A New Model of Care: A Combined Pediatric/ Adult Thrombosis and Hemostasis (PATH) Clinic – One Center's Experience.

Blood ◽  
2009 ◽  
Vol 114 (22) ◽  
pp. 4553-4553
Author(s):  
Matthew W Richardson ◽  
Richard H Steingart
Keyword(s):  
Chart Review ◽  
Conflicts Of Interest ◽  
Asymptomatic Patient ◽  
Family Members ◽  
Model Of Care ◽  
Adult Age ◽  
Adolescent Women ◽  
Simultaneous Evaluation ◽  
Recent Diagnosis ◽  
Developmental Traits

Abstract Abstract 4553 Background Patients of all ages with thrombosis are frequently tested for heritable thrombophilias (HT). Similarly, patients with bleeding or bruising may be tested for heritable bleeding (HB) conditions. We developed the Pediatric/Adult Thrombosis & Hemostasis (PATH) Clinic, a once-monthly clinic where children, adults and their families in whom the diagnosis of HT or HB was established or being considered could be assessed simultaneously by a pediatric and “adult” hematologist. Reasons for the clinic's creation included 1. HT/ HB conditions are lifelong. A combined clinic aids transition from a pediatric provider to an internist at the same institution. 2. Adolescence is when many HT/ HB disorders manifest themselves. This group has medical and developmental traits that cross pediatric and internal medicine approaches and expertise. 3. Adult experience. Much treatment for pediatric thromboses is extrapolated from adult data. An adult hematologist present at the evaluation of a pediatric patient with HT provides a valuable resource for the child and pediatric hematologist. 4. The finding of HT or HB in a patient has implications for family members regardless of age. 5. Convenience. All family members can be evaluated at a single visit where several members might need screening. Objective To review the experience of a combined pediatric/adult clinic created to evaluate potential HT/ HB in patients of all ages. Method IRB-approved chart review. Results 92 patients have been evaluated (61 for HT, 31 HB). Mean age 18 yr., median 16 yr. Female 64%. The most common reason for referral was evaluation of HT in an asymptomatic patient (42%) because of a family member having had a thrombosis or recent diagnosis of HT. Those evaluated for potential HT were less likely to be symptomatic (i.e. had not experienced a thrombosis) than those with HB (31% vs. 65%, p < 0.01). Adolescents (13–21 yr old) comprised 52% of all patients (57% of all females). Adolescents were more likely to be referred for HT than other ages (75% vs. 56%, p < 0.01). Conclusions The model of the PATH clinic – simultaneous evaluation of patients of all ages with or suspicion for HT/ HB by a pediatric and “adult” hematologist – may be useful to other centers. Adolescents (in transition from the pediatric to adult age group) comprised the single largest cohort, emphasizing the potential importance of a combined approach. Adolescent women were especially represented, likely due to the new potential for bleeding (menarche) leading to a diagnosis of an HB and the emergence of acquired thrombophilic risk factors (estrogen contraception and pregnancy) in this group that have implications in families with HT. Physicians in such a clinic should have particular knowledge of bleeding and thrombophilic conditions in adolescent women and of counseling for asymptomatic HT. Disclosures: No relevant conflicts of interest to declare.

“Consideration of patients as networked units to identify opportunities and motivation to enhance capability”: A mixed methods study to explore a personalised Digital Health Hub Model of Care for hip fractures in South Australia (Preprint)

2021 ◽  
Author(s):  
Lalit Yadav ◽  
Tiffany K Gill ◽  
Anita Taylor ◽  
Jen DeYoung ◽  
Mellick J Chehade
Keyword(s):  
Hip Fractures ◽  
Digital Health ◽  
Family Members ◽  
South Australia ◽  
Aged Care ◽  
Mixed Methods Study ◽  
Residential Aged Care ◽  
Model Of Care ◽  
Factors Influencing

