Translating Microbiome Research From and To the Clinic.

Extensive research has elucidated the influence of the gut microbiota on human health and disease susceptibility and resistance. We review recent clinical and laboratory-based experimental studies associating the gut microbiota with certain human diseases. We also highlight ongoing translational advances that manipulate the gut microbiota to treat human diseases and discuss opportunities and challenges in translating microbiome research from and to the bedside.

Questioning Established Theories and Treatment Methods Related to Iron and Other Metal Metabolic Changes, Affecting All Major Diseases and Billions of Patients.

The medical and scientific literature is dominated by highly cited historical theories and findings [...].

The 2018 update of the WHO-EORTC classification for primary cutaneous lymphomas.

Primary cutaneous lymphomas are a heterogeneous group of T- and B-cell lymphomas that present in the skin with no evidence of extracutaneous disease at the time of diagnosis. The 2005 World Health Organization-European Organization for Research and Treatment of Cancer (WHO-EORTC) consensus classification has served as a golden standard for the diagnosis and classification of these conditions. In September 2018, an updated version of the WHO-EORTC was published in the fourth edition of the WHO Classification of Skin Tumours Blue Book. In this classification, primary cutaneous acral CD8+ T-cell lymphoma and Epstein-Barr virus positive (EBV+) mucocutaneous ulcer are included as new provisional entities, and a new section on cutaneous forms of chronic active EBV disease has been added. The term "primary cutaneous CD4+ small/medium T-cell lymphoma" was modified to "primary cutaneous CD4+ small/medium T-cell lymphoproliferative disorder" because of its indolent clinical behavior and uncertain malignant potential. Modifications have also been made in the sections on lymphomatoid papulosis, increasing the spectrum of histologic and genetic types, and primary cutaneous marginal zone lymphomas recognizing 2 different subtypes. Herein, the characteristic features of these new and modified entities as well as the results of recent molecular studies with diagnostic, prognostic, and/or therapeutic significance for the different types of primary cutaneous lymphomas are reviewed. An update of the frequency and survival of the different types of primary cutaneous lymphomas is provided.

Biopolymer Microparticles Prepared by Microfluidics for Biomedical Applications.

Biopolymers are macromolecules that are derived from natural sources and have attractive properties for a plethora of biomedical applications due to their biocompatibility, biodegradability, low antigenicity, and high bioactivity. Microfluidics has emerged as a powerful approach for fabricating polymeric microparticles (MPs) with designed structures and compositions through precise manipulation of multiphasic flows at the microscale. The synergistic combination of materials chemistry afforded by biopolymers and precision provided by microfluidic capabilities make it possible to design engineered biopolymer-based MPs with well-defined physicochemical properties that are capable of enabling an efficient delivery of therapeutics, 3D culture of cells, and sensing of biomolecules. Here, an overview of microfluidic approaches is provided for the design and fabrication of functional MPs from three classes of biopolymers including polysaccharides, proteins, and microbial polymers, and their advances for biomedical applications are highlighted. An outlook into the future research on microfluidically-produced biopolymer MPs for biomedical applications is also provided.

The Role of Protein Engineering in Biomedical Applications of Mammalian Synthetic Biology.

Engineered proteins with enhanced or altered functionality, generated for example by mutation or domain fusion, are at the core of nearly all synthetic biology endeavors in the context of precision medicine, also known as personalized medicine. From designer receptors sensing elevated blood markers to effectors rerouting signaling pathways to synthetic transcription factors and the customized therapeutics they regulate, engineered proteins play a crucial role at every step of novel therapeutic approaches using synthetic biology. Here, recent developments in protein engineering aided by advances in directed evolution, de novo design, and machine learning are discussed. Building on clinical successes already achieved with chimeric antigen receptor (CAR-) T cells and other cell-based therapies, these developments are expected to further enhance the capabilities of mammalian synthetic biology in biomedical and other applications.

Water-Splitting Based and Related Therapeutic Effects: Evolving Concepts, Progress, and Perspectives.

Water-splitting has been extensively studied especially for energy applications. It is often not paid with enough attention for biomedical applications. In fact, several innovative breakthroughs have been achieved in the past few years by employing water-splitting for treating cancer and other diseases. Interestingly, among these important works, only two reports have mentioned the term "water-splitting." For this reason, the importance of water-splitting for biomedical applications is significantly underestimated. This progress work is written with the aims to explain and summarize how the principle of water-splitting is employed to achieve therapeutic results not offered by conventional approaches. It is expected that this progress report will not only explain the importance of water-splitting to scientists in the biomedical fields, it should also draw attention from scientists working on energy applications of water-splitting.

