Durvalumab After Chemoradiotherapy in Patients With Unresectable Stage III Non-Small Cell Lung Cancer.

Importance: The PACIFIC trial established consolidation durvalumab as the standard of care following chemoradiotherapy (CRT) for patients with unresectable stage III non-small cell lung cancer (NSCLC). Understanding its benefit in routine US clinical practice is critical.

Objective: To report characteristics, treatment patterns, and outcomes of patients who did or did not receive durvalumab.

Rapid Renal Regulation of Peroxisome Proliferator-activated Receptor γ Coactivator-1α by Extracellular Signal-Regulated Kinase 1/2 in Physiological and Pathological Conditions.

Previous studies have shown that extracellular signal-regulated kinase 1/2 (ERK1/2) directly inhibits mitochondrial function during cellular injury. We evaluated the role of ERK1/2 on the expression of peroxisome proliferator-activated receptor γ coactivator-1α (PGC-1α) gene, a master regulator of mitochondrial function. The potent and specific MEK1/2 inhibitor trametinib rapidly blocked ERK1/2 phosphorylation, decreased cytosolic and nuclear FOXO3a/1 phosphorylation, and increased PGC-1α gene expression and its downstream mitochondrial biogenesis (MB) targets under physiological conditions in the kidney cortex and in primary renal cell cultures.

Striatal Mitochondrial Disruption following Severe Traumatic Brain Injury.

Traumatic brain injury (TBI) results in oxidative stress and calcium dysregulation in mitochondria. However, little work has examined perturbations of mitochondrial homeostasis in peri-injury tissue. We examined mitochondrial homeostasis after a unilateral controlled cortical impact over the sensorimotor cortex in adult male rats.

Mitochondrial Biogenesis as a Pharmacological Target: A New Approach to Acute and Chronic Diseases.

Mitochondrial dysfunction is a key pathophysiological component of many acute and chronic diseases. Maintenance of mitochondrial homeostasis through the balance of mitochondrial turnover, fission and fusion, and generation of new mitochondria via mitochondrial biogenesis is critical for tissue health. Pharmacological activation of mitochondrial biogenesis can enhance oxidative metabolism and tissue bioenergetics, and improve organ function in conditions characterized by mitochondrial dysfunction.

Urinary mitochondrial DNA is a biomarker of mitochondrial disruption and renal dysfunction in acute kidney injury.

Recent studies show the importance of mitochondrial dysfunction in the initiation and progression of acute kidney injury (AKI). However, no biomarkers exist linking renal injury to mitochondrial function and integrity. To this end, we evaluated urinary mitochondrial DNA (UmtDNA) as a biomarker of renal injury and function in humans with AKI following cardiac surgery.

Urinary ATP Synthase Subunit β Is a Novel Biomarker of Renal Mitochondrial Dysfunction in Acute Kidney Injury.

Although the importance of mitochondrial dysfunction in acute kidney injury (AKI) has been documented, noninvasive early biomarkers of mitochondrial damage are needed. We examined urinary ATP synthase subunit β (ATPSβ) as a biomarker of renal mitochondrial dysfunction during AKI. Mice underwent sham surgery or varying degrees (5, 10, or 15 min ischemia) of ischemia/reperfusion (I/R)-induced AKI.

Agonism of the 5-hydroxytryptamine 1F receptor promotes mitochondrial biogenesis and recovery from acute kidney injury.

Many acute and chronic conditions, such as acute kidney injury, chronic kidney disease, heart failure, and liver disease, involve mitochondrial dysfunction. Although we have provided evidence that drug-induced stimulation of mitochondrial biogenesis (MB) accelerates mitochondrial and cellular repair, leading to recovery of organ function, only a limited number of chemicals have been identified that induce MB. The goal of this study was to assess the role of the 5-hydroxytryptamine 1F (5-HT1F) receptor in MB.

Suppressed mitochondrial biogenesis in folic acid-induced acute kidney injury and early fibrosis.

Acute kidney injury (AKI) is a disease with mitochondrial dysfunction and a newly established risk factor for the development of chronic kidney disease (CKD) and fibrosis. We examined mitochondrial homeostasis in the folic acid (FA)-induced AKI model that develops early fibrosis over a rapid time course. Mice given a single dose of FA had elevated serum creatinine (3-fold) and urine glucose (2.

cGMP-selective phosphodiesterase inhibitors stimulate mitochondrial biogenesis and promote recovery from acute kidney injury.

Recent studies demonstrate that mitochondrial dysfunction is a mediator of acute kidney injury (AKI). Consequently, restoration of mitochondrial function after AKI may be key to the recovery of renal function. Mitochondrial function can be restored through the generation of new, functional mitochondria in a process called mitochondrial biogenesis (MB).

Calpain 10 homology modeling with CYGAK and increased lipophilicity leads to greater potency and efficacy in cells.

Calpain 10 is a ubiquitously expressed mitochondrial and cytosolic Ca(2+)-regulated cysteine protease in which overexpression or knockdown leads to mitochondrial dysfunction and cell death. We previously identified a potent and specific calpain 10 peptide inhibitor (CYGAK), but it was not efficacious in cells. Therefore, we created a homology model using the calpain 10 amino acid sequence and calpain 1 3-D structure and docked CYGAK in the active site.

Systemic administration of optimized aptamer-siRNA chimeras promotes regression of PSMA-expressing tumors.

Prostate cancer cells expressing prostate-specific membrane antigen (PSMA) have been targeted with RNA aptamer-small interfering (si)RNA chimeras, but therapeutic efficacy in vivo was demonstrated only with intratumoral injection. Clinical translation of this approach will require chimeras that are effective when administered systemically and are amenable to chemical synthesis. To these ends, we enhanced the silencing activity and specificity of aptamer-siRNA chimeras by incorporating modifications that enable more efficient processing of the siRNA by the cellular machinery.