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Resumen Introducción: El estado epiléptico refractario (EER) constituye una emergencia médica grave, donde la crisis no cede a pesar del tratamiento farmacológico convencional. Se describe como estado epiléptico superrefractario (EESR) la continua presencia de episodios con una duración de 24 horas o más. Este reporte de caso detalla la complejidad en el manejo y explora un enfoque multidisciplinario. Presentación del caso: Paciente masculino de 32 años con antecedente de epilepsia focal secundaria a traumatismo craneoencefálico en la niñez, quien ingresó en contexto de EESR, el cual recibió coma barbitúrico, plasmaféresis y dieta cetogénica. En los exámenes, la resonancia magnética reveló una lesión en la región frontotemporal insular derecha; en la tomografía por emisión de positrones se observaron zonas de hipermetabolismo y en el videoelectroencefalograma una continua actividad epileptiforme. Se optó por la cirugía paliativa, logrando la resolución exitosa del EESR y una clasificación Engels IA a los 14 meses. Discusión: El EESR es un evento neurológico crítico con pronóstico reservado y opciones terapéuticas desafiantes. Se describen opciones terapéuticas desde anticonvulsivantes, inmunoterapia y cirugía, donde el abordaje quirúrgico emerge como una opción eficaz, especialmente en casos con lesiones estructurales. La identificación temprana y la terapia adecuada son vitales para prevenir complicaciones. Conclusiones: El EESR representa un desafío crítico con alta carga de morbimortalidad, sin embargo, la cirugía de epilepsia muestra promisorios resultados en el contexto de causa cerebral estructural, responsable de la actividad epileptiforme. Se destaca la importancia de la identificación temprana y el manejo quirúrgico paliativo como opción viable, mejorando la calidad de vida de los pacientes.
Abstract Introduction: Refractory Status Epilepticus (RSE) is a serious medical emergency where the seizure does not subside despite conventional pharmacological treatment. The continuous presence of episodes lasting 24 hours or more is described as super-refractory status epilepticus (SRSE). This case report details the complex in teraphy management and explores a multidisciplinary approach. Case presentation: A 32-year-old male with a history of focal epilepsy secondary to head trauma in childhood. Enters emergency with a RSE episode. Barbiturate coma, plasmapheresis and ketogenic diet were administered. The Magnetic Resonance Imaging revealed a lesion in the right fronto-temporo-insular cortex, areas of hypermetabolism on Positron Emission Tomography and continuous epileptiform activity on video-electroencephalogram. Palliative surgery was chosen, achieving successful resolution of the SRSE and Engel Scale IA classification at 14 months of follow up. Discussion: The SRSE is a critical neurological event with a guarded prognosis and complex therapeutic options. Therapeutic options are described from anticonvulsants, immunotherapy and surgery. The surgical approach emerges as an effective option, especially in cases with structural injuries. Early identification and appropriate therapy are vital to prevent complications. Conclusions: SRSE represents a critical challenge with a high burden of morbidity and mortality. However, epilepsy surgery shows promising results in the context of the structural brain cause responsible for epileptiform activity. The importance of early identification and palliative surgical management as a viable option is highlighted, improving the quality of life of patients.
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Leprosy is a chronic granulomatous disease caused by mycobacterium leprae. As a result of immunological alterations evoked by organism, patients suffer from acute inflammatory episodes known as leprosy reactions, which can continue to occur before, during and after stoppage of therapy and are a cause of concern for the resulting morbidity. Understanding the beneficial effects of immunotherapy with chemotherapy will help in reducing reactions as well the duration of treatment. Five untreated patients of middle age with MI=0 was enrolled in our study who were presented with lepra reactions started on Multi-drug therapy (MDT) and then sent for BCG vaccination. Patients were evaluated monthly for clinical improvement 60% of patients showed improvement within 3 to 4 months whereas 40% patient showed improvement in 7 to 8 months of immunotherapy. Despite of available effective MDT, persisting viable organisms as well as persisting clinical activity are significant problems in leprosy patients. Immunotherapy combined with chemotherapy is good and more promising options to overcome these problems.
