Minimally Invasive Therapies for Knee Osteoarthritis.

Knee osteoarthritis (KOA) is a musculoskeletal disorder characterized by articular cartilage degeneration and chronic inflammation, affecting one in five people over 40 years old. The purpose of this study was to provide an overview of traditional and novel minimally invasive treatment options and role of artificial intelligence (AI) to streamline the diagnostic process of KOA. This literature review provides insights into the mechanisms of action, efficacy, complications, technical approaches, and recommendations to intra-articular injections (corticosteroids, hyaluronic acid, and plate rich plasma), genicular artery embolization (GAE), and genicular nerve ablation (GNA). Overall, there is mixed evidence to support the efficacy of the intra-articular injections that were covered in this study with varying degrees of supported recommendations through formal medical societies. While GAE and GNA are more novel therapeutic options, preliminary evidence supports their efficacy as a potential minimally invasive therapy for patients with moderate to severe KOA. Furthermore, there is evidentiary support for the use of AI to assist clinicians in the diagnosis and potential selection of treatment options for patients with KOA. In conclusion, there are many exciting advancements within the diagnostic and treatment space of KOA.

Use of empirical medical therapies for idiopathic male infertility in Australia and New Zealand.

OBJECTIVE: Idiopathic male infertility is common, yet there is no approved treatment. This study aimed to understand practice patterns towards empirical medical therapy (EMT) for idiopathic male infertility in Australia and New Zealand (NZ). DESIGN: Clinical members of the Endocrine Society of Australia, Fertility Society of Australia & NZ, and Urological Society of Australia & NZ were invited to complete a survey. Questions included demographics, EMT practice habits, and thoughts regarding infertility case scenarios. Unadjusted group differences between specialists, those with and without additional training in male infertility, and frequency of managing it were evaluated. RESULTS: Overall, 147 of 2340 members participated (6.3%); majority were endocrinologists and gynaecologists. Participants were experienced; 35% had completed additional training in male infertility and 36.2% reported they frequently manage male infertility. Gynaecologists were more likely to manage male infertility and attend education courses than endocrinologists and urologists. Beliefs about the effect of EMT on sperm concentration and pregnancy did not differ between speciality types. Many respondents considered all patient scenarios suitable for EMT. Of medications, hCG and clomiphene were selected most. Two respondents indicated they would use testosterone to treat male infertility. CONCLUSIONS: This study demonstrates common use of EMT in Australia and NZ for idiopathic male infertility. The breadth of responses reflects a lack of consensus within the current literature, highlighting the need for further research to clarify their role in the management of idiopathic male infertility.

New Weapons to Fight against Staphylococcus aureus Skin Infections.

The treatment of Staphylococcus aureus skin and soft tissue infections faces several challenges, such as the increased incidence of antibiotic-resistant strains and the fact that the antibiotics available to treat methicillin-resistant S. aureus present low bioavailability, are not easily metabolized, and cause severe secondary effects. Moreover, besides the susceptibility pattern of the S. aureus isolates detected in vitro, during patient treatment, the antibiotics may never encounter the bacteria because S. aureus hides within biofilms or inside eukaryotic cells. In addition, vascular compromise as well as other comorbidities of the patient may impede proper arrival to the skin when the antibiotic is given parenterally. In this manuscript, we revise some of the more promising strategies to improve antibiotic sensitivity, bioavailability, and delivery, including the combination of antibiotics with bactericidal nanomaterials, chemical inhibitors, antisense oligonucleotides, and lytic enzymes, among others. In addition, alternative non-antibiotic-based experimental therapies, including the delivery of antimicrobial peptides, bioactive glass nanoparticles or nanocrystalline cellulose, phototherapies, and hyperthermia, are also reviewed.

