Bortezomib treatment causes remission in a Ph+ALL patient and reveals FoxO as a theranostic marker

BCR-ABL is a key mediator in the pathogenesis of all cases of chronic myelogenous leukemia (CML) and a subset of precursor B-acute lymphoblastic leukemia (Ph+ALL). Previous animal and cell-based studies have shown that the expression of members of the Forkhead family of tumor suppressors, including FoxO3, is suppressed in BCR-ABL-expressing cells. Furthermore, it has been reported that the proteasomal degradation pathway plays an important role in suppression of FoxO expression in BCR-ABL-transformed cells. In this study, a patient diagnosed with Ph+ALL and refractory to standard therapies was treated with a proteasome inhibitor (bortezomib)-based chemotherapy regimen. This treatment resulted in complete hematologic, cytogenetic and molecular remission with excellent performance status for > 4 years since her initial diagnosis. FoxO3 was not detectable within the blasts of this patient at diagnosis and was 'rescued' following treatment with bortezomib therapy, leading to her recovery. As a next step, in the attempt to propose FoXO3 as a therapeutic target and a theranostic marker, we further validated FoxO3 expression in human bone marrow biopsy samples. Human core biopsy samples of Ph+ALL and Ph-negative-negative ALL, along with uninvolved controls, revealed that FoxO3 down-regulation was specific to Ph+ALL. This study provides support that FoxO3 is a good biomarker for BCR-ABL-mediated leukemogenesis. Additionally, proteasomal inhibition by bortezomib may be a promising therapeutic option in Philadelphia-positive ALL, where FoxO3 is downregulated.     

Association of changes in oxidative and proinflammatory states with changes in vascular function after a lifestyle modification trial among obese children

BACKGROUND: The association of changes in oxidative and proinflammatory states with vascular function after diet and exercise intervention among obese children has not been previously explored. METHODS: In this 6-week diet and exercise intervention study in 35 obese children, age 12 to 18 years, we evaluated the relationship between changes in anthropometric indices, measures of insulin resistance, C-reactive protein (CRP), oxidized LDL (ox-LDL), and oxidative stress markers with changes in carotid intima-media thickness (C-IMT) and flow mediated dilation (FMD) of the brachial artery. RESULTS: At the end of the study, body mass index (BMI), waist circumference, and percentage body fat were decreased (P <0.05), but participants remained overweight (BMI > or = 95th percentile). Although FMD improved (P <0.05), the improvement in C-IMT did not reach statistical significance. The changes in BMI, waist circumference, fat mass, ox-LDL, malondialdehyde (MDA), CRP, insulin, and homeostasis model assessment for insulin resistance (HOMA-IR) had an inverse correlation with the changes in mean FMD after adjustment for age and sex, with the highest correlations documented for ox-LDL, CRP, and WC. The age- and sex-adjusted changes in ox-LDL, waist circumference, CRP, MDA, and body fat mass had the highest correlations with changes in C-IMT. CONCLUSIONS: Our findings suggest that a common inflammatory stress condition associated with childhood obesity, notably with abdominal fat deposition, may play a role in the development of the earliest stages of proatherosclerotic inflammatory processes and subsequent vascular dysfunction. These changes might be partially reversible by short-term diet and exercise intervention, even if patients do not reach ideal body weight.     

Severe fetal anemia caused by anti-Jra: Burst forming unit-erythroid colony formation inhibition assay suggesting possible erythroid suppression mechanism

Background

The Jr blood group system includes a single, high-prevalence antigen, Jr^a, encoded by the ABCG2 gene. The impact of anti-Jr^a in pregnancy is variable, ranging from no clinical effect to severe anemia including some fetal deaths. Case reports have postulated that anti-Jr^a mediated fetal anemia is poorly hemolytic, suggesting other mechanisms of anemia may be involved.

Study Design and Methods

We describe the case of severe anti-Jr^a mediated fetal anemia. At Canadian Blood Services laboratories, maternal anti-Jr^a was tested for phagocytic activity via a monocyte monolayer assay (MMA) and erythroid suppression via inhibition of burst forming unit-erythroid (BFU-E) colony formation assays. The New York Blood Center sequenced exons 4 and 7 of the ABCG2 gene.

