Adoptive T‐cell therapies have been successfully used as prophylaxis or treatment for immunocompromised patients at risk of viral infections or advanced cancers. Unfortunately, for some refractory ...cancers, they have failed. To overcome this, checkpoint inhibitors are used to rescue immune antitumor responses. We hypothesized that in vitro checkpoint blockade during T‐cell stimulation and expansion with messenger RNA (mRNA)–pulsed DCs may enhance the activity of antigen‐specific T cells and improve the efficacy of adoptive cellular therapy platforms. Human peripheral blood mononuclear cells were isolated from cytomegalovirus (CMV)‐seropositive donors to generate DCs. These were pulsed with CMV matrix phosphoprotein 65 (CMVpp65)‐mRNA to educate T cells in coculture for 15 days. Three checkpoint blockade conditions were evaluated (anti‐PD1, anti‐Tim3, and anti‐PD1 + Tim3). IL‐2 and antibodies blockades were added every 3 days. Immunophenotyping was performed on Day 0 and Day 15. Polyfunctional antigen‐specific responses were evaluated upon rechallenge with CMVpp65 peptides. CMVpp65‐activated CD8+ T cells upregulate Lag3 and Tim3 (P ≤ 0.0001). Tim3 antibody blockade alone or in combination led to a significant upregulation of Lag3 expression on CD8+ pp65Tetramer+ central memory, effector memory, and terminal effector memory cells re‐expressing RA (TEMRA) T cells. This latter T‐cell subset uniquely maintains double‐positive Tim3/Lag3 expression after checkpoint blockade. By contrast, PD1 blockade had minimal effects on Tim3 or Lag3 expression. In addition, IFN‐γ secretion was reduced in T cells treated with Tim3 blockade in a dose‐dependent manner (P = 0.004). In this study, we have identified a potential activating component of Tim3 and linkage between Tim3 and Lag3 signaling upon blocking the Tim3 axis during T‐cell–antigen‐presenting cell interactions that should be considered when targeting immune checkpoints for clinical use.
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FZAB, GIS, IJS, KILJ, NLZOH, NUK, OILJ, SAZU, SBCE, SBMB, UL, UM, UPUK
We understand only a small fraction of the events happening in our brains; therefore, despite all the progress made thus far, a whole array of questions remains. Nonetheless, neurosurgeons invented ...new tools to circumvent the challenges that had plagued their predecessors. With the manufacturing boom of the 20th century, technological innovations blossomed enabling the neuroscientific community to study and operate upon the living brain in finer detail and with greater precision while avoiding harm to the nervous system. The purpose of this chronological review is to 1) raise awareness among future neurosurgeons about the latest advances in the field, 2) become familiar with innovations such as augmented reality (AR) that should be included in education given their ready applicability in surgical training, and 3) be comfortable with customizing these technologies to real-life cases like in the case of mixed reality.
In the last decades big data has facilitating and improving our daily duties in the medical research and clinical fields; the strategy to get to this point is understanding how to organize and ...analyze the data in order to accomplish the final goal that is improving healthcare system, in terms of cost and benefits, quality of life and outcome patient. The main objective of this review is to illustrate the state-of-art of big data in healthcare, its features and architecture. We also would like to demonstrate the different application and principal mechanisms of big data in the latest technologies known as blockchain and artificial intelligence, recognizing their benefits and limitations. Perhaps, medical education and digital anatomy are unexplored fields that might be profitable to investigate as we are proposing. The healthcare system can be revolutionized using these different technologies. Thus, we are explaining the basis of these systems focused to the medical arena in order to encourage medical doctors, nurses, biotechnologies and other healthcare professions to be involved and create a more efficient and efficacy system.
OBJECTIVE The expanded endonasal endoscopic transsphenoidal approach has become increasingly used for craniopharyngioma surgery in the pediatric population, but questions still persist regarding its ...utility in younger children, in recurrent and irradiated tumors, and in masses primarily located in the suprasellar region. The narrow corridor, incomplete pneumatization, and fear of hypothalamic injury have traditionally relegated this approach to application in older children with mostly cystic craniopharyngiomas centered in the sella. The authors present a series of consecutive pediatric patients in whom the endonasal endoscopic approach was used to remove craniopharyngiomas from patients of varied ages, regardless of the location of the tumor and previous treatments or surgeries, to ascertain if the traditional concerns about limitations of this approach are worth reevaluating METHODS Eleven consecutive pediatric patients (age ≤ 18 years) underwent surgery via an endoscopic transsphenoidal approach at NewYork-Presbyterian/Weill Cornell Medical Center from 2007 to 2016. The authors recorded the location, consistency, and size of the lesion, assessed for hypothalamic invasion radiographically, calculated skull base measurements, and assessed parameters such as extent of resection, visual function, endocrinological function, weight gain, and return-to-school status. RESULTS The average age at the time of surgery was 7.9 years (range 4-17 years) and the tumor sizes ranged from 1.3 to 41.7 cm
. Five cases were purely suprasellar, 5 had solid components, 4 were reoperations, and 5 had a conchal sphenoid aeration. Nevertheless, gross-total resection was achieved in 45% of the patients and 50% of those in whom it was the goal of surgery, without any correlation with the location, tumor consistency, or the age of the patient. Near-total resection, subtotal resection, or biopsy was performed intentionally in the remaining patients to avoid hypothalamic injury. Anterior pituitary dysfunction occurred in 81.8% of the patients, and 63.3% developed diabetes insipidus . Two patients (18%) had a greater than 9% increase in body mass index. Visual function was stable or improved in 73%. All children returned to an academic environment, with 10 of them in the grade appropriate for their age. There was a single case of each of the following: CSF leak, loss of vision unilaterally, and abscess. CONCLUSIONS The endoscopic transsphenoidal approach is suitable for removing pediatric craniopharyngiomas even in young children with suprasellar tumors, conchal sphenoid sinus, recurrent tumors, and tumors with solid components. The extent of resection is dictated by intrinsic hypothalamic tumor invasiveness rather than the approach. The endoscopic transsphenoidal approach affords the ability to directly inspect the hypothalamus to determine invasion, which may help spare the patient from hypothalamic injury. Irrespective of approach, the rates of postoperative endocrinopathy remain high and the learning curve for the approach to a relatively rare tumor is steep.