Valor terapéutico de la restauración de microARNs supresores tumorales en el desarrollo de cáncer de pulmón / Therapeutic value of restoration of tumor suppressor microRNAs in the development of lung cancer

Los MicroARNs (miARNs) son moléculas reguladoras de la expresión de genes y como tales colaboran para determinar cuántas proteínas se producen en las células de un determinador gen. Como su nombre indican son moléculas funcionales pese a su pequeño tamaño (micro) y están constituidas por ácido ribonucleico (ARN), en contraste con los reguladores de la expresión génica más extensamente estudiados, que son de naturaleza proteica. Debido a su pequeño tamaño y su naturaleza peculiar, la presencia de los genes que codifican a los microARNs fue descubierta en el genoma humano en etapas posteriores a la de su secuenciación, ya en el siglo XXI. Los microARNs juegan un papel fundamental en el establecimiento de la identidad y el funcionamiento celular. Por lo que componentes de la maquinaria de síntesis de microARNs o microARNs per se, han sido asociados con diversas patologías humanas, incluyendo el cáncer. Se ha descubierto que los microARNs juegan un papel importante en muchos procesos celulares que están alterados en cáncer como: diferenciación, proliferación y apoptosis. Los genes que codifican para los microARNs se han encontrado en regiones cromosómicas frecuentemente ganadas o perdidas en cáncer. Algunos microARNs presentan niveles de expresión alterados en cáncer y han demostrado su capacidad para afectar la transformación celular, carcinogénesis y metástasis actuando como oncogenes o genes supresores de tumores. Así, la presencia de determinados microARNs se ha visto con utilidad clínica diagnóstica y pronóstica y se están intentando validar terapias basadas en la actividad de microARNs relevantes en cáncer. La familia de microARNs let-7 fue la primera descubierta en humanos. Muchos de sus miembros están en regiones cromosómicas frecuentemente delecionadas en tumores de cáncer de pulmón. Además, se ha correlacionado una expresión reducida de estos genes con un peor pronóstico cáncer de pulmón.(AU)

MicroRNAs (miRNAs) are molecules that regulate gene expression and as such they collaborate to determine how many proteins are produced in the cells of a given gene. As their name indicates, they are functional molecules despite their small size (micro) and are made up of ribonucleic acid (RNA), in contrast to the most extensively studied regulators of gene expression, which are protein in nature. Due to its small size and peculiar nature, the presence of the genes that encode microRNAs was discovered in the human genome in stages after its sequencing, already in the 21st century.MicroRNAs play a fundamental role in establishing cellular identity and function. Therefore, components of the microRNA synthesis machinery, or microRNAs per se, have been associated with various human pathologies, including cancer.It has been discovered that microRNAs play an important role in many cellular processes that are altered in cancer such as: differentiation, proliferation, and apoptosis. The genes that code for microRNAs have been found in chromosomal regions frequently gained or lost in cancer. Some microRNAs have altered expression levels in cancer and have demonstrated their ability to affect cellular transformation, carcinogenesis, and metastasis by acting as oncogenes or tumor suppressor genes. Thus, the presence of certain microRNAs has been seen to have clinical diagnostic and prognostic utility and attempts are being made to validate therapies based on the activity of relevant microRNAs in cancer.The let-7 family of microRNAs was the first discovered in humans. Many of its members are in chromosomal regions frequently deleted in lung cancer tumors.(AU)

ONCOmicroARNs y sus futuras aplicaciones farmacológicas / OncomicroARNs and their future pharmacological applications

Desde el descubrimiento del dogma central de la Biología Molecular, el ácido ribonucleico (ARN) se postuló como una molécula mensajera, que transmitía la información de la síntesis de proteínas del ADN, en núcleo de la célula, al citoplasma. Sin embargo, trabajos de investigación, han puesto de manifiesto que el ARN también ejerce funciones más allá de la de actuar como mensajero. Así, hoy en día se conoce que existe una gran cantidad de moléculas de ARN no codificantes de proteína que ejercen un papel fundamental en la célula. Los microARNs (miARNs), pertenecen a este ARN no codificante de proteínas y su estudio ha revolucionado nuestro conocimiento sobre la funcionalidad de los ARNs.Los microARNs son moléculas reguladoras de la expresión de génica que colaboran para determinar cuando o donde los genes se traducen a proteína. Como su nombre indica estas moléculas están compuestas por ácidos nucleicos (ARN) y no por proteína, en contraste con los reguladores de la expresión génica previamente conocidos. Debido a su pequeño tamaño (los genes humanos están codificados por miles de nucleótidos y los microARNs por sólo una veintena) y su naturaleza peculiar, los microARNs fueron descubiertos una vez se secuenció el genoma humano .Los microARNs juegan un papel fundamental en el establecimiento de la identidad celular. Componentes de la maquinaria de síntesis de microARNs o microARNs per se, han sido asociados con patologías humanas. Se ha descubierto que los microARNs juegan un papel importante en muchos procesos celulares que están alterados en cáncer como: diferenciación, proliferación y apoptosis. (AU)