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A systematic review of published articles based on randomized clinical trials was conducted to ascertain the efficacy or perspective of using CAR-T cell therapy for refractory multiple myeloma. The PubMed database was searched with the combination of terms "multiple myeloma", "refractory multiple myeloma", "CAR T-cell", and the PRISMA criteria were followed. Of the 78 articles found, only 5 were selected. The studies used different treatment protocols and four different types of CAR-T cells. All studies obtained interesting results in terms of increased progression-free survival and negative minimal residual disease responses. Some authors detected an expansion of CAR-T cells and noted dose-dependent relationship between treatment effectiveness and serum BCMA levels. Although the results were promising, a small number of patients still relapsed a few months after CAR-T cell infusion. Therefore, this new line of therapy should be further investigated, as it significantly increases progression-free survival and improves quality of life.
Uma revisão sistemática de artigos publicados com base em ensaios clínicos randomizados foi realizada para verificar a eficácia ou perspectiva do uso da terapia com células CAR-T para mieloma múltiplo refratário. Foi pesquisada a base de dados PubMed com a combinação dos termos "multiple myeloma", "refratory multiple myeloma", "CAR T-cell" e foram seguidos os critérios PRISMA. Dos 78 artigos encontrados, apenas 5 foram selecionados. Os estudos utilizaram diferentes protocolos de tratamento e quatro tipos diferentes de células CAR-T. Todos os estudos obtiveram resultados interessantes em termos de aumento da sobrevida livre de progressão e respostas negativas à doença residual mínima. Alguns autores detectaram uma expansão das células CAR-T e observaram uma relação dose-dependente entre a eficácia do tratamento e os níveis séricos de BCMA. Embora os resultados tenham sido promissores, um pequeno número de pacientes ainda apresentou recaída alguns meses após a infusão de células CAR-T. Portanto, esta nova linha de terapia deve ser mais investigada, pois aumenta significativamente a sobrevida livre de progressão e melhora a qualidade de vida.
Subject(s)
Multiple Myeloma , NeoplasmsABSTRACT
Autoimmune encephalitis has been an emerging disease in the pediatric age group for the last few years. It is of utmost importance to recognize the disease for the timely initiation of immunotherapy. The antibody-mediated encephalitis should be considered in the differentials apart from vasculitic, metabolic encephalopathy after ruling out bacterial, viral, tubercular, parasitic, and rickettsial causes. It can even coexist with herpes encephalitis in a quarter of the cases. The prodromal symptoms and progression to psychiatric, memory, speech disturbance, movement disorder, altered mental status, dysautonomia, and seizures within a span of a month characterize the disease. The approach to diagnosis involves various antibody testing in serum and cerebrospinal fluid along with brain imaging and electroencephalography. Early treatment with steroids, intravenous immunoglobulin, and plasmapheresis leads to better outcomes. A literature search was made using keywords in the Google Scholar and Pubmed databases before January 2024. The collected materials were reviewed for appropriate titles and content focusing on diagnosis and management. The article aims to provide a comprehensive review regarding the differential diagnosis and management of autoimmune encephalitis in children.
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Introduction Dendritic cell (DC) vaccines have demonstrated good efficacy in preventing relapse and in increasing survival of patients affected by a variety of both solid and hematological tumors. Most protocols used to generate these cells involve the automated separation of peripheral blood monocytes from patients. This approach requires specialized equipment, which elevates the cost of this type of therapy, potentially limiting the widespread access to patients. Method: In this study, we compare the yield and quality of dendritic cells generated from monocytes and isolated by an automated method or by manual methods using gradient centrifugation. Results The results demonstrate the equivalence of the 3 methods in relation to the yield and final quality of the product, however with considerable differences between the costs of these procedures. In addition, this study also demonstrates the feasibility of the antigenic pulse with autologous tumor cell lysates, constituting a source of antigens, not only easily obtained and manipulated, but also specific to the patient's tumor. Conclusion These findings may have important implications for emerging centers interested in using this medical approach and potentially increase the access of a greater number of patients to this therapeutic option.
