RESUMEN
Myotonic dystrophy type 1 (DM1) is the most prevalent adult-onset muscular dystrophy affecting 1 in 8,000 individuals. It is characterized by multisystemic symptoms, primarily myopathy. The root cause of DM1 is a heterozygous CTG triplet expansion beyond the normal size threshold in the non-coding region of the DM1 protein kinase gene (DMPK). In our study, we generated and characterized three distinct DM1 induced pluripotent stem cell (iPSC) lines with CTG repeat expansions ranging from 900 to 2000 in the DMPK gene. These iPSC lines maintained normal karyotypes, exhibited distinctive colony morphology, robustly expressed pluripotency markers, differentiated into the three primary germ layers, and lacked residual viral vectors.
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Células Madre Pluripotentes Inducidas , Distrofia Miotónica , Adulto , Humanos , Distrofia Miotónica/genética , Distrofia Miotónica/metabolismo , Células Madre Pluripotentes Inducidas/metabolismo , Expansión de Repetición de Trinucleótido , Experimentación Humana Terapéutica , Línea Celular , Proteína Quinasa de Distrofia Miotónica/genéticaAsunto(s)
Investigadores , Experimentación Humana Terapéutica , Infección por el Virus Zika , Femenino , Humanos , Incidencia , Transmisión Vertical de Enfermedad Infecciosa/prevención & control , Experimentación Humana Terapéutica/ética , Vacunas Virales , Virus Zika/patogenicidad , Infección por el Virus Zika/epidemiología , Infección por el Virus Zika/prevención & control , Infección por el Virus Zika/transmisión , Infección por el Virus Zika/virologíaRESUMEN
HIV-related neuropathic pain (HRNP) is a neurodegeneration that gradually develops during the long-term course of acquired immune deficiency syndrome (AIDS) and manifests as abnormal sock/sleeve-like symmetrical pain and nociceptive hyperalgesia in the extremities, which seriously reduces patient quality of life. To date, the pathogenesis of HRNP is not completely clear. There is a lack of effective clinical treatment for HRNP and it is becoming a challenge and hot spot for medical research. In this study, we conducted a systematic review of the progress of HRNP research in recent years including (1) the etiology, classification and clinical symptoms of HRNP, (2) the establishment of HRNP pathological models, (3) the pathological mechanisms underlying HRNP from three aspects: molecules, signaling pathways and cells, (4) the therapeutic strategies for HRNP, and (5) the limitations of recent HRNP research and the future research directions and prospects of HRNP. This detailed review provides new and systematic insight into the pathological mechanism of HRNP, which establishes a theoretical basis for the future exploitation of novel target drugs. HIV infection, antiretroviral therapy and opioid abuse contribute to the etiology of HRNP with symmetrical pain in both hands and feet, allodynia and hyperalgesia. The pathogenesis involves changes in cytokine expression, activation of signaling pathways and neuronal cell states. The therapy for HRNP should be patient-centered, integrating pharmacologic and nonpharmacologic treatments into multimodal intervention.
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Infecciones por VIH , Neuralgia , Humanos , Animales , Hiperalgesia/metabolismo , Infecciones por VIH/complicaciones , Infecciones por VIH/tratamiento farmacológico , VIH , Experimentación Humana Terapéutica , Calidad de Vida , Neuralgia/tratamiento farmacológico , Neuralgia/metabolismo , Modelos Animales de EnfermedadRESUMEN
This article aims to examine Paul Martini's early therapeutic research. It traces the development and early practice of his methodology by focussing on four clinical studies which Martini conducted in the years 1928 to 1932. The studies show a methodological transition from uncontrolled drug evaluation to systematic method-based drug testing and the production of increasingly valid results. In addition, we address Martini's inaugural lecture in Bonn (1932) as a source of important conceptual considerations. With its publication in 1932, the "Methodenlehre der therapeutischen Untersuchung" became a firm basis and standard for therapeutic research practice for Martini, which he applied not only to his own, but to all clinical studies.
