scholarly journals CDK6 Inhibition: A Novel Approach in AML Management

2020 ◽  
Vol 21 (7) ◽  
pp. 2528 ◽  
Author(s):  
Iris Z. Uras ◽  
Veronika Sexl ◽  
Karoline Kollmann
Keyword(s):  
Myeloid Leukemia ◽  
Complex Disease ◽  
Treatment Options ◽  
Standard Of Care ◽  
Cyclin Dependent Kinase ◽  
Independent Manner ◽  
The Past ◽  
Novel Approach ◽  
Aggressive Clinical Course ◽  
Cell Cycle Inhibitors

Acute myeloid leukemia (AML) is a complex disease with an aggressive clinical course and high mortality rate. The standard of care for patients has only changed minimally over the past 40 years. However, potentially useful agents have moved from bench to bedside with the potential to revolutionize therapeutic strategies. As such, cell-cycle inhibitors have been discussed as alternative treatment options for AML. In this review, we focus on cyclin-dependent kinase 6 (CDK6) emerging as a key molecule with distinct functions in different subsets of AML. CDK6 exerts its effects in a kinase-dependent and -independent manner which is of clinical significance as current inhibitors only target the enzymatic activity.

STI571 Suppresses Proliferation by Restoring Nuclear Cyclin Dependent Kinase Inhibitors (CDKIs) while STI571+TRAIL Promotes Cell Death by Decreasing Cytoplasmic CDKIs.

Blood ◽  
2004 ◽  
Vol 104 (11) ◽  
pp. 1992-1992
Author(s):  
Mo A. Dao ◽  
Catherine M. Verfaillie
Keyword(s):  
Cell Cycle ◽  
Cell Death ◽  
Myeloid Leukemia ◽  
Kinase Inhibitors ◽  
Hematopoietic Cells ◽  
Cyclin Dependent Kinase ◽  
The Past ◽  
Cell Cycle Inhibitors ◽  
Nuclear Cell ◽  
Resistant Cells

Abstract Cyclin dependent kinase inhibitors (CDKIs), p27Kip1 and p21Cip1, function as cell cycle inhibitors when located in the nucleus. When localized to the cytoplasm, these CDKIs can function as anti-apoptotic molecules by sequestering/preventing the activation of pro-apoptotic proteins such as ASK1 and procaspase-3. Our lab has reported elevated cytoplasmic CDKIs and decreased nuclear CDKIs in hematopoietic cells expressing BCR/ABL, the oncogene found in more than 90% of cases of chronic myeloid leukemia. Within the past decade, STI571 has been shown highly promising for CML treatment. However, there is increasing evidence suggesting that the drug might function more as a suppressor of proliferation and less as a promoter of cell death. In the current studies, we differentiate the effect of STI571 on proliferation vs. survival by tracking the subcellular increase/decrease in CDKIs using MO7e cells engineered to express BCR/ABL. To determine if a correlation exists between STI571 resistance and levels of cytoplasmic anti-apoptotic CDKIs, we also investigated changes in levels of nuclear vs. cytoplasmic CDKIs in LAMA84 -S (sensitive to STI571) vs. LAMA84-R (resistant to STI571). And lastly, we tested whether activation of TRAIL would enhance cell death in STI571-resistant cells. STI571 treatment increases nuclear CDKIs, correlating directly with a decrease in proliferation of MO7e/p210 cells. However, the high levels of cytoplasmic CDKIs in MO7e/p210bcr/abl was not modulated following STI571 treatment and cell death was not prominent, unless growth factors were removed. Moreover, cytoplasmic p21Cip co-immunoprecipitated with ASK1 and procaspase 3. When compared with LAMA-S cells, LAMA-R cells expressed even higher levels of cytoplasmic CDKIs. Treatment with STI571 decreased cytoplasmic CDKIs in LAMA84-S cells and resulted in cell death. As hypothesized, LAMA84-R cells did not show reduction in cytoplasmic CDKIs and did not enter apoptosis. However, when treated with STI571 and TRAIL, LAMA84-R cells showed a decrease in cytoplasmic CDKIs, and increase in apoptosis. Based on these observations, we conclude that: 1. BCR/ABL expression reduces nuclear CDKIs but increases cytoplasmic CDKIs. 2. STI571 treatment restores nuclear CDKIs and reduces cell proliferation of BCR/ABL expressing cells under physiological conditions. 3. Treatment of STI571+TRAIL reduces cytoplasmic CDKIs and increases cell death of BCR/ABL expressing cells, most notably, the STI571-resistant cells. In conclusion, we show that the imbalance between nuclear (cell cycle inhibitor) and cytoplasmic (cell survival enhancer) CDKIs exist in BCR/ABL-hematopoietic cells.

scholarly journals Overcoming Shellfish Allergy: How Far Have We Come?

