Pathogenic Variants Associated with Epigenetic Control and the NOTCH Pathway Are Frequent in Classic Hodgkin Lymphoma.

Classic Hodgkin lymphoma (cHL) constitutes a B-cell neoplasm derived from germinal center lymphocytes. Despite high cure rates (80-90%) obtained with the current multiagent protocols, a significant proportion of cHL patients experience recurrences, characterized by a lower sensitivity to second-line treatments. The genomic background of chemorefractory cHL is still poorly understood, limiting personalized treatment strategies based on molecular features. In this study, using a targeted next-generation sequencing (NGS) panel specifically designed for cHL research, we compared chemosensitive and chemorefractory diagnostic tissue samples of cHL patients. Furthermore, we longitudinally examined paired diagnosis-relapsesamples of chemorefractory cHL in order to define patterns of dynamic evolution and clonal selection. Pathogenic variants in NOTCH1 and NOTCH2 genes frequently arise in cHL. Mutations in genes associated with epigenetic regulation (CREBBP and EP300) are particularly frequent in relapsed/refractory cHL. The appearance of novel clones characterized by mutations previously not identified at diagnosis is a common feature in cHL cases showing chemoresistance to frontline treatments. Our results expand current molecular and pathogenic knowledge of cHL and support the performance of molecular studies in cHL prior to the initiation of first-line therapies.

Precision Medicine Approaches in Cardiology and Personalized Therapies for Improved Patient Outcomes: A systematic review.

Personalized medicine is a novel and rapidly evolving approach to clinical practice that involves making decisions about disease prediction, prevention, diagnosis, and treatment by utilizing modern technologies. The concepts of precision medicine have grown as a result of ongoing developments in genomic analysis, molecular diagnostics, and technology. These advancements have enabled a deeper understanding and interpretation of the human genome, allowing for a personalized approach to clinical care. The primary objective of this research is to assess personalized medicine in terms of its indications, advantages, practical clinical uses, potential future directions, problems, and effects on healthcare. An extensive analysis of the scientific literature regarding this topic demonstrated the new medical approach's relevance and usefulness, as well as the fact that personalized medicine is becoming increasingly prevalent in various sectors. The online, internationally indexed databases PubMed and Cochrane Reviews were used to conduct searches for and critically evaluate the most relevant published research including original papers and reviews in the scientific literature. The findings suggest that precision medicine has a lot of potential and its implementation lowers the incidence of stroke as well as coronary heart disease and improves patient health in cardiology.

Revolutionizing in vivo therapy with CRISPR/Cas genome editing: breakthroughs, opportunities and challenges.

Genome editing using the CRISPR/Cas system has revolutionized the field of genetic engineering, offering unprecedented opportunities for therapeutic applications in vivo. Despite the numerous ongoing clinical trials focusing on ex vivo genome editing, recent studies emphasize the therapeutic promise of in vivo gene editing using CRISPR/Cas technology. However, it is worth noting that the complete attainment of the inherent capabilities of in vivo therapy in humans is yet to be accomplished. Before the full realization of in vivo therapeutic potential, it is crucial to achieve enhanced specificity in selectively targeting defective cells while minimizing harm to healthy cells. This review examines emerging studies, focusing on CRISPR/Cas-based pre-clinical and clinical trials for innovative therapeutic approaches for a wide range of diseases. Furthermore, we emphasize targeting cancer-specific sequences target in genes associated with tumors, shedding light on the diverse strategies employed in cancer treatment. We highlight the various challenges associated with in vivo CRISPR/Cas-based cancer therapy and explore their prospective clinical translatability and the strategies employed to overcome these obstacles.

A Leukemic Target with a Thousand Faces: The Mitochondria.

In the era of personalized medicine greatly improved by molecular diagnosis and tailor-made therapies, the survival rate of acute myeloid leukemia (AML) at 5 years remains unfortunately low. Indeed, the high heterogeneity of AML clones with distinct metabolic and molecular profiles allows them to survive the chemotherapy-induced changes, thus leading to resistance, clonal evolution, and relapse. Moreover, leukemic stem cells (LSCs), the quiescent reservoir of residual disease, can persist for a long time and activate the recurrence of disease, supported by significant metabolic differences compared to AML blasts. All these points highlight the relevance to develop combination therapies, including metabolism inhibitors to improve treatment efficacy. In this review, we summarized the metabolic differences in AML blasts and LSCs, the molecular pathways related to mitochondria and metabolism are druggable and targeted in leukemia therapies, with a distinct interest for Venetoclax, which has revolutionized the therapeutic paradigms of several leukemia subtype, unfit for intensive treatment regimens.

