Comparison of acute myeloid leukemia and myelodysplastic syndromes with TP53 aberrations.

TP53 aberrations are found in approximately 10% of patients with acute myeloid leukemia (AML) and myelodysplastic syndromes (MDS) and are considered early driver events affecting leukemia stem cells. In this study, we compared features of a total of 84 patients with these disorders seen at a tertiary cancer center. Clinical and cytogenetic characteristics as well as immunophenotypes of immature blast cells were similar between AML and MDS patients. Median overall survival (OS) was 226 days (95% confidence interval [CI], 131-300) for the entire cohort with an estimated 3-year OS rate of 11% (95% CI, 6-22). OS showed a significant difference between MDS (median, 345 days; 95% CI, 235-590) and AML patients (median, 91 days; 95% CI, 64-226) which is likely due to a different co-mutational pattern as revealed by next-generation sequencing. Transformation of TP53 aberrant MDS occurred in 60.5% of cases and substantially reduced their survival probability. Cox regression analysis revealed treatment class and TP53 variant allele frequency as prognostically relevant parameters but not the TP53-specific prognostic scores EAp53 and RFS. These data emphasize similarities between TP53 aberrant AML and MDS and support previous notions that they should be classified and treated as a distinct disorder.

The critical need to accelerate cerebral palsy research with consumer engagement, global networks, and adaptive designs.

The prevalence of cerebral palsy (CP) varies globally, with higher rates and burden of disease in low- and middle-income countries. CP is a lifelong condition with no cure, presenting diverse challenges such as motor impairment, epilepsy, and mental health disorders. Research progress has been made but more is needed, especially given consumer demands for faster advancements and improvements in the scientific evidence base for interventions. This paper explores three strategies to accelerate CP research: consumer engagement, global clinical trial networks, and adaptive designs. Consumer engagement involving individuals with lived experience enhances research outcomes. Global clinical trial networks provide efficiency through larger and more diverse participant pools. Adaptive designs, unlike traditional randomized controlled trials, allow real-time modifications based on interim analyses, potentially answering complex questions more efficiently. The establishment of a CP Global Clinical Trials Network, integrating consumer engagement, global collaboration, and adaptive designs, marks a paradigm shift. The Network aims to address consumer-set research priorities. While challenges like ethical considerations and capacity building exist, the potential benefits for consumers, clinicians, researchers, and funding bodies are substantial. This paper underscores the urgency of transforming CP research methodologies for quicker translation of novel treatments into clinical practice to improve quality of life for those with CP.

The classical progesterone receptor mediates the rapid reduction of fallopian tube ciliary beat frequency by progesterone.

BACKGROUND: The transport of gametes as well as the zygote is facilitated by motile cilia lining the inside of the fallopian tube. Progesterone reduces the ciliary beat frequency within 30 minutes in both cows and mice. This rapid reduction suggest the involvement of a non-genomic signaling mechanism, although it is not known which receptors that are involved. Here we investigated the possible involvement of the classical progesterone receptor in this process. METHOD: The ciliary beat frequency of mice fallopian tube was measured ex vivo using an inverted bright field microscope and a high speed camera. The effects of the agonists progesterone and promegestone and an antagonist, mifeprestone, were investigated in wildtype mice. The effect of progesterone was also investigated in mice lacking the classical progesterone receptor. RESULTS: Progesterone, as well as the more specific PR agonist promegestone, significantly reduced the CBF at concentrations of 10-100 nanomolar within 10-30 minutes. In the absence of progesterone, the PR antagonist mifeprestone had no effect on the ciliary beat frequency at a concentration of 1 micromolar. When ciliated cells were pre-incubated with 1 micromolar mifeprestone, addition of progesterone did not reduce the ciliary beat frequency. Accordingly, in ciliated cells from mice not expressing the classical progesterone receptor, exposure to 100 nanomolar progesterone did not reduce the ciliary beat frequency. CONCLUSIONS: This is the first study to provide comprehensive evidence that the classical progesterone receptor mediates the rapid reduction of the tubal ciliary beat frequency by progesterone.

Germline mutations in the DNA damage response genes BRCA1, BRCA2, BARD1 and TP53 in patients with therapy related myeloid neoplasms.

