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1.  Paclitaxel-Induced Apoptosis Is BAK-Dependent, but BAX and BIM-Independent in Breast Tumor 
PLoS ONE  2013;8(4):e60685.
Paclitaxel (Taxol)-induced cell death requires the intrinsic cell death pathway, but the specific participants and the precise mechanisms are poorly understood. Previous studies indicate that a BH3-only protein BIM (BCL-2 Interacting Mediator of cell death) plays a role in paclitaxel-induced apoptosis. We show here that BIM is dispensable in apoptosis with paclitaxel treatment using bim−/− MEFs (mouse embryonic fibroblasts), the bim−/− mouse breast tumor model, and shRNA-mediated down-regulation of BIM in human breast cancer cells. In contrast, both bak−/− MEFs and human breast cancer cells in which BAK was down-regulated by shRNA were more resistant to paclitaxel. However, paclitaxel sensitivity was not affected in bax−/− MEFs or in human breast cancer cells in which BAX was down-regulated, suggesting that paclitaxel-induced apoptosis is BAK-dependent, but BAX-independent. In human breast cancer cells, paclitaxel treatment resulted in MCL-1 degradation which was prevented by a proteasome inhibitor, MG132. A Cdk inhibitor, roscovitine, blocked paclitaxel-induced MCL-1 degradation and apoptosis, suggesting that Cdk activation at mitotic arrest could induce subsequent MCL-1 degradation in a proteasome-dependent manner. BAK was associated with MCL-1 in untreated cells and became activated in concert with loss of MCL-1 expression and its release from the complex. Our data suggest that BAK is the mediator of paclitaxel-induced apoptosis and could be an alternative target for overcoming paclitaxel resistance.
doi:10.1371/journal.pone.0060685
PMCID: PMC3618047  PMID: 23577147
2.  Clinical reliability of closed techniques and comparison with open strategies to achieve union at the docking site 
International Orthopaedics  2011;36(4):817-825.
Purpose
This retrospective review follows 31 tibial nonunions to compare union at the docking site using closed versus open strategies. In this cohort of patients, all but five were infected nonunions.
Methods
Thirteen patients initially treated with single compression were compared with 18 patients treated by open revision of the docking site. In the single compression group, an average of 6.5 cm of bone was resected and index lengthening was 2.04. In the open revision group, a mean of 9.4 cm was resected and the index lengthening was 1.73.
Results
Consolidation at the docking site occurred in all subjects in both groups. There was no statistical difference between the two groups. Conclusive evidence of superiority of one modality of treatment over the other cannot be drawn from our data.
Conclusions
The simple compression procedure requires less invasive surgery and is probably less demanding and more cost-effective in short transports.
doi:10.1007/s00264-011-1260-4
PMCID: PMC3311812  PMID: 21505801
4.  Posterior Malleolar Stabilization of Syndesmotic Injuries is Equivalent to Screw Fixation 
Background
Fixation of unstable ankle fractures, including fixation of posterior malleolus fracture fragments with the attached, intact posteroinferior tibiofibular ligament (PITFL), reportedly provides more stable fixation than transsyndesmotic screws.
Questions/Purposes
To confirm this observation we compared the Foot and Ankle Outcome Score (FAOS) and radiographic maintenance of fixation for fractures treated through direct posterior malleolar fixation versus syndesmotic screw fixation.
Methods
We prospectively followed 31 one patients with unstable ankle fractures treated with (1) open posterior malleolus fixation whenever the posterior malleolus was fractured, regardless of fragment size (PM group; n = 9); (2) locked syndesmotic screws in the absence of a posterior malleolar fracture (S group; n = 14); or (3) combined fixation in fracture-dislocations and more severe soft tissue injury (C group; n = 8). All patients had preoperative MRI confirming syndesmotic injury and an intact PITFL; postoperative and followup radiographs were evaluated for syndesmotic congruence. The minimum followup was 12 months (mean, 15 months; range, 12–31 months).
Results
Postoperative and followup FAOS scores were similar in the three groups. The tibiofibular clear space was greater in the S versus the PM group, but we found no other differences in the postoperative versus followup measurements between the PM, S, and C groups.
Conclusions
Syndesmotic fixation through the posterior malleolus and PITFL is maintained at followup, and these patients have functional outcomes at least equivalent to outcomes for patients having syndesmotic screw fixation.