A living ex vivo platform for functional, personalized brain cancer diagnosis.

Functional precision medicine platforms are emerging as promising strategies to improve pre-clinical drug testing and guide clinical decisions. We have developed an organotypic brain slice culture (OBSC)-based platform and multi-parametric algorithm that enable rapid engraftment, treatment, and analysis of uncultured patient brain tumor tissue and patient-derived cell lines. The platform has supported engraftment of every patient tumor tested to this point: high- and low-grade adult and pediatric tumor tissue rapidly establishes on OBSCs among endogenous astrocytes and microglia while maintaining the tumor's original DNA profile. Our algorithm calculates dose-response relationships of both tumor kill and OBSC toxicity, generating summarized drug sensitivity scores on the basis of therapeutic window and allowing us to normalize response profiles across a panel of U.S. Food and Drug Administration (FDA)-approved and exploratory agents. Summarized patient tumor scores after OBSC treatment show positive associations to clinical outcomes, suggesting that the OBSC platform can provide rapid, accurate, functional testing to ultimately guide patient care.

A Novel Molecular Analysis Approach in Colorectal Cancer Suggests New Treatment Opportunities.

Colorectal cancer (CRC) is a molecular and clinically heterogeneous disease. In 2015, the Colorectal Cancer Subtyping Consortium classified CRC into four consensus molecular subtypes (CMS), but these CMS have had little impact on clinical practice. The purpose of this study is to deepen the molecular characterization of CRC. A novel approach, based on probabilistic graphical models (PGM) and sparse k-means-consensus cluster layer analyses, was applied in order to functionally characterize CRC tumors. First, PGM was used to functionally characterize CRC, and then sparse k-means-consensus cluster was used to explore layers of biological information and establish classifications. To this aim, gene expression and clinical data of 805 CRC samples from three databases were analyzed. Three different layers based on biological features were identified: adhesion, immune, and molecular. The adhesion layer divided patients into high and low adhesion groups, with prognostic value. The immune layer divided patients into immune-high and immune-low groups, according to the expression of immune-related genes. The molecular layer established four molecular groups related to stem cells, metabolism, the Wnt signaling pathway, and extracellular functions. Immune-high patients, with higher expression of immune-related genes and genes involved in the viral mimicry response, may benefit from immunotherapy and viral mimicry-related therapies. Additionally, several possible therapeutic targets have been identified in each molecular group. Therefore, this improved CRC classification could be useful in searching for new therapeutic targets and specific therapeutic strategies in CRC disease.

Towards the personalization of gelatin-based 3D patches: a tunable porous carrier for topical applications.

Cell-free based therapies, for example, the use of the cell secretome, have emerged as a promising alternative to conventional skin therapies using bioactive and, when combined with 3D printing technologies, allow the development of personalized dosage forms. This research work aimed to develop gelatin-based patches with controlled network topology via extrusion 3D printing, loaded with cell culture medium as a model of the secretome, and applicable as vehicles for topical delivery. Inks were optimized through rheological and printing assays, and the incorporation of medium had minor effects in printability. Regarding network topology, grid infills rendered more defined structures than the triangular layout, depicting clearer pores and pore area consistency. Release studies showed that filament spacing and infill pattern influenced the release of rhodamine B (model bioactive) and bovine serum albumin (model protein). Moreover, the grid patches (G-0.7/1/0.7), despite having around a seven-fold higher mean pore area than 0.7-mm triangular ones (T-0.7), showed a similar release profile, which can be linked to the network topology of the printed structures This work provided insight on employing (bio)printing in the production of carriers with reproducible and controlled pore area, able to incorporate cell-derived secretome and to be quickly tailored to the patient's lesions.

Providing Brief Personalized Therapies for Insomnia Among Workers Using a Sleep Prompt App: Randomized Controlled Trial.