BACKGROUND: Therapy related myeloid neoplasms (t-MNs) are complex diseases originating from an interplay between exogenous toxicities and a susceptible organism. It has been hypothesised that in a subset of cases t-MNs develop in the context of hereditary cancer predisposition syndromes. METHODS: The study systematically evaluated pedigrees of patients with t-MNs for cancer incidences and the possibility of a hereditary cancer predisposition syndrome. In addition, mutational analyses were performed using constitutional DNA from index patients, and deleterious heterozygous germline mutations were assessed for loss of heterozygosity in sorted leukaemic cells by single nucleotide polymorphism array. RESULTS: A nuclear pedigree was obtained in 51/53 patients with t-MNs resulting in a total of 828 individuals analysed. With a standardised incidence ratio of 1.03 (95% CI 0.74 to 1.39), the tumour incidence of first- degree relatives was not increased. However, six pedigrees were suggestive for a hereditary breast and ovarian cancer syndrome, three of a Li-Fraumeni like syndrome, and three index patients showed multiple primary neoplasms. Mutational analysis revealed two BRCA1 (c.3112G→T, c.5251C→T), one BRCA2 (c.4027A→G), two BARD1 (C557S) and four TP53 germline mutations (g.18508_18761delinsGCC, c.847C→T, c.845_848dupGGCG, c.1146delA) in nine of 53 (17%) index patients with t-MNs. Loss of heterozygosity in leukaemic cells was demonstrated for the BRCA1c.3112G→T and TP53c.845_848dupGGCG mutations, respectively. CONCLUSION: It is concluded that a proportion of patients with t-MNs carry cancer susceptibility mutations which are likely to contribute to therapy related leukaemogenesis.

Frequency, onset and clinical impact of somatic DNMT3A mutations in therapy-related and secondary acute myeloid leukemia.

The recent identification of DNMT3A mutations in de novo acute myeloid leukemia prompted us to determine their frequency, patterns and clinical impact in a cohort of 98 patients with either therapy-related or secondary acute myeloid leukemia developing from an antecedent hematologic disorder. We identified 24 somatic mutations in 23 patients with a significantly higher frequency in secondary acute myeloid leukemia (35.1%) as compared to therapy-related acute myeloid leukemia (16.4%, P=0.0486). DNMT3A mutations were associated with a normal karyotype and IDH1/2 mutations, but did not affect survival. In contrast to de novo acute myeloid leukemia, most mutations did not affect arginine on position 882, but were predominantly found in the methyltransferase domain. All DNMT3A mutations identified in secondary acute myeloid leukemia were already present in the antecedent disorders indicating an early event. Reduction to homozygosity by uniparental disomy was observed in 2 patients with secondary acute myeloid leukemia during disease progression.

Low cerebrospinal fluid sulfatide predicts progression of white matter lesions: The LADIS study.

BACKGROUND/AIMS: Demyelination and axonal degeneration are the hallmarks of established white matter lesions (WML). The neurochemistry of ongoing WML is only partially known. We explored cerebrospinal fluid (CSF) substances as markers of brain tissue damage in relation to progression of WML rated on magnetic resonance imaging. METHODS: CSF from elderly individuals with WML was analyzed for amyloid markers, total τ, hyperphosphorylated τ, neurofilament protein light subunit, sulfatide and CSF/serum-albumin ratio. After 3 years, a follow-up magnetic resonance imaging was performed. Progression of WML was rated using the Rotterdam Progression Scale (RPS). RESULTS: 37 subjects (age 73.6 ± 4.6 years) were included. Subjects with more pronounced progression (RPS > 2; n = 15) had lower mean sulfatide concentration at baseline as compared to subjects with no or minimal progression (RPS 0-2; n = 22) according to univariate analyses (p = 0.009). Sulfatide was the only biomarker that predicted the RPS score according to regression analysis, explaining 18.9% of the total variance (r = 0.38, p = 0.015). CONCLUSION: The correlation of CSF sulfatide levels and RPS scores may reflect a remyelination response to the demyelination process associated with WML. Furthermore, the results strengthen the notion that WML pathology is different from that of Alzheimer's disease.

Western Ontario Osteoarthritis Shoulder (WOOS) index: a cross-cultural adaptation into Swedish, including evaluation of reliability, validity, and responsiveness in patients with subacromial pain.

BACKGROUND: The aim of the present study was to translate the Western Ontario Osteoarthritis Shoulder (WOOS) index into Swedish and to test its validity, reliability, and responsiveness in patients with subacromial pain. METHODS: The validity of the WOOS translation was tested in 54 patients who completed the WOOS and the Shoulder Rating Questionnaire, Swedish version (SRQs). Of these patients, 46 were retested to assess reliability. Responsiveness was evaluated in 29 subjects who completed the WOOS and SRQs before surgery and again at 3 months after surgery, when they also rated perceived change in shoulder function. The relationship between the questionnaires and patient-perceived improvement was assessed. RESULTS: A high correlation was found between the Swedish version of WOOS and the SRQs. The correlations were similar in a group of working patients (r = -0.832) and in all patients (r = -0.843; P < .001). A high degree of agreement between WOOS at test and retest was also observed. A Bland-Altman plot showed a small mean difference and no trend across the range of WOOS values. A strong significant agreement was also shown by a κ value of 0.649 (P < .001) and an intraclass correlation coefficient of 0.95 (95% confidence interval, 0.92-0.97, P < .001) as well as by a low difference between the test and retest means. Responsiveness, calculated by standardized response mean, was excellent (1.02). CONCLUSION: The results of the present study provide evidence that the Swedish version of WOOS is valid, reliable, and responsive in patients with subacromial pain and performs similarly to the original Canadian version.

