scholarly journals The Clonal Trajectories of SF3B1 Mutations in Myeloid Neoplasia

Blood ◽  
2020 ◽  
Vol 136 (Supplement 1) ◽  
pp. 8-8
Author(s):  
Hassan Awada ◽  
Cassandra M. Kerr ◽  
Vera Adema ◽  
Carmelo Gurnari ◽  
Simona Pagliuca ◽  
...  

Molecular lesions have diagnostic and prognostic impacts in myeloid neoplasia (MN). The beau idéal is the presence of SF3B1MT in MDS with ringed sideroblasts. Although most of these patients have a classic phenotype, little is known about the factors diverting it during the clonal evolution. Clinical trajectories of patients with SF3B1MT might depend on clonal hierarchy, dynamics and subclonal diversity in relation to other lesions. Herein, we studied the molecular architecture of patients with SF3B1MT to determine whether clonality and rank might infer distinct MDS features. We collected molecular and clinical information of 3561 patients with MN from Cleveland Clinic and publicly shared data. Results of targeted deep sequencing of 176 MDS/ AML genes were included. We applied an in-house variant allele frequency (VAF) based bioanalytic method to resolve clonal hierarchy. VAF (adjusted for copy number and zygosity) was used to classify the mutations into dominant (if a cutoff of at least 5% difference between VAFs existed), secondary (any subsequent subclonal hit) and codominant hits (<5% difference of VAFs between 2 hits). SF3B1 MT were detected in 9% of patients (n=335): 140 were SF3B1DOM (42%), 121 were SF3B1SEC (36%) and 74 were codominant (SF3B1COD, 22%). Comparison of SF3B1MT VAFs among the 3 groups showed no significant difference (40 vs 39 vs 44%, P= .6). Due to lack of distinct partition, we delved into the implications of SF3B1COD on mutational stability, disease phenotypes, molecular associations and overall survival (OS) as compared to the other 2 configurations. Serially-collected samples (n=21) showed clear scenarios of dominant clones remaining stable or switching to secondary due to impending acquisition of other hits or secondary clones remaining as such but denoted an ambivalent framework of codominant clones with "sweeping" features. Cases with SF3B1COD had a trend of OS similar to that of SF3B1SEC (median OS: 18 vs 15.9 mo.) and as such a poorer outcome compared to that of SF3B1DOM (39.8 mo.; P= .02). Moreover, the mutational profile of SF3B1CODvsSF3B1DOM was partially similar to that of SF3B1SECvs.SF3B1DOM with significantly higher odd ratios for DNMT3A (P< .0001), ASXL1, FLT3, RUNX1, TET2 (P≤ .05 for each). No variant morphologic features were observed when comparing SF3B1COD to the other 2 groups. By virtue, we strictly compared only cases with SF3B1DOM and SF3B1SEC, further supported by our single cell analysis(n=5), to showan unambiguous distinction between these two statii. Mutational burden analysis revealed that SF3B1DOM patients had a fewer number of mutations than those with SF3B1SEC (median 1.0 vs 2.6). SF3B1DOM was mostly detected in patients with a normocellular bone marrow as compared to SF3B1SEC (46 vs 29%, P= .02) and had a lower proportion of multidysplastic myeloid cells (29 vs 53%, P= .01). On the other side, SF3B1SEC were often present in the context of bilineage dysplasia (47vs. 26%, P= .02). Focused morphologic analysis revealed that SF3B1DOM cases were significantly associated with a higher RS% (median 37 vs 3%, P= .002; frequency of RS ≥15%: 77 vs 44%, P= .003) with higher VAF% significantly correlating with higher RS%. Patients with SF3B1SEC had shorter OS than those with SF3B1DOM (15.9 vs 39.7 mo., P< .0001). Even by dichotomizing according to VAF, the median OS of cases with VAF>40% was significantly shorter than those with VAF<20% (14.4 vs 33.9 mo.; P= .001) and between 20% and 40% (39.3 mo.). When the VAF of SF3B1SEC was >40%, the OS was shortened compared to SF3B1DOM (31 vs 11.6 mo., P= .001) and similarly when it laid between 20% and 40% (49.7 vs 25.6 mo., P= .01) suggesting a strong impact of associated hits. In SF3B1SEC, univariate analyses showed significantly higher odds of hits in RUNX1 (43 vs 19%, P< .0001), TET2 (29 vs 11%, P= .0005), FLT3 (22 vs 11%, P= .02), DNMT3A (20 vs 7%, P= .004), ASXL1 (16 vs 5%, P= .06), BCOR/L1 (17 vs 5%, P= .005), IDH1/2 (11 vs 2%, P= .008), CBL (8 vs 1%, P= .009) and CEBPA (7 vs 2%, P= .04) compared to SF3B1DOM. Interestingly, cases with co-existing TET2 mutations had a marked decrease in OS in SF3B1SECvsSF3B1DOM(10.1 vs 96.1 mo., P= .02) suggesting that the mutational ranking in a disease triggered by SF3B1MT can be skewed by stronger hits. In sum, our study suggests that molecular ranking in the context of SF3B1 clonal configuration is a key factor diverting the clinical and phenotypic trajectories of patients with MN and SF3B1MT. Disclosures Carraway: BMS: Consultancy, Other: Research support, Speakers Bureau; Jazz: Consultancy, Speakers Bureau; Stemline: Consultancy, Speakers Bureau; Takeda: Other: Independent Advisory Committe (IRC); ASTEX: Other: Independent Advisory Committe (IRC); Abbvie: Other: Independent Advisory Committe (IRC); Novartis: Consultancy, Speakers Bureau. Sekeres:Pfizer: Consultancy; BMS: Consultancy; Takeda/Millenium: Consultancy. Maciejewski:Alexion, BMS: Speakers Bureau; Novartis, Roche: Consultancy, Honoraria.

