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Background: Distal chevron osteotomy has been widely employed to treat mild to moderate hallux valgus deformity. The purpose of the present study was to evaluate the outcomes of distal chevron osteotomy with a distal soft tissue procedure for the correction of moderate to severe hallux valgus. Materials and Methods: We reviewed 76 patients (86 feet) that underwent distal chevron osteotomy with a distal soft tissue procedure for symptomatic moderate to severe hallux valgus deformity. At a mean followup of 31 months, all patients were evaluated using subjective, objective and radiographic measurements. Results: Ninety-four percent of the patients were very satisfied or satisfied. Average AOFAS score improved from 54.7 points preoperatively to 92.9 at final followup. Average hallux valgus angle changed from 36.2 degrees preoperatively to 12.4 degrees at final followup, and average firstsecond intermetatarsal angle changed from 17.1 to 7.3 degrees. Average tibial sesamoid position changed from 2.4 preoperatively to 1.2 at final followup. Dorsal angulation of the head was observed in two feet, and plantaflexion of the head in four feet. There were no cases of avascular necrosis of the metatarsal head. Conclusion: Our results indicate that distal chevron osteotomy with a distal soft tissue procedure provides an effective and reliable means of correcting moderate to severe hallux valgus deformity, and that it does so with high levels of patient satisfaction and low incidence of complications. [ABSTRACT FROM AUTHOR]

Objective: To compare myocarditis/pericarditis risk after COVID-19 mRNA vaccination versus SARS-CoV-2 infection, and to assess if myocarditis/pericarditis risk varies by vaccine dosing interval., Methods: In this retrospective cohort study, we used linked databases in Quebec, Ontario, and British Columbia between January 26, 2020, and September 9, 2021. We included individuals aged 12 or above who received an mRNA vaccine as the second dose or were SARS-CoV-2-positive by RT-PCR. The outcome was hospitalization/emergency department visit for myocarditis/pericarditis within 21 days of exposure. We calculated age- and sex-stratified incidence ratios (IRs) of myocarditis/pericarditis following mRNA vaccination versus SARS-CoV-2 infection. We also calculated myocarditis/pericarditis incidence by vaccine type, homologous/heterologous schedule, and dosing interval. We pooled province-specific estimates using meta-analysis., Results: Following 18,860,817 mRNA vaccinations and 860,335 SARS-CoV-2 infections, we observed 686 and 160 myocarditis/pericarditis cases, respectively. Myocarditis/pericarditis incidence was lower after vaccination than infection (IR [BNT162b2/SARS-CoV-2], 0.14; 95%CI, 0.07-0.29; IR [mRNA-1273/SARS-CoV-2], 0.28; 95%CI, 0.20-0.39). Within the vaccinated cohort, myocarditis/pericarditis incidence was lower with longer dosing intervals; IR (56 or more days/15-30 days) was 0.28 (95%CI, 0.19-0.41) for BNT162b2 and 0.26 (95%CI, 0.18-0.38) for mRNA-1273., Conclusion: Myocarditis/pericarditis risk was lower after mRNA vaccination than SARS-CoV-2 infection, and with longer intervals between primary vaccine doses., Competing Interests: The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: Naveed Z. Janjua reports a relationship with 10.13039/100006483AbbVie Inc that includes: consulting or advisory and speaking and lecture fees. Naveed Z. Janjua reports a relationship with 10.13039/100005564Gilead Sciences that includes: consulting or advisory and speaking and lecture fees. If there are other authors, they declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Crown Copyright © 2024 Published by Elsevier Ltd.)

