Publications by authors named "Long Trinh"

20 Publications

  • Page 1 of 1

Impact of the COVID-19 Pandemic on Breast Imaging Education.

J Breast Imaging 2021 May-Jun;3(3):354-362. Epub 2021 Mar 9.

Stanford University School of Medicine, Department of Radiology, Stanford, CA,USA.

Objective: To determine the impact of the COVID-19 pandemic on breast imaging education.

Methods: A 22-item survey addressing four themes during the early pandemic (time on service, structured education, clinical training, future plans) was emailed to Society of Breast Imaging members and members-in-training in July 2020. Responses were compared using McNemar's and Mann-Whitney tests; a general linear model was used for multivariate analysis.

Results: Of 136 responses (136/2824, 4.8%), 96 U.S. responses from radiologists with trainees, residents, and fellows were included. Clinical exposure declined during the early pandemic, with almost no medical students on service (66/67, 99%) and fewer clinical days for residents (78/89, 88%) and fellows (48/68, 71%). Conferences shifted to remote live format (57/78, 73%), with some canceled (15/78, 19%). Compared to pre-pandemic, resident diagnostic (75/78, 96% vs 26/78, 33%) ( < 0.001) and procedural (73/78, 94% vs 21/78, 27%) ( < 0.001) participation fell, as did fellow diagnostic (60/61, 98% vs 47/61, 77%) ( = 0.001) and procedural (60/61, 98% vs 43/61, 70%) ( < 0.001) participation. Most thought that the pandemic negatively influenced resident and fellow screening (64/77, 83% and 43/60, 72%, respectively), diagnostic (66/77, 86% and 37/60, 62%), and procedural (71/77, 92% and 37/61, 61%) education. However, a majority thought that decreased time on service (36/67, 54%) and patient contact (46/79, 58%) would not change residents' pursuit of a breast imaging fellowship.

Conclusion: The pandemic has had a largely negative impact on breast imaging education, with reduction in exposure to all aspects of breast imaging. However, this may not affect career decisions.
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http://dx.doi.org/10.1093/jbi/wbab021DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7989417PMC
March 2021

Long-Term Humoral Immune Response in Persons with Asymptomatic or Mild SARS-CoV-2 Infection, Vietnam.

Emerg Infect Dis 2021 02;27(2):663-666

Antibody response against nucleocapsid and spike proteins of SARS-CoV-2 in 11 persons with mild or asymptomatic infection rapidly increased after infection. At weeks 18-30 after diagnosis, all remained seropositive but spike protein-targeting antibody titers declined. These data may be useful for vaccine development.
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http://dx.doi.org/10.3201/eid2702.204226DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7853537PMC
February 2021

Impact of a chemotherapy workload and productivity dashboard on pharmacy technician turnover.

Am J Health Syst Pharm 2019 Jun;76(13):992-997

Department of Pharmacy & Clinical Nutrition Services, Oregon Health & Science University, Portland, OR.

Purpose: To describe the methods used in the development of an intravenous chemotherapy workload and productivity dashboard and its impact on symptoms of burnout and technician turnover.

Summary: In February 2017, chemotherapy sterile preparation pharmacy technicians reported symptoms of burnout as a result of perceived increase in workload. In response, an i.v. chemotherapy workload and productivity dashboard was developed at an academic medical center to validate workload in comparison to the reported job stress of pharmacy technicians. The dashboard provided pharmacy leadership objective data to validate staff concerns and leveraged lean principles to level-load the work prior to requesting additional full-time equivalents (FTEs) to senior leadership. The rate of turnover of i.v. chemotherapy technicians was assessed before (December 2016-June 2017) and after (July 2017-January 2018) dashboard implementation and approval of an additional i.v. chemotherapy technician FTE. The addition of the new FTE resulted in a decrease in productivity from an average of 106% (range 67%-151%) to 84% (range 65%-110%). The interventions allowed for the ability to leverage a staffing-to-demand model, resulting in the observed improvement in technician symptoms of burnout and a notable decrease in the overall turnover rate of i.v. chemotherapy technicians.