2015 ◽  
Vol 33 (3_suppl) ◽  
pp. 370-370
Author(s):  
Smit Singla ◽  
Kristopher Attwood ◽  
Charles Levea ◽  
Garin Tomaszewski ◽  
Boris W. Kuvshinoff ◽  
...  

370 Background: Patients with metastatic neuroendocrine tumors (NETs) benefit from treatment with yttrium-90 radioembolization (Y-90) or transarterial chemoembolization (TACE), however the criteria for patient selection are not well defined. We sought to determine if the proliferative index (Ki67 score) could be utilized to select patients for one therapy over the other. Methods: A single institution analysis of all patients treated with Y-90 or TACE between 2001 and 2014. Pathologists blinded to clinical information performed Ki67 scoring, and the data was analyzed using multivariate association for survival outcomes. Results: Amongst 72 patients (M: 39, F: 33; median age, 57 years) included in the study, the most common site of tumor origin was small bowel (n=35, 49%), and the most common histology subtype was carcinoid (n=58, 85%). Forty-four patients were treated with Y-90 (61%) and 28 patients received TACE (39%). Ki67 score was available in 28 patients (64%) treated with Y-90 and 16 patients (57%) in the TACE group. In Y-90 group, there was a higher concomitant use of sandostatin (94% vs 75%, p=0.023), longer time between diagnosis and treatment (median, 32 vs 11 months, p=<0.001), and less number of total treatments completed (89% vs 46%, p<0.001). There was no significant difference in overall survival (OS) between the groups (median, 69 vs 82 months, respectively; p=0.477); however when adjusted for Ki67 score of 3, patients with Ki67 score >3% were found to have better OS when treated with Y-90 as compared to TACE (HR, 0.083; CI, 0.008-0.854). On the other hand, in patients with Ki67 <3%, OS was better when treated with TACE (HR, 13.5; CI, 1.2-148.8). Further, patients in Y-90 group had higher incidence of carcinoid syndrome (39% vs 21%, p=0.195) and bilobar liver disease (95% vs 89%, p=0.371), whereas hepatic tumor burden >25% was greater in the TACE group (26% vs 20%, p=0.614), but these differences were not significant. Conclusions: In patients with metastatic NETs, Ki-67 score >3% may be predictive of treatment benefit with Y-90 and <3% with TACE. A longer time from diagnosis and an increased number of prior therapies may indicate a need for aggressive therapy; however a prospective validation is warranted.


1976 ◽  
Vol 41 (4) ◽  
pp. 523-529 ◽  
Author(s):  
Daniel R. Boone ◽  
Harold M. Friedman

Reading and writing performance was observed in 30 adult aphasic patients to determine whether there was a significant difference when stimuli and manual responses were varied in the written form: cursive versus manuscript. Patients were asked to read aloud 10 words written cursively and 10 words written in manuscript form. They were then asked to write on dictation 10 word responses using cursive writing and 10 words using manuscript writing. Number of words correctly read, number of words correctly written, and number of letters correctly written in the proper sequence were tallied for both cursive and manuscript writing tasks for each patient. Results indicated no significant difference in correct response between cursive and manuscript writing style for these aphasic patients as a group; however, it was noted that individual patients varied widely in their success using one writing form over the other. It appeared that since neither writing form showed better facilitation of performance, the writing style used should be determined according to the individual patient’s own preference and best performance.


