RESUMEN
Nano ferroelectrics holds the potential application promise in information storage, electro-mechanical transformation, and novel catalysts but encounters a huge challenge of size limitation and manufacture complexity on the creation of long-range ferroelectric ordering. Herein, as an incipient ferroelectric, nanosized SrTiO3 was indued with polarized ordering at room temperature from the nonpolar cubic structure, driven by the intrinsic three-dimensional (3D) tensile strain. The ferroelectric behavior can be confirmed by piezoelectric force microscopy and the ferroelectric TO1 soft mode was verified with the temperature stability to 500 K. Its structural origin comes from the off-center shift of Ti atom to oxygen octahedron and forms the ultrafine head-to-tail connected 90° nanodomains about 2 to 3 nm, resulting in an overall spontaneous polarization toward the short edges of nanoparticles. According to the density functional theory calculations and phase-field simulations, the 3D strain-related dipole displacement transformed from [001] to [111] and segmentation effect on the ferroelectric domain were further proved. The topological ferroelectric order induced by intrinsic 3D tensile strain shows a unique approach to get over the nanosized limitation in nanodevices and construct the strong strain-polarization coupling, paving the way for the design of high-performance and free-assembled ferroelectric devices.
RESUMEN
PLK1 (Polo-like kinase 1) plays a critical role in the progression of lung adenocarcinoma (LUAD). Recent studies have unveiled that targeting PLK1 improves the efficacy of immunotherapy, highlighting its important role in the regulation of tumor immunity. Nevertheless, our understanding of the intricate interplay between PLK1 and the tumor microenvironment (TME) remains incomplete. Here, using genetically engineered mouse model and single-cell RNA-seq analysis, we report that PLK1 promotes an immunosuppressive TME in LUAD, characterized with enhanced M2 polarization of tumor associated macrophages (TAM) and dampened antigen presentation process. Mechanistically, elevated PLK1 coincides with increased secretion of CXCL2 cytokine, which promotes M2 polarization of TAM and diminishes expression of class II major histocompatibility complex (MHC-II) in professional antigen-presenting cells. Furthermore, PLK1 negatively regulates MHC-II expression in cancer cells, which has been shown to be associated with compromised tumor immunity and unfavorable patient outcomes. Taken together, our results reveal PLK1 as a novel modulator of TME in LUAD and provide possible therapeutic interventions.
Asunto(s)
Adenocarcinoma del Pulmón , Proteínas de Ciclo Celular , Neoplasias Pulmonares , Quinasa Tipo Polo 1 , Proteínas Serina-Treonina Quinasas , Proteínas Proto-Oncogénicas , Análisis de la Célula Individual , Microambiente Tumoral , Animales , Humanos , Ratones , Adenocarcinoma del Pulmón/genética , Adenocarcinoma del Pulmón/inmunología , Adenocarcinoma del Pulmón/patología , Presentación de Antígeno/genética , Proteínas de Ciclo Celular/genética , Proteínas de Ciclo Celular/metabolismo , Línea Celular Tumoral , Quimiocina CXCL2/genética , Quimiocina CXCL2/metabolismo , Regulación Neoplásica de la Expresión Génica , Antígenos de Histocompatibilidad Clase II/genética , Antígenos de Histocompatibilidad Clase II/metabolismo , Neoplasias Pulmonares/genética , Neoplasias Pulmonares/inmunología , Neoplasias Pulmonares/patología , Proteínas Serina-Treonina Quinasas/genética , Proteínas Serina-Treonina Quinasas/metabolismo , Proteínas Proto-Oncogénicas/genética , Proteínas Proto-Oncogénicas/metabolismo , Microambiente Tumoral/inmunología , Microambiente Tumoral/genética , Macrófagos Asociados a Tumores/inmunología , Macrófagos Asociados a Tumores/metabolismoRESUMEN
It is now well known that solids under ultra-high-pressure shock compression will enter the warm dense matter (WDM) regime which connects condensed matter and hot plasma. How condensed matter turns into the WDM, however, remains largely unexplored due to the lack of data in the transition pressure range. In this letter, by employing the unique high-Z three-stage gas gun launcher technique developed recently, we compress gold into TPa shock pressure to fill the gap inaccessible by the two-stage gas gun and laser shock experiments. With the aid of high-precision Hugoniot data obtained experimentally, we observe a clear softening behavior beyond ~560 GPa. The state-of-the-art ab-initio molecular dynamics calculations reveal that the softening is caused by the ionization of 5d electrons in gold. This work quantifies the partial ionization effect of electrons under extreme conditions, which is critical to model the transition region between condensed matter and WDM.