Conclusion: The i.v. chemotherapy workload and productivity dashboard confirmed frontline staff perception and provided data to support the addition of labor resource and an opportunity to leverage a staffing-to-demand model to decrease symptoms of burnout and technician turnover.
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http://dx.doi.org/10.1093/ajhp/zxz081DOI Listing
June 2019

Impact of a quality-assessment dashboard on the comprehensive review of pharmacist performance.

Am J Health Syst Pharm 2017 Sep;74(17 Supplement 3):S75-S83

Cleveland Clinic, Cleveland, OH.

Purpose: The impact of a quality-assessment dashboard and individualized pharmacist performance feedback on the adherence of order verification was evaluated.

Methods: A before-and-after study was conducted at a 1,440-bed academic medical center. was defined as orders verified according to institution-derived, medication-related guidelines and policies. Formulas were developed to assess the adherence of verified orders to dosing guidelines using patient-specific height, weight, and serum creatinine clearance values from the electronic medical record at the time of pharmacist verification. A total of 5 medications were assessed by the formulas for adherence and displayed on the dashboard: ampicillin-sulbactam, ciprofloxacin, piperacillin-tazobactam, acyclovir, and enoxaparin. Adherence of order verification was assessed before (May 1-July 31, 2015) and after (November 1, 2015-January 31, 2016) individualized performance feedback was given based on trends identified by the quality-assessment dashboard.

Results: There was a significant increase in the overall adherence rate postintervention (90.1% versus 91.9%, = 0.040). Among the 34 pharmacists who participated, the percentage of pharmacists with at least 90% overall adherence increased postintervention (52.9% versus 70.6%, = 0.103). Time to verification was similar before and after the study intervention (median, 6.0 minutes; interquartile range, 3-13 minutes). The rate of documentation for nonadherent orders increased significantly postintervention (57.1% versus 68.5%, = 0.019).

Conclusion: The implementation of the quality-assessment dashboard, educational sessions, and individualized performance feedback significantly improved pharmacist order-verification adherence to institution-derived, medication-related guidelines and policies and the documentation rate of nonadherent orders.
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http://dx.doi.org/10.2146/ajhp160556DOI Listing
September 2017

CT-Guided Wire Localization for Involved Axillary Lymph Nodes After Neo-adjuvant Chemotherapy in Patients With Initially Node-Positive Breast Cancer.

Breast J 2016 Jul 9;22(4):390-6. Epub 2016 Apr 9.

Division of Breast Imaging, Department of Radiology, Stanford University School of Medicine, Stanford, California.

Resection of biopsy-proven involved axillary lymph nodes (iALNs) is important to reduce the false-negative rates of sentinel lymph node (SLN) biopsy after neo-adjuvant chemotherapy (NAC) in patients with initially node-positive breast cancer. Preoperative wire localization for iALNs marked with clips placed during biopsy is a technique that may help the removal of iALNs after NAC. However, ultrasound (US)-guided localization is often difficult because the clips cannot always be reliably visible on US. Computed tomography (CT)-guided wire localization can be used; however, to date there have been no reports on CT-guided wire localization for iALNs. The aim of this study was to describe a series of patients who received CT-guided wire localization for iALN removal after NAC and to evaluate the feasibility of this technique. We retrospectively analyzed five women with initially node-positive breast cancer (age, 41-52 years) who were scheduled for SLN biopsy after NAC and received preoperative CT-guided wire localization for iALNs. CT visualized all the clips that were not identified on post-NAC US. The wire tip was deployed beyond or at the target, with the shortest distance between the wire and the index clip ranging from 0 to 2.5 mm. The total procedure time was 21-38 minutes with good patient tolerance and no complications. In four of five cases, CT wire localization aided in identification and resection of iALNs that were not identified with lymphatic mapping. Residual nodal disease was confirmed in two cases: both had residual disease in wire-localized lymph nodes in addition to SLNs. Although further studies with more cases are required, our results suggest that CT-guided wire localization for iALNs is a feasible technique that facilitates identification and removal of the iALNs as part of SLN biopsy after NAC in situations where US localization is unsuccessful.
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http://dx.doi.org/10.1111/tbj.12597DOI Listing
July 2016

Patient awareness of breast density and interest in supplemental screening tests: comparison of an academic facility and a county hospital.

J Am Coll Radiol 2015 Mar 4;12(3):249-55. Epub 2014 Nov 4.

