Conventional vaccines are very efficient in the prevention of bacterial infections caused by extracellular pathogens due to effective stimulation of pathogen-specific antibodies. In contrast, ...considering that intracellular surveillance by antibodies is not possible, they are typically less effective in preventing or treating infections caused by intracellular pathogens such as
. The objective of the current study was to use so-called photochemical internalization (PCI) to deliver a live bacterial vaccine to the cytosol of antigen-presenting cells (APCs) for the purpose of stimulating major histocompatibility complex (MHC) I-restricted CD8 T-cell responses. For this purpose,
BCG (BCG) was combined with the photosensitiser tetraphenyl chlorine disulfonate (TPCS2a) and injected intradermally into mice. TPCS2a was then activated by illumination of the injection site with light of defined energy. Antigen-specific CD4 and CD8 T-cell responses were monitored in blood, spleen, and lymph nodes at different time points thereafter using flow cytometry, ELISA and ELISPOT. Finally, APCs were infected and PCI-treated
for analysis of their activation of T cells
or
after autologous vaccination of mice. Combination of BCG with PCI induced stronger BCG-specific CD4 and CD8 T-cell responses than treatment with BCG only or with BCG and TPCS2a without light. The overall T-cell responses were multifunctional as characterized by the production of IFN-γ, TNF-α, IL-2 and IL-17. Importantly, PCI induced cross-presentation of BCG proteins for stimulation of antigen-specific CD8 T-cells that were particularly producing IFN-γ and TNF-α. PCI further facilitated antigen presentation by causing up-regulation of MHC and co-stimulatory proteins on the surface of APCs as well as their production of TNF-α and IL-1β
. Furthermore, PCI-based vaccination also caused local inflammation at the site of vaccination, showing strong infiltration of immune cells, which could contribute to the stimulation of antigen-specific immune responses. This study is the first to demonstrate that a live microbial vaccine can be combined with a photochemical compound and light for cross presentation of antigens to CD8 T cells. Moreover, the results revealed that PCI treatment strongly improved the immunogenicity of
BCG.
Abstract
Importance: Children with hemiparesis experience limitations in activities of daily living (ADLs) as a result of upper limb impairments. To address these limitations, we developed a ...group-based Personalized Upper Limb Intensive Therapy (PULIT) program combining modified constraint-induced movement therapy, bimanual intensive therapy, and exergame-based robotics.
Objective: To determine the effectiveness of PULIT in helping children with upper limb impairments achieve individually set goals and enable transfer of the attained motor skills into ADLs.
Design: Retrospective analysis.
Setting: Day camp at a pediatric rehabilitation clinic in Switzerland.
Participants: Twenty-three children with upper limb impairment (unilateral cerebral palsy, n = 16; acquired brain injury, n = 7); 13 boys and 10 girls (M age = 7 yr, 8 mo, SD = 2 yr, 1 mo; Manual Ability Classification System Level I–IV).
Intervention: Thirty hours of PULIT over the course of 8 days.
Outcomes and Measures: Goal attainment scaling (GAS) was assessed on the first and last day of intervention. The Canadian Occupational Performance Measure (COPM) and dexterity tests, such as the Box and Block Test (BBT), were administered 3 wk before and 3 wk after the intervention.
Results: Total goal achievement was 85.7%. GAS, parent- and child-rated COPM Performance and Satisfaction, and the BBT of the affected and dominant upper limb improved significantly.
Conclusions and Relevance: PULIT effectively increases children’s dexterity of the impaired and dominant upper limb, improves ADL performance, and achieves individual goals. This retrospective analysis could serve as a basis for a future randomized trial.
What This Article Adds: This article informs occupational therapy practitioners about a therapy program that includes conventional and rehabilitation technology interventions and enables children with hemiparesis of the upper limb to improve relevant ADL tasks in 8 days’ time.
Abstract
Calcifying fibrous tumor (CFT) is a benign tumor entity which can present in a variety of different sites. Till date, eight cases with a mediastinal manifestation have been published in ...literature. Surgical removal is the treatment of choice for this often incidentally detected tumor. Surgery of thoracic CFT may be challenging due to its localization within the mediastinum. A 10-year old boy with a right-sided thoracic pectus carinatum-like deformity was referred for further evaluation, incidentally, revealing a mediastinal mass in computed tomography (CT). Laboratory results were all within normal range. Magnetic resonance imaging (MRI) showed a large tumor in the upper anterior mediastinum suggesting expansive but not infiltrative character. The tumor was displacing surrounding structures like the heart and the diaphragm. Lower venous stasis with dilation of the inferior cava vein could be demonstrated. The tumor was considered to be of benign dignity and surgical removal was indicated. Complete tumor resection could be achieved through a sternotomy approach, along with thymectomy. A partial resection of both the pericardium and diaphragm was required due to adhesion with soft tissue at those sites. The specimen's size was 320 mm × 145 mm × 100 mm, histologically confirmed as CFT. The patient showed no residual tumor at 3- and 9-month follow-up. This case is a report on a large mediastinal CFT which underwent successful complete surgical removal. Following tumor resection, prognosis is considered to be good; however, key issue is complete resection to avoid local tumor recurrence.