Importance: The risk of myocarditis or pericarditis after COVID-19 messenger RNA vaccines varies by age and sex, and there is some evidence to suggest increasing risk with shorter intervals between dose 1 and 2 (ie, interdose interval)., Objective: To estimate the incidence of reported myocarditis or pericarditis after BNT162b2 vaccine among adolescents and to describe the clinical information associated with these events., Design, Setting, and Participants: This was a population-based cohort study using passive vaccine safety surveillance data linked to the provincial COVID-19 vaccine registry. Included in the study were all adolescents aged 12 to 17 years in Ontario, Canada, who received 1 or more doses of BNT162b2 vaccine between December 14, 2020, and November 21, 2021, and reported an episode of myocarditis or pericarditis. Data were analyzed from December 15, 2021, to April 22, 2022., Exposure: Receipt of BNT162b2 (Comirnaty [Pfizer-BioNTech]) vaccine., Main Outcomes and Measure: Reported incidence of myocarditis or pericarditis meeting level 1 to 3 of the Brighton Collaboration case definition per 100 000 doses of BNT162b2 administered by age group (12-15 years vs 16-17 years), sex, dose number, and interdose interval. All clinical information associated with symptoms, health care usage, diagnostic test results, and treatment at the time of the acute event were summarized., Results: There were approximately 1.65 million doses of BNT162b2 administered and 77 reports of myocarditis or pericarditis among those aged 12 to 17 years, which met the inclusion criteria during the study period. Of the 77 adolescents (mean [SD] age, 15.0 [1.7] years; 63 male individuals [81.8%]), 51 (66.2%) developed myocarditis or pericarditis after dose 2 of BNT162b2. Overall, 74 individuals (96.1%) with an event were assessed in the emergency department, and 34 (44.2%) were hospitalized (median [IQR] length of stay, 1 [1-2] day). The majority of adolescents (57 [74.0%]) were treated with nonsteroidal anti-inflammatory drugs only, and 11 (14.3%) required no treatment. The highest reported incidence was observed among male adolescents aged 16 to 17 years after dose 2 (15.7 per 100 000; 95% CI, 9.7-23.9). Among those aged 16 to 17 years, the reporting rate was highest in those with a short (ie, ≤30 days) interdose interval (21.3 per 100 000; 95% CI, 11.0-37.2)., Conclusions and Relevance: Results of this cohort study suggest that there was variation in the reported incidence of myocarditis or pericarditis after BNT162b2 vaccine among adolescent age groups. However, the risk of these events after vaccination remains very rare and should be considered in relation to the benefits of COVID-19 vaccination.

Importance: Increased rates of myocarditis or pericarditis following receipt of COVID-19 mRNA vaccines have been observed. However, few available data are associated with differences in rates of myocarditis or pericarditis specific to vaccine products, which may have important implications for vaccination programs., Objective: To estimate rates of reported myocarditis or pericarditis following receipt of a COVID-19 mRNA vaccine by product, age, sex, dose number, and interdose interval., Design, Setting, and Participants: This population-based cohort study was conducted in Ontario, Canada (population: 14.7 million) from December 2020 to September 2021 and used data from Ontario's COVID-19 vaccine registry and passive vaccine-safety surveillance system. All individuals in Ontario, Canada, who received at least 1 dose of COVID-19 mRNA vaccine between December 14, 2020, and September 4, 2021, and had a reported episode of myocarditis or pericarditis following receipt of the COVID-19 vaccine during this period were included. We obtained information on all vaccine doses administered in the province to calculate reported rates of myocarditis or pericarditis., Exposures: Receipt of a COVID-19 mRNA vaccine (mRNA-1273 [Moderna Spikevax] or BNT162b2 [Pfizer-BioNTech Comirnaty])., Main Outcomes and Measures: All reports of myocarditis or pericarditis meeting levels 1 to 3 of the Brighton Collaboration case definitions were included. Rates and 95% CIs of reported cases of myocarditis or pericarditis per 1 000 000 mRNA vaccine doses administered were calculated by age, sex, dose number, vaccine product, and interdose interval., Results: Among 19 740 741 doses of mRNA vaccines administered, there were 297 reports of myocarditis or pericarditis meeting the inclusion criteria; 228 (76.8%) occurred in male individuals, and the median age of individuals with a reported event was 24 years (range, 12-81 years). Of the reported cases, 207 (69.7%) occurred following the second dose of the COVID-19 mRNA vaccine. When restricted to individuals who received their second dose during the period of enhanced passive surveillance (on or after June 1, 2021), the highest rate of myocarditis or pericarditis was observed in male individuals aged 18 to 24 years following mRNA-1273 as the second dose (299.5 cases per 1 000 000 doses; 95% CI, 171.2-486.4 cases per 1 000 000 doses); the rate following BNT162b2 as the second dose was 59.2 cases per 1 000 000 doses (95% CI, 19.2-138.1 cases per 1 000 000 doses). Overall rates for both vaccine products were significantly higher when the interdose interval was 30 or fewer days (BNT162b2: 52.1 cases per 1 000 000 doses [95% CI, 31.8-80.5 cases per 1 000 000 doses]; mRNA-1273: 83.9 cases per 1 000 000 doses [95% CI, 47.0-138.4 cases per 1 000 000 doses]) compared with 56 or more days (BNT162b2: 9.6 cases per 1 000 000 doses [95% CI, 6.5-13.6 cases per 1 000 000 doses]; mRNA-1273: 16.2 cases per 1 000 000 doses [95% CI, 10.2-24.6 cases per 1 000 000 doses])., Conclusions and Relevance: The findings of this population-based cohort study of Ontario adolescents and adults with myocarditis or pericarditis following mRNA COVID-19 vaccination suggest that vaccine products and interdose intervals, in addition to age and sex, may be associated with the risk of myocarditis or pericarditis after receipt of these vaccines. Vaccination program strategies, such as age-based product considerations and longer interdose intervals, may reduce the risk of myocarditis or pericarditis following receipt of mRNA vaccines.