Subject(s)
Dendritic Cells , Vaccines , Cell Culture Techniques , ImmunotherapyABSTRACT
Abstract Introduction Chimeric Antigen Receptor (CAR) T cells have tremendous potentials for cancer treatment; however, various challenges impede their universal use. These restrictions include the poor function of T cells in tumor microenvironments, the shortage of tumor-specific antigens and, finally, the high cost and time-consuming process, as well as the poor scalability of the method. Creative gene-editing tools have addressed each of these limitations and introduced next generation products for cell therapy. The clustered regularly interspaced short palindromic repeats-associated endonuclease 9 (CRISPR/Cas9) system has triggered a revolution in biology fields, as it has a great capacity for genetic manipulation. Method In this review, we considered the latest development of CRISPR/Cas9 methods for the chimeric antigen receptor T cell (CAR T)-based immunotherapy. Results The ability of the CRISPR/Cas9 system to generate the universal CAR T cells and also potent T cells that are persistent against exhaustion and inhibition was explored. Conclusion: We explained CRISPR delivery methods, as well as addressing safety concerns related to the use of the CRISPR/Cas9 system and their potential solutions.
Subject(s)
Neoplasms , Genetic Therapy , Immunotherapy, Adoptive , Clustered Regularly Interspaced Short Palindromic Repeats , Receptors, Chimeric AntigenABSTRACT
Objective: In this study, albino mice were injected with a sub-lethal dosage of purified wasp Ropalidia Marginata venom toxins to assess the effectiveness of polyclonal anti-venom antibodies.Methods: To neutralize the toxic effects, polyclonal antibodies were generated by immunizing albino mice. The antibody underwent partial purification using ammonium sulphate treatment and octanoic acid precipitation. To detect the presence of antibodies in the antiserum, an immunodouble diffusion test was conducted using Ouchterlony's method (1962). This involved allowing both antigens and antibodies to diffuse radially towards each other from their respective wells. When they reached an equivalence zone, a precipitation complex of antigen and antibody became visible as a concentric band, indicating the development of the combination. To quantitatively determine the amount of antibodies in the antiserum, the equivalency zone approach was used.Results: Experimental mice were injected with a combination containing 400, 800, and 1200 µg of pure antibody, which had been treated serum biomolecules, including metabolic enzymes, completely reversed in the experimental with 40% of the LD50 of wasp venom the elevated serum parameters were glucose, pyruvic acid, lipid, protein and free amino acid, reached to normal (100%) in the treated with 40% of LD50 of the venom and polyclonal treated after 6 h of administration. Anti-serum treatment also successfully normalized the alteration in serum enzyme just after 4h.Similarly, anti-serum treatment also successfully normalized the alteration in serum enzyme just after 4h treated with 40% of LD50 of the venom. Serum ACP content was obtained as 125.35% after 40% of LD50 venom injection, which was get normalized up to 102.81% after 4 h of the anti-venom treatment. Serum ALP content of 114.8% elevation was reversed back to 102.40% after anti-venom treatment. The GPT level significantly reversed up to 102.5%, while it was 130% in the venom-treated mice. A complete reversal was obtained in GPT level, which was obtained as 104.54% in the venom-treated animal. Similarly, LDH which was elevated up to 112.45 % in venom-injected mice was successfully reversed up to 100.25% after anti-venom treatment. Similarly, Ache concentration was fully recovered after anti-venom treatment 6 h, all animals (group B-E) that had received 40% of the LD50 of venom treated with pure antiserum.Conclusion: The venom-injected group showed a complete restoration of serum protein, free amino acid, uric acid, cholesterol, pyruvic acid, total lipid, and glucose level in experimental mice.