RESUMEN
Metastasis of lung adenocarcinoma (LUAD) is a major cause of death in patients. Aryl hydrocarbon receptor (AHR), an important transcription factor, is involved in the initiation and progression of lung cancer. Polo-like kinase 1 (PLK1), a serine/threonine kinase, acts as an oncogene promoting the malignancy of multiple cancer types. However, the interaction between these two factors and their significance in lung cancer remain to be determined. In this study, we demonstrate that PLK1 phosphorylates AHR at S489 in LUAD, leading to epithelial-mesenchymal transition (EMT) and metastatic events. RNA-seq analyses reveal that type 2 deiodinase (DIO2) is responsible for EMT and enhanced metastatic potential. DIO2 converts tetraiodothyronine (T4) to triiodothyronine (T3), activating thyroid hormone (TH) signaling. In vitro and in vivo experiments demonstrate that treatment with T3 or T4 promotes the metastasis of LUAD, whereas depletion of DIO2 or a deiodinase inhibitor disrupts this property. Taking together, our results identify the AHR phosphorylation by PLK1 and subsequent activation of DIO2-TH signaling as mechanisms leading to LUAD metastasis. These findings can inform possible therapeutic interventions for this event.
Asunto(s)
Adenocarcinoma del Pulmón , Neoplasias Pulmonares , Humanos , Fosforilación , Yoduro Peroxidasa/metabolismo , Receptores de Hidrocarburo de Aril/genética , Proteínas Serina-Treonina Quinasas/genética , Proteínas Serina-Treonina Quinasas/metabolismo , Adenocarcinoma del Pulmón/genética , Hormonas Tiroideas/genética , Neoplasias Pulmonares/genética , Neoplasias Pulmonares/patología , Transición Epitelial-Mesenquimal/genética , Proliferación Celular/fisiología , Quinasa Tipo Polo 1RESUMEN
Thrombocytopenia, hemorrhage, anemia, and infection are life-threatening issues following accidental or intentional radiation exposure. Since few therapeutics are available, safe and efficacious small molecules to mitigate radiation-induced injury need to be developed. Our previous study showed the synthetic TLR2/TLR6 ligand fibroblast stimulating lipopeptide (FSL-1) prolonged survival and provided MyD88-dependent mitigation of hematopoietic acute radiation syndrome (H-ARS) in mice. Although mice and humans differ in TLR number, expression, and function, nonhuman primate (NHP) TLRs are like those of humans; therefore, studying both animal models is critical for drug development. The objectives of this study were to determine the efficacy of FSL-1 on hematopoietic recovery in small and large animal models subjected to sublethal total body irradiation and investigate its mechanism of action. In mice, we demonstrate a lack of adverse effects, an easy route of delivery (subcutaneous) and efficacy in promoting hematopoietic progenitor cell proliferation by FSL-1. NHP given radiation, followed a day later with a single subcutaneous administration of FSL-1, displayed no adversity but showed elevated hematopoietic cells. Our analyses revealed that FSL-1 promoted red blood cell development and induced soluble effectors following radiation exposure. Cytologic analysis of bone marrow aspirates revealed a striking enhancement of mononuclear progenitor cells in FSL-1-treated NHP. Combining the efficacy of FSL-1 in promoting hematopoietic cell recovery with the lack of adverse effects induced by a single administration supports the application of FSL-1 as a viable countermeasure against H-ARS.
