bluuebunny/crossref_metadata_2025 huggingface dataset:
Anti-HIV Antiviral Activity of Stavudine in a Thymidine Kinase-Deficient Cellular Line
Authors: Turriziani Ombretta , Simeoni Eleonora , Dianzani Ferdinando , Antonelli Guido
Published: April 2022

Stavudine (d4T) is a potent inhibitor of human immunodeficiency virus type 1 (HIV-1) reverse transcriptase. It is known that stavudine is metabolized in cells to the mono-, di- and triphosphate nucleotides but the enzymes responsible for its phosphorylation are as yet unidentified. In particular, there are conflicting results concerning the role of thymidine kinase 1 (TK1) in stavudine metabolism. To gain new insights into this phenomenon we analysed the antiviral activity of stavudine in a TK1-deficient, resistant cell line. The results indicate that TK1 is responsible for the phosphorylation of stavudine but it is not the only enzyme involved in its activation. The other enzyme(s) that might be involved in the metabolism of stavudine, however, are not able to phosphorylate stavudine with the same efficiency as TK1. Since it has been shown that prolonged treatment with zidovudine may induce an in vivo defect in TK1 activity, it is tempting to speculate that patients treated for a long time with zidovudine could be resistant to further treatment with stavudine.
Laboratory Markers of Antiviral Activity
Authors: Christopherson Cindy , Lu Shi-Da , Kwok Shirley
Published: April 2022

Quantitative assays for viral nucleic acids have been instrumental in monitoring the response of patients to various antiviral therapies. The level of viraemia is predictive of clinical outcome in that a reduced risk of progression to AIDS or death was observed with lower plasma human immunodeficiency virus (HIV) RNA levels. Rebound in viral levels often signals therapeutic failures, some of which are associated with the development of drug resistance. Quantitative plasma assays for HIV, hepatitis C virus (HCV), cytomegalovirus (CMV) and hepatitis B virus (HBV) have been developed. Over time, modifications to these assays have been required to meet new demands. For example, as antiviral therapies have become more effective, HIV and HCV assays of greater sensitivity are required in order to follow patients for longer periods of time and to fully assess the extent of viral suppression. For HIV-1, a large percentage of patients treated with combination therapies had viral loads that were below the detection limit of the ultrasensitive assay (50 copies/ml). To assess the residual viral burden in this patient population an assay to quantify HIV-1 proviral DNA in peripheral blood mononuclear cells was developed. Studies to date indicate that proviral DNA remains easily detectable despite undetectable plasma RNA and may be useful in monitoring this patient population. To increase assay throughput, a new generation of quantitative assays that will provide real-time detection and a 6 log10 detection range from a single amplification is under development.
Hepatitis B Virus Antiviral Drug Resistance: From the Laboratory to the Patient
Authors: Mutimer David
Published: April 2022

The development and application of nucleoside (and nucleotide) analogues for the treatment of chronic hepatitis B infection will transform the management of this condition. For instance, treatment with lamivudine effects a dramatic and measurable reduction of serum virus titre. This is associated with biochemical and histological improvements. Unfortunately, for the majority, replication resumes when treatment is withdrawn. Prolongued lamividine treatment may be associated with the emergence of drug-resistant species with specific polymerase mutations. Compared with the observed rate for the development of drug resistance observed during monotherapy of HIV infection, resistance is slow to emerge during treatment of hepatitis B. The rate of emergence might be dependent on the rate of infected hepatocyte turnover, which is extremely variable in chronic HBV infection (and significantly slower than infected lymphocyte turnover during HIV infection). Preliminary data suggest that pretreatment serum virus titre may be an important predictor of the development of drug resistance, an observation consistent with pre-existance of the resistant virus in the hepatitis B virus quasispecies. Akin to developments in antiviral treatment of HIV infection, further progress in the treatment of chronic hepatitis B will depend on the development of drugs for use in combination therapy.
Opportunistic Infections Shortly after Beginning Highly Active Antiretroviral Therapy
Authors: Rodríguez-Rosado Rafael , Soriano Vicente , Dona Carmen , González-Lahoz Juan
Published: April 2022

The clinical benefit of highly active antiretroviral therapy (HAART) has been attributed to its suppression of viral replication and improvement in the CD4 lymphocyte count. However, the development of clinical symptoms secondary to previously silent opportunistic pathogens shortly after beginning HAART has been reported as a distinct clinical syndrome and seems to be associated with inflammatory phenomena surrounding a rapid restoration of the immune system in previously immunosuppressed patients. Herein, we report nine (3.6%) episodes of opportunistic infections (OI) in 247 human immunodeficiency virus (HlV)-infected patients undergoing HAART in a reference HIV/AIDS institution located in Madrid, Spain. In all instances, OI clustered within the first 3 months after beginning HAART. Episodes of cerebral toxoplasmosis (three cases), Pneumocystis carinii pneumonia (two cases), and herpes zoster (two cases) occurred in persons without a previous AIDS-defining illness, in addition a relapse of cytomegalovirus retinitis and a rebound in Kaposi's sarcoma were seen, respectively, in another two patients. Four of the nine subjects had a CD4 count above 200 cells/mm3 before HAART began. Of these, one developed Pneumocystis pneumonia and one other cerebral toxoplasmosis. In conclusion, prophylaxis and close clinical monitoring of HIV-infected patients should be considered for the first 3 months after beginning HAART, even for subjects without severe immunosuppression.
Loss of Lamivudine Resistance in a Zidovudine and Lamivudine Dual-Resistant HIV-1 Isolate after Discontinuation of In Vitro Lamivudine Drug Pressure
Authors: Rusconi Stefano , De Pasquale Maria Pia , Milazzo Laura , Kurtagic Semir , Bulgheroni Elisabetta , Citterio Paola , Galazzi Morena , La Seta Catamancio Simona , Galli Massimo
Published: April 2022

