Forty patients, with mainly poor risk haematological malignancies, were given the new regimen FLAG, comprising fludarabine, arabinosyl cytosine and G-CSF. Twenty four patients had acute myeloid leukaemia (AML), 8 patients myelodysplastic syndrome (MDS) and a further 8 patients had a variety of other haematological malignancies. The response rates for 19 relapsed and 4 refractory AML patients were 68% and 100% respectively and comparable to those attained using other regimens, although the numbers are small. Of 8 patients with MDS, 7 showed some response with 4 remaining in an improved disease status 5-12 months after FLAG. Follow-up has been too short thus far to provide any survival data in both patient groups. In general, the other smaller group of 8 patients (3 transformed chronic myeloid leukaemia (CML), 3 acute lymphoblastic leukaemia (ALL), 2 granulocytic sarcoma (GS) did poorly with response shown in 1 only. The regimen was well tolerated with 4 procedure-related neutropenic deaths. The neutropenic and thrombocytopenic periods are generally short when compared with those from current protocols. The overall modest toxicity may encourage combination with other anti-leukaemic agents and be of particular use in the aged or heavily pre-treated patients. Preliminary results may favour the setting up of controlled trials to properly evaluate the benefit of FLAG.
Passively collected smartphone sensor data provide an opportunity to study physical activity and mobility unobtrusively over long periods of time and may enable disease monitoring in people with amyotrophic lateral sclerosis (PALS).
The next generation of coal-fired boilers targeted for both the domestic and overseas markets must meet and maintain very low emission levels in order to be competitive. Cost of electricity and generation cycle efficiency will also be market drivers. To meet this challenge and to maximize the use of tried and true coal-fired steam cycle technology, Babcock & Wilcox (B&W) and the U.S. Department of Energy are partnering to demonstrate break-through emission control technologies capable of less than 0.1 lb NO{sub x}/MBtu fired (without the added financial burden of backend NO{sub x} cleanup). The key to the B&W approach is the use of advanced diagnostics to measure and control key process parameters during deeply staged combustion. Per burner air/fuel ratio control is achieved by advanced processing of flame scanner signals combined with an advanced burner design. The resulting computer-controlled system is analogous to automobile engine diagnostic systems introduced in recent years. This paper will cover the conceptual design and preliminary tests of LEBS NO{sub x} control diagnostics components in test facilities and existing boilers. Implications of the preliminary results on future testing and commercial designs will also be discussed.
Background: Passively collected smartphone sensor data provides an opportunity to study physical activity and mobility unobtrusively over long periods of time and may enable disease monitoring in people with ALS (PALS).Methods: Forty-five PALS were enrolled. The Beiwe application passively collected participants’ smartphone accelerometer and GPS data and administered the self-entry ALS Functional Rating Scale-Revised (ALSFRS-RSE) survey. We used a validated, open-source walking recognition method to identify individual steps from subsecond-level accelerometer data and used the Activity Index measure to aggregate those data at the minute level. Walking, Activity Index and GPS outcomes were then aggregated as day-level (24-hour) measures. We used linear mixedeffects models (LMMs) to estimate baseline and monthly change for ALSFRS-RSE scores (total score, subscores Q13, Q4-6, Q7-9, Q10-12) and day-level measures of smartphone sensor data, as well as the associations between them.Findings: The analysis sample (N = 45) was 64.4% male with a mean age of 60.1 years (SD = 10.7). The mean observation period was 292.3 days (SD = 87.4). The mean number of days included in the analysis sample was 113.7 days (SD = 58.9) for accelerometer data and 217.4 days (SD = 86.4) for GPS data. The LMM-estimated ALSFRS-RSE total score baseline mean was 35.8 and had a monthly rate of decline -0.48 (p-value < 0.001). We observed statistically significant change over time and association with ALSFRS-RSE total score for four smartphone sensor data-derived measures: walking cadence from top 1 minute and log-transformed step count, step count from top 1 minute, and Activity Index from top 1 minute.Interpretation: In a functionally heterogeneous group of PALS, passively collected smartphone accelerometer and GPS data can characterize daily physical activity, mobility, and functional change over time.Funding: This research was supported in part by Mitsubishi Tanabe Pharma Corporation.Declaration of Interest: Marta Karas – reports no competing interests. Julia Olsen – reports no competing interests. Stephen A. Johnson – reports research support from the ALS Association. Marcin Straczkiewicz – reports no competing