UNSTRUCTURED Introduction Majority of older people with hip fractures once admitted to acute hospital care are unable to return to their pre-fracture level of independence and a significant number are either newly admitted or return to residential aged care. Patient education involves family members and/or residential aged care staff as networked units, crucial for empowerment through improving health literacy. Advancement of digital technology has led to evolving solutions around optimising health care including self-management of chronic disease conditions and telerehabilitation. The aim of this study is to understand perspectives of older patients with hip fractures, their family members and residential aged carers, to inform the development of a digitally enabled model of care using a personalised digital health hub (pDHH). Methods A mixed methods study was conducted at a public tertiary care hospital in South Australia involving patients aged 50 years and above along with their family members and residential aged carers. Quantitative data, including basic demographic characteristics, access to computers and Internet were analysed using descriptive statistics. Spearman’s Rank Order Correlation was used to examine correlations between the perceived role of a pDHH in improving health and likelihood of subsequent usage. Whereas qualitative data included series of open-ended questions and findings were interpreted using constructs of capability, opportunity and motivation to help understand the factors influencing the likelihood of potential pDHH use Results Overall, 100 people were recruited in the study, representing 55 patients, 13 family members and 32 residential aged carers. The mean age of patients was 76.4 years (SD-8.4, age range 54-88) and females represented 60% of patients. Although a moderate negative correlation existed with increasing age and likelihood of pDHH usage (ρ= -0.50, p<0.001) the perceived role of the DHH in improving health had a strong positive correlation with the likelihood of pDHH usage by self (ρ=0.71, p<0.001) and by society, including friends and family members (ρ=0.75, p<0.001). Of particular note, almost all the patients (98%) believed they had a family member or friend /carer who would be able to help them to use a digital health platform. Whereas our qualitative findings suggest emphasising on complex interplay of capability, opportunity and motivation as crucial factors while designing a pDHH enabled model of care for hip fractures at a local context level. Conclusion Findings from this study contributed to understand the dynamics around capabilities, motivation and opportunities of patients, family members and formal carers as a “patient networked unit”. Future research recommendation must involve co-creation guided by iterative processes through improving understanding of factors influencing development and successful integration of complex digital healthcare interventions in real-world scenarios.

scholarly journals 763. 30 Day Readmission Outcomes in Patients Over 80 Years of Age Enrolled in an Outpatient Parenteral Antibiotic Therapy (OPAT) Program

2019 ◽  
Vol 6 (Supplement_2) ◽  
pp. S339-S340
Author(s):  
Kathleen R Sheridan ◽  
Joshua Wingfield ◽  
Lauren McKibben ◽  
Natalie Clouse
Keyword(s):  
Readmission Rate ◽  
Chart Review ◽  
Age Groups ◽  
Retrospective Chart Review ◽  
Model Of Care ◽  
Readmission Rates ◽  
Parenteral Antibiotic ◽  
Patient Demographics

Abstract Background OPAT is a well-established model of care for the monitoring of patients requiring long-term IV antibiotics1. We have previously reported a reduction in the 30-day readmission rate to our facility for patients managed in our OPAT program. However, little has been published to date regarding outcomes in OPAT patients over 80 years of age 2–3. Our OPAT program was established in 2013. Patients can be discharged to a facility or home to complete their course of antibiotics. Methods We conducted a retrospective chart review of all OPAT patients discharged from our facility from 2015 to 2018. Patients were divided into two groups based on age, <80 (n = 4618) and >80 (n = 562). Results Patient demographics are listed in Table 1. The overall 30-day readmission rate for patients older than 80 was 27.8%. For patients over 80 that had a follow-up ID clinic appointment, the 30-day readmission rate decreased to 15.7%. For patients younger than 80, the 30-day readmission rate was 36.0% with a decrease to 16.2% if patients were evaluated in the outpatient clinic. Figure 1. Staphylococcus Aureus was the predominant organism in both age categories. Vancomycin was the most common antibiotic used in both age groups followed by β lactams. Conclusion In general, patients aged over 80 years were more likely to be discharged to a facility to complete their antibiotic course than younger patients. These patients also were more likely to have other comorbidities. The 30-day readmission rate in each age group was relatively similar. OPAT in patients over age 80 can have similar 30-day readmission rates as for patients less than 80 years of age Disclosures All authors: No reported disclosures.