Asunto(s)
Síndrome de Radiación Aguda , Receptor Toll-Like 2 , Humanos , Ratones , Animales , Receptor Toll-Like 6 , Ligandos , Síndrome de Radiación Aguda/tratamiento farmacológico , Primates , FibroblastosRESUMEN
BACKGROUND: Pancreatic ductal adenocarcinoma (PDAC) is frequently accompanied by perineural invasion (PNI), which is associated with excruciating neuropathic pain and malignant progression. However, the relationship between PNI and tumour stromal cells has not been clarified. METHODS: The dorsal root ganglia or sciatic nerves nerve model was used to observe the paracrine interaction and the activation effect among Schwann cells, tumour-associated macrophages (TAMs), and pancreatic cancer cells in vitro. Next generation sequencing, enzyme-linked immunosorbent assay and chromatin immunoprecipitation were used to explore the specific paracrine signalling between TAMs and Schwann cells. RESULTS: We demonstrated that more macrophages were expressed around nerves that have been infiltrated by pancreatic cancer cells compared with normal nerves in murine and human PNI specimens. In addition, high expression of CD68 or GFAP is associated with an increased incidence of PNI and indicates a poor 5-year survival rate in patients with PDAC. Mechanistically, tumour-associated macrophages (TAMs) activate Schwann cells via the bFGF/PI3K/Akt/c-myc/GFAP pathway. Schwann cells secrete IL-33 to recruit macrophages into the perineural milieu and facilitate the M2 pro-tumourigenic polarisation of macrophages. CONCLUSIONS: Our study demonstrates that the bFGF/IL-33 positive feedback loop between Schwann cells and TAMs is essential in the process of PNI of PDAC. The bFGF/PI3K/Akt/c-myc/GFAP pathway would open potential avenues for targeted therapy of PDAC.
Asunto(s)
Carcinoma Ductal Pancreático , Neoplasias Pancreáticas , Humanos , Ratones , Animales , Interleucina-33 , Macrófagos Asociados a Tumores/metabolismo , Macrófagos Asociados a Tumores/patología , Fosfatidilinositol 3-Quinasas , Proteínas Proto-Oncogénicas c-akt , Neoplasias Pancreáticas/patología , Carcinoma Ductal Pancreático/patología , Células de Schwann/metabolismo , Células de Schwann/patología , Invasividad NeoplásicaRESUMEN
As one of the most abundant stromal cells, fibroblasts are primarily responsible for the production and remodeling of the extracellular matrix. Traditionally, fibroblasts have been viewed as quiescent cells. However, recent advances in multi-omics technologies have demonstrated that fibroblasts exhibit remarkable functional diversity at the single-cell level. Additionally, fibroblasts are heterogeneous in their origins, tissue locations, and transitions with stromal cells. The dynamic nature of fibroblasts is further underscored by the fact that disease stages can impact their heterogeneity and behavior, particularly in immune-mediated inflammatory diseases such as psoriasis, inflammatory bowel diseases, and rheumatoid arthritis, etc. Fibroblasts can actively contribute to the disease initiation, progression, and relapse by responding to local microenvironmental signals, secreting downstream inflammatory factors, and interacting with immune cells during the pathological process. Here we focus on the development, plasticity, and heterogeneity of fibroblasts in inflammation, emphasizing the need for a developmental and dynamic perspective on fibroblasts.
Asunto(s)
Artritis Reumatoide , Enfermedades Inflamatorias del Intestino , Humanos , Suelo , Inflamación , Enfermedades Inflamatorias del Intestino/patología , FibroblastosRESUMEN
The skin epidermis is continually influenced by a myriad of internal and external elements. At its basal layer reside epidermal stem cells, which fuels epidermal renovation and hair regeneration with powerful self-renewal ability, as well as keeping diverse signals that direct their activity under surveillance with quick response. The importance of epidermal stem cells in wound healing and immune-related skin conditions has been increasingly recognized, and their potential for clinical applications is attracting attention. In this review, we delve into recent advancements and the various physiological and psychological factors that govern distinct epidermal stem cell populations, including psychological stress, mechanical forces, chronic aging, and circadian rhythm, as well as providing an overview of current methodological approaches. Furthermore, we discuss the pathogenic role of epidermal stem cells in immune-related skin disorders and their potential clinical applications.