Despite advancements in the successful use of immunotherapy in treating a variety of solid tumors, applications in treating brain tumors have lagged considerably. This is due, at least in part, to ...the lack of well-characterized antigens expressed within brain tumors that can mediate tumor rejection; the low mutational burden of these tumors that limits the abundance of targetable neoantigens; and the immunologically "cold" tumor microenvironment that hampers the generation of sustained and productive immunologic responses. The field of mRNA-based therapeutics has experienced a boon following the universal approval of COVID-19 mRNA vaccines. mRNA-based immunotherapeutics have also garnered widespread interest for their potential to revolutionize cancer treatment. In this study, we developed a novel and scalable approach for the production of personalized mRNA-based therapeutics that target multiple tumor rejection antigens in a single therapy for the treatment of refractory brain tumors.
Tumor-specific neoantigens and aberrantly overexpressed tumor-associated antigens were identified for glioblastoma and medulloblastoma tumors using our cancer immunogenomics pipeline called Open Reading Frame Antigen Network (O.R.A.N). Personalized tumor antigen-specific mRNA vaccine was developed for each individual tumor model using selective gene capture and enrichment strategy. The immunogenicity and efficacy of the personalized mRNA vaccines was evaluated in combination with anti-PD-1 immune checkpoint blockade therapy or adoptive cellular therapy with ex vivo expanded tumor antigen-specific lymphocytes in highly aggressive murine GBM models.
Our results demonstrate the effectiveness of the antigen-specific mRNA vaccines in eliciting robust anti-tumor immune responses in GBM hosts. Our findings substantiate an increase in tumor-infiltrating lymphocytes characterized by enhanced effector function, both intratumorally and systemically, after antigen-specific mRNA-directed immunotherapy, resulting in a favorable shift in the tumor microenvironment from immunologically cold to hot. Capacity to generate personalized mRNA vaccines targeting human GBM antigens was also demonstrated.
We have established a personalized and customizable mRNA-therapeutic approach that effectively targets a plurality of tumor antigens and demonstrated potent anti-tumor response in preclinical brain tumor models. This platform mRNA technology uniquely addresses the challenge of tumor heterogeneity and low antigen burden, two key deficiencies in targeting the classically immunotherapy-resistant CNS malignancies, and possibly other cold tumor types.
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IZUM, KILJ, NUK, PILJ, PNG, SAZU, UL, UM, UPUK
The art of surgery is becoming increasingly complex and dependent on scopes, screens, and technology, inviting a complex learning curve and development of hand-eye coordination and dexterity among ...other skills. We introduce an affordable, do-it-yourself microsurgical simulator that can be set up using a smartphone and a pair of reflective prism glasses. The glasses employ periscopic prisms on either side that reflect light perpendicularly. When the visual input is combined with the magnification of a smartphone camera, a real-time microsurgical experience can be simulated.
We analyzed the performance of 2 trainee residents in performing their first 5 successful sutures with 5-0 polypropylene thread on the cut ends of a glove over the course of 3 months. The module was also assessed in a survey at an international conference of neurosurgeons.
A significant improvement was observed in both residents at the end of each month versus baseline (P < 0.05). Of 27 survey participants, 3 (11%) reported access to a training laboratory in their institute. The module was rated 4/5 in terms of hand-eye coordination, 3.5/5 in management of microsurgical field, and 3.5/5 in depth perception.