scholarly journals Request Strategies in the American TV Series Full House

Lexicon ◽  
2019 ◽  
Vol 6 (1) ◽  
Author(s):  
Yemima Febriani ◽  
Sharifah Hanidar
Keyword(s):  
Social Distance ◽  
Family Members ◽  
Age Groups ◽  
The Other ◽  
Relative Power ◽  
Adult Age ◽  
Other Hand ◽  
Younger Age ◽  
The Social ◽  
Request Strategies

This research aims to analyze the request strategies used in an American TV Series entitled Full House season 7 episodes 1-12. The main characters are family members from three different age groups (adult, teenager, and children). This research attempts to see if there is any difference on the choice of request strategies used by the three age groups. Blum-Kulka and Olshtain’s (1984) theory on request directness level is used to classify the requests. Relative power and social distance are also studied to see how they influence the characters in making their requests. The results show that mood derivable is the most frequent strategy used by all age groups. Specifically, direct request is highly used by the adult age groups. On the other hand, indirect request is mostly used by the younger age groups. The results also show that all age groups tend to use direct strategy when the social distance is negative. However, when the social distance is positive, the choice of strategy depends on the authority of the speaker.

scholarly journals Grandma plays favourites: X-chromosome relatedness and sex-specific childhood mortality

2009 ◽  
Vol 277 (1681) ◽  
pp. 567-573 ◽  
Author(s):  
Molly Fox ◽  
Rebecca Sear ◽  
Jan Beise ◽  
Gillian Ragsdale ◽  
Eckart Voland ◽  
...  
Keyword(s):  
X Chromosome ◽  
Genetic Relatedness ◽  
Family Members ◽  
Childhood Mortality ◽  
Human Populations ◽  
Kin Investment ◽  
Grandmother Hypothesis ◽  
New Perspective ◽  
Post Menopausal ◽  
Developmental Traits

Biologists use genetic relatedness between family members to explain the evolution of many behavioural and developmental traits in humans, including altruism, kin investment and longevity. Women's post-menopausal longevity in particular is linked to genetic relatedness between family members. According to the ‘grandmother hypothesis’, post-menopausal women can increase their genetic contribution to future generations by increasing the survivorship of their grandchildren. While some demographic studies have found evidence for this, others have found little support for it. Here, we re-model the predictions of the grandmother hypothesis by examining the genetic relatedness between grandmothers and grandchildren. We use this new model to re-evaluate the grandmother effect in seven previously studied human populations. Boys and girls differ in the per cent of genes they share with maternal versus paternal grandmothers because of differences in X-chromosome inheritance. Here, we demonstrate a relationship between X-chromosome inheritance and grandchild mortality in the presence of a grandmother. With this sex-specific and X-chromosome approach to interpreting mortality rates, we provide a new perspective on the prevailing theory for the evolution of human female longevity. This approach yields more consistent support for the grandmother hypothesis, and has implications for the study of human evolution.

Noval Mutation in Four Saudi Families with Glanzmann Thrombasthenia

Blood ◽  
2011 ◽  
Vol 118 (21) ◽  
pp. 1136-1136
Author(s):  
Tarek Owaidah ◽  
Hala Abalkhail ◽  
Abdulrahman Al Musa ◽  
Hasan Mosmali ◽  
Albanyan Abdulmajeed ◽  
...  
Keyword(s):  
Conflicts Of Interest ◽  
Stop Codon ◽  
Direct Sequencing ◽  
Family Members ◽  
Premature Stop Codon ◽  
Type I ◽  
Bleeding Tendency ◽  
Coding Region ◽  
Glanzmann Thrombasthenia ◽  
Exon 1