Department of Radiology, Stanford University School of Medicine, Stanford, California.

Purpose: The aim of this study was to measure women's knowledge of breast density and their attitudes toward supplemental screening tests in the setting of the California Breast Density Notification Law at an academic facility and a county hospital, serving women with higher and lower socioeconomic status, respectively.

Methods: Institutional review board exemptions were obtained. A survey was administered during screening mammography at two facilities, assessing women's awareness of and interest in knowing their breast density and interest in and willingness to pay for supplemental whole breast ultrasound and contrast-enhanced spectral mammography (CEMG). The results were compared by using Fisher exact tests between groups.

Results: A total of 105 of 130 and 132 of 153 women responded to the survey at the academic and county facilities, respectively. Among respondents at the academic and county facilities, 23% and 5% were aware of their breast density, and 94% and 79% wanted to know their density. A majority were interested in supplemental ultrasonography and CEMG at both sites; however, fewer women had a willingness to pay for the supplemental tests at the county hospital compared with those at the academic facility (22% and 70%, respectively, for ultrasound, P < .0001; 20% and 65%, respectively, for CEMG, P < .0001).

Conclusions: Both groups of women were interested in knowing their breast density and in supplemental screening tests. However, women at the county hospital were less willing to incur out-of-pocket expenses, suggesting a potential for a disparity in health care access for women of lower socioeconomic status after the enactment of breast density notification legislation.
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http://dx.doi.org/10.1016/j.jacr.2014.10.027DOI Listing
March 2015

High fluorescence in situ hybridization percentage of deletion 11q in patients with chronic lymphocytic leukemia is an independent predictor of adverse outcome.

Am J Hematol 2015 Jun 30;90(6):471-7. Epub 2015 Mar 30.

Department of Leukemia, the University of Texas MD Anderson Cancer Center, Houston, Texas.

We have analyzed patients with previously untreated chronic lymphocytic leukemia with del11q fluorescence in situ hybridization (FISH) abnormality (n = 196) in this study. Detection of the 11q22.3 used a multicolor FISH technique. Patients with del11q fell into two major FISH subsets-sole del11q (n = 64) and del11q with del13q (n = 132). FISH subsets were compared using the median del11q FISH% (>58%, high vs. ≤58%, low). Overall survival (OS) and time to first treatment (TTFT) were estimated using Kaplan-Meier plots (log rank). Multivariate analysis was performed to assess the association between FISH% of del11q and outcomes. Patients with sole del11q were similar to del11q with del13q in terms of TTFT and OS. Patients with high FISH% of del11q had significantly shorter OS and TTFT as compared with patients with low FISH%, particularly in sole del11q; this negative impact of high FISH% of del11q on OS and TTFT was diminished with coexistent del13q. In multivariate analysis, high FISH% of del11q was a significant predictor for shorter OS and TTFT. A comparison of these del11q subsets with a separate cohort of (n = 673) previously untreated patients with sole del13q showed that the high FISH% del11q cohort had a significantly shorter TTFT and OS. In addition, bulky disease by physical examination or computed tomography imaging was infrequent at presentation in patients with del11q. High FISH% of del11q can reliably discriminate higher risk patients with chronic lymphocytic leukemia. Presence of coexistent del13q should be accounted for while prognosticating patients with del11q.
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http://dx.doi.org/10.1002/ajh.23978DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4521389PMC
June 2015

Second cancers in patients with chronic lymphocytic leukemia who received frontline fludarabine, cyclophosphamide and rituximab therapy: distribution and clinical outcomes.

Leuk Lymphoma 2015 Jun 19;56(6):1643-50. Epub 2014 Nov 19.

Department of Leukemia.