Concepts toward directing human astroplasticity to promote neuroregeneration.

Astrocytes exhibit dynamic and complex reactions to various insults. Recently, investigations into the transitions that occur during cellular specification, differentiation, maturation, and disease responses have provided insights into understanding the mechanisms that underlie these altered states of reactivity and function. Here we summarize current concepts in how astrocyte state transitions, termed astroplasticity, are regulated, as well as how this affects neural circuit function through extracellular signaling. We postulate that a promising future approach toward enhancing functional repair after injury and disease would be to steer astrocytes away from an inhibitory response and toward one that is beneficial to neuroplasticity and neuroregeneration. Toward this goal, we discuss emerging biotechnological advancements, with a focus on human pluripotent stem cell bioengineering, which has high potential for effective manipulation and control of astroplasticity. Highlights include innovations in cellular transdifferentiation techniques, nanomedicine, organoid and three-dimensional (3D) spheroid microcircuit development, and the use of biomaterials to influence the extracellular environment. Current barriers and future applications are also summarized in order to augment the design of future preclinical trials aimed toward astrocyte-targeted neuroregeneration with a concept termed astrocellular therapeutics. Developmental Dynamics 248:21-33, 2019. © 2018 Wiley Periodicals, Inc.

Recent trends in treatment of thalassemia.

Thalassemia is a common inherited monogenic disease. It is characterized by chronic hemolysis, ineffective erythropoiesis (IE) and iron overload. Despite advances in transfusion practices and chelation therapy, still many limitations in delivering these standard therapies exist. Challenges of currently available standard care and advances in understanding the underlying pathophysiological mechanisms in thalassemia stimulated research towards development of novel therapeutic targets. Agents reducing IE as Jak 2 inhibitors and Activin II receptor traps are promising and are currently in clinical trials. Other approaches targeting iron dysregulation as mini-hepcidins, exogenous transferrin and erythroferrone inhibitors are in preclinical studies. Gene therapy, a rapidly evolving field, has exhibited remarkable progress in recent years. Studies have focused on ß or γ-globin addition, over expression of endogenous γ-globin-activating transcription factors, silencing of γ-globin repressors and genome editing of ß-globin mutations or γ-globin repressors. In this article we provide an overview of emerging recent trends in treatment of thalassemia targeting IE, iron dysregulation and novel curative treatments as gene therapy and gene editing.

How I treat myeloma with new agents.

At present, multiple classes of agents with distinct mechanisms of action are available for the treatment of patients with multiple myeloma (MM), including alkylators, steroids, immunomodulatory agents (IMiDs), proteasome inhibitors (PIs), histone deacetylase inhibitors (DACIs), and monoclonal antibodies (mAbs). Over the last 5 years, several new agents, such as the third-generation IMiD pomalidomide, the second-generation PIs carfilzomib and ixazomib, the DACI panobinostat, and 2 mAbs, elotuzumab and daratumumab, have been approved, incorporated into clinical guidelines, and have transformed our approach to the treatment of patients. These agents may be part of doublet or triplet combinations, or incorporated into intensive strategies with autologous stem cell transplantation. In this review, I discuss the different treatment options available today for the treatment of MM in frontline and relapse settings.

Clinical utility of viscoelastic testing (TEG and ROTEM analyzers) in the management of old and new therapies for hemophilia.

Hemophilia A and B are rare inherited bleeding disorders resulting from deficiency of coagulation factors VIII and IX respectively. In the past few decades, the field of hemophilia has witnessed pivotal management challenges and therapeutic advances. Routine coagulation and factor assays, while useful in the classification of severity and treatment monitoring in hemophilia patients, have been shown to be of limited use in managing clinical presentations and outcomes. This prompted the investigation of viscoelastic studies in hemophilia care, which have established their utility in various bleeding and thrombotic states. In this review, we will discuss and critically assess the current literature highlighting the use of viscoelastic studies in various aspects of hemophilia including the determination of clinical phenotype, management of patients with inhibitors, perioperative management, and monitoring of novel agents.

Waldenström macroglobulinemia: 2019 update on diagnosis, risk stratification, and management.

