Although acute promyelocytic leukemia (APL) is one of the most characterized forms of acute myeloid leukemia (AML), the molecular mechanisms involved in the development and progression of this ...disease are still a matter of study. APL is defined by the
rearrangement as a consequence of the translocation t(15;17)(q24;q21). However, this abnormality alone is not able to trigger the whole leukemic phenotype and secondary cooperating events might contribute to APL pathogenesis. Additional somatic mutations are known to occur recurrently in several genes, such as
,
,
and
, whereas mutations in other common AML genes are rarely detected, resulting in a different molecular profile compared to other AML subtypes. How this mutational spectrum, including point mutations in the
fusion gene, could contribute to the 10%-15% of relapsed or resistant APL patients is still unknown. Moreover, due to the uncertain impact of additional mutations on prognosis, the identification of the APL-specific genetic lesion is still the only method recommended in the routine evaluation/screening at diagnosis and for minimal residual disease (MRD) assessment. However, the gene expression profile of genes, such as
, and
once combined with the molecular events, might improve future prognostic models, allowing us to predict clinical outcomes and to categorize APL patients in different risk subsets, as recently reported. In this review, we will focus on the molecular characterization of APL patients at diagnosis, relapse and resistance, in both children and adults. We will also describe different standardized molecular approaches to study MRD, including those recently developed. Finally, we will discuss how novel molecular findings can improve the management of this disease.
The significance of metal ions for the function and properties of DNA and RNA, long seen primarily under biological aspects and medicinal uses, has recently gained a renewed momentum. This is a ...consequence of the advent of novel applications in the fields of materials science, biotechnology, and analytical sensor chemistry that relate to the designed incorporation of transition metal ions into nucleic acid base pairs. Ag+ and Hg2+ ions, binding to pyrimidine (pym) nucleobases, represent major players in this development. Interestingly, these metal ions were the ones that some 60 years ago started the field! At the same time, the mentioned metal ions had demonstrated a “special relationship” with the pym nucleobases cytosine, thymine, and uracil! Parallel work conducted with oligonucleotides and model nucleobases fostered numerous significant details of these interactions, in particular when X-ray crystallography was involved, correcting earlier views occasionally. Our own activities during the past three to four decades have focused on, among others, the coordination chemistry of transition and main-group metal ions with pym model nucleobases, with an emphasis on PtII and PdII. It has always been our goal to deduce, if possible, the potential relevance of our findings for biological processes. It is interesting to put our data, in particular for trans-a2PtII (a = NH3 or amine), into perspective with those of other metal ions, notably Ag+ and Hg2+. Irrespective of major differences in kinetics and lability/inertness between d8 and d10 metal ions, there is also a lot of similarity in structural aspects as a result of the preferred linear coordination geometry of these species. Moreover, the apparent clustering of metal ions to the pym nucleobases, which is presumably essential for the formation of nanoclusters on oligonucleotide scaffolds, is impressively reflected in model systems, as are reasons for inter-nucleobase cross-links containing more than a single metal ion. The present understanding of these interrelationships is a consequence of intensive research carried out during the last 60 years by numerous laboratories. For space restrictions in this Account, it was impossible to adequately highlight the valuable contributions of all of the researchers in the field of metal–pym nucleobase interactions. Explicitly this refers to colleagues not cited in the references, e.g., R. Stuart Tobias, Robert Bau, R. Bruce Martin, Colin J. L. Lock, Katsuyuki Aoki, Helmut Sigel, and Michael J. Clarke, among others.
Abstract
Infections by multidrug-resistant
Enterobacteriaceae
(MRE) are life-threatening to patients. The intestinal microbiome protects against MRE colonization, but antibiotics cause collateral ...damage to commensals and open the way to colonization and subsequent infection. Despite the significance of this problem, the specific commensals and mechanisms that restrict MRE colonization remain largely unknown. Here, by performing a multi-omic prospective study of hospitalized patients combined with mice experiments, we find that
Lactobacillus
is key, though not sufficient, to restrict MRE gut colonization.
Lactobacillus rhamnosus
and
murinus
increase the levels of Clostridiales bacteria, which induces a hostile environment for MRE growth through increased butyrate levels and reduced nutrient sources. This mechanism of colonization resistance, an interaction between
Lactobacillus
spp. and Clostridiales involving cooperation between microbiota members, is conserved in mice and patients. These results stress the importance of exploiting microbiome interactions for developing effective probiotics that prevent infections in hospitalized patients.