BACKGROUND: Insomnia is the most common sleep disorder and the foremost health concern among workers. We developed a new sleep prompt app (SPA) for smartphones to positively alter the users' consciousness and behavior by sending timely short messages for mild sleep problems at an early stage. OBJECTIVE: The aim of this study is to investigate the effectiveness of the SPA in providing brief personalized therapy for insomnia among workers. METHODS: We conducted a 2-arm parallel randomized controlled trial. The intervention group used the SPA, and the control group received no intervention. Participants were recruited between November 2020 and January 2021. The researcher sent emails for recruitment to more than 3000 workers of 2 companies and 1 university in Japan. The SPA provided personalized prompt messages, sleep diaries, sleep hygiene education, stimulus control therapy, and sleep restriction therapy. The prompt messages were sent automatically to the participants to encourage them to improve their sleep habits and sleep status and were optimized to the individual's daily rhythm. The intervention program duration was 4 weeks. The primary outcome was a change in the Insomnia Severity Index (ISI) for the study period. The ISI was obtained weekly using a web questionnaire. RESULTS: A total of 116 Japanese workers (intervention group n=60, control group n=56) with sleep disorders were recruited. Two participants in the intervention group were excluded from the analyses because of challenges in installing the SPA. The mean ISI scores at baseline were 9.2 for both groups; however, after 4 weeks, the mean ISI scores declined to 6.8 and 8.0 for the intervention and control groups, respectively. Primary analysis using a linear mixed model showed a significant improvement in the temporal trends of the ISI in the SPA group and in the total population (P=.03). Subgroup analyses of ISI-8-insomniacs revealed a significant improvement in the temporal trends of ISI in the SPA group (P=.01), and the CFS score for physical condition significantly improved following the intervention (P=.02). CONCLUSIONS: This study demonstrates the effectiveness of the SPA in providing brief personalized therapy for insomnia among Japanese workers with mild insomnia. The physical fatigue score significantly improved in ISI-8-insomniacs. Thus, SPA could play an important role in reducing the adverse effects of sleep disorders in workers. To promote the wide use of the SPA in the future, further studies are required to examine its effectiveness in other age groups and individuals with health problems. TRIAL REGISTRATION: University Medical Information Network Clinical Trials Registry (UMIN-CTR) UMIN000042263; https://center6.umin.ac.jp/cgi-open-bin/ctr_e/ctr_view.cgi?recptno=R000046295.

A Reference Architecture for Data-Driven and Adaptive Internet-Delivered Psychological Treatment Systems: Software Architecture Development and Validation Study.

BACKGROUND: Internet-delivered psychological treatment (IDPT) systems are software applications that offer psychological treatments via the internet. Such IDPT systems have become one of the most commonly practiced and widely researched forms of psychotherapy. Evidence shows that psychological treatments delivered by IDPT systems can be an effective way of treating mental health morbidities. However, current IDPT systems have high dropout rates and low user adherence. The primary reason is that the current IDPT systems are not flexible, adaptable, and personalized as they follow a fixed tunnel-based treatment architecture. A fixed tunnel-based architecture follows predefined, sequential treatment content for every patient, irrespective of their context, preferences, and needs. Moreover, current IDPT systems have poor interoperability, making it difficult to reuse and share treatment materials. There is a lack of development and documentation standards, conceptual frameworks, and established (clinical) guidelines for such IDPT systems. As a result, several ad hoc forms of IDPT models exist. Consequently, developers and researchers have tended to reinvent new versions of IDPT systems, making them more complex and less interoperable. OBJECTIVE: This study aimed to design, develop, and evaluate a reference architecture (RA) for adaptive systems that can facilitate the design and development of adaptive, interoperable, and reusable IDPT systems. METHODS: This study was conducted in collaboration with a large interdisciplinary project entitled INTROMAT (Introducing Mental Health through Adaptive Technology), which brings together information and communications technology researchers, information and communications technology industries, health researchers, patients, clinicians, and patients' next of kin to reach its vision. First, we investigated previous studies and state-of-the-art works based on the project's problem domain and goals. On the basis of the findings from these investigations, we identified 2 primary gaps in current IDPT systems: lack of adaptiveness and limited interoperability. Second, we used model-driven engineering and Domain-Driven Design techniques to design, develop, and validate the RA for building adaptive, interoperable, and reusable IDPT systems to address these gaps. Third, based on the proposed RA, we implemented a prototype as the open-source software. Finally, we evaluated the RA and open-source implementation using empirical (case study) and nonempirical approaches (software architecture analysis method, expert evaluation, and software quality attributes). RESULTS: This paper outlines an RA that supports flexible user modeling and the adaptive delivery of treatments. To evaluate the proposed RA, we developed an open-source software based on the proposed RA. The open-source framework aims to improve development productivity, facilitate interoperability, increase reusability, and expedite communication with domain experts. CONCLUSIONS: Our results showed that the proposed RA is flexible and capable of adapting interventions based on patients' needs, preferences, and context. Furthermore, developers and researchers can extend the proposed RA to various health care interventions.