Abstract Abstract 1136 Introduction: Glanzmann thrombasthenia (GT) is a rare autosomal recessive inherited bleeding disorder characterized by an impaired platelet aggregation and variable bleeding tendency. Inherited genetic mutations in integrin alpha IIb and beta3 (ITGA2B, ITGB3) result in a heterogeneity of the thrombasthenia phenotypes. It is phenotypically expressed in homozygotes or compound heterozygotes, given that 50% of normal aIIbb3 is sufficient to guarantee unimpaired platelet function that result in asymptomatic carriers. Defects in ITGB3 result in failure of binding of B3 and alpha IIb. These defects had been reported in Arabs (Iraqi Jews). We are reporting some results of Saudi GT genotype project. Materials & Methods: In this study, we analyzed the entire coding region ITGB3 gene using polymerase chain reaction (PCR) and direct sequencing with primers specifically designed to amplify the coding region of exon 1–15 and exon /Intron boundaries in a cohort of 51 GT patients diagnosed and treated in our institute. Results: Out of 51 cases from 20 families had mutational screening of the ITGB3 gene with the aim to detect the causative pathogenic mutations to enable the pre-symptomatic diagnosis in at risk family members. In this study we detect 1 novel germline mutation c.2190delC (p.Ser703fs) in exon 13. The mutation is predicted to result in premature stop codon and protein truncation. The mutation was detected in 6 patients in homozygous stat (3 males and 3 females). Three tested samples from the patients family members detected the mutation in heterozygous state and all of them were asymptomatic with normal PFA and Intact expression of Platelet Glycoprotiens CD41(Gpllb), CD42a(GPIX), CD42b(GPlb), and CD61(Gpllla). All the GT patients with this mutation were type I GT with Prolonged PFA and complete absence of CD41(Gpllb) and CD61(Gpllla) glycoprotein. Conclusion: The result of this study represents the first Molecular analysis of ITGB3 gene in Saudi Arabia and displays the existence of novel pathogenic and possibly a founder effect in Saudi families. Disclosures: No relevant conflicts of interest to declare.

Differential Expression and Functions of NOTCH Family Members and Involvement of NR4A1 in the Regulation of Apoptosis in CLL

Blood ◽  
2012 ◽  
Vol 120 (21) ◽  
pp. 3919-3919
Author(s):  
Rainer Hubmann ◽  
Martin Hilgarth ◽  
Susanne Schnabl ◽  
Elena Ponath ◽  
Dita Demirtas ◽  
...  
Keyword(s):  
Cell Viability ◽  
Mrna Expression ◽  
Target Gene ◽  
Conflicts Of Interest ◽  
Family Members ◽  
Dependent Manner ◽  
Rt Pcr ◽  
Activated State ◽  
Induced Apoptosis ◽  
The Individual