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Medicina Clínica , Experimentación Humana Terapéutica , Humanos , Alemania , Proyectos de InvestigaciónRESUMEN
The most prevalent oral cancer globally is oral squamous cell carcinoma (OSCC). The invasion of adjacent bones and the metastasis to regional lymph nodes often lead to poor prognoses and shortened survival times in patients with OSCC. Encouraging immunotherapeutic responses have been seen with immune checkpoint inhibitors (ICIs); however, these positive responses to monotherapy have been limited to a small subset of patients. Therefore, it is urgent that further investigations into optimizing immunotherapies are conducted. Areas of research include identifying novel immune checkpoints and targets and tailoring treatment programs to meet the needs of individual patients. Furthermore, the advancement of combination therapies against OSCC is also critical. Thus, additional studies are needed to ensure clinical trials are successful. Mice models are advantageous in immunotherapy research with several advantages, such as relatively low costs and high tumor growth success rate. This review paper divided methods for establishing OSCC mouse models into four categories: syngeneic tumor models, chemical carcinogen induction, genetically engineered mouse, and humanized mouse. Each method has advantages and disadvantages that influence its application in OSCC research. This review comprehensively surveys the literature and summarizes the current mouse models used in immunotherapy, their advantages and disadvantages, and details relating to the cell lines for oral cancer growth. This review aims to present evidence and considerations for choosing a suitable model establishment method to investigate the early diagnosis, clinical treatment, and related pathogenesis of OSCC.
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Carcinoma de Células Escamosas , Neoplasias de Cabeza y Cuello , Neoplasias de la Boca , Animales , Carcinoma de Células Escamosas/tratamiento farmacológico , Carcinoma de Células Escamosas/metabolismo , Modelos Animales de Enfermedad , Inhibidores de Puntos de Control Inmunológico/farmacología , Inhibidores de Puntos de Control Inmunológico/uso terapéutico , Ratones , Neoplasias de la Boca/patología , Carcinoma de Células Escamosas de Cabeza y Cuello/terapia , Experimentación Humana TerapéuticaRESUMEN
We are pleased to present this Special Issue of Cells, entitled 'Feature Papers in Stem Cells' [...].
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Investigación con Células Madre , Experimentación Humana TerapéuticaRESUMEN
BACKGROUND: Advocates of the therapeutic use of psychedelic drugs have argued that a promising approach to treatment was prematurely abandoned in the 1960s primarily because of Richard Nixon's 'War on Drugs'.This paper (1) briefly describes research in the 1950s and 1960s in North America on the use of LSD to treat alcohol dependence, anxiety in terminal illness, and anxiety and depression; and (2) discusses the factors that led to its abandonment. METHOD: An analysis of historical scholarship on psychedelic research in the 1950s, 1960s and 1970s in North America. RESULTS: Research on psychedelic drugs in psychiatry was abandoned for a number of reasons that acted in concert. A major factor was that clinical research on psychedelic drugs was caught up in the tighter regulation of pharmaceutical research after the Thalidomide disaster in 1963. Psychedelic drugs also presented special challenges for randomised, placebo-controlled clinical trials in the 1970s that were not as positive as the claims made by their advocates in the 1950s and 1960s. Clinical research became more difficult after 1965 when Sandoz ceased providing psychedelic drugs for research and their nonmedical use was prohibited in 1970. CONCLUSIONS: The demise of psychedelic drug research was not solely due to the 'War on Drugs'. It was hastened by tighter regulation of pharmaceutical research, the failure of controlled clinical trials to live up to the claims of psychedelic advocates, and the pharmaceutical industry's lack of interest in funding clinical trials.
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Alucinógenos , Psiquiatría , Humanos , Alucinógenos/farmacología , Alucinógenos/uso terapéutico , Dietilamida del Ácido Lisérgico/farmacología , Dietilamida del Ácido Lisérgico/uso terapéutico , Experimentación Humana Terapéutica , Trastornos de Ansiedad/tratamiento farmacológicoRESUMEN
The current version of the Declaration of Helsinki states that 'the benefits, risks, burdens and effectiveness of a new intervention must be tested against those of the best current proven intervention(s) '. This wording implies that it is acceptable for patients to be assigned to receive an unproven new intervention and to be denied a best current proven intervention. We assert that patients being invited to participate in controlled trials cannot, ethically, be expected to forego proven beneficial forms of care. Patients being treated in controlled trials should not knowingly be disadvantaged compared with similar patients being treated in usual clinical care, where they have access to beneficial care. In this article, we have tried to separate for discussion 'the withholding of effective care from trial participants', 'informed consent to treatment', 'blinding' and 'use of placebos'.
