Recent Molecular Discoveries Research Articles

Chronic myelomonocytic leukemia: molecular pathogenesis and therapeutic innovations.

Chronic myelomonocytic leukemia (CMML) is an aggressive clonal stem cell disorder categorized amongst myelodysplastic/myeloproliferative (MDS/MPN) overlap neoplasms. While sharing features with both MDS and MPN, CMML has distinct molecular and clinical profiles. The presence of CMML-specific prognostic models, response criteria, and dedicated clinical trials underscores a unique and complex biology. Agerelated changes affecting the bone marrow microenvironment, immune responses, and the intricate balance between epigenetic deregulation and proinflammatory signaling are characteristic of this disease, collectively posing significant scientific and clinical challenges in management. CMML is an ageing-related, clinically heterogeneous neoplasm with limited approved therapeutic options, representing an area of unmet medical need. This review offers a comprehensive analysis of the current understanding of the molecular mechanisms driving CMML evolution and its clinical manifestations within the ever-evolving landscape of precision medicine. In light of the most recent molecular discoveries, we highlight the pitfalls of existing therapies and underscore promising investigational agents. Many of the biological findings discussed are shared across a spectrum of acute and chronic myeloid neoplasms, as well as clonal hematopoiesis, broadening the scope of this review.

The Evolving Classification of Meningiomas: Integration of Molecular Discoveries to Inform Patient Care.

Meningioma classification and treatment have evolved over the past eight decades. Since Bailey, Cushing, and Eisenhart's description of meningiomas in the 1920s and 1930s, there have been continual advances in clinical stratification by histopathology, radiography and, most recently, molecular profiling, to improve prognostication and predict response to therapy. Precise and accurate classification is essential to optimizing management for patients with meningioma, which involves surveillance imaging, surgery, primary or adjuvant radiotherapy, and consideration for clinical trials. Currently, the World Health Organization (WHO) grade, extent of resection (EOR), and patient characteristics are used to guide management. While these have demonstrated reliability, a substantial number of seemingly benign lesions recur, suggesting opportunities for improvement of risk stratification. Furthermore, the role of adjuvant radiotherapy for grade 1 and 2 meningioma remains controversial. Over the last decade, numerous studies investigating the molecular drivers of clinical aggressiveness have been reported, with the identification of molecular markers that carry clinical implications as well as biomarkers of radiotherapy response. Here, we review the historical context of current practices, highlight recent molecular discoveries, and discuss the challenges of translating these findings into clinical practice.

Human Skin Aging and the Anti-Aging Properties of Retinol.

The skin is the most-extensive and -abundant tissue in the human body. Like many organs, as we age, human skin experiences gradual atrophy in both the epidermis and dermis. This can be primarily attributed to the diminishing population of epidermal stem cells and the reduction in collagen, which is the primary structural protein in the human body. The alterations occurring in the epidermis and dermis due to the aging process result in disruptions to the structure and functionality of the skin. This creates a microenvironment conducive to age-related skin conditions such as a compromised skin barrier, slowed wound healing, and the onset of skin cancer. This review emphasizes the recent molecular discoveries related to skin aging and evaluates preventive approaches, such as the use of topical retinoids. Topical retinoids have demonstrated promise in enhancing skin texture, diminishing fine lines, and augmenting the thickness of both the epidermal and dermal layers.

A Comparison of the Fifth World Health Organization and the International Consensus Classifications of Mature T-Cell Lymphomas.

Peripheral T-cell lymphomas (PTCLs) are a rare subset of non-Hodgkin lymphomas that often carry significant difficulty in diagnosis and classification because of their rarity and biological complexity. Previous editions of the World Health Organization (WHO) classifications of hemopoietic neoplasms in 2001, 2008, and 2017 aimed to standardize hemopoietic neoplasm diagnosis in general. Since then, crucial clinico-pathological, immunophenotypic, and recent molecular discoveries have been made in the field of lymphomas, contributing to refining diagnostic criteria of several diseases, upgrading entities previously defined as provisional, and identifying new entities. In 2022, two different models were proposed to classify hematolymphoid neoplasms: the 5th edition of the WHO classification (WHO-HAEM5) and the International Consensus Classification (ICC). Of note, a common nosography is mandatory to ensure progress in health science and ensure the basis for a real precision medicine. In this article, the authors summarized the main differences with the previous fourth WHO edition and reviewed the main discrepancies between the two newest classifications, as far as PTCLs are concerned.