We examined the in vitro phenotypic and genotypic profiles of an extensively passaged human immunodeficiency virus type 1 clinical isolate which has been selected for lamivudine resistance, with an M184V mutation in a zidovudine-resistant genetic background, and then cultured with zidovudine alone. Our passaging strategy led to a decrease in lamivudine IC50 values, which were comparable to those prior to lamivudine exposure, and the genotypic restoration of the wild-type sequence at codon 184 of reverse transcriptase.
Analysis of Hepatitis B Virus Quasispecies Changes during Emergence and Reversion of Lamivudine Resistance in Liver Transplantation
Authors: Cane Patricia A , Mutimer David , Ratcliffe Daina , Cook Pamela , Beards Graham , Elias Elwyn , Pillay Deenan
Published: April 2022

This report describes nucleotide sequence analysis of part of the polymerase gene of hepatitis B virus (HBV) during the development of lamivudine-resistant HBV in five patients who received lamivudine treatment in conjunction with liver transplantation. Samples from patients were analysed before, during and after drug treatment in conjunction with serum HBV quantification by PCR. Lamivudine resistance was found to be associated with L526M and M550V changes in two patients and M550I change in three patients. Other changes associated with lamivudine resistance in some patients were V509I, A546V, S565A and A568T. The effects on HBV surface antigen are also described. Some patients were subsequently treated with famciclovir and/or ganciclovir with variable outcomes. In two out of three patients who stopped lamivudine treatment, reversion (partial or complete) to wild-type virus was observed after about 5 months. In contrast, a complex mixture of mutant viruses emerged in a third patient who stopped lamivudine treatment.
Stavudine Resistance: An Update on Susceptibility following Prolonged Therapy
Authors: Lin Pin-Fang , González Charles J , Griffith Brigitte , Friedland Gerald , Calvez Vincent , Ferchal Francoise , Schinazi Raymond F , Shepp David H , Ashraf Amar B , Wainberg Mark A , Soriano Vincent , Mellors John W , Colonno Richard J
Published: April 2022

The current report summarizes the available published and unpublished data from several investigators on resistance in clinical isolates following prolonged stavudine therapy. Results suggest that stavudine resistance is both modest in degree and infrequent in appearance. Phenotypic evaluation of 61 patients on stavudine therapy showed only modest changes in drug sensitivity following up to 29 months of treatment. The post-treatment isolates from 15 patients exhibited an increase in EC50 value >fourfold (level above variability of assay) when compared with the corresponding pretreatment isolates. However, the vast majority (11) of these pretreatment isolates either had unexpectedly low EC50 levels and/or had post-treatment isolates that lacked any amino acid changes within their reverse transcriptase (RT) gene to account for the observed change in sensitivity. Of the four remaining isolates, two appeared to have a multi-resistant phenotype to several nucleoside analogues and two had no detectable RT amino acid changes to account for the observed change in stavudine sensitivity. To date, clinical HIV-1 isolates displaying stavudine-specific resistance have yet to be reported. Furthermore, full or partial RT sequence analysis of 194 post-treatment isolates failed to identify any consistent amino acid changes. The strain-specific V75T mutation reported to confer stavudine resistance to the HXB2 HIV-1 strain in vitro, was found in only six isolates and did not correlate with stavudine resistance. This low incidence of stavudine resistance is in striking contrast to that observed with other nucleoside analogues and further supports the use of stavudine in first-line combination therapy for HIV patients.
Different Outcome in the First Two Patients with an HIV-1 Multinucleoside Drug-Resistant T69SSS Insertion in Spain
Authors: Briones Carlos , Soriano Vincent
Published: April 2022

A novel multidrug-resistance mechanism has been described in human immunodeficiency virus type 1 (HIV-1), which involves the insertion of 6 bp between codons 69 and 70 in the reverse transcriptase (RT) gene. Herein, we report the first two patients in Spain carrying viral populations with the 69-SS insert coupled to the T69S mutation. Both patients were selected because of the lack of signal at positions 69/70 in the LiPA RT test despite being reactive to the remaining probes on the LiPA strip. The presence of the T69SSS complex was confirmed by sequence analysis. A common feature for both subjects was their past history with zidovudine monotherapy and zidovudine plus either didanosine or zalcitabine later on in the presence of persistent virus replication. Remarkably, the introduction of triple therapy in patient 1 soon after the emergence of the insert-containing viral strain produced its total displacement, which correlated with a sustained suppression in viral load.
Genotypic Analysis Methods for Detection of Drug Resistance Mutations in the HIV-1 Proteinase and Reverse Transcriptase Genes
Authors: Sheldon Jonathan G , Condra Jon H
Published: April 2022