1993 ◽  
Vol 69 (01) ◽  
pp. 035-040 ◽  
Author(s):  
A M H P van den Besselaar ◽  
R M Bertina

SummaryFour thromboplastin reagents were tested by 18 laboratories in Europe, North-America, and Australasia, according to a detailed protocol. One thromboplastin was the International Reference Preparation for ox brain thromboplastin combined with adsorbed bovine plasma (coded OBT/79), and the second was a certified reference material for rabbit brain thromboplastin, plain (coded CRM 149R). The other two thromboplastin reagents were another rabbit plain brain thromboplastin (RP) with a lower ISI than CRM 149R and a rabbit brain thromboplastin combined with adsorbed bovine plasma (RC). Calibration of the latter two reagents was performed according to methods recommended by the World Health Organization (W. H. O.).The purpose of this study was to answer the following questions: 1) Is the calibration of the RC reagent more precise against the bovine/combined (OBT/79) than against the rabbit/plain reagent (CRM 149R)? 2) Is the precision of calibration influenced by the magnitude of the International Sensitivity Index (ISI)?The lowest inter-laboratory variation of ISI was observed in the calibration of the rabbit/plain reagent (RP) against the other rabbit/plain reagent (CRM 149R) (CV 1.6%). The highest interlaboratory variation was obtained in the calibration of rabbit/plain (RP) against bovine/combined (OBT/79) (CV 5.1%). In the calibration of the rabbit/combined (RC) reagent, there was no difference in precision between OBT/79 (CV 4.3%) and CRM 149R (CV 4.2%). Furthermore, there was no significant difference in the precision of the ISI of RC obtained with CRM 149R (ISI = 1.343) and the rabbit/plain (RP) reagent with ISI = 1.14. In conclusion, the calibration of RC could be performed with similar precision with either OBT/79 or CRM 149R, or RP.The mean ISI values calculated with OBT/79 and CRM 149R were practically identical, indicating that there is no bias in the ISI of these reference preparations and that these reference preparations have been stable since their original calibration studies in 1979 and 1987, respectively.International Normalized Ratio (INR) equivalents were calculated for a lyophilized control plasma derived from patients treated with oral anticoagulants. There were small but significant differences in the mean INR equivalents between the bovine and rabbit thromboplastins. There were no differences in the interlaboratory variation of the INR equivalents, when the four thromboplastins were compared.


1966 ◽  
Vol 53 (4) ◽  
pp. 673-680 ◽  
Author(s):  
Torsten Deckert ◽  
Kai R. Jorgensen

ABSTRACT The purpose of this study was to investigate whether a difference could be demonstrated between crystalline insulin extracted from normal human pancreas, and crystalline insulin extracted from bovine and porcine pancreas. Using Hales & Randle's (1963) immunoassay no immunological differences could be demonstrated between human and pig insulin. On the other hand, a significant difference was found, between pig and ox insulin. An attempt was also made to determine whether an immunological difference could be demonstrated between crystalline pig insulin and crystalline human insulin from non diabetic subjects on the one hand and endogenous, circulating insulin from normal subjects, obese subjects and diabetic subjects on the other. No such difference was found. From these experiments it is concluded that endogenous insulin in normal, obese and diabetic human sera is immunologically identical with human, crystalline insulin from non diabetic subjects and crystalline pig insulin.


2020 ◽  
Vol 17 (2) ◽  
pp. 172
Author(s):  
HARMAN AGUSAPUTRA ◽  
MARIA SUGENG ◽  
AYLY SOEKAMTO ◽  
ATIK WULANDARI

<p><strong>Abstract</strong></p><p><strong>Background:</strong> Hydrogen peroxide (H<sub>2</sub>O<sub>2</sub>) as antiseptic has been used frequently to clean woundsin in hospitals and clinics. Hydrogen peroxide has the effectof strong oxidative that can kill pathogens. It can clean up debris and necrotic tissuesin wounds. Hydrogen peroxidealso has hemostatic effect that can help to stop bleeding. Besides antiseptic effects, hydrogen peroxide i s suspected of having negative effect in wound healing. Hydrogen peroxide presumably could cause delayed wound healing by exudate formation and delayed epithelial growth.</p><p><strong>Method</strong>: This study was conducted in the laboratory using 48 white mice that were divided into 2 groups. All the mice were purposely wounded. Afterwards in one group the wounds were clean up using hydrogen peroxide, while in the other group without hydrogen peroxide as control. The wounds of both groups were observed on day 1, day 3 and day 7. On day 1 and day 3, both groups did not show significant difference.</p><p><strong>R</strong><strong>esult</strong> : on day 7 showed that the wound healing in hydrogen peroxide group were delayed. Fifty percent of them had the formation of exudate and 62.5% of them showed delayed epithelial growth.</p><p><strong>Conclusion </strong>: This study could show hydrogen peroxide as wound antiseptic has delayed wound healing effect.</p><p><strong>Keyword</strong>: hydrogen peroxide, wound healing</p>


Author(s):  
Pavithra. S. ◽  
H. G. Gouda ◽  
Rajalakshmi M. G.