Level of Evidence
Level II, therapeutic study. See Guidelines for Authors for a complete description of levels of evidence.
doi:10.1007/s11999-009-1111-4
PMCID: PMC2835618  PMID: 19798540
5.  Chronic Physical Effects and Health Care Utilization in Long-Term Ovarian Germ Cell Tumor Survivors: A Gynecologic Oncology Group Study 
Journal of Clinical Oncology  2009;27(25):4142-4149.
Purpose
This study compares late effects of treatment on physical well-being and utilization of health care resources between ovarian germ cell tumor (OGCT) survivors and age/race/education-matched controls.
Patients and Methods
Eligible patients had OGCT treated with surgery and chemotherapy and were disease-free for at least 2 years at time of enrollment. The matched control group was selected from acquaintances recommended by survivors. Symptoms and function were measured using previously validated scales. Health care utilization was assessed by questions regarding health insurance coverage and health services utilization.
Results
One hundred thirty-two survivors and 137 controls completed the study. Survivors were significantly more likely to report a diagnosis of hypertension (17% v 8%, P = .02), and marginally hypercholesterolemia (9.8% v 4.4%, P = .09), and hearing loss (5.3% v 1.5%, P = .09) compared with controls. There were no significant differences in the rates of self-reported arthritis, heart, pulmonary or kidney disease, diabetes, non-OGCT malignancies, anxiety, hearing loss, or eating disorders between groups. Among chronic functional problems, numbness, tinnitus, nausea elicited by reminders of chemotherapy (v general nausea triggers for controls), and Raynaud's symptoms were reported more frequently by survivors. Patients who received vincristine, dactinomycin, and cyclophosphamide in addition to cisplatin therapy had increased functional complaints, particularly numbness and nausea. Health care utilization was similar, but 15.9% of survivors reported being denied health insurance versus 4.4% of controls (P < .001).
Conclusion
Although a few sequelae of treatment persist, in general, OGCT survivors enjoy a healthy life comparable to that of controls.
doi:10.1200/JCO.2008.20.9189
PMCID: PMC2734426  PMID: 19636015
6.  Incidence of Ceramic Liner Malseating in Trident® Acetabular Shell 
The low wear rates associated with ceramic hip articulations have made them a popular bearing for younger patients. Although few complications have been observed, one report revealed several instances of incomplete seating of the ceramic liner in the metallic shell. We performed a cohort study of consecutive THAs using a ceramic-ceramic bearing. Radiographic analysis showed 50 (7.2%) of the group of 694 hips had evidence of incomplete seating of the liner in the metallic shell. Although we observed no adverse effects at 6 to 12 weeks, we encourage surgeons to carefully assess liner placement in the metal shell at the time of surgery to avoid this unintended consequence and to assess placement at the time of followup so patients can be properly followed when incomplete seating is identified.
Level of Evidence: Level IV, therapeutic study. See the Guidelines for Authors for a complete description of levels of evidence.
doi:10.1007/s11999-009-0770-5
PMCID: PMC2674179  PMID: 19280269
7.  Lapatinib resistance in HCT116 cells is mediated by elevated MCL-1 expression, decreased BAK activation, and not by ERBB receptor mutation 
Molecular pharmacology  2008;74(3):807-822.
We have defined some of the mechanisms by which the kinase inhibitor Lapatinib kills HCT116 cells. Lapatinib inhibited radiation-induced activation of ERBB1/2, ERK1/2 and AKT, and radiosensitized HCT116 cells. Prolonged incubation of HCT116 cells with Lapatinib caused cell killing followed by outgrowth of Lapatinib adapted cells. Adapted cells were resistant to serum-starvation –induced cell killing and were cross resistant to multiple therapeutic drugs. Lapatinib was competent to inhibit basal and EGF-stimulated ERBB1 phosphorylation in adapted cells. Co-expression of dominant negative ERBB1 and dominant negative ERBB2 inhibited basal and EGF-stimulated ERBB1 and ERBB2 phosphorylation in parental cells. However in neither parental nor adapted cells did expression of dominant negative ERBB1 and dominant negative ERBB2 recapitulate the cell death promoting effects of Lapatinib. Adapted cells had increased expression of MCL-1, decreased expression of BAX, and decreased activation of BAX and BAK. Over-expression of BCL-XL protected parental cells from Lapatinib toxicity. Knock down of MCL-1 expression enhanced Lapatinib toxicity in adapted cells that was reverted by knock down of BAK expression. Inhibition of caspase function modestly reduced Lapatinib toxicity in parental cells whereas knock down of AIF expression suppressed Lapatinib toxicity. Thus in HCT116 cells Lapatinib adaptation can be mediated by altered expression of pro- and anti-apoptotic proteins that maintain mitochondrial function.