Understanding the basis of human immunodeficiency virus (HIV) drug resistance represents a key requirement for individualized HIV patient care. The genotypic data generated to date have already provided significant insight. However, it is clear that the relationship between genotype, phenotype and clinical outcome is complex and still poorly defined. In this review, we describe methods currently available to obtain genotypic data for the HIV-1 proteinase and reverse transcriptase genes. Different sample preparation strategies and DNA sequencing methods are discussed dividing the latter into two categories, those that give sequence information at specific positions and those that provide continuous sequence data for a particular region. In addition, we also address some of the broad biological and technical issues, which must be considered when interpreting the results of these tests and describe the advantages and disadvantages of individual methods.
Antiretroviral Effect of Two Different Dose Regimens of Ritonavir and Saquinavir on HIV-Infected Adults in a Population-Based Setting
Authors: Jahnke Natalie , Seminari Elena , Hogg Robert S , Yip Benita , O'Shaughnessy Michael V , Montaner Julio SG
Published: April 2022

Objective

To characterize the antiviral effect and tolerability of higher dose (HD, 600 mg two times daily) and lower dose (LD, 400 mg two times daily) combination regimens of ritonavir and saquinavir in British Columbia (BC), Canada.

Design

Intent-to-treat analysis with suppression of plasma viral load to levels below 500 copies/ml as the main outcome measure.

Patients

Adult human immunodeficiency virus (HIV)-positive individuals in the province of British Columbia prescribed ritonavir and saquinavir in combination between 1 September 1996 and 30 June 1997, with a minimum of two plasma viral loads, one at baseline and one after the initiation of therapy.

Results

A total of 84 participants [27 HD (32%) and 57 LD (68%)] were prescribed ritonavir and saquinavir. There was no difference at baseline in the two groups with respect to age ( P=0.466), CD4 cell count ( P=0.373) and baseline plasma viral load ( P=0.656). However, LD were more likely to have had prior protease experience than HD participants (65 versus 40%, P=0.037). The median follow-up time was 9 months. A total of 44 (52%) subjects demonstrated a decrease in plasma viral load to levels <500 copies/ml. After adjusting for length of follow-up, baseline CD4 cell count and prior AIDS diagnosis, HD participants were as likely to be suppressed to <500 copies/ml as LD individuals ( P=0.760). HD participants did report more adverse effects ( P=0.042) than LD subjects.

Conclusion

Our results provide confirmatory evidence that lower doses of ritonavir and saquinavir in combination are better tolerated and as effective as the standard doses of these drugs. This response, however, is seriously compromised by prior exposure to protease inhibitors.
Percentage of Adherence Correlates with the Risk of Protease Inhibitor (PI) Treatment Failure in HIV-Infected Patients
Authors: Casado Jose L , Sabido Raquel , Perez-Elías María J , Antela Antonio , Oliva Jesús , Dronda Fernando , Mejía Blanca , Fortún Jesús
Published: April 2022

Objectives

To determine the effect of adherence on the rate of protease inhibitor (PI) treatment failure among human immunodeficiency virus (HIV)-infected patients.

Methods

A prospective study of a cohort of 282 patients who initiated PI therapy from March 1996 to December 1997. Adherence was quantified as the percentage of prescribed doses reportedly taken and treatment failure was defined as HIV RNA levels above 200 copies/ml after 1 year on therapy.

Results

Overall, 190 patients (67%) missed prescribed doses. However, mean percentage of doses taken was 91% (range, 21–100%). Demographic, virological and immunological characteristics could not predict adherence outcomes. The causes of non-adherence included intolerance or side effects (35%), complexity of treatment (23%), or recurrence in active drug abuse (17%), whereas abandonment owing to HIV-related disease was uncommon (6%). A degree of adherence above 90% correlated significantly with viral suppression [relative risk (RR) 1.69; 95% confidence interval (CI) 1.1–2.56; P<0.01]. In a multivariate analysis, a lower degree of adherence (RR, 0.96; P=0.006), a higher HIV viral load (RR, 2.03; P=0.0001), prior antiretroviral therapy (RR, 2.5; P=0.01), and use of saquinavir-hard gel capsules (saquinavir-HGC) (RR, 1.77; P=0.03) were strongly associated with treatment failure.

Conclusion

The percentage of adherence and initial HIV viral load are the most important determinants of virological response to PI therapy and non-adherence is related to treatment-related factors in the majority of cases.
A social identity analysis of how pay inequality divides the workplace
Authors: Tanjitpiyanond Porntida , Jetten Jolanda , Peters Kim
Published: April 2022

The present research examines why organizations with more unequal pay structures have been found to be characterized by a range of negative workplace outcomes. Drawing on the social identity approach, we propose that higher pay disparity can increase the comparative fit of pay categories whereby the organizational “haves” (the highest paid employees) and “have nots” (the lowest paid employees) are more likely to be categorized into distinct social groups. In turn, this can lead to poorer organizational functioning. In two studies, a field survey ( N = 413) and an experiment ( N = 286), we found that higher pay inequality increased the comparative fit of pay categories, which, in turn, was associated with lower superordinate (organizational) identification, higher perceived workplace conflict, higher leader toxicity, and lower perceptions of identity leadership (i.e., a leader who creates a sense of shared identity in the organization). Our research provides novel insights into how higher inequality affects employees’ categorization processes, thereby creating a psychological divide and contributing to organizational dysfunction.
Victimhood beliefs are linked to willingness to engage in intergroup contact with the former adversary through empathy and trust
Authors: Voca Shpend , Graf Sylvie , Rupar Mirjana
Published: April 2022