Abstract Abstract 3919 Chronic lymphocytic leukemia (CLL) cells express constitutively activated NOTCH2 in a protein kinase C (PKC) dependent manner linking NOTCH2 to the activated state of the leukemic cells. The transcriptional activity of NOTCH2 is associated with the expression of CD23 and enhanced CLL cell viability. However, the regulation and possible functions of the individual NOTCH family members (NOTCH1–4) in CLL cells remain to be clarified. We took advantage of targeting nuclear NOTCH2 using the recently identified NOTCH2 transactivation inhibitor gliotoxin (WO 2006/135949). We also analysed the regulation and possible function of NOTCH1–4 in PKC stimulated CLL cells using a PMA model (Hubmann et al., BJH 2010) and a microenvironment model where CLL lymphocytes were co-cultured with primary bone marrow stromal cells (BMSC) (Shehata et al., BLOOD 2010). Electrophoretic mobility shift assays (EMSA) demonstrated that gliotoxin inhibited DNA-bound NOTCH2 complexes in PMA stimulated CLL cells in parallel to increasing the rate of apoptosis (mean±SD: 67±31% in gliotoxin treated cells versus 13±14% in the untreated controls, n=21). This was associated with downregulation of CD23A mRNA expression and CD23 surface expression (mean±SD: 42±32% versus 83±17%, n=21) as assessed by RT-PCR and FACS analysis. Exceptionally, one CLL case with a recently described NOTCH1 gain of function mutation appeared to be less sensitive to gliotoxin and had a persistent high expression of CD23. We next tested whether NOTCH2 inhibition by gliotoxin is a selective process or indirectly mediated by effects on proteasome regulated apoptosis. Proteasome assays showed that gliotoxin had a minimal or no effect on the chymotrypsin like activity of the proteasome in CLL cells. In addition, the activity of the proteasome regulated transcription factor NFκB and the expression of its target genes like BCL2 and MCL1 were also not influenced by gliotoxin. These data point to the selectivity of targeting NOTCH2 signaling by gliotoxin rather than indirectly through the regulation of proteasome activity. Short term (4 hours) exposure of CLL cells revealed that NOTCH1 was equally transcribed in unstimulated and in PMA activated CLL cells. NOTCH2 was upregulated in PMA activated CLL lymphocytes whereas NOTCH4 was only weakly detectable in unstimulated CLL cells. Gliotoxin treatment resulted in the downregulation of NOTCH1, NOTCH2 and NOTCH4 mRNA expression. Interestingly, the inhibition of NOTCH2 activity by gliotoxin was associated with the concomitant induction of NOTCH3 signaling especially in the presence of PMA. This was indicated by the induced mRNA expression of NOTCH3 and its preferred target gene HEY1. Moreover, the induced transcription of HEY1 correlated with the upregulation of NR4A1, a key regulator of apoptosis in activated lymphocytes. These data may thus point to a pro-apoptotic role for NOTCH3/HEY1/NR4A1 signaling in CLL cells. The data also suggest that gliotoxin induced apoptosis is associated with differential regulation of the anti-apoptotic and pro-apoptotic arms of NOTCH signalling in CLL cells. RT-PCR revealed that NOTCH1 and NOTCH2 are the main NOTCH family members which are expressed in CLL cells under co-culture conditions with BMSC and in freshly isolated CLL cells. Exposure to gliotoxin in co-culture selectively induced apoptosis in CLL cells and led to downregulation of NOTCH1 and NOTCH2 together with upregulation of NOTCH3 mRNA expression. In summary, the data suggest that nuclear NOTCH2 activity might protect activated CLL cells from apoptosis by modulating the expression of NR4A1. The induced expression of NOTCH3 and its target gene HEY1 by gliotoxin reveals the complex role of different NOTCH family members in the regulation of apoptosis in CLL cells. Therefore, the individual NOTCH receptors may have opposite effects on CLL cell viability which should be considered in therapeutic approaches aimed to target NOTCH signaling in CLL. Disclosures: No relevant conflicts of interest to declare.

Molecular Diagnosis of One Pedigree with Protein S Deficiency and Antithrombin Deficiency

Blood ◽  
2012 ◽  
Vol 120 (21) ◽  
pp. 5140-5140
Author(s):  
Rong-Fu Zhou ◽  
Hong Tao ◽  
Jian Ouyang ◽  
Xian Zhang ◽  
Yonggong Yang ◽  
...  
Keyword(s):  
Conflicts Of Interest ◽  
Novel Mutation ◽  
Color Doppler ◽  
Femoral Vein ◽  
Family Members ◽  
Protein S ◽  
Heterozygous Mutation ◽  
Sequencing Analysis ◽  
Antithrombin Deficiency ◽  
Exon 4

