Amyloid-Based Therapeutics: Findings Translated into Novel Treatments

CNS Spectrums ◽  
2008 ◽  
Vol 13 (S16) ◽  
pp. 36-38 ◽  
Author(s):  
Paul S. Aisen
Keyword(s):  
Vitamin E ◽  
Memory Impairment ◽  
Cholinesterase Inhibitors ◽  
Treatment Options ◽  
Nmda Receptor Antagonist ◽  
Novel Treatments ◽  
Therapeutic Class ◽  
Positive Treatment ◽  
Underlying Mechanisms ◽  
With Memory

For decades following the 1906 identification of Alzheimer’s disease (AD), it was believed that the disorder was untreatable. Only in the late 1970s, with the introduction of the cholinergic hypothesis of the underlying mechanisms of AD, were treatment options considered possible. The first positive treatment study was conducted in 1985. In 1993, tacrine, a cholinesterase inhibitor, was approved for the treatment of AD; three similar drugs soon followed. Memantine, an NMDA receptor antagonist, was approved in 2003, representing a second therapeutic class for AD.Cholinesterase inhibitors were the first therapeutic options successfully employed, and there is strong evidence these agents confer benefits. The addition of memantine to the standard course of therapy can be beneficial as well, particularly at the moderate stages of the disorder (Mini-Mental State Exam score of ≤14). For patients without cardiovascular disease, diabetes, or statin use, 1,000 IU vitamin E BID is a consideration to mitigate the effects of AD. However, there is presently concern over the risks involved in vitamin E therapy. Unfortunately, there are no established treatments for mild cognitive impairment (MCI). Vitamin E is ineffective in treating MCI, and cholinesterase inhibitors, while possibly risky, are only minimally effective. The need for effective treatment remains expansive. The benefits of the available agents are modest, and there are currently no treatments for individuals with memory impairment who do not yet meet the diagnostic criteria for AD.

EXCITE: Experiences of Patients with Adjuvant and Metastatic Melanoma using Disease- Specific Social Media Communities in the Advent of Novel Therapies (Preprint)

2021 ◽  
Author(s):  
Guy Faust ◽  
Alison Booth ◽  
Evie Merinopoulou ◽  
Sonia Halhol ◽  
Heena Tosar ◽  
...  
Keyword(s):  
Social Media ◽  
Targeted Therapy ◽  
Metastatic Melanoma ◽  
Language Processing ◽  
Treatment Options ◽  
Symptom Duration ◽  
Novel Treatments ◽  
Health Related ◽  
Positive Treatment ◽  
The Impact

BACKGROUND Immunotherapy and targeted therapy treatments are novel treatments available for patients with metastatic and adjuvant melanoma. As recently approved treatments, information surrounding the patients and caregiver’s experience with these therapies, perceptions of treatments, and the effect the treatments have on their day-to-day life are lacking. Such insights would be valuable for any future decision making with regards to treatment options. OBJECTIVE This study aimed to use health-related social media data to understand the experience of patients with adjuvant and metastatic melanoma who are receiving either immunotherapy or targeted therapies. This study also included caregivers’ perspectives. METHODS Publicly available social media posts by patients with self-reported adjuvant or metastatic melanoma (and their caregivers) between January 2014 to October 2019 were programmatically extracted, de-identified, cleaned and analysed using a combination of natural language processing and qualitative data analyses. This study identified spontaneously reported symptoms and their impacts, symptom duration, and the impact of treatment for both treatment groups. RESULTS Overall 1,037 users (9,023 posts) and 114 users (442 posts) were included in the metastatic group and adjuvant group, respectively. The most commonly identified symptoms in both groups were fatigue, pain or exanthema. Symptom impacts reported by both groups were physical impacts, impacts on family, and impacts on work. Positive treatment impacts were reported in both groups and covered the areas of work, social and family life, and general health and quality of life. CONCLUSIONS This study explored health-related social media to better understand the experience and perspectives of patients with melanoma receiving immunotherapy or targeted therapy treatments as well as the experience of their caregivers. This exploratory work uncovered the most commonly discussed concerns among patients and caregivers on the forums including symptoms and their impacts, thus contributing to a deeper understanding of the patient/caregiver experience. CLINICALTRIAL None

scholarly journals Molecular and Cellular Mechanisms of Metformin in Cervical Cancer