doi:10.1124/mol.108.047365
PMCID: PMC2574656  PMID: 18544666
Lapatinib; Ras; cell death
8.  Acetoacetate reduces growth and ATP concentration in cancer cell lines which over-express uncoupling protein 2 
Background
Recent evidence suggests that several human cancers are capable of uncoupling of mitochondrial ATP generation in the presence of intact tricarboxylic acid (TCA) enzymes. The goal of the current study was to test the hypothesis that ketone bodies can inhibit cell growth in aggressive cancers and that expression of uncoupling protein 2 is a contributing factor. The proposed mechanism involves inhibition of glycolytic ATP production via a Randle-like cycle while increased uncoupling renders cancers unable to produce compensatory ATP from respiration.
Methods
Seven aggressive human cancer cell lines, and three control fibroblast lines were grown in vitro in either 10 mM glucose medium (GM), or in glucose plus 10 mM acetoacetate [G+AcA]. The cells were assayed for cell growth, ATP production and expression of UCP2.
Results
There was a high correlation of cell growth with ATP concentration (r = 0.948) in a continuum across all cell lines. Controls demonstrated normal cell growth and ATP with the lowest density of mitochondrial UCP2 staining while all cancer lines demonstrated proportionally inhibited growth and ATP, and over-expression of UCP2 (p < 0.05).
Conclusion
Seven human cancer cell lines grown in glucose plus acetoacetate medium showed tightly coupled reduction of growth and ATP concentration. The findings were not observed in control fibroblasts. The observed over-expression of UCP2 in cancer lines, but not in controls, provides a plausible molecular mechanism by which acetoacetate spares normal cells but suppresses growth in cancer lines. The results bear on the hypothesized potential for ketogenic diets as therapeutic strategies.
doi:10.1186/1475-2867-9-14
PMCID: PMC2694762  PMID: 19480693
9.  Sphingosine Kinases and Sphingosine-1-Phosphate Are Critical for Transforming Growth Factor β-Induced Extracellular Signal-Regulated Kinase 1 and 2 Activation and Promotion of Migration and Invasion of Esophageal Cancer Cells▿  
Molecular and Cellular Biology  2008;28(12):4142-4151.
Transforming growth factor β (TGFβ) plays a dual role in oncogenesis, acting as both a tumor suppressor and a tumor promoter. These disparate processes of suppression and promotion are mediated primarily by Smad and non-Smad signaling, respectively. A central issue in understanding the role of TGFβ in the progression of epithelial cancers is the elucidation of the mechanisms underlying activation of non-Smad signaling cascades. Because the potent lipid mediator sphingosine-1-phosphate (S1P) has been shown to transactivate the TGFβ receptor and activate Smad3, we examined its role in TGFβ activation of extracellular signal-regulated kinases 1 and 2 (ERK1/2) and promotion of migration and invasion of esophageal cancer cells. Both S1P and TGFβ activate ERK1/2, but only TGFβ activates Smad3. Both ligands promoted ERK1/2-dependent migration and invasion. Furthermore, TGFβ rapidly increased S1P, which was required for TGFβ-induced ERK1/2 activation, as well as migration and invasion, since downregulation of sphingosine kinases, the enzymes that produce S1P, inhibited these responses. Finally, our data demonstrate that TGFβ activation of ERK1/2, as well as induction of migration and invasion, is mediated at least in part by ligation of the S1P receptor, S1PR2. Thus, these studies provide the first evidence that TGFβ activation of sphingosine kinases and formation of S1P contribute to non-Smad signaling and could be important for progression of esophageal cancer.
doi:10.1128/MCB.01465-07
PMCID: PMC2423114  PMID: 18426913
10.  The feasibility of preventing mother-to-child transmission of HIV using peer counselors in Zimbabwe 
Background
Prevention of mother-to-child transmission of HIV (PMTCT) is a major public health challenge in Zimbabwe.
Methods
Using trained peer counselors, a nevirapine (NVP)-based PMTCT program was implemented as part of routine care in urban antenatal clinics.
