Indolent lymphomas: introduction to a series highlighting progress and ongoing challenges.
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ABSTRACT:
SUBMITTER: Smith SM
PROVIDER: S-EPMC8719072 | biostudies-literature |
REPOSITORIES: biostudies-literature
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Project description:Over the past decades, tremendous progress has been made in the field of Gaucher disease, the inherited deficiency of the lysosomal enzyme glucocerebrosidase. Many of the colossal achievements took place during the course of the sixty-year tenure of Dr. Roscoe Brady at the National Institutes of Health. These include the recognition of the enzymatic defect involved, the isolation and characterization of the protein, the localization and characterization of the gene and its nearby pseudogene, as well as the identification of the first mutant alleles in patients. The first treatment for Gaucher disease, enzyme replacement therapy, was conceived of, developed and tested at the Clinical Center of the National Institutes of Health. Advances including recombinant production of the enzyme, the development of mouse models, pioneering gene therapy experiments, high throughput screens of small molecules and the generation of induced pluripotent stem cell models have all helped to catapult research in Gaucher disease into the twenty-first century. The appreciation that mutations in the glucocerebrosidase gene are an important risk factor for parkinsonism further expands the impact of this work. However, major challenges still remain, some of which are described here, that will provide opportunities, excitement and discovery for the next generations of Gaucher investigators.
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Project description:Indolent non-Hodgkin's lymphomas (iNHLs) include follicular lymphomas (FL), marginal-zone lymphoma, lymphoplasmacytic lymphoma/Waldenström macroglobulinemia and small lymphocytic lymphoma. First-line standard therapy in advanced, symptomatic iNHL consists of rituximab-based immunochemotherapy. The recent rediscovery of the 'old' chemotherapeutic agent bendamustine, an alkylating agent with a peculiar mechanism of action, has added a new effective and well-tolerated option to the therapeutic armamentarium in iNHL, increasing response rates and duration. However, patients invariably relapse and subsequent active and well-tolerated agents are needed. In recent years a large number of new targeted agents have been tested in preclinical and clinical experimentation in FL and indolent nonfollicular lymphoma (iNFL), including the new monoclonal antibodies binding CD20 or other surface antigens, immunoconjugates and bispecific antibodies. Moreover novel agents directed against intracellular processes such as proteasome inhibitors, mTOR inhibitors and agents that target the tumour microenvironment, notably the immunomodulatory agent lenalidomide, are under active clinical investigation. The development of these new drugs may change in the near future the approach to iNHL patients, leading to better tolerated and effective therapy regimens.
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Project description:This report summarizes a symposium sponsored by the American Society for Pharmacology and Experimental Therapeutics at Experimental Biology held April 20-24 in Boston, MA. Presentations discussed the status of cytochrome P450 (P450) knowledge, emphasizing advances and challenges in relating structure with function and in applying this information to drug design. First, at least one structure of most major human drug-metabolizing P450 enzymes is known. However, the flexibility of these active sites can limit the predictive value of one structure for other ligands. A second limitation is our coarse-grain understanding of P450 interactions with membranes, other P450 enzymes, NADPH-cytochrome P450 reductase, and cytochrome b5. Recent work has examined differential P450 interactions with reductase in mixed P450 systems and P450:P450 complexes in reconstituted systems and cells, suggesting another level of functional control. In addition, protein nuclear magnetic resonance is a new approach to probe these protein/protein interactions, identifying interacting b5 and P450 surfaces, showing that b5 and reductase binding are mutually exclusive, and demonstrating ligand modulation of CYP17A1/b5 interactions. One desired outcome is the application of such information to control drug metabolism and/or design selective P450 inhibitors. A final presentation highlighted development of a CYP3A4 inhibitor that slows clearance of human immunodeficiency virus drugs otherwise rapidly metabolized by CYP3A4. Although understanding P450 structure/function relationships is an ongoing challenge, translational advances will benefit from continued integration of existing and new biophysical approaches.
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| S-EPMC8409318 | biostudies-literature
Project description:Chemoimmunotherapy has been a hallmark of treatment of indolent B-cell non-Hodgkin lymphomas for the past 2 decades, with high response rates seen but relapses nearly inevitable and patients spending, on average, 20 years on and off treatment. Treatment advances, then, should be aimed at maintaining efficacy while minimizing toxicity or at achieving cure. Improved understanding of the genetic and molecular features of these diseases, as well as of the interaction between the tumor cell and its immune microenvironment, has resulted in an accelerated expansion of tolerable treatment options for patients, with new combinations of therapy holding promise that definitive therapy in these diseases is possible. These drugs include immunomodulating agents such as lenalidomide, small-molecule inhibitors of the B-cell receptor signaling pathway such as ibrutinib and idelalisib, B-cell lymphoma 2 homology 3 mimetics such as venetoclax, and enhancer of zeste homolog 2 inhibitors such as tazemetostat. Therapies that improve the host immune response against the malignant B cell are also of great interest, given the durable remission seen after allogeneic stem cell transplant in these diseases, and immune checkpoint inhibitors, agonist antibodies against immunostimulatory T-cell receptors, antibody-drug conjugates, bispecific antibodies, and finally chimeric antigen receptor T cells are all being investigated, with promising early efficacy signals. These treatments may not necessarily replace chemotherapy but rather augment it in an attempt to improve quality of life and survival for these patients.
| S-EPMC6913469 | biostudies-literature
Project description:Mature B cell neoplasms, previously indolent non-Hodgkin lymphomas (iNHLs), are a heterogeneous group of malignancies sharing similar disease courses and treatment paradigms. Most patients with iNHL have an excellent prognosis, and in many, treatment can be deferred for years. However, some patients will have an accelerated course and may experience transformation into aggressive lymphomas. In this review, we focus on management concepts shared across iNHLs, as well as histology-specific strategies. We address open questions in the field, including the influence of genomics and molecular pathway alterations on treatment decisions. In addition, we review the management of uncommon clinical entities including nodular lymphocyte-predominant Hodgkin lymphoma, hairy cell leukemia, splenic lymphoma and primary lymphoma of extranodal sites. Finally, we include a perspective on novel targeted therapies, antibodies, antibody-drug conjugates, bispecific T cell engagers and chimeric antigen receptor T cell therapy.