Cancers ◽  
2021 ◽  
Vol 13 (11) ◽  
pp. 2545
Author(s):  
Ya-Hui Chen ◽  
Po-Hui Wang ◽  
Pei-Ni Chen ◽  
Shun-Fa Yang ◽  
Yi-Hsuan Hsiao
Keyword(s):  
Cervical Cancer ◽  
Potential Role ◽  
Treatment Options ◽  
Cellular Mechanisms ◽  
Anticancer Effects ◽  
Clinical Benefits ◽  
Underlying Mechanisms

Cervical cancer is one of the major gynecologic malignancies worldwide. Treatment options include chemotherapy, surgical resection, radiotherapy, or a combination of these treatments; however, relapse and recurrence may occur, and the outcome may not be favorable. Metformin is an established, safe, well-tolerated drug used in the treatment of type 2 diabetes; it can be safely combined with other antidiabetic agents. Diabetes, possibly associated with an increased site-specific cancer risk, may relate to the progression or initiation of specific types of cancer. The potential effects of metformin in terms of cancer prevention and therapy have been widely studied, and a number of studies have indicated its potential role in cancer treatment. The most frequently proposed mechanism underlying the diabetes–cancer association is insulin resistance, which leads to secondary hyperinsulinemia; furthermore, insulin may exert mitogenic effects through the insulin-like growth factor 1 (IGF-1) receptor, and hyperglycemia may worsen carcinogenesis through the induction of oxidative stress. Evidence has suggested clinical benefits of metformin in the treatment of gynecologic cancers. Combining current anticancer drugs with metformin may increase their efficacy and diminish adverse drug reactions. Accumulating evidence is indicating that metformin exerts anticancer effects alone or in combination with other agents in cervical cancer in vitro and in vivo. Metformin might thus serve as an adjunct therapeutic agent for cervical cancer. Here, we reviewed the potential anticancer effects of metformin against cervical cancer and discussed possible underlying mechanisms.

scholarly journals EEG Fractal Analysis Reflects Brain Impairment after Stroke

Entropy ◽  
2021 ◽  
Vol 23 (5) ◽  
pp. 592
Author(s):  
Maria Rubega ◽  
Emanuela Formaggio ◽  
Franco Molteni ◽  
Eleonora Guanziroli ◽  
Roberto Di Marco ◽  
...  
Keyword(s):  
Early Stage ◽  
Brain Activity ◽  
Phase 1 ◽  
Behavioral Changes ◽  
Stroke Survivors ◽  
Eeg Signals ◽  
Novel Treatments ◽  
Fractal Measures ◽  
Underlying Mechanisms ◽  
Random Fluctuations

Stroke is the commonest cause of disability. Novel treatments require an improved understanding of the underlying mechanisms of recovery. Fractal approaches have demonstrated that a single metric can describe the complexity of seemingly random fluctuations of physiological signals. We hypothesize that fractal algorithms applied to electroencephalographic (EEG) signals may track brain impairment after stroke. Sixteen stroke survivors were studied in the hyperacute (<48 h) and in the acute phase (∼1 week after stroke), and 35 stroke survivors during the early subacute phase (from 8 days to 32 days and after ∼2 months after stroke): We compared resting-state EEG fractal changes using fractal measures (i.e., Higuchi Index, Tortuosity) with 11 healthy controls. Both Higuchi index and Tortuosity values were significantly lower after a stroke throughout the acute and early subacute stage compared to healthy subjects, reflecting a brain activity which is significantly less complex. These indices may be promising metrics to track behavioral changes in the very early stage after stroke. Our findings might contribute to the neurorehabilitation quest in identifying reliable biomarkers for a better tailoring of rehabilitation pathways.

scholarly journals Propolis Extract and Chitosan Improve Health of Nosema ceranae Infected Giant Honey Bees, Apis dorsata Fabricius, 1793