Asunto(s)
Células Epidérmicas , Células Madre , Humanos , Células Madre/citología , Animales , Epidermis , Piel/patología , Cicatrización de HeridasRESUMEN
BACKGROUND: Skin barrier dysfunction may both initiate and aggravate skin inflammation. However, the mechanisms involved in the inflammation process remain largely unknown. OBJECTIVES: We sought to determine how skin barrier dysfunction enhances skin inflammation and molecular mechanisms. METHODS: Skin barrier defect mice were established by tape stripping or topical use of acetone on wildtype mice, or filaggrin deficiency. RNA-Seq was employed to analyse the differentially expressed genes in mice with skin barrier defects. Primary human keratinocytes were transfected with formylpeptide receptor (FPR)1 or protein kinase R-like endoplasmic reticulum (ER) kinase (PERK) small interfering RNA to examine the effects of these gene targets. The expressions of inflammasome NOD-like receptor (NLR)C4, epidermal barrier genes and inflammatory mediators were evaluated. RESULTS: Mechanical (tape stripping), chemical (acetone) or genetic (filaggrin deficiency) barrier disruption in mice amplified the expression of proinflammatory genes, with transcriptomic profiling revealing overexpression of formylpeptide receptor (Fpr1) in the epidermis. Treatment with the FPR1 agonist fMLP in keratinocytes upregulated the expression of the NLRC4 inflammasome and increased interleukin-1ß secretion through modulation of ER stress via the PERK-eIF2α-C/EBP homologous protein pathway. The activation of the FPR1-NLRC4 axis was also observed in skin specimens from old healthy individuals with skin barrier defect or elderly mice. Conversely, topical administration with a FPR1 antagonist, or Nlrc4 silencing, led to the normalization of barrier dysfunction and alleviation of inflammatory skin responses in vivo. CONCLUSIONS: In summary, our findings show that the FPR1-NLRC4 inflammasome axis is activated upon skin barrier disruption and may explain exaggerated inflammatory responses that are observed in disease states characterized by epidermal dysfunction. Pharmacological inhibition of FPR1 or NLRC4 represents a potential therapeutic target.
Asunto(s)
Dermatitis , Proteínas Filagrina , Animales , Humanos , Ratones , Acetona/metabolismo , Acetona/farmacología , Dermatitis/metabolismo , Epidermis/metabolismo , Inflamasomas/metabolismo , Inflamación , Queratinocitos/metabolismo , Proteínas NLR/metabolismoRESUMEN
Fibroblasts are critical pro-inflammatory regulators in chronic inflammatory and fibrotic skin diseases. However, fibroblast heterogeneity and the absence of a unified cross-disease taxonomy have hindered our understanding of the shared/distinct pathways in non-communicable skin inflammation. By integrating 10× single-cell data from 75 skin samples, we constructed a single-cell atlas across inflammatory and fibrotic skin diseases and identified 9 distinct subsets of skin fibroblasts. We found a shared subset of CCL19+ fibroblasts across these diseases, potentially attracting and educating immune cells. Moreover, COL6A5+ fibroblasts were a distinct subset implicated in the initiation and relapse of psoriasis, which tended to differentiate into CXCL1+ fibroblasts, inducing neutrophil chemotaxis and infiltration; while CXCL1+ fibroblasts exhibited a more heterogeneous response to certain inflammatory conditions. Differentiation trajectory and regulatory factors of these fibroblast subsets were also revealed. Therefore, our study presents a comprehensive atlas of skin fibroblasts and highlights pathogenic fibroblast subsets in skin disorders.
RESUMEN
Glucose-Regulated Protein 78 (GRP78) is a chaperone protein that is predominantly expressed in the lumen of the endoplasmic reticulum. GRP78 plays a crucial role in protein folding by assisting in the assembly of misfolded proteins. Under cellular stress conditions, GRP78 can translocate to the cell surface (csGRP78) were it interacts with different ligands to initiate various intracellular pathways. The expression of csGRP78 has been associated with tumor initiation and progression of multiple cancer types. This review provides a comprehensive analysis of the existing evidence on the roles of GRP78 in various types of cancer and other human pathology. Additionally, the review discusses the current understanding of the mechanisms underlying GRP78's involvement in tumorigenesis and cancer advancement. Furthermore, we highlight recent innovative approaches employed in downregulating GRP78 expression in cancers as a potential therapeutic target.