2020 ◽  
Vol 21 (6) ◽  
pp. 2234 ◽  
Author(s):  
Christine Y.Y. Wai ◽  
Nicki Y.H. Leung ◽  
Ka Hou Chu ◽  
Patrick S.C. Leung ◽  
Agnes S.Y. Leung ◽  
...  
Keyword(s):  
Treatment Options ◽  
Standard Of Care ◽  
Specific Ige ◽  
Diagnostic Methods ◽  
Asia Pacific ◽  
Prick Test ◽  
Immunological Responses ◽  
The Past ◽  
Molecular Features ◽  
Shellfish Allergy

Shellfish allergy caused by undesirable immunological responses upon ingestion of crustaceans and mollusks is a common cause of food allergy, especially in the Asia-Pacific region. While the prevalence of shellfish allergy is increasing, the mainstay of clinical diagnosis for these patients includes extract-based skin prick test and specific IgE measurement while clinical management consists of food avoidance and as-needed use of adrenaline autoinjector should they develop severe allergic reactions. Such a standard of care is unsatisfactory to both patients and healthcare practitioners. There is a pressing need to introduce more specific diagnostic methods, as well as effective and safe therapies for patients with shellfish allergy. Knowledge gained on the identifications and defining the immuno-molecular features of different shellfish allergens over the past two decades have gradually translated into the design of new diagnostic and treatment options for shellfish allergy. In this review, we will discuss the epidemiology, the molecular identification of shellfish allergens, recent progress in various diagnostic methods, as well as current development in immunotherapeutic approaches including the use of unmodified allergens, hypoallergens, immunoregulatory peptides and DNA vaccines for the prevention and treatment of shellfish allergy. The prospect of a “cure “for shellfish allergy is within reach.

scholarly journals Advances in Acute Myeloid Leukemia Genomics, where do we stand in 2018?

2019 ◽  
Vol 48 (1) ◽  
pp. 35
Author(s):  
Yazan F. Madanat ◽  
Matt E. Kalaycio ◽  
Aziz Nazha
Keyword(s):  
Acute Myeloid Leukemia ◽  
Myeloid Leukemia ◽  
Complex Disease ◽  
Clinical Decision Making ◽  
Standard Of Care ◽  
Clinical Decision ◽  
World Health ◽  
Disease Evolution ◽  
Disease Biology ◽  
Acute Myeloid

<p>The aim of this review is to summarize the data on commonly mutated genes and genomic pathways in acute myeloid leukemia (AML) with a focus on recently approved targeted therapies. AML is a heterogeneous disease with recurrent cytogenetic and genomic abnormalities that define the disease biology and pathogenesis. Classification of the disease categories and their prognostication was updated in the past 2 years to reflect the most recent advances in understanding the complex disease biology of AML. This review highlights major updates in the World Health Organization classification, including cytogenetic re-classifications, provisional entities, and updates to the European Leukemia Net (ELN) AML risk group stratification. An overview of pivotal studies that used novel sequencing techniques to define the mutational landscape of AML is also provided. In these studies, mutations are classified into subgroups based on functional pathways and are used to understand various interactions and mutual exclusivity of some mutations, suggesting important roles in disease evolution and AML pathogenesis. The complex interactions between mutations can dictate outcomes as well as possibly predict disease phenotypes after correcting for clinical variables.</p><p><strong>Conclusion. </strong>Genomic testing in AML using next generation sequencing has become widely available and a new standard of care for all patients. Therefore, it is vital to use novel methods to incorporate these data in clinical decision making.</p>

scholarly journals Emerging agents and regimens for AML

2021 ◽  
Vol 14 (1) ◽  
Author(s):  
Hongtao Liu
Keyword(s):  
Myeloid Leukemia ◽  
Treatment Options ◽  
Treatment Resistance ◽  
Therapeutic Agents ◽  
Mechanisms Of Resistance ◽  
Car T Cells ◽  
The Past ◽  
Car T ◽  
Recent Developments ◽  
Molecular Landscape

AbstractUntil recently, acute myeloid leukemia (AML) patients used to have limited treatment options, depending solely on cytarabine + anthracycline (7 + 3) intensive chemotherapy and hypomethylating agents. Allogeneic stem cell transplantation (Allo-SCT) played an important role to improve the survival of eligible AML patients in the past several decades. The exploration of the genomic and molecular landscape of AML, identification of mutations associated with the pathogenesis of AML, and the understanding of the mechanisms of resistance to treatment from excellent translational research helped to expand the treatment options of AML quickly in the past few years, resulting in noteworthy breakthroughs and FDA approvals of new therapeutic treatments in AML patients. Targeted therapies and combinations of different classes of therapeutic agents to overcome treatment resistance further expanded the treatment options and improved survival. Immunotherapy, including antibody-based treatment, inhibition of immune negative regulators, and possible CAR T cells might further expand the therapeutic armamentarium for AML. This review is intended to summarize the recent developments in the treatment of AML.