interests. Katherine M. Burke – reports no competing interests. Satoshi Iwasaki – employee of Mitsubishi Tanabe Pharma Holdings America, Inc. Amir Lahav – paid strategic advisor for digital health at Mitsubishi Tanabe Pharma America, Inc. He has been paid for consulting services for Pfizer, Redenlab, Curebase, Castor, Lapsi Health, Solo AI, Quantificare, Modality AI, Videra Health, Neuralight, and the Global Platform Alzheimer’s Foundation. Zoe A. Scheier – reports no competing interests. Alison P. Clark – reports no competing interests. Amrita S. Iyer – reports no competing interests. Emily Huang – reports no competing interests. James D. Berry – reports research support from Biogen, MT Pharma Holdings of America, Transposon Therapeutics, Alexion, Rapa Therapeutics, ALS Association, Muscular Dystrophy Association, ALS One, Tambourine, ALS Finding a Cure. He has been a paid member of an advisory panel for Regeneron, Biogen, Clene Nanomedicine, Mitsubishi Tanabe Pharma Holdings America, Inc., Janssen, RRT. He received an honorarium for educational events for Projects in Knowledge and the Muscular Dystrophy Association. He has unpaid roles on the advisory boards for the non-profits Everything ALS and ALS One. Jukka-Pekka Onnela – reports no competing interests.Ethical Approval: Approvals from the Institutional Review Board (IRB) at Massachusetts General Brigham (MGB) and the Information Security Office at Massachusetts General Hospital (MGH) were obtained before study initiation. All data collection and management adhered to MGB, state, and national guidelines and regulations. Participants provided informed consent prior to engaging in study procedures.
We report a case of chronic lymphocytic leukaemia (CLL) with telomeric associations and a p53 intronic point mutation. Karyotypic analysis revealed clonal and non-clonal telomeric associations, accompanied by clonal cytogenetic abnormalities and also in isolation. The p53 mutation, which occurred at the invariant base pair -2 of the splice acceptor site in intron 7 resulted in the abolition of correct splicing of exon 7 to exon 8. Multiple aberrant splice products were characterized, all of which differed from wildtype in the DNA binding domain. Fluorescence in situ hybridization demonstrated that the clone retained two copies of the p53 gene and wild-type p53 transcript was detected on cloning of reverse transcriptase polymerase chain reaction (RT-PCR) product, indicating that one wild-type allele remained. However, a plasmid clone with correct splicing at the exon 7/8 boundary, but with a 21 bp deletion in exon 8, was also found at low frequency. This finding indicates clonal evolution, resulting in complete loss of wild-type p53. The intronic point mutation was not present in DNA extracted from cervical tissue indicating that it was a leukaemic phenomenon. This is the first case of an intronic point mutation to be reported in CLL. This mutation led to chaotic p53 expression and, interestingly, occurred in a case showing telomeric associations, a rare phenomenon in B-CLL.
The zinc, content of serum was consistently higher than the zinc concentration in plasma by an average of 16%. Because platelets are largely disintegrated in the clotting process, zinc was determined in platelets concentrated from 10 individuals and was present in a significant amount. It was demonstrated that 39% of the increased concentration of zinc in serum can be attributed to a slightly greater dilution in plasma, 44% being derived from platelets and 4.0% from hemolysis. This is the first known report demonstrating zinc in platelets.
The nucleoside analogues are a group of antimetabolite cytotoxics which generally have to be metabolised to the equivalent nucleotide before incorporation into DNA. Cytarabine is a well established component of the treatment of acute leukaemias and has its principal action on dividing cells. New formulations include a liposome encapsulated product for intrathecal use and oral cytarabine ocfosfate which may be suitable for long-term out-patient use. Pentostatin acts by causing accumulation of deoxynucleotides and, although active against hairy cell leukaemia, is associated with a poor tolerance profile. Cladribine and fludarabine have substantial activity in the treatment of chronic lymphocytic leukaemia (CLL) and low-grade non-Hodgkin's lymphoma (NHL). Fludarabine is the more thoroughly investigated of the two and is currently being developed in combination therapies for CLL and NHL and also in a combination with cytarabine for acute myeloid leukaemia. Fludarabine's immunosuppressive activity is being exploited in the conditioning of patients for non-myeloablative stem cell transplantation. Gemcitabine is an established agent in the treatment of a number of solid tumours but also has activity in haematological malignancies which might be exploited by the use of extended infusion schedules. Newer agents including nelarabine, clofarabine and troxacitabine are undergoing clinical evaluation and show promising activity.
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