SF3B1
is a highly mutated gene in myelodysplastic syndrome (MDS) patients, related to a specific subtype and parameters of good prognosis in MDS without excess blasts. More than 40% of MDS patients ...carry at least two myeloid-related gene mutations but little is known about the impact of concurrent mutations on the outcome of MDS patients. In applying next-generation sequencing (NGS) with a 117 myeloid gene custom panel, we analyzed the co-occurrence of
SF3B1
with other mutations to reveal their clinical, biological, and prognostic implications in very low/low- and intermediate-risk MDS patients. Mutations in addition to those of
SF3B1
were present in 80.4% of patients (median of 2 additional mutations/patient, range 0–5). The most frequently mutated genes were as follows:
TET2
(39.2%),
DNMT3A
(25.5%),
SRSF2
(10.8%),
CDH23
(5.9%), and
ASXL1
,
CUX1
, and
KMT2D
(4.9% each). The presence of at least two mutations concomitant with that of
SF3B1
had an adverse impact on survival compared with those with the
SF3B1
mutation and fewer than two additional mutations (median of 54 vs. 87 months, respectively:
p
= 0.007). The co-occurrence of
SF3B1
mutations with specific genes is also linked to a dismal prognosis:
SRSF2
mutations were associated with shorter overall survival (OS) than
SRSF2
wt (median, 27 vs. 75 months, respectively;
p
= 0.001), concomitant
IDH2
mutations (median OS, 11 mut vs. 75 wt months;
p
= 0.001),
BCOR
mutations (median OS, 11 mut vs. 71 wt months;
p
= 0.036), and
NUP98
and
STAG2
mutations (median OS, 27 and 11 vs. 71 months, respectively;
p
= 0.008 and
p
= 0.002). Mutations in CHIP genes (
TET2
,
DNMT3A
) did not significantly affect the clinical features or outcome. Our results suggest that a more comprehensive NGS study in low-risk MDS
SF3B1
mut
patients is essential for a better prognostic evaluation.
The results of previous studies suggest that prenatal exposure to bisp-chlorophenyl-1,1,1-trichloroethane (DDT) and to its main metabolite, 2,2-bis(p-chlorophenyl)-1,1-dichloroethylene (DDE), impairs ...psychomotor development during the first year of life. However, information about the persistence of this association at later ages is limited.
We assessed the association of prenatal DDE exposure with child neurodevelopment at 42-60 months of age.
Since 2001 we have been monitoring the neurodevelopment in children who were recruited at birth into a perinatal cohort exposed to DDT, in the state of Morelos, Mexico. We report McCarthy Scales of Children's Abilities for 203 children at 42, 48, 54, and 60 months of age. Maternal DDE serum levels were available for at least one trimester of pregnancy. The Home Observation for Measurement of the Environment scale and other covariables of interest were also available.
After adjustment, a doubling of DDE during the third trimester of pregnancy was associated with statistically significant reductions of -1.37, -0.88, -0.84, and -0.80 points in the general cognitive index, quantitative, verbal, and memory components respectively. The association between prenatal DDE and the quantitative component was weaker at 42 months than at older ages. No significant statistical interactions with sex or breastfeeding were observed.
These findings support the hypothesis that prenatal DDE impairs early child neurodevelopment; the potential for adverse effects on development should be considered when using DDT for malaria control.
Celotno besedilo
Dostopno za:
CEKLJ, DOBA, IZUM, KILJ, NUK, OILJ, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK, VSZLJ
IL-6 is one of the major mediators of the hyper-inflammatory responses with complex biological functions as it can signal
different modes of action. IL-6 by classical signalling has anti-inflammatory ...and antibacterial activities, while trans-signalling mediates pro-inflammatory effects. The net biological effect of IL-6 is established by multiple factors beyond its absolute concentration. Here, we assess the relationship between IL-6 signalling variables IL-6, soluble IL-6R (sIL-6R) and soluble gp130 (sgp130) and outcomes in a cohort of 366 COVID-19 patients. The potential trans-signalling was evaluated by a ratio between the pro-inflammatory binary IL-6:sIL-6R complex and the inactive ternary IL-6:sIL-6R:sgp130 complex (binary/ternary complex) and the fold molar excess of sgp130 over sIL-6R (FME). Our data provide new evidence that high levels of IL-6, sIL-6R, sgp130, binary/ternary complex ratio, and low FME are independent predictors of COVID-19 severity in survivor patients (without death), and the combination of IL-6 + sIL-6R + sgp130 exhibited the most robust classification capacity. Conversely, in a subgroup of patients with a very poor prognosis, we found that high levels of IL-6 and low levels of sIL-6R, sgp130, and binary/ternary complex ratio were predictors of death. In this context, the highest predictive capacity corresponded to the combined analysis of IL-6 + FME + lymphopenia + creatinine. Herein, we present IL-6 signalling variables as a helpful tool for the early identification and stratification of patients with clear implications for treatment and clinical decision-making.