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Se presenta el caso clínico de un paciente de 37 años de edad con el antecedente de haber recibido radioterapia por una lesión tumoral en la región frontal derecha, el cual acudió a consulta en el Instituto de Neurología y Neurocirugía de Cuba por presentar cefalea intensa y hemiparesia izquierda. Luego de realizados los exámenes necesarios, se estableció el diagnóstico clínico-imagenológico de lesión por radionecrosis en el hemisferio contralateral, que fue corroborado en el estudio anatomopatológico una vez que se extirpó el tumor; seguidamente, se indicó inmunoterapia. La evolución del paciente fue satisfactoria, pues se logró el control de la enfermedad y la resolución de los síntomas.
The case report of a 37-year-old patient with history of having received radiotherapy due to a tumor lesion in the right frontal region is presented, who attended to the Institute of Neurology and Neurosurgery in Cuba because of intense headache and left hemiparesis. After carrying out the necessary examinations, the clinical-imaging diagnosis of a radionecrosis lesion in the contralateral hemisphere was established, which was corroborated in the pathological examination once the tumor was removed; then, immunotherapy was indicated. The patient had a favorable clinical course because the control of the disease was achieved as well as the resolution of symptoms.
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Tuberculosis (TB), caused by Mycobacterium tuberculosis, remains the leading cause of mortality by a single infectious agent in the world. M. tuberculosis infection could also result in clinical chronic infection, known as latent TB infection (LTBI). Compared to the current limited treatment, several subunit vaccines showed immunotherapeutic effects and were included in clinical trials. In this study, a subunit vaccine of Ag85B with a novel mucosal adjuvant c-di-AMP (Ag85B:c-di-AMP) was delivered intranasally to a persistent M. tuberculosis H37Ra infection mouse model, which also presented the asymptomatic characteristics of LTBI. Compared with Ag85B immunization, Ag85B:c-di-AMP vaccination induced stronger humoral immune responses, significantly higher CD4+ T cells recruitment, enhanced Th1/Th2/Th17 profile response in the lung, decreased pathological lesions of the lung, and reduced M. tuberculosis load in mice. Taken together, Ag85B:c-di-AMP mucosal route immunization provided an immunotherapeutic effect on persistent M. tuberculosis H37Ra infection, and c-di-AMP, as a promising potential mucosal adjuvant, could be further used in therapeutic or prophylactic vaccine strategies for persistent M. tuberculosis infection as well as LTBI.
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@#Objective To construct a yeast two-hybrid recombinant bait plasmid of human programmed cell death ligand 1(PD-L1)immunoglobulin variable region(IgV)domain gene,detect its expression in yeast and detect the cytotoxicity and self-activation of PD-L1 IgV protein as well as the interaction between PD-L1 IgV and human thioredoxin(hTrx).Methods Human PD-L1 was analyzed by bioinformatics method,and primers were designed to amplify PD-L1 IgV domain based on the coding region of PD-L1 gene registered in NCBI GenBank database. PCR amplification was carried out with pENTERPD-L1 plasmid as template,and then cloned into yeast two-hybrid bait vector pGBKT7. The recombinant bait plasmid and pGBKT7 empty vector were transformed into Y2HGold yeast cells respectively,and the PD-L1 IgV gene and its expression were detected by PCR and Western blot;Meanwhile,the protein toxicity and self-activation of PD-L1 IgV were detected,and the interaction between PD-L1 IgV and hTrx was detected by drip plate method.Results The bioinformatics analysis results of PD-L1 were consistent with related reports. The recombinant bait plasmid pGBKT7-PD-L1 IgV was correctly constructed,and Y2HGold positive clone was obtained,in which PD-L1 IgV was stably expressed. The empty vector pGBKT7 and recombinant bait plasmid pGBKT7-PD-L1 IgV grew well on SD/-Trp and SD/-Trp/X-α-Gal plates with the same colony size and number and white colony,but they did not grow on SD/-Trp/X-α-Gal/AbA plates,which indicated that PD-L1 IgV protein had no toxicity and no self-activation effect on yeast. The results of drip plates test showed that all experimental groups grew well on SD/-Trp/-Leu plate,while only positive control group grew on SD/-Trp/-Leu/X-α-Gal/AbA plate and showed blue color,which indicated that bait protein PD-L1 IgV and hTrx did not self-activate,and there was no interaction between them.Conclusion Recombinant human PD-L1 IgV bait plasmid was successfully constructed. PD-L1 IgV protein showed no toxicity and self-activation effect on yeast cells,and there was no interaction between PD-L1 IgV and hTrx. Subsequently,hTrx can be used to construct a peptide aptamer library,from which peptide aptamers that specifically bind to PD-L1 IgV can be screened.