Since the discovery of the central dogma of Molecular Biology, ribonucleic acid (RNA) was postulated as a messenger molecule, which transmitted the information of protein synthesis from DNA, in the cell nucleus, to the cytoplasm. However, research work has shown that RNA also performs functions beyond that of acting as a messenger. Thus, today it is known that there is a large number of non-protein coding RNA molecules that play a fundamental role in the cell. MicroRNAs (miRNAs) belong to this non-protein-coding RNA and their study has revolutionized our knowledge about the functionality of RNAs.MicroRNAs are gene expression regulatory molecules that help determine when or where genes are translated into protein. As their name indicates, these molecules are composed of nucleic acids (RNA) and not protein, in contrast to previously known regulators of gene expression. Due to their small size (human genes are encoded by thousands of nucleotides and microRNAs by only twenty) and their peculiar nature, microRNAs were discovered in the human genome once it was sequenced.MicroRNAs play a fundamental role in establishing cell identity. Components of the microRNA synthesis machinery, or microRNAs per se, have been associated with human pathologies. MicroRNAs have been found to play an important role in many cellular processes that are altered in cancer, such as differentiation, proliferation, and apoptosis. Thus, genes that code for microRNAs have been found in chromosomal regions frequently gained or lost in cancer. Some microRNAs have altered expression levels in cancer and have demonstrated their ability to affect cell transformation, carcinogenesis, and metastasis by acting as oncogenes or tumor suppressors. These microRNAs that are involved in tumor development have been called onco-microRNAs, and their name gives the title to this work. (AU)

Microtumor Models as a Preclinical Investigational Platform for Photodynamic Therapy.

Classic preclinical investigations on the mechanisms and effects of photodynamic therapy (PDT) are typically performed in two-dimensional cell cultures that have some, albeit limited, relevance to cancer biology. Bioengineered three-dimensional (3D) culture models of cancer are gaining traction in translational oncology as microtumors recapitulate the tumor architectures and cellular heterogeneity more faithfully than conventional 2D cultures. These 3D models bridge a gap between highly relevant but low-throughput in vivo animal models and high-throughput two-dimensional cultures with low clinical relevance, and thus hold promise as preclinical testing platforms in PDT research. Here, we discuss the potential applications of organotypic cancer models for PDT research and provide two well-established methodologies for generating 3D cultures of cancer: a liquid-suspended spheroid model and an adherent microtumor culture model grown on extracellular matrix scaffolds. Particular emphasis is given to harvesting the cultures for the purpose of immunoblotting and flow cytometry.

ONCOmicroARNs y sus futuras aplicaciones farmacológicas / OncomicroARNs and their future pharmacological applications

Los microARNs juegan un papel fundamental en el establecimiento de la identidad celular. Componentes de la maquinaria de síntesis de microARNs o microARNs per se, han sido asociados con patologías humanas. Se ha descubierto que los microARNs juegan un papel importante en muchos procesos celulares que están alterados en cáncer como: diferenciación, proliferación y apoptosis. Así, genes que codifican para los microARNs se han encontrado en regiones cromosómicas frecuentemente ganadas o perdidas en cáncer. Algunos microARNs presentan niveles de expresión alterados en cáncer y han demostrado su capacidad para afectar la transformación celular, carcinogénesis y metástasis actuando como oncogenes o tumores supresores. Estos microARNs que está implicados en el desarrollo tumoral se han denominado onco-microARNs, y su nombre da título a este trabajo. Estamos sólo al principio de comprender las repercusiones funcionales de la ganancia o pérdida de un microARN particular en cáncer, y aun se están ensayando las primeras aplicaciones farmacológicas para el tratamiento del cáncer. A pesar de todo, este campo está aportando una serie de prometedoras aplicaciones médicas en el diagnóstico, pronóstico y tratamiento del cáncer que podrían aportar nuevas herramientas a la medicina del futuro.(AU)