Patients with chronic lymphocytic leukemia (CLL) are known to have an increased incidence of second cancers, but the contribution of commonly used frontline therapies to the incidence of second cancers is unclear. We report on the characteristics, incidence, outcomes and factors associated with second cancers in 234 patients receiving fludarabine, cyclophosphamide and rituximab (FCR) based regimens in the frontline setting. The risk of second cancers was 2.38 times higher than the expected risk in the general population. Ninety-three patients (40%) had other cancers before and 66 patients (28%) after FCR. Rates of therapy related acute myeloid leukemia/myelodysplastic syndrome (t-AML/MDS) (5.1%) and Richter transformation (RT) (9%) were high, while solid tumors were not increased. Overall survival of patients with second cancers after frontline FCR was shorter (median of 4.5 years) compared to patients with and without prior cancers. Second cancer risk after frontline FCR is mainly due to high rates of t-AML/MDS and RT, and as speculated the survival of affected patients is shorter.
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http://dx.doi.org/10.3109/10428194.2014.957203DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4437921PMC
June 2015

Initial results with preoperative tattooing of biopsied axillary lymph nodes and correlation to sentinel lymph nodes in breast cancer patients.

Ann Surg Oncol 2015 Feb 28;22(2):377-82. Epub 2014 Aug 28.

Department of Surgery, Stanford University School of Medicine and the Stanford Cancer Institute, Stanford, CA, USA.

Background: Pretreatment evaluation of axillary lymph nodes (ALNs) and marking of biopsied nodes in patients with newly diagnosed breast cancer is becoming routine practice. We sought to test tattooing of biopsied ALNs with a sterile black carbon suspension (Spot™). The intraoperative success of identifying tattooed ALNs and their concordance to sentinel nodes was determined.

Methods: Women with suspicious ALNs and newly diagnosed breast cancer underwent palpation and/or ultrasound-guided fine needle aspiration or core needle biopsy, followed by injection of 0.1 to 0.5 ml of Spot™ ink into the cortex of ALNs and adjacent soft tissue. Group I underwent surgery first, and group II underwent neoadjuvant therapy followed by surgery. Identification of black pigment and concordance between sentinel and tattooed nodes was evaluated.

Results: Twenty-eight patients were tattooed, 16 in group I and 12 in group II. Seventeen cases had evidence of atypia or metastases, 8 (50 %) in group I and 9 (75 %) in group II. Average number of days from tattooing to surgery was 22.9 (group I) and 130 (group II). Black tattoo ink was visualized intraoperatively in all cases, except one case with microscopic black pigment only. Fourteen group I and 10 group II patients had black pigment on histological examination of ALNs. Sentinel nodes corresponded to tattooed nodes in all except one group I patient with a tattooed non-sentinel node.

Conclusion: Tattooed nodes are visible intraoperatively, even months later. This approach obviates the need for additional localization procedures during axillary staging.
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http://dx.doi.org/10.1245/s10434-014-4034-6DOI Listing
February 2015

Correlation between FDG/PET, histology, characteristics, and survival in 332 patients with chronic lymphoid leukemia.

Blood 2014 May 10;123(18):2783-90. Epub 2014 Mar 10.

Department of Leukemia.

Richter syndrome (RS) is associated with poor outcome. The prognosis of patients with histologically aggressive chronic lymphocytic leukemia (CLL), or HAC, has not been studied. We aimed to correlate 2-deoxy-2-[(18)F]fluoroglucose/positron emission tomography (FDG/PET) data, histological diagnosis, clinical characteristics, and survival in patients with CLL. A total of 332 patients with CLL were histologically classified as: 95 RS, 117 HAC, and 120 histologically indolent CLL (HIC). HAC and RS patients had higher maximum standardized uptake value (SUVmax), more frequent constitutional symptoms, poorer performance status (PS), lower hemoglobin and platelets, and higher lactate dehydrogenase and β-2-microglobulin. An SUVmax ≥10 strongly correlated with mortality (overall survival [OS], 56.7 vs 6.9 months in patients with SUVmax <10 vs ≥10). Survival of patients with RS and HAC was similar among patients with SUVmax <10 or ≥10. SUVmax ≥10, PS ≥2, bulky disease, and age ≥65 were independently associated with shorter OS. In patients undergoing both fine-needle aspiration and biopsy, the former proved diagnostically inadequate in 23%, 29%, and 53% of HIC, HAC, and RS, respectively. FDG/PET is a useful diagnostic tool in patients with CLL and suspected transformation. Patients with HAC show different characteristics and worse prognosis compared with those with HIC. Patients with different CLL phases, but similar SUVmax have similar outcome. Tissue biopsy should be preferred for diagnosing RS.
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http://dx.doi.org/10.1182/blood-2013-11-536169DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4123418PMC
May 2014

Tyrosine kinase inhibitors as initial therapy for patients with chronic myeloid leukemia in accelerated phase.