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@#Epigenetic modification plays an important role in the biological regulatory process of eukaryotic cells. Tumor immunotherapy is an important means and clinical strategy for the treatment of some cancers. 5-Methylcytosine (m5C) is an important component of the epigenetic regulatory network discovered after m6A and has become a new topic for life science research in recent years. The m5C methylation of RNA can affect the fate of the modified RNA molecules and play an important role in various biological processes, including RNA stability, protein synthesis and transcriptional regulation. Recent studies have shown that m5C writers, erasers and readers are related to a variety of cellular biological processes and systemic diseases, including the occurrence, metastasis and tumor immune microenvironment. m5C methylation can widely affect gene expression and the biological process of tumorigenesis and development at multiple levels, but its specific mechanism and potential interaction with other epigenetic modifications in tumor immunotherapy are still unclear, and its regulatory mechanism, risk assessment and role in targeted therapy for malignant tumors need to be further studied. This article will review the dynamic regulatory network of m5C, the biological role of m5C modification in solid tumors and potential targets in tumor immunotherapy.
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T cell dysfunction is a common feature in patients with acute myeloid leukemia (AML). The up-regulation of immune checkpoint (IC) proteins resulting in T cell exhaustion is a key reason for T cell dysfunction. Immunotherapy with IC inhibitors exerts a remarkable effect on AML. However, due to the heterogeneity of T cell exhaustion and other factors that impair T cell function in patients with AML, the optimization of targeted T cell immunotherapy strategy for AML might be based on the multidimensional investigation of immune deficiency with different T cell subtypes.
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Gastric cancer (GC) is a common malignant tumor of the digestive tract in China. It is characterized by high morbidity, mortality, and proportion of patients in advanced stages. In the past years, chemotherapy was used as the main treatment for GC. Subsequently, targeted therapy with trastuzumab was approved to treat HER2-positive GC. However, the progress of drug development and clinical studies has been limited by the high heterogeneity of GC. In recent years, research on immunotherapy and new targets for therapeutic exploration in GC has made great strides. Herein, we provide a brief review of the progress of the research on targeted therapy and immunotherapy for GC.
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The vast majority of thyroid cancers show a good prognosis. However, the treatment of locally advanced thyroid cancer presents a huge problem. The wide application of targeted and immunotherapy in neoadjuvant therapy for locally advanced thyroid cancer has become a new therapeutic direction. This article summarizes the research on neoadjuvant chemotherapy, radiotherapy, and targeted therapy and immunotherapy related to various pathological types of thyroid cancer, with a focus on the recent advancements and thoughts on the application of targeted and immunotherapeutic drugs in neoadjuvant therapy. The results provide additional options for the clinical treatment of locally advanced thyroid cancer.
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@#Abstract: Upon monitoring cytoplasmic aberrant double-stranded DNA, cGAS-STING signaling pathway induces the expression of type I interferons and pro-inflammatory cytokines, which activates the host immune response and enhances anti-tumor immune response and resistance to pathogen infection. However, sustained activation of the cGAS-STING signaling pathway drives diseases such as autoimmune diseases, aging-associated inflammation, and neurodegenerative pathologies. Herein, we describe the mechanism by which cGAS-STING signaling pathway participates in regulating the development of various immune-related diseases, with a particular review of the research and development progress of STING agonists, cGAS inhibitors, and STING inhibitors, aiming to provide some theoretical reference for the future development of cGAS-STING modulators.