Haemophilus influenzae can cause serious invasive disease. We report the epidemiology and antimicrobial susceptibility of invasive H. influenzae in Ontario, Canada, from 2014 to 2018 from laboratory-based data. Blood was the most common specimen source (89.5%). Consistent with widespread vaccination against serotype b (Hib), the incidence of Hib in Ontario remained low (0.04 cases per 100,000 population). H. influenzae disease primarily afflicted those <1 and ≥65 years of age. From 2014 to 2018, cases of invasive H. influenzae increased 5.6%, from 1.67 to 2.06 cases per 100,000 population, the majority of which were attributed to a 7.6% increase in the incidence of H. influenzae in those ≥65 years old. H. influenzae disease was primarily caused by nontypeable H. influenzae (NTHi) (74.2%) and, to a much lesser extent, serotype a (Hia) (8.9%) and serotype f (Hif) (10.2%). Serotype-dependent trends in antimicrobial susceptibility were observed. Hia and Hif isolates were predominantly susceptible to all antibiotics tested, while 27.2% of NTHi isolates were nonsusceptible to ampicillin. Resistance to ceftriaxone and meropenem, first-line antibiotics for invasive disease treatment, was nonexistent. The incidence of invasive H. influenzae in Ontario is increasing. The incidence and antimicrobial susceptibility of all serotypes and nontypeable H. influenzae should be monitored. IMPORTANCE H. influenzae can cause serious invasive, life-threatening disease and is considered 1 of 12 priority pathogens by the World Health Organization. Widespread vaccination against H. influenzae serotype b (Hib) has resulted in very low incidence of Hib in Ontario and other regions that have vaccination programs. However, the epidemiology of non-Hib serotypes and nontypeable H. influenzae (NTHi) remains poorly understood. Here, we describe the epidemiology of all invasive H. influenzae isolates (N = 1,338) received by our laboratory over the 5-year period and report on the antimicrobial susceptibility patterns by serotype. Overall, we observed an increase in the incidence of invasive disease over the study period, primarily driven by NTHi. Serotype-dependent trends in antimicrobial susceptibility were also observed. This work contributes to the global understanding of H. influenzae epidemiology and antimicrobial resistance and is additionally important for further vaccine planning initiatives.

