Altered RNA export by SF3B1 mutants confers sensitivity to nuclear export inhibition.

SF3B1 mutations frequently occur in cancer yet lack targeted therapies. Clinical trials of XPO1 inhibitors, selinexor and eltanexor, in high-risk myelodysplastic neoplasms (MDS) revealed responders were enriched with SF3B1 mutations. Given that XPO1 (Exportin-1) is a nuclear exporter responsible for the export of proteins and multiple RNA species, this led to the hypothesis that SF3B1-mutant cells are sensitive to XPO1 inhibition, potentially due to altered splicing. Subsequent RNA sequencing after XPO1 inhibition in SF3B1 wildtype and mutant cells showed increased nuclear retention of RNA transcripts and increased alternative splicing in the SF3B1 mutant cells particularly of genes that impact apoptotic pathways. To identify novel drug combinations that synergize with XPO1 inhibition, a forward genetic screen was performed with eltanexor treatment implicating anti-apoptotic targets BCL2 and BCLXL, which were validated by functional testing in vitro and in vivo. These targets were tested in vivo using Sf3b1K700E conditional knock-in mice, which showed that the combination of eltanexor and venetoclax (BCL2 inhibitor) had a preferential sensitivity for SF3B1 mutant cells without excessive toxicity. In this study, we unveil the mechanisms underlying sensitization to XPO1 inhibition in SF3B1-mutant MDS and preclinically rationalize the combination of eltanexor and venetoclax for high-risk MDS.

Powering prescription: Mitochondria as "Living Drugs" - Definition, clinical applications, and industry advancements.

Mitochondria's role as engines and beacons of metabolism and determinants of cellular health is being redefined through their therapeutic application as "Living Drugs" (LDs). Artificial mitochondrial transfer/transplant (AMT/T), encompassing various techniques to modify, enrich, or restore mitochondria in cells and tissues, is revolutionizing acellular therapies and the future of medicine. This article proposes a necessary definition for LDs within the Advanced Therapeutic Medicinal Products (ATMPs) framework. While recognizing different types of LDs as ATMPs, such as mesenchymal stem cells (MSCs) and chimeric antigen receptor T (CAR T) cells, we focus on mitochondria due to their unique attributes that distinguish them from traditional cell therapies. These attributes include their inherent living nature, diverse sources, industry applicability, validation, customizability for therapeutic needs, and their capability to adapt and respond within recipient cells. We trace the journey from initial breakthroughs in AMT/T to the current state-of-the-art applications by emerging innovative companies, highlighting the need for manufacturing standards to navigate the transition of mitochondrial therapies from concept to clinical practice. By providing a comprehensive overview of the scientific, clinical, and commercial landscape of mitochondria as LDs, this article contributes to the essential dialogue among regulatory agencies, academia, and industry to shape their future in medicine.

Scientific venturing for early-stage professionals (ESPs), a key concept in the innovation ecosystem.

Early-stage professionals (ESPs) and senior scientists who want to transition from academia to the industry need support to develop new skills and know-how to endeavor this challenge. However, this topic is significantly underserved in the field of cell and gene therapy, slowing down ESPs' potential to make this step. The authors of this article, members of the ESPs in the South and Central America Subcommittee at the International Society for Cell and Gene Therapy, propose the concept of "scientific venturing," which stands for the process by which scientists become entrepreneurs or part of a company. In our article, we provide key aspects to understand this concept, considering key personality traits that need to be developed and a discussion about the "innovation ecosystem." Later, we consider how scientific venturing may result in an increase in difficulty in nascent innovation ecosystems such as Latin America, in comparison with those more advanced and mature in high-income countries. Finally, we provide key information for the ESPs and other professionals about the stages of private and public investment, including information about the resources needed for the sustainability of companies and startups. Understanding what scientific venturing involves for ESPs is key to taking advantage of the maturity of an innovation ecosystem, its network, and available opportunities.

A new hope: Mitochondria, a critical factor in the war against prions.