Importance: Children with hemiparesis experience limitations in activities of daily living (ADLs) as a result of upper limb impairments. To address these limitations, we developed a group-based ...Personalized Upper Limb Intensive Therapy (PULIT) program combining modified constraint-induced movement therapy, bimanual intensive therapy, and exergame-based robotics. Objective: To determine the effectiveness of PULIT in helping children with upper limb impairments achieve individually set goals and enable transfer of the attained motor skills into ADLs. Design: Retrospective analysis. Setting: Day camp at a pediatric rehabilitation clinic in Switzerland. Participants: Twenty-three children with upper limb impairment (unilateral cerebral palsy, n = 16; acquired brain injury, n = 7); 13 boys and 10 girls (M age = 7 yr, 8 mo, SD = 2 yr, 1 mo; Manual Ability Classification System Level I-IV). Intervention: Thirty hours of PULIT over the course of 8 days. Outcomes and Measures: Goal attainment scaling (GAS) was assessed on the first and last day of intervention. The Canadian Occupational Performance Measure (COPM) and dexterity tests, such as the Box and Block Test (BBT), were administered 3 wk before and 3 wk after the intervention. Results: Total goal achievement was 85.7%. GAS, parent- and child-rated COPM Performance and Satisfaction, and the BBT of the affected and dominant upper limb improved significantly. Conclusions and Relevance: PULIT effectively increases children's dexterity of the impaired and dominant upper limb, improves ADL performance, and achieves individual goals. This retrospective analysis could serve as a basis for a future randomized trial. What This Article Adds: This article informs occupational therapy practitioners about a therapy program that includes conventional and rehabilitation technology interventions and enables children with hemiparesis of the upper limb to improve relevant ADL tasks in 8 days' time.
Calcifying fibrous tumor (CFT) is a benign tumor entity which can present in a variety of different sites. Till date, eight cases with a mediastinal manifestation have been published in literature. ...Surgical removal is the treatment of choice for this often incidentally detected tumor. Surgery of thoracic CFT may be challenging due to its localization within the mediastinum. A 10-year old boy with a right-sided thoracic pectus carinatum-like deformity was referred for further evaluation, incidentally, revealing a mediastinal mass in computed tomography (CT). Laboratory results were all within normal range. Magnetic resonance imaging (MRI) showed a large tumor in the upper anterior mediastinum suggesting expansive but not infiltrative character. The tumor was displacing surrounding structures like the heart and the diaphragm. Lower venous stasis with dilation of the inferior cava vein could be demonstrated. The tumor was considered to be of benign dignity and surgical removal was indicated. Complete tumor resection could be achieved through a sternotomy approach, along with thymectomy. A partial resection of both the pericardium and diaphragm was required due to adhesion with soft tissue at those sites. The specimen's size was 320 mm × 145 mm × 100 mm, histologically confirmed as CFT. The patient showed no residual tumor at 3- and 9-month follow-up. This case is a report on a large mediastinal CFT which underwent successful complete surgical removal. Following tumor resection, prognosis is considered to be good; however, key issue is complete resection to avoid local tumor recurrence.
Many higher plants establish symbiotic relationships with arbuscular mycorrhizal (AM) fungi that improve their ability to acquire nutrients from the soil. In addition to establishing AM symbiosis, ...legumes also enter into a nitrogen-fixing symbiosis with bacteria known as rhizobia that results in the formation of root nodules. Several genes involved in the perception and transduction of bacterial symbiotic signals named “Nod factors” have been cloned recently in model legumes through forward genetic approaches. Among them, DMI3(Doesn't Make Infections 3) is a calcium- and calmodulin-dependent kinase required for the establishment of both nodulation and AM symbiosis. We have identified, by a yeast two-hybrid system, a novel protein interacting with DMI3 named IPD3 (Interacting Protein of DMI3). IPD3 is predicted to interact with DMI3 through a C-terminal coiled-coil domain. Chimeric IPD3GFP is localized to the nucleus of transformed Medicago truncatula root cells, in which split yellow fluorescent protein assays suggest that IPD3 and DMI3 physically interact in Nicotiana benthamiana. Like DMI3, IPD3 is extremely well conserved among the angiosperms and is absent from Arabidopsis. Despite this high level of conservation, none of the homologous proteins have a demonstrated biological or biochemical function. This work provides the first evidence of the involvement of IPD3 in a nuclear interaction with DMI3.
