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A pathological hallmark of Alzheimer's disease is the senile plaque, containing beta-amyloid fibrils, microglia and astrocytes. Beta-amyloid fibrils exert a cytotoxic effect on neurons, and stimulate microglia to produce neurotoxins, such as reactive oxygen species. Mononuclear phagocytes, including microglia, express scavenger receptors that mediate endocytosis of oxidized low-density lipoproteins, and adhesion to glucose-modified extra-cellular matrix proteins. Here we report that class A scavenger receptors mediate adhesion of rodent microglia and human monocytes to beta-amyloid fibril-coated surfaces leading to secretion of reactive oxygen species and cell immobilization. Thus, class A scavenger receptors are potential therapeutic targets in Alzheimer's disease.

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Pfizer, and Takeda. Dr. Finley reports receiving consultancy fees from Roche, Bayer, and Secura Bio; speakers bureau fees from Bristol Myers Squibb; and support for travel, accommodation, and expenses from Roche. Dr. Kong is an employee of Genentech. Dr. Lee is an employee of and reports having stock ownership in Genentech. Dr. Coleman is an employee of Genentech and reports having stock ownership in Roche, Bristol Myers Squibb, Johnson & Johnson, TEVA, and Gilead Sciences. Dr. Zou is an employee of Roche. Dr. McCleland is an employee of Genentech/Roche. Dr. Shankar is an employee of Genentech/Roche and reports having a pending patent to disclose. Dr. Reck reports receiving honoraria for consultancy and lecture roles from Amgen,

Infections with gram-positive bacteria are a major cause of morbidity and mortality in humans. Opsonin-dependent phagocytosis plays a major role in protection against and recovery from gram-positive infections. Inborn and acquired defects in opsonin generation and/or recognition by phagocytes are associated with an increased susceptibility to bacterial infections. In contrast, the physiological significance of opsonin-independent phagocytosis is unknown. Type I and II class A scavenger receptors (SR-AI/II) recognize a variety of polyanions including bacterial cell wall products such as lipopolysaccharide (LPS) and lipoteichoic acid (LTA), suggesting a role for SR-AI/II in innate immunity to bacterial infections. Here, we show that SR-AI/II–deficient mice (MSR-A−/−) are more susceptible to intraperitoneal infection with a prototypic gram-positive pathogen, Staphylococcus aureus, than MSR-A+/+ control mice. MSR-A−/− mice display an impaired ability to clear bacteria from the site of infection despite normal killing of S. aureus by neutrophils and die as a result of disseminated infection. Opsonin-independent phagocytosis of gram-positive bacteria by MSR-A−/− macrophages is significantly decreased although their phagocytic machinery is intact. Peritoneal macrophages from control mice phagocytose a variety of gram-positive bacteria in an SR-AI/II–dependent manner. Our findings demonstrate that SR-AI/II mediate opsonin-independent phagocytosis of gram-positive bacteria, and provide the first evidence that opsonin-independent phagocytosis plays a critical role in host defense against bacterial infections in vivo.

studies, higher plasma 25-hydroxyvitamin D (25[OH]D) levels have been associated with improved survival in metastatic colorectal cancer (CRC). OBJECTIVE To determine if high-dose vitamin D 3 added to standard chemotherapy improves outcomes in patients with metastatic CRC. DESIGN, SETTING, AND PARTICIPANTS Double-blind phase 2 randomized clinical trial of 139 patients with advanced or metastatic CRC conducted at 11 US academic and community cancer centers from March 2012 through November 2016 (database lock: September 2018). INTERVENTIONS mFOLFOX6 plus bevacizumab chemotherapy every 2 weeks and either high-dose vitamin D 3 (n = 69) or standard-dose vitamin D 3 (n = 70) daily until disease progression, intolerable toxicity, or withdrawal of consent. MAIN OUTCOMES AND MEASURES The primary end point was progression-free survival (PFS) assessed by the log-rank test and a supportive Cox proportional hazards model. Testing was 1-sided. Secondary end points included tumor objective response rate (ORR), overall survival (OS), and change in plasma 25(OH)D level. RESULTS Among 139 patients (mean age, 56 years; 60 [43%] women) who completed or discontinued chemotherapy and vitamin D 3 (median follow-up, 22.9 months), the median PFS for high-dose vitamin D 3 was 13.0 months (95% CI, 10.1 to 14.7; 49 PFS events) vs 11.0 months (95% CI, 9.5 to 14.0; 62 PFS events) for standard-dose vitamin D 3 (log-rank P = .07); multivariable hazard ratio for PFS or death was 0.64 (1-sided 95% CI, 0 to 0.90; P = .02). There were no significant differences between high-dose and standard-dose vitamin D 3 for tumor ORR (58% vs 63%, respectively; difference, −5% [95% CI, −20% to 100%], P = .27) or OS (median, 24.3 months vs 24.3 months; log-rank P = .43). The median 25(OH)D level at baseline for high-dose vitamin D 3 was 16.1 ng/mL vs 18.7 ng/mL for standard-dose vitamin D 3 (difference, −2.6 ng/mL [95% CI, −6.6 to 1.4], P = .30); at first restaging, 32.0 ng/mL vs 18.7 ng/mL (difference, 12.8 ng/mL [95% CI, 9.0 to 16.6], P < .001); at second restaging, 35.2 ng/mL vs 18.5 ng/mL (difference, 16.7 ng/mL [95% CI, 10.9 to 22.5], P < .001); and at treatment discontinuation, 34.8 ng/mL vs 18.7 ng/mL (difference, 16.2 ng/mL [95% CI, 9.9 to 22.4], P < .001). The most common grade 3 and higher adverse events for chemotherapy plus high-dose vs standard-dose vitamin D 3 were neutropenia (n = 24 [35%] vs n = 21 [31%], respectively) and hypertension (n = 9 [13%] vs n = 11 [16%]). CONCLUSIONS AND RELEVANCE Among patients with metastatic CRC, addition of high-dose vitamin D 3 , vs standard-dose vitamin D 3 , to standard chemotherapy resulted in a difference in median PFS that was not statistically significant, but with a significantly improved supportive hazard ratio. These findings warrant further evaluation in a larger multicenter randomized clinical trial.