studied in recent years. With the irreversible pathological changes of AD, there is an urgent need to find biomarkers that can be used to predict the presence of the disease before it is clinically expressed. The aim of this review is to summarize and analyze recent findings that are relevant to the important role of EC in the diagnosis of mild cognitive impairment (MCI) and mild AD and to describe a range of neuroimaging techniques used to define the EC boundary. A comprehensive literature search for articles published up to May 2015 was performed. Our research highlights the finding that atrophy in EC reflects the early pathological changes of AD and can be a strong predictor of prodromal AD. The early changes in EC are a good imaging biomarker that can be used to discriminate individuals with MCI from normal control subjects. A larger degree of atrophy in EC predicts increased disease severity, and the right EC in patients with mild AD exhibited greater changes than the left side. In addition, the EC seems to have an obvious advantage over the hippocampus as a biomarker when predicting future conversion to AD in individuals with MCI, and it may be of help in following the course of disease progression. In this review, we also summarize the main differences observed between the hippocampus and the EC when differentiating diseases. These findings will hopefully provide an opportunity for the effective prevention and early treatment of AD.

Multiple system atrophy (MSA) is a neurodegenerative disease that presents as an autonomic dysfunction in combination with varying degrees of parkinsonism and cerebellar ataxia. It comprises a pathologically widespread neuronal loss accompanied by gliosis in the basal ganglia, cerebellum, pons, inferior olivary nuclei, and spinal cord. As a rapidly progressive disorder, MSA develops with autonomic dysfunction and mobility problems in several years. These autonomic and motor function impairments severely disrupt the patients' daily lives. Currently, the therapeutic management of this disease is only symptomatic. An early and accurate diagnosis is helpful not only in the clinical field but also in the research for new therapies. The biomarkers in cerebrospinal fluid (CSF) and serum facilitate the differential diagnosis of MSA when the disease is difficult to recognize based on the clinical features or even presymptomatic. This review will summarize the biomarkers present in CSF that are potential candidates to accurately differentiate MSA from other similar neurodegenerative disorders.