DISEASE OVERVIEW: Waldenström macroglobulinemia (WM) is a lymphoplasmacytic lymphoma with immunoglobulin M (IgM) monoclonal protein. Clinical features include anemia, thrombocytopenia, hepatosplenomegaly, lymphadenopathy, and rarely hyperviscosity. DIAGNOSIS: Presence of IgM monoclonal protein associated with ≥10% clonal lymphoplasmacytic cells in bone marrow confirms the diagnosis. The L265P mutation in MYD88 is detectable in >90% of patients and is found in the majority of IgM monoclonal gammopathy of undetermined significance patients. RISK STRATIFICATION: Age, hemoglobin level, platelet count, ß2 microglobulin, and monoclonal IgM concentrations are characteristics that are predictive of outcomes. RISK-ADAPTED THERAPY: Not all patients who fulfill WM criteria require therapy; these patients can be observed until symptoms develop. Rituximab-monotherapy is inferior to regimens that combine it with bendamustine, an alkylating agent, a proteosome inhibitor, or ibrutinib. Purine nucleoside analogs are active but usage is declining for less toxic alternatives. The preferred Mayo Clinic induction is rituximab and bendamustine. Potential for stem cell transplantation should be considered in selected younger patients. MANAGEMENT OF REFRACTORY DISEASE: Bortezomib, fludarabine, thalidomide, everolimus, ibrutinib, carfilzomib, lenalidomide, and bendamustine have all been shown to have activity in relapsed WM. Given WM's natural history, reduction of therapy toxicity is an important part of treatment selection.

Defining and Managing High-Priced Cures: Healthcare Payers' Opinions.

OBJECTIVES: Recent regulatory approvals of potentially curative but high-cost treatments have made these therapies a focus of health policy discussions. Cures present new challenges to healthcare payers because they have high upfront costs but have life-long health benefits. The objectives of this study are to understand how healthcare payers define and manage cures. We investigated payers' views on key features of curative treatments and the affordability and value challenges they present. METHODS: We conducted semistructured interviews in 2016 with key informants in US payer organizations. Interviewees were directly involved in coverage determination for highly effective and curative therapies. RESULTS: We contacted 24 individuals and 18 participated. When asked what aspects of cures were important for coverage determination, an equal percentage of respondents (61% each) mentioned clinical and economic factors. In defining a cure, half of respondents included an economic element such as no downstream costs associated with the disease. When asked about challenges, 72% of respondents mentioned uncertainty regarding long-term outcomes and 56% mentioned membership churn and competition. CONCLUSIONS: Payers expressed a novel definition of a cure-which we call a "healthcare cost cure"-that captures both the clinical and economic consequences of treatment. This definition may be more pertinent in fragmentary financing systems that unevenly distribute cure costs and benefits across payers. Overall findings indicate that decision makers desire evidence to ensure that the long-term real-world consequences of covering cures match the expected benefits. Future policies need to balance upfront acquisition costs with downstream financial benefits.

[Alzheimer's disease therapy: challenges and perspectives.]

Here we review both clinically applied and newly emerging approaches for Alzheimer's disease management. Alzheimer's disease or Alzheimer's type dementia is the most common type of primary dementia affecting late and senile age. Hallmarks of the disorder include progressive memory loss and highest nervous activity disruption; these cause dramatic consequences to the psychological activity. The disease course is characterized by continuous (lasting years and decades) decline, increasing degree of disability, and eventual death. Despite long-lasting attempts, researchers and medical professionals were not able to elaborate effective treatment so far. The problem is tightly connected to elucidating of Alzheimer's disease molecular mechanisms as well as development of novel therapeutics and early diagnostics approaches.

Healing activities construct the objects of therapy: Medicine's way of seeking truth, organizing forms of reality, regulating patients' bodies, illness and culture?

In this paper, I will explore the concept that healing activities shape the objects of therapy and seek to construct those objects through therapeutic activities. Objects of therapy are the persons, patients, human bodies, diseases, physiological processes and personal suffering-that which clinical medicine constructs through its distinctive formative processes, practices and knowledge. The rationale for choice of philosophical sources namely, Cassirer, Foucault, the anthropological perspective of Good and the sociological account of Frank will be discussed. The claim articulated by Good will be examined and its relationship to culture, illness, medical knowledge, practice, truth, and science. I then focus on Frank's concepts of the patient and the body and how medical knowledge and practices affects it. The concept that the medicalization of the illness narrative silences the patient's voice requiring an ethic of listening will be emphasized, described and further supported by Charon's (2006, Narrative medicine: Honoring the stories of illness. New York, NY: Oxford University Press) and Cassell's (2015, The nature of suffering and the goals of medicine. New York, NY: Oxford University Press) thoughts on narrative of illness in clinical medicine. My position concludes that healing activities construct the objects of therapy: as the medical culture's way of seeking truth; as medicine's way of mediating and organizing forms of reality through culture and symbolic forms; and, as medicine's way of entering the body and constructing the disease. Lastly, I suggest that in spite of the remarkable progress in the control of disease, the failure to address the interpretation of illness meanings is a fundamental flaw in the work of "doctoring." The experience and meanings of illness are at the centre of clinical practice and is a moral, political, ethical and professional obligation. The person is a cultural construct, a complex and culturally shaped way of experiencing self and other, and cultural "work" is required to constitute the person who is the object of medical attention and it also necessitates the ethic of listening.