The advent of all-trans-retinoic acid (ATRA) and its combination with anthracycline-containing chemotherapy have contributed in the past 2 decades to optimize the antileukemic efficacy in acute ...promyelocytic leukemia (APL), leading to complete remission rates greater than 90%, virtual absence of resistance, and cure rates of nearly 80%. Recently reported studies from large cooperative trials have also shown that more rational delivery of treatment and improved outcomes may derive from the use of risk-adapted protocols. In particular, patients at higher risk of relapse (ie, those presenting with WBC > 10 × 10(9)/L) seem to benefit from treatments that include cytarabine in the ATRA-plus-chemotherapy scheme, whereas patients with standard-risk disease can be successfully managed with less-intensive regimens that contain ATRA and anthracycline-based chemotherapy. After the outstanding results with arsenic trioxide (ATO) in the treatment of APL relapse, several experimental trials have been designed to explore the role of ATO in front-line therapy with the aim not only of minimizing the use of chemotherapy but also to reinforce standard ATRA-plus-chemotherapy regimens and additionally improve therapeutic efficacy. In this review article, we discuss most recent advances in the treatment of patients with newly diagnosed and relapsed APL.
Differentiation syndrome (DS), formerly known as retinoic acid syndrome, is a relatively common and potentially severe complication seen in patients with acute promyelocytic leukemia treated with ...all-trans retinoic acid and/or arsenic trioxide. The full-blown syndrome consists of unexplained fever, weight gain, dyspnea with pulmonary infiltrates, pleuropericardial effusion, hypotension, and renal failure. Most measures currently used for management of DS have very little evidence-based support, and therefore, many remain controversial. Despite the lack of evidence supporting DS prophylaxis, several groups have adopted a preventive strategy with corticosteroids, especially for patients with leukocyte levels higher than from 5 to 10 × 109/L. DS diagnosis should be suspected in the presence of any of the above-mentioned signs and symptoms, and preemptive treatment with dexamethasone should be started immediately. Other supportive measures can also be crucial for the correct management of DS, especially in those patients with life-threatening complications. Temporary discontinuation of all-trans retinoic acid or arsenic trioxide is indicated only for patients in very poor clinical condition or with severe renal or pulmonary dysfunction, sometimes requiring admission to the intensive care unit. Recognition of specific biomarkers and a better understanding of DS pathogenesis can be helpful for the development of specific therapies to counteract DS in a timely manner.
In this paper we present a new computational framework for anisotropic elastoplasticity with mixed hardening which presents the following characteristics: (1) it is motivated by a one-dimensional ...rheological model where the main differences are due to geometric nonlinearities and three-dimensional effects; (2) it uses the Lee multiplicative decomposition; (3) it is valid for anisotropic yield functions; (4) it is valid for any anisotropic stored energy, either linear or nonlinear in logarithmic strains; (5) it is valid for (non-moderate) large elastic strains; (6) it results in a six-dimensional additive corrector update, parallel to that of the infinitesimal theory; (7) it does not explicitly employ plastic strain tensors or plastic metrics, circumventing definitely the “rate issue”; (8) the incremental plastic flow is isochoric using a simple backward-Euler scheme, without explicitly using exponential mappings; (9) no hypothesis is needed for the plastic spin in order to integrate the symmetric flow derived from the dissipation equation; (10) the Mandel stress tensor plays no role in the formulation; (11) it yields a fully symmetric algorithmic linearization consistent with its associative nature and the principle of maximum dissipation; and (12) it recovers the formulation of Simó for isotropy as a particular case.
•New computational framework for multiplicative anisotropic elastoplasticity.•Based on a six-dimensional additive corrector update for elastic logarithmic strains.•No hypothesis needed for the plastic spin in order to integrate the symmetric flow.•Yields a fully symmetric finite element formulation parallel to the infinitesimal one.•Overcomes the so-called “rate issue” from a computational standpoint.