How Molecular Discoveries Have Changed Liver Tumor Pathology: A Brief Review.

Recent molecular discoveries have led to improved understanding of tumor biology and the development of new diagnostic assays. To review primarily 3 examples of liver tumors and to briefly illustrate how recent molecular discoveries have altered clinical liver pathology practice. First, we will discuss fibrolamellar carcinoma, which will be the main focus of discussion, as an example for new diagnostic tests that have been developed as a result of molecular discoveries. Additional information on the role of molecular diagnostics in hepatocellular adenoma and hepatocellular carcinoma will be provided. Second, we will use the example of epithelioid hemangioendothelioma as an example of how new diagnostic tools, based on molecular discoveries, may support improved prognostication. Finally, we will use the example of intrahepatic cholangiocarcinoma as an example of a liver tumor where new molecular discoveries have identified tractable therapeutic targets and led to new effective therapies. This portion of the manuscript will also include a description of the anatomic and molecular differences between intrahepatic, hilar, and extrahepatic cholangiocarcinoma. Fueled by molecular discoveries, new and better diagnostic tests and therapeutic targets have improved clinical care in patients affected by liver tumors.

Proceedings of the North American Society of Head and Neck Pathology Companion Meeting, New Orleans, LA, March 12, 2023: Classification of Salivary Gland Tumors: Remaining Controversial Issues?

The salivary gland section in the 5th edition of the World Health Organization Classification of Head and Neck Tumours includes a description of several new entities. In addition, numerous tumor variants were described and new concepts proposed, most of which have been based on recent molecular discoveries. However, there are still some controversial issues that remain to be resolved, and some of them are discussed in this review.

Utility of the burmese Python as a model for studying plasticity of extreme physiological systems.

Non-traditional animal models present an opportunity to discover novel biology that has evolved to allow such animals to survive in extreme environments. One striking example is the Burmese python (Python molurus bivittatus), which exhibits extreme physiological adaptation in various metabolic organs after consuming a large meal following long periods of fasting. The response to such a large meal in pythons involves a dramatic surge in metabolic rate, lipid overload in plasma, and massive but reversible organ growth through the course of digestion. Multiple studies have reported the physiological responses in post-prandial pythons, while the specific molecular control of these processes is less well-studied. Investigating the mechanisms that coordinate organ growth and adaptive responses offers the opportunity to gain novel insight that may be able to treat various pathologies in humans. Here, we summarize past research on the post-prandial physiological changes in the Burmese python with a focus on the gastrointestinal tract, heart, and liver. Specifically, we address our recent molecular discoveries in the post-prandial python liver which demonstrate transient adaptations that may reveal new therapeutic targets. Lastly, we explore new biology of the aquaporin 7 gene that is potently upregulated in mammalian cardiac myocytes by circulating factors in post-prandial python plasma.

Recent Advances in Frontotemporal Dementia.

Frontotemporal dementia (FTD) is a devastating neurodegenerative condition for which there is currently no effective treatment. Although it is much less common than Alzheimer's disease, the impact of FTD is increased by its relatively early onset and high heritability. Clinical heterogeneity and overlap with other neurodegenerative and psychiatric syndromes complicate diagnosis. However, recent advances in our understanding of the molecular basis of FTD provide a foundation for the development of much-needed biomarkers and targeted therapies. This review provides a summary of the recently revised clinical criteria for FTD, highlights diagnostic challenges, briefly summarizes recent molecular discoveries and then focuses on promising developments in biomarkers and clinical trials.

Liverwort oil bodies: diversity, biochemistry, and molecular cell biology of the earliest secretory structure of land plants.

Liverworts are known for their large chemical diversity. Much of this diversity is synthesized and enclosed within oil bodies (OBs), a synapomorphy of the lineage. OBs contain the enzymes to biosynthesize and store large quantities of sesquiterpenoids and other compounds while limiting their cytotoxicity. Recent important biochemical and molecular discoveries related to OB formation, diversity, and biochemistry allow comparison with other secretory structures of land plants from an evo-devo perspective. This review addresses and discusses the most recent advances in OB origin, development, and function towards understanding the importance of these organelles in liverwort physiology and adaptation to changing environments. Our mapping of OB types and chemical compounds to the current liverwort phylogeny suggests that OBs were present in the most recent common ancestor of liverworts, supporting that OBs evolved as the first secretory structures in land plants. Yet, we require better sampling to define the macroevolutionary pattern governing the ancestral type of OB. We conclude that current efforts to find molecular mechanisms responsible for the morphological and chemical diversity of secretory structures will help understand the evolution of each major group of land plants, and open new avenues in biochemical research on bioactive compounds in bryophytes and vascular plants.

