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Pathognomonic features of in utero premature restriction/closure of the ductus arteriosus (DA) are increased right ventricular afterload, impaired right ventricular function, and consequently tricuspid regurgitation and right heart dilation. The most common reason for constriction-closure of DA is maternal administration of non-steroidal anti-inflammatory drugs (NSAIDs) during the 3rd trimester of gestation. The idiopathic form is a rare event and, maybe, an underestimated abnormality that, if it is not promptly recognized, may result in severe fetal-neonatal compromise. We describe a case of a 38-year-old woman presenting at 34+0 weeks of gestation with a normally grown male fetus whose fetal echocardiography had shown right ventricular hypertrophy, a tortuous S-shaped DA and a significant pulmonary hyperflow. All signs were consistent of an idiopathic severe constriction of DA with a significant fetal cardiac involvement. The patient was admitted to a tertiary care center equipped with Neonatal Intensive Care Unit (NICU), and delivered by cesarean section at 34+4 weeks with a good maternal and neonatal outcome. Based on our experience and a review of the Literature we propose a management algorithm to use when dealing with preterm or early term pregnancy complicated by this fetal hemodynamic malfunction. [ABSTRACT FROM AUTHOR]

Competing Interests: Paolo Ghia received honoraria from AbbVie, AstraZeneca, BeiGene, BMS, Galapagos, Janssen, Lilly/LoxoOncology, MSD, and Roche, and research funding from AbbVie, AstraZeneca, BMS, and Janssen, and is an Editor of HemaSphere. Marzia Varettoni received honoraria from AbbVie, AstraZeneca, BeiGene, and Janssen. The remaining authors declare no conflict of interest.

Background: This monocentric retrospective study describes the treatment patterns and outcomes of chronic lymphocytic leukemia (CLL) patients., Methods: Adult CLL patients treated between 1992 and 2022 were included. The time to next treatment (TTNT) was defined as the time from the treatment's start to the start of a subsequent therapy or death. The time to next treatment failure or death (TTNTF) was defined as the time from treatment discontinuation to the discontinuation of a subsequent therapy or death., Results: Of 637 registered patients, 318 (49.9%) received treatment. We evaluated 157 cBTKi-exposed, 34 BCL2i-exposed cBTKi-naïve, and 26 double-exposed patients. The five-year TTNT values in the cBTKi-exposed patients were 80% (median NR), 40% (median 40 months), and 21% (median 24 months) months in the first line (1L), second line (2L), and beyond the second line (>2L), respectively ( p < 0.0001). The five-year TTNT values in the BCL2i-exposed patients were 83% (median NR), 72% (median NR), 12% (median 28 months) in the 1L, 2L, and >2L, respectively ( p = 0.185). The median TTNTF was 9 months (range 1-87) after cBTKi and 17 months (range 8-49) after both a cBTKi and BCL2i., Conclusions: This study suggests that, in CLL patients, the earlier we used targeted therapies, the better was the outcome obtained. Nonetheless, the poor outcomes in the advanced lines of therapy highlight the need for more effective treatments.

Chronic lymphocytic leukemia can evolve to an aggressive lymphoma-in most of the cases diffuse large B cells lymphoma, rarely Hodgkin lymphoma-and this complication is defined Richter syndrome (RS). Immunogenotypic features that characterize RS include unmutated IgHV status with high prevalence of IgHV4-39/D6-13/J5 sequence; deletion of chromosome 17p or 11q; activation of oncogenes as NOTCH1 and c-MYC; inactivation of onco-suppressors as TP53 and CDKN2A; high expression of CD38 in lymph-nodes. The prognosis of this condition is very poor: patients experience a rapid clinical deterioration with frequent therapeutic failure since the current options include suboptimal strategies as standard chemo-immunotherapy followed by hematopoietic stem cells transplantation or enrollment in clinical trials which investigate the efficacy of target drugs. Understanding the biology of such a heterogeneous condition is crucial to personalize the treatment and improve patient's survival., (© 2022 John Wiley & Sons Ltd.)