Abstract Abstract 5140 Objective To identify gene mutations for one patient and his family members with protein S and antithrombin deficiency. Methods ELISA were used to detect protein S (PS), protein C (PC) and antithrombin (AT) activities for the proband and family members, respectively. The genomic DNA was extracted from the peripheral blood of proband and family members. All exons and their flanks of protein S gene and antithrombin gene were amplified by polymerase chain reaction (PCR). The PCR products were sequenced directly. The mutation-related exons of his famliy members were amplified by PCR and sequenced directly. Results The proband was a 49-year-old male. He presented with sudden left lower extremity swelling and pain without casues. Regular examination revealed that his APTT, PT, and TT were all in normal levels, but D- dimmer was 5. 62mg/L, Color doppler ultrasonography showed thrombosis in his left femoral vein. The activity of PS for his family members was ‡1 0%, ‡2 0%, ‡3 0%, ‡4 130. 8%, ‡5 8. 4%, ‡1 0%, ‡2 0%, and that of AT was ‡1 129. 1%, ‡2 51. 9%, ‡3 73.2%, ‡4 119. 1%, ‡5 136. 2%, ‡1 65. 5% and ‡2 60. 1%, respectively. The sequencing analysis showed that a heterozygous missense mutation G68395T (NG_009813. 1) was detected in Exon 4 of PS gene leading to the substitution of Arg90 by Leu (NP_000304. 2) for the propositus. The heterozygous mutation (Arg90Leu) was also found in other family members. A heterozygous (nonsense) mutation G12444A (NG_012462. 1) was detected in Exon 4 of AT gene leading to Trp257Ter (NP_000479. 1) for the propositus. The mutation (Trp257Ter) was found in other family members with reduced activity of AT. These two mutations (G68395T in PS gene and G12444A in AT gene) were not reported before and were thus novel ones. Conclusion The novel mutation G68395T in PS gene and G12444A in AT gene might be the causes of deficiency of PS and AT for the family. Disclosures: No relevant conflicts of interest to declare.

Second Primary Malignancies In Adult Acute Lymphoblastic Leukemia

Blood ◽  
2013 ◽  
Vol 122 (21) ◽  
pp. 3871-3871
Author(s):  
Binay K. Shah ◽  
Krishna B Ghimire
Keyword(s):  
Acute Lymphoblastic Leukemia ◽  
General Population ◽  
Conflicts Of Interest ◽  
Lymphoblastic Leukemia ◽  
Adult Patients ◽  
P Value ◽  
Second Primary ◽  
Adult Age ◽  
Absolute Excess Risk ◽  
Second Primary Malignancies

Abstract Background Pediatric acute lymphoblastic leukemia (ALL) patients have higher rates of second primary malignancies. There is limited data on second primary malignancies (SPM) among adult patients with ALL. This study was conducted to evaluate SPM in adult ALL patients using US Surveillance, Epidemiology and End Results (SEER) cancer registry database. Methods We analyzed the SEER 13 Registries using multiple primary standardized incidence ratio (MP-SIR) session. We analyzed secondary cancer rates among adult ALL patients during the period 1992 - 2010. We used SEER*Stat software provided by national cancer institute for statistical analysis. Results There were 3,259 adult (age ≥20 years) ALL patients reported in SEER database during 1992-2010. Among them, 65 ALL patients developed 75 second primary malignancies. Fifty-nine ALL patients developed 1 SPM each, 3 ALL patients developed 2 SPM each, 2 ALL patients developed 3 SPM each and 1 ALL patient developed 4 SPM. All site cancers were significantly higher among adult ALL patients compared to general population with observed/expected ratio (O/E): 1.47, p value< 0.05, an absolute excess risk of 24.43 per 10,000 populations. Similarly, oral cavity cancer, respiratory system cancer and hematological SPM were significantly higher in ALL patients than expected in general population. (Table) Conclusions Adult patients with ALL have higher rates of second primary malignancies compared to general population. Disclosures: No relevant conflicts of interest to declare.