After intergroup conflicts end, beliefs about past suffering of the ingroup compared to an outgroup influence relations between former adversaries. In Kosovo and Bosnia and Herzegovina, we simultaneously examined the effects of inclusive victimhood (i.e., a belief that both the ingroup and a former adversary suffered similarly) and competitive victimhood (i.e., a belief that the ingroup suffered more than a former adversary) on willingness to engage in contact with a former adversary, a precursor of positive changes in postconflict societies. In one correlational ( NAlbanians = 159; NCroat s = 227) and two experimental studies ( NAlbanians = 161; NCroats = 341, preregistered), inclusive victimhood was linked to higher willingness to engage in contact with former adversaries through higher empathy (Studies 1 to 3) and trust (Studies 1 and 2). In contrast, competitive victimhood was associated with lower willingness to engage in contact through lower empathy (Study 1) and trust (Studies 1 and 3). We discuss the practical implications of our findings for interventions in postconflict societies.
Is all Russian news the same? Framing in Russian news media generated by the Yandex news algorithm for the United States, Estonia, and Russia
Authors: Erbsen Heidi , Põldre Siim
Published: April 2022

In light of the growing concern about the potential for Russian state sponsored media to be used as a propaganda tool, this study uses the Yandex News algorithm to show the differences in Russian news generated for the United States, Estonia, and Russia. The authors apply and build on the traditional studies of news framing in order to (1) identify cases where headlines and articles are framed differently, (2) determine the relationship between the topic and frame used, (3) compare these findings across three countries, and (4) generate discussion surrounding the reasons for similarities and differences in each case. The use of the Yandex news algorithm, which has been a subject of speculation when it comes to Russian news media, sheds light on how the tool displays information in different country contexts and shows that there is a statistical difference in the issues that appear in the algorithm-generated headlines for each country.
Standardized Preoperative Pathways Determining Preoperative Echocardiogram Usage Continue to Improve Hip Fracture Quality
Authors: Esper Garrett , Anil Utkarsh , Konda Sanjit , Furgiuele David , Zaretsky Jonah , Egol Kenneth
Published: April 2022

Introduction

The purpose of this study was to assess the hospital quality measures and outcomes of operative hip fracture patients before and after implementation of an anesthesiology department protocol assigning decision for a preoperative transthoracic echocardiogram (TTE) to the hospitalist co-managing physician.

Materials and Methods

Demographics, injury details, hospital quality measures, and outcomes were reviewed for a consecutive series of patients presenting to our institution with an operative hip fracture. In May of 2019, a new protocol assigning the responsibility to indicate a patient for preoperative TTE was mandated to the co-managing hospitalist at the institution. Patients were split into pre-protocol and post-protocol cohorts. Linear regression modeling and comparative analyses were conducted with a Bonferroni adjusted alpha as appropriate.

Results

Between September 2015 and June 2021, 1002 patients presented to our institution and were diagnosed with a hip fracture. Patients in the post-protocol cohort were less likely to undergo a preoperative echocardiogram, experienced a shorter time (days) to surgery, shorter length of stay, an increase in amount of home discharges, and lower complication risks for urinary tract infection and acute blood loss anemia as compared to those in the pre-protocol cohort. There were no differences seen in inpatient or 30-day mortality. Multivariable linear regression demonstrated a patient’s comorbidity profile (Charlson Comorbidity Index (CCI)) and their date of presentation (pre- or post-protocol), were both associated with (P<0.01) a patients' time to surgery.

Conclusion

A standardized preoperative work flow protocol regarding which physician evaluates and determines which patients require a preoperative TTE allows for a streamlined perioperative course for hip fracture patients. This allows for a shortened time to surgery and length of stay with an increase in home discharges and was associated with a reduced risk of common index hospitalization complications including UTI and anemia.
Influence of surface functionalization of ceramic nanofibers on morphological, physical and mechanical properties of unsaturated polyester nanocomposites
Authors: Kallagunta Harish , Tate Jitendra S
Published: April 2022

Alumina nanofibers at 0.25wt%, 0.5wt%, 0.75wt%, and 1wt% concentration were used to modify unsaturated polyester resin. Additionally, vinyl silane treated alumina nanofibers were used at the same concentrations and were compared to pristine alumina nanofibers. The SEM images showed a variation in the surface morphology when alumina nanofibers and the BET measurement showed surface area increase from 111 m2/g to 122 m2/g when nanofibers were treated with silane agent. The dispersion of alumina nanofibers into the host unsaturated polyester resin was successfully achieved by three roll mill dispersion. The TEM images showed good dispersion of alumina nanofibers in polyester resin. Although pristine nanofibers showed greater agglomeration at 1wt% concentration, the effect of agglomeration was reduced in the 1wt% concentration. The weight loss measurements from TGA showed that the thermal stability of nanocomposites increased with addition of nanofibers and the lower onset degradation temperature can be tailored to improve by a maximum of 5.5% for silane treated nanofiber. Viscosity and contact angle which are key factors affecting the processability has seen to be positively altered by silane treatment. Additional tensile, flexural, and Izod impact properties were evaluated for the nine material systems and the properties were summarized.
First study of extended half-life rFVIIIFc in previously untreated patients with hemophilia A: PUPs A-LONG final results
Authors: Königs Christoph , Ozelo Margareth C. , Dunn Amy , Kulkarni Roshni , Nolan Beatrice , Brown Simon A. , Schiavulli Michele , Gunawardena Sriya , Mukhopadhyay Sutirtha , Jayawardene Deepthi , Winding Bent , Carcao Manuel
Published: April 2022

