FancD2 plays a central role in the human Fanconi anemia DNA damage response (DDR) pathway. Fancd2−/− mice exhibit many features of human Fanconi anemia including cellular DNA repair defects. Whether the DNA repair defect in Fancd2−/− mice results in radiologic changes in all cell lineages is unknown. We measured stress of hematopoiesis in long-term marrow cultures and radiosensitivity in clonogenic survival curves, as well as comet tail intensity, total antioxidant stores and radiation-induced gene expression in hematopoietic progenitor compared to bone marrow stromal cell lines. We further evaluated radioprotection by a mitochondrial-targeted antioxidant GS-nitroxide, JP4-039. Hematopoiesis longevity in Fancd2−/− mouse long-term marrow cultures was diminished and bone marrow stromal cell lines were radiosensitive compared to Fancd2+/+ stromal cells (Fancd2−/− D0 = 1.4 ± 0.1 Gy, ñ = 5.0 ± 0.6 vs. Fancd2+/+ D0 = 1.6 ± 0.1 Gy, ñ = 6.7 ± 1.6), P = 0.0124 for D0 and P = 0.0023 for ñ, respectively). In contrast, Fancd2−/− IL-3-dependent hematopoietic progenitor cells were radioresistant (D0 = 1.71 ± 0.04 Gy and ñ = 5.07 ± 0.52) compared to Fancd2+/+ (D0 = 1.39 ± 0.09 Gy and ñ = 2.31 ± 0.85, P = 0.001 for D0). CFU-GM from freshly explanted Fancd2−/− marrow was also radioresistant. Consistent with radiosensitivity, irradiated Fancd2−/− stromal cells had higher DNA damage by comet tail intensity assay compared to Fancd2+/+ cells (P < 0.0001), slower DNA damage recovery, lower baseline total antioxidant capacity, enhanced radiation-induced depletion of antioxidants, and increased CDKN1A-p21 gene transcripts and protein. Consistent with radioresistance, Fancd2−/− IL-3-dependent hematopoietic cells had higher baseline and post irradiation total antioxidant capacity. While, there was no detectable alteration of radiation-induced cell cycle arrest with Fancd2−/− stromal cells, hematopoietic progenitor cells showed reduced G2/M cell cycle arrest. The absence of the mouse Fancd2 gene product confers radiosensitivity to bone marrow stromal but not hematopoietic progenitor cells.

Elevated serum Ang-2 levels on admission are associated with and may be a useful biomarker of predicting persistent organ failure and ongoing endothelial cell activation in AP.

Two types of cemeteries occur at Punic Carthage and other Carthaginian settlements: one centrally situated housing the remains of older children through adults, and another at the periphery of the settlement (the “Tophet”) yielding small urns containing the cremated skeletal remains of very young animals and humans, sometimes comingled. Although the absence of the youngest humans at the primary cemeteries is unusual and worthy of discussion, debate has focused on the significance of Tophets, especially at Carthage, as burial grounds for the young. One interpretation, based on two supposed eye-witness reports of large-scale Carthaginian infant sacrifice [Kleitarchos (3rd c. BCE) and Diodorus Siculus (1st c. BCE)], a particular translation of inscriptions on some burial monuments, and the argument that if the animals had been sacrificed so too were the humans, is that Tophets represent burial grounds reserved for sacrificial victims. An alternative hypothesis acknowledges that while the Carthaginians may have occasionally sacrificed humans, as did their contemporaries, the extreme youth of Tophet individuals suggests these cemeteries were not only for the sacrificed, but also for the very young, however they died. Here we present the first rigorous analysis of the largest sample of cremated human skeletal remains (348 burial urns, N = 540 individuals) from the Carthaginian Tophet based on tooth formation, enamel histology, cranial and postcranial metrics, and the potential effects of heat-induced bone shrinkage. Most of the sample fell within the period prenatal to 5-to-6 postnatal months, with a significant presence of prenates. Rather than indicating sacrifice as the agent of death, this age distribution is consistent with modern-day data on perinatal mortality, which at Carthage would also have been exacerbated by numerous diseases common in other major cities, such as Rome and Pompeii. Our diverse approaches to analyzing the cremated human remains from Carthage strongly support the conclusion that Tophets were cemeteries for those who died shortly before or after birth, regardless of the cause.

Fanconi anemia (FA) is an inherited disorder characterized by defective DNA repair and cellular sensitivity to DNA crosslinking agents. Clinically, FA is associated with high risk for marrow failure, leukemia and head and neck squamous cell carcinoma (HNSCC). Radiosensitivity in FA patients compromises the use of total-body irradiation for hematopoietic stem cell transplantation and radiation therapy for HNSCC. A radioprotector for the surrounding tissue would therefore be very valuable during radiotherapy for HNSCC. Clonogenic radiation survival curves were determined for pre- or postirradiation treatment with the parent nitroxide Tempol or JP4-039 in cells of four FA patient-derived cell lines and two transgene-corrected subclonal lines. FancG–/– (PD326) and FancD2–/– (PD20F) patient lines were more sensitive to the DNA crosslinking agent mitomycin C (MMC) than their transgene-restored subclonal cell lines (both P < 0.0001). FancD2–/– cells were more radiosensitive than the transgene restored subclonal cell line (ñ = 2.0 ± 0.7 and 4.7 ± 2.2, respectively, P = 0.03). In contrast, FancG–/– cells were radioresistant relative to the transgene-restored subclonal cell line (ñ = 9.4 ± 1.5 and 2.2 ± 05, respectively, P = 0.001). DNA strand breaks measured by the comet assay correlated with radiosensitivity. Cell lines from a Fanc-C and Fanc-A patients showed radiosensitivity similar to that of Fanc-D2–/– cells. A fluorophore-tagged JP4-039 (BODIPY-FL) analog targeted the mitochondria of the cell lines. Preirradiation or postirradiation treatment with JP4-039 at a lower concentration than Tempol significantly increased the radioresistance and stabilized the antioxidant stores of all cell lines. Tempol increased the toxicity of MMC in FancD2–/– cells. These data provide support for the potential clinical use of JP4-039 for normal tissue radioprotection during chemoradiotherapy in FA patients.

Writing about the ‘Tophet’, a children's cemetery in Carthage, Smith et al. argued in these pages that the age distribution of the children peaks at 1–1.49 months, supplying “another link in the chain of evidence—funerary practices, texts, iconography—that supports the interpretation of the Phoenician Tophets as ritual sites set aside for infant sacrifice” (2011: 871). In this they had challenged Jeffrey Schwartz and colleagues, who previously argued (2010) that “skeletal remains from Punic Carthage do not support systematic sacrifice of infants”. Here Schwartz et al. restate their position for Antiquity readers, showing that the verdict on the Phoenician practice of child sacrifice is, at best, not proven.