Proceedings of the North American Society of Head and Neck Pathology, Los Angeles, CA, March 20, 2022: Emerging Entities in Salivary Gland Tumor Pathology.

Salivary gland tumor pathology is one of the most challenging areas in all head and neck surgical pathology. Compounding its inherent difficulty are numerous novel entities, variants and concepts, most of which have been based on recent molecular discoveries. This review will serve to update the practicing pathologist on a selected group of emerging entities in salivary gland tumor pathology.

History of Ataxias and Paraplegias with an Annotation on the First Description of Striatonigral Degeneration.

The aim of this paper is to carry out a historical overview of the evolution of the knowledge on degenerative cerebellar disorders and hereditary spastic paraplegias, over the last century and a half. Original descriptions of the main pathological subtypes, including Friedreich's ataxia, hereditary spastic paraplegia, olivopontocerebellar atrophy and cortical cerebellar atrophy, are revised. Special attention is given to the first accurate description of striatonigral degeneration by Hans Joachim Scherer, his personal and scientific trajectory being clarified. Pathological classifications of ataxia are critically analysed. The current clinical-genetic classification of ataxia is updated by taking into account recent molecular discoveries. We conclude that there has been an enormous progress in the knowledge of the nosology of hereditary ataxias and paraplegias, currently encompassing around 200 genetic subtypes.

Responses of the Plant Cell Wall to Sub-Zero Temperatures: A Brief Update.

Our general understanding of plant responses to sub-zero temperatures focuses on mechanisms that mitigate stress to the plasma membrane. The plant cell wall receives comparatively less attention, and questions surrounding its role in mitigating freezing injury remain unresolved. Despite recent molecular discoveries that provide insight into acclimation responses, the goal of reducing freezing injury in herbaceous and woody crops remains elusive. This is likely due to the complexity associated with adaptations to low temperatures. Understanding how leaf cell walls of herbaceous annuals promote tissue tolerance to ice does not necessarily lead to understanding how meristematic tissues are protected from freezing by tissue-level barriers formed by cell walls in overwintering tree buds. In this mini-review, we provide an overview of biological ice nucleation and explain how plants control the spatiotemporal location of ice formation. We discuss how sugars and pectin side chains alleviate adhesive injury that develops at sub-zero temperatures between the matrix polysaccharides and ice. The importance of site-specific cell-wall elasticity to promote tissue expansion for ice accommodation and control of porosity to impede ice growth and promote supercooling will be presented. How specific cold-induced proteins modify plant cell walls to mitigate freezing injury will also be discussed. The opinions presented in this report emphasize the importance of a plant’s developmental physiology when characterizing mechanisms of freezing survival.

An unusual biphasic pulmonary lesion: late metastasis from a mandibular ameloblastoma

Ameloblastoma is mostly a benign odontogenic tumour most frequently arising within the mandible and maxilla. Although ameloblastoma can be locally aggressive and prone to local recurrence, metastasis is a rare (and usually late) complication. We report a case of a metastatic ameloblastoma to the lung following an original presentation with a traumatic jaw fracture through what was thought to be a mandibular odontogenic cyst in 1988. The definitive diagnosis of ameloblastoma was not reached until a local recurrence occurred ten years later; this was managed with hemimandibulectomy and post-operative radiotherapy. A single lung lesion was identified incidentally 33 years after the original presentation: it demonstrated typical morphological features of ameloblastoma and FOXP1 immunostaining was confirmatory. Recent advances in understanding the genetic pathogenesis of ameloblastoma demonstrate frequent BRAFV600E mutations as well as mutations in other MAP kinase pathway genes such as KRAS, NRAS, HRAS and FGFR2.1 Several case reports have indicated promising results with BRAF inhibitor therapy in metastatic ameloblastoma.2 1.Brown N, Betz B. Ameloblastoma: a review of recent molecular pathogenetic discoveries. Biomark Cancer 2015; 7 (Suppl 2): 19–24.2.González-González R, López-Verdín S, Lavalle-Carrasco J, et al. Current concepts in ameloblastoma-targeted therapies in B-raf proto-oncogene serine/threonine kinase V600E mutation: Systematic review. World J Clin Oncol 2020; 11: 31–42.

