scholarly journals Liver Cancer Gene Discovery Using Gene Targeting, Sleeping Beauty, and CRISPR/Cas9

2019 ◽  
Vol 39 (02) ◽  
pp. 261-274 ◽  
Author(s):  
Julia Kieckhaefer ◽  
Flavio Maina ◽  
Rebecca Wells ◽  
Kirk Wangensteen
Keyword(s):  
Cancer Biology ◽  
Treatment Options ◽  
A Priori ◽  
Sleeping Beauty ◽  
Model Systems ◽  
Gene Interactions ◽  
Genetic Screens ◽  
Technological Advances ◽  
New Treatments ◽  
Crispr Activation

AbstractHepatocellular carcinoma (HCC) is a devastating and prevalent cancer with limited treatment options. Technological advances have enabled genetic screens to be employed in HCC model systems to characterize genes regulating tumor initiation and growth. Relative to traditional methods for studying cancer biology, such as candidate gene approaches or expression analysis, genetic screens have several advantages: they are unbiased, with no a priori selection; can directly annotate gene function; and can uncover gene–gene interactions. In HCC, three main types of screens have been conducted and are reviewed here: (1) transposon-based mutagenesis screens, (2) knockdown screens using RNA interference (RNAi) or the CRISPR/Cas9 system, and (3) overexpression screens using CRISPR activation (CRISPRa) or cDNAs. These methods will be valuable in future genetic screens to delineate the mechanisms underlying drug resistance and to identify new treatments for HCC.

scholarly journals Klotho and the Treatment of Human Malignancies

Cancers ◽  
2020 ◽  
Vol 12 (6) ◽  
pp. 1665 ◽  
Author(s):  
Aishani Sachdeva ◽  
Jerome Gouge ◽  
Christos Kontovounisios ◽  
Stella Nikolaou ◽  
Alan Ashworth ◽  
...  
Keyword(s):  
Cancer Biology ◽  
Treatment Options ◽  
Signalling Pathways ◽  
Unfolded Protein ◽  
Related Disease ◽  
Age Related ◽  
Technological Advances ◽  
Potential Therapeutic Role ◽  
The Unfolded Protein Response ◽  
Protein Response

Klotho was first discovered as an anti-ageing protein linked to a number of age-related disease processes, including cardiovascular, renal, musculoskeletal, and neurodegenerative conditions. Emerging research has also demonstrated a potential therapeutic role for Klotho in cancer biology, which is perhaps unsurprising given that cancer and ageing share similar molecular hallmarks. In addition to functioning as a tumour suppressor in numerous solid tumours and haematological malignancies, Klotho represents a candidate therapeutic target for patients with these diseases, the majority of whom have limited treatment options. Here, we examine contemporary evidence evaluating the anti-neoplastic effects of Klotho and describe the modulation of downstream oncogenic signalling pathways, including Wnt/β-catenin, FGF, IGF1, PIK3K/AKT, TGFβ, and the Unfolded Protein Response. We also discuss possible approaches to developing therapeutic Klotho and consider technological advances that may facilitate the delivery of Klotho through gene therapy.

scholarly journals Direct Sarcomere Modulators Are Promising New Treatments for Cardiomyopathies

2019 ◽  
Vol 21 (1) ◽  
pp. 226
Author(s):  
Osamu Tsukamoto
Keyword(s):  
Molecular Mechanisms ◽  
Treatment Options ◽  
Systolic Heart Failure ◽  
Reverse Remodeling ◽  
Subtle Change ◽  
Beneficial Effects ◽  
Technological Advances ◽  
History Of ◽  
Promising Treatment ◽  
New Treatments

Mutations in sarcomere genes can cause both hypertrophic cardiomyopathy (HCM) and dilated cardiomyopathy (DCM). However, the complex genotype-phenotype relationships in pathophysiology of cardiomyopathies by gene or mutation location are not fully understood. In addition, it is still unclear how mutations within same molecule result in different clinical phenotypes such as HCM and DCM. To clarify how the initial functional insult caused by a subtle change in one protein component of the sarcomere with a given mutation is critical for the development of proper effective treatments for cardiomyopathies. Fortunately, recent technological advances and the development of direct sarcomere modulators have provided a more detailed understanding of the molecular mechanisms that govern the effects of specific mutations. The direct inhibition of sarcomere contractility may be able to suppress the development and progression of HCM with hypercontractile mutations and improve clinical parameters in patients with HCM. On the other hand, direct activation of sarcomere contractility appears to exert unexpected beneficial effects such as reverse remodeling and lower heart rate without increasing adverse cardiovascular events in patients with systolic heart failure due to DCM. Direct sarcomere modulators that can positively influence the natural history of cardiomyopathies represent promising treatment options.

scholarly journals The Lung Microbiome: A Central Mediator of Host Inflammation and Metabolism in Lung Cancer Patients?