In 2017 Ontario experienced the largest mumps outbreak in the province in 8 years, at a time when multiple outbreaks were occurring across North America. Of 259 reported cases, 143 occurred in Toronto, primarily among young adults. Routine genotyping of the small hydrophobic gene indicated that the outbreak was due to mumps virus genotype G. We performed a retrospective study of whole genome sequencing of 26 mumps virus isolates from early in the outbreak, using a tiling amplicon method. Results indicated that two of the cases were genetically divergent, with the remaining 24 cases belonging to two major clades and one minor clade. Phylogeographic analysis confirmed circulation of virus from each clade between Toronto and other regions in Ontario. Comparison with other genotype G strains from North America suggested that the presence of co-circulating major clades may have been due to separate importation events from outbreaks in the United States. A transmission network analysis performed with the software program TransPhylo was compared with previously collected epidemiological data. The transmission tree correlated with known epidemiological links between nine patients and identified new potential clusters with no known epidemiological links.

Background: The combined measles, mumps, rubella (MMR) and measles, mumps, rubella, and varicella (MMRV) vaccines are part of Ontario's routine immunization schedule., Objective: To assess adverse events following immunization (AEFIs) reported in Ontario following administration of MMR and MMRV vaccines between 2012 and 2016., Methods: Reports of AEFIs were extracted from the provincial surveillance database on May 9, 2017. Events were grouped by provincial surveillance definitions. Reporting rates were calculated using provincial population estimates or net doses distributed as the denominator. A serious AEFI is defined as an AEFI that resulted in an in-patient hospitalization or death., Results: Overall, 289 AEFIs were reported following administration of MMR (n=246) or MMRV (n=43) vaccines, for annualized reporting rates of 16.6 and 8.8 reports per 100,000 distributed doses, respectively. The highest age-specific reporting rate was in children aged 1 to 3 years for MMR (7.7 per 100,000 population) and children aged 4 to 9 years for MMRV (0.8 per 100,000 population). Systemic reactions were the most frequently reported event category, while rash was the most frequently reported event for both vaccines. There were 22 serious AEFIs, 19 following MMR and 3 following MMRV (1.3 and 0.6 per 100,000 doses distributed, respectively)., Conclusions: Our assessment found a low reporting rate of adverse events following MMR and MMRV vaccines in Ontario. No safety concerns were identified. Our findings are consistent with the safety profiles of these vaccines. Continued monitoring of vaccine safety is necessary to maintain timely detection of unusual postvaccine events and public confidence in vaccine safety., (© The Author(s) 2019. Published by Oxford University Press on behalf of the Canadian Paediatric Society. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

This study evaluated the feasibility of utilizing a 3D-printed anthropomorphic patient-specific head phantom for patient-specific quality assurance (QA) in intensity-modulated radiotherapy (IMRT). Contoured left and right head phantoms were converted from DICOM to STL format. Fused deposition modeling (FDM) was used to construct an anthropomorphic patient-specific head phantom with a 3D printer. An established QA technique and the patient-specific head phantom were used to compare the calculated and measured doses. When the established technique was used to compare the calculated and measured doses, the gamma passing rate for γ ≤ 1 was 97.28%, while the gamma failure rate for γ > 1 was 2.72%. When the 3D-printed patient-specific head phantom was used, the gamma passing rate for γ ≤ 1 was 95.97%, and the gamma failure rate for γ > 1 was 4.03%. The 3D printed patient-specific head phantom was concluded to be highly feasible for patient-specific QA prior to complicated radiotherapy procedures such as IMRT.