Rosette morphology in zona glomerulosa formation and function

How morphology informs function is a fundamental biological question. Here, we review the morphological features of the adrenal zona glomerulosa (zG), highlighting recent cellular and molecular discoveries that govern its formation. The zG consists of glomeruli enwrapped in a Laminin-β1-enriched basement membrane (BM). Within each glomerulus, zG cells are organized as rosettes, a multicellular structure widely used throughout development to mediate epithelial remodeling, but not often found in healthy adult tissues. Rosettes arise by constriction at a common cellular contact point mediated/facilitated by adherens junctions (AJs). In mice, small, dispersed AJs first appear postnatally and enrich along the entire cell-cell contact around 10 days after birth. Subsequently, these AJ-rich contacts contract, allowing rosettes to form. Concurrently, flat sheet-like domains in the nascent zG, undergo invagination and folding, gradually giving rise to the compact round glomeruli that comprise the adult zG. How these structures impact adrenal function is discussed.

Liquid biopsy in ovarian cancer: Catching the silent killer before it strikes.

Epithelial ovarian cancer (EOC) is the most lethal gynaecological malignancy in the western world. The majority of women presenting with the disease are asymptomatic and it has been dubbed the “silent killer”. To date there is no effective minimally invasive method of stratifying those with the disease or screening for the disease in the general population. Recent molecular and pathological discoveries, along with the advancement of scientific technology, means there is a real possibility of having disease-specific liquid biopsies available within the clinical environment in the near future. In this review we discuss these discoveries, particularly in relation to the most common and aggressive form of EOC, and their role in making this possibility a reality.

Historical Anecdotes and Breakthroughs of Histamine: From Discovery to Date.

Investigating about the history of allergies and discovery of the histamine's role in the immune response through historical references, starting with ancient anecdotes, analysing the first immunization attempts on animals to understand its importance as the anaphylaxis mediator. Moreover, we shortly resume the most recent discoveries on mast cell role in allergic diseases throughout the latest updates on its antibody-independent receptors. Publications, including reviews, treatment guidelines, historical and medical books, on the topic of interest were found on Medline, PubMed, Web of Knowledge, Web of Science, Google Scholar, Elsevier's (EMBASE.comvarious internet museum archives. Texts from the National Library of Greece (Stavros Niarchos Foundation), from the School of Health Sciences of the National and Kapodistrian University of Athens (Greece). We selected key articles which could provide ahistorical and scientific insight into histamine molecule and its mechanism of action's discovery starting with Egyptian, Greek and Chinese antiquity to end with the more recent pharmacological and molecular discoveries. Allergic diseases were described by medicine since ancient times, without exactly understanding the physio-pathologic mechanisms of immuno-mediated reactions and of their most important biochemical mediator, histamine. Researches on histamine and allergic mechanisms started at the beginning of the 20th century with the first experimental observations on animals of anaphylactic reactions. Histamine was then identified as their major mediator of many allergic diseases and anaphylaxis, but also of several physiologic body's functions, and its four receptors were characterized. Modern researches focus their attention on the fundamental role of the antibody-independent receptors of mast cells in allergic mechanisms, such as MRGPRX2, ADGRE2 and IL-33 receptor. New research should investigate how to modulate immunity cells activity in order to better investigate possible multi-target therapies for host's benefits in preclinical and clinical studies on allergic diseases in which mast cells play a major role.

Primary Vascular Tumors of Bone: A Monoinstitutional Morphologic and Molecular Analysis of 427 Cases With Emphasis on Epithelioid Variants.