MicroRNAs play a fundamental role in establishing cell identity. Components of the microRNA synthesis machinery, or microRNAs per se, have been associated with human pathologies. MicroRNAs have been found to play an important role in many cellular processes that are altered in cancer, such as differentiation, proliferation, and apoptosis. Thus, genes that code for microRNAs have been found in chromosomal regions frequently gained or lost in cancer. Some microRNAs have altered expression levels in cancer and have demonstrated their ability to affect cell transformation, carcinogenesis, and metastasis by acting as oncogenes or tumor suppressors. These microRNAs that are involved in tumor development have been called onco-microRNAs, and their name gives the title to this work. We are only at the beginning of understanding the functional implications of the gain or loss of a particular microRNA in cancer, and early pharmacological applications for cancer treatment are still being tested. Despite everything, this field is providing a series of promising medical applications in the diagnosis, prognosis and treatment of cancer that could provide new tools for the medicine of the future.(AU)

New Approaches to Myelodysplastic Syndrome Treatment.

OPINION STATEMENT: The treatment of myelodysplastic syndromes (MDS) begins with risk stratification using a validated tool such as the International Prognostic Scoring System (IPSS) or its revised version (IPSS-R). This divides patients into lower- and higher- risk categories. Although treatment objectives in lower-risk MDS (LR-MDS) have traditionally been directed at improving cytopenias (usually anemia) as well as quality of life, recent data supports a potential role for early intervention in delaying transfusion dependency. In addition, careful individualized risk stratification incorporating clinical, cytogenetic, and mutational data might help identify patients at higher-than-expected risk for progression. Given the need for supportive care with red blood cell (RBC) transfusions leading to iron overload, iron chelation should be considered for patients with heavy transfusion requirements at risk for end-organ complications. For patients with LR-MDS and isolated anemia, no high-risk features, and endogenous erythropoietin (EPO) levels below 500 U/L, erythropoiesis-stimulating agents (ESAs) can be attempted to improve anemia. Some LR-MDS patient subgroups may also benefit from specific therapies including luspatercept (MDS with ring sideroblasts), lenalidomide (MDS with deletion 5q), or immunosuppressive therapy (hypocellular MDS). LR-MDS patients failing the above options, or those with multiple cytopenias and/or higher-risk features, can be considered for oral low-dose hypomethylating agent (HMA) therapy. Alternatively, these patients may be enrolled on a clinical trial with promising agents targeting the transforming-growth factor beta (TGF-ß) pathway, the hypoxia-inducible factor (HIF) pathway, telomerase activity, inflammatory signaling, or the splicing machinery. In higher-risk MDS (HR-MDS), therapy seeks to modify the natural history of the disease and prolong survival. Eligible patients should be considered for curative allogeneic hematopoietic stem cell transplantation (aHSCT). Despite promising novel combinations, the HMAs azacitidine (AZA) or decitabine (DAC) are still the standard of care for these patients, with intensive chemotherapy-based approaches being a potential option in a small subset of patients. Individuals who fail to respond or progress after HMA experience dismal outcomes and represent a major unmet clinical need. Such patients should be treated as part of a clinical trial if possible. Experimental agents to consider include venetoclax, myeloid cell leukemia 1 (MCL-1) inhibitors, eprenetapopt, CPX-351, immunotherapies (directed towards CD47, TIM3, or CD70), interleukin-1 receptor-associated kinase 4 (IRAK4) inhibitors, pevonedistat, seclidemstat, and eltanexor. In this review, we extensively discuss the current landscape of experimental therapies for both LR- and HR-MDS.