Background: Since the widespread use of Haemophilus influenzae (Hi) type b (Hib) vaccines among children aged <5 years, an increase in invasive non-Hib disease incidence has been reported internationally. We sought to describe the epidemiology of invasive non-Hib disease in Ontario, Canada (population ~13.5 million)., Methods: Confirmed invasive non-Hib cases (non-typeable [NTHi] and serotypes a, c, d, e, and f) were obtained from the provincial laboratory data system from 2004-2013. Data were deterministically linked to the provincial reportable disease system to provide further case information. Antibiotic resistance data were analysed separately from 2010-2014. Descriptive analyses included incidence rates, age group, serotype, site of specimen collection and resistance patterns; ethnicity data were not available. Temporal trends were evaluated by Poisson regression and p-values <0.05 were considered significant., Results: A total of 1307 cases of invasive non-Hib disease were included, increasing from 0.67 cases to 1.60 cases /100,000 from 2004 to 2013. Significant increases in the incidence of NTHi (0.50 to 1.28 cases/100 000 population), Hia (0.02 to 0.08 cases/100, 000) and Hif (0.13 to 0.18 cases/100, 000 population) were seen. Among persons aged 40-64 years, 3 Hi strains significantly increased over time; NTHi (0.22 to 0.99 cases/100, 000), Hia (0.00 to 0.06 cases/100, 000) and Hif (0.05 to 0.21 cases/100, 000). Among persons aged 65-84 years, there was a significant increase of NTHi (1.62 to 3.14 cases/100, 000) and Hia (0.00 to 0.34 cases/100, 000). Among persons aged 85+ years, only NTHi significantly increased from 4.89 to 10.28 cases/100, 000). Antimicrobial resistance (AMR) to ampicillin and clarithromycin was seen in greater than 25% of isolates but AMR did not increase over the duration of this study., Conclusions: The incidence of invasive non-Hib disease has increased over time; NTHi, Hif and Hia are emerging pathogens, and should be monitored.

Background: Under Ontario legislation, for select vaccine-preventable diseases nonimmunized or under-immunized students must undergo vaccination or provide a statement of exemption, or risk suspension from school. At the time of this assessment, these diseases included measles, mumps, rubella, diphtheria, tetanus and polio., Methods: Exemptions data for the school years 2002/03 to 2012/13 were obtained from the Immunization Records Information System used in Ontario. Temporal trends were expressed for 7- and 17-year-old students by exemption classification (medical, prior immunity, religious or conscientious belief, total) at the provincial level, by school year and by birth cohort. Regional analysis was conducted for the 2012/13 school year. A temporal trend analysis of exemptions for measles-containing vaccines was performed by using a Poisson distribution with a 2-sided test (α = 5%)., Results: For both 7- and 17-year-old students, religious or conscientious exemptions for measles-containing vaccines significantly increased over the study period (p < 0.001 in both age groups), whereas medical exemptions decreased (p < 0.001 in both age groups). The trends were reproduced when examined by birth cohort. The percentage of Ontario students with any exemption classification (total exemptions) remained low (< 2.5%) during the study period, although considerable geographic variation was noted., Interpretation: Ontario data suggest that nonmedical exemptions have increased during the last 11 years, consistent with trends reported elsewhere. The trend toward increasing religious or conscientious exemptions coupled with declining medical exemptions explains why total exemptions have remained stable or decreased at the provincial level. The prominent geographic variability in exemptions suggests that targeted interventions may be suitable for consideration.