Pathogens ◽  
2021 ◽  
Vol 10 (7) ◽  
pp. 785
Author(s):  
Sanchai Naree ◽  
Rujira Ponkit ◽  
Evada Chotiaroonrat ◽  
Christopher L. Mayack ◽  
Guntima Suwannapong
Keyword(s):  
Honey Bees ◽  
Treatment Options ◽  
Survival Rates ◽  
Nosema Ceranae ◽  
Apis Dorsata ◽  
Propolis Extract ◽  
Bee Health ◽  
Honey Bee Health ◽  
Underlying Mechanisms ◽  
Honey Solution

Nosema ceranae is a large contributing factor to the most recent decline in honey bee health worldwide. Developing new alternative treatments against N. ceranae is particularly pressing because there are few treatment options available and therefore the risk of increased antibiotic resistance is quite high. Recently, natural products have demonstrated to be a promising avenue for finding new effective treatments against N. ceranae. We evaluated the effects of propolis extract of stingless bee, Tetrigona apicalis and chito-oligosaccharide (COS) on giant honey bees, Apis dorsata, experimentally infected with N. ceranae to determine if these treatments could improve the health of the infected individuals. Newly emerged Nosema-free bees were individually inoculated with 106N. ceranae spores per bee. We fed infected and control bees the following treatments consisting of 0%, 50%, propolis extracts, 0 ppm and 0.5 ppm COS in honey solution (w/v). Propolis extracts and COS caused a significant increase in trehalose levels in hemolymph, protein contents, survival rates and acini diameters of the hypopharyngeal glands in infected bees. Our results suggest that propolis and COS could improve the health of infected bees. Further research is needed to determine the underlying mechanisms responsible for the improved health of the infected bees.

scholarly journals Early stages of tau pathology and its associations with functional connectivity, atrophy and memory

Brain ◽  
2021 ◽  
Author(s):  
David Berron ◽  
Jacob W Vogel ◽  
Philip S Insel ◽  
Joana B Pereira ◽  
Long Xie ◽  
...  
Keyword(s):  
Functional Connectivity ◽  
Entorhinal Cortex ◽  
Temporal Lobe ◽  
Medial Temporal Lobe ◽  
Memory Impairment ◽  
Memory Performance ◽  
Hippocampal Atrophy ◽  
Tau Pathology ◽  
Β Amyloid ◽  
With Memory

Abstract In Alzheimer’s disease, postmortem studies have shown that the first cortical site where neurofibrillary tangles appear is the transentorhinal region, a subregion within the medial temporal lobe that largely overlaps with area 35, and the entorhinal cortex. Here we used tau-PET imaging to investigate the sequence of tau pathology progression within the human medial temporal lobe and across regions in the posterior-medial system. Our objective was to study how medial temporal tau is related to functional connectivity, regional atrophy, and memory performance. We included 215 β-amyloid negative cognitively unimpaired, 81 β-amyloid positive cognitively unimpaired and 87 β-amyloid positive individuals with mild cognitive impairment, who each underwent [18]F-RO948 tau and [18]F-flutemetamol amyloid PET imaging, structural T1-MRI and memory assessments as part of the Swedish BioFINDER-2 study. First, event-based modelling revealed that the entorhinal cortex and area 35 show the earliest signs of tau accumulation followed by the anterior and posterior hippocampus, area 36 and the parahippocampal cortex. In later stages, tau accumulation became abnormal in neocortical temporal and finally parietal brain regions. Second, in cognitively unimpaired individuals, increased tau load was related to local atrophy in the entorhinal cortex, area 35 and the anterior hippocampus and tau load in several anterior medial temporal lobe subregions was associated with distant atrophy of the posterior hippocampus. Tau load, but not atrophy, in these regions was associated with lower memory performance. Further, tau-related reductions in functional connectivity in critical networks between the medial temporal lobe and regions in the posterior-medial system were associated with this early memory impairment. Finally, in patients with mild cognitive impairment, the association of tau load in the hippocampus with memory performance was partially mediated by posterior hippocampal atrophy. In summary, our findings highlight the progression of tau pathology across medial temporal lobe subregions and its disease-stage specific association with memory performance. While tau pathology might affect memory performance in cognitively unimpaired individuals via reduced functional connectivity in critical medial temporal lobe-cortical networks, memory impairment in mild cognitively impaired patients is associated with posterior hippocampal atrophy.