Introducing in vivo pancreatic cancer models for the study of new therapeutic regimens

Introduction: Pancreatic cancer is a severe oncological disease with an ever-increasing incidence and a high rate of morbidity and mortality. Therapeutic options are limited and the five-year overall survival rate is 7­20%, depending on the possibility of surgical resection and the earliness of detection. Most patients with this diagnosis die due to the resistance of tumour cells and their microenvironment to the used treatment regimes. Methods: In our study, we focused on the implementation of two in vivo models, which are the cell-line derived xenograft (CDX) and the patient-derived xenograft (PDX). These two models differ significantly from each other methodologically, technically, financially, but also in their achieved results. Results: In a pilot study, we managed to successfully implement the CDX model with a very aggressive and resistant PaCa-44 line of pancreatic cancer in a total of 30 NU/NU strain mice. Furthermore, we created three PDX models with various subtypes of pancreatic cancer from patients operated at the University Hospital Kralovske Vinohrady, Department of General Surgery. These tumours were re-transplanted into subsequent generations of 23 individuals of NOD/SCID strain and 47 NU/NU strain mice. The established CDX and PDX models are then used to compare conventional and experimental chemotherapy regimens. Conclusion: The next steps will be to evaluate the effects of treatment regimens by using imaging and molecular genetic methods and to optimise the entire process for further use in precise personalised medicine for patients with pancreatic cancer. The upcoming goal is to create a library of PDX models of the most common pancreatic ductal adenocarcinoma and other rare subtypes of pancreatic cancer.

Regulatory oversight on the use of experimental therapies during a pandemic: The case of early access to convalescent plasma therapy in three LMICs.

Clinicians, especially in low- and middle-income countries (LMICs), contend with limited economic and healthcare resources in deciding appropriate and feasible care for their patients. Some of the LMICs affected by COVID-19 implemented convalescent plasma therapy without sufficient regulatory guidance. Based on this experience, there are several requirements going forward, including: the need for an immediately accessible data gathering and processing system; the necessity of establishing regulatory pathways for early access to experimental treatment during emergency situations; and the accompanying reporting and monitoring requirements must be set. The different stakeholders must also be properly incorporated in the system that such a pathway will create, without neglecting to properly inform the public of the patient rights especially during an emergency situation.

An Assessment of Which Sociodemographic and Spinal Cord Injury-Specific Characteristics Influence Engagement With Experimental Therapies and Participation in Clinical Trials.

Background: Although a number of experimental therapies for spinal cord injury (SCI) have recently emerged, few authors have examined the goals of individuals with SCI considering experimental therapies, and none have determined whether sociodemographic and injury-specific characteristics influence that engagement. Objectives: To determine (a) the goals of individuals with SCI who are considering experimental therapies; (b) whether sociodemographic factors, injury-specific characteristics, and concerns over adverse events influence those goals and/or participation in experimental therapies and clinical trials; and (c) whether people with SCI feel they have adequate information about experimental therapies and clinical trials. Methods: An online survey that yielded 364 responses. Results: Most respondents (83.7%) had sought information about experimental therapies, and just under half (47.8%) had received one. The most frequently cited functional goals were improvement in bowel and bladder function and elimination of dysreflexia (60.4%). Several goals were influenced by age and level and completeness of injury, and most respondents (93.4%) wanted more information about experimental therapies. Just over one-third (34.6%) of respondents had participated in a clinical trial, and nearly all (96.9%) wanted more information about them. Having received experimental therapies and participated in clinical trials was positively correlated with seeking SCI-specific care from an SCI specialist rather than from a primary care physician. Most (83.9%) respondents would avoid or be reluctant to engage with a medical center if they were made aware of harm done to trial participants. Conclusion: This work suggests that there are unmet information needs among people with SCI, specifically pertaining to experimental therapies and clinical trials. It also reveals that improved access to SCI specialists may enhance access to novel treatments and research efforts. Being made aware of harm to trial participants may influence the decision of individuals with SCI to seek care at or enroll in trials at these clinical sites.

Enrolment of older adults with cancer in early phase clinical trials-an observational study on the experience in the north west of England.