Time for order in chaos! A health system framework for foreign medical teams in earthquakes.

The number of reported natural disasters is increasing, as is the number of foreign medical teams (FMTs) sent to provide relief. Studies show that FMTs are not coordinated, nor are they adapted to the medical needs of victims. Another key challenge to the response has been the lack of common terminologies, definitions, and frameworks for FMTs following disasters.In this report, a conceptual health system framework that captures two essential components of health care response by FMTs after earthquakes is presented. This framework was developed using expert panels and personal experience, as well as an exhaustive literature review.The framework can facilitate decisions for deployment of FMTs, as well as facilitate coordination in disaster-affected countries. It also can be an important tool for registering agencies that send FMTs to sudden onset disasters, and ultimately for improving disaster response.

The Cognitive Assessment Battery (CAB): a rapid test of cognitive domains.

BACKGROUND: The study aimed to evaluate the Cognitive Assessment Battery (CAB) in a specialist clinic setting in order to find out if it if it could be a supplement to the Mini-mental State Examination (MMSE) and distinguish between normal aging, mild cognitive impairment (MCI) and dementia, as well as MCI of different severities. METHODS: CAB consists of six short tests covering the cognitive domains of speed/attention, episodic memory, visuospatial functions, language and executive functions. It takes about 20 minutes to carry out and provides a quick overview of the patient's cognitive profile. Three groups were compared: healthy controls (N = 41), MCI (N = 83) and mild dementia (N = 28). RESULTS: CAB distinguished very clearly between controls and MCI as well as MCI and dementia. On further analysis CAB also distinguished between MCI of different severities. It also showed to have good sensitivity and specificity for identifying more severe MCI. CONCLUSIONS: CAB seems to be a useful supplement to MMSE and a screening instrument for MCI and dementia with good sensitivity and specificity.

3D NLTE spectral line formation of lithium in late-type stars.

Accurately known stellar lithium abundances may be used to shed light on a variety of astrophysical phenomena such as big bang nucleosynthesis, radial migration, ages of stars and stellar clusters, and planet engulfment events. We present a grid of synthetic lithium spectra that are computed in non-local thermodynamic equilibrium (NLTE) across the stagger grid of three-dimensional (3D) hydrodynamic stellar atmosphere models. This grid covers three Li lines at 610.4, 670.8, and 812.6 nm for stellar parameters representative of FGK-type dwarfs and giants, spanning T eff = 4000-7000 K, log g = 1.5-5.0, [Formula: see text]-0.5, and A(Li) = -0.5-4.0. We find that our abundance corrections are up to 0.15 dex more negative than in previous work, due to a previously overlooked NLTE effect of blocking of UV lithium lines by background opacities, which has important implications for a wide range of science cases. We derive a new 3D NLTE solar abundance of A(Li) = 0.96 ± 0.05, which is 0.09 dex lower than the commonly used value. We make our grids of synthetic spectra and abundance corrections publicly available through the breidablik package. This package includes methods for accurately interpolating our grid to arbitrary stellar parameters through methods based on Kriging (Gaussian process regression) for line profiles, and multilayer perceptrons (a class of fully connected feedforward neural networks) for NLTE corrections and 3D NLTE abundances from equivalent widths, achieving interpolation errors of the order of 0.01 dex.

Thyroid hormones are associated with poorer cognition in mild cognitive impairment.