Clin Lymphoma Myeloma Leuk 2014 Apr 9;14(2):155-162.e1. Epub 2013 Dec 9.

Department of Leukemia, M.D. Anderson Cancer Center, Houston, TX. Electronic address:

Background: Accelerated phase CML most frequently represents a progression state in CML. However, some patients present with AP features at the time of diagnosis. There is limited information on the outcome of these patients who received TKIs as initial therapy.

Patients And Methods: We analyzed the outcome of 51 consecutive patients with CML who presented with features of AP at the time of diagnosis, including blasts ≥ 15% (n = 6), basophils ≥ 20% (n = 22), platelets < 100 × 10(9)/L (n = 3), cytogenetic clonal evolution (n = 17), or more than 1 feature (n = 3). Patients received initial therapy with imatinib (n = 30), dasatinib (n = 5), or nilotinib (n = 16).

Results: The rate of complete cytogenetic response for patients treated with imatinib was 80%, and with dasatinib or nilotinib was 90%. Major molecular response (MMR) (Breakpoint Cluster Region (BCR)-Abelson (ABL)/ABL ≤ 0.1%, International Scale [IS]) was achieved in 69% of patients including complete molecular response (BCR-ABL/ABL ≤ 0.0032% IS) in 49%. MMR rates for patients treated with imatinib were 63%, and with 2GTKIs, 76%. Overall survival at 36 months was 87% with imatinib and 95% with 2GTKIs.

Conclusion: TKIs should be considered standard initial therapy for patients with AP at the time of diagnosis.
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http://dx.doi.org/10.1016/j.clml.2013.08.008DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3959284PMC
April 2014

IRF4 is a suppressor of c-Myc induced B cell leukemia.

PLoS One 2011 27;6(7):e22628. Epub 2011 Jul 27.

Department of Genetics, Cell Biology and Anatomy, University of Nebraska Medical Center, Omaha, Nebraska, United States of America.

Interferon regulatory factor 4 (IRF4) is a critical transcriptional regulator in B cell development and function. We have previously shown that IRF4, together with IRF8, orchestrates pre-B cell development by limiting pre-B cell expansion and by promoting pre-B cell differentiation. Here, we report that IRF4 suppresses c-Myc induced leukemia in EμMyc mice. Our results show that c-Myc induced leukemia was greatly accelerated in the IRF4 heterozygous mice (IRF4(+/-)Myc); the average age of mortality in the IRF4(+/-)Myc mice was only 7 to 8 weeks but was 20 weeks in the control mice. Our results show that IRF4(+/-)Myc leukemic cells were derived from large pre-B cells and were hyperproliferative and resistant to apoptosis. Further analysis revealed that the majority of IRF4(+/-)Myc leukemic cells inactivated the wild-type IRF4 allele and contained defects in Arf-p53 tumor suppressor pathway. p27(kip) is part of the molecular circuitry that controls pre-B cell expansion. Our results show that expression of p27(kip) was lost in the IRF4(+/-)Myc leukemic cells and reconstitution of IRF4 expression in those cells induced p27(kip) and inhibited their expansion. Thus, IRF4 functions as a classical tumor suppressor to inhibit c-Myc induced B cell leukemia in EμMyc mice.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0022628PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3144921PMC
December 2011

Hyponatraemia, rhabdomyolysis, alterations in blood pressure and persistent mydriasis in patients envenomed by Malayan kraits (Bungarus candidus) in southern Viet Nam.

Toxicon 2010 Nov 14;56(6):1070-5. Epub 2010 Jul 14.

The Venom research & Antivenom production Unit, The National Poison Control Center Bach Mai Hospital, Hanoi, Viet Nam.