INTRODUCTION: older patients represent the majority of cancer patients but are under-represented in trials, particularly early phase clinical trials (EPCTs). MATERIAL AND METHODS: observational retrospective study of patients referred for EPCTs (January-December 2018) at a specialist cancer centre in the UK. The primary aim was to analyse the successful enrolment into EPCTs according to age (<65/65+). The secondary aims were to identify enrolment obstacles and the outcomes of enrolled patients. Patient data were analysed at: referral; in-clinic assessment and after successful enrolment. Among patients assessed in clinic, a sample was defined by randomly matching the older cohort with the younger cohort (1:1) by tumour type. RESULTS: 555 patients were referred for EPCTs with a median age of 60 years, of whom 471 were assessed in new patient clinics (38% were 65+). From those assessed, a randomly tumour-matched sample of 318 patients (159 per age cohort) was selected. Older patients had a significantly higher comorbidity score measured by ACE-27 (P < 0.0001), lived closer to the hospital (P = 0.045) and were referred at a later point in their cancer management (P = 0.002). There was no difference in suitability for EPCTs according to age with overall 84% deemed suitable. For patients successfully enrolled into EPCTs, there was no difference between age cohorts (20.1 vs. 22.6% for younger and older, respectively; P = 0.675) and no significant differences in their safety and efficacy outcomes. DISCUSSION: older age did not affect the enrolment into EPCTs. However, the selected minority referred for EPCTs suggests a pre-selection upstream by primary oncologists.

Mucopolysaccharidosis Type I: Current Treatments, Limitations, and Prospects for Improvement.

Mucopolysaccharidosis type I (MPS I) is a lysosomal disease, caused by a deficiency of the enzyme alpha-L-iduronidase (IDUA). IDUA catalyzes the degradation of the glycosaminoglycans dermatan and heparan sulfate (DS and HS, respectively). Lack of the enzyme leads to pathologic accumulation of undegraded HS and DS with subsequent disease manifestations in multiple organs. The disease can be divided into severe (Hurler syndrome) and attenuated (Hurler-Scheie, Scheie) forms. Currently approved treatments consist of enzyme replacement therapy (ERT) and/or hematopoietic stem cell transplantation (HSCT). Patients with attenuated disease are often treated with ERT alone, while the recommended therapy for patients with Hurler syndrome consists of HSCT. While these treatments significantly improve disease manifestations and prolong life, a considerable burden of disease remains. Notably, treatment can partially prevent, but not significantly improve, clinical manifestations, necessitating early diagnosis of disease and commencement of treatment. This review discusses these standard therapies and their impact on common disease manifestations in patients with MPS I. Where relevant, results of animal models of MPS I will be included. Finally, we highlight alternative and emerging treatments for the most common disease manifestations.

Animal Models of Parkinson's Disease: Are They Useful or Not?

The use of animal models in Parkinson's disease research has been controversial in terms of how well they relate to the clinical condition and thus their utility for translating therapies from the lab to the clinic. In this article, two researchers debate this issue with Roger Barker taking the view that such models are not useful and may even be misleading, while Anders Björklund defends their use and highlights their value in better understanding and treating this condition.

Efficacy of experimental phage therapies in livestock.

Bacteriophages are the most abundant form of life on earth and are present everywhere. The total number of bacteriophages has been estimated to be 1032 virions. The main division of bacteriophages is based on the type of nucleic acid (DNA or RNA) and on the structure of the capsid. Due to the significant increase in the number of multi-drug-resistant bacteria, bacteriophages could be a useful tool as an alternative to antibiotics in experimental therapies to prevent and to control bacterial infections in people and animals. The aim of this review was to discuss the history of phage therapy as a replacement for antibiotics, in response to EU regulations prohibiting the use of antibiotics in livestock, and to present current examples and results of experimental phage treatments in comparison to antibiotics. The use of bacteriophages to control human infections has had a high success rate, especially in mixed infections caused mainly by Staphylococcus, Pseudomonas, Enterobacter, and Enterococcus. Bacteriophages have also proven to be an effective tool in experimental treatments for combating diseases in livestock.

Marketing Experimental Stem Cell Therapies in the UK: Biomedical Lifestyle Products and the Promise of Regenerative Medicine in the Digital Era.

Stem cell research has attracted much public and biomedical anticipation centred on the possibility of using stem cells to treat various diseases and conditions, but the number of evidence-based therapies is currently limited. Numerous commercial direct-to-consumer (DTC) businesses are nonetheless marketing experimental stem cell therapies online for myriad medical conditions and aesthetic ailments, which has attracted critique due to safety and efficacy concerns. Existing research has largely focused on the problem of unproven therapies and regulatory pathways for addressing it. The proliferation of these experimental products must also be examined, however, in the broader socio-technological context of consumer culture and changing practices of knowledge-making in the digital era. DTC stem cell therapies have emerged as a new biomedical 'lifestyle' product that blurs the boundaries between 'science,' 'medicine,' and 'consumer culture.' In using, conceptualising and marketing stem cells, commercial businesses build on and commercially co-opt alternative epistemic and ontological frames that challenge scientific medicine. They advance promissory narratives about their potential that tap on cultural aspirations around the future of medicine and health. This is key, not only for understanding how and why these therapies have proliferated but also in conceptualising what the 'problem' around them actually is.

