Basic Science Discoveries Research Articles

Advancing scientific discovery with the aid of robotics.

Robots can be powerful tools to advance basic scientific discovery.

From amoeboid myosin to unique targeted medicines for a genetic cardiac disease

The importance of fundamental basic research in the quest for much needed clinical treatments is a story that constantly must be retold. Funding of basic science in the USA by the National Institutes of Health and other agencies is provided under the assumption that fundamental research eventually will lead to improvements in healthcare worldwide. Understanding how basic research is connected to clinical developments is important, but just part of the story. Many basic science discoveries never see the light of day in a clinical setting because academic scientists are not interested in or do not have the inclination and/or support for entering the world of biotechnology. Even if the interest and inclination are there, often the unknowns about how to enter that world inhibit taking the initial step. Young investigators often ask me how I incorporated biotech opportunities into my otherwise purely academic research endeavors. Here I tell the story of the foundational basic science and early events of my career that led to forming the biotech companies responsible for the development of unique cardiac drugs, including mavacamten, a first in class human β-cardiac myosin inhibitor that is changing the lives of hypertrophic cardiomyopathy patients.

From Bench to Bedside: A Team's Approach to Multidisciplinary Strategies to Combat Therapeutic Resistance in Head and Neck Squamous Cell Carcinoma.

Head and neck squamous cell carcinoma (HNSCC) is diagnosed in more than 71,000 patients each year in the United States, with nearly 16,000 associated deaths. One significant hurdle in the treatment of HNSCC is acquired and intrinsic resistance to existing therapeutic agents. Over the past several decades, the University of Wisconsin has formed a multidisciplinary team to move basic scientific discovery along the translational spectrum to impact the lives of HNSCC patients. In this review, we outline key discoveries made throughout the years at the University of Wisconsin to deepen our understanding of therapeutic resistance in HNSCC and how a strong, interdisciplinary team can make significant advances toward improving the lives of these patients by combatting resistance to established therapeutic modalities. We are profoundly grateful to the many scientific teams worldwide whose groundbreaking discoveries, alongside evolving clinical paradigms in head and neck oncology, have been instrumental in making our work possible.

In Vitro Models for Peripheral Nerve Regeneration.

Peripheral nerve injury (PNI) resulting in lesions is highly prevalent clinically, but current therapeutic approaches fail to provide satisfactory outcomes in many patients. While peripheral nerves have intrinsic regenerative capacity, the regenerative capabilities of peripheral nerves are often insufficient to restore full functionality. This highlights an unmet need for developing more effective strategies to repair damaged peripheral nerves and improve regenerative success. Consequently, researchers are actively exploring a variety of therapeutic strategies, encompassing the local delivery of trophic factors or bioactive molecules, the design of advanced biomaterials that interact with regenerating axons, and augmentation with nerve guidance conduits or complex prostheses. However, clinical translation of these technologies remains limited, emphasizing the need for continued research on peripheral nerve regeneration modalities that can enhance functional restoration. Experimental models that accurately recapitulate key aspects of peripheral nerve injury and repair biology can accelerate therapeutic development by enabling systematic testing of new techniques. Advancing regenerative therapies for PNI requires bridging the gap between basic science discoveries and clinical application. This review discusses different in vitro models of peripheral nerve injury and repair, including their advantages, limitations, and potential applications.

Targeted therapies for vascular malformations.

Targeted medical therapies for the treatment of vascular malformations is an exciting and evolving area of research. As the identification of specific causative genetic mutations involved in vascular malformations becomes more accessible and inexpensive, the development of targeted therapies to address these genetic anomalies becomes all the more enticing. It is an excellent example of the potential of translational research where basic science discoveries are translated to clinical practise from 'bench to bedside'. In this mini-review we aim to synopsise some of the recent studies published in this area with specific focus on the paediatric population. We also aim to highlight the growing demand for future research in the field to elucidate further the optimum duration of treatments, strategies for discontinuation, potential for combination of therapies and the effects of prolonged use of these medications.

FSO2N3-Mediated On-DNA Diazo-Transfer Chemistry.

DNA-encoded library (DEL) is a powerful hit selection technique in both basic science and innovative drug discovery. In this study, we report a robust and straightforward DNA-compatible diazo-transfer reaction utilizing FSO2N3 as the diazo-transfer reagent in solution. This reaction demonstrates high conversions and facile operation while being metal-free and maintaining high levels of DNA fidelity. It is also compatible with a wide range of substrates, allowing for convenient access to both aliphatic and aromatic amines. Consequently, it will further enrich the DEL chemistry toolbox.

Oxidative stress and food as medicine.

