The growth factor progranulin (PGRN) has been implicated in embryonic development, tissue repair, tumorigenesis, and inflammation, but its receptors remain unidentified. We report that PGRN bound directly to tumor necrosis factor receptors (TNFR), and disturbed the TNFα/TNFR interaction. PGRN-deficient mice were susceptible to collagen-induced arthritis, and administration of PGRN reversed inflammatory arthritis. Atsttrin, an engineered protein composed of three PGRN fragments, exhibited selective TNFR binding. PGRN and Atsttrin prevented inflammation in multiple arthritis mouse models and inhibited TNFα-activated intracellular signaling. Collectively, these findings demonstrate that PGRN is a ligand of TNFR, an antagonist of TNFα signaling and plays a critical role in the pathogenesis of inflammatory arthritis in mice. They also suggest new potential therapeutic interventions for various TNFα-mediated pathologies and conditions, including rheumatoid arthritis.

IMPORTANCE Statistically significant overall survival (OS) benefits of CDK4 and CDK6 inhibitors in combination with fulvestrant for hormone receptor (HR)-positive, ERBB2 (formerly HER2)-negative advanced breast cancer (ABC) in patients regardless of menopausal status after prior endocrine therapy (ET) has not yet been demonstrated. OBJECTIVE To compare the effect of abemaciclib plus fulvestrant vs placebo plus fulvestrant on OS at the prespecified interim of MONARCH 2 (338 events) in patients with HR-positive, ERBB2-negative advanced breast cancer that progressed during prior ET. DESIGN, SETTING, AND PARTICIPANTS MONARCH 2 was a global, randomized, placebocontrolled, double-blind phase 3 trial of abemaciclib plus fulvestrant vs placebo plus fulvestrant for treatment of premenopausal or perimenopausal women (with ovarian suppression) and postmenopausal women with HR-positive, ERBB2-negative ABC that progressed during ET. Patients were enrolled between August 7, 2014, and December 29, 2015. Analyses for this report were conducted at the time of database lock on June 20, 2019. INTERVENTIONS Patients were randomized 2:1 to receive abemaciclib or placebo, 150 mg, every 12 hours on a continuous schedule plus fulvestrant, 500 mg, per label. Randomization was stratified based on site of metastasis (visceral, bone only, or other) and resistance to prior ET (primary vs secondary). MAIN OUTCOMES AND MEASURES The primary end point was investigator-assessed progressionfree survival. Overall survival was a gated key secondary end point. The boundary P value for the interim analysis was .02. RESULTS Of 669 women enrolled, 446 (median [range] age, 59 [32-91] years) were randomized to the abemaciclib plus fulvestrant arm and 223 (median [range] age, 62 [32-87] years) were randomized to the placebo plus fulvestrant arm. At the prespecified interim, 338 deaths (77% of the planned 441 at the final analysis) were observed in the intent-to-treat population, with a median OS of 46.7 months for abemaciclib plus fulvestrant and 37.3 months for placebo plus fulvestrant (hazard ratio [HR], 0.757; 95% CI, 0.606-0.945; P = .01). Improvement in OS was consistent across all stratification factors. Among stratification factors, more pronounced effects were observed in patients with visceral disease (HR, 0.675; 95% CI, 0.511-0.891) and primary resistance to prior ET (HR, 0.686; 95% CI, 0.451-1.043). Time to second disease progression (median, 23.1 months vs 20.6 months), time to chemotherapy (median, 50.2 months vs 22.1 months), and chemotherapy-free survival (median, 25.5 months vs 18.2 months) were also statistically significantly improved in the abemaciclib arm vs placebo arm. No new safety signals were observed for abemaciclib. CONCLUSIONS AND RELEVANCE Treatment with abemaciclib plus fulvestrant resulted in a statistically significant and clinically meaningful median OS improvement of 9.4 months for patients with HR-positive, ERBB2-negative ABC who progressed after prior ET regardless of menopausal status. Abemaciclib substantially delayed ...

Angiogenesis is a significant event in a wide range of healthy and diseased conditions. This process frequently involves vasodilation and an increase in vascular permeability. Numerous players referred to as angiogenic factors, work in tandem to facilitate the outgrowth of endothelial cells (EC) and the consequent vascularity. Conversely, angiogenic factors could also feature in pathological conditions. Angiogenesis is a critical factor in the development of tumors and metastases in numerous cancers. An increased level of angiogenesis is associated with decreased survival in breast cancer patients. Therefore, a good understanding of the angiogenic mechanism holds a promise of providing effective treatments for breast cancer progression, thereby enhancing patients' survival. Disrupting the initiation and progression of this process by targeting angiogenic factors such as vascular endothelial growth factor (Vegf)-one of the most potent member of the VEGF family-or by targeting transcription factors, such as Hypoxia-Inducible Factors (HIFs) that act as angiogenic regulators, have been considered potential treatment options for several types of cancers. The objective of this review is to highlight the mechanism of angiogenesis in diseases, specifically its role in the progression of malignancy in breast cancer, as well as to highlight the undergoing research in the development of angiogenesis-targeting therapies.

Mitochondrial dysfunction is considered as a key mediator in the pathogenesis of diabetic nephropathy (DN). Therapeutic strategies targeting mitochondrial dysfunction hold considerable promise for the treatment of DN. In this study, we investigated the role of progranulin (PGRN), a secreted glycoprotein, in mediating mitochondrial homeostasis and its therapeutic potential in DN. We found that the level of PGRN was significantly reduced in the kidney from STZ-induced diabetic mice and patients with biopsy-proven DN compared with healthy controls. In DN model, PGRN-deficient mice aggravated podocyte injury and proteinuria versus wild-type mice. Functionally, PGRN deficiency exacerbated mitochondrial damage and dysfunction in podocytes from diabetic mice. In vitro, treatment with recombinant human PGRN (rPGRN) attenuated high glucose-induced mitochondrial dysfunction in podocytes accompanied by enhanced mitochondrial biogenesis and mitophagy. Inhibition of mitophagy disturbed the protective effects of PGRN in high glucose-induced podocytotoxicity. Mechanistically, we demonstrated that PGRN maintained mitochondrial homeostasis via PGRN-Sirt1-PGC-1α/FoxO1 signaling-mediated mitochondrial biogenesis and mitophagy. Finally, we provided direct evidence for therapeutic potential of PGRN in mice with DN. This study provides new insights into the novel role of PGRN in maintaining mitochondrial homeostasis, suggesting that PGRN may be an innovative therapeutic strategy for treating patients with DN.