Comparison of SP142 and 22C3 Immunohistochemistry PD-L1 Assays for Clinical Efficacy of Atezolizumab in Non-Small Cell Lung Cancer: Results From the Randomized OAK Trial.

BACKGROUND: This phase III OAK trial (NCT02008227) subgroup analysis (data cutoff, January 9, 2019) evaluated the predictive value of 2 PD-L1 IHC tests (VENTANA SP142 and Dako 22C3) for benefit from atezolizumab versus docetaxel by programmed death ligand 1 (PD-L1) status in patients with previously treated metastatic non-small cell lung cancer. METHODS: PD-L1 expression was assessed prospectively with SP142 on tumor cells (TC) and tumor-infiltrating immune cells (IC) and retrospectively with 22C3 using a tumor proportion score (TPS) based on TC membrane staining. Efficacy was assessed in the 22C3 biomarker-evaluable population (22C3-BEP) (n = 577; 47.1% of SP142-intention-to-treat population) and non-22C3-BEP (n = 648) in PD-L1 subgroups (high, low, and negative) and according to selection by 1 or both assays. RESULTS: In the 22C3-BEP, overall survival benefits with atezolizumab versus docetaxel were observed across PD-L1 subgroups; benefits were greatest in SP142-defined PD-L1-high (TC3 or IC3: hazard ratio [HR], 0.39 [95% confidence interval (CI), 0.25-0.63]) and 22C3-defined PD-L1-high (TPS ≥ 50%: HR, 0.56 [95% CI, 0.38-0.82]) and low (TPS, 1% to < 50%: HR, 0.55 [95% CI, 0.37-0.82]) groups. Progression-free survival improved with increasing PD-L1 expression for both assays. SP142 and 22C3 assays identified overlapping and unique patient populations in PD-L1-high, positive, and negative subgroups. Overall survival and progression-free survival benefits favored atezolizumab over docetaxel in double PD-L1-positive and negative groups; patients with both SP142- and 22C3-positive tumors derived the greatest benefit. CONCLUSIONS: Despite different scoring algorithms and differing sensitivity levels, the SP142 and 22C3 assays similarly predicted atezolizumab benefit at validated PD-L1 thresholds in patients with non-small cell lung cancer.

DEL1 protects against chondrocyte apoptosis through integrin binding.

BACKGROUND: Osteoarthritis (OA) is a debilitating disease process, affecting mobility and overall health of millions. Current treatment is for symptomatic relief and discovery of approaches to halt or reverse damage is imperative. Deletion of developmental endothelial locus-1 (Del1) has been shown to increase severity of OA in knockout mice. We examined the intracellular pathways involved in the ability of DEL1 to protect chondrocytes from apoptosis and anoikis and hypothesized that it functioned via integrin signaling. MATERIALS AND METHODS: Primary human chondrocytes were treated with various inducers of apoptosis, including anoikis, in the presence of added DEL1 or bovine serum albumin as control. Various inhibitors of integrin binding were examined for their effect on DEL1 activity. Downstream signaling pathway components were detected by immunoblotting. RESULTS: The addition of DEL1 protected chondrocytes from multiple inducers of apoptosis as measured by cell survival, terminal deoxynucleotidyl transferase dUTP nick end labeling and caspase 3/7 assays (P < 0.05). The effect of DEL1 was blocked by RGD peptides and by antibodies directed to integrin αVß3, but not by controls or antibody to integrin α1 (P < 0.05). Treatment with DEL1 promoted ERK and AKT activation when cells were attached, but only AKT activation under conditions of anoikis. CONCLUSIONS: DEL1 protected chondrocytes from apoptosis in response to activators of either the intrinsic or extrinsic pathways, and to anoikis. This effect was mediated primarily through integrin αVß3. This represents a therapeutic target for therapies to prevent cartilage degeneration in OA.

Inhibition of IRE1 results in decreased scar formation.

Wound healing is characterized by the production of large amounts of protein necessary to replace lost cellular mass and extracellular matrix. The unfolded protein response (UPR) is an important adaptive cellular response to increased protein synthesis. One of the main components of the UPR is IRE1, an endoplasmic reticulum transmembrane protein with endonuclease activity that produces the activated form of the transcription factor XBP1. Using luciferase reporter mice for Xbp1 splicing, we showed that IRE1 was up-regulated during excisional wound healing at the time in wound healing consistent with that of the proliferative phase, when the majority of protein synthesis for cellular proliferation and matrix deposition occurs. Furthermore, using a small molecule inhibitor of IRE1 we demonstrated that inhibition of IRE1 led to decreased scar formation in treated mice. Results were recapitulated in a hypertrophic scar mouse model. These data help provide a cellular pathway to target in the treatment of hypertrophic scarring and keloid disorders.

Del1 Knockout Mice Developed More Severe Osteoarthritis Associated with Increased Susceptibility of Chondrocytes to Apoptosis.

OBJECTIVE: We identified significant expression of the matricellular protein, DEL1, in hypertrophic and mature cartilage during development. We hypothesized that this tissue-specific expression indicated a biological role for DEL1 in cartilage biology. METHODS: Del1 KO and WT mice had cartilage thickness evaluated by histomorphometry. Additional mice underwent medial meniscectomy to induce osteoarthritis, and were assayed at 1 week for apoptosis by TUNEL staining and at 8 weeks for histology and OA scoring. In vitro proliferation and apoptosis assays were performed on primary chondrocytes. RESULTS: Deletion of the Del1 gene led to decreased amounts of cartilage in the ears and knee joints in mice with otherwise normal skeletal morphology. Destabilization of the knee led to more severe OA compared to controls. In vitro, DEL1 blocked apoptosis in chondrocytes. CONCLUSION: Osteoarthritis is among the most prevalent diseases worldwide and increasing in incidence as our population ages. Initiation begins with an injury resulting in the release of inflammatory mediators. Excessive production of inflammatory mediators results in apoptosis of chondrocytes. Because of the limited ability of chondrocytes to regenerate, articular cartilage deteriorates leading to the clinical symptoms including severe pain and decreased mobility. No treatments effectively block the progression of OA. We propose that direct modulation of chondrocyte apoptosis is a key variable in the etiology of OA, and therapies aimed at preventing this important step represent a new class of regenerative medicine targets.

Association of Mothers' Perception of Neighborhood Quality and Maternal Resilience with Risk of Preterm Birth.

We examined the associations of mothers' perception of neighborhood quality and maternal resilience with risk of preterm birth and whether maternal resilience moderated the effect of neighborhood quality perception. We analyzed data from 10,758 women with singleton births who participated in 2010-2012 Los Angeles Mommy and Baby surveys. Multilevel logistic regression models assessed the effects of mothers' perception of neighborhood quality and maternal resilience on preterm birth (yes/no), controlling for potential confounders and economic hardship index, a city-level measure of neighborhood quality. Interaction terms were assessed for moderation. Mothers' perception of neighborhood quality and maternal resilience were each uniquely associated with preterm birth, independent of potential confounders (p-values < 0.05). The risk of preterm birth among mothers who perceived their neighborhood as of poor quality was about 30% greater compared to mothers who perceived their neighborhood as of good quality; the risk was 12% greater among mothers with low resilience compared to those with high resilience. Effects of neighborhood quality were not modified by maternal resilience. The findings suggest that mothers' perception of neighborhood quality and resilience are associated with the risk of preterm birth. Further research should explore whether initiatives aimed at improving neighborhood quality and women's self-esteem may improve birth outcomes.