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Ensayos Clínicos Controlados como Asunto/ética , Ensayos Clínicos Controlados como Asunto/normas , Placebos/uso terapéutico , Nivel de Atención , Experimentación Humana Terapéutica/ética , Privación de Tratamiento/ética , Método Doble Ciego , Declaración de Helsinki , Humanos , Consentimiento InformadoRESUMEN
BACKGROUND: Progress in therapeutic research is slowed by the regulatory burden of clinical trials, which provide the best evidence for guiding treatment. There is a long delay from evidence generation to adoption, highlighting the need for designs that link evidence generation to implementation. OBJECTIVE: To identify clinical trial designs that confer minimal risk above that inherent in clinical care, to obviate the need for cumbersome consenting processes to enrol patients in prospective clinical research studies. These designs extend the scope of the Learning Healthcare System, a framework for leveraging retrospective 'big data' to advance clinical research, to include data collected from prospective controlled trials. SUMMARY: Pragmatic trials may use simplified eligibility criteria, unblinded interventions and objective outcome measures that can all be monitored through the electronic health records (EHR), to reduce costs and speed study conduct. Most pragmatic trials continue to suffer from substantial regulatory burden. Written consent to participate in research can be waived only if the research produces minimal risk above what is encountered in everyday life. However, the 'consent' processes for prescribing Federal Drug Administration-approved medications in clinical medicine are informal, even when they involve decisions of uncertain benefit and higher levels of risk. We propose that trial designs that mimic clinical decision-making in areas of uncertainty (clinical equipoise) and in which no data are generated outside of usual care (ideally by EHR embedding) confer minimal additional risk. Trial designs meeting this standard could, therefore, be conducted with minimal documentation of consent, even when interventions contain different risks. To align with risk encountered in clinical practice, allocation to treatment arms should change (adaptive randomisation) as data are collected and analysed. Embedding of informatics tools into the EHR has the additional benefit that, as adaptive randomisation progresses, evidence-generation transitions into implementation via decision-support tools-the ultimate realisation of the Learning Healthcare System.
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Consentimiento Informado , Experimentación Humana Terapéutica , Registros Electrónicos de Salud , Humanos , Estudios Prospectivos , Estudios RetrospectivosRESUMEN
BACKGROUND: Recent advances made in cell and gene therapies for cancer suggest that they represent plausible strategies to cure HIV. However, the health risks and constraints associated with these therapies require a deeper understanding of the expectations of such treatments among people living with HIV (PLWH). METHODS: We conducted 15 semistructured in-depth interviews among patients from 2 HIV units in Switzerland. After a conversation about their perceptions of research on HIV therapies, participants were provided with a trial description using a gene-modified cell therapy as a potentially curative approach. They were invited to discuss how they might consider participation in the trial. Content analysis was performed to identify core themes. RESULTS: Participants perceived the trial as burdensome and uncertain. Most were aware that cure was not guaranteed, and 6 of the 15 considered that they would participate. Two main concerns were expressed about potential participation: (1) the impact on the professional life and fear to be stigmatized because of this and (2) the fact that stopping antiretroviral treatment would challenge the balance currently achieved in their lives. The decision to participate would depend on their understanding of the trial, the availability of sufficient information, and the relationship with health care professionals. CONCLUSION: Involving PLWH in early stages of research would be crucial to improve their understanding of gene-modified cell therapies. It could also help adapt trials to address key factors, including the anticipation of stigma, which may discourage PLWH from participating in treatment research.
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Tratamiento Basado en Trasplante de Células y Tejidos/métodos , Terapia Genética/métodos , Infecciones por VIH/terapia , Experimentación Humana Terapéutica , Humanos , Investigación Cualitativa , SuizaRESUMEN
AIM: To synthesize the most recent evidence investigating the effectiveness and safety of therapeutic touch as a complementary therapy in clinical health applications. DESIGN: A rapid evidence assessment (REA) approach was used to review recent TT research adopting PRISMA 2009 guidelines. METHODS: CINAHL, PubMed, MEDLINE, Cochrane databases, Web of Science, PsychINFO and Google Scholar were screened between January 2009-March 2020 for studies exploring TT therapies as an intervention. The main outcome measures were for pain, anxiety, sleep, nausea and functional improvement. RESULTS: Twenty-one studies covering a range of clinical issues were identified, including 15 randomized-controlled trials, four quasi-experimental studies, one chart review study and one mixed methods study including 1,302 patients. Eighteen of the studies reported positive outcomes. Only four exhibited a low risk of bias. All others had serious methodological flaws, bias issues, were statistically underpowered and scored as low-quality studies. No high-quality evidence was found for any of the benefits claimed.