BACKGROUND: Alterations in interrelated endocrine axes may be related to the pathogenesis of mild cognitive impairment (MCI) and dementia. METHODS: Salivary cortisol before and after a 0.5-mg dexamethasone test, and serum levels of thyroid-stimulating hormone, total thyroxine (T(4)), free T(4), total triiodothyronine (TT(3)), estradiol, testosterone and insulin-like growth factor 1 were measured in 43 MCI cases and 26 healthy controls. All participants underwent a comprehensive neuropsychological test battery covering the cognitive domains of speed/attention, memory, visuospatial functions, language and executive functions. RESULTS: The MCI group did not differ in basal levels of endocrine markers compared to controls. Among those with MCI, TT(3) levels were inversely associated with cognitive performance across all domains. After stratifying MCI cases according to TT(3) levels, those with relatively high TT(3) levels showed impairment in memory as well as in visuospatial and executive functions. Those with TT(3) levels at or below the lower boundary of the normal range performed comparably to healthy controls. Other endocrine markers were not related to cognitive performance. CONCLUSIONS: Among those with MCI, TT(3) was associated with a neuropsychological profile typical of prodromal Alzheimer's disease. While the mechanisms remain unclear, optimal levels of thyroid hormone under a compromising condition such as MCI and related neuropathology need reconsideration.

Subcortical vascular dementia biomarker pattern in mild cognitive impairment.

BACKGROUND: Mild cognitive impairment (MCI) is an etiologically unclear disorder. Cerebrospinal fluid (CSF) biomarkers are potentially useful for the differentiation between various MCI etiologies. AIM: The aim of the study was to assess whether baseline CSF hyperphosphorylated tau (P-tau), total tau (T-tau), amyloid beta 1-42 (Abeta(42)) and neurofilament light (NF-L) in patients with MCI could predict subcortical vascular dementia (SVD) and Alzheimer's disease (AD) at follow-up. METHODS: Biomarker levels were assessed by Luminex xMAP technology and ELISA. RESULTS: Increased baseline concentrations of NF-L significantly separated MCI-SVD from stable MCI. The MCI-SVD patients were inseparable from stable MCI but separable from patients developing AD (MCI-AD) on the basis of Abeta(42,) T-tau and P-tau(181) levels. CONCLUSION: A combination of the biomarkers Abeta(42), T-tau, P-tau(181) and NF-L has the potential to improve the clinical separation of MCI-SVD patients from stable MCI and MCI-AD patients.

STAT3ß is a tumor suppressor in acute myeloid leukemia.

Signal transducer and activator of transcription 3 (STAT3) exists in 2 alternatively spliced isoforms, STAT3α and STAT3ß. Although truncated STAT3ß was originally postulated to act as a dominant-negative form of STAT3α, it has been shown to have various STAT3α-independent regulatory functions. Recently, STAT3ß gained attention as a powerful antitumorigenic molecule in cancer. Deregulated STAT3 signaling is often found in acute myeloid leukemia (AML); however, the role of STAT3ß in AML remains elusive. Therefore, we analyzed the STAT3ß/α messenger RNA (mRNA) expression ratio in AML patients, where we observed that a higher STAT3ß/α mRNA ratio correlated with a favorable prognosis and increased overall survival. To gain better understanding of the function of STAT3ß in AML, we engineered a transgenic mouse allowing for balanced Stat3ß expression. Transgenic Stat3ß expression resulted in decelerated disease progression and extended survival in PTEN- and MLL-AF9-dependent AML mouse models. Our findings further suggest that the antitumorigenic function of STAT3ß depends on the tumor-intrinsic regulation of a small set of significantly up- and downregulated genes, identified via RNA sequencing. In conclusion, we demonstrate that STAT3ß plays an essential tumor-suppressive role in AML.

Episodic memory and speed/attention deficits are associated with Alzheimer-typical CSF abnormalities in MCI.

UNLABELLED: Mild cognitive impairment (MCI) is regarded as the prodromal stage of dementia disorders, such as Alzheimer's disease (AD). OBJECTIVE: To compare the neuropsychological profiles of MCI subjects with normal concentrations of total tau (T-tau) and Abeta42 in CSF (MCI-norm) to MCI subjects with deviating concentrations of the biomarkers (MCI-dev). MCI-norm (N = 73) and MCI-dev (N = 73) subjects were compared to normal controls (N = 50) on tests of speed/attention, memory, visuospatial function, language and executive function. RESULTS: MCI-norm performed overall better than MCI-dev, specifically on tests of speed and attention and episodic memory. When MCI-dev subjects were subclassified into those with only high T-tau (MCI-tau), only low Abeta42 (MCI-Abeta) and both high T-tau and low Abeta42 (MCI-tauAbeta), MCI-tauAbeta tended to perform slightly worse. MCI-tau and MCI-Abeta performed quite similarly. CONCLUSIONS: Considering the neuropsychological differences, many MCI-norm probably had more benign forms of MCI, or early non-AD forms of neurodegenerative disorders. Although most MCI-dev performed clearly worse than MCI-norm on the neuropsychological battery, some did not show any deficits when compared to age norms. A combination of CSF analyses and neuropsychology could be a step toward a more exact diagnosis of MCI as prodromal AD.