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Project description:BackgroundDiseases of the ear, nose and throat (ENT) are common and are a major cause of morbidity and mortality. In many low income countries like Zambia, the high ENT disease burden has not received the required resources for treatment. We investigated ENT service provision in hospitals in Zambia by documenting the profile of hospitals offering ENT services and examining the country's ENT services with regards to human resource, infrastructure and availability of equipment based on the levels of care of various hospitals.MethodsThe study was a cross-sectional descriptive survey conducted using a structured and piloted questionnaire which was administered to the 109 Ministry of Health (MoH) registered hospitals across the country. Ethical clearance was granted by University of KwaZulu-Natal and the Zambia National Health Research Authority. Participation in the study was voluntary and all respondents signed informed consent. Descriptive statistics were used to analyse the data.ResultsOf the 109 hospitals approached to participate in the study, 61 (55.9%) hospitals responded. This represented 83.3% (n = 5) of Third Level Hospitals (TLH), 89.5% (n = 17) of Second Level Hospitals (SLH) and 41.7% (n = 35) of First Level Hospitals (FLH) countrywide. Of the participating hospitals, 6.6% (n = 4) were unclassified. Within this sample, 8.6% (n = 3) FLH, 11.8% (n = 2) SLH and 60.0% (n = 3) TLH had an ENT examination room. Only 2.9% (n = 4) hospitals had an audiology booth and 1.6% (n = 1) had a speech therapy room. Of the second and third level hospitals, 9.1% (n = 2) had flexible rhinolaryngoscopes, 18.2% (n = 4) had operating microscopes and 68.2% (n = 15) adenotonsillectomy sets. The data revealed that there were 4 ENT surgeons, 1 Audiologist and no Speech Therapists across the country.ConclusionZambia's ENT services were deficient at all levels of hospital care. There were deficiencies in infrastructure, human resource and equipment in hospitals. With the current burden of disease, critical intervention is required. These findings should be used to direct national policy on the improvement of ENT service provision in Zambia.
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Project description:Mantle cell lymphoma (MCL) comprises 3-10% of NHL, with survival times ranging from 3 and 5 years. Indolent lymphomas represent approximately 30% of all NHLs with patient survival largely dependent on validated prognostic scores. High response rates are typically achieved in these patients with current first-line chemoimmunotherapy. However, most patients will eventually relapse and become chemorefractory with poor outcome. Alternative chemoimmunotherapy regimens are often used as salvage strategy and stem cell transplant remains an option for selected patients. However, novel approaches are urgently needed for patients no longer responding to conventional chemotherapy. Lenalidomide is an immunomodulatory drug with activity in multiple myeloma, myelodisplastic syndrome and chronic lymphoproliferative disorders. In phase II studies of indolent NHL and MCL lenalidomide has shown activity with encouraging response rates, both as a single agent and in combination with other drugs. Some of these responses may be durable. Optimal dose of lenalidomide has not been defined yet. The role of lenalidomide in the therapeutic armamentarium of patients with indolent NHL or MCL will be discussed in the present paper.
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Project description:Epstein-Barr virus (EBV) was the first human tumor virus discovered more than 50 years ago. EBV-associated lymphomagenesis is still a significant viral-associated disease as it involves a diverse range of pathologies, especially B-cell lymphomas. Recent development of high-throughput next-generation sequencing technologies and in vivo mouse models have significantly promoted our understanding of the fundamental molecular mechanisms which drive these cancers and allowed for the development of therapeutic intervention strategies. This review will highlight the current advances in EBV-associated B-cell lymphomas, focusing on transcriptional regulation, chromosome aberrations, in vivo studies of EBV-mediated lymphomagenesis, as well as the treatment strategies to target viral-associated lymphomas.
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Project description:Osteoporosis is an enormous and growing public health problem. Once considered an inevitable consequence of ageing, it is now eminently preventable and treatable. Ironically, despite tremendous therapeutic advances, there is an increasing treatment gap for patients at high fracture risk. In this Series paper, we trace the evolution of drug therapy for osteoporosis, which began in the 1940s with the demonstration by Fuller Albright that treatment with oestrogen could reverse the negative calcium balance that developed in women after menopause or oophorectomy. We note a watershed in osteoporosis drug discovery around the year 2000, when the approach to developing novel therapeutics shifted from one driven by discoveries in animal studies and clinical observations (eg, oestrogen, calcitonin, and teriparatide) or opportunistic repurposing of existing compounds (eg, bisphosphonates) to one driven by advances in fundamental bone biology (eg, denosumab) coupled with clues from patients with rare bone diseases (eg, romosozumab, odanacatib). Despite these remarkable advances, concerns about rare side-effects of anti-resorptive drugs, particularly bisphosphonates, and the absence of clear evidence in support of their long-term efficacy is leading many patients who could benefit from drug therapy to not take these drugs. As such, there remains an important clinical need to develop ways to enhance patient acceptance and compliance with these effective drugs, and to continue to develop new drugs that do not cause these side-effects and have prolonged anabolic effects on bone. Such changes could lead to a true reversal of this potentially devastating disease of ageing.
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