Aim
This study aimed to summarise the views and experiences of the participants in the workshop of the XIII International Conference on Kangaroo Mother Care (KMC).
Methods
The results of the ...discussions held during the workshop of the XIII International Conference on KMC were summarised. There were 152 participants from 47 countries. Four main KMC topics were discussed: good practices, immediate implementation, nutrition and basic ventilation.
Results
Several agreements were reached, namely that professional societies and governments should develop official recommendations to promote KMC as standard care for preterm and low birth weight infants and that parents should be involved as active caregivers in neonatal care units. Moreover, the criteria for referring community‐born infants to KMC require standardisation.
Important inequalities in resource availability among high‐, middle‐ and low‐income countries were recognised for all topics. Specific needs were identified for parenteral nutrition and fortifiers, nasal continuous positive airway pressure (nCPAP) and oxygen blenders, which are rarely available in low‐ and middle‐income countries.
Immediate implementation of KMC was discussed as a new concept. Its benefits were recognised, but its application has some variability.
Conclusion
Adequate preterm care requires a basic neonatal package, including KMC, nCPAP, immediate management protocols and adequate nutrition and feeding strategies. The differences in resources among high‐, middle‐ and low‐income countries highlight the wide disparities in neonatal care according to the place of birth.
In the last years, the use of thrombopoietin receptor agonists (TPO-RA), eltrombopag and romiplostim, has improved the management of immune thrombocytopenia (ITP). Moreover, eltrombopag is also ...active in patients with aplastic anemia and myelodysplastic syndrome. However, their mechanisms of action and signaling pathways still remain controversial. In order to gain insight into the mechanisms underlying eltrombopag therapy, a gene expression profile (GEP) analysis in patients treated with this drug was carried out. Fourteen patients with chronic ITP were studied by means of microarrays before and during eltrombopag treatment. Median age was 78 years (range, 35-87 years); median baseline platelet count was 14 × 10
9
/L (range, 2-68 × 10
9
/L). Ten patients responded to the therapy, two cases relapsed after an initial response and the remaining two were refractory to the therapy. Eltrombopag induced relevant changes in the hematopoiesis, platelet activation and degranulation, as well as in megakaryocyte differentiation, with overexpression of some transcription factors and the genes PPBP, ITGB3, ITGA2B, F13A1, F13A1, MYL9 and ITGA2B. In addition, GP1BA, PF4, ITGA2B, MYL9, HIST1H4H and HIST1H2BH, genes regulated by RUNX1 were also significantly enriched after eltrombopag therapy. Furthermore, in non-responder patients, an overexpression of Bcl-X gene and genes involved in erythropoiesis, such as SLC4A1 and SLC25A39, was also observed. To conclude, overexpression in genes involved in megakaryopoiesis, platelet adhesion, degranulation and aggregation was observed in patients treated with eltrombopag. Moreover, an important role regarding heme metabolism was also present in non-responder patients.
Celotno besedilo
Dostopno za:
DOBA, IJS, IZUM, KILJ, NUK, PILJ, PNG, SAZU, UILJ, UKNU, UL, UM, UPUK
Killer-cell immunoglobulin-like receptors (KIR) are expressed by natural killer (NK) and effector T cells. Although KIR+ T cells accumulate in oncologic patients, their role in cancer immune response ...remains elusive. This study explored the role of KIR+CD8+ T cells in cancer immunosurveillance by analyzing their frequency at diagnosis in the blood of 249 patients (80 melanomas, 80 bladder cancers, and 89 ovarian cancers), their relationship with overall survival (OS) of patients, and their gene expression profiles. KIR2DL1+ CD8+ T cells expanded in the presence of HLA-C2-ligands in patients who survived, but it did not in patients who died. In contrast, presence of HLA-C1-ligands was associated with dose-dependent expansions of KIR2DL2/S2+ CD8+ T cells and with shorter OS. KIR interactions with their specific ligands profoundly impacted CD8+ T cell expression profiles, involving multiple signaling pathways, effector functions, the secretome, and consequently, the cellular microenvironment, which could impact their cancer immunosurveillance capacities. KIR2DL1/S1+ CD8+ T cells showed a gene expression signature related to efficient tumor immunosurveillance, whereas KIR2DL2/L3/S2+CD8+ T cells showed transcriptomic profiles related to suppressive anti-tumor responses. These results could be the basis for the discovery of new therapeutic targets so that the outcome of patients with cancer can be improved.