Asunto(s)
Chaperón BiP del Retículo Endoplásmico , Neoplasias , Humanos , Neoplasias/genética , Transformación Celular Neoplásica , Retículo EndoplásmicoRESUMEN
Patients with chronic graft-versus-host disease (cGVHD) have increased B cell-activating factor (BAFF) levels, but whether BAFF promotes disease after allogeneic bone marrow transplantation (allo-BMT) remains unknown. In a major histocompatibility complex-mismatched model with cGVHD-like manifestations, we first examined B-lymphopenic µMT allo-BMT recipients and found that increased BAFF levels in cGVHD mice were not merely a reflection of B-cell number. Mice that later developed cGVHD had significantly increased numbers of recipient fibroblastic reticular cells with higher BAFF transcript levels. Increased BAFF production by donor cells also likely contributed to cGVHD, because BAFF transcript in CD4+ T cells from diseased mice and patients was increased. cGVHD manifestations in mice were associated with high BAFF/B-cell ratios and persistence of B-cell receptor (BCR)-activated B cells in peripheral blood and lesional tissue. By employing BAFF transgenic (Tg) mice donor cells, we addressed whether high BAFF contributed to BCR activation in cGVHD. BAFF increased NOTCH2 expression on B cells, augmenting BCR responsiveness to surrogate antigen and NOTCH ligand. BAFF Tg B cells had significantly increased protein levels of the proximal BCR signaling molecule SYK, and high SYK protein was maintained by BAFF after in vitro BCR activation or when alloantigen was present in vivo. Using T cell-depleted (BM only) BAFF Tg donors, we found that BAFF promoted cGVHD manifestations, circulating GL7+ B cells, and alloantibody production. We demonstrate that pathologic production of BAFF promotes an altered B-cell compartment and augments BCR responsiveness. Our findings compel studies of therapeutic targeting of BAFF and BCR pathways in patients with cGVHD.
Asunto(s)
Factor Activador de Células B/metabolismo , Trasplante de Médula Ósea/efectos adversos , Enfermedad Injerto contra Huésped/patología , Proteínas Proto-Oncogénicas c-bcr/metabolismo , Receptor Notch2/metabolismo , Quinasa Syk/metabolismo , Linfocitos T/inmunología , Animales , Factor Activador de Células B/genética , Femenino , Enfermedad Injerto contra Huésped/etiología , Enfermedad Injerto contra Huésped/metabolismo , Isoanticuerpos/inmunología , Isoantígenos/inmunología , Activación de Linfocitos/inmunología , Ratones , Ratones Endogámicos BALB C , Ratones Endogámicos C57BL , Proteínas Proto-Oncogénicas c-bcr/genética , Receptor Notch2/genética , Quinasa Syk/genética , Trasplante HomólogoRESUMEN
The infiltration of neutrophils in the epidermis and the release of neutrophil extracellular traps (NETs) are important events in the pathogenesis of psoriasis, but the regulatory roles and internal mechanism of NETs in psoriasis are largely unknown. Here, we demonstrate that NETs can activate the absent-in-melanoma-2 (AIM2) inflammasome in keratinocytes through the p38-MAPK signalling pathway, and targeting NETs with CI-amidine in vivo reduces AIM2 expression and ameliorates imiquimod-induced psoriasis-like phenotype in mice. Notably, NETs-activated AIM2 in keratinocytes not only promotes IL-1ß production through the classical inflammasome pathway but also promotes IFN-γ production via X-linked inhibitor of apoptosis protein (XIAP), thereby mediating the immune responses of keratinocytes. In conclusion, our study demonstrates that the NETs-AIM2 axis exerts multiple pro-inflammatory effects on keratinocytes and may serve as a potential target for psoriasis therapy.