Results
Between October 2002 and December 2004, a total of 19,279 women presented for antenatal care. Of these, 18,817 (98%) underwent pre-test counseling; 10,513 (56%) accepted HIV testing, of whom 1986 (19%) were HIV-infected. Overall, 9696 (92%) of women collected results and received individual post-test counseling. Only 288 men opted for HIV testing. Of the 1807 HIV-infected women who received posttest counseling, 1387 (77%) collected NVP tablet and 727 (40%) delivered at the clinics. Of the 1986 HIV-infected women, 691 (35%) received NVPsd at onset of labor, and 615 (31%) infants received NVPsd. Of the 727 HIV-infected women who delivered in the clinics, only 396 women returned to the clinic with their infants for the 6-week follow-up visit; of these mothers, 258 (59%) joined support groups and 234 (53%) opted for contraception. By the end of the study period, 209 (53%) of mother-infant pairs (n = 396) came to the clinic for at least 3 follow-up visits.
Conclusion
Despite considerable challenges and limited resources, it was feasible to implement a PMTCT program using peer counselors in urban clinics in Zimbabwe.
doi:10.1186/1742-6405-5-17
PMCID: PMC2517064  PMID: 18673571
11.  QUALITY OF LIFE IN LONG-TERM SURVIVORS OF OVARIAN GERM CELL TUMORS: A GYNECOLOGIC ONCOLOGY GROUP STUDY 
Gynecologic oncology  2007;105(3):687-694.
Purpose
This report describes the strength and significance of the association between antecedent and mediating variables across four categories of quality of life (QOL) outcomes in 132 disease free women with ovarian germ cell tumors.
Methods
Survivors (n=132) participated in a mailed questionnaire and computer-assisted telephone survey. Participants in four prospective GOG protocols were contacted their treating physician for verbal consent to be approached by investigators at the Indiana University Cancer Center about a quality of life study. Similar patients treated at the MD Anderson Cancer Center were also included. If women verbally consented after being contacted by investigators at Indiana University, an informed consent and questionnaire packet was sent via mail. After return of the written informed consent and background questionnaire, a trained research assistant scheduled a computer-assisted interview to complete data collection.
Results
Median follow-up from diagnosis was 10.2 years. Mediating variables of self efficacy and social support played a significant role (p=.001) in all four QOL categories: physical functioning, psychological functioning, sexual functioning, and spiritual functioning. Being a younger age at diagnosis and married were positively related to sexual functioning (p=.05). Menstrual and gynecological symptoms were inversely related.
Implications
Results indicate that clinicians may want to be especially sensitive to identifying a survivor’s social support and confidence (self efficacy) in handling issues evolving from treatment since these skills may be related to overall quality of life outcomes.
doi:10.1016/j.ygyno.2007.01.042
PMCID: PMC1995655  PMID: 17355890
Ovarian Germ Cell Tumors; Cancer Survivorship; Quality of Life
12.  Prevention of mother to child transmission of HIV: evaluation of a pilot programme in a district hospital in rural Zimbabwe 
BMJ : British Medical Journal  2004;329(7475):1147-1150.
Problem Zimbabwe has one of the highest rates of HIV seroprevalence in the world. In 2001 only 4% of women and children in need of services for prevention of mother to child transmission of HIV were receiving them.
Design Pilot implementation of the first programme for prevention of mother to child transmission of HIV in rural Zimbabwe.
Setting 120 bed district hospital in Buhera district (285 000 inhabitants), Manicaland, Zimbabwe.
Key measures for improvement Programme uptake indicators monitored for 18 months; impact of policy evaluated by assessing up-scaling of programme.
Strategies for change Voluntary counselling and testing services for HIV were provided in the hospital antenatal clinic. Women identified as HIV positive and informed of their serostatus and their newborn were offered a single dose antiretroviral treatment of nevirapine; mother-child pairs were followed up through routine health services. Nursing staff and social workers were trained, and community mobilisation was conducted.
Effects of change No services for prevention of mother to child transmission of HIV were available at baseline. Within 18 months, 2298 pregnant women had received pretest counselling, and the acceptance of HIV testing reached 93.0%. Of all 2137 women who had an HIV test, 1588 (74.3%) returned to collect their result; 326 of the 437 HIV positive women diagnosed had post-test counselling, and 104 (24%) mother-child pairs received nevirapine prophylaxis.
Lessons learnt Minimum staffing, an enhanced training programme, and involvement of district health authorities are needed for the implementation and successful integration of services for prevention of mother to child transmission of HIV. Voluntary counselling and testing services are important entry points for HIV prevention and care and for referral to community networks and medical HIV care services. A district approach is critical to extend programmes for prevention of mother to child transmission of HIV in rural settings. The lessons learnt from this pilot programme have contributed to the design of the national expansion strategy for prevention of mother to child transmission of HIV in Zimbabwe.
PMCID: PMC527692  PMID: 15539670

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