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Tacto Terapéutico , Humanos , Evaluación de Resultado en la Atención de Salud , Prohibitinas , Ensayos Clínicos Controlados Aleatorios como Asunto , Experimentación Humana TerapéuticaAsunto(s)
Vacunas contra la COVID-19 , COVID-19/prevención & control , Ensayos Clínicos como Asunto/ética , Complicaciones Infecciosas del Embarazo/prevención & control , Ensayos Clínicos como Asunto/legislación & jurisprudencia , Femenino , Regulación Gubernamental , Humanos , Lactancia , Embarazo , Experimentación Humana Terapéutica/éticaRESUMEN
Various approaches to first-in-human (FIH) starting dose selection for new molecular entities (NMEs) are designed to minimize risk to trial subjects. One approach uses the minimum anticipated biological effect level (MABEL), which is a conservative method intended to maximize subject safety and designed primarily for NMEs having high perceived safety risks. However, there is concern that the MABEL approach is being inappropriately used for lower risk molecules with negative impacts on drug development and time to patient access. In addition, ambiguity exists in how MABEL is defined and the methods used to determine it. The International Consortium for Innovation and Quality in Pharmaceutical Development convened a working group to understand current use of MABEL and its impact on FIH starting dose selection, and to make recommendations for FIH dose selection going forward. An industry-wide survey suggested the achieved or estimated maximum tolerated dose, efficacious dose, or recommended phase II dose was > 100-fold higher than the MABEL-based starting dose for approximately one third of NMEs, including trials in patients. A decision tree and key risk factor table were developed to provide a consistent, data driven-based, and risk-based approach for selecting FIH starting doses.
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Ensayos Clínicos como Asunto/normas , Desarrollo de Medicamentos/métodos , Preparaciones Farmacéuticas/administración & dosificación , Ensayos Clínicos como Asunto/legislación & jurisprudencia , Ensayos Clínicos Fase III como Asunto , Desarrollo de Medicamentos/legislación & jurisprudencia , Industria Farmacéutica , Efectos Colaterales y Reacciones Adversas Relacionados con Medicamentos/epidemiología , Humanos , Dosis Máxima Tolerada , Proyectos de Investigación , Encuestas y Cuestionarios , Experimentación Humana Terapéutica , ToxicologíaAsunto(s)
Vacunas contra la COVID-19/inmunología , COVID-19/prevención & control , COVID-19/transmisión , Voluntarios Sanos , Experimentación Humana Terapéutica/ética , Vacunas contra la COVID-19/administración & dosificación , Ensayos Clínicos como Asunto/ética , Humanos , Riesgo , Medición de Riesgo , VacunaciónRESUMEN
The purpose of this article, the last in a series of three exploring the legal framework for the regulation of faecal microbiota transplantation (FMT) in South Africa (SA), is to determine the regulatory framework that applies to microbial-based treatments involving a level of manipulation that exceeds that of basic stool transplantation, e.g. processed FMT-derived products in capsule form. The article highlights the legal requirements for the registration of these products as biological medicines in SA law. Although human stool banks are not regulated in terms of the National Health Act 61 of 2003 (NHA) and regulations, the earlier articles point out that human stool fits the definition of human tissue and human biological material as defined by the NHA. For this reason, stool banks should be considered tissue banks in terms of the NHA and regulations. Healthcare practitioners and researchers involved in FMT banking and transplantation should strive to comply with these regulations in the absence of clear legal direction at present.
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Trasplante de Microbiota Fecal , Experimentación Humana Terapéutica , Obtención de Tejidos y Órganos/legislación & jurisprudencia , Bancos de Muestras Biológicas/legislación & jurisprudencia , Heces , Humanos , Sudáfrica , Experimentación Humana Terapéutica/ética , Experimentación Humana Terapéutica/legislación & jurisprudenciaRESUMEN
Faecal microbiota transplantation (FMT) has been shown to be an effective treatment for recurrent Clostridioides difficile infection. The purpose of this article, the second of a series of three articles, is to explore the legal framework governing human FMT in South Africa (SA). FMT involves different modes of administration that require different regulatory considerations. The focus of this article is to explore the legal classification of human stool as tissue in terms of the National Health Act 61 of 2003, as well as the regulation of human stool banks as tissue banks. The article concludes with specific recommendations aimed at improving the current regulatory vacuum relating to the regulation of FMT in SA.