Asunto(s)
Trampas Extracelulares , Melanoma , Psoriasis , Animales , Ratones , Trampas Extracelulares/metabolismo , Inflamasomas/metabolismo , Proteína Inhibidora de la Apoptosis Ligada a X/metabolismo , Proteína Inhibidora de la Apoptosis Ligada a X/farmacología , Queratinocitos/metabolismo , Psoriasis/metabolismo , Inflamación/metabolismo , Melanoma/metabolismo , Proteínas de Unión al ADNRESUMEN
Multiple myeloma (MM) remains an incurable disease and there is an unmet medical need for novel therapeutic drugs that do not share similar mechanisms of action with currently available agents. Sphingosine kinase 2 (SK2) is an innovative molecular target for anticancer therapy. We previously reported that treatment with SK2 inhibitor opaganib inhibited myeloma tumor growth in vitro and in vivo in a mouse xenograft model. In the current study, we performed a phase I study of opaganib in patients with relapsed/refractory multiple myeloma (RRMM). Thirteen patients with RRMM previously treated with immunomodulatory agents and proteasome inhibitors were enrolled and treated with single-agent opaganib at three oral dosing regimens (250 mg BID, 500 mg BID, or 750 mg BID, 28 days as a cycle). Safety and maximal tolerated dose (MTD) were determined. Pharmacokinetics, pharmacodynamics, and correlative studies were also performed. Opaganib was well tolerated up to a dose of 750 mg BID. The most common possibly related adverse event (AE) was decreased neutrophil counts. There were no serious AEs considered to be related to opaganib. MTD was determined as at least 750 mg BID. On an intent-to-treat basis, one patient (7.7%) in the 500 mg BID dose cohort showed a very good partial response, and one other patient (7.7%) achieved stable disease for 3 months. SK2 is an innovative molecular target for antimyeloma therapy. The first-in-class SK2 inhibitor opaganib is generally safe for administration to RRMM patients, and has potential therapeutic activity in these patients. Clinicaltrials.gov: NCT02757326.
Asunto(s)
Mieloma Múltiple , Humanos , Animales , Ratones , Mieloma Múltiple/tratamiento farmacológico , Mieloma Múltiple/patología , Fosfotransferasas (Aceptor de Grupo Alcohol)/uso terapéutico , Inhibidores de Proteasoma/uso terapéutico , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , DexametasonaRESUMEN
BACKGROUND: Invasive fungal infection (IFI) prophylaxis is recommended in patients with acute myeloid leukemia (AML) during induction chemotherapy. Posaconazole (POSA) is the recommended agent of choice; however, this medication can be associated with QTc prolongation, hepatotoxicity, and drug-drug interactions. Furthermore, there is conflicting evidence for the role of isavuconazole (ISAV) in this setting as an alternative to POSA. OBJECTIVE: The primary objective of this study was to evaluate the use of ISAV prophylaxis for primary IFI prevention in patients with AML undergoing induction. Additionally, the study investigated the use of ISAV trough concentration monitoring and compared these results to the efficacy of POSA therapeutic drug monitoring (TDM). Other secondary objectives included assessing the rates of toxicities associated with either prophylactic agent. This study analyzed the impact these toxicities had on patient outcomes by examining the need to hold or discontinue therapy. The final endpoint considered the efficacy associated with multiple dosing strategies employed at the study institution. Specifically, this included the use of loading doses or foregoing these when initiating prophylaxis. METHODS: This was a retrospective, single-center, cohort study. Patients included in this study were adults with AML admitted to Duke University Hospital between June 30, 2016 and June 30, 2021, who received induction chemotherapy and primary IFI prophylaxis for at least 7 days. Exclusion criteria included patients who received concomitant antifungal agents and patients who received antifungal agents as secondary prophylaxis. RESULTS: 241 patients met inclusion criteria with 12 (4.98%) participants in the ISAV group and 229 (95.02%) participants in the POSA group. The IFI incidence in the POSA group was 14.5%, while the ISAV group did not have any occurrences of IFI. No significant difference was found in the rate of IFI occurrence between the two treatment groups (p = 0.3805). Furthermore, it was demonstrated that the use of a loading dose when initiating prophylaxis could impact rates of IFI for this patient population. CONCLUSION: Due to no difference in incidence, patient specific factors such as concomitant medications and baseline QTc should influence the choice between prophylactic agent.