There has been a sea of change in our understanding of the contribution of food to both our well-being and disease states. When one addresses "food as medicine," the concept of oxidative stress needs to be included. This review interconnects the basic science findings of oxidative stress and redox balance with the medicinal use of food, emphasizing optimization of the redox balance. To better illustrate the impacts of oxidative stress, the concept of the "triple oxidant sink" is introduced as a theoretical gauge of redox balance. Utilizing the concept, the true importance of dietary and lifestyle factors can be emphasized, including the limitations of supplements or a handful of "superfoods," if the remainder of the factors are pro-oxidant. The effects of a whole plant food diet compared with those of dietary supplements, processed foods, animal based nutrients, or additional lifestyle factors can be visually demonstrated with this concept. This paper provides an overview of the process, acknowledging that food is not the only mechanism for balancing the redox status, but one that can be strategically used to dramatically improve the oxidative state, and thus should be used as medicine.

The Translational Medicine of 2030: Bedside to Biosphere.

For over two decades, translational medicine has accelerated basic science discovery into clinical application using a bench-to-bedside framework. Given that climate change represents the single greatest health threat facing humanity, the authors propose extending this framework to now include bedside to the biosphere. Several potential opportunities in clinical operations, research, and advocacy using this framework are provided. In addition, we propose that technology assessment studies of diagnostic imaging measure planetary outcomes alongside patient outcomes.

Translational research in psychiatry

Translational research in psychiatry bridges the gap between basic scientific discoveries and clinical applications, aiming to improve the diagnosis, treatment, and prevention of mental illnesses. By elucidating the neurobiological mechanisms underlying psychiatric disorders through neuroimaging, genetics, and animal models, researchers can identify novel therapeutic targets and biomarkers for personalized interventions. This brief communication provides an overview of the importance, approaches, and a few examples of translation psychiatry research and challenges. Moving forward, collaboration between researchers, clinicians, industry partners, and regulatory agencies is essential to address the unmet needs of individuals affected by mental illness and to realize the full potential of translational psychiatry.

Estrogen deficiency in the menopause and the role of hormone therapy: integrating the findings of basic science research with clinical trials.

Menopause, defined by the cessation of menstrual cycles after 12 months of amenorrhea not due to other causes, is associated with significant hormonal changes, primarily a decrease in estrogen, androgen, and progesterone levels. This review delves into the effects of estrogen deficiency during the perimenopausal transition and postmenopause, integrating the findings of basic science with clinical trials. Here, we first outline the variation in endogenous estrogens before and after menopause, exploring both genomic and nongenomic actions of estrogen and its estrogen receptors throughout the body. Next, we detail the spectrum of menopausal symptoms, from acute vasomotor, urogenital, and psychological issues during perimenopause to chronic reproductive, cardiovascular, neurological, skeletal, dermatologic, immune, and digestive changes postmenopause. Finally, we evaluate the role of hormone therapy in alleviating these symptoms, weighing its benefits against known risks. Publicizing these findings and an accurate representation of the risks and benefits of estrogen replacement to our aging patients is fundamental to improving their care, quality, and even quantity of life.

Basic immunologic study as a foundation for engineered therapeutic development.

Bioengineering and drug delivery technologies play an important role in bridging the gap between basic scientific discovery and clinical application of therapeutics. To identify the optimal treatment, the most critical stage is to diagnose the problem. Often these two may occur simultaneously or in parallel, but in this review, we focus on bottom-up approaches in understanding basic immunologic phenomena to develop targeted therapeutics. This can be observed in several fields; here, we will focus on one of the original immunotherapy targets-cancer-and one of the more recent targets-regenerative medicine. By understanding how our immune system responds in processes such as malignancies, wound healing, and medical device implantation, we can isolate therapeutic targets for pharmacologic and bioengineered interventions.

Cardiac Remodeling and Ventricular Pacing: From Genes to Mechanics.

Cardiac remodeling and ventricular pacing represent intertwined phenomena with profound implications for cardiovascular health and therapeutic interventions. This review explores the intricate relationship between cardiac remodeling and ventricular pacing, spanning from the molecular underpinnings to biomechanical alterations. Beginning with an examination of genetic predispositions and cellular signaling pathways, we delve into the mechanisms driving myocardial structural changes and electrical remodeling in response to pacing stimuli. Insights into the dynamic interplay between pacing strategies and adaptive or maladaptive remodeling processes are synthesized, shedding light on the clinical implications for patients with various cardiovascular pathologies. By bridging the gap between basic science discoveries and clinical translation, this review aims to provide a comprehensive understanding of cardiac remodeling in the context of ventricular pacing, paving the way for future advancements in cardiovascular care.

Challenges in IBD Research 2024: Precision Medicine.

