Expression Ratios of the Antiapoptotic BCL2 Family Members Dictate the Selective Addiction of Kaposi's Sarcoma-Associated Herpesvirus-Transformed Primary Effusion Lymphoma Cell Lines to MCL1.

Kaposi's sarcoma-associated herpesvirus (KSHV) causes several malignancies in people living with HIV, including primary effusion lymphoma (PEL). PEL cell lines exhibit oncogene addictions to both viral and cellular genes. Using CRISPR screens, we previously identified cellular oncogene addictions in PEL cell lines, including MCL1. MCL1 is a member of the BCL2 family, which functions to prevent intrinsic apoptosis and has been implicated in several cancers. Despite the overlapping functions of the BCL2 family members, PEL cells are dependent only on MCL1, suggesting that MCL1 may have nonredundant functions. To investigate why PEL cells exhibit selective addiction to MCL1, we inactivated the intrinsic apoptosis pathway by engineering BAX/BAK1 double knockout cells. In this context, PEL cells become resistant to MCL1 knockdown or MCL1 inactivation by the MCL1 inhibitor S63845, indicating that the main function of MCL1 in PEL cells is to prevent BAX/BAK1-mediated apoptosis. The selective requirement to MCL1 is due to MCL1 being expressed in excess over the BCL2 family. Ectopic expression of several BCL2 family proteins, as well as the KSHV BCL2 homolog, significantly decreased basal caspase 3/7 activity and buffered against staurosporine-induced apoptosis. Finally, overexpressed BCL2 family members can functionally substitute for MCL1, when it is inhibited by S63845. Together, our data indicate that the expression levels of the BCL2 family likely explain why PEL tumor cells are highly addicted to MCL1. Importantly, our results suggest that caution should be taken when considering MCL1 inhibitors as a monotherapy regimen for PEL because resistance can develop easily. IMPORTANCE Primary effusion lymphoma (PEL) is caused by Kaposi's sarcoma-associated herpesvirus. We showed previously that PEL cell lines require the antiapoptotic protein MCL1 for survival but not the other BCL2 family proteins. This selective dependence on MCL1 is unexpected as the BCL2 family functions similarly in preventing intrinsic apoptosis. Recently, new roles for MCL1 not shared with the BCL2 family have emerged. Here, we show that noncanonical functions of MCL1 are unlikely essential. Instead, MCL1 functions mainly to prevent apoptosis. The specific requirement to MCL1 is due to MCL1 being expressed in excess over the BCL2 family. Consistent with this model, shifting these expression ratios changes the requirement away from MCL1 and toward the dominant BCL2 family gene. Together, our results indicate that although MCL1 is an attractive chemotherapeutic target to treat PEL, careful consideration must be taken, as resistance to MCL1-specific inhibitors easily develops through BCL2 family overexpression.

Utilizing the Regional Acceleratory Phenomenon and Dental Implant Anchorage for Distalization and Intrusion of a Mesially Tipped Mandibular Molar: A Case Report.

INTRODUCTION: Introduction of a surgical insult in conjunction with orthodontic therapy has been shown to accelerate treatment in minor tooth movement and comprehensive orthodontic cases by induction of the regional acceleratory phenomenon (RAP). When applying this concept to a molar tipped into an adjacent edentulous site, a dental implant can be planned to anchor the movement. CASE PRESENTATION: A generally and periodontally healthy 25-year-old patient presented missing tooth #19, with tooth #18 mesially tipped into the first molar crown space. A dental implant was placed in the #19 position. Following osseointegration, the implant anchored orthodontic movement of the adjacent tooth, which was initiated in conjunction with third molar extraction. CONCLUSION: Favorable biomechanics for molar uprighting can be achieved using an osseointegrated implant and a customized orthodontic device. The presented technique facilitates implant site development without delaying placement of the fixture and simplifies fabrication of a harmonious and anatomic implant-supported restoration. Induction of the RAP may hasten treatment completion.

Frequency of failure to inform patients of clinically significant outpatient test results.

BACKGROUND: Failing to inform a patient of an abnormal outpatient test result can be a serious error, but little is known about the frequency of such errors or the processes for managing results that may reduce errors. METHODS: We conducted a retrospective medical record review of 5434 randomly selected patients aged 50 to 69 years in 19 community-based and 4 academic medical center primary care practices. Primary care practice physicians were surveyed about their processes for managing test results, and individual physicians were notified of apparent failures to inform and asked whether they had informed the patient. Blinded reviewers calculated a "process score" ranging from 0 to 5 for each practice using survey responses. RESULTS: The rate of apparent failures to inform or to document informing the patient was 7.1% (135 failures divided by 1889 abnormal results), with a range of 0% to 26.2%. The mean process score was 3.8 (range, 0.9-5.0). In mixed-effects logistic regression, higher process scores were associated with lower failure rates (odds ratio, 0.68; P < .001). Use of a "partial electronic medical record" (paper-based progress notes and electronic test results or vice versa) was associated with higher failure rates compared with not having an electronic medical record (odds ratio, 1.92; P = .03) or with having an electronic medical record that included both progress notes and test results (odds ratio, 2.37; P = .007). CONCLUSIONS: Failures to inform patients or to document informing patients of abnormal outpatient test results are common; use of simple processes for managing results is associated with lower failure rates.

Dietary differences among women of Polish descent by country of birth and duration of residency in the United States.

OBJECTIVES: Changes in breast and gastric cancers and coronary artery disease among people of Polish descent after migration to the United States suggest there may be potentially modifiable factors affecting incidence of these diseases. We examined relationships of dietary factors associated with these diseases with stage of migration among Polish women in Chicago. DESIGN: Women of Polish descent (N = 396) were selected from Polish women's social organizations. Women completed a modified Health Habits and History Questionnaire. SETTING: The questionnaire was completed either at the participant's home or at a Polish social organization. PARTICIPANTS: Participants ranged in age from 17-81 years, and included women born in Poland or the United States, who had at least one parent of Polish. INTERVENTIONS: Participants were stratified by country of birth and migration period (1935-1979, 1980-1989, 1990-1997). MAIN OUTCOME MEASURES: The average daily intake of food groups and nutrients was assessed using multiple linear regression. RESULTS: We found statistically significant differences by birth country for 19 of 34 nutrients, 4 of 7 food groups, and for 21 nutrients, and 5 food groups among the different migration tertiles. CONCLUSIONS: Women from Poland and more recent migrants had generally more nutritious intakes, compared to US-born women, or earlier migrants. APPLICATIONS/CONCLUSIONS: There are significant dietary differences among women of Polish descent that vary by duration of US residency and birth country. Women with dietary intakes which place them at higher risk for cancers and cardiovascular disease could be targeted for interventions to lower their disease risk.