scholarly journals Vitamin E beyond Its Antioxidant Label

Antioxidants ◽  
2021 ◽  
Vol 10 (5) ◽  
pp. 634
Author(s):  
Anca Ungurianu ◽  
Anca Zanfirescu ◽  
Georgiana Nițulescu ◽  
Denisa Margină
Keyword(s):  
Vitamin E ◽  
Signaling Pathways ◽  
Molecular Mechanisms ◽  
Protective Effects ◽  
Cellular Effects ◽  
Inflammatory Status ◽  
Anti Cancer ◽  
Key Factor ◽  
Exciting Potential ◽  
Underlying Mechanisms

Vitamin E, comprising tocopherols and tocotrienols, is mainly known as an antioxidant. The aim of this review is to summarize the molecular mechanisms and signaling pathways linked to inflammation and malignancy modulated by its vitamers. Preclinical reports highlighted a myriad of cellular effects like modulating the synthesis of pro-inflammatory molecules and oxidative stress response, inhibiting the NF-κB pathway, regulating cell cycle, and apoptosis. Furthermore, animal-based models have shown that these molecules affect the activity of various enzymes and signaling pathways, such as MAPK, PI3K/Akt/mTOR, JAK/STAT, and NF-κB, acting as the underlying mechanisms of their reported anti-inflammatory, neuroprotective, and anti-cancer effects. In clinical settings, not all of these were proven, with reports varying considerably. Nonetheless, vitamin E was shown to improve redox and inflammatory status in healthy, diabetic, and metabolic syndrome subjects. The anti-cancer effects were inconsistent, with both pro- and anti-malignant being reported. Regarding its neuroprotective properties, several studies have shown protective effects suggesting vitamin E as a potential prevention and therapeutic (as adjuvant) tool. However, source and dosage greatly influence the observed effects, with bioavailability seemingly a key factor in obtaining the preferred outcome. We conclude that this group of molecules presents exciting potential for the prevention and treatment of diseases with an inflammatory, redox, or malignant component.

A CSF biomarker of intrathecal B cells activation correlates with memory impairment in multiple sclerosis

2021 ◽  
Vol 429 ◽  
pp. 117772
Author(s):  
Lorenzo Gaetani ◽  
Giovanni Brachelente ◽  
Nicola Salvadori ◽  
Elena Chipi ◽  
Elena Di Sabatino ◽  
...  
Keyword(s):  
Multiple Sclerosis ◽  
B Cells ◽  
Memory Impairment ◽  
Csf Biomarker ◽  
With Memory

Novel Non-invasive Approaches to the Treatment of Obesity: From Pharmacotherapy to Gene Therapy

2021 ◽  
Author(s):  
Angeliki M Angelidi ◽  
Matthew J Belanger ◽  
Alexander Kokkinos ◽  
Chrysi C Koliaki ◽  
Christos S Mantzoros
Keyword(s):  
Gene Therapy ◽  
Drug Targets ◽  
Energy Homeostasis ◽  
Treatment Options ◽  
Gastrointestinal Hormones ◽  
Interindividual Variation ◽  
Obesity Epidemic ◽  
Treatment Of Obesity ◽  
Underlying Mechanisms ◽  
Novel Therapeutic Strategies