PUPs A-LONG evaluated the safety and efficacy of recombinant factor VIII Fc fusion protein (rFVIIIFc) in previously untreated patients (PUPs) with hemophilia A. This open-label, phase 3 study enrolled male PUPs (<6 years) with severe hemophilia A to receive rFVIIIFc. The primary endpoint was the occurrence of inhibitor development. Secondary endpoints included annualized bleed rate (ABR). Of 103 subjects receiving ≥1 dose of rFVIIIFc, 80 (78%) were aged <1 year at the study start, 20 (19%) had a family history of inhibitors, and 82 (80%) had high-risk F8 mutations. Twenty subjects began on prophylaxis, while 81 began an on-demand regimen (69 later switched to prophylaxis). Eighty-seven (81%) subjects completed the study. Inhibitor incidence was 31.1% (95% confidence interval [CI], 21.8% to 41.7%) in subjects with ≥10 exposure days (or inhibitor); high-titer inhibitor incidence was 15.6% (95% CI, 8.8% to 24.7%). The median (range) time to high-titer inhibitor development was 9 (4-14) exposure days. Twenty-eight (27%) subjects experienced 32 rFVIIIFc treatment-related adverse events; most were inhibitor development. There was 1 nontreatment-related death due to intracranial hemorrhage (onset before the first rFVIIIFc dose). The overall median (interquartile range [IQR]) ABR was 1.49 (0.00-4.40) for subjects on variable prophylaxis dosing regimens. In this study of rFVIIIFc in pediatric PUPs with severe hemophilia A, overall inhibitor development was within the expected range, although high-titer inhibitor development was on the low end of the range reported in the literature. rFVIIIFc was well-tolerated and effective for prophylaxis and treatment of bleeds. This trial is registered at www.clinicaltrials.gov (NCT02234323).
BMP2/SMAD pathway activation in JAK2/p53-mutant megakaryocyte/erythroid progenitors promotes leukemic transformation
Authors: Li Bing , An Wenbin , Wang Hua , Baslan Timour , Mowla Shoron , Krishnan Aishwarya , Xiao Wenbin , Koche Richard P. , Liu Ying , Cai Sheng F. , Xiao Zhijian , Derkach Andriy , Iacobucci Ilaria , Mullighan Charles G. , Helin Kristian , Lowe Scott W. , Levine Ross L. , Rampal Raajit K.
Published: April 2022

Leukemic transformation (LT) of myeloproliferative neoplasm (MPN) has a dismal prognosis and is largely fatal. Mutational inactivation of TP53 is the most common somatic event in LT; however, the mechanisms by which TP53 mutations promote LT remain unresolved. Using an allelic series of mouse models of Jak2/Trp53 mutant MPN, we identify that only biallelic inactivation of Trp53 results in LT (to a pure erythroleukemia [PEL]). This PEL arises from the megakaryocyte-erythroid progenitor population. Importantly, the bone morphogenetic protein 2/SMAD pathway is aberrantly activated during LT and results in abnormal self-renewal of megakaryocyte-erythroid progenitors. Finally, we identify that Jak2/Trp53 mutant PEL is characterized by recurrent copy number alterations and DNA damage. Using a synthetic lethality strategy, by targeting active DNA repair pathways, we show that this PEL is highly sensitive to combination WEE1 and poly(ADP-ribose) polymerase inhibition. These observations yield new mechanistic insights into the process of p53 mutant LT and offer new, clinically translatable therapeutic approaches.
CD34+CD19−CD22+ B-cell progenitors may underlie phenotypic escape in patients treated with CD19-directed therapies
Authors: Bueno Clara , Barrera Susana , Bataller Alex , Ortiz-Maldonado Valentín , Elliot Natalina , O’Byrne Sorcha , Wang Guanlin , Rovira Montse , Gutierrez-Agüera Francisco , Trincado Juan L. , González-González María , Morgades Mireia , Sorigué Marc , Bárcena Paloma , Zanetti Samanta Romina , Torrebadell Montse , Vega-Garcia Nerea , Rives Susana , Mallo Mar , Sole Francesc , Mead Adam J. , Roberts Irene , Thongjuea Supat , Psaila Bethan , Juan Manel , Delgado Julio , Urbano-Ispizúa Alvaro , Ribera Josep María , Orfao Alberto , Roy Anindita , Menendez Pablo
Published: April 2022