The microsurgical simulation technique proved to be useful in performing complex microsurgical tasks. A significant improvement in microsurgical skills was observed among our trainees. The cost of building the module can be as low as U.S. $5. We endorse the use of this technique for resident training and skill development, especially in resource-challenged environments.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
The promising outcomes of chimeric antigen receptor (CAR) T cell therapy in hematologic malignancies potentiates its capability in the fight against many cancers. Nevertheless, this immunotherapy ...modality needs significant improvements for the treatment of solid tumors. Researchers have incrementally identified limitations and constantly pursued better CAR designs. However, even if CAR T cells are armed with optimal killer functions, they must overcome and survive suppressive barriers imposed by the tumor microenvironment (TME). In this review, we will discuss in detail the important role of TME in CAR T cell trafficking and how the intrinsic barriers contribute to an immunosuppressive phenotype and cancer progression. It is of critical importance that preclinical models can closely recapitulate the in vivo TME to better predict CAR T activity. Animal models have contributed immensely to our understanding of human diseases, but the intensive care for the animals and unreliable representation of human biology suggest in vivo models cannot be the sole approach to CAR T cell therapy. On the other hand, in vitro models for CAR T cytotoxic assessment offer valuable insights to mechanistic studies at the single cell level, but they often lack in vivo complexities, inter-individual heterogeneity, or physiologically relevant spatial dimension. Understanding the advantages and limitations of preclinical models and their applications would enable more reliable prediction of better clinical outcomes.
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IZUM, KILJ, NUK, PILJ, PNG, SAZU, UL, UM, UPUK
The COVID-19 pandemic has caused about seven million deaths worldwide. Preventative vaccines have been developed including Spike gp mRNA-based vaccines that provide protection to immunocompetent ...patients. However, patients with primary immunodeficiencies, patients with cancer, or hematopoietic stem cell transplant recipients are not able to mount robust immune responses against current vaccine approaches. We propose to target structural SARS-CoV-2 antigens (i.e., Spike gp, Membrane, Nucleocapsid, and Envelope) using circulating human antigen-presenting cells electroporated with full length SARS-CoV-2 structural protein-encoding mRNAs to activate and expand specific T cells. Based on the Th1-type cytokine and cytolytic enzyme secretion upon antigen rechallenge, we were able to generate SARS-CoV-2 specific T cells in up to 70% of unexposed unvaccinated healthy donors (HDs) after 3 subsequent stimulations and in 100% of recovered patients (RPs) after 2 stimulations. By means of SARS-CoV-2 specific TCRβ repertoire analysis, T cells specific to Spike gp-derived hypomutated regions were identified in HDs and RPs despite viral genomic evolution. Hence, we demonstrated that SARS-CoV-2 mRNA-loaded antigen-presenting cells are effective activating and expanding COVID19-specific T cells. This approach represents an alternative to patients who are not able to mount adaptive immune responses to current COVID-19 vaccines with potential protection across new variants that have conserved genetic regions.
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In this study, Ogando-Rivas and colleagues generated SARS-CoV-2 specific T cells using human APCs transduced with full length structural antigen encoding mRNAs. The manufactured T cells also recognized immunogenic hypomutated regions within the Spike gp in healthy donors and COVID-19 recovered donors, suggesting protection against ancient and new variants.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
Abstract
BACKGROUND
Identifying tumor rejection antigens remains a major barrier to developing effective antigen-directed immunotherapeutics and their application to pediatric brain tumors. Recent ...progress in the field of cancer immunogenomics has facilitated the search for tumor-specific antigens by applying comprehensive cancer genomics to tumor antigen discovery. Using a custom antigen prediction pipeline, we performed in silico antigen prediction across a broad array of antigen classes including neoantigens, tumor-associated antigens (TAAs), and fusion proteins for human and murine medulloblastoma tumors. We generated antigen-specific T-cells and validated the antigen-mediated immune responses for the development of precision adoptive cellular therapy.
METHODS
We evaluated WES and RNA-seq data from 170 medulloblastoma patients available through ICGC and performed a comprehensive immunogenomic analysis of subgroup-specific transcription profiles to identify candidate antigen targets. Antigen-specific T-cells were generated from healthy donor PBMCs stimulated against commonly recurring neoantigens and TAAs and immune response was evaluated using IFNγ secretion. Furthermore, we performed tumor antigen discovery for preclinical medulloblastoma models Ptch1 (sonic hedgehog driven) and NSC (Group 3 MYC-driven) and validated the antigen-mediated immune responses of ex vivo expanded antigen-specific T-cells.
RESULTS
Antigen prediction analysis revealed most tumors expressed a higher proportion of immunogenic TAAs than neoantigens and fusion proteins. The neoantigens and TAAs evaluated in this study showed significantly higher IFN-γ secretion in an antigen-dependent manner for both the human and murine platform validation. We thus confirmed the capability to produce functional tumor antigen-specific T-cells that can be leveraged into adoptive cellular therapy for the treatment of medulloblastoma.
CONCLUSION
Medulloblastomas are immunologically heterogeneous, and identifying potential tumor rejection antigens is desirable to develop personalized immunotherapies for the patients. Using a custom antigen prediction and ex vivo antigen-specific T-cell expansion pipeline, we identified potential tumor rejection antigens with important implications for the development of antigen-directed cellular therapies.
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