Intriguingly, among the 97 patients receiving allogeneic HSCT, either in first CR (n = 45) or beyond (n = 52), the poor prognostic impact of SF mutation on OS and DFS was lost (P = 0.439 and P = 0.348, respectively). It seems that HSCT may ameliorate the poor survival impact of SF mutations, similar to RUNX1 mutations.[12, 13] However, because the number of patients who had SF mutations and received HSCT was limited in our cohort, further studies in more patients are needed to clarify this point.
Few studies regarding the prognostic relevance of SF mutations in de novo AML have been reported. In a study of Taskesen et al, only one distinct SF-mutant patient cluster enriched for NRAS/KRAS mutation (cluster 3, 7.3% of 344 patients) had poorer prognosis. Patients with isolated trisomy 13 reported by Herold et al, in whom high frequencies of mutations in SRSF2 (81%) and RUNX1 (75%) were noted, had a dismal outcome.[16] In this study, we distinctly identified that SF mutation was an important prognostic factor, independent from all other variables in both total cohort and patients with intermediate-risk cytogenetics. Although SF3B1 mutations have been shown to predict better OS in MDS patients,[3, 19, 23, 24] we found the mutation was associated with a lower CR rate (Supplementary Table 2A) and shorter survival in de novo AML patients (Supplementary Figure 1A, B). The reason why SF3B1 mutation has different impact on clinical outcome between patients with MDS and AML remains to be explored. In fact, the reports concerning the prognostic impact of SF3B1 mutation in MDS showed inconsistent and conflicting results.[3, 19, 23, 24] The good prognostic impact of SF3B1 mutation could not be demonstrated in MDS patients in some studies.[3, 19, 23, 24] It was suggested the close association of SF3B1 mutation with old age and DNMT3A mutation and different treatment regimens might influence the implication of this mutation on survival of MDS patients.[19, 24] In AML, Lindsley et al[25] first showed that SF mutations as well as ASXL1, EZH2, BCOR, and STAG2 mutations were highly specific for secondary AML, and were secondary-type mutations in therapy-related AML and elderly de novo AML that defined a distinct subgroup of patients with poor outcome. In this study, we only recruited de novo AML patients, the same cohort as we reported previously.[14, 15] Secondary AML patients were carefully excluded and SF mutations in this study were closely associated with intermediate-risk cytogenetics, but not poor-risk cytogenetics or complex karyotype, which is frequently seen in secondary AML. The findings from this study reflected the poor prognostic implication of SF mutations in de novo AML patients.
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Intriguingly, the poor prognostic impact of SF mutation in OS and DFS was lost if the patients received allogeneic HSCT. In other words, HSCT may ameliorate the poor survival impact of SF mutations. Further studies in more patients are needed to clarify this point. To better stratify AML patients into different risk groups, a survival scoring system incorporating SF mutation and ten other prognostic factors, including age, WBC counts, cytogenetics, NPM1/FLT3-ITD, CEBPA, IDH2, RUNX1, WT1, DNMT3A and TP53 mutations, into survival analysis was formulated. Indeed, this scoring system was more powerful than single marker to separate patients into different prognostic groups. Further studies in independent cohorts are needed to validate the clinical implication of the proposed scoring system.
There was one potential flaw and limitation in this study. We did not analyze the mutations of all 21 spliceosome genes; the results we obtained might only reflect the clinical relevance of mutations in the three SF genes we analyzed. However, SF3B1, U2AF1 and SRSF2 mutations are the most frequent SF mutations in myeloid neoplasms and can be easily detected by Sanger's sequencing.[2, 11] The finding that mutations in these three SF genes predict poor prognosis suggests routine test of these mutations may be helpful in the clinical management of AML patients.
A soil sample has been done by a technician from Trugreen according them my soil need phosphorus 2 lbs / 1000 sq ft and potassium 1 lbs / 1000 sq ft. He told us the lack of Phosphorus in the soil results an poor growth an color of the grass. I tried to buy this at local stores like Lowes and Home depot. But they cannot help me. I tried to find it online, but also without any result. Do you have any idea where to buy Phosphorus and Potassium ?
make sure you have a soil test done to analyze this. You may or may not have a phosphorus deficiency. Adding more than is needed can result in poorly performing crops and harmful runoff into watersheds. So before you add any chemicals, find out what is really needed. The only way to do that is to have your soil tested while giving them the information on what you plan to grow.As for what type of phosphorus to use, just select a brand that sells it in a fertilizer mixture created for agriculture.