Agni is termed as Vaishwanara as it takes the person from Mruthyuloka to Swargaloka. It is an important factor and is equitant to Prana; is one among Dashaprana Ayatana. Agni in Shareera is present in different forms with different actions. It is the responsible factor for both health and disease; on the other hand the successful outcome of treatment is also dependant on Agni. Chikitsa (treatment) is the process of bestowing normalcy which is either brought by Shodhana (purificatory) or Shamana (palliative) Karma. Snehapana is a pre-operative procedure for Shodhana Chikitsa where in Sneha Dravya (medicated fat) is administered for attainment of Upasthita Dosha Avastha and further ease in elimination of the vitiated Doshas. Assessment of Dosha, Dushya, Vyadhi Avastha, Roga Bala, Rogi Bala, Agni, Koshta etc. factors are essential for the attainment of Chikitsa Phala. Assessment of Agni not only helps in understanding Vyadhi but also enables to plan the dosage of Sneha to be administered. Thus this paper is an attempt to throw light on the importance of Agni, assessment of Agni and Agni Bala prior to Shodhananga Snehapana.


2017 ◽  
Vol 05 (02) ◽  
pp. 084-089
Author(s):  
Alisha Dhingra ◽  
Ashu Gupta ◽  
Anshu Minocha ◽  
Nayantara Sen

Abstract Aim: The aim of this study was to compare the reversal of shear bond strength of composite to bleached enamel immediately after bleaching followed by application of various antioxidant solutions. Material and Methods: Seventy central incisors were divided into seven groups. Groups I and II served as unbleached and bleached controls respectively. Groups III, IV, V, VI and VII served as the experimental groups and were subjected to 37.5% hydrogen peroxide bleaching followed by 10 min application of 10% sodium ascorbate, 25% alpha-tocopherol, 6.5% grape seed extract, 5% lycopene and 5% green tea extract respectively. Following composite bonding, shear bond strength was determined and the results were analyzed using ANOVA followed by Post Hoc Multiple Comparisons test. Results: The bond strength values for Group I (positive control) were maximum and significantly different than all the other groups except Grape seed extract group (Group V). When compared to Group II (bleached control), all the groups showed significantly higher bond strength. Significant difference in the bond strength values were seen between Group III (10% sodium ascorbate) and Group V. Also values for Group V were significantly different from Group VI (5% lycopene). All the other values showed insignificantly different results. Conclusion: All the antioxidant solutions improved the shear bond strength values after bleaching but only Grape seed extract application reversed the values to the non bleached levels. Lycopene was least effective. Other antioxidants showed comparable results.


Animals ◽  
2021 ◽  
Vol 11 (2) ◽  
pp. 309
Author(s):  
Deise Aline Knob ◽  
André Thaler Neto ◽  
Helen Schweizer ◽  
Anna C. Weigand ◽  
Roberto Kappes ◽  
...  

Crossbreeding in dairy cattle has been used to improve functional traits, milk composition, and efficiency of Holstein herds. The objective of the study was to compare indicators of the metabolic energy balance, nonesterified fatty acids (NEFA), beta-hydroxybutyrate (BHBA), glucose, body condition score (BCS) back fat thickness (BFT), as well as milk yield and milk composition of Holstein and Simmental cows, and their crosses from the prepartum period until the 100th day of lactation at the Livestock Center of the Ludwig Maximilians University (Munich, Germany). In total, 164 cows formed five genetic groups according to their theoretic proportion of Holstein and Simmental genes as follows: Holstein (100% Holstein; n = 9), R1-Hol (51–99% Holstein; n = 30), first generation (F1) crossbreds (50% Holstein, 50% Simmental; n = 17), R1-Sim (1–49% Holstein; n = 81) and Simmental (100% Simmental; n = 27). The study took place between April 2018 and August 2019. BCS, BFT blood parameters, such as BHBA, glucose, and NEFA were recorded weekly. A mixed model analysis with fixed effects breed, week (relative to calving), the interaction of breed and week, parity, calving year, calving season, milking season, and the repeated measure effect of cow was used. BCS increased with the Simmental proportion. All genetic groups lost BCS and BFT after calving. Simmental cows showed lower NEFA values. BHBA and glucose did not differ among genetic groups, but they differed depending on the week relative to calving. Simmental and R1-Sim cows showed a smaller effect than the other genetic groups regarding changes in body weight, BCS, or back fat thickness after a period of a negative energy balance after calving. There was no significant difference for milk yield among genetic groups, although Simmental cows showed a lower milk yield after the third week after calving. Generally, Simmental and R1-Simmental cows seemed to deal better with a negative energy balance after calving than purebred Holstein and the other crossbred lines. Based on a positive heterosis effect of 10.06% for energy corrected milk (ECM), the F1, however, was the most efficient crossbred line.