RESUMEN
INTRODUCTION: It has long been established that high-dose methotrexate is an essential part of therapy for primary central nervous system lymphoma. When regimens utilizing high-dose methotrexate were first studied, a dose of 8â g/m2 was used. More recently, reduced dosing strategies have been studied and adopted in attempts to reduce rates of adverse events. Studies utilizing 3.5â g/m2 of methotrexate have shown promising outcomes and improved rates of adverse events but there have never been any randomized head-to-head studies of differing dose levels of high-dose methotrexate. The purpose of this study was to compare efficacy and safety of different dosing strategies of high-dose methotrexate (HD-MTX) for primary central nervous system lymphoma (PCNSL). METHODS: This single center retrospective review was conducted between 07/01/2013 to 6/3/2020. The patient population was separated into two arms based upon dose of methotrexate. The high intensity (HiHD) arm was defined as patients who received doses > 3.5â g/m2, while the low intensity (LiHD) arm received ≤ 3.5â g/m2. The primary endpoint was overall response rate (ORR) and secondary endpoints include efficacy via 2-year overall survival (OS), progression to transplant, and utilization of consolidation or salvage therapy. Safety was assessed through monitoring of relevant laboratory studies. RESULTS: A total of 92 patients were included in this analysis. Baseline demographics were similar between groups, with the LiHD group trending toward older age. There were 78 patients eligible for assessment for ORR; there was no significant difference between the two groups (42.0% LiHD vs. 44.4% HiHD; p = 1.0). Rates of OS, progression to transplant and progression to consolidation chemotherapy were not different between groups. There were statistically significantly higher rates of renal and/or hepatic dysfunction with the first dose in the HiHD group compared with the LiHD group (11.5% LiHD vs. 64.3% HiHD; p ≤ 0.01). CONCLUSIONS: In this PCNSL patient cohort, there is no difference in terms of efficacy between HiHD LiHD methotrexate, but patients in the HiHD group had higher rates of renal and hepatic dysfunction. Limitations include small sample size and disparity between group sizes.
RESUMEN
BACKGROUND: Multiple digital data sources can capture moment-to-moment information to advance a robust understanding of opioid use disorder (OUD) behavior, ultimately creating a digital phenotype for each patient. This information can lead to individualized interventions to improve treatment for OUD. OBJECTIVE: The aim is to examine patient engagement with multiple digital phenotyping methods among patients receiving buprenorphine medication for OUD. METHODS: The study enrolled 65 patients receiving buprenorphine for OUD between June 2020 and January 2021 from 4 addiction medicine programs in an integrated health care delivery system in Northern California. Ecological momentary assessment (EMA), sensor data, and social media data were collected by smartphone, smartwatch, and social media platforms over a 12-week period. Primary engagement outcomes were meeting measures of minimum phone carry (≥8 hours per day) and watch wear (≥18 hours per day) criteria, EMA response rates, social media consent rate, and data sparsity. Descriptive analyses, bivariate, and trend tests were performed. RESULTS: The participants' average age was 37 years, 47% of them were female, and 71% of them were White. On average, participants met phone carrying criteria on 94% of study days, met watch wearing criteria on 74% of days, and wore the watch to sleep on 77% of days. The mean EMA response rate was 70%, declining from 83% to 56% from week 1 to week 12. Among participants with social media accounts, 88% of them consented to providing data; of them, 55% of Facebook, 54% of Instagram, and 57% of Twitter participants provided data. The amount of social media data available varied widely across participants. No differences by age, sex, race, or ethnicity were observed for any outcomes. CONCLUSIONS: To our knowledge, this is the first study to capture these 3 digital data sources in this clinical population. Our findings demonstrate that patients receiving buprenorphine treatment for OUD had generally high engagement with multiple digital phenotyping data sources, but this was more limited for the social media data. INTERNATIONAL REGISTERED REPORT IDENTIFIER (IRRID): RR2-10.3389/fpsyt.2022.871916.
Asunto(s)
Buprenorfina , Trastornos Relacionados con Opioides , Femenino , Humanos , Masculino , Participación del Paciente , Buprenorfina/uso terapéutico , Evaluación Ecológica Momentánea , Etnicidad , Trastornos Relacionados con Opioides/tratamiento farmacológicoRESUMEN
Sacbrood virus (SBV) is a significant problem that impedes brood development in both eastern and western honeybees. Whole-genome sequencing has become an important tool in researching population genetic variations. Numerous studies have been conducted using multiple techniques to suppress SBV infection in honeybees, but the genetic markers and molecular mechanisms underlying SBV resistance have not been identified. To explore single nucleotide polymorphisms (SNPs), insertions, deletions (Indels), and genes at the DNA level related to SBV resistance, we conducted whole-genome resequencing on 90 Apis cerana cerana larvae raised in vitro and challenged with SBV. After filtering, a total of 337.47 gigabytes of clean data and 31,000,613 high-quality SNP loci were detected in three populations. We used ten databases to annotate 9359 predicted genes. By combining population differentiation index (FST) and nucleotide polymorphisms (π), we examined genome variants between resistant (R) and susceptible (S) larvae, focusing on site integrity (INT < 0.5) and minor allele frequency (MAF < 0.05). A selective sweep analysis with the top 1% and top 5% was used to identify significant regions. Two SNPs on the 15th chromosome with GenBank KZ288474.1_322717 (Guanine > Cytosine) and KZ288479.1_95621 (Cytosine > Thiamine) were found to be significantly associated with SBV resistance based on their associated allele frequencies after SNP validation. Each SNP was authenticated in 926 and 1022 samples, respectively. The enrichment and functional annotation pathways from significantly predicted genes to SBV resistance revealed immune response processes, signal transduction mechanisms, endocytosis, peroxisomes, phagosomes, and regulation of autophagy, which may be significant in SBV resistance. This study presents novel and useful SNP molecular markers that can be utilized as assisted molecular markers to select honeybees resistant to SBV for breeding and that can be used as a biocontrol technique to protect honeybees from SBV.