Results and Discussion

Sequencing of exons 4 and 7 of the ABCG2 gene revealed maternal compound heterozygosity for two nonsense mutations at exon 7 (c.706 C > T and c.784G > T). Fetal sequencing revealed the c.706C > T polymorphism. The MMA showed a borderline phagocytic index (around the cutoff of five for both donor segments tested [5 ± 1 and 7 ± 3]). The BFU-E colony formation inhibition assay suggested a dose-dependent inhibition of BFU-E colony formation with inhibition percentages of 4%, 11%, and 43% at maternal serum concentrations of 2%, 5%, and 10%, respectively. Our findings support the hypothesis that anti-Jr^a may impair erythropoiesis leading to clinically significant fetal/neonatal anemia. A referral to maternal fetal medicine is recommended if anti-Jr^a is detected in pregnancy, regardless of the titer.     

An ultrasonographic investigation of deep neck flexor muscles cross-sectional area in forward and normal head posture

Background

As one of the most common work-related musculoskeletal disorders and postural deviations, forward head posture (FHP), is considered to lead to muscle imbalance.

Exploring Mental Health and Substance use Treatment Needs of Commercially Sexually Exploited Youth Participating in a Specialty Juvenile Court

The study sought to: (1) describe the mental health and substance use profiles among participants of a specialty trafficking court program (the Succeed Though Achievement and Resilience Court); (2) describe youths' mental health and substance use treatment prior to participating in the program; and (3) examine whether abuse influences report of mental health problems and/or substance use. Retrospective case review of court files was performed on commercially sexually exploited youth who volunteered to participate in the court from 2012 to 2014 (N = 184). All participants were female. Mental health problems and report of substance use was high among this population. Substance use differed at statistically significant levels between youth with a documented abuse history compared to those with no abuse history. Substance use also differed by report of mental health problems. Unexpected findings included the high rate of hospitalization for mental health problems and relatively low substance use treatment prior to STAR Court participation. Opportunities for improvement in critical points of contact to identify commercially sexually exploited youth and address their health needs are discussed.     

Imaging data in COVID-19 patients: focused on echocardiographic findings

To assess imaging data in COVID-19 patients and its association with clinical course and survival and 86 consecutive patients (52 males, 34 females, mean age?=?58.8 year) with documented COVID-19 infection were included. Seventy-eight patients (91%) were in severe stage of the disease. All patients underwent transthoracic echocardiography. Mean LVEF was 48.1% and mean estimated systolic pulmonary artery pressure (sPAP) was 27.9 mmHg. LV diastolic dysfunction was mildly abnormal in 49 patients (57.6%) and moderately abnormal in 7 cases (8.2%). Pericardial effusion was present in 5/86 (minimal in size in 3 cases and mild- moderate in 2). In 32/86 cases (37.2%), the severity of infection progressed from “severe” to “critical”. Eleven patients (12.8%) died. sPAP and computed tomography score were associated with disease progression (P value?=?0.002, 0.002 respectively). Tricuspid annular plane systolic excursion (TAPSE) was significantly higher in patients with no disease progression compared with those who deteriorated (P value?=?0.005). Pericardial effusion (minimal, mild or moderate) was detected more often in progressive disease (P?=?0.03). sPAP was significantly lower among survivors (P value?=?0.007). Echocardiographic findings (including systolic PAP, TAPSE and pericardial effusion), total CT score may have prognostic and therapeutic implication in COVID-19 patients.

     

Evaluation of thyroglobulin expression in murine reproductive organs during pregnancy

Citation Moravej A, Jeddi‐Tehrani M, Salek‐Moghaddam AR, Dokouhaki P, Ghods R, Rabbani H, Kazemi‐Sefat GE, Shahbazi M, Zarnani AH. Evaluation of thyroglobulin expression in murine reproductive organs during pregnancy. Am J Reprod Immunol 2010; 64: 97–103 Problem In pregnant women with antithyroglobulin antibody, prevalence of abortion is 2–4 fold higher compared to normal controls. Direct effect of such harmful autoantibodies on female reproductive organs may serve a role in pregnancy loss. Method of study Expression of thyroglobulin in decidua, placenta, and ovary of pregnant Balb/c mice ((Balb/c×Balb/c and Balb/c×C57BL/6) during early, middle, and late stages of pregnancy was evaluated. Expression of thyroglobulin was investigated in these tissues by semi‐quantitative RT‐PCR. In addition, polyclonal antithyroglobulin antibody was produced, and expression of thyroglobulin protein in aforesaid tissues was evaluated by immunohistochemistry and dot‐blot analysis. Results The results showed that thyroglobulin message is not expressed in placenta, decidua, or ovary in any stages of pregnancy. The same results were obtained at the protein level. Conclusion It is likely that antithyroglobulin antibodies have no direct detrimental effect on such organs in patients with thyroid autoimmunity suffering from recurrent abortion.