Neuronal types in the central nervous system differ dramatically in their resilience to injury or other insults. Here we studied the selective resilience of mouse retinal ganglion cells (RGCs) following optic nerve crush (ONC), which severs their axons and leads to death of $80% of RGCs within 2 weeks. To identify expression programs associated with differential resilience, we first used single-cell RNA-seq (scRNA-seq) to generate a comprehensive molecular atlas of 46 RGC types in adult retina. We then tracked their survival after ONC; characterized transcriptomic, physiological, and morphological changes that preceded degeneration; and identified genes selectively expressed by each type. Finally, using loss-and gain-of-function assays in vivo, we showed that manipulating some of these genes improved neuronal survival and axon regeneration following ONC. This study provides a systematic framework for parsing type-specific responses to injury and demonstrates that differential gene expression can be used to reveal molecular targets for intervention.

Although three-dimensional (3D) bioprinting technology has gained much attention in the field of tissue engineering, there are still several significant engineering challenges to overcome, including lack of bioink with biocompatibility and printability. Here, we show a bioink created from silk fibroin (SF) for digital light processing (DLP) 3D bioprinting in tissue engineering applications. The SF-based bioink (Sil-MA) was produced by a methacrylation process using glycidyl methacrylate (GMA) during the fabrication of SF solution. The mechanical and rheological properties of Sil-MA hydrogel proved to be outstanding in experimental testing and can be modulated by varying the Sil-MA contents. This Sil-MA bioink allowed us to build highly complex organ structures, including the heart, vessel, brain, trachea and ear with excellent structural stability and reliable biocompatibility. Sil-MA bioink is well-suited for use in DLP printing process and could be applied to tissue and organ engineering depending on the specific biological requirements.

In the presence of obesity, beta-cell mass needs to be increased to compensate for the accompanying demands and maintain euglycemia. However, in Korea, the majority of type 2 diabetic patients are nonobese. We determined the absolute masses, relative volumes, and ratio of alpha- and beta-cell in the pancreas and islets in normal and diabetic Korean subjects to correlate these findings with the clinical characteristics. Whole pancreases procured from organ donors were divided into 24 parts (control 1, n = 9). Tissue was also obtained by surgical resection after 35 partial pancreatectomies: in 25 diabetic patients, 10 age- and body mass index (BMI)-matched patients of benign or malignant pancreatic tumor without diabetes mellitus (DM) (control 2). Morphometric quantifications were performed. In control 1, the relative volume of beta-cells was 2.1 +/- 0.9%, and the total beta-cell mass was 1.3 +/- 0.3 g. The relative volume of beta-cells was found to be variable (control 1, 2.1 +/- 0.9%; control 2, 1.9 +/- 0.7%; DM, 1.4 +/- 1.0%; P < 0.05 DM vs. control 1 and 2) and showed good correlation with BMI (control 1, r(2) = 0.64; DM, r(2) = 0.55; all subjects, r(2) = 0.38; P < 0.05). Notably, in type 2 diabetic patients, the ratio of alpha-cell area to beta-cell area in the islet was higher than in control 1 and 2 (0.81 +/- 0.4 vs. 0.29 +/- 0.2, 0.20 +/- 0.1, P < 0.05). Additionally, significant alpha-cell expansion and a decreased beta-cell fraction were predominantly observed in larger islets (islet area, >6415 micro m(2); P < 0.05) in control 1 and diabetic patients. The relative volume of beta-cell was found to be correlated with BMI in diabetic patients and normal organ donors. Moreover, decreased beta-cell but increased alpha-cell proportion in the islets suggests for a selective beta-cell loss in the pathogenesis of Korean type 2 diabetes.

Background Olaparib is an oral poly(ADP-ribose) polymerase inhibitor and cediranib is an oral anti-angiogenic with activity against VEGFR-1, 2, and 3. Both agents have antitumor activity in women with recurrent ovarian cancer, and the combination of these agents was active and had manageable toxicities in a Phase 1 trial. We asked whether the combination of cediranib and olaparib could improve progression-free survival compared to olaparib monotherapy in women with recurrent platinum-sensitive ovarian cancer. Methods We conducted a randomized, open-label, phase 2 study to evaluate the activity of olaparib monotherapy compared with combination cediranib and olaparib in women with ovarian cancer with measurable platinum-sensitive, relapsed, high-grade serous or endometrioid disease or those with deleterious germline BRCA1/2 mutations (gBRCAm). Patients were randomized using permuted blocks within stratum defined by gBRCA status and prior anti-angiogenic therapy to receive olaparib capsules 400mg twice daily or the combination at the recommended phase 2 dose of cediranib 30mg daily and olaparib capsules 200mg twice daily. The primary endpoint was progression-free survival (PFS) analyzed under intention to treat. The trial is registered with ClinicalTrials.gov, NCT01116648. The Phase 2 portion of the trial reported here is no longer accruing patients. Findings Forty-six of 90 randomized patients received olaparib alone, and 44 received cediranib/olaparib. Median PFS was significantly longer with cediranib/olaparib (17.7 vs. 9.0 mos, HR 0.42; p = 0.005). Grade 3 and 4 adverse events were more common with cediranib/olaparib, including fatigue (12 vs. 5), diarrhea (10 vs. 0), and hypertension (18 vs. 0). Subset analysis within stratum defined by BRCA1/2 status demonstrated activity of cediranib/olaparib in both gBRCAm and gBRCAwt/u (wild-type/unknown) patients. Significant improvement in PFS occurred in gBRCAwt/u women receiving cediranib/olaparib (16.5 vs. 5.7 mos, p = 0.008) with a smaller trend towards increased PFS in gBRCAm patients (19.4 vs. 16.5 mos, p = 0.16). Interpretation The combination of cediranib and olaparib significantly extended PFS by 8.7 months compared to olaparib alone in recurrent platinum-sensitive ovarian cancer. The activity observed with this oral combinaton in both gBRCAmt and gBRCAwt/u patients is encouraging and should be further explored as a potential alternative to cytotoxic chemotherapy. Given the side effect profile, such explorations should include assessments on quality of life and patient-reported outcomes to understand the effects of an ongoing oral regimen to that of intermittent chemotherapy.