One of the benefits of FFPE samples is that these are stable at room temperature and amenable for long-term storage10. Standardized methods for FFPE preparation have led to accumulation of large FFPE sample archives worldwide. In addition, availability of long-term clinical follow-up data makes these archives particularly attractive. Nevertheless, gene expression analysis on FFPE samples is challenging because RNA extracted from FFPE material is of very poor quality, impairing detection sensitivity7,11,12.
Cancer is one of the foremost causes of death globally. Despite efforts to mitigate risk factors in recent decades, the prevalence of cancer is continuing to increase [1]. Current standards of care combine precise staging of cancer with chemotherapy, radiotherapy, and/or surgical resection. Radiotherapy and chemotherapy are known for significant adverse effects [2], with most methods targeting non-specifically any rapidly dividing cells irrespective of whether they are tumorous or not. Furthermore, poor pharmacokinetic characteristics of anticancer drugs arising from poor solubility, stability, and metabolism pose different challenges of toxicity, inefficacy and limited bio-distribution. Thus, it is imperative to develop effective formulations that can address the above cited challenges and provide selective targeting of tumor sites without significant damage to the viability of healthy tissues [3,4,5,6,7,8,9].
Among B cell ALL, Ph-like ALL is a newly identified aggressive subtype that is characterized by a genomic signature similar to Ph-positive ALL, however, without the presence of BCR-ABL1 rearrangement [83,84,85]. The incidence of Ph-like ranges from 15% in pediatric ALL to > 50% among young adults of Hispanic ethnicity [86]. Prognosis is poor with an estimated survival of IKZF1 deletions are commonly found in Ph-like ALL ( 70%) [85, 86]. More than half of patients have cytokine receptor-like factor 2 (CRLF2) rearrangement, among whom, 50% have concomitant activating mutations of Janus kinases (JAK1, JAK2, and JAK3). In patients without CRLF2 rearrangement/overexpression, genomic profiling may identify a variety of kinase-activating alterations, including rearrangements in ABL class genes (e.g., ABL1, ABL2, CSF1R, PDGFRA, and PDGFRB), EPOR, JAK2, and mutations involving FLT3, IL7R, or SH2B3, among others [88]. Adult patients with Ph-like ALL treated with conventional cytotoxic regimens, not only have approximately half the rate of MRD negativity, but their outcomes remain poor even when MRD negativity is achieved [89]. Whether the addition of novel agents (InO or blinatumomab) or HSCT is superior to intensive chemotherapy remains uncertain and this represents an area of active research. Notably, there may be a role for TKIs or other targeted therapies in a subset of patients with targetable fusions (e.g., dasatinib for ABL gene alterations; NCT02420717) [87, 90]. Given the prevalence of JAK/STAT alterations in Ph-like ALL, a few studies of ruxolitinib combination with chemotherapy are ongoing (NCT03117751, NCT02420717), although it is uncertain how beneficial this approach may be, as preclinical data suggests that lymphoblasts may not be dependent on continued activation of this pathway for maintenance of the malignant phenotype [91].
The advent of MRD assessment has refined the treatment landscape of ALL. Persistent MRD is generally considered an indication for HSCT in CR1 [106, 135, 136, 140, 146]. However, outcomes remain poor for patients with MRD positivity even when HSCT is performed. It is currently unclear whether patients who clear their MRD with blinatumomab or other novel agents would still derive benefit from HSCT. A post hoc analysis of the BLAST trial showed no difference in RFS or OS rates between patients who underwent HSCT after receiving blinatumomab and those who did not [15]. However, numbers were small and the equivalent survival outcome may be explained, at least partly, by the fact that HSCT-related mortality may offset the decreased relapse risk seen with HSCT. Furthermore, the role of consolidative HSCT after CAR T cell therapy remains controversial despite being favored by most experts, especially in HSCT-naive and fit patients [150].
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We first analyzed the reproducibility and reliability of retinal OCT measurements in mice. Altogether, volume scans offered the best results, while the poorest were obtained with the peripapillary ring scans which, in fact, have been studied as an outcome parameter in animal models of MS [29]. A possible explanation is that the variability of the segmentation of single B-scans is averaged out when analyzing the mean of the 49 scans making up the volume scan. Our data indicate that in mice, the separate assessment of the RNFL and GCIPL thickness can be challenging, since the segmentation of the limit between them is not very reproducible. We, therefore, also analyzed them jointly as the IRL, which yielded much more robust results. Another advantage of evaluating these layers together is that it reflects a combined outcome parameter for axonal (RNFL) and neuronal (GCIPL) loss. 2ff7e9595c
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