CD19-directed immunotherapies have revolutionized the treatment of advanced B-cell acute lymphoblastic leukemia (B-ALL). Despite initial impressive rates of complete remission (CR) many patients ultimately relapse. Patients with B-ALL successfully treated with CD19-directed T cells eventually relapse, which, coupled with the early onset of CD22 expression during B-cell development, suggests that preexisting CD34+CD22+CD19− (pre)-leukemic cells represent an “early progenitor origin-related” mechanism underlying phenotypic escape to CD19-directed immunotherapies. We demonstrate that CD22 expression precedes CD19 expression during B-cell development. CD34+CD19−CD22+ cells are found in diagnostic and relapsed bone marrow samples of ∼70% of patients with B-ALL, and their frequency increases twofold in patients with B-ALL in CR after CD19 CAR T-cell therapy. The median of CD34+CD19−CD22+ cells before treatment was threefold higher in patients in whom B-ALL relapsed after CD19-directed immunotherapy (median follow-up, 24 months). Fluorescence in situ hybridization analysis in flow-sorted cell populations and xenograft modeling revealed that CD34+CD19−CD22+ cells harbor the genetic abnormalities present at diagnosis and initiate leukemogenesis in vivo. Our data suggest that preleukemic CD34+CD19−CD22+ progenitors underlie phenotypic escape after CD19-directed immunotherapies and reinforce ongoing clinical studies aimed at CD19/CD22 dual targeting as a strategy for reducing CD19− relapses. The implementation of CD34/CD19/CD22 immunophenotyping in clinical laboratories for initial diagnosis and subsequent monitoring of patients with B-ALL during CD19-targeted therapy is encouraged.
The dynamic alteration of transcriptional regulation by crucial TFs during tumorigenesis of gastric cancer
Authors: Yu Beiqin , Dai Wentao , Pang Li , Sang Qingqing , Li Fangyuan , Yu Junxian , Feng Haoran , Li Jianfang , Hou Junyi , Yan Chao , Su Liping , Zhu Zhenggang , Li Yuan-Yuan , Liu Bingya
Published: April 2022

Background

The mechanisms of Gastric cancer (GC) initiation and progression are complicated, at least partly owing to the dynamic changes of gene regulation during carcinogenesis. Thus, investigations on the changes in regulatory networks can improve the understanding of cancer development and provide novel insights into the molecular mechanisms of cancer.

Methods

Differential co-expression analysis (DCEA), differential gene regulation network (GRN) modeling and differential regulation analysis (DRA) were integrated to detect differential transcriptional regulation events between gastric normal mucosa and cancer samples based on GSE54129 dataset. Cytological experiments and IHC staining assays were used to validate the dynamic changes of CREB1 regulated targets in different stages.

Results

A total of 1955 differentially regulated genes (DRGs) were identified and prioritized in a quantitative way. Among the top 1% DRGs, 14 out of 19 genes have been reported to be GC relevant. The four transcription factors (TFs) among the top 1% DRGs, including CREB1, BPTF, GATA6 and CEBPA, were regarded as crucial TFs relevant to GC progression. The differentially regulated links (DRLs) around the four crucial TFs were then prioritized to generate testable hypotheses on the differential regulation mechanisms of gastric carcinogenesis. To validate the dynamic alterations of gene regulation patterns of crucial TFs during GC progression, we took CREB1 as an example to screen its differentially regulated targets by using cytological and IHC staining assays. Eventually, TCEAL2 and MBNL1 were proved to be differentially regulated by CREB1 during tumorigenesis of gastric cancer.

Conclusions

By combining differential networking information and molecular cell experiments verification, testable hypotheses on the regulation mechanisms of GC around the core TFs and their top ranked DRLs were generated. Since TCEAL2 and MBNL1 have been reported to be potential therapeutic targets in SCLC and breast cancer respectively, their translation values in GC are worthy of further investigation.
Roles of ARID1A variations in colorectal cancer: a collaborative review
Authors: Zhao Shankun , Wu Weizhou , Jiang Zufu , Tang Fuqin , Ding Lingzhi , Xu Weifang , Ruan Libin
Published: April 2022

Colorectal cancer (CRC), a common malignancy, is one of the leading cause of cancer death in adults. AT-rich interaction domain 1A (ARID1A), a critical portion of the SWItch/sucrose non-fermentation (SWI/SNF) chromatin remodeling complexes, shows one of the most frequent mutant genes across different human cancer types. Deleterious variations of ARID1A has been recognized to be correlated the tumorigenesis and the poor prognosis of CRC. Here, we summarize recent advances in the clinical implications and molecular pathogenesis of ARID1A variations in CRC. According to independent data of 23 included studies, ARID1A is mutated in 3.6–66.7%. Consistently, all of the 23 relevant studies report that ARID1A functions as a specific tumor suppressor in CRC. Clinically, ARID1A variation status serves as a biomarker for survival prognosis and various therapies for CRC. Mechanistically, the pathophysiologic impacts of ARID1A variations on CRC may be associated with the co-occurrence variations of other genes (i.e., TP53, KRAS, APC, FBXW7, and PIK3CA) and the regulation of several signaling pathways being affected (i.e., WNT signaling, Akt signaling, and MEK/ERK pathway), leading to cell cycle arrest, chromatin remodeling, chromosome organization, and DNA hypermethylation of the cancer cells. The present review highlights ARID1A serving as a potent tumor suppressor and an important prognostic factor in CRC. ARID1A variations hint towards a promising tool for diagnostic tumor profiling and individualized therapeutic targets for CRC in the future.
A comparison of mRNA sequencing (RNA-Seq) library preparation methods for transcriptome analysis
Authors: Ura Hiroki , Togi Sumihito , Niida Yo
Published: April 2022

Background

mRNA sequencing is a powerful technique, which is used to investigate the transcriptome status of a gene of interest, such as its transcription level and splicing variants. Presently, several RNA sequencing (RNA-Seq) methods have been developed; however, the relative advantage of each method has remained unknown. Here we used three commercially available RNA-Seq library preparation kits; the traditional method (TruSeq), in addition to full-length double-stranded cDNA methods (SMARTer and TeloPrime) to investigate the advantages and disadvantages of these three approaches in transcriptome analysis.