Precision medicine is part of 5 focus areas of the Challenges in IBD Research 2024 research document, which also includes preclinical human IBD mechanisms, environmental triggers, novel technologies, and pragmatic clinical research. Building on Challenges in IBD Research 2019, the current Challenges aims to provide a comprehensive overview of current gaps in inflammatory bowel diseases (IBDs) research and deliver actionable approaches to address them with a focus on how these gaps can lead to advancements in interception, remission, and restoration for these diseases. The document is the result of multidisciplinary input from scientists, clinicians, patients, and funders, and represents a valuable resource for patient-centric research prioritization. In particular, the precision medicine section is focused on the main research gaps in elucidating how to bring the best care to the individual patient in IBD. Research gaps were identified in biomarker discovery and validation for predicting disease progression and choosing the most appropriate treatment for each patient. Other gaps were identified in making the best use of existing patient biosamples and clinical data, developing new technologies to analyze large datasets, and overcoming regulatory and payer hurdles to enable clinical use of biomarkers. To address these gaps, the Workgroup suggests focusing on thoroughly validating existing candidate biomarkers, using best-in-class data generation and analysis tools, and establishing cross-disciplinary teams to tackle regulatory hurdles as early as possible. Altogether, the precision medicine group recognizes the importance of bringing basic scientific biomarker discovery and translating it into the clinic to help improve the lives of IBD patients.

T cells in obesity-associated inflammation: The devil is in the details.

Obesity presents a significant health challenge, affecting 41% of adults and 19.7% of children in the United States. One of the associated health challenges of obesity is chronic low-grade inflammation. In both mice and humans, T cells in circulation and in the adipose tissue play a pivotal role in obesity-associated inflammation. Changes in the numbers and frequency of specific CD4+ Th subsets and their contribution to inflammation through cytokine production indicate declining metabolic health, that is, insulin resistance and T2D. While some Th subset alterations are consistent between mice and humans with obesity, some changes mainly characterize male mice, whereas female mice often resist obesity and inflammation. However, protection from obesity and inflammation is not observed in human females, who can develop obesity-related T-cell inflammation akin to males. The decline in female sex hormones after menopause is also implicated in promoting obesity and inflammation. Age is a second underappreciated factor for defining and regulating obesity-associated inflammation toward translating basic science findings to the clinic. Weight loss in mice and humans, in parallel with these other factors, does not resolve obesity-associated inflammation. Instead, inflammation persists amid modest changes in CD4+ T cell frequencies, highlighting the need for further research into resolving changes in T-cell function after weight loss. How lingering inflammation after weight loss affecting the common struggle to maintain lower weight is unknown. Semaglutide, a newly popular pharmaceutical used for treating T2D and reversing obesity, holds promise for alleviating obesity-associated health complications, yet its impact on T-cell-mediated inflammation remains unexplored. Further work in this area could significantly contribute to the scientific understanding of the impacts of weight loss and sex/hormones in obesity and obesity-associated metabolic decline.

Immune Checkpoint Inhibitors in Geriatric Oncology.

This manuscript will update prior reviews of immune checkpoint inhibitors (ICIs) in light of basic science, translational, and clinical discoveries in the field of cancer immunology and aging. ICIs have led to significant advancements in the treatment of cancer. Landmark trials of ICIs have cited the efficacy and toxicity experienced by older patients, but most trials are not specifically designed to address outcomes in older patients. Underlying mechanisms of aging, like cellular senescence, affect the immune system and may ultimately alter the host's response to ICIs. Validated tools are currently used to identify older adults who may be at greater risk of developing complications from their cancer treatment. We review changes in the aging immune system that may alter responses to ICIs, report outcomes and toxicities in older adults from recent ICI clinical trials, and discuss clinical tools specific to older patients with cancer.

Cardiac arrhythmia in individuals with steroid sulfatase deficiency (X-linked ichthyosis): candidate anatomical and biochemical pathways.

Circulating steroids, including sex hormones, can affect cardiac development and function. In mammals, steroid sulfatase (STS) is the enzyme solely responsible for cleaving sulfate groups from various steroid molecules, thereby altering their activity and water solubility. Recent studies have indicated that Xp22.31 genetic deletions encompassing STS (associated with the rare dermatological condition X-linked ichthyosis), and common variants within the STS gene, are associated with a markedly elevated risk of cardiac arrhythmias, notably atrial fibrillation/flutter. Here, we consider emerging basic science and clinical findings which implicate structural heart abnormalities (notably septal defects) as a mediator of this heightened risk, and propose candidate cellular and biochemical mechanisms. Finally, we consider how the biological link between STS activity and heart structure/function might be investigated further and the clinical implications of work in this area.

The integrated stress response pathway and neuromodulator signaling in the brain: lessons learned from dystonia.

