Arterial remodelling: an independent pathophysiological component of atherosclerotic disease progression and regression. Insights from serial pharmacological intervention trials

TPS5097 Background: Prostate cancer (PC) patients (pts) who select active surveillance (AS) are a heterogeneous population with varying risks for disease progression. Studies have estimated that approximately 31–42% of pts electing AS have experienced disease progression (pathological or therapeutic) over 1.8 and 2.3 years. There is no evidence-based pharmacological intervention which has effectively lessened this progression event. Pharmacological intervention with enzalutamide (ENZ), an androgen receptor inhibitor approved for treatment of metastatic castration-resistant PC, may lessen this progression. The aims of this study are to evaluate the efficacy of ENZ versus AS alone for delaying time to progression in pts with clinically localized PC undergoing AS. This study examines the effects of ENZ on progression in a subset of pts with low- or intermediate-risk PC who would otherwise elect an AS protocol. Methods: This is a multicenter, randomized, open-label study (NCT02799745). Eligibility criteria include histologically confirmed prostate adenocarcinoma within 6 months of screening, low or intermediate risk PC (T1c−T2c, prostate-specific antigen [PSA] < 20, N0, M0, Gleason score ≤7 [3+4 pattern only]), Eastern Cooperative Oncology Group status ≤2 and estimated life expectancy > 5 years. Exclusion criteria include any prior PC intervention. Pts will be randomized to receive open-label oral ENZ 160 mg/day once daily or to AS during the 1-year study treatment period. After the first year, all pts will be followed for one additional year with no other intervention. All pts will undergo prostate biopsy at 1 and 2 years. The primary end point is time to PC progression (pathological or therapeutic). Secondary end points include safety, incidence of negative biopsies for cancer at 1 and 2 years, percentage of cancer positive cores at 1 and 2 years, time to PSA progression, incidence of secondary rise in serum PSA, and quality-of-life questionnaires. Exploratory end points include biomarker assessment and genomic analysis. Study enrolment commenced in June 2016, with study completion expected in March 2019. Planned total enrolment is 222 pts from ~60 United States/Canadian sites. Clinical trial information: NCT02799745.

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Autophagy Dysregulation in Diabetic Kidney Disease: From Pathophysiology to Pharmacological Interventions

Cells ◽

10.3390/cells10092497 ◽

2021 ◽

Vol 10 (9) ◽

pp. 2497

Author(s):

Claudio D. Gonzalez ◽

María Paula Carro Carro Negueruela ◽

Catalina Nicora Santamarina ◽

Roxana Resnik ◽

Maria I. Vaccaro

Keyword(s):

Kidney Disease ◽

Disease Progression ◽

Diabetic Kidney Disease ◽

Cell Damage ◽

Cellular Level ◽

Pharmacological Intervention ◽

Diabetic Kidney ◽

Treatment And Prevention ◽

Improved Outcomes ◽

The Relationship

Diabetic kidney disease (DKD) is a frequent, potentially devastating complication of diabetes mellitus. Several factors are involved in its pathophysiology. At a cellular level, diabetic kidney disease is associated with many structural and functional alterations. Autophagy is a cellular mechanism that transports intracytoplasmic components to lysosomes to preserve cellular function and homeostasis. Autophagy integrity is essential for cell homeostasis, its alteration can drive to cell damage or death. Diabetic kidney disease is associated with profound autophagy dysregulation. Autophagy rate and flux alterations were described in several models of diabetic kidney disease. Some of them are closely linked with disease progression and severity. Some antidiabetic agents have shown significant effects on autophagy. A few of them have also demonstrated to modify disease progression and improved outcomes in affected patients. Other drugs also target autophagy and are being explored for clinical use in patients with diabetic kidney disease. The modulation of autophagy could be relevant for the pharmacological treatment and prevention of this disease in the future. Therefore, this is an evolving area that requires further experimental and clinical research. Here we discuss the relationship between autophagy and Diabetic kidney disease and the potential value of autophagy modulation as a target for pharmacological intervention.

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The Ambiguous Role of Microglia in Aβ Toxicity: Chances for Therapeutic Intervention

Current Neuropharmacology ◽

10.2174/1570159x18666200131105418 ◽

2020 ◽

Vol 18 (5) ◽

pp. 446-455 ◽

Cited By ~ 1

Author(s):

Sara Merlo ◽

Simona Federica Spampinato ◽

Grazia Ilaria Caruso ◽

Maria Angela Sortino

Keyword(s):

Disease Progression ◽

Therapeutic Intervention ◽

Microglial Activation ◽

Wide Spectrum ◽

Direct Interaction ◽

Pharmacological Intervention ◽

High Complexity ◽

Regenerative Processes ◽

Multiple Receptors

Amyloid-β (Aβ) has long been shown to be critical in Alzheimer’s disease pathophysiology. Microglia contributes to the earliest responses to Aβ buildup, by direct interaction through multiple receptors. Microglial cells operate Aβ clearance and trigger inflammatory/regenerative processes that take place in the long years of silent disease progression that precede symptomatic appearance. But in time and with aging, the fine balance between pro- and anti-inflammatory activity of microglia deranges, negatively impacting its Aβ-clearing ability. Furthermore, in recent years, microglial activation has proven to be much more complex than the mere dichotomic pro/antiinflammatory polarization previously accepted. Microglia can display a wide spectrum of phenotypes, which can even be mixed. On these bases, it is evident that while pharmacological intervention aiding microglia to prolong its ability to cope with Aβ buildup could be extremely relevant, its feasibility is hampered by such high complexity, which still needs to be completely understood.

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