A State-of-the-Art Roadmap for Biomarker-Driven Drug Development in the Era of Personalized Therapies.

Advances in biotechnology have enabled us to assay human tissue and cells to a depth and resolution that was never possible before, redefining what we know as the "biomarker", and how we define a "disease". This comes along with the shift of focus from a "one-drug-fits-all" to a "personalized approach", placing the drug development industry in a highly dynamic landscape, having to navigate such disruptive trends. In response to this, innovative clinical trial designs have been key in realizing biomarker-driven drug development. Regulatory approvals of cancer genome sequencing panels and associated targeted therapies has brought personalized medicines to the clinic. Increasing availability of sophisticated biotechnologies such as next-generation sequencing (NGS) has also led to a massive outflux of real-world genomic data. This review summarizes the current state of biomarker-driven drug development and highlights examples showing the utility and importance of the application of real-world data in the process. We also propose that all stakeholders in drug development should (1) be conscious of and efficiently utilize real-world evidence and (2) re-vamp the way the industry approaches drug development in this era of personalized medicines.

Altering Landscape of Cancer Vaccines: Unique Platforms, Research on Therapeutic Applications and Recent Patents.

Recent developments in several areas are rekindling interest and empowering progress in improving therapeutic cancer vaccines. These advances have been made in target selection, vaccine technology, and approaches for reversing the immunosuppressive mechanisms exploited by cancers. Studies on diverse tumor antigens have revealed target properties, including high cell specificity and adequate immunogenicity, to affect clinical efficiency. Therefore, one of the principal goals of cancer vaccinology is the development of efficient therapeutic cancer vaccines that are capable of eliciting an effector as well as memory T cell response specific to tumor antigens. Neoantigens, which arise from mutated proteins in cancer cells, are cancer-specific and may be highly immunogenic. However, the vast majority of these are distinctive to each patient's cancer and hence require the development of personalised therapies. Novel immunotherapeutic strategies are focused on breaking immune tolerance to tumor antigens, improving the immunogenicity of tumor vaccines, in addition to overcoming mechanisms of tumor escape. However, current developments and patents in cancer immune therapies, together with associated technologies, are significant. Supreme achievements in immune inhibitor-centered therapies and neo-antigen identification tools envisage probable improvements in cancer vaccines with respect to treatments of malignancies. Antibody modulation of T cell function through checkpoint blockade or co-stimulatory activation may restore survival, proliferation, and effector function. Thus, these tumor-infiltrating T cells with genetically engineered therapeutic vaccines have the potential to act as curative cancer immune therapeutics. In this review, target tumor antigens employed in recent years in the development of therapeutic cancer vaccine approaches are described, and the patents involved in the process are highlighted.

Metabolomics of COPD Pulmonary Rehabilitation Outcomes via Exhaled Breath Condensate.

Chronic obstructive pulmonary disease (COPD) is characterized by different phenotypes and clinical presentations. Therefore, a single strategy of pulmonary rehabilitation (PR) does not always yield the expected clinical outcomes as some individuals respond excellently, others discreetly, or do not respond at all. Fifty consecutive COPD patients were enrolled. Of them, 35 starting a 5-week PR program were sampled at admission (T0), after 2 (T2W) and 5 (T5W) weeks, while 15 controls not yet on PR were tested at T0 and T5W. Nuclear magnetic resonance (NMR) profiling of exhaled breath condensate (EBC) and multivariate statistical analysis were applied to investigate the relationship between biomarkers and clinical parameters. The model including the three classes correctly located T2W between T0 and T5W, but 38.71% of samples partially overlapped with T0 and 32.26% with T5W, suggesting that for some patients PR is already beneficial at T2W (32.26% overlapping with T5W), while for others (38.71% overlapping with T0) more time is required. Rehabilitated patients presented several altered biomarkers. In particular, methanol from T0 to T5W decreased in parallel with dyspnea and fatigue, while the walk distance increased. Methanol could be ascribed to lung inflammation. We demonstrated that the metabolic COPD phenotype clearly evolves during PR, with a strict relationship between clinical and molecular parameters. Methanol, correlating with clinical parameters, represents a useful biomarker for monitoring personalized outcomes and establishing more targeted protocols.