Objective: To determine if reductions in medically-attended pediatric varicella and herpes zoster occurred in Ontario, Canada, after publicly-funded varicella immunization was implemented in 2004., Methods: For fiscal years (FY) 1992-2011, we examined data on varicella and herpes zoster physician office visits, emergency department (ED) visits, hospitalizations (including for varicella-associated skin and soft tissue infections [SSTI]), and intensive care unit (ICU) admissions, among those aged <18 years. The pre-vaccine, privately-available, and vaccine program eras were FY1992-1998, FY1999-2003, and FY2004-2011, respectively. We used Poisson regressionand Kruskal-Wallis tests (all at the p<0.05 level of significance), and compared rates using incidence rate ratios (IRRs) and 95% confidence intervals (CIs)., Results: Incidence of varicella office visits declined over the study period from a high of 25.1/1,000 in FY1994 to a low of 3.2/1,000 in FY2011. ED visits and hospitalizations followed similar patterns of decreasing rates later in the study period. IRRs comparing the vaccine program versus pre-vaccine eras were 0.29 (95%CI: 0.26-0.32) for office visits, 0.29 (95%CI: 0.21-0.40) for ED visits, and 0.41 (95%CI: 0.10-1.69) for hospitalizations. Annual declines in varicella office visits were 7.7%, 9.1%, 8.4%, and 8.4% per year among children aged <1 year, 1-4 years, 5-11 years, and ≥12 years, respectively (all p<0.001). Age-specific rates of varicella-associated SSTI declined significantly among children <12 years (p<0.001) and rates of ICU admissions decreased significantly for children <1 year (p = 0.02). (p<0.001) over the study period. For children aged 5-17 years, herpes zoster office visits decreased whereas ED visits increased (both p<0.001) and there was a small, non-significant (p = 0.07), decrease in hospitalizations., Conclusion: Medically-attended varicella decreased during the study period, particularly since varicella vaccine was publicly-funded. Results suggest immunization program-related changes in varicella epidemiology, including herd effects, demonstrated by reductions in varicella in program-ineligible age groups. We did not observe a consistent impact on herpes zoster.

Extraskeletal mesenchymal chondrosarcomas (EMCs) are relatively uncommon, and a location in the upper extremity, especially in the shoulder or axillary region, is rare. Furthermore, the radiographic findings of EMCs do not show any features that distinguish them from other neoplasms, and therefore, definitive diagnoses are made based on histological features. EMC is an aggressive tumor with a poor prognosis, and requires wide surgical excision. However, its treatment may involve peculiarities such as a difficulty in obtaining a proper surgical margin in the axillary region or shoulder. In this report, the authors present two rare cases of EMCs in the axillary region.

Purpose: Recent studies have shown that 15-deoxy-Delta(12, 14)-prostaglandin J(2) (15d-PGJ(2)), a natural ligand for peroxisome proliferator-activated receptor-gamma (PPARgamma), inhibits cell proliferation and induces apoptosis. The specific molecular mechanisms underlying this effect remain to be elucidated. We examined whether 15d-PGJ(2) has antitumor activity in vitro and in vivo, and investigated the underlying mechanism., Experimental Design: We examined 15d-PGJ(2)-induced apoptosis in human leukemia cells in the context of mitochondrial injury, oxidative damage, and signaling pathway disturbances. In addition, we investigated the antitumor effect of 15d-PGJ(2) in a mouse CT-26 s.c. tumor model and HL-60 leukemia xenograft model., Results: 15d-PGJ(2) induced apoptosis in leukemia and colorectal cancer cells in a dose-dependent manner and led to generation of reactive oxygen species (ROS) through mitochondria and NADPH oxidase activation, activation of JNK, and inactivation of Akt, a serine/threonine-specific protein kinase. Constitutive activation of Akt for an engineered myristoylated protein prevented 15d-PGJ(2)-mediated apoptosis but not ROS generation. Collectively, these findings suggest a hierarchical model of apoptosis induced by 15d-PGJ(2) in human leukemia cells: oxidative injury represents a primary event resulting in Akt inactivation, which in turn leads to mitochondrial injury and apoptosis. Moreover, 15d-PGJ(2) markedly reduced growth of mouse CT-26 s.c. tumors and HL-60 xenograft tumors and down-regulated p-Akt and Akt expression in vivo., Conclusions: These results suggest that Akt inactivation through ROS production may contribute to 15d-PGJ(2)-induced apoptosis in leukemia and colorectal cancer cell lines and that 15d-PGJ(2) may have therapeutic relevance in the treatment of human leukemia and colorectal cancer.