A Proposed Roadmap for Parkinson's Disease Proof of Concept Clinical Trials Investigating Compounds Targeting Alpha-Synuclein.

The convergence of human molecular genetics and Lewy pathology of Parkinson's disease (PD) have led to a robust, clinical-stage pipeline of alpha-synuclein (α-syn)-targeted therapies that have the potential to slow or stop the progression of PD and other synucleinopathies. To facilitate the development of these and earlier stage investigational molecules, the Michael J. Fox Foundation for Parkinson's Research convened a group of leaders in the field of PD research from academia and industry, the Alpha-Synuclein Clinical Path Working Group. This group set out to develop recommendations on preclinical and clinical research that can de-risk the development of α-syn targeting therapies. This consensus white paper provides a translational framework, from the selection of animal models and associated end-points to decision-driving biomarkers as well as considerations for the design of clinical proof-of-concept studies. It also identifies current gaps in our biomarker toolkit and the status of the discovery and validation of α-syn-associated biomarkers that could help fill these gaps. Further, it highlights the importance of the emerging digital technology to supplement the capture and monitoring of clinical outcomes. Although the development of disease-modifying therapies targeting α-syn face profound challenges, we remain optimistic that meaningful strides will be made soon toward the identification and approval of disease-modifying therapeutics targeting α-syn.

Phase 1 Single- and Multiple-Ascending-Dose Randomized Studies of the Safety, Pharmacokinetics, and Pharmacodynamics of AG-348, a First-in-Class Allosteric Activator of Pyruvate Kinase R, in Healthy Volunteers.

Pyruvate kinase deficiency is a chronic hemolytic anemia caused by mutations in PK-R, a key glycolytic enzyme in erythrocytes. These 2 phase 1 randomized, placebo-controlled, double-blind healthy-volunteer studies assessed the safety, tolerability, and pharmacokinetics/pharmacodynamics of AG-348, a first-in-class allosteric PK-R activator. Twelve sequential cohorts were randomized 2:6 to receive oral placebo or AG-348, respectively, as a single dose (30-2500 mg) in the single-ascending-dose (SAD) study (ClinicalTrials.gov: NCT02108106) or 15-700 mg every 12 hours or 120 mg every 24 hours, for 14 days in the multiple-ascending-dose (MAD) study (ClinicalTrials.gov: NCT02149966). All 48 subjects completed the fasted SAD part; 44 of 48 completed the MAD (2 discontinued because of adverse events [AEs], 2 withdrew consent). The most common treatment-related AEs in AG-348-treated subjects were headache (16.7% [SAD] and 13.9% [MAD]) and nausea (13.9%, both studies). AE frequency increased at AG-348 doses ≥ 700 mg (SAD) and at 700 mg every 12 hours (MAD); 1 grade ≥ 3 AE occurred in the latter cohort. Pharmacokinetics were favorable with low variability. Dose-dependent changes in blood glycolytic intermediates consistent with glycolytic pathway activation were observed at all MAD doses, supporting future trials investigating the potential of AG-348 for treating PK deficiency or other anemias.

Hypoxia and Noncoding RNAs in Taxane Resistance.

Taxanes are chemotherapeutic drugs employed in the clinic to treat a variety of malignancies. Despite their overall efficacy, cancer cells often display resistance to taxanes. Therefore, new strategies to increase the effectiveness of taxane-based chemotherapeutics are urgently needed. Multiple molecular players are linked to taxane resistance; these include efflux pumps, DNA repair mechanisms, and hypoxia-related pathways. In addition, emerging evidence indicates that both non-coding RNAs and epigenetic effectors might also be implicated in taxane resistance. Here we focus on the causes of taxane resistance, with the aim to envisage an integrated model of the 'taxane resistance phenome'. This model could help the development of novel therapeutic strategies to treat taxane-resistant neoplasms.