A pinboard by
Hitesh Arora

PhD Student, University of British Columbia


Abcf1 is necessary for survival

ABCF1 is an ABC transporter family protein that has been shown to regulate innate immune response and is a risk gene for autoimmune pancreatitis and arthritis. Unlike other members of ABC transporter family, ABCF1 lacks trans-membrane domains and is thought to function in translation initiation through an interaction with eukaryotic translation initiation factor 2 (eIF2). To study ABCF1 expression and function in development and disease, we used a single gene trap insertion in the Abcf1 gene in murine embryonic stem cells (ES cells) that allowed lineage tracing of the endogenous Abcf1 promoter by following the expression of a β-galactosidase reporter gene. From the ES cells, heterozygous mice (Abcf1+/-) were produced. No live born Abcf1-/- progeny were ever generated, and the lethality was not mouse strain-specific. Thus, we have determined that Abcf1 is an essential gene in development. Abcf1-/- mice were found to be embryonic lethal at 3.5 days post coitum (dpc), while Abcf1 +/- mice appeared developmentally normal. Abcf1+/- mice were fertile and showed no significant differences in their anatomy when compared with their wild type littermates. The Abcf1 promoter was found to be active in all organs in adult mice, but varies in levels of expression in specific cell types within tissues. Furthermore, we observed high promoter activity in the blastocysts and embryos. Overall, Abcf1 expression in embryos is required for development and its expression in adults was highly correlated with actively proliferating and differentiating cell types.


Durable Chimerism and Long-Term Survival Following Unrelated Umbilical Cord Blood Transplantation for Pediatric Hemophagocytic Lymphohistiocytosis: a Single Center Experience.

Abstract: Hemophagocytic Lymphohistiocytosis (HLH) is a life-threatening disorder of immune dysregulation characterized by fever, hepatosplenomegaly, cytopenias, CNS disease, increased inflammatory markers and hemophagocytosis. Currently, allogeneic hematopoietic stem cell transplantation is the only curative approach for patients with HLH with reported survival ranging from 50-70% with myeloablative conditioning (MAC) regimens. However, donor availability and transplant related mortality associated with conventional MAC are major barriers to success. Unrelated umbilical cord blood transplantation (UCBT) provides a readily available alternative donor source for patients lacking matched related donors. Accordingly, we report the results of UCBT in 14 children treated between 1998 and 2016. All children received standard HLH chemotherapy prior to UCBT. The median age at diagnosis was 2.7 months (range 0.8-10.4) and at transplant was 7.5 months (3.8-17). Ten patients received MAC with Busulfan (Bu)/cyclophosphamide (Cy)/VP16/anti-thymocyte globulin (ATG) (n=5), Bu/Cy/ATG (n=4), or Bu/Melphalan (Mel)/ATG (n=1). Four patients received reduced toxicity conditioning (RTC) with alemtuzumab/fludarabine/melphalan/hydroxyurea ± thiotepa. Cord blood units were mismatched at either 1 (n=9), or 2 (n=5) loci and delivered a median total nucleated cell dose of 11.9x10(7)/kg (range 4.6-27.9) and CD34+ dose of 3.1 x 10(5)/kg (range 1.1-6.8). The cumulative incidence of neutrophil engraftment by day 42 was 78.6% (95% CI; 42.9% to 93.4%) with a median of 19 days (range 13-27), and that for platelet (50K) engraftment by day 100 was 64.3% (95% CI; 28.2% to 85.7%) with a median of 51 days (range 31 to 94). Six patients developed either grade II (n=5) or grade IV (n=1) acute graft-versus-host disease (GVHD); no extensive chronic GVHD was seen. Ten patients (71.4%) are alive and well at a median of 11.2 years post-transplant (range 0.85 - 18.25), 9 of whom maintain sustained full donor chimerism after a single UCBT, whereas 1 patient with autologous recovery after first UCBT with RTC has achieved full donor chimerism after a second UCBT with MAC. This series demonstrates that, in combination with standard HLH therapy, UCBT, after MAC or RTC conditioning, can provide long-term survival with durable complete donor chimerism comparable to conventional donors. UCBT should be considered for patients with HLH lacking a fully matched related or unrelated adult donor.

Pub.: 26 Jun '17, Pinned: 28 Jun '17

Sentinel node biopsy for axillary management after neoadjuvant therapy for breast cancer: a single-center retrospective analysis with long follow-up.

Abstract: Sentinel node biopsy (SNB) after neoadjuvant therapy (NAT) for breast cancer remains controversial. We conducted a retrospective study of patients who underwent SNB after NAT to evaluate the effectiveness of this procedure.A consecutive 105 women with locally advanced breast cancer (cT1-4, cN0-3, M0) were treated with NAT between 2006 and 2015. The subjects were 80 of these patients who became or remained clinically node-negative after NAT, 53 of whom had axillary management determined by SNB (group A) and the other 27 underwent axillary lymph node dissection (ALND) without SNB (group B). SNB was performed using a modified dye method.The sentinel node (SN) identification rate was 94.3% and the mean number of removed SNs was 2.4. ALND was avoided in 33 patients, who were confirmed as SN-negative. There was no difference in recurrence-free and overall survival rates between groups A and B (p = 0.71 and p = 0.46, respectively) during the median follow-up time of 63 months. Of the 33 patients who did not undergo ALND, 10 suffered recurrence (33%). One patient (3%) had recurrence in an axillary lymph node and four had recurrence in a supraclavicular lymph node.Axillary SNB after NAT did not affect the axillary failure rate or the prognosis. SNB may be a reliable procedure, even after NAT.

Pub.: 26 Jun '17, Pinned: 28 Jun '17

Outcome and Treatment of Antenatally Diagnosed Nonimmune Hydrops Fetalis.

Abstract: The objectives of this study were to evaluate the outcome of nonimmune hydrops fetalis in an attempt to identify independent predictors of perinatal mortality.A retrospective cohort study was conducted including all cases of nonimmune hydrops from two tertiary care centers. Perinatal outcome was evaluated after classifying nonimmune hydrops into ten etiological groups. We examined the effect of etiology, site of fluid accumulation, and gestational age at delivery on postnatal survival. Neonatal mortality and hospital discharge survival were compared between the expectant management and fetal intervention groups among those with idiopathic etiology.A total of 142 subjects were available for analysis. Generally, nonimmune hydrops carried 37% risk of neonatal mortality and 50% chance of survival to discharge, which varies markedly based on the underlying etiology. Ascites was an independent predictor of perinatal mortality (p value = 0.003). There was nonsignificant difference in neonatal mortality and hospital discharge survival among idiopathic cases that were managed expectantly versus those in whom fetal intervention was carried out.The outcome of nonimmune hydrops varies largely according to the underlying etiology and the presence of ascites is an independent risk factor for perinatal mortality. In our series, fetal intervention did not offer survival advantage among fetuses with idiopathic nonimmune hydrops.

Pub.: 26 Jun '17, Pinned: 28 Jun '17