Measurable residual disease (MRD) is defined as the presence of residual cancer cells after treatment in patients with clinically undetectable disease, who would otherwise be considered in complete remission. It is a highly sensitive parameter which indicates the disease burden and predicts survival in this setting of patients. In recent years, MRD has gained a role in many hematological malignancies as a surrogate endpoint for clinical trials: undetectable MRD has been correlated to longer progression free survival (PFS) and overall survival (OS). New drugs and combinations have been developed with the aim to achieve MRD negativity, which would indicate favorable prognosis. Different methods to measure MRD have also been devised, which include flow cytometry, polymerase chain reaction (PCR) and next generation sequencing (NGS), with different sensitivity and accuracy in evaluating deep remission after treatment. In this review, we will analyze the current recommendations for the detection of MRD, with particular focus on its role in Chronic Lymphocytic Leukemia (CLL), as well as the different detection methods. Moreover, we will discuss the results of clinical trials and the role of MRD in new therapeutic schemes with inhibitors and monoclonal antibodies. MRD is not currently used in the clinical practice to evaluate response to treatment, due to technical and economical limitations, but it's gaining more and more interest in trials settings, especially since the introduction of venetoclax. The use of MRD in trials will likely be followed by a broader practical application in the future. The aim of this work is to provide a reader-friendly summary of the state of art in the field, as MRD will soon become an accessible tool to evaluate our patients, predict their survival and guide physician's therapeutic choices and preferences., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2023 Benintende, Pozzo, Innocenti, Autore, Fresa, D’Arena, Gattei and Lurenti.)

Rhizobium adhering proteins or 'Raps' are secreted proteins identified in a very restricted group of rhizobial strains, specifically those belonging to R. leguminosarum and R. etli . The distinctive feature of members of the Rap family is the presence of one or two cadherin-like domains or CHDLs that are also present in numerous extracellular bacterial and archaeal proteins and were proposed to confer carbohydrate binding ability. We have previously made an in-depth characterization of RapA2, a calcium-binding lectin, composed by two CHDLs, involved in biofilm matrix remodelling in R. leguminosarum bv. viciae 3841. In this study, CHDLs derived from RapA2 were analysed in detail, finding significant structural and functional differences despite their considerable sequence similarity. Only the carboxy-terminal CHDL retained properties similar to those displayed by RapA2. Our findings were used to obtain a novel fluorescent probe to study biofilm matrix development by confocal laser scanning microscopy, and also to shed some light on the role of the ubiquitous CHDL domains in bacterial secreted proteins.

Competing Interests: Conflict of interest: The authors declare no conflict of Interest.

Bone marrow transplantation is a major therapeutic option for patients with acquired severe aplastic anaemia: improved survival has been achieved in younger patients, thanks to better donor selection, conditioning regimens and graft versus host disease prophylaxis, together with improved supportive care, including diagnosis and treatment of opportunistic infections. This has not been the case for older patients over the age of 40 years. We will discuss transplantation platforms as used for different donor types and we will analyse major breakthroughs of the last years: the combination of Fludarabine and cyclophosphamide as a conditioning regimen, the use of alternative donors including HLA haploidentical related donors and new strategies to prevent acute and chronic graft versus host disease, including post transplantation Cyclophosphamide. These changes extend the option of a bone marrow transplantation for patients who lack an HLA matched donor and appear to improve engraftment and reduce graft versus host disease: whether this will be true for all age groups is currently being investigated., (Copyright © 2021. Published by Elsevier Ltd.)

The aim of this review is to update the current status of allogeneic hemopoietic stem cell transplants (HSCT) for patients with myelofibrosis (MF). We have first summarized the issue of an indication for allogeneic HSCT, discussing several prognostic scoring systems, developed to predict the outcome of MF, and therefore to identify patients who will benefit of an allogeneic HSCT. Patients with low risk MF are usually not selected for a transplant, whereas patients with intermediate or high risk MF are eligible. A separate issue, is how to predict the outcome of HSCT: we will outline a clinical molecular myelofibrosis transplant scoring system (MTSS), which predicts overall survival, ranging from 90% for low risk patients, to 20% for very high risk patients. We will also discuss transfusion burden and spleen size, as predictors of transplant outcome. The choice of a transplant platform including the conditioning regimen, the stem cell source and GvHD prophylaxis, are crucial for a successful program in MF, and will be outlined. Complications such as poor graft function, graft failure, GvHD and relapse of the disease, will also be reviewed. Finally we discuss monitoring the disease after HSCT with donor chimerism, driver mutations and hematologic data. We have made an effort to make this review as comprehensive and up to date as possible, and we hope it will provide some useful data for the clinicians., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2021 Bacigalupo, Innocenti, Rossi, Sora, Galli, Autore, Metafuni, Chiusolo, Giammarco, Laurenti, Benintende, Sica and De Stefano.)