Since the introduction of all-trans retinoic acid and, more recently, arsenic trioxide into the therapy of acute promyelocytic leukemia (APL), significant improvements in patient outcomes have been ...achieved, and this disease has become the most curable subtype of acute myeloid leukemia. However, while primary leukemia resistance has virtually disappeared, a sizable fraction of APL patients still die before or during induction therapy. Hemorrhagic death still remains the major problem during this early phase of treatment and, to a lesser extent, deaths due to infection, differentiation syndrome and other causes. Patients with APL typically present with a range of laboratory abnormalities consistent with the diagnosis of disseminated intravascular coagulation and hyperfibrinolysis. This APL-associated coagulopathy, as a result of a dysregulation of the hemostatic system due to the imbalance between procoagulant, anticoagulant and profibrinolytic mechanisms, may show a variety of clinical manifestations, ranging from minimal bleeding or localized thrombosis to lethal or life-threatening hemorrhages or thrombotic events that sometimes occur concomitantly. Hemorrhagic events are the most common cause of death associated with APL coagulopathy, but thrombosis, a less recognized and probably underestimated life-threatening manifestation of the thrombo-hemorrhagic syndrome, is also a non-negligible cause of morbidity and mortality in patients with APL. In this article, we aim to discuss recent advances in the knowledge of pathogenesis, predictors of thrombo-hemorrhagic events, management of coagulopathy associated with APL and the controversial issues that still persist.
Gyrencephalic species develop folds in the cerebral cortex in a stereotypic manner, but the genetic mechanisms underlying this patterning process are unknown. We present a large‐scale transcriptomic ...analysis of individual germinal layers in the developing cortex of the gyrencephalic ferret, comparing between regions prospective of fold and fissure. We find unique transcriptional signatures in each germinal compartment, where thousands of genes are differentially expressed between regions, including ~80% of genes mutated in human cortical malformations. These regional differences emerge from the existence of discrete domains of gene expression, which occur at multiple locations across the developing cortex of ferret and human, but not the lissencephalic mouse. Complex expression patterns emerge late during development and map the eventual location of folds or fissures. Protomaps of gene expression within germinal layers may contribute to define cortical folds or functional areas, but our findings demonstrate that they distinguish the development of gyrencephalic cortices.
Synopsis
Complex patterns of gene expression emerge in germinal layers during early cortical development of gyrencephalic animals. These modular expression patterns map the eventual location of folds and fissures.
Microarray analysis of developing ferret cerebral cortex reveals transcriptomic differences between prospective folds and fissures.
Differential gene expression delineates mosaic patterns along proliferative zones prior to the emergence of folds.
Some mosaics of gene expression correlate with the prospective location of folds versus fissures.
Differentially expressed genes in our microarray analysis include 80% of those mutated in human cortical malformations.
Complex patterns of gene expression emerge in germinal layers during early cortical development of gyrencephalic animals. These modular expression patterns map the eventual location of folds and fissures.
Post-transplant lymphoproliferative disorders (PTLD) are a rare complication after both solid organ (SOT) and allogeneic hematopoietic stem cell transplantation (allo-HSCT). In this single center ...retrospective study, we compared clinical, biological, and histological features, and outcomes of PTLD after both types of transplant. We identified 82 PTLD (61 after SOT and 21 after allo-HSCT). The presence of B symptoms, Waldeyer ring, spleen, central nervous system, and liver involvement, and advanced Ann-Arbor stage were more frequent in allo-HSCT recipients. PTLD had an earlier onset in allo-HSCT than in SOT cohort (4 vs. 64 months, p < .0001). PTLD was EBV-positive in 100% of allo-HSCT, in contrast to 47% of SOT (p = .0002). Four years after PTLD diagnosis, median overall survival was 32% (95% CI, 22-48) and 10% (95% CI, 2-49) in SOT and allo-HSCT recipients, respectively (p = .002). In conclusion, the clinical presentation and the outcome of PTLD varies greatly depending on the type of transplant.
Since the comprehensive recommendations for the management of acute promyelocytic leukemia (APL) reported in 2009, several studies have provided important insights, particularly regarding the role of ...arsenic trioxide (ATO) in frontline therapy. Ten years later, a European LeukemiaNet expert panel has reviewed the recent advances in the management of APL in both frontline and relapse settings in order to develop updated evidence- and expert opinion–based recommendations on the management of this disease. Together with providing current indications on genetic diagnosis, modern risk-adapted frontline therapy, and salvage treatment, the review contains specific recommendations for the identification and management of the most important complications such as the bleeding disorder APL differentiation syndrome, QT prolongation, and other all-trans retinoic acid– and ATO-related toxicities, as well as recommendations for molecular assessment of the response to treatment. Finally, the approach to special situations is also discussed, including management of APL in children, elderly patients, and pregnant women. The most important challenges remaining in APL include early death, which still occurs before and during induction therapy, and optimizing treatment in patients with high-risk disease.
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