Approximately half of cancer-affected patients receive radiotherapy (RT). The doses delivered have been determined upon empirical experience based upon average radiation responses. Ideally higher curative radiation doses might be employed in patients with genuinely normal radiation responses and importantly radiation hypersensitive patients would be spared the consequences of excessive tissue damage if they were indentified before treatment. Rad21 is an integral subunit of the cohesin complex, which regulates chromosome segregation and DNA damage responses in eukaryotes. We show here, by targeted inactivation of this key cohesin component in mice, that Rad21 is a DNA-damage response gene that markedly affects animal and cell survival. Biallelic deletion of Rad21 results in early embryonic death. Rad21 heterozygous mutant cells are defective in homologous recombination (HR)-mediated gene targeting and sister chromatid exchanges. Rad21+/− animals exhibited sensitivity considerably greater than control littermates when challenged with whole body irradiation (WBI). Importantly, Rad21+/− animals are significantly more sensitive to WBI than Atm heterozygous mutant mice. Since supralethal WBI of mammals most typically leads to death via damage to the gastrointestinal tract (GIT) or the haematopoietic system, we determined the functional status of these organs in the irradiated animals. We found evidence for GIT hypersensitivity of the Rad21 mutants and impaired bone marrow stem cell clonogenic regeneration. These data indicate that Rad21 gene dosage is critical for the ionising radiation (IR) response. Rad21 mutant mice thus represent a new mammalian model for understanding the molecular basis of irradiation effects on normal tissues and have important implications in the understanding of acute radiation toxicity in normal tissues.

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Perinatal death, of a fetus or newborn, is a devastating event for families. Following nationwide multicentre recruitment, we assessed 'genomic autopsy' as an adjunct to standard autopsy for 200 families who experienced perinatal death, and provided a de nite or candidate genetic diagnosis in 105 families. From this understudied cohort, half of the (candidate) diagnoses were phenotype expansions or novel disease genes, revealing previously unknown in-utero presentations of existing developmental disorders, and genomic disorders that are likely incompatible with life. Among the de nite diagnoses, 43% were recessively or dominantly inherited, posing a 25% or 50% recurrence risk for future pregnancies. Ten families used their diagnosis for preimplantation or prenatal diagnosis of 12 pregnancies, facilitating the delivery of ten healthy newborns and management of two affected pregnancies. We emphasize the clinical importance of genomic investigations of perinatal death, with short turn-around times, enabling accurate counselling and options for families to prevent recurrence.

Approximately half of cancer-affected patients receive radiotherapy (RT). The doses delivered have been determined upon empirical experience based upon average radiation responses. Ideally higher curative radiation doses might be employed in patients with genuinely normal radiation responses and importantly radiation hypersensitive patients would be spared the consequences of excessive tissue damage if they were indentified before treatment. Rad21 is an integral subunit of the cohesin complex, which regulates chromosome segregation and DNA damage responses in eukaryotes. We show here, by targeted inactivation of this key cohesin component in mice, that Rad21 is a DNA-damage response gene that markedly affects animal and cell survival. Biallelic deletion of Rad21 results in early embryonic death. Rad21 heterozygous mutant cells are defective in homologous recombination (HR)-mediated gene targeting and sister chromatid exchanges. Rad21 +/2 animals exhibited sensitivity considerably greater than control littermates when challenged with whole body irradiation (WBI). Importantly, Rad21 +/2 animals are significantly more sensitive to WBI than Atm heterozygous mutant mice. Since supralethal WBI of mammals most typically leads to death via damage to the gastrointestinal tract (GIT) or the haematopoietic system, we determined the functional status of these organs in the irradiated animals. We found evidence for GIT hypersensitivity of the Rad21 mutants and impaired bone marrow stem cell clonogenic regeneration. These data indicate that Rad21 gene dosage is critical for the ionising radiation (IR) response. Rad21 mutant mice thus represent a new mammalian model for understanding the molecular basis of irradiation effects on normal tissues and have important implications in the understanding of acute radiation toxicity in normal tissues.

provides long-term patient reported metrics in women treated with APBI at one institution. Materials/Methods: Records of 164 women treated with APBI using balloon catheter high dose rate brachytherapy (BCHDRB) in 34 Gy in 10 fractions from 2005 to 2013 were reviewed after institutional review board approval. Women with ipsilateral or distant recurrence, poor prognosis, second primary, or known dates of death were excluded; women with contralateral recurrence were included if mastectomy was not performed. The Decisional Regret and Satisfaction Scales, quality of life, and cosmesis were captured using questions adapted from NSABP B39. Instruments were administered via mail, telephone, or email to eligible women. Results: Of 141 women who met inclusion criteria, 74 participated, 9 declined, and 58 have yet to be reached. Median age at diagnosis was 62 years(SDZ9), and median time from RT completion to surveys was 95 months(SDZ8). Histology was pure DCIS(25%), invasive ductal carcinoma(51%), and mixed(24%). The majority had estrogen/progesterone receptor positive disease. Decisional satisfaction was high, and regret was low; 94% felt satisfied with their decision, and 92% would make the same choice again. Factors that were important in decision making included convenience, physician recommendation, financial considerations, novelty of treatment, desire to avoid mastectomy, and recovery time; 46% reported convenience to be the most important factor. Prior to radiation 74% of women were totally satisfied with their breast size, and 96% continued to be totally/somewhat satisfied after APBI. Women were neutral, somewhat/ completely dissatisfied in the appearance of their breast before and after APBI in 18% and 19% respectively. After ABPI, 32% reported moderate/ large changes in breast size, while 68% reported slight/no changes. Seroma or needle aspiration of seroma were reported in 14% of women, and 89% of those reported this as little/somewhat/very much bothersome. Other side effects reported, were moderate or large hardening of breast(29%), thickening of breast skin(22%), swelling of breast(11%), skin reddening(7%) or darkening(8%). Despite these cosmetic changes, a majority of women(85%) reported total satisfaction with therapy. Overall breast appearance was reported as good/excellent in 70% of women, while 21% and 8% reported fair and poor overall appearance, respectively. Conclusion: Decisional satisfaction remains high 9 years after APBI, even in women with treatment sequela. This study highlights the importance of patient reported cosmesis and quality of life metrics as an adjunct to provider assessment of treatment outcomes.