Cancers ◽  
2020 ◽  
Vol 13 (1) ◽  
pp. 13
Author(s):  
Frank Weinberg ◽  
Robert P. Dickson ◽  
Deepak Nagrath ◽  
Nithya Ramnath
Keyword(s):  
Lung Cancer ◽  
Cancer Patients ◽  
Cancer Biology ◽  
Treatment Options ◽  
Lung Cancer Patients ◽  
Lung Microbiome ◽  
Molecularly Targeted Agents ◽  
Melanoma Patients ◽  
New Treatments

Lung cancer is the leading cause of cancer-related death. Over the past 5–10 years lung cancer outcomes have significantly improved in part due to better treatment options including immunotherapy and molecularly targeted agents. Unfortunately, the majority of lung cancer patients do not enjoy durable responses to these new treatments. Seminal research demonstrated the importance of the gut microbiome in dictating responses to immunotherapy in melanoma patients. However, little is known regarding how other sites of microbiota in the human body affect tumorigenesis and treatment responses. The lungs were traditionally thought to be a sterile environment; however, recent research demonstrated that the lung contains its own dynamic microbiota that can influence disease and pathophysiology. Few studies have explored the role of the lung microbiome in lung cancer biology. In this review article, we discuss the links between the lung microbiota and cancer, with particular focus on immune responses, metabolism and strategies to target the lung microbiome for cancer prevention.

scholarly journals Patient-derived triple negative breast cancer organoids provide robust model systems that recapitulate tumor intrinsic characteristics

2021 ◽  
Author(s):  
Sonam Bhatia ◽  
Melissa Kramer ◽  
Suzanne Russo ◽  
Payal Naik ◽  
Gayatri Arun ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Cancer Progression ◽  
Triple Negative Breast Cancer ◽  
Cancer Biology ◽  
Triple Negative ◽  
Treatment Options ◽  
Cell Types ◽  
Model Systems ◽  
Breast Cancers ◽  
Robust Model

Triple negative breast cancer (TNBC) is an aggressive form of breast cancer with poor patient outcomes, and an unmet clinical need for targeted therapies and better model systems. Here, we developed and comprehensively characterized a diverse biobank of normal and breast cancer patient-derived organoids (PDOs) with a focus on TNBCs. PDOs recapitulated patient tumor intrinsic properties and a subset of PDOs can be propagated for long-term culture (LT-TNBCs). Single cell profiling of PDOs identified cell types and gene candidates affiliated with different aspects of cancer progression. The LT-TNBC organoids exhibit signatures of aggressive MYC-driven basal-like breast cancers and are largely comprised of luminal progenitor (LP)-like cells. The TNBC LP-like cells are distinct from normal LPs and exhibit hyperactivation of NOTCH and MYC signaling. Overall, our study validates TNBC PDOs as robust models for understanding breast cancer biology and progression, paving the way for personalized medicine and better treatment options.

scholarly journals Challenges in Treating Tardive Dyskinesia: Assessing the Impact of Virtual Medical Education

CNS Spectrums ◽  
2021 ◽  
Vol 26 (2) ◽  
pp. 165-165
Author(s):  
Amanda Glazar ◽  
Cecilia Peterson ◽  
Michael Lemon ◽  
Chirag Shah ◽  
Prakash Masand
Keyword(s):  
Medical Education ◽  
Tardive Dyskinesia ◽  
Treatment Options ◽  
Respiratory Muscles ◽  
Educational Activity ◽  
Activity Participation ◽  
Chi Square ◽  
Practice Performance ◽  
New Treatments ◽  
The Impact