A New Mutation Of The ALAS2 Gene In a Chinese Family With X-linked

Blood ◽  
2013 ◽  
Vol 122 (21) ◽  
pp. 4674-4674
Author(s):  
Rui Cui ◽  
Guoqing Zhu ◽  
Zefeng Xu ◽  
Yue Zhang ◽  
Gang Huang ◽  
...  
Keyword(s):  
Conflicts Of Interest ◽  
Iron Status ◽  
Family Members ◽  
Iron Chelation ◽  
Microcytic Anemia ◽  
Chinese Family ◽  
Sideroblastic Anemia ◽  
Distribution Width ◽  
Aminolevulinate Synthase ◽  
Status Data

X-linked sideroblastic anemia (XLSA; OMIM 301300) is one of the most common inherited sideroblastic anemia, which results from mutations in the erythroid-specific isozyme of 5-aminolevulinate synthase. An amino acid (AA) substitution for arginine at the 452 AA position of the ALAS2 protein is the most frequent mutation, which has been found in approximately one-quarter of patients with XLSA. Here we first report a 3-generation pedigree including 10 individuals with a K156E substitution in ALAS2 gene in China. A 34 year-old man, complained with a microcytic anemia (hemoglobin (Hb) 84 g/dl, MCV 63.8 fl and MCH 16.5pg), increased ferritin serum (3123ng/ml) and transferrin sat (93%), and dyserythropoiesis with 50% of ring sideroblasts (RS) in BM. A diagnosis of XLSA was made. On treatment with 300mg/d pyridoxine and iron chelation therapy with deferoxamine allowed a correction of anemia and reduction of the S-ferritin (1096 ng/ml) in the proband. The peripheral blood samples had been extracted from proband and his family members. All exons containing exon-intron boundaries of ALAS2, SLC25A38 and GLRX5, the promoter region and intron 8 of ALAS2 were amplified and directly sequenced. He is a heterozygous for ALAS2 K156E substituion. The pedigree of the proband's family is shown in Figure 1, while hematologic and iron status data for the family members are reported in Table 1. All 4 heterozygous females from this family showed marginally increased red-cell distribution width (RDW) without phenotypic expression.Figure 1The pedigree of the probandFigure 1. The pedigree of the probandTable1Clinical and hematological features of the pedigreeSubjectSex/age,yHb g/dLMCV fLRDW%Ferritin μg/LALAS2I-1F/6811585.221.4136.7+II-1F/381288912.532.89-II-2M/348463.832.83123+II-3F/3213691.914.816.8-III-1M/2015288.212.1123.6-III-2F/1812384.813.321.84-III-3M/71449212.951.9-III-4F/101338513.716.8+III-5F/812681.418.831.2- In summary, this is a novel K156E substitution in ALAS2 gene discovered in a 3-generation pedigree in China. Furthermore, early diagnosis of XLSA allows preventing the complications of the iron overload by chelators or by iterative phlebotomies. Disclosures: No relevant conflicts of interest to declare.

scholarly journals Induction of Resistance to Proteasome Inhibition Preferentially Switches Survival Dependence from Bcl-2 to XIAP in Preclinical Models of Waldenstrom Macroglobulinemia: Pre-Clinical Rationale for Early Clinical Sequencing of ABT199

Blood ◽  
2015 ◽  
Vol 126 (23) ◽  
pp. 4839-4839
Author(s):  
Sharoon Akhtar ◽  
Aneel Paulus ◽  
Kelara Samuel ◽  
Hassan Yousaf ◽  
Davitte Cogen ◽  
...  
Keyword(s):  
Gene Expression ◽  
Cell Lines ◽  
Conflicts Of Interest ◽  
Family Members ◽  
Specific Inhibitor ◽  
Cross Resistance ◽  
Preclinical Models ◽  
Waldenström Macroglobulinemia ◽  
Waldenstrom Macroglobulinemia ◽  
Resistant Cells

