Frequent co-expression of the HOXA9 and MEIS1 homeobox genes in human myeloid leukemias.

There is increasing evidence that HOX homeobox genes play a role in leukemogenesis. Recent studies have demonstrated that enforced co-expression of HOXA9 and MEIS1 in murine marrow leads to rapid development of myeloid leukemia, and that these proteins exhibit cooperative DNA binding. However, it is unclear whether co-activation of HOXA9 and MEIS genes is a common occurrence in human leukemias. We surveyed expression of HOXA9 and MEIS1 in 24 leukemic cell lines and 80 patient samples, using RNase protection analyses and immunohistochemistry. We demonstrate that the expression of HOXA9 and MEIS1 in leukemia cells is uniquely myeloid, and that these genes are commonly co-expressed in myeloid cell lines and in samples of acute myelogenous leukemia (AML) of all subtypes except in promyelocytic leukemia. While HOXA9 is expressed in most cases of chronic myelogenous leukemia, MEIS1 is weakly expressed or not at all. Immunohistochemical staining of selected AML samples showed moderate to high levels of HOXA9 protein, primarily cytoplasmic, in leukemic myeloblasts, with weaker and primarily nuclear staining for MEIS1. These data support the concept that co-activation of HOXA9 and MEIS1 is a common event in AML, and may represent a common pathway of many different oncogenic mutations.     

A Virtual Reality Endoscopic Simulator Augments General Surgery Resident Cancer Education as Measured by Performance Improvement

Colorectal cancer is the second most common cause of death in the USA. The need for screening colonoscopies, and thus adequately trained endoscopists, particularly in rural areas, is on the rise. Recent increases in required endoscopic cases for surgical resident graduation by the Surgery Residency Review Committee (RRC) further emphasize the need for more effective endoscopic training during residency to determine if a virtual reality colonoscopy simulator enhances surgical resident endoscopic education by detecting improvement in colonoscopy skills before and after 6 weeks of formal clinical endoscopic training. We conducted a retrospective review of prospectively collected surgery resident data on an endoscopy simulator. Residents performed four different clinical scenarios on the endoscopic simulator before and after a 6-week endoscopic training course. Data were collected over a 5-year period from 94 different residents performing a total of 795 colonoscopic simulation scenarios. Main outcome measures included time to cecal intubation, “red out” time, and severity of simulated patient discomfort (mild, moderate, severe, extreme) during colonoscopy scenarios. Average time to intubation of the cecum was 6.8 min for those residents who had not undergone endoscopic training versus 4.4 min for those who had undergone endoscopic training (p?<?0.001). Residents who could be compared against themselves (pre vs. post-training), cecal intubation times decreased from 7.1 to 4.3 min (p?<?0.001). Post-endoscopy rotation residents caused less severe discomfort during simulated colonoscopy than pre-endoscopy rotation residents (4 vs. 10 %; p?=?0.004). Virtual reality endoscopic simulation is an effective tool for both augmenting surgical resident endoscopy cancer education and measuring improvement in resident performance after formal clinical endoscopic training.     

Perceptions of barriers and facilitators to cervical cancer screening among low-income,HIV-infected women from an integrated HIV clinic

Significantly elevated rates of cervical cancer and low rates of Papanicolaou (Pap) smear screening have been documented among HIV-infected women. However, little is known about women's perceptions of cervical cancer screening utilization. Hence, this study describes barriers and facilitators related to cervical cancer screening in a sample of HIV-infected women seeking care at an integrated HIV clinic in Houston, Texas. Using an inductive qualitative methodological approach, data were obtained from five focus group discussions with a total of 33, HIV-infected women. The majority of the study sample consisted of women who self-identified as Black (69.7%), and reported heterosexual contact as the mode of HIV acquisition (75.8%). Barriers to cervical cancer screening were described as pain and discomfort associated with receiving Pap smears and subsequent procedures; lack of awareness of cervical cancer as a preventable disease; limited transportation access; and systemic issues as it relates to scheduling gynecological appointments. Facilitators were described as awareness of HIV-infected women's increased risk of cervical cancer and strong provider–patient relationships. To address disparities in cervical cancer screening among low-income HIV-infected women, programs should capitalize on the identified facilitators and alleviate modifiable barriers using multilevel strategies.     

Identification of the modifier of Min 2 (Mom2) locus, a new mutation that influences Apc-induced intestinal neoplasia.

Min (Multiple intestinal neoplasia) mice carry a dominant mutation in the adenomatous polyposis coli (Apc) gene and develop multiple adenomas throughout their intestinal tract (Moser et al. 1990; Su et al 1992). Polyp multiplicity in Min mice is greatly influenced by genetic background. A modifier locus, Mom1 (Modifier of Min 1), was identified and localized to distal mouse chromosome 4 (Moser et al. 1992; Dietrich et al. 1993), and accounts for some of the genetic variance in polyp multiplicity. Mom1 is a semidominant modifier of polyp size and multiplicity in Min mice (Gould and Dove 1997), and encodes the secretory type II nonpancreatic phospholipase A2 (Pla2g2a) gene (MacPhee et al. 1995; Cornier et al. 1997, 2000). We now report the identification of a second Modifier of Min 2 (Mom2) locus that is the result of a spontaneous mutation. One resistant Mom2 allele can suppress 88%-95% of polyps detected in Apc(Min)/+ mice, indicating that Mom2 acts in a dominant fashion. Linkage analysis has localized Mom2 to distal mouse chromosome 18. The effects of the Mom2 locus on reducing polyp multiplicity are stronger than the effects of the Mom1 locus, in both the small and large intestines. Some Apc(Min)/+ mice that carried one resistant Mom2 allele were tumor-free at 21 weeks of age, even in the absence of a resistant Mom1 allele. Thus, the resistant Mom2 allele can, in some cases, completely suppress the penetrance of the Apc(Min) mutation.     

The modifier of Min 2 (Mom2) locus: embryonic lethality of a mutation in the Atp5a1 gene suggests a novel mechanism of polyp suppression

Inactivation of the APC gene is considered the initiating event in human colorectal cancer. Modifier genes that influence the penetrance of mutations in tumor-suppressor genes hold great potential for preventing the development of cancer. The mechanism by which modifier genes alter adenoma incidence can be readily studied in mice that inherit mutations in the Apc gene. We identified a new modifier locus of ApcMin-induced intestinal tumorigenesis called Modifier of Min 2 (Mom2). The polyp-resistant Mom2R phenotype resulted from a spontaneous mutation and linkage analysis localized Mom2 to distal chromosome 18. To obtain recombinant chromosomes for use in refining the Mom2 interval, we generated congenic DBA.B6 ApcMin/+, Mom2R/+ mice. An intercross revealed that Mom2R encodes a recessive embryonic lethal mutation. We devised an exclusion strategy for mapping the Mom2 locus using embryonic lethality as a method of selection. Expression and sequence analyses of candidate genes identified a duplication of four nucleotides within exon 3 of the alpha subunit of the ATP synthase (Atp5a1) gene. Tumor analyses revealed a novel mechanism of polyp suppression by Mom2R in Min mice. Furthermore, we show that more adenomas progress to carcinomas in Min mice that carry the Mom2R mutation. The absence of loss of heterozygosity (LOH) at the Apc locus, combined with the tendency of adenomas to progress to carcinomas, indicates that the sequence of events leading to tumors in ApcMin/+ Mom2R/+ mice is consistent with the features of human tumor initiation and progression.