Prion diseases encompass a group of incurable neurodegenerative disorders that occur due to the misfolding and aggregation of infectious proteins. The most well-known prion diseases are Creutzfeldt-Jakob disease (CJD), bovine spongiform encephalopathy (also known as mad cow disease), and kuru. It is estimated that around 1-2 persons per million worldwide are affected annually by prion disorders. Infectious prion proteins propagate in the brain, clustering in the cells and rapidly inducing tissue degeneration and death. Prion disease alters cell metabolism and energy production damaging mitochondrial function and dynamics leading to a fast accumulation of damage. Dysfunction of mitochondria could be considered as an early precursor and central element in the pathogenesis of prion diseases such as in sporadic CJD. Preserving mitochondria function may help to resist the rapid spread and damage of prion proteins and even clearance. In the war against prions and other degenerative diseases, studying how to preserve the function of mitochondria by using antioxidants and even replacing them with artificial mitochondrial transfer/transplant (AMT/T) may bring a new hope and lead to an increase in patients' survival. In this perspective review, we provide key insights about the relationship between the progression of prion disease and mitochondria, in which understanding how protecting mitochondria function and viability by using antioxidants or AMT/T may help to develop novel therapeutic interventions.

The war against Alzheimer, the mitochondrion strikes back!

Alzheimer's disease (AD) is a leading neurodegenerative pathology associated with aging worldwide. It is estimated that AD prevalence will increase from 5.8 million people today to 13.8 million by 2050 in the United States alone. AD effects in the brain are well known; however, there is still a lack of knowledge about the cellular mechanisms behind the origin of AD. It is known that AD induces cellular stress affecting the energy metabolism in brain cells. During the pathophysiological advancement of AD, damaged mitochondria enter a vicious cycle, producing reactive oxygen species (ROS), harming mitochondrial DNA and proteins, leading to more ROS and cellular death. Additionally, mitochondria are interconnected with the plaques formed by amyloid-ß in AD and have underlying roles in the progression of the disease and severity. For years, the biomedical field struggled to develop new therapeutic options for AD without a significant advancement. However, mitochondria are striking back existing outside cells in a new mechanism of intercellular communication. Extracellular mitochondria are exchanged from healthy to damaged cells to rescue those with a perturbed metabolism in a process that could be applied as a new therapeutic option to repair those brain cells affected by AD. In this review we highlight key aspects of mitochondria's role in CNS' physiology and neurodegenerative disorders, focusing on AD. We also suggest how mitochondria strikes back as a therapeutic target and as a potential agent to be transplanted to repair neurons affected by AD.

Fighting Parkinson's disease: The return of the mitochondria.

Parkinson's disease (PD) is the most common neurodegenerative movement disorder, worldwide. PD neuro-energetically affects the extrapyramidal system, by the progressive loss of striatal dopaminergic neurons in the substantia nigra pars compacta, leading to motor impairment. During the progression of PD, there will be an increase in mitochondrial dysfunction, reactive oxygen species (ROS), stress and accumulation of α-synuclein in neurons. This results in mitochondrial mutations altering their function and fission-fusion mechanisms and central nervous system (CNS) degeneration. Intracellular mitochondrial dysfunction has been studied for a long time in PD due to the decline of mitochondrial dynamics inside neurons. Mitochondrial damage-associated molecular patterns (DAMPs) have been known to contribute to several CNS pathologies especially PD pathogenesis. New and exciting evidence regarding the exchange of mitochondria between healthy to damaged cells in the central nervous system (CNS) and the therapeutic use of the artificial mitochondrial transfer/transplant (AMT) marked a return of this organelle to develop innovative therapeutic procedures for PD. The focus of this review aims to shed light on the role of mitochondria, both intra and extracellularly in PD, and how AMT could be used to generate new potential therapies in the fight against PD. Moreover, we suggest that mitochondrial therapy could work as a preventative measure, motivating the field to move towards this goal.

Long-acting reversible contraceptives effects in abnormal uterine bleeding, a review of the physiology and management.