Recent molecular discoveries have refined vascular bone tumor classification. To investigate the clinical relevance of these refinements, we reviewed all cases of primary vascular bone tumors treated at our Institute. On the basis of morphology, cases were assessed immunohistochemically and molecularly. A total of 427 cases of primary vascular tumor of bone with available follow-up and histologic material were retrieved and reclassified according to the most recent diagnostic criteria as follows: 289 hemangiomas, 38 epithelioid hemangiomas, 21 epithelioid hemangioendotheliomas, 2 retiform hemangioendotheliomas, 1 intraosseous papillary intralymphatic angioendothelioma, 24 pseudomyogenic hemangioendotheliomas, and 52 angiosarcomas (of these, 45 were epithelioid angiosarcomas and 7 spindle cell secondary angiosarcoma). Both epithelioid and classic hemangiomas behave as benign tumors with excellent prognosis. The distinction between cellular and conventional type of epithelioid hemangioma was not associated with a different clinical course. Conversely, epithelioid hemangioendothelioma exhibited a more aggressive clinical behavior than hemangioma, with higher rates of multifocality and distant spread. Immunohistochemical positivity for CAMTA1 or TFE3 did not have a prognostic implication. In epithelioid hemangioendothelioma, the presence of morphologic malignant features was associated with reduced disease-free (P=0.064) and overall survival (P=0.055). Pseudomyogenic hemangioendothelioma featured local aggressiveness in 5/24 patients exhibiting a clinical behavior closer to epithelioid hemangioma than epithelioid hemangioendothelioma. Last, 32/45 patients with epithelioid angiosarcoma died of disease with a median survival time of 10 months from diagnosis. In conclusion, the integration of morphologic, immunohistochemical, and molecular features allows a better stratification of primary vascular tumors of bone with significant prognostic and therapeutic implications.

Targets and Antibody Formats for Immunotherapy of Neuroblastoma.

Neuroblastoma (NB) is a malignant embryonal tumor of the sympathetic nervous system that is most commonly diagnosed in the abdomen, often presenting with signs and symptoms of metastatic spread. Three decades ago, high-risk NB metastatic to bone and bone marrow in children was not curable. Today, with multimodality treatment, 50% of these patients will survive, but most suffer from debilitating treatment-related complications. Novel targeted therapies to improve cure rates while minimizing toxicities are urgently needed. Recent molecular discoveries in oncology have spawned the development of an impressive array of targeted therapies for adult cancers, yet the paucity of recurrent somatic mutations or activated oncogenes in pediatric cancers poses a major challenge to the evolving paradigm of personalized medicine. Although low tumor mutational burden is a major hurdle for immune checkpoint inhibitors, an immature or impaired immune system and inhibitory tumor microenvironment can further complicate the prospects for successful immunotherapy. In this regard, despite the poor immunogenic properties of NB, the success of antibody-based immunotherapy and radioimmunotherapy directed at single targets (eg, GD2 and B7-H3) is both encouraging and surprising, given that most solid tumor antibodies that use Fc-dependent mechanisms or radioimmunotargeting have largely failed. Here, we summarize the current information on the immunologic properties of this tumor, its potential immunotherapeutic targets, and novel antibody-based strategies on the horizon.

Molecular and cellular discoveries in inflammatory dermatoses.

It was no earlier than 1986 that T helper (Th)1 and Th2 cells were described for the first time, opening the field of lymphocyte diversity and the investigation of the physiopathology of inflammatory diseases such as atopic dermatitis and psoriasis. Since that time, much research has been carried out showing a very complex communication network leading to inflammatory responses. Nowadays, understanding the cellular and molecular components of the inflammatory network and of the different crosstalks not only for groups of diseases but also for the individual patient is mandatory for developing and personalizing treatments. The aim of the present proceeding was to provide an update concerning some of the most recent molecular and cellular discoveries in inflammatory skin diseases and especially of AD.

Is now the time for molecular driven therapy for diffuse large B-cell lymphoma?

ABSTRACTIntroduction: Recent genetic and molecular discoveries regarding alterations in diffuse large B-cell lymphoma (DLBCL) deeply changed the approach to this lymphoproliferative disorder. Novel additional predictors of outcomes and new therapeutic strategies are being introduced to improve outcomes.Areas covered: This review aims to analyse the recent molecular discoveries in DLBCL, the rationale of novel molecular driven treatments and their impact on DLBCL prognosis, especially in ABC-DLBCL and High Grade B Cell Lymphoma. Pre-clinical and clinical evidences are reviewed to critically evaluate the novel DLBCL management strategies.Expert commentary: New insights in DLBCL molecular characteristics should guide the therapeutic approach; the results of the current studies which are investigating safety and efficacy of novel ‘X-RCHOP’ will probably lead, in future, to a cell of origin (COO) based upfront therapy. Moreover, it is necessary to identify early patients with DLBCL who carried MYC, BCL2 and/or BCL6 rearrangements double hit lymphomas (DHL) because they should not receive standard R-CHOP but high intensity treatment as reported in many retrospective studies. New prospective trials are needed to investigate the more appropriate treatment of DHL.