[Poly(ADP-ribose) polymerase (PARP-)inhibitors as genetically based precision therapy in metastatic castration-resistent prostate cancer (mCRPC)]. / Poly-ADP-Ribose-Polymerase(PARP)-Inhibitoren als genetisch basierte Präzisionstherapie beim metastasierten kastrationsresistenten Prostatakarzinom (mCRPC).

With PARP inhibitors, the therapeutic landscape for metastatic castration-resistant prostate cancer (mCRPC) has been expanded by a new substance class since November 2020. Currently, the indication for this innovative therapy requires the presence of a mutation in one of the BRCA1/2 genes and prior hormonal therapy. This short review explains the molecular background and summarizes current clinical trials on PARP inhibition-also in combination with other therapy strategies. In view of positive data from the cited studies and the relatively high proportion of patients with "actionable" mutations, the personalized therapy concept of BRCA1/2 mutation-dependent PARP inhibition for mCRPC is now reflected in various guidelines including S3 guidelines.

Precision Oncology, Signaling, and Anticancer Agents in Cancer Therapeutics.

BACKGROUND: The global alliance for genomics and healthcare facilities provides innovative solutions to expedite research and clinical practices for complex and incurable health conditions. Precision oncology is an emerging field explicitly tailored to facilitate cancer diagnosis, prevention, and treatment based on patients' genetic profiles. Advancements in "omics" techniques, next-generation sequencing, artificial intelligence, and clinical trial designs provide a platform for assessing the efficacy and safety of combination therapies and diagnostic procedures. METHODS: Data were collected from PubMed and Google Scholar using keywords "Precision medicine," "precision medicine and cancer," "anticancer agents in precision medicine," and reviewed comprehensively. RESULTS: Personalized therapeutics, including immunotherapy and cancer vaccines, serve as a groundbreaking solution for cancer treatment. Herein, we take a measurable view of precision therapies and novel diagnostic approaches targeting cancer treatment. The contemporary applications of precision medicine have also been described, along with various hurdles identified in the successful establishment of precision therapeutics. CONCLUSION: This review highlights the key breakthroughs related to immunotherapies, targeted anticancer agents, and target interventions related to cancer signaling mechanisms. The success story of this field in context to drug resistance, safety, patient survival, and improving quality of life is yet to be elucidated. We conclude that, in the near future, the field of individualized treatments may truly revolutionize the nature of cancer patient care.

Breast Cancer Treatments: Updates and New Challenges.

Breast cancer (BC) is the most frequent cancer diagnosed in women worldwide. This heterogeneous disease can be classified into four molecular subtypes (luminal A, luminal B, HER2 and triple-negative breast cancer (TNBC)) according to the expression of the estrogen receptor (ER) and the progesterone receptor (PR), and the overexpression of the human epidermal growth factor receptor 2 (HER2). Current BC treatments target these receptors (endocrine and anti-HER2 therapies) as a personalized treatment. Along with chemotherapy and radiotherapy, these therapies can have severe adverse effects and patients can develop resistance to these agents. Moreover, TNBC do not have standardized treatments. Hence, a deeper understanding of the development of new treatments that are more specific and effective in treating each BC subgroup is key. New approaches have recently emerged such as immunotherapy, conjugated antibodies, and targeting other metabolic pathways. This review summarizes current BC treatments and explores the new treatment strategies from a personalized therapy perspective and the resulting challenges.

Resistant starch, microbiome, and precision modulation.