Increased Survival for Children With Acute Myeloid Leukemia Results From Improved Postrelapse Treatment.

BACKGROUND: The treatment for pediatric acute myeloid leukemia (AML) has not changed significantly over the past 3 decades, yet outcomes have improved with cure rates increasing from 30% to over 60% of all newly diagnosed children over this period. This improvement in survival has been attributed to both treatment intensification and improved supportive care over the decades, although the precise impact of each remains unknown. PATIENTS AND METHODS: We retrospectively analyzed a unique cohort of 276 patients with de novo AML diagnosed in childhood, all treated with the same chemotherapy protocol over a 25-year period from 1986 to 2012. RESULTS: The contemporary cohort (2000-2012), compared with the historical cohort (1986-1999) had significantly improved overall survival (75% vs. 50%; hazard ratio, 2.17; 95% confidence interval, 1.15-2.93), lower disease-related mortality (38% vs. 19%, P=0.02) and were significantly more likely to receive an allogeneic transplant after relapse (stem cell transplantation [SCT], 73% vs. 12%; P<0.0001). Allogeneic transplant postrelapse was associated with a significantly improved survival across the entire cohort (overall survival 50% for allogeneic SCT vs. 12% for autologous or none, P<0.0001). There was no significant difference between the contemporary and historical cohorts in treatment-related mortality (13% vs. 7%, P=0.42) or relapse rates after induction (50% in older cohort vs. 40% in recent era, P=0.25), suggesting consistency of induction treatment efficacy and toxicity across the 2 periods. CONCLUSIONS: This data suggests improved survival in pediatric AML in the modern era has predominantly resulted from changes in treatment after relapse, including increased use of allogeneic SCT.

Challenges and Opportunities of Nontraditional Approaches to Treating Bacterial Infections.

Due to increasing rates of antimicrobial-resistant infections and the current inadequacy of the antibiotic pipeline, there is increasing interest in nontraditional approaches to antibacterial therapies. We define "traditional" agents as small-molecule agents that directly target bacterial components to exert a bacteriostatic or bactericidal effect, and "nontraditional approaches" as antimicrobial therapeutics that work through other means (ie, not a small molecule and/or utilizes a nontraditional target). Due to their atypical features, such therapies may be less susceptible to the emergence of resistance than traditional antibiotics. They include approaches such as monoclonal antibodies, virulence disruptors, immunomodulators, phage therapies, microbiome-based therapies, antibiotic potentiators, and antisense approaches. This article discusses both the developmental and regulatory advantages and challenges associated with each of these technologies. By identifying existing regulatory and developmental gaps, we hope to provide a sense of where focusing resources may provide the greatest impact on successful product development.

[Intestinal microbiota: towards therapeutic applications]. / Microbiote intestinal :vers des applications thérapeutiques.

Due to technological advances in DNA sequencing, the number of microbiota studies has increased exponentially in recent years. The intestinal microbiota, characterized by high diversity and bacterial richness, received particular interest. The studies showed that the modifications of the intestinal microbiota derive from and lead to different mechanisms and explain various pathologies, including those outside the digestive system.The aim of this short article is to comment on some recent findings on the human microbiota in a clinical context. We attempt to identify the strengths of current research as well as the trends that emerge from an abundant literature of a rather heterogeneous quality.

Favorisé par les avancées technologiques du séquençage de l'ADN, le nombre d'études sur le microbiote a augmenté de manière exponentielle ces dernières années. Le microbiote intestinal, caractérisé par sa diversité et sa richesse bactérienne, a suscité un intérêt tout particulier. Il en ressort que les conséquences associées aux modifications du microbiote intestinal peuvent provenir de mécanismes très différents et expliquer ainsi une variété de pathologies s'étendant bien au-delà du système digestif. Le but de ce bref article est de repositionner les découvertes récentes sur le microbiote humain dans un contexte clinique. Il nous paraît judicieux de tenter d'identifier les points forts de la recherche actuelle ainsi que les tendances qui se dessinent au travers d'une littérature foisonnante et de qualité assez hétérogène.