scholarly journals Choice of treatment options for metastatic hormone-sensitive prostate cancer

2020 ◽  
pp. 90-99
Author(s):  
R. A. Gafanov ◽  
A. G. Dzidzaria ◽  
I. B. Kravtsov ◽  
S. V. Fastovets
Keyword(s):  
Prostate Cancer ◽  
Radiation Therapy ◽  
Treatment Options ◽  
Standard Of Care ◽  
External Beam Radiation ◽  
Beam Radiation ◽  
The Past ◽  
Choice Of Treatment ◽  
Hormone Sensitive ◽  
The Impact

The arsenal of available treatments and treatments for metastatic hormone-sensitive prostate cancer (mHRPC) has increased significantly over the past 5 years. Although androgen-preferential therapy (ADT) remains the mainstay of treatment, the addition of docetaxel, abiraterone, enzalutamide, apalutamide, or local external beam radiation therapy improves the outcome of patients with mHRPC and becomes the standard of care. Choosing a therapy to improve treatment outcomes for patients with mHRPC is becoming increasingly challenging as there are different options for this stage of the disease. This article provides an overview of clinical trials that included ADT in combination with chemotherapy, new hormonal therapy, and radiation therapy. We will also consider recent advances in the choice of treatment for men diagnosed with mHPCR and the impact of previous therapy on the subsequent biology of the disease. Options include chemohormone therapy, androgen receptor (AR) targeted therapy in addition to ADT or, less commonly, ADT alone. The choice of treatment should be based on a consideration of the clinical characteristics and characteristics of the disease, as well as taking into account the patient’s preferences, territorial constraints and financial resources.

scholarly journals Changing Paradigms in the Treatment of Advanced Urothelial Carcinoma: A 2020 Update

EMJ Oncology ◽  
2020 ◽  
Keyword(s):  
Targeted Therapies ◽  
Treatment Options ◽  
Growth Factor Receptor ◽  
Standard Of Care ◽  
The Past ◽  
Drug Conjugates ◽  
Regulatory Status ◽  
Platinum Based Chemotherapy ◽  
Treatment Paradigm ◽  
Advanced Urothelial Carcinoma

Advanced urothelial cancer (aUC) is invariably lethal and standard of care, platinum-based chemotherapy has changed little over the past 25 years. However, the past 5 years have been transformational with the advent of immunotherapies and targeted therapies. In this review, the authors focus on the therapies that are showing the greatest promise and have changed, or will imminently impact, the treatment landscape of aUC. Checkpoint inhibition is showing deep and durable responses in some patients and trial activity is concentrated on identifying the most suitable position within the treatment paradigm along with the most appropriate patients and therapeutic combinations. Novel targeted therapies in aUC are gaining renewed interest with nectin-4 antibody drug conjugates and fibroblast growth factor receptor inhibitors, both receiving recent regulatory approvals. Bispecific antibodies, capable of binding to two targets at the same time, are also showing promise. This review discusses the preclinical data, the relevant past, and present clinical trials along with regulatory status to provide a concise overview of the current and impending treatment options for aUC.

scholarly journals Advances in acute myeloid leukemia

BMJ ◽  
2021 ◽  
pp. n2026
Author(s):  
Laura F Newell ◽  
Rachel J Cook
Keyword(s):  
Risk Factors ◽  
Acute Myeloid Leukemia ◽  
Myeloid Leukemia ◽  
Treatment Options ◽  
Standard Of Care ◽  
Patient Specific ◽  
Ongoing Research ◽  
Standard Of Care Treatment ◽  
New Treatment ◽  
Acute Myeloid

ABSTRACT Acute myeloid leukemia (AML) is an uncommon but potentially catastrophic diagnosis with historically high mortality rates. The standard of care treatment remained unchanged for decades; however, recent discoveries of molecular drivers of leukemogenesis and disease progression have led to novel therapies for AML. Ongoing research and clinical trials are actively seeking to personalize therapy by identifying molecular targets, discovering patient specific and disease specific risk factors, and identifying effective combinations of modalities and drugs. This review focuses on important updates in diagnostic and disease classifications that reflect new understanding of the biology of AML, its mutational heterogeneity, some important genetic and environmental risk factors, and new treatment options including cytotoxic chemotherapy, novel targeted agents, and cellular therapies.

