Mutant U2AF1-expressing cells are sensitive to pharmacological modulation of the spliceosome

Somatic mutations in spliceosome genes are detectable in ∼50% of patients with myelodysplastic syndromes (MDS). We hypothesize that cells harbouring spliceosome gene mutations have increased sensitivity to pharmacological perturbation of the spliceosome. We focus on mutant U2AF1 and utilize sudemycin compounds that modulate pre-mRNA splicing. We find that haematopoietic cells expressing mutant U2AF1(S34F), including primary patient cells, have an increased sensitivity to in vitro sudemycin treatment relative to controls. In vivo sudemycin treatment of U2AF1(S34F) transgenic mice alters splicing and reverts haematopoietic progenitor cell expansion induced by mutant U2AF1 expression. The splicing effects of sudemycin and U2AF1(S34F) can be cumulative in cells exposed to both perturbations—drug and mutation—compared with cells exposed to either alone. These cumulative effects may result in downstream phenotypic consequences in sudemycin-treated mutant cells. Taken together, these data suggest a potential for treating haematological cancers harbouring U2AF1 mutations with pre-mRNA splicing modulators like sudemycins

Diet diversity in pastoral and agro-pastoral households in Ugandan rangeland ecosystems

We explore how diet diversity differs with agricultural seasons and between households within pastoral and agro-pastoral livelihood systems, using variety of foods consumed as a less complex proxy indicator of food insecurity than benchmark indicators like anthropometry and serum nutrients. The study was in the central part of the rangelands in Uganda. Seventy nine households were monitored for three seasons, and eight food groups consumed during a 24 hour diet recall period used to create a household diet diversity score (HDDS). Mean HDDS was 3.2, varied significantly with gender, age, livelihood system and season (p < .001, F = 15.04), but not with household size or household head’s education level. Agro-pastoralists exhibited lower mean diet diversity than pastoralists (p < .01, F = 7.84) and among agro-pastoralists, households headed by persons over 65 years were most vulnerable (mean HDDS 2.1). This exploratory study raises issues requiring further investigation to inform policies on nutrition security in the two communities

How Treatment Partners Help: Social Analysis of an African Adherence Support Intervention

Treatment partnering is an adherence intervention developed in sub-Saharan Africa. This paper describes the additional social functions that treatment partners serve and shows how these functions contribute to health and survival for patients with HIV/AIDS. Ninety-eight minimally structured interviews were conducted with twenty pairs of adult HIV/AIDS patients (N = 20) and treatment partners (N = 20) treated at a public HIV-care setting in Tanzania. Four social functions were identified using inductive, category construction and interpretive methods of analysis: (1) encouraging disclosure; (2) combating stigma; (3) restoring hope; and (4) reducing social difference. These functions work to restore social connections and reverse the isolating effects of HIV/AIDS, strengthening access to essential community safety nets. Besides encouraging ARV adherence, treatment partners contribute to the social health of patients. Social health as well as HIV treatment success is essential to survival for persons living with HIV/AIDS in sub-Saharan Africa

“Reproducing the social”: Contradictory interconnections between land, cattle production and household relations in the Besters Land Reform Project, South Africa

Land redistribution policy in South Africa emphasises commercial farming as the legitimate use of land. This production-oriented framework fails to take into account the intertwined but unstable relationship between the production of market value and social reproduction, and how this shapes social differentiation. Drawing on a case study of the Besters Land Reform Project in the province of KwaZulu-Natal, the paper shows that land and cattle are not simply moments in the production of beef but material and discursive resources in (re)making the social conditions of the household. Cattle are used in drawn-out ceremonies that occur in specific spaces and stitch together families and communities pulled apart by rising inequality, making land constitutive of identity and belonging as well as of capitalist value production. Until land reform policy recognises the multi-functionality of land and cattle, and the contradictory relationship between functions, agricultural production will be a limited indicator of “success” or “failure.

The Origin and Evolution of Mutations in Acute Myeloid Leukemia

SummaryMost mutations in cancer genomes are thought to be acquired after the initiating event, which may cause genomic instability and drive clonal evolution. However, for acute myeloid leukemia (AML), normal karyotypes are common, and genomic instability is unusual. To better understand clonal evolution in AML, we sequenced the genomes of M3-AML samples with a known initiating event (PML-RARA) versus the genomes of normal karyotype M1-AML samples and the exomes of hematopoietic stem/progenitor cells (HSPCs) from healthy people. Collectively, the data suggest that most of the mutations found in AML genomes are actually random events that occurred in HSPCs before they acquired the initiating mutation; the mutational history of that cell is “captured” as the clone expands. In many cases, only one or two additional, cooperating mutations are needed to generate the malignant founding clone. Cells from the founding clone can acquire additional cooperating mutations, yielding subclones that can contribute to disease progression and/or relapse

Track D Social Science, Human Rights and Political Science

Peer Reviewedhttps://deepblue.lib.umich.edu/bitstream/2027.42/138414/1/jia218442.pd

Integrated genomic characterization of endometrial carcinoma

SummaryWe performed an integrated genomic, transcriptomic, and proteomic characterization of 373 endometrial carcinomas using array- and sequencing-based technologies. Uterine serous tumors and ~25% of high-grade endometrioid tumors have extensive copy number alterations, few DNA methylation changes, low ER/PR levels, and frequent TP53 mutations. Most endometrioid tumors have few copy number alterations or TP53 mutations but frequent mutations in PTEN, CTNNB1, PIK3CA, ARID1A, KRAS and novel mutations in the SWI/SNF gene ARID5B. A subset of endometrioid tumors we identified had a dramatically increased transversion mutation frequency, and newly identified hotspot mutations in POLE. Our results classified endometrial cancers into four categories: POLE ultramutated, microsatellite instability hypermutated, copy number low, and copy number high. Uterine serous carcinomas share genomic features with ovarian serous and basal-like breast carcinomas. We demonstrated that the genomic features of endometrial carcinomas permit a reclassification that may impact post-surgical adjuvant treatment for women with aggressive tumors