Tumor genomic instability and selective treatment pressures result in clonal disease evolution; molecular stratification for molecularly targeted drug administration requires repeated access to tumor ...DNA. We hypothesized that circulating plasma DNA (cpDNA) in advanced cancer patients is largely derived from tumor, has prognostic utility, and can be utilized for multiplex tumor mutation sequencing when repeat biopsy is not feasible. We utilized the Sequenom MassArray System and OncoCarta panel for somatic mutation profiling. Matched samples, acquired from the same patient but at different time points were evaluated; these comprised formalin-fixed paraffin-embedded (FFPE) archival tumor tissue (primary and/or metastatic) and cpDNA. The feasibility, sensitivity, and specificity of this high-throughput, multiplex mutation detection approach was tested utilizing specimens acquired from 105 patients with solid tumors referred for participation in Phase I trials of molecularly targeted drugs. The median cpDNA concentration was 17 ng/ml (range: 0.5-1600); this was 3-fold higher than in healthy volunteers. Moreover, higher cpDNA concentrations associated with worse overall survival; there was an overall survival (OS) hazard ratio of 2.4 (95% CI 1.4, 4.2) for each 10-fold increase in cpDNA concentration and in multivariate analyses, cpDNA concentration, albumin, and performance status remained independent predictors of OS. These data suggest that plasma DNA in these cancer patients is largely derived from tumor. We also observed high detection concordance for critical 'hot-spot' mutations (KRAS, BRAF, PIK3CA) in matched cpDNA and archival tumor tissue, and important differences between archival tumor and cpDNA. This multiplex sequencing assay can be utilized to detect somatic mutations from plasma in advanced cancer patients, when safe repeat tumor biopsy is not feasible and genomic analysis of archival tumor is deemed insufficient. Overall, circulating nucleic acid biomarker studies have clinically important multi-purpose utility in advanced cancer patients and further studies to pursue their incorporation into the standard of care are warranted.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Molibresib is an orally bioavailable, selective, small molecule BET protein inhibitor. Results from a first time in human study in solid tumors resulted in the selection of a 75 mg once daily dose of ...the besylate formulation of molibresib as the recommended Phase 2 dose (RP2D). Here we present the results of Part 2 of our study, investigating safety, pharmacokinetics, pharmacodynamics and clinical activity of molibresib at the RP2D for nuclear protein in testis carcinoma (NC), small cell lung cancer, castration‐resistant prostate cancer (CRPC), triple‐negative breast cancer, estrogen receptor‐positive breast cancer and gastrointestinal stromal tumor. The primary safety endpoints were incidence of adverse events (AEs) and serious AEs; the primary efficacy endpoint was overall response rate. Secondary endpoints included plasma concentrations and gene set enrichment analysis (GSEA). Molibresib 75 mg once daily demonstrated no unexpected toxicities. The most common treatment‐related AEs (any grade) were thrombocytopenia (64%), nausea (43%) and decreased appetite (37%); 83% of patients required dose interruptions and 29% required dose reductions due to AEs. Antitumor activity was observed in NC and CRPC (one confirmed partial response each, with observed reductions in tumor size), although predefined clinically meaningful response rates were not met for any tumor type. Total active moiety median plasma concentrations after single and repeated administration were similar across tumor cohorts. GSEA revealed that gene expression changes with molibresib varied by patient, response status and tumor type. Investigations into combinatorial approaches that use BET inhibition to eliminate resistance to other targeted therapies are warranted.
What's new?
Molibresib is a BET inhibitor currently being tested against various solid tumors. Part 1 of this study, published previously, established a recommended dosage in patients with nuclear protein in testis carcinoma. Here, the authors present part 2, reporting on the safety and efficacy of molibresib in a wider array of tumor types. While they found no unexpected toxicities, adverse events caused 83% of patients to pause treatment, and 29% to lower their dosage. Molibresib showed some anti‐tumor activity, although clinically meaningful response rates were not observed by the end of the trial.
This symposium is the third PSL (Paris Sciences & Lettres) Chemical Biology meeting (2016, 2019, 2023) held at Institut Curie. This initiative originally started at Institut de Chimie des Substances ...Naturelles (ICSN) in Gif‐sur‐Yvette (2013, 2014), under the directorship of Professor Max Malacria, with a strong focus on chemistry. It was then continued at the Institut Curie (2015) covering a larger scope, before becoming the official PSL Chemical Biology meeting. This latest edition was postponed twice for the reasons that we know. This has given us the opportunity to invite additional speakers of great standing. This year, Institut Curie hosted around 300 participants, including 220 on site and over 80 online. The pandemic has had, at least, the virtue of promoting online meetings, which we came to realize is not perfect but has its own merits. In particular, it enables those with restricted time and resources to take part in events and meetings, which can now accommodate unlimited participants. We apologize to all those who could not attend in person this time due to space limitation at Institut Curie.
Third time lucky: After having to be postponed twice, the third PSL Chemical Biology symposium meeting was held at the Institut Curie in Paris and also virtually on 12th and 13th January 2023. Chemical biology, the science of building molecular systems to investigate biology, delivers otherwise inaccessible knowledge and provides the means to control cellular processes with unique spatiotemporal resolution and efficacy.
PDF