Endovenous procedures in varicose veins

Phlebologie ◽  
2008 ◽  
Vol 37 (05) ◽  
pp. 229-236
Author(s):  
N. Cayne ◽  
G. Jacobowitz ◽  
P. Lamparello ◽  
T. Maldonado ◽  
C. Rockman ◽  
...  
Keyword(s):  
Varicose Veins ◽  
Treatment Options ◽  
Postoperative Recovery ◽  
Comparable Efficacy ◽  
Intense Pulse Light ◽  
Efficacy And Safety ◽  
Endovenous Laser Ablation ◽  
The Past ◽  
Early Evidence ◽  
Endovenous Treatment

SummaryOver the past ten years endoveous treatment options for varicose veins have evovled considerably, offering clinicians a multitude of options to meet the needs of their patients. The endothermal ablation procedures have moved to the forefront as the choice modality for treating truncal reflux. Both radiofrequency ablation and endovenous laser ablation are widely accepted and interchangeable, showing comparable efficacy and safety. Although numerous endovenous laser wavelengths exist, the data indicates that the differences do not affect the efficacy or postoperative recovery of the procedure. The endovenous laser innovation that has shown early evidence of improved patient outcome is the jacket-tip fiber. The versatility of sclerotherapy makes it a critical component in the endovenous treatment of varicosities. Although not approved by the Food and Drug Administration (USA), the use of a foamed sclerosing agent is the fastest growing segment of sclerotherapy and an important treatment modality in the future of varicose vein treatment. Cutaneous lasers and intense pulse light devices contribute a crucial element, enabling clinicians to treat minute veins that may be impossible to treat with other therapies.

Conventional versus Mindfulness-based Interventions for Anxiety and Worry: A Review and Recommendations

2020 ◽  
Vol 16 (1) ◽  
pp. 60-67
Author(s):  
Deah Jo Abbott ◽  
Caleb Wayne Lack
Keyword(s):  
Treatment Options ◽  
Additional Treatment ◽  
Third Wave ◽  
Stage Model ◽  
Pharmacological Treatments ◽  
The Past ◽  
Behavioral Therapies ◽  
Cognitive Behavioral Therapies ◽  
Specific Disorders ◽  
Psychiatric Problems

Anxiety disorders are among the most prevalent and most functionally impairing psychiatric problems experienced by the population. Both pharmacological and psychological evidencebased treatments exist for a number of specific disorders, but may fail to fully relieve symptoms, pointing to the need for additional treatment options. Often considered to be part of the “third wave” of cognitive-behavioral therapies, treatments incorporating mindfulness have emerged in the past two decades as increasingly popular with clinicians and frequently sought out by consumers. The present article reviews the extant literature regarding the efficacy and effectiveness of mindfulnessbased treatments for anxiety, worry, and related problems. Although they have not attained the solid empirical status of CBT or certain pharmacological treatments, the extant research shows mindfulness- based interventions appear to be a promising and useful treatment for people suffering from anxiety and worry. Further work should be done, levels 3-5 of the NIH stage model to determine whether or not they should be further implemented.

scholarly journals Selective Inhibition of Aurora Kinase A by AK-01/LY3295668 Attenuates MCC Tumor Growth by Inducing MCC Cell Cycle Arrest and Apoptosis

Cancers ◽  
2021 ◽  
Vol 13 (15) ◽  
pp. 3708
Author(s):  
Bhaba K. Das ◽  
Aarthi Kannan ◽  
Quy Nguyen ◽  
Jyoti Gogoi ◽  
Haibo Zhao ◽  
...  
Keyword(s):  
Cell Cycle ◽  
Cell Cycle Arrest ◽  
Checkpoint Inhibitors ◽  
Treatment Options ◽  
Standard Of Care ◽  
Aurora Kinase ◽  
Selective Inhibition ◽  
Potential Candidate ◽  
Cycle Arrest

Merkel cell carcinoma (MCC) is an often-lethal skin cancer with increasing incidence and limited treatment options. Although immune checkpoint inhibitors (ICI) have become the standard of care in advanced MCC, 50% of all MCC patients are ineligible for ICIs, and amongst those treated, many patients develop resistance. There is no therapeutic alternative for these patients, highlighting the urgent clinical need for alternative therapeutic strategies. Using patient-derived genetic insights and data generated in our lab, we identified aurora kinase as a promising therapeutic target for MCC. In this study, we examined the efficacy of the recently developed and highly selective AURKA inhibitor, AK-01 (LY3295668), in six patient-derived MCC cell lines and two MCC cell-line-derived xenograft mouse models. We found that AK-01 potently suppresses MCC survival through apoptosis and cell cycle arrest, particularly in MCPyV-negative MCC cells without RB expression. Despite the challenge posed by its short in vivo durability upon discontinuation, the swift and substantial tumor suppression with low toxicity makes AK-01 a strong potential candidate for MCC management, particularly in combination with existing regimens.

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