Results

We observed that the number of expressed genes detected from the TeloPrime sequencing method was fewer than that obtained using the TruSeq and SMARTer. We also observed that the expression patterns between TruSeq and SMARTer correlated strongly. Alternatively, SMARTer and TeloPrime methods underestimated the expression of relatively long transcripts. Moreover, genes having low expression levels were undetected stochastically regardless of any three methods used. Furthermore, although TeloPrime detected a significantly higher proportion at the transcription start site (TSS), its coverage of the gene body was not uniform. SMARTer is proposed to be yielded for nonspecific genomic DNA amplification. In contrast, the detected splicing event number was highest in the TruSeq. The percent spliced in index (PSI) of the three methods was highly correlated.

Conclusions

TruSeq detected transcripts and splicing events better than the other methods and measured expression levels of genes, in addition to splicing events accurately. However, although detected transcripts and splicing events in TeloPrime were fewer, the coverage at TSS was highest. Additionally, SMARTer was better than TeloPrime with regards to the detected number of transcripts and splicing events among the understudied full-length double-stranded cDNA methods. In conclusion, for short-read sequencing, TruSeq has relative advantages for use in transcriptome analysis.
Ventricular tachycardia ablation guided or aided by scar characterization with cardiac magnetic resonance: rationale and design of VOYAGE study
Authors: Lilli Alessio , Parollo Matteo , Mazzocchetti Lorenzo , De Sensi Francesco , Rossi Andrea , Notarstefano Pasquale , Santoro Amato , Aquaro Giovanni Donato , Cresti Alberto , Lapira Federica , Faggioni Lorenzo , Tessa Carlo , Pauselli Luca , Bongiorni Maria Grazia , Berruezo Antonio , Zucchelli Giulio
Published: April 2022

Background

Radiofrequency ablation has been shown to be a safe and effective treatment for scar-related ventricular arrhythmias (VA). Recent preliminary studies have shown that real time integration of late gadolinium enhancement cardiac magnetic resonance (LGE-CMR) images with electroanatomical map (EAM) data may lead to increased procedure efficacy, efficiency, and safety.

Methods

VOYAGE is a prospective, randomized, multicenter controlled open label study designed to compare in terms of efficacy, efficiency, and safety a CMR aided/guided workflow to standard EAM-guided ventricular tachycardia (VT) ablation. Patients with an ICD or with ICD implantation expected within 1 month, with scar related VT, suitable for CMR and multidetector computed tomography (MDCT) will be randomized to a CMR-guided or CMR-aided approach, whereas subjects unsuitable for imaging or with image quality deemed not sufficient for postprocessing will be allocated to standard of care ablation. Primary endpoint is defined as VT recurrences (sustained or requiring appropriate ICD intervention) during 12 months follow-up, excluding the first month of blanking period. Secondary endpoints will include procedural efficiency, safety, impact on quality of life and comparison between CMR-guided and CMR-aided approaches. Patients will be evaluated at 1, 6 and 12 months.

Discussion

The clinical impact of real time CMR-guided/aided ablation approaches has not been thoroughly assessed yet. This study aims at defining whether such workflow results in more effective, efficient, and safer procedures. If proven to be of benefit, results from this study could be applied in large scale interventional practice.

Trial registrationClinicalTrials.gov, NCT04694079, registered on January 1, 2021.
Nasal cartilage destruction associated to cutaneous histoplasmosis in AIDS
Authors: Escalante Luis , Granizo-Rubio Jennyfer , Pinos-León Victor , Tello Sonia , Maldonado Astrid , Cherrez-Ojeda Iván
Published: April 2022

Background

Systemic histoplasmosis is a disease of high morbidity and mortality in immunocompromised patients. Patients with AIDS get the infection through inhalation of spores, triggering a primary lung infection with a subsequent hematogenous spread to multiple organs, including the skin. Tissue necrosis have been documented in cutaneous histoplasmosis with multiple clinical manifestations that mimic other diseases.

Case presentation

We report the case of nasal cartilage destruction associated to cutaneous histoplasmosis in AIDS. A 24-year-old man, resident in Ecuadorian coast, with a history of HIV for 7 years without any treatment. In the last 3 months, he has been presenting a molluscum-like lesions on his nasal bridge with subsequent dissemination to the trunk and extremities. He was admitted to the emergency department for dyspnoea, cough, and malaise. Due to his respiratory failure, he was admitted to the intensive care unit (ICU) with mechanical ventilation. Physical examination reveals a crusted surface ulcer that involves the nose and cheeks, associated with erythematous papules, some with a crusted surface which are spread to the face, trunk, and upper limbs. The patient has a specific skin involvement with a butterfly-like ulcer appearance and destruction of the upper and lower lateral cartilage of the nose. At admission CD4 cell count was 11/mm3 with a HIV viral load of 322,908 copies. Mycological cultures identified Histoplasma capsulatum. A treatment with highly active antiretroviral therapy (HAART) was stablished, associated with liposomal amphotericin B at a dose of 3 mg/kg/day and itraconazole 200 mg twice a day for 12 months.