Between 1998 and 2007, 42 patients admitted to Choray hospital, Ho Chi Minh City, and to two hospitals in adjacent regions in southern Viet Nam brought the Malayan kraits (Bungarus candidus) that had been responsible for biting them. Half of the patients had been bitten while they were asleep. Fang marks and numbness were the only local features of the bites. Common signs of neurotoxic envenoming included bilateral ptosis, persistently dilated pupils, limb weakness, breathlessness, hypersalivation, dysphonia and dysphagia. Thirty patients (71.4%) required endotracheal intubation of whom all but one were mechanically ventilated. Fourteen patients (33.3%) developed hypertension, 13 (31.0%) shock, 31 (73.8%) hyponatraemia (plasma sodium concentration < 130 mEq/l) and 30 (71.4%) showed evidence of mild rhabdomyolysis (peak plasma creatine kinase concentration 1375 +/- 140 micro/l). None developed acute kidney injury. All the patients were treated with a new monospecific B. candidus antivenom. There were no fatalities. Hyponatraemia has been reported previously in victims of Chinese kraits (Bungarus multicinctus) in northern Viet Nam and rhabdomyolysis in patients envenomed by B. niger in Bangladesh. These features of envenoming pose new problems for the management of krait bite cases in South east Asia and should stimulate a search for the causative venom toxins.
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http://dx.doi.org/10.1016/j.toxicon.2010.06.026DOI Listing
November 2010

Ikaros and Aiolos inhibit pre-B-cell proliferation by directly suppressing c-Myc expression.

Mol Cell Biol 2010 Sep 21;30(17):4149-58. Epub 2010 Jun 21.

Department of Genetics, Cell Biology, and Anatomy, University of Nebraska Medical Center, Omaha, NE 68198-5805, USA.

Pre-B-cell expansion is driven by signals from the interleukin-7 receptor and the pre-B-cell receptor and is dependent on cyclin D3 and c-Myc. We have shown previously that interferon regulatory factors 4 and 8 induce the expression of Ikaros and Aiolos to suppress pre-B-cell proliferation. However, the molecular mechanisms through which Ikaros and Aiolos exert their growth inhibitory effect remain to be determined. Here, we provide evidence that Aiolos and Ikaros bind to the c-Myc promoter in vivo and directly suppress c-Myc expression in pre-B cells. We further show that downregulation of c-Myc is critical for the growth-inhibitory effect of Ikaros and Aiolos. Ikaros and Aiolos also induce expression of p27 and downregulate cyclin D3 in pre-B cells, and the growth-inhibitory effect of Ikaros and Aiolos is compromised in the absence of p27. A time course analysis further reveals that downregulation of c-Myc by Ikaros and Aiolos precedes p27 induction and cyclin D3 downregulation. Moreover, downregulation of c-Myc by Ikaros and Aiolos is necessary for the induction of p27 and downregulation of cyclin D3. Collectively, our studies identify a pre-B-cell receptor signaling induced inhibitory network, orchestrated by Ikaros and Aiolos, which functions to terminate pre-B-cell expansion.
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http://dx.doi.org/10.1128/MCB.00224-10DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2937562PMC
September 2010

A role for interferon regulatory factor 4 in receptor editing.

Mol Cell Biol 2008 Apr 19;28(8):2815-24. Epub 2008 Feb 19.

Department of Genetics, Cell Biology, and Anatomy, University of Nebraska Medical Center, Omaha, NE 68198, USA.

Receptor editing is the primary means through which B cells revise antigen receptors and maintain central tolerance. Previous studies have demonstrated that interferon regulatory factor 4 (IRF-4) and IRF-8 promote immunoglobulin light-chain rearrangement and transcription at the pre-B stage. Here, the roles of IRF-4 and -8 in receptor editing were analyzed. Our results show that secondary rearrangement was impaired in IRF-4 but not IRF-8 mutant mice, suggesting that receptor editing is defective in the absence of IRF-4. The role of IRF-4 in receptor editing was further examined in B-cell-receptor (BCR) transgenic mice. Our results show that secondary rearrangement triggered by membrane-bound antigen was defective in the IRF-4-deficient mice. Our results further reveal that the defect in secondary rearrangement is more severe at the immunoglobulin lambda locus than at the kappa locus, indicating that IRF-4 is more critical for the lambda rearrangement. We provide evidence demonstrating that the expression of IRF-4 in immature B cells is rapidly induced by self-antigen and that the reconstitution of IRF-4 expression in the IRF-4 mutant immature B cells promotes secondary rearrangement. Thus, our studies identify IRF-4 as a nuclear effector of a BCR signaling pathway that promotes secondary rearrangement at the immature B-cell stage.
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http://dx.doi.org/10.1128/MCB.01946-07DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2293099PMC
April 2008

Interferon regulatory factors 4 and 8 induce the expression of Ikaros and Aiolos to down-regulate pre-B-cell receptor and promote cell-cycle withdrawal in pre-B-cell development.