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@#Abstract: As potential immunomodulators, platinum-based drugs could trigger immunogenic cell death (ICD). Hence, combination of platinum-based chemotherapy and immunotherapy could have better synergistic anticancer effect. Pt(II)-based drugs are the most common chemotherapeutic agents in cancer treatment yet with limited clinical application due to their toxic side-effects and drug resistance. Pt(IV) complexes have been widely investigated in the past decades due to their kinetic inertness and unique mechanisms . This article summarizes the progress in the pharmacological activities and mechanisms of Pt(IV) antitumor complexes via introducing different immunomodulators into chemotherapeutic agents in literature over recent years and highlights the potential targets and molecular signaling pathways so as to provide some reference for further development and potential clinical application of platinum-based chemo-immunotherapeutic agents.
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@#C-C motif chemokine ligand 2 (CCL2) and its receptor CCR2 are closely related to tumorigenesis and tumor progression. The CCL2/CCR2 signaling axis promotes tumor progression through multiple mechanisms: CCL2 binds to CCR2 on the surface of tumor cells, and thus promotes tumor growth/survival and metastasis; more importantly, CCL2 recruits a variety of immunosuppressive cells to aggregate in the tumor microenvironment, and inhibits the function and activity of immune cells, promoting tumor progression. The article reviews the CCL2/CCR2 signaling axis and its role in tumors and tumor microenvironment, with particular focus on the advances in clinical research on drugs targeting CCL2/CCR2 signaling axis, in order to gain an in-depth and overall understanding of the mechanism of action of CCL2/CCR2 axis in tumor progression and develop more effective anti-tumor immunotherapeutic agents.
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@#Abstract: S-palmitoylation, a reversible and dynamic post-translational modification in cells, is involved in regulating the transcription and expression of downstream target genes as well as signal transduction, thereby affecting cell life activities. Studies have shown that thousands of human proteins undergo S-palmitoylation modification, suggesting that S-palmitoylation is closely related to the progression and treatment of diseases. T cells play central roles in anti-tumor immune responses. A variety of T cell immune-related proteins are regulated by S-palmitoylation. In the present study, we focus on the impact of S-palmitoylation on T cell signal transduction and its application in T cell immunotherapy, aiming to provide new ideas for the development of new targets and peptide inhibitors for T cell immunotherapy.
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@#Acute myeloid leukemia (AML) is a disease caused by abnormal cloning of hematopoietic stem cells in the bone marrow, which leads to accumulation of a large number of abnormally differentiated myeloid cells. It is difficult to cure by traditional treatment. The successful application of chimeric antigen receptor T cell (CAR-T) immunotherapy indicates that the treatment of hematological tumors has entered a new stage of precision immunotherapy. However, CAR-T immunotherapy has been found to have many problems in clinical applications, including long treatment cycle, expensive prices, off-target effects, cytokine release syndrome, etc. Therefore, it is necessary to expand the application of CAR or adopt improved measures to enhance the therapeutic effect. This article reviews the new strategies for genetic engineering modification of CAR immune cells and the research progress and application of in situ programming to generate CAR-T, and besides, briefly introduces the new methods about the delivery of gene drugs in vivo, aiming to provide new ideas and theoretical basis for expanding and improving the application of precision immunotherapy in AML.
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In recent years, bispecific antibodies (BsAb), including targeting B cell maturation antigen (BCMA) ×CD3 and G protein-coupled orphan receptor class C group 5 member D (GPRC5D) ×CD3, have been extensively studied for relapsed/refractory multiple myeloma (RRMM) patients. Teclistamab (BCMA×CD3) was the first BsAb approved for RRMM in 2022 by Food and Drug Administration (FDA), and elranatamab was approved in 2023. BsAb targeting BCMA×CD3 including alnuctamab, WVT078, ABBV-383, linvoseltamab, and F182112, as well as talquetamab and LBL-034 targeting GPRC5D×CD3 are currently being evaluated in clinical trials. Combining with the reports in the 65th Annual Meeting of the American Society of Hematology (ASH), this paper reviews the progress of BsAb in treatment of RRMM.