AbstractIntroductionTardive Dyskinesia (TD) refers to abnormal, involuntary, choreoathetoid movements of the tongue, lips, face, trunk, and extremities and is associated with long-term exposure to dopamine-blocking agents, such as antipsychotic medications. Once established, these movements usually persist. The movements are disfiguring and can bring unwanted attention to affected individuals. When severe, especially if the respiratory muscles are affected, the movements can be disabling, limit activity, and reduce quality of life. The prevalence is 7.2% in individuals on newer antipsychotics who have never been exposed to older neuroleptics. Until recently, there were no effective treatments for TD. In recent years, many new treatments have been investigated for the treatment of TD, including valbenazine, deutetrabenazine, and branched chain amino acids. Valbenazine first, followed by deutetrabenazine are FDA approved to treat TD. A virtual broadcast was developed to assess the ability of continuing medical education (CME) to improve awareness of the recognition and treatment of TD among psychiatrists.MethodsThe virtual broadcast (May 9, 2020) consisted of a two-hour, live-streamed discussion between two expert faculty. Impact of the educational activity was assessed by comparing psychiatrists’ responses to four identical questions presented before and directly after activity participation. A follow-up survey was sent to all participants six-weeks post-activity to measure performance in practice changes. A chi-square test was used to identify significant differences between pre- and post-assessment responses. Cohen’s d was used to calculate the effect size of the virtual broadcast.ResultsActivity participation resulted in a noticeable educational effect among psychiatrists (n=621; d=6.12, P<.001). The following areas showed significant (P<0.05) pre- vs post-educational improvements: recognition of movements in patients with TD, rate of TD in SGA exposed patients, treatment options for TD (on and off-label), and treatment of TD using VMAT inhibitors. Additionally, 54% of psychiatrists reported a change in practice performance as a result of the education received in the activity, including utilization of a standard scale to evaluate movement disorders and educate patients and family members about potential for TD, how to recognize symptoms, and when to treat.ConclusionsThe results indicated that a CME-certified two-hour virtual broadcast was effective at improving knowledge among psychiatrists for the recognition and treatment of TD. This knowledge also resulted in positive changes in practice performance post-activity. Future education should continue to address best practices in the diagnosis, treatment and management of patients with TD, as there remains an increased need for tailored CME among psychiatrists.FundingNeurocrine Biosciences, Inc.

Treatment Given Near the End of Life in Castration-Resistant Prostate Cancer

2012 ◽  
Vol 29 (7) ◽  
pp. 536-540 ◽  
Author(s):  
Hanna A. Zaghloul ◽  
Jose R. Murillo
Keyword(s):  
Quality Of Life ◽  
Prostate Cancer ◽  
End Of Life ◽  
Treatment Options ◽  
Castration Resistant Prostate Cancer ◽  
Castration Resistant ◽  
Related Quality ◽  
Impact On Survival ◽  
New Treatments

Chemotherapy treatment options are limited for patients with castration-resistant prostate cancer (CRPC). The purpose of this study is to report treatment use and adverse effects (AEs) within the last three months of life in patients with CRPC. Of the 88 patients identified, 32% received treatment within 3 months of death, and documented AEs occurred in 25% of patients. Of those, neutropenia (18.3%), nausea/vomiting (18.3%), and febrile neutropenia (13.6%) were the most frequent. Results of this study show high treatment utility towards the end-of-life in patients with CRPC, with one fourth of patients experiencing AEs. Attention to health-related quality of life becomes increasingly important as new treatments appear to have small impact on survival, and AEs of those treatments may significantly impact patient quality of life.

TMOD-02. GENERATION OF A NOVEL MOUSE MODEL FOR BRAIN TUMORS OF THE DNA METHYLATION CLASS “GBM MYCN”

2021 ◽  
Vol 23 (Supplement_6) ◽  
pp. vi215-vi216
Author(s):  
Melanie Schoof ◽  
Carolin Göbel ◽  
Dörthe Holdhof ◽  
Sina Al-Kershi ◽  
Ulrich Schüller
Keyword(s):  
Dna Methylation ◽  
Brain Tumors ◽  
Molecular Mechanisms ◽  
Treatment Options ◽  
Tumor Development ◽  
Model Systems ◽  
Preclinical Research ◽  
Human Gbm