Resistant starch, microbiome, and precision modulation. Mounting evidence has positioned the gut microbiome as a nexus of health. Modulating its phylogenetic composition and function has become an attractive therapeutic prospect. Resistant starches (granular amylase-resistant α-glycans) are available as physicochemically and morphologically distinguishable products. Attempts to leverage resistant starch as microbiome-modifying interventions in clinical studies have yielded remarkable inter-individual variation. Consequently, their utility as a potential therapy likely depends predominantly on the selected resistant starch and the subject's baseline microbiome. The purpose of this review is to detail i) the heterogeneity of resistant starches, ii) how resistant starch is sequentially degraded and fermented by specialized gut microbes, and iii) how resistant starch interventions yield variable effects on the gut microbiome.

Discovery of CFTR modulators for the treatment of cystic fibrosis.

INTRODUCTION: Cystic fibrosis (CF) is a life-threatening inherited disease caused by mutations in the gene encoding the CF transmembrane conductance regulator (CFTR) protein, an anion channel expressed at the apical membrane of secretory epithelia. CF leads to multiorgan dysfunction with progressive deterioration of lung function being the major cause of untimely death. Conventional CF therapies target only symptoms and consequences downstream of the primary genetic defect and the current life expectancy and quality of life of these individuals are still very limited. AREA COVERED: CFTR modulator drugs are novel-specialized therapies that enhance or even restore functional expression of CFTR mutants and have been approved for clinical use for individuals with specific CF genotypes. This review summarizes classical approaches used for the pre-clinical development of CFTR correctors and potentiators as well as emerging strategies aiming to accelerate modulator development and expand theratyping efforts. EXPERT OPINION: Highly effective CFTR modulator drugs are expected to deeply modify the disease course for the majority of individuals with CF. A multitude of experimental approaches have been established to accelerate the development of novel modulators. CF patient-derived specimens are valuable cell models to predict therapeutic effectiveness of existing (and novel) modulators in a precision medicine approach.

Diagnosis and Management of Glioblastoma: A Comprehensive Perspective.

Glioblastoma is the most common malignant brain tumor in adults. The current management relies on surgical resection and adjuvant radiotherapy and chemotherapy. Despite advances in our understanding of glioblastoma onset, we are still faced with an increased incidence, an altered quality of life and a poor prognosis, its relapse and a median overall survival of 15 months. For the past few years, the understanding of glioblastoma physiopathology has experienced an exponential acceleration and yielded significant insights and new treatments perspectives. In this review, through an original R-based literature analysis, we summarize the clinical presentation, current standards of care and outcomes in patients diagnosed with glioblastoma. We also present the recent advances and perspectives regarding pathophysiological bases as well as new therapeutic approaches such as cancer vaccination and personalized treatments.

The Ins and Outs of RAS Effector Complexes.

RAS oncogenes are among the most commonly mutated proteins in human cancers. They regulate a wide range of effector pathways that control cell proliferation, survival, differentiation, migration and metabolic status. Including aberrations in these pathways, RAS-dependent signaling is altered in more than half of human cancers. Targeting mutant RAS proteins and their downstream oncogenic signaling pathways has been elusive. However, recent results comprising detailed molecular studies, large scale omics studies and computational modeling have painted a new and more comprehensive portrait of RAS signaling that helps us to understand the intricacies of RAS, how its physiological and pathophysiological functions are regulated, and how we can target them. Here, we review these efforts particularly trying to relate the detailed mechanistic studies with global functional studies. We highlight the importance of computational modeling and data integration to derive an actionable understanding of RAS signaling that will allow us to design new mechanism-based therapies for RAS mutated cancers.

Present and Future of Anti-Glioblastoma Therapies: A Deep Look into Molecular Dependencies/Features.

Glioblastoma (GBM) is aggressive malignant tumor residing within the central nervous system. Although the standard treatment options, consisting of surgical resection followed by combined radiochemotherapy, have long been established for patients with GBM, the prognosis is still poor. Despite recent advances in diagnosis, surgical techniques, and therapeutic approaches, the increased patient survival after such interventions is still sub-optimal. The unique characteristics of GBM, including highly infiltrative nature, hard-to-access location (mainly due to the existence of the blood brain barrier), frequent and rapid recurrence, and multiple drug resistance mechanisms, pose challenges to the development of an effective treatment. To overcome current limitations on GBM therapy and devise ideal therapeutic strategies, efforts should focus on an improved molecular understanding of GBM pathogenesis. In this review, we summarize the molecular basis for the development and progression of GBM as well as some emerging therapeutic approaches.