Aim: Evaluate the relationship between neonatal weight and pregnancy-associated plasma protein-A., Methods: Retrospective study on 2564 singleton pregnancies with healthy term neonates in three groups of women with different values of pregnancy-associated plasma protein-A who underwent the combined test during the first trimester. Non-parametric test and correlation analysis for statistical elaboration were carried out., Results: There exists a correlation between the serum levels of pregnancy-associated plasma protein-A in the first trimester of pregnancy and neonatal weight. Values of pregnancy-associated plasma protein-A lower than the 25th percentile are associated with neonatal weight in a significant way. There was no significant association between pregnancy-associated plasma protein-A values above 1.50 MoM and neonatal weight., Conclusion: This study confirms the positive correlation between circulating concentrations of pregnancy-associated plasma protein-A and fetal growth. Low neonatal weight and factors that can cause this could be determined from the first trimester by measuring the concentrations of pregnancy-associated plasma protein-A in maternal serum. Even if the association between the levels of pregnancy-associated plasma protein-A and a low neonatal weight has been demonstrated, however, we have to say that the sensitivity of a such screening method for the prediction of low birth weight and perinatal complications seems to be rather low. The variations of pregnancy-associated plasma protein-A during the first trimester cannot be used as a marker of excessive fetal growth.

Bacillus thuringiensis is classified into serovars on the basis of H-flagellar antigens. Several alternative typing methods have been described. Among them, a B. cereus group-specific repetitive extragenic palindromic (Rep)-PCR fingerprinting technique was shown to be discriminative and able to identify B. thuringiensis serovars. The aim of this study was to investigate the genomic diversity and relationship among B. thuringiensis strains collected from different Argentinean ecosystems. Thirty-seven B. thuringiensis reference strains and 131 Argentinean isolates were analyzed using a B. cereus group-specific Rep-PCR. Fourteen different patterns were identified among the Argentinean isolates. Eight could not be associated to any pattern obtained from a reference strain. The pattern identical to the serovar kurstaki HD-1 strain was the most frequently identified in 68 native isolates. The profiles allowed tracing a single dendrogram with two groups and eight main lineages. Some strains showed distinctive patterns despite belonging to the same serovar. An intraspecific diversity resulted from this analysis that was highlighted by this technique since strains from a given serovar showed distinct profiles. This study may help to establish a system of B. thuringiensis classification with a higher discrimination level than established by the H antigen serotyping., (Copyright © 2012 S. Karger AG, Basel.)

A polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) method for detection of cry11 genes from Bacillus thuringiensis was established. Based on the analysis of conserved regions of the cry11 genes, 2 oligonucleotide primers were designed to amplify a 1459-bp fragment of the cry11Aa gene, and a 1471-bp of the cry11Ba and cry11Bb genes. The amplification products were digested with restriction endonuclease HinfI. Exotic B. thuringiensis strains and native isolates collected from soils, leaves and stored product dust of Argentina were analyzed to study the distribution of cry11 genes. The PCR-RFLP patterns revealed the detection of cry11 genes in 3 of 64 exotic strains and in 10 of 107 native B. thuringiensis isolates tested. Just the cry11Aa gene subclass was detected among these bacteria. Since the methodology was also developed to detect cry11Ba and cry11Bb genes, an experimental future confirmation will be required. Based on the results obtained, the PCR-RFLP method presented may be a valuable tool for specific detection of the mosquitocidal toxin genes encoding Cry11 proteins from B. thuringiensis.

Bacillus thuringiensis strains isolated from Latin American soil samples that showed toxicity against three Spodoptera frugiperda populations from different geographical areas (Mexico, Colombia, and Brazil) were characterized on the basis of their insecticidal activity, crystal morphology, sodium dodecyl sulfate-polyacrylamide gel electrophoresis of parasporal crystals, plasmid profiles, and cry gene content. We found that the different S. frugiperda populations display different susceptibilities to the selected B. thuringiensis strains and also to pure preparations of Cry1B, Cry1C, and Cry1D toxins. Binding assays performed with pure toxin demonstrated that the differences in the toxin binding capacities of these insect populations correlated with the observed differences in susceptibility to the three Cry toxins analyzed. Finally, the genetic variability of the three insect populations was analyzed by random amplification of polymorphic DNA-PCR, which showed significant genetic diversity among the three S. frugiperda populations analyzed. The data presented here show that the genetic variability of S. frugiperda populations should be carefully considered in the development of insect pest control strategies, including the deployment of genetically modified maize in different geographical regions.