Around two-thirds of women who are of reproductive age use some type of contraception. Two of the most effective long-acting reversible contraceptives (LARC) are the intrauterine device (IUD) and the subdermal contraceptive implant (SCI). Despite their effectiveness, women often report abnormal uterine bleeding as the reason for discontinuation. In this review, we analyze key aspects regarding the mechanisms of action of IUDs (both copper-containing and levonorgestrel-releasing) and SCIs, as well as how they change the intrauterine environment in order to provide effective contraception at a physiological level. Additionally, we introduce the pathophysiology of different types of abnormal intrauterine bleeding provoked by the mentioned LARCs. These three contraceptive methods work in diverse ways, thus, the etiology of abnormal uterine bleeding is different and multifactorial according to each LARC. This review intends to provide information in order to better our understanding of bleeding induced by these contraceptive methods, as well as introduce current and potential new therapies. Furthermore, this review intends to provide updated and concise information that could be available firsthand not only to health care providers but scientists who are innovating and revolutionizing this field. In 2013, the American College of Obstetricians and Gynecologists published a management of abnormal uterine bleeding, however, there is limited updated data regarding the physiology and pathophysiology of abnormal uterine bleeding and its treatment based on different LARCs (hormonal and non-hormonal).

Progressive Vaccinia Acquired through Zoonotic Transmission in a Patient with HIV/AIDS, Colombia.

In March 2015, a patient in Colombia with HIV/AIDS was hospitalized for disseminated ulcers after milking cows that had vesicular lesions on their udders. Vaccinia virus was detected, and the case met criteria for progressive vaccinia acquired by zoonotic transmission. Adherence to an optimized antiretroviral regimen resulted in recovery.

Prevalencia de cáncer de cuello uterino y cáncer de seno en Yopal, Casanare, Colombia / Prevalence of cervical cancer and breast cancer in Yopal, Casanare, Colombia

Antecedentes: el cáncer de cuello uterino y el cáncer de seno son las principales causas de morbilidad/mortalidad por cáncer a nivel mundial. En Colombia para el 2004, el cáncer de seno ocupó el tercer lugar como causa de muerte por cáncerentre mujeres, después del cáncer de cuello uterino y de estómago. La autoridad sanitaria de Yopal se interesó en calcular la prevalencia de cáncer de cuello uterino/cáncer de seno a través del diagnóstico citológico/tejido mamario por mamografía, para mejorar medidas e intervenciones en salud.Método: estudio retrospectivo transversal; 13.461 registros de citologías practicadas a mujeres entre 10-93 años de edad, del programa de prevención de cáncer de cuello uterino de once instituciones de salud y 2.182 registros de mamografías por cualquier causa, practicadas a mujeres entre 25-97 años de edad en dos IPS certificadas, durante 2008. Análisis de datos en Epi Info® 3.5.1 mediante estadística descriptiva. Resultados: para cáncer de cuello uterino, pertenecían a las IPS de la red pública 52,6 porciento; privadas 43,1 porciento y régimen especial 4,37 porciento. Edad promedio 35,2 años; área rural 11 porciento. El sistema Bethesda de clasificación patológica reportó una prevalencia ASC-US 1,77. De los 2.182 registros de cáncer de seno, edad promedio 50,7. Según el diagnóstico BIRADS. La prevalencia de B0=32,72. Conclusiones: se sugiere monitorear la calidad de lectura de muestras citológicas; generar acciones encaminadas a preservar datos y mejorar el Sistema de Garantía deCalidad en IPS EN LA toma de muestras de citología e imágenes de mamografía.

Background: cervical cancer and breast cancer are the main causes for mortalitydue to cancer in the world. In Colombia, during the year 2004, breast cancer hadthe third place in deaths due to cancer among women, following cervical cancerand stomach cancer. The health authorities in Yopal, took interest in calculating the prevalence of cervical cancer/breast cancer through pap smears/mammary tissue taken via mammograms, in order to improve health measures and surgeries.Methods: transversal retrospective study; 13,461 records of pap smears performed on women between the ages of 10 – 93, from the program for prevention of cervical cancer among eleven health institutions and 2,182 records of mammograms taken for any reason, on women between the ages of 25 -97 in two certified IPS during 2008. Data analysis in Epi Info@ 3.5.1 through descriptive statistics. Results: for cervical cancer, the results came from the public sector of IPS 52.6%;private sector 43.1% and special regime 4.37%. The average age was 35.2 years old, rural area 11%. The Bethesda system of pathological classification reported an ASC-US 1, 77 prevalence. Of the 2,182 records of breast cancer, the average age was 50, 7 years old. According to the BIRADS diagnose the prevalence was BO=32.72.Conclusion: it is suggested that the reading of pap smear results be monitored; create actions directed toward the preservation of data and improving a guaranteed quality system in the IPS, when collecting samples through pap smears and mammogram images.