The integrated stress response (ISR) is a highly conserved biochemical pathway involved in maintaining proteostasis and cell health in the face of diverse stressors. In this Review, we discuss a relatively noncanonical role for the ISR in neuromodulatory neurons and its implications for synaptic plasticity, learning, and memory. Beyond its roles in stress response, the ISR has been extensively studied in the brain, where it potently influences learning and memory, and in the process of synaptic plasticity, which is a substrate for adaptive behavior. Recent findings demonstrate that some neuromodulatory neuron types engage the ISR in an "always-on" mode, rather than the more canonical "on-demand" response to transient perturbations. Atypical demand for the ISR in neuromodulatory neurons introduces an additional mechanism to consider when investigating ISR effects on synaptic plasticity, learning, and memory. This basic science discovery emerged from a consideration of how the ISR might be contributing to human disease. To highlight how, in scientific discovery, the route from starting point to outcomes can often be circuitous and full of surprise, we begin by describing our group's initial introduction to the ISR, which arose from a desire to understand causes for a rare movement disorder, dystonia. Ultimately, the unexpected connection led to a deeper understanding of its fundamental role in the biology of neuromodulatory neurons, learning, and memory.

Rationale and design of the Nephrotic Syndrome Study Network (NEPTUNE) Match in glomerular diseases: designing the right trial for the right patient, today

Glomerular diseases are classified using a descriptive taxonomy that is not reflective of the heterogeneous underlying molecular drivers. This limits not only diagnostic and therapeutic patient management, but also impacts clinical trials evaluating targeted interventions. The Nephrotic Syndrome Study Network (NEPTUNE) is poised to address these challenges. The study has enrolled >850 pediatric and adult patients with proteinuric glomerular diseases who have contributed to deep clinical, histologic, genetic, and molecular profiles linked to long-term outcomes. The NEPTUNE Knowledge Network, comprising combined, multiscalar data sets, captures each participant's molecular disease processes at the time of kidney biopsy. In this editorial, we describe the design and implementation of NEPTUNE Match, which bridges a basic science discovery pipeline with targeted clinical trials. Noninvasive biomarkers have been developed for real-time pathway analyses. A Molecular Nephrology Board reviews the pathway maps together with clinical, laboratory, and histopathologic data assembled for each patient to compile a Match report that estimates the fit between the specific molecular disease pathway(s) identified in an individual patient and proposed clinical trials. The NEPTUNE Match report is communicated using established protocols to the patient and the attending nephrologist for use in their selection of available clinical trials. NEPTUNE Match represents the first application of precision medicine in nephrology with the aim of developing targeted therapies and providing the right medication for each patient with primary glomerular disease.

Translating Bcell immunology to the treatment of antibody-mediated allograft rejection.

Antibody-mediated rejection (AMR), including chronic AMR (cAMR), causes ~50% of kidney allograft losses eachyear. Despite attempts to develop well-tolerated and effective therapeutics for the management of AMR, to date, none has obtained FDA approval, thereby highlighting an urgent unmet medical need. Discoveries over the past decade from basic, translational and clinical studies of transplant recipients have provided a foundation for developing novel therapeutic approaches to preventing and treating AMR and cAMR. These interventions are aimed at reducing donor-specific antibody levels, decreasing graft injury and fibrosis, and preserving kidney function. Innovative approaches emerging from basic science findings include targeting interactions between alloreactive T cells and Bcells, and depleting alloreactive memory Bcells, as well as donor-specific antibody-producing plasmablasts and plasma cells. Therapies aimed at reducing the cytotoxic antibody effector functions mediated by natural killercells and the complement system, and their associated pro-inflammatory cytokines, are also undergoing evaluation. The complexity of the pathogenesis of AMR and cAMR suggest that multiple approaches will probably be required to treat these disease processes effectively. Definitive answers await results from large, double-blind, multicentre, randomized controlled clinical trials.

Depression, Cancer, Inflammation, and Endogenous Opioids: Pathogenic Relationships and Therapeutic Options.

Endogenous opioids and their associated receptors form a system that maintains survival by positively reinforcing behaviors that are vital to life. Cancer and cancer treatment side effects capitalize on this system pathogenically, leading to maladaptive biological responses (e.g., inflammation), as well as cognitive and emotional consequences, most notably depression. Psychologists who treat people with cancer frequently find depression to be a primary target for intervention. However, in people with cancer, the etiology of depression is unique and complex. This complexity necessitates that psycho-oncologists have a fundamental working knowledge of the biological substrates that underlie depression/cancer comorbidity. Building on other chapters in this volume pertaining to cancer and endogenous opioids, this chapter focuses on the clinical applications of basic scientific findings.