Blood 2008 Feb 30;111(3):1396-403. Epub 2007 Oct 30.

Department of Genetics, Cell Biology and Anatomy, University of Nebraska Medical Center, Omaha, NE 68198-5805, USA.

Pre-B lymphocytes consist of 2 distinct cell populations: large pre-B and small pre-B. The large pre-B cells are newly generated pre-B cells that express pre-B-cell receptor (pre-BCR) on the surface and are highly proliferative; small pre-B cells are derived from large pre-B cells that have down-regulated pre-BCR and withdrawn from cell cycle. The molecular events that mediate the transition from cycling pre-B to small, resting pre-B have not been fully elucidated. Here, we show that interferon regulatory factors 4 and 8 (IRF4,8) suppress surrogate light chain expression and down-regulate pre-BCR in pre-B cells. Our studies further reveal that IRF4,8 induce the expression of Ikaros and Aiolos in pre-B cells, and reconstitution of expression of either one is sufficient to suppress surrogate light chain expression and down-regulate pre-BCR in pre-B cells lacking IRF4,8. Interestingly, our results also indicate that pre-B cells undergo growth inhibition and cell-cycle arrest in the presence of IRF4,8. Moreover, we provide evidence that Ikaros and Aiolos are indispensable for the down-regulation of pre-BCR and the cell-cycle withdrawal mediated by IRF4,8. Thus, IRF4,8 orchestrate the transition from large pre-B to small pre-B cells by inducing the expression of Ikaros and Aiolos.
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http://dx.doi.org/10.1182/blood-2007-08-110106DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2214771PMC
February 2008

IFN regulatory factor 4 and 8 promote Ig light chain kappa locus activation in pre-B cell development.

J Immunol 2006 Dec;177(11):7898-904

Department of Genetics, Cell Biology, and Anatomy, University of Nebraska Medical Center, Omaha, NE 68198, USA.

Previous studies have shown that B cell development is blocked at the pre-B cell stage in IFN regulatory factor (IRF)4 (pip) and IRF8 (IFN consensus sequence binding protein) double mutant mice (IRF4,8(-/-)). In this study, the molecular mechanism by which IRF4,8 regulate pre-B cell development was further investigated. We show that IRF4,8 function in a B cell intrinsic manner to control pre-B cell development. IRF4,8(-/-) mice expressing a Bcl-2 transgene fail to rescue pre-B cell development, suggesting that the defect in B cell development in IRF4,8(-/-) mice is not due to a lack of survival signal. IRF4,8(-/-) pre-B cells display a high proliferation index that may indirectly inhibit the L chain rearrangement. However, forced cell cycle exit induced by IL-7 withdrawal fails to rescue the development of IRF4,8(-/-) pre-B cells, suggesting that cell cycle exit by itself is not sufficient to rescue the development of IRF4,8(-/-) pre-B cells and that IRF4,8 may directly regulate the activation of L chain loci. Using retroviral mediated gene transduction, we show that IRF4 and IRF8 function redundantly to promote pre-B cell maturation and the generation of IgM(+) B cells. Molecular analysis indicates that IRF4, when expressed in IRF4,8(-/-) pre-B cells, induces kappa germline transcription, enhances V(D)J rearrangement activity at the kappa locus, and promotes L chain rearrangement and transcription. Chromatin immunoprecipitation assay further reveals that IRF4 expression leads to histone modifications and enhanced chromatin accessibility at the kappa locus. Thus, IRF4,8 control pre-B cell development, at least in part, by promoting the activation of the kappa locus.
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http://dx.doi.org/10.4049/jimmunol.177.11.7898DOI Listing
December 2006

Chimeragenesis of the fatty acid binding site of cytochrome P450BM3. Replacement of residues 73-84 with the homologous residues from the insect cytochrome P450 CYP4C7.

Biochemistry 2004 Feb;43(7):1771-80

Department of Chemistry, University of Arizona, Tucson, Arizona 85721-0041, USA.