2020 ◽  
Vol 98 (Supplement_3) ◽  
pp. 238-238
Author(s):  
Olivia Harrison ◽  
Samantha Tauer ◽  
Brent Frederick

Abstract Number of pigs born alive has been a key factor of the increasing efficiency of the U.S. swine industry. However, with increased pigs in the uterus, birth weight has been negatively impacted, with more small or at-risk pigs being born per litter. In order to overcome these changes, a study testing three commercial oral drenches against a control to determine which would increase average daily gain and decrease preweaning mortality. In a completely randomized design, 877 one-day-old suckling pigs from a high-health farm were selected for the experiment if they appeared to be in the bottom 20% of bodyweight compared to their contemporaries. Selected pigs were given one of four drenching treatments: 1) none (control), 2) bioactive proteins (BP), 3) high energy sugars (HES), and 4) immunoglobulins (IgY). Pigs were weighed on d 1 and d 19 of age (weaning), with mortality tracked during the suckling period. Data were analyzed using SAS v 9.4 (Cary, NC), with pig as the experimental unit and an accepted alpha of 0.05. Treatment had no detected effect on birth weight, weaning weight, ADG, or mortality (P = 0.79, 0.96, 0.86, 0.38 respectively). Likewise, statistical contrasts were used to determine there was no detected impact (P &gt; 0.10) of drench, regardless of type, compared to the control in any measured response criteria. Interesting, pigs drenched with BP or IgY had numerically lower preweaning mortality (11.2 and 11.5% respectively), than those administered the control or HES (15.4 and 15.2%, respectively). In conclusion, this experiment showed no significant difference in the performance between piglets given no product vs. those drenched with bioactive proteins, high energy sugars, or immunoglobulins. However, additional research is warranted with greater replication or disease stressors to better understand if oral drenches may improve preweaning performance or mortality in different situations.


2011 ◽  
Vol 142 ◽  
pp. 233-237
Author(s):  
Han Wen Yuan ◽  
Fang Chen ◽  
Qiao Qing Xu ◽  
Shi Yuan Gong ◽  
Zhang Jie Chu ◽  
...  

The effects of stocking density on various growth parameters and sex reversal in the rice field eel (Monopterus albus) were investigated by evaluating steroid hormone, the gonadosomatic index (GSI) and sex ratio. Fish (mean initial weight of 9.88 ± 0.70 g) were stocked to densities of 4, 20, 36, 52, 68, 84 or 100 fish/m2 in cages (2 m × 1 m × 1.5 m) in a pond, with five replicate cages for each density. Fish were fed for 420 days on a formulated isocaloric diet containing 40.22% crude protein and 12.86 MJ/kg. Serum E2 and T concentrations were determined by radioimmunoassays. There were no significant differences in final bodyweight (FBW) and daily weight gain (DWG) for fish in the groups containing less than 52 fish/m2, while FBW and DWG were significant lower in groups at 68 fish/m2 or more. Specific growth rate (SGR) differed significantly between the 84 and 100 fish/m2 groups compared with the 4, 20 and 36 fish/m2 groups. There was no significant difference in SGR in groups containing less than 84 fish/m2. There were no significant difference between the 4 and 20 fish/m2 groups in net yield (NY), but these groups did differ significantly from the other groups. The final condition factors of fish stocked at 84 or 100 fish/m2 were significantly lower than fish stocked at the other densities. E2 and T hormone concentrations declined as stocking density increased, while GSI values increased initially but then reduced with increasing stocking density. Female ratio and survival decreased with increasing stocking density. The proportion of male fish was significantly greater in the three highest stocking density groups. Therefore, high stocking density may promote sex change from female to male in M. albus.


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