Asunto(s)
Polimorfismo de Nucleótido Simple , Virus ARN , Abejas/genética , Animales , Larva/genética , Filogenia , Virus ARN/genéticaRESUMEN
Background: The feasibility of using laparoscopic proximal gastrectomy (LPG) for the treatment of proximal early gastric cancer (EGC) has not been addressed. This study aimed to comparatively evaluate the effects on LPG with piggyback jejunal interposition double-tract reconstruction (PJIDTR) versus laparoscopic total gastrectomy (LTG) with Roux-en-Y reconstruction (overlap method) using propensity score matching for proximal EGC. Materials and Methods: We examined the clinical outcomes of LPG with PJIDTR for proximal EGC. We retrospectively collected data from patients with proximal EGC who were treated at Shanxi Cancer Hospital between January 2012 and December 2015. The complication rate, nutritional indicators, reflux oesophagitis incidence and overall survival were compared between LTG and LPG with PJIDTR. Results: Of the 424 patients, 200 were excluded, and 50 of the remaining patients received LPG with PJIDTR. Fifty matched LTG patients were screened. The incidence of early complications was 14% in the LPG group and 16% in the LTG group (P > 0.05). At 1 year after surgery, nutrition indices in the LPG group were significantly better than those in the LTG group (P < 0.05). One year after surgery, the Visick score II rate was 2% and 4%, and the endoscopic oesophagitis rate was 4% and 6% in the LPG and LTG groups, respectively. No tumour recurrence was observed in either group. The 5-year overall survival rates of the two groups were 98% and 90% (P = 0.08). Conclusions: LPG with PJIDTR may be suitable for proximal EGC.
RESUMEN
BACKGROUND: Grazing disturbance plays an important role in the desert steppe ecosystem in Inner Mongolia, China. Previous studies found that grazing affected the spatial distribution of species in a community, and showed patchiness characteristics of species under different grazing treatments. Artemisia frigida is the dominant species and semi-shrub in desert steppe, and whether grazing interference will affect the spatial distribution of A. frigida is studied. In this study, geo-statistical methods were mainly used to study the spatial distribution characteristics of A. frigida population in desert steppe of Inner Mongolia at two scales (quadrat size 2.5 m × 2.5 m, 5 m × 5 m) and four stocking rates (control, CK, 0 sheep·ha-1·month-1; light grazing, LG, 0.15 sheep·ha-1·month-1, moderate grazing, MG, 0.30 sheep·ha-1·month-1, heavy grazing, HG, 0.45 sheep·ha-1·month-1). RESULTS: The results showed that the spatial distribution of A. frigida tended to be simplified with the increase of stocking rate, and tended to be banded with increased spatial scale. The density and height of A. frigida increased with increasing scale. With increased stocking rate, the density of A. frigida population decreased linearly, while its height decreased in a step-wise fashion. The spatial distribution of A. frigida was mainly affected by structural factors at different scales and stocking rate. The density of A. frigida was more sensitive to change in stocking rate, and the patchiness distribution of A. frigida was more obvious with increase in scale. CONCLUSIONS: Stocking rate has a strong regulatory effect on the spatial pattern of A. frigida population in the desert steppe. Heavy grazing reduced the spatial heterogeneity of A. frigida in the desert steppe. The smaller dominant populations are unfavourable for its survival in heavy grazing condition, and affects the stability and productivity of the grassland ecosystem.