Background: Proximal chevron osteotomy (PCO) for hallux valgus is inherently more stable than the other forms of proximal metatarsal osteotomy, but complications, such as, delayed union, nonunion, and malunion can occur. In this study, we have compared results of two axial Kirschner wire fixation with or without transverse Kirschner wires in PCO for moderate to severe hallux valgus deformities., Methods: A prospective study was conducted on 65 patients (85 feet) that underwent PCO and a distal soft tissue procedure for moderate to severe hallux valgus. Patients were divided into two groups, two axial Kirschner wire fixation (Group I) and two axial and supplementary transverse Kirschner wire fixation (Group II). Group I comprised 41 feet of 32 patients and Group II 44 feet of 33 patients., Results: Average AOFAS scores were 52.8 points in group I and 49.6 points in group II preoperatively, and 92.8 and 89.6 points, respectively, at last followup. Patients were very satisfied or satisfied in 92.7% in Group I and 93.2% in Group II. Average hallux valgus angles in Groups I and II changed from 34.9 degrees and 37.2 degrees preoperatively to 12.3 degrees and 13.9 degrees postoperatively, and intermetatarsal angles in Groups I and II changed from an average of 17.9 degrees and 17.2 degrees preoperatively to 10.3 degrees and 10.4 degrees postoperatively. No significant inter-group differences were found., Conclusion: Supplementary transverse Kirschner wire fixation is not recommended for proximal metatarsal chevron osteotomy since two axial Kirschner wires provided sufficient stability.

While tumor necrosis factor (TNF)-related apoptosis-inducing ligand (TRAIL) is a promising new agent for the treatment of cancer, resistance to TRAIL remains a therapeutic challenge. Identifying agents to use in combination with TRAIL to enhance apoptosis in leukemia cells would increase the potential utility of this agent as a therapy for leukemia. Here, we show that 15-deoxy-Delta(12,14)-prostaglandin J2 (15d-PGJ2), a natural ligand for peroxisome proliferator-activated receptor gamma (PPARgamma), can sensitize TRAIL-resistant leukemic HL-60 cells to TRAIL-induced apoptosis. The sensitization to TRAIL-induced apoptosis by 15d-PGJ2 was not blocked by a PPARgamma inhibitor (GW9662), suggesting a PPARgamma-independent mechanism. This process was accompanied by activation of caspase-8, caspase-9, and caspase-3 and was concomitant with Bid and PARP cleavage. We observed significant decreases in XIAP, Bcl-2, and c-FLIP after cotreatment with 15d-PGJ2 and TRAIL. We also observed the inhibition of Akt expression and phosphorylation by cotreatment with 15d-PGJ2 and TRAIL. Furthermore, inactivation of Akt by Akt inhibitor IV sensitized human leukemic HL-60 cells to TRAIL, indicating a key role for Akt inhibition in these events. Taken together, these findings indicate that 15d-PGJ2 may augment TRAIL-induced apoptosis in human leukemia cells by down-regulating the expression and phosphorylation of Akt.

No published data are available about the expression of peroxisome proliferator-activated receptor gamma (PPARgamma) and the role of PPARgamma in retinoblastoma protein (RB)-deficient human colorectal cancer (CRC) cells (SNU-C4 and SNU-C2A). Our aim was to investigate whether PPARgamma is expressed in SNU-C4 and SNU-C2A cells and to elucidate possible molecular mechanisms underlying the effect of pioglitazone, a synthetic ligand for PPARgamma, on cell growth in these cell lines. RT-PCR and Western blot analysis showed that both human CRC cell lines expressed PPARgamma mRNA and protein. Pioglitazone inhibited the cell growth of both cell lines through G2/M phase block and apoptosis. In addition, pioglitazone caused a down-regulation of the X chromosome-linked inhibitor of apoptosis (XIAP), Bcl-2, and cyclooxygenase-2 (COX-2) under conditions leading to PPARgamma down-regulation. These results suggest that pioglitazone may have therapeutic relevance or significance in the treatment of human CRC, and the down-regulation of XIAP, Bcl-2, and COX-2 may contribute to pioglitazone-induced apoptosis in these and other RB-deficient cell lines and tumors.