A protein fragment of P450BM3 (residues 73-84) which participates in palmitoleate binding was subjected to scanning chimeragenesis. Amino acids 73-84, 73-78, 75-80, and 78-82 were replaced with the homologous fragments of the insect terpenoid hydroxylase CYP4C7. The four chimeric proteins, C(73-84), C(73-78), C(75-80), and C(78-82), were expressed, purified, and characterized. All the chimeric proteins contained all the cofactors and catalyzed monooxygenation of palmitate and of the sesquiterpene farnesol. Chimeragenesis altered substrate binding as shown by the changes in the amplitude of the palmitate-induced type I spectral shift. C(78-82) had monooxygenase activities close to those of P450BM3, while the rest of the chimeric proteins had monooxygenase activities that were inhibited relative to that of wild-type P450BM3. The extent of inhibition of the chimeric proteins varied depending on the substrate, and in the case of C(73-84), farnesol and palmitate oxidation was inhibited by 1 and 4 orders of magnitude, respectively. (1)H NMR spectroscopy and GC-MS were used to identify products of farnesol and palmitate oxidation. Wild-type P450BM3 and all chimeric proteins catalyzed oxidation of farnesol with formation of 9-hydroxyfarnesol and farnesol 10,11- and 2,3-epoxides. Three of the four chimeric proteins also formed a new compound, 5-hydroxyfarnesol, which was the major product in the case of C(73-78). In addition to hydroxylation of the C13-C15 atoms, the chimeric enzymes catalyze significant hydroxylation of the C10-C12 atoms of palmitate. In the case of C(78-82), the rates of formation of 11- and 12-hydroxypalmitates increased 7-fold compared to that of wild-type P450BM3 to 106 and 212 min(-)(1), respectively, while the rate of 10-hydroxypalmitate synthesis increased from zero to 106 min(-)(1). Thus, chimeragenesis of the region of residues 73-84 of the substrate binding site shifted the regiospecificity of substrate oxidation toward the center of the farnesol and palmitate molecules.
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http://dx.doi.org/10.1021/bi035674bDOI Listing
February 2004

Structure and characterization of flavolipids, a novel class of biosurfactants produced by Flavobacterium sp. strain MTN11.

Appl Environ Microbiol 2004 Jan;70(1):114-20

Department of Earth and Environmental Science, The University of Texas-San Antonio, San Antonio, Texas 78249, USA.

Herein we report the structure and selected properties of a new class of biosurfactants that we have named the flavolipids. The flavolipids exhibit a unique polar moiety that features citric acid and two cadaverine molecules. Flavolipids were produced by a soil isolate, Flavobacterium sp. strain MTN11 (accession number AY162137), during growth in mineral salts medium, with 2% glucose as the sole carbon and energy source. MTN11 produced a mixture of at least 37 flavolipids ranging from 584 to 686 in molecular weight (MW). The structure of the major component (23%; MW = 668) was determined to be 4-[[5-(7-methyl-(E)-2-octenoylhydroxyamino)pentyl]amino]-2-[2-[[5-(7-methyl-(E)-2-octenoylhydroxyamino)pentyl]amino]-2-oxoethyl]-2-hydroxy-4-oxobutanoic acid. The partially purified flavolipid mixture isolated from strain MTN11 exhibited a critical micelle concentration of 300 mg/liter and reduced surface tension to 26.0 mN/m, indicating strong surfactant activity. The flavolipid mixture was a strong and stable emulsifier even at concentrations as low as 19 mg/liter. It was also an effective solubilizing agent, and in a biodegradation study, it enhanced hexadecane mineralization by two isolates, MTN11 (100-fold) and Pseudomonas aeruginosa ATCC 9027 (2.5-fold), over an 8-day period. The flavolipid-cadmium stability constant was measured to be 3.61, which is comparable to that for organic ligands such as oxalic acid and acetic acid. In summary, the flavolipids represent a new class of biosurfactants that have potential for use in a variety of biotechnological and industrial applications.
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http://www.ncbi.nlm.nih.gov/pmc/articles/PMC321267PMC
http://dx.doi.org/10.1128/AEM.70.1.114-120.2004DOI Listing
January 2004