This work describes a novel rolling-circle replicating (RCR) plasmid pBMBt1 from Bacillus thuringiensis subsp. darmstadiensis (INTA Mo14-4) encoding an insecticidal crystal protein-like gene. pBMBt1 (6700 bp) contains three ORFs and their putative transcription initiation sites and Shine-Dalgarno sequences were localized. ORF1 encodes a 34.6 kDa protein which showed identity with the protein CryC53 from B. thuringiensis subsp. cameroun (24.6%), the Cry15Aa insecticidal crystal protein from B. thuringiensis subsp. thompsoni (21.9%) and the Mtx3 protein from Bacillus sphaericus (27.8%). The ORF2 (52.3 kDa) showed a 74% identity with the Mob protein coded by pUIBI-1 from B. thuringiensis subsp. entomocidus and 64% identity with the Mob protein of pBMY1 from Bacillus mycoides; both Mob proteins belong to the pMV158 superfamily. To evaluate the Mob protein, the plasmid pHTMob14-4 was constructed. This plasmid shows transfer frequencies of 9.1x10(-6) in B. thuringiensis subsp. israelensis (4Q7Gm(R)). The ORF3 (23.6 kDa) gene product is homologous to the Rep protein from the plasmid pBMYdx of B. mycoides (37.6%). A putative double-strand origin with significant homology to that of B. thuringiensis plasmids, and an ssoA-type single-strand origin were also identified. Detection of single-stranded pBMBt1 DNA replicating intermediaries suggests that replication occurs via the rolling-circle mechanism.

Bacillus thuringiensis INTA 7-3, INTA 51-3, INTA Mo9-5 and INTA Mo14-4 strains were obtained from Argentina and characterized by determination of serotype, toxicity, plasmid composition, insecticidal gene content ( cry and vip ) and the cloning of the single- vip3A gene of the INTA Mo9-5 strain. The serotype analysis identified the serovars tohokuensis and darmstadiensis for the INTA 51-3 and INTA Mo14-4 strains, respectively, whereas the INTA Mo9-5 strain was classified as "autoagglutinated". In contrast to the plasmid patterns of INTA 7-3, INTA 51-3 and INTA Mo9-5 (which were similar to B. thuringiensis HD-1 strain), strain INTA Mo14-4 showed a unique plasmid array. PCR analysis of the four strains revealed the presence of cry genes and vip3A genes. Interestingly, it was found that B. thuringiensis 4Q7 strain, which is a plasmid cured strain, contained vip3A genes indicating the presence of these insecticidal genes in the chromosome. Bioassays towards various lepidopteran species revealed that B. thuringiensis INTA Mo9-5 and INTA 7-3 strains were highly active. In particular, the mean LC(50) obtained against A. gemmatalis larvae with the INTA Mo9-5 and INTA 7-3 strains were 7 (5.7-8.6) and 6.7 (5.6-8.0) ppm, respectively. The INTA Mo14-4 strain was non-toxic and strain INTA 51-3 showed only a weak larvicidal activity.

The characterization of selected Bacillus thuringiensis strains isolated from different Latin America countries is presented. Characterization was based on their insecticidal activity against Aedes aegypti, Culex quinquefasciatus, and Anopheles albimanus larvae, scanning electron microscopy, sodium dodecyl sulfate-polyacrylamide gel electrophoresis, and plasmid profiles as well as PCR analysis using novel general and specific primers for cry and cyt genes encoding proteins active against mosquitoes (cyt1, cyt2, cry2, cry4A, cry4B, cry10, cry11, cry17, cry19, cry24, cry25, cry27, cry29, cry30, cry32, cry39, and cry40). Strains LBIT315, LBIT348, and IB604 showed threefold higher mosquitocidal activity against A. aegypti and C. quinquefasciatus larvae than B. thuringiensis subsp. israelensis and displayed high similarities with the B. thuringiensis subsp. israelensis used in this study with regard to protein and plasmid profiles and the presence of cry genes. Strain 147-8906 has activity against A. aegypti similar to that of B. thuringiensis subsp. israelensis but has different protein and plasmid profiles. This strain, harboring cry11, cry30, cyt1, and cyt2 genes, could be relevant for future resistance management interventions. Finally, the PCR screening strategy presented here led us to identify a putative novel cry11B gene.

Several isolates of Bacillus thuringiensis native to Argentina obtained in a nationwide screening program showed atypical crystal morphology. One of these strains, INTA 51-3, was further characterized in order to determine other features like protein composition of its parasporal crystal, plasmid pattern, identification of cry genes and toxicological properties. B. thuringiensis INTA 51-3 (serovar tohokuensis) had an amorphous inclusion containing a major protein component of ca. 130 kDa. After trypsin digestion of solubilized crystals, SDS-PAGE resolved a unique protease-resistant peptide of ca. 90 kDa. The plasmid pattern from INTA 51-3 resembled that of the standard strain HD-1. However, Southern analysis showed no hybridization to fragments of cry1Aa, cry2Aa, cry3A, and cry11A genes. Degenerate primers were used for identification of the cry1 genes by PCR. Nevertheless, the presence of cry1 type gene(s) in B. thuringiensis INTA 51-3 was confirmed. Highly concentrated crystal suspensions showed to be weakly toxic only to lepidopteran species.