Electrons feed into the mitochondrial electron transport chain (mETC) from NAD- or FAD-dependent enzymes. A shift from glucose to fatty acids increases electron flux through FAD, which can saturate ...the oxidation capacity of the dedicated coenzyme Q (CoQ) pool and result in the generation of reactive oxygen species. To prevent this, the mETC superstructure can be reconfigured through the degradation of respiratory complex I, liberating associated complex III to increase electron flux via FAD at the expense of NAD. Here, we demonstrate that this adaptation is driven by the ratio of reduced to oxidized CoQ. Saturation of CoQ oxidation capacity induces reverse electron transport from reduced CoQ to complex I, and the resulting local generation of superoxide oxidizes specific complex I proteins, triggering their degradation and the disintegration of the complex. Thus, CoQ redox status acts as a metabolic sensor that fine-tunes mETC configuration in order to match the prevailing substrate profile.
Display omitted
•High CoQH2/CoQ ratio induces reverse electron transport under physiological conditions•RET-generated ROS induces partial complex I degradation•Increase in the CIII fraction detached of CI optimizes mETC to consume fatty acids•The CoQH2/CoQ ratio serves as a sensor of respiratory chain efficiency
Guarás et al. show how the mitochondrial electron transport chain (mtETC) is optimized to better oxidize different nutrients or fuels using the reducing status of ubiquinone as a metabolic sensor and ROS generated by complex I by reverse electron transport as an executor.
Cancer cells have unlimited replicative potential, insensitivity to growth-inhibitory signals, evasion of apoptosis, cellular stress, and sustained angiogenesis, invasiveness and metastatic ...potential. Cancer cells adequately adapt cell metabolism and integrate several intracellular and redox signaling to promote cell survival in an inflammatory and hypoxic microenvironment in order to maintain/expand tumor phenotype. The administration of tyrosine kinase inhibitor (TKI) constitutes the recommended therapeutic strategy in different malignancies at advanced stages.
There are important interrelationships between cell stress, redox status, mitochondrial function, metabolism and cellular signaling pathways leading to cell survival/death. The induction of apoptosis and cell cycle arrest widely related to the antitumoral properties of TKIs result from tightly controlled events involving different cellular compartments and signaling pathways. The aim of the present review is to update the most relevant studies dealing with the impact of TKI treatment on cell function. The induction of endoplasmic reticulum (ER) stress and Ca2+ disturbances, leading to alteration of mitochondrial function, redox status and phosphatidylinositol 3-kinase (PI3K)-protein kinase B (Akt)-mammalian target of rapamycin (mTOR) and AMP-activated protein kinase (AMPK) signaling pathways that involve cell metabolism reprogramming in cancer cells will be covered. Emphasis will be given to studies that identify key components of the integrated molecular pattern including receptor tyrosine kinase (RTK) downstream signaling, cell death and mitochondria-related events that appear to be involved in the resistance of cancer cells to TKI treatments.
Introduction
The prognosis of relapsed B cell precursor acute lymphoblastic leukemia (B‐ALL) is poor and few patients can be successfully rescued with conventional therapies. Inotuzumab ozogamicin ...(IO), an antibody against the CD22 antigen linked to calicheamicin, has been approved as a rescue treatment in relapsed/refractory (R/R) B‐ALL.
Patients and Methods
This was an observational, retrospective, multicenter study of adult patients included in the Spanish program of compassionate use of IO in centers from the PETHEMA group (Programa Español de Tratamientos en Hematología).
Results
Thirty‐four patients with a median age of 43 years (range, 19–73) were included. Twenty patients (59%) were refractory to the last treatment, IO treatment was given as ≥3rd salvage treatment in 25 patients (73%) and 20 patients (59%) received allogeneic hematopoietic stem cell transplantation before IO treatment. After a median of 2 cycles of IO, 64% of patients achieved complete response (CR)/complete response with incomplete recovery. The median response duration, progression‐free survival and overall survival (OS) were 4.7 (95%CI, 2.4–7.0 months), 3.5 (95%CI, 1.0–5.0 months) and 4 months (95%CI, 1.9–6.1 months) respectively, with better OS for patients with relapsed B‐ALL versus refractory disease (10.4 vs. 2.5 months, respectively) (p = .01). There was a trend for better OS for patients with first CR duration >12 months (7.2 months 95%CI, 3.2–11.2 vs. 3 months 95% CI, 1.8–4.2 respectively) (p = .054). There was no sinusoidal obstruction syndrome (SOS) event during IO treatment, but three patients (9%) developed grade 3–4 SOS during alloHSCT after IO treatment.
Conclusions
Our study showed slightly inferior outcomes of the pivotal trial probably due to poorer risk factors and late onset of IO therapy of recruited patients. Our results support early use of IO in relapsed/refractory ALL patients.
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