The Patriarchal Bargain in a Context of Rapid Changes to Normative Gender Roles: Young Arab Women’s Role Conflict in Qatar

Social norms in patriarchal countries in the Middle East are changing at differing rates. In Qatar, expectations about education have shifted, and women’s participation in higher education is normative. However, women’s participation in the workforce remains relatively low, and women still are expected to perform all household and child-rearing activities. Interviews with 27 18–25 year-old Qatari women enrolled in college in Qatar are used to illustrate the conflict between norms about education, workforce, and family. Many young women resolve this normative conflict by giving preference to family over work and education. Other women hold conflicting norms and goals for their future without acknowledging the normative conflict. Overall, young women in this sample feared divorce, were uncertain about customary family safety nets, and thus desired financial independence so they would be able to support themselves if they were left alone later in life due to divorce, or the death of their husband. The Qatari government should revisit the appropriateness of continuing to emphasize the patriarchal family structure and socially conservative family norms, if they desire to advance women in their society

The pathology of familial breast cancer: Morphological aspects

A small proportion of breast cancers are due to a heritable predisposition. Recently, two predisposition genes, BRCA1 and BRCA2, have been identified and cloned. The morphological features of tumours from patients harbouring mutations in the BRCA1 and BRCA2 genes differ from each other and from sporadic breast cancers. Both are of higher grade than are sporadic cases. An excess of medullary/atypical medullary carcinoma has been reported in patients with BRCA1 mutations. Multifactorial analysis, however, shows that the only features independently associated with BRCA1 mutations are a high mitotic count, pushing tumour margins and a lymphocytic infiltrate. For BRCA2 mutation, an association with tubular/lobular carcinoma has been suggested, but not substantiated in a larger Breast Cancer Linkage Consortium study. In multifactorial analysis, the independent features were a lack of tubule formation and pushing tumour margins only. The morphological analysis has implications for clinical management of patients

Maximizing the potential of aggressive mouse tumor models in preclinical drug testing.

Atypical teratoid rhabdoid tumor (ATRT) is an aggressive embryonal brain tumor among infants and young children. Two challenges exist for preclinical testing in ATRT. First, genetically quiet, ATRT is a difficult tumor to target molecularly. Tumor cells need to divide to propagate tumor growth-intercepting the common crossroads in cell cycle progression is a feasible strategy. KIF11 is needed for bipolar spindle formation in metaphase. We identified KIF11 as a universal target of all ATRT-molecular-subtypes. Ispinesib, a KIF11-inhibitor, effectively inhibited tumor proliferation in all seven cell lines. A second challenge-a major challenge in preclinical drug testing in-vivo among aggressive tumor models, is the narrow therapeutic window to administer drugs within the limited murine lifespan. Our most aggressive ATRT tumor model was lethal in all mice within ~ 1 month of tumor implantation. Such short-surviving mouse models are difficult to employ for preclinical drug testing due to the narrow time window to administer drugs. To overcome this time restriction, we developed a clinical staging system which allowed physically-fit mice to continue treatment, in contrast to the conventional method of fixed drug-dose-duration regimen in preclinical testing which will not be feasible in such short-surviving mouse models. We validated this approach in a second embryonal brain tumor, medulloblastoma. This is a clinically relevant, cost-efficient approach in preclinical testing for cancer and non-cancer disease phenotypes. Widely used preclinical mouse models are not the most accurate and lack the aggressive tumor spectrum found within a single tumor type. Mice bearing the most aggressive tumor spectrum progress rapidly in the limited murine life-span, resulting in a narrow therapeutic window to administer drugs, and are thus difficult to employ in preclinical testing. Our approach overcomes this challenge. We discovered ispinesib is efficacious against two embryonal brain tumor types

Nuclear factor IA is expressed in astrocytomas and is associated with improved survival

Nuclear factor IA (NFIA) is a transcription factor that specifies glial cell identity and promotes astrocyte differentiation during embryonic development. Its expression and function in gliomas are not known. Here, we examined NFIA protein expression in gliomas and its association with clinical outcome in pediatric malignant astrocytomas. We analyzed expression of NFIA by immunohistochemistry in 88 existing glioma specimens from Childrens Hospital Los Angeles and the University of Southern California. Association between NFIA expression and progression-free survival (PFS) was examined in high-grade astrocytomas for which clinical data were available (n = 23, all children). NFIA was highly expressed in astrocytomas of all grades, but only in a minority of cells in oligodendroglial tumors. NFIA was expressed on a higher percentage of tumor cells in low-grade astrocytomas (91 ± 5% and 77 ± 14% in World Health Organization [WHO] I and II, respectively) compared with high-grade astrocytomas (48 ± 18% and 37 ± 16% in WHO III and IV, respectively; P < .001, low- vs high-grade astrocytomas). There was a significant association between NFIA expression and PFS in children with astrocytoma WHO grade III or IV (Cox regression P = .019; logrank trend test for NFIA tertiles P = .0040 and NFIA quartiles P = .014). The association was not consistently significant in this small series of patients after adjustment was made for WHO grade III or IV. This is the first study to demonstrate expression of NFIA protein in astrocytomas and its association with grades of astrocytoma and PFS, suggesting that NFIA may play a role in astrocytoma biology

The Chromatin-Modifying Protein HMGA2 Promotes Atypical Teratoid/Rhabdoid Cell Tumorigenicity

Atypical teratoid/rhabdoid tumor (AT/RT) is an aggressive pediatric central nervous system tumor. The poor prognosis of AT/RT warrants identification of novel therapeutic targets and strategies. High mobility group A2 (HMGA2) is a developmentally important chromatin modifying protein that positively regulates tumor growth, self-renewal and invasion in other cancer types. HMGA2 was recently identified as being upregulated in AT/RT tissue, but the role of HMGA2 in brain tumors remains unknown. We used lentiviral short hairpin RNA to suppress HMGA2 in AT/RT cell lines and found that loss of HMGA2 led to decreased cell growth, proliferation, colony formation and increased apoptosis. We also found that suppression of HMGA2 negatively affected in vivo orthotopic xenograft tumor growth, more than doubling median survival of the mice from 58 days to 153 days. Our results indicate a role for HMGA2 in AT/RT in vitro and in vivo and demonstrate that HMGA2 is a potential therapeutic target in these lethal pediatric tumors