Abstract Recent insights into the pathophysiologic underlying mechanisms of obesity have led to the discovery of several promising drug targets and novel therapeutic strategies to address the global obesity epidemic and its comorbidities. Current pharmacologic options for obesity management are largely limited in number and of modest efficacy/safety profile. Therefore, the need for safe and more efficacious new agents is urgent. Drugs which are currently under investigation modulate targets across a broad range of systems and tissues, including the central nervous system, gastrointestinal hormones, adipose tissue, kidney, liver, and skeletal muscle. Beyond pharmacotherapeutics, other potential antiobesity strategies are being explored, including novel drug delivery systems, vaccines, modulation of the gut microbiome, and gene therapy. The present review summarizes the pathophysiology of energy homeostasis, and highlights pathways being explored in the effort to develop novel antiobesity medications and interventions but does not cover devices and bariatric methods. Emerging pharmacologic agents and alternative approaches targeting these pathways and relevant research in both animals and humans are presented in detail. Special emphasis is given to treatment options at the end of the development pipeline and closer to the clinic, i.e., compounds that have a higher chance to be added to our therapeutic armamentarium in the near future. Ultimately, advancements in our understanding of the pathophysiology and interindividual variation of obesity may lead to multimodal and personalized approaches to obesity treatment that will result in safe, effective and sustainable weight loss until the root causes of the problem are identified and addressed.

Abstract 13820: Diastolic Dysfunction is Not Associated With Increased Diastolic Calcium During Experimental Uremic Cardiomyopathy

Circulation ◽  
2014 ◽  
Vol 130 (suppl_2) ◽  
Author(s):  
Pamela D Winterberg ◽  
Rong Jiang ◽  
Bo Wang ◽  
Sonal Harbaran ◽  
Mary B Wagner
Keyword(s):  
Sarcoplasmic Reticulum ◽  
Left Ventricular Hypertrophy ◽  
Diastolic Dysfunction ◽  
Ventricular Hypertrophy ◽  
Sarcomere Length ◽  
Treatment Options ◽  
Strain Analysis ◽  
Left Ventricular ◽  
Uremic Cardiomyopathy ◽  
Underlying Mechanisms

Introduction: The underlying mechanisms contributing to uremic cardiomyopathy during chronic kidney disease (CKD) are poorly understood, limiting treatment options. Hypothesis: We aimed to determine if altered calcium (Ca2+) handling in cardiomyocytes contributes to diastolic dysfunction in a mouse model of CKD. Methods: CKD was induced in male 129X1/SvJ mice through five-sixths nephrectomy in a two-stage surgery. Age-matched mice served as controls. Transthoracic echocardiography and speckle-tracking based strain analysis (Vevo2100, VisualSonics, Toronto, Canada) were performed at 8 weeks post-CKD (n=7-8) to assess heart structure and function. Cardiomyocytes isolated from mice with or without CKD (n=3 mice per group, 10-12 cells/mouse) were loaded with Fura 2-AM, paced by field stimulation (1 Hz), and imaged with a dual-excitation fluorescence photomultiplier system (IonOptix Inc, Milton, MA) to measure Ca2+ transients and sarcomere length. Sarcoplasmic reticulum Ca2+ content was determined following rapid application of caffeine.[[Unable to Display Character: &#8232;]] Results: CKD mice displayed left ventricular hypertrophy (LVAW;d 1.46 ± 0.134 vs 1.04 ± 0.129 mm; p<0.001) and decreased longitudinal strain (19 ± 4.1% vs 30 ± 2.3%; p<0.0001) compared to control mice. Resting sarcomere length was significantly shorter in cardiomyocytes isolated from CKD mice compared to normal mice (1.86 ± 0.054 vs 1.89 ± 0.047 nm; p = 0.016), but relaxation time was unchanged (0.21 ± 0.12 vs 0.21 ± 0.15 seconds, p=0.4). Unexpectedly, the baseline cytosolic Ca2+ content was lower in uremic myocytes (1.22 ± 0.353 vs 1.46 ± 0.252 AU, p=0.002). However, the Ca2+ transient amplitude (0.39 ± 0.177 vs 0.41 ± 0.167 AU, p=0.4) and sarcoplasmic reticulum Ca2+ content (1.15 ± 0.321 vs 1.24 ± 0.550 AU, p=0.4) were comparable between CKD and normal cardiomyocytes.[[Unable to Display Character: &#8232;]] Conclusions: Mice with CKD have signs of left ventricular hypertrophy and diastolic dysfunction on echocardiography. Cardiomyocytes isolated from mice with CKD have shorter diastolic sarcomere length implying impaired relaxation, yet paradoxically have decreased diastolic calcium. Thus Ca2+ accumulation during diastole does not appear to contribute to impaired relaxation in this model.

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