SUMMARY Retinoblastomas develop due to the loss of the Rb protein, yet the cell type in which Rb suppresses retinoblastoma, and the cellular circuitry that underlies the need for Rb are undefined. Here, we show that retinoblastoma cells express markers of post-mitotic cone precursors, but not markers of other retinal cell types. We also demonstrate that human cone precursors prominently express MDM2 and N-Myc, that retinoblastoma cells require both of these proteins for proliferation and survival, and that MDM2 is specifically needed to suppress ARF-induced apoptosis in cultured retinoblastoma cells. Interestingly, retinoblastoma cell MDM2 expression was regulated by the cone-specific RXRγ transcription factor and a human-specific RXRγ consensus binding site, and proliferation required RXRγ as well as the cone-specific thyroid hormone receptor-β2. These findings provide support for a cone precursor origin of retinoblastoma and suggest that human cone-specific signaling circuitry sensitizes to the oncogenic effects of RB1 mutations.

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PURPOSE Patients with relapsed or refractory T-cell acute lymphoblastic leukemia (r/r T-ALL) have few options and poor prognosis. The aim was to assess donor-derived anti-CD7 chimeric antigen receptor (CAR) T-cell safety and efficacy in patients with r/r T-ALL. METHODS In this single-center, phase I trial, we administered anti-CD7 CAR T cells, manufactured from either previous stem-cell transplantation donors or new donors, to patients with r/r T-ALL, in single infusions at doses of 5 × 105 or 1 × 106 (±30%) cells per kilogram of body weight. The primary end point was safety with efficacy secondary. RESULTS Twenty participants received infusions. Adverse events including cytokine release syndrome grade 1-2 occurred in 90% (n = 18) and grade 3-4 in 10% (n = 2), cytopenia grade 3-4 in 100% (n = 20), neurotoxicity grade 1-2 in 15% (n = 3), graft-versus-host disease grade 1-2 in 60% (n = 12), and viral activation grade 1-2 in 20% (n = 4). All adverse events were reversible, except in one patient who died through pulmonary hemorrhage related to fungal pneumonia, which occurred at 5.5 months, postinfusion. Ninety percent (n = 18) achieved complete remission with seven patients proceeding to stem-cell transplantation. At a median follow-up of 6.3 months (range 4.0-9.2), 15 remained in remission. CAR T cells were still detectable in five of five patients assessed in month 6, postinfusion. Although patients' CD7-positive normal T cells were depleted, CD7-negative T cells expanded and likely alleviated treatment-related T-cell immunodeficiency. CONCLUSION Among 20 patients with r/r T-ALL enrolled in this trial, donor-derived CD7 CAR T cells exhibited efficient expansion and achieved a high complete remission rate with manageable safety profile. A multicenter, phase II trial of donor-derived CD7 CAR T cells is in progress ( NCT04689659 ).

BackgroundThere are conflicting reports as to the association between smoking, radiotherapy, diabetes and osteoporosis and the risk of dental implant failure. We undertook a meta-analysis to evaluate the association between smoking, radiotherapy, diabetes and osteoporosis and the risk of dental implant failure.MethodsA comprehensive research on MEDLINE and EMBASE, up to January 2013, was conducted to identify potential studies. References of relevant studies were also searched. Screening, data extraction and quality assessment were conducted independently and in duplicate. A random-effects meta-analysis was used to pool estimates of relative risks (RRs) with 95% confidence intervals (CIs).ResultsA total of 51 studies were identified in this meta-analysis, with more than 40,000 dental implants placed under risk-threatening conditions. The pooled RRs showed a direct association between smoking (n = 33; RR = 1.92; 95% CI, 1.67–2.21) and radiotherapy (n = 16; RR = 2.28; 95% CI, 1.49–3.51) and the risk of dental implant failure, whereas no inverse impact of diabetes (n = 5; RR = 0.90; 95% CI, 0.62–1.32) on the risk of dental implant failure was found. The influence of osteoporosis on the risk of dental implant failure was direct but not significant (n = 4; RR = 1.09; 95% CI, 0.79–1.52). The subgroup analysis indicated no influence of study design, geographical location, length of follow-up, sample size, or mean age of recruited patients.ConclusionsSmoking and radiotherapy were associated with an increased risk of dental implant failure. The relationship between diabetes and osteoporosis and the risk of implant failure warrant further study.

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Pan and colleagues report one of the first prospective evaluations of planned sequential chimeric antigen receptor (CAR) T-cell therapy targeting CD19 and then CD22 in a phase 1 trial, indicating acceptable toxicity and encouraging durable efficacy in pediatric patients with relapsed/refractory (r/r) acute lymphoblastic leukemia (ALL).

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