Abstract Background: The proteasome is an established and druggable target for the treatment of plasma cell-related malignancies including Waldenstrom macroglobulinemia (WM). WM cells as a consequence of high immunoglobulin production and increased B-cell receptor (BCR) mediated proliferation upregulate proteasome activity. Additionally, microenvironmental influence mediated through BCR signaling directly influences Bcl-2 and its BH3 family members, supporting tumor cell survival. Indeed, WM patients derive significant clinical benefit from proteasome-inhibitor (PI) based therapy with agents such as bortezomib and carfilzomib. However, resistance to PI develops over time and for these patients the optimal choice and sequence of therapy has yet to be determined. Using our WM models of PI-resistance we interrogated molecular events within the BCR and Bcl-2 pathways to determine therapeutic potential of targeting these crucial pathway in PI-resistance. Materials & Methods: WM cell lines (BCWM.1 and MWCL-1) and carfilzomib-resistant (CR) subclones (BCWM.1/CR and MWCL-1/CR) were used in experiments. Gene-expression and long-noncoding (LNC) RNA analysis was performed (Arraystar) and validated by real-time PCR. Bortezomib, carfilzomib, ABT199 and ibrutinib were purchased from Sellekchem. Results: To determine the functional impact of BCR and Bcl-2 signaling in PI-resistance, as well as therapeutic sensitivity of PI-resistant cells to their inhibitors (ibrutinib, ABT-199, respectively), we established and characterized WM cell lines resistant to carfilzomib. BCWM.1/CR cells showed approximately 20-fold resistance to carfilzomib (IC50 = 92.75nM) and MWCL-1/CR cells approximately 10-fold resistance (Fig. 1A). Both CR clones also displayed some cross-resistance to bortezomib. Gene expression and LNC-RNA profiling demonstrated several changes between carfilzomib-resistant vs. sensitive WM cells. Analysis of proteasome-related mRNA revealed downregulation of PSMB5, PSMB1, PSMB2 and PSMB8. Similarly, profiling of BCR-associated genes demonstrated decreased expression of several components, including BTK and SPI1. This observation functionally manifested as reduced sensitivity to the BTK-inhibitor ibrutinib, wherein CR cells displayed 1.5 - 2 fold growth resistance to ibrutinib on 72hr MTS assay. Next we examined the expression of Bcl-2 family members in CR cells. Intriguingly, we observed that Bcl-2 and Mcl-1 were significantly downregulated but XIAP (inhibitor of apoptosis) was significantly increased in CR cells vs. wildtype WM cells- both at transcriptional and translational levels. This suggested that upon acquisition of CR, a transcriptional shift towards XIAP occurs to accommodate sustained therapeutic stress from carfilzomib and maintain steady antiapoptotic composure. To test if the PI-resistant cells have moved away from their survival dependence on Bcl-2, we treated CR cells to increasing concentrations of the Bcl-2-specific inhibitor, ABT199, and as anticipated, CR cells displayed reduced apoptosis in presence of ABT199 compared to wildtype WM cells (32% annexin-V staining vs. 50%, respectively) (Fig. 1B). Conclusions: Our study sheds insight into the differential drivers of PI-resistance particularly towards carfilzomib, in WM cells. We demonstrate that acquisition of CR is associated with downregulation of Bcl-2 and Mcl-1, which is countered by upregulation of XIAP- an event that renders CR cells resistant to ABT199 (as it targets only Bcl-2). Likewise, downregulation of BCR-related components in CR cells was associated with reduced sensitivity towards ibrutinib. These observations suggest that acquisition of resistance to PI such as carfilzomib can impact future treatment with agents such as ibrutinib or ABT199. Our preclinical models provide rationale or early sequencing of ibrutinib or ABT199 in therapeutic planning of WM patients prior to induction of PI resistance. Figure 1. Figure 1. Disclosures No relevant conflicts of interest to declare.

Sign in / Sign up

Export Citation Format

Share Document