Abstract DNA methylation based classification of brain tumors has revealed a high heterogeneity between tumors and led to the description of multiple distinct subclasses. The increasing subdivision of tumors can help to understand molecular mechanisms of tumor development and to improve therapy if appropriate model systems for preclinical research are available. Multiple recent publications have described a subgroup of pediatric glioblastoma which is clearly separable from other pediatric and adult glioblastoma in its DNA methylation profile (GBM MYCN). Many cases in this group are driven by MYCN amplifications and harbor TP53 mutations. These tumors almost exclusively occur in children and were further described as highly aggressive with a median overall survival of only 14 months. In order to further investigate the biology and treatment options of these tumors, we generated hGFAP-cre::TP53 Fl/Fl ::lsl-MYCN mice. These mice carry a loss of TP53 and show aberrant MYCN expression in neural precursors of the central nervous system. The animals develop large forebrain tumors within the first 80 days of life with 100 % penetrance. These tumors resemble human GBM MYCN tumors histologically and are sensitive to AURKA and ATR inhibitors in vitro. We believe that further characterization of the model and in vivo treatment studies will pave the way to improve treatment of patients with these highly aggressive tumors.

Nocturnal Hypertension and Heart Failure: Mechanisms, Evidence, and New Treatments

Hypertension ◽  
2021 ◽  
Author(s):  
Kazuomi Kario ◽  
Bryan Williams
Keyword(s):  
Heart Failure ◽  
Ejection Fraction ◽  
Cardiovascular Events ◽  
Treatment Options ◽  
Left Ventricular ◽  
Nocturnal Hypertension ◽  
Reduced Ejection Fraction ◽  
Nighttime Blood Pressure ◽  
Evidence Based Treatments ◽  
New Treatments

Heart failure (HF) is a common condition with an increasing prevalence. Despite a variety of evidence-based treatments for patients with HF with reduced ejection fraction, morbidity and mortality rates remain high. Furthermore, there are currently no treatments that have yet been shown to reduce complication and death rates in patients who have HF with preserved ejection fraction. Hypertension is a common comorbidity in patients with HF, contributing to disease development and prognosis. For example, hypertension is closely associated with the development of left ventricular hypertrophy, which an important precursor of HF. In particular, nighttime blood pressure (BP) appears to be an important, modifiable risk factor. Both nighttime BP and an abnormal circadian pattern of nighttime BP dipping have been shown to predict development of HF and the occurrence of cardiovascular events, independent of office BP. Key mechanisms for this association include sodium handling/salt sensitivity and increased sympathetic activation. These pathogenic mechanisms are targeted by several new treatment options, including sodium-glucose cotransporter 2 inhibitors, angiotensin receptor neprilysin inhibitors, mineralocorticoid receptor antagonists, and renal denervation. All of these could form part of antihypertensive strategies designed to control nighttime BP and contribute to the goal of achieving perfect 24-hour BP management. Nevertheless, additional research is needed to determine the effects of reducing nighttime BP and improving the circadian BP profile on the rate of HF, other cardiovascular events, and mortality.

Psychiatric disorders

2019 ◽  
pp. 153-176
Author(s):  
Risto Näätänen ◽  
Teija Kujala ◽  
Gregory Light
Keyword(s):  
Psychiatric Illness ◽  
Psychometric Validation ◽  
Repeated Measure ◽  
Post Traumatic Stress ◽  
Brain Functioning ◽  
Psychiatric Illnesses ◽  
Technological Advances ◽  
Post Traumatic ◽  
New Treatments ◽  
Neural Dysfunction

Psychiatric illnesses including schizophrenia, major depressive disorder (MDD), bipolar disorder (BD), post-traumatic stress disorder (PTSD), panic disorder, and alcohol use disorders are common and leading causes of global disability. Conventionally, diagnosis and treatment of these disorders has relied solely on clinicical observation of symptoms and inference of underlying neural dysfunction. Recently, however, technological advances have allowed for direct measurement of brain functioning in these disorders, and there has been increased interest in the exploration of sensory processing deficits involved. In this context, MMN is regarded as a ‘breakthrough biomarker’ for advancing the understanding and treatment of psychiatric illness. As MMN is among the most widely studied translational biomarkers and has already undergone extensive psychometric validation (e.g. reliability, suitability for use as a repeated measure, sensitivity to pharmacologica and non-pharmacological interventions), it is widely used for development of new treatments for brain disorders.

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