Conclusions

Cutaneous histoplasmosis is a rare manifestation of pulmonary histoplasmosis in patients with AIDS. The cutaneous manifestations included papules, nodules, plaques, and ulcers. A histology examination is required to rule out other fungal or parasitic infections. Treatment includes highly active antiretroviral therapy (HAART), amphotericin B liposomal and itraconazole, the latest for at least 12 months.
Factors associated with fetal karyotype in spontaneous abortion: a case-case study
Authors: Xu Qinghua , Chan Ying , Feng Yun , Zhu Baosheng , Yang Bicheng , Zhu Shu , Su Lingyun , Zou Li , Feng Na , Li Yan
Published: April 2022

Background

Most embryos that spontaneously abort during early pregnancy are found to have chromosomal abnormalities. The purpose of this study is to explore the factors involved in chromosome aberrations during embryogenesis.

Methods

A case-case study was performed to compare the risk factors for spontaneous abortion with and without embryo chromosome aberration. A total of 160 cases of spontaneous abortion were enrolled from a tertiary general hospital in Kunming. KaryoLite BACs-on-Beads (KL-BoBs) and fluorescence in situ hybridization (FISH) were employed to determine chromosomal constitution of abortion chorion villus samples. Maternal serum levels of homocysteine (Hcy) were detected by high performance liquid chromatography-tandem mass spectrometry (HPLC-MS/MS). Information about clinical background and environmental exposure was collected through a self-designed questionnaire. To identify the inherited chromosomal abnormalities, couples with chromosomal abnormalities in abortus were recalled for karyotyping.

Results

The overall rate of chromosomal abnormalities was 62.5% (100/160, KL-BoBs combined with FISH) including 51.9% (83/160) aneuploidies, 6.3% (10/160) polyploidies, and 4.4% (7/160) structural abnormalities. Only one case of structural abnormality was found to be inherited from maternal balanced translocation. Compared to abortus with normal karyotype, abortus with abnormal karyotype showed a positive association with parental age and elevated maternal serum homocysteine (Hcy) level, but negative association with previous miscarriage and perceived noise.

Conclusions

Embryonic chromosomal aberrations accounted for the majority of spontaneous abortion cases. A combination of internal and external factors may induce spontaneous abortion through fetal chromosomal aberrations or other pathogenic mechanisms.
Breaking the silence about obstetric violence: Body mapping women’s narratives of respect, disrespect and abuse during childbirth in Bihar, India
Authors: Mayra Kaveri , Sandall Jane , Matthews Zoë , Padmadas Sabu S.
Published: April 2022

Background

Evidence on obstetric violence is reported globally. In India, research shows that almost every woman goes through some level of disrespect and abuse during childbirth, more so in states such as Bihar where over 70% of women give birth in hospitals.

Objective

1) To understand how women experience and attach meaning to respect, disrespect and abuse during childbirth; and 2) document women’s expectations of respectful care.

Methods

‘Body mapping’, an arts-based participatory method, was applied. The analysis is based on in-depth interviews with eight women who participated in the body mapping exercise at their homes in urban slums and rural villages. Analysis was guided by feminist relational discourse analysis.

Findings

Women reported their experiences of birthing at home, public facilities, and private hospitals in simple terms of what they felt ‘good’ and ‘bad’. Good experiences included being spoken to nicely, respecting privacy, companion of choice, a bed to rest, timely care, lesser interventions, obtaining consent for vaginal examination and cesarean section, and better communication. Bad experiences included unconsented interventions including multiple vaginal examinations by different care providers, unanesthetized episiotomy, repairs and uterine exploration, verbal, physical, sexual abuse, extortion, detention and lack of privacy.

Discussion

The body maps capturing birth experiences, created through a participatory method, accurately portray women’s respectful and disrespectful births and are useful to understand women’s experience of a sensitive issue in a patriarchal culture. An in-depth understanding of women’s choices, experiences and expectations can inform changes practices in and policies and help to develop a culture of sharing birth experiences.
Mistreatment during childbirth and postnatal period reported by women in Nepal —a multicentric prevalence study
Authors: Gurung Rejina , Moinuddin Md , Sunny Avinash K. , Bhandari Amit , Axelin Anna , KC Ashish
Published: April 2022

Introduction

Trust of women and families toward health institutions has led to increased use of their services for childbirth. Whilst unpleasant experience of care during childbirth will halt this achievement and have adverse consequences. We examined the experience of women regarding the care received during childbirth in health institutions in Nepal.

Method

A prospective cohort study conducted in 11 hospitals in Nepal for a period of 18 months. Using a semi-structured questionnaire based on the typology of mistreatment during childbirth, information on childbirth experience was gathered from women (n = 62,926) at the time of discharge. Using those variables, principal component analysis was conducted to create a single mistreatment index. Bivariate and multivariate linear regression analyses were conducted to assess the association of the mistreatment index with sociodemographic, obstetric and newborn characteristics.

Result

A total of 62,926 women were consented and enrolled in the study. Of those women, 84.3% had no opportunity to discuss any concerns, 80.4% were not adequately informed before providing care, and 1.5% of them were refused for care due to inability to pay. According to multivariate regression analysis, women 35 years or older (β, − 0.3587; p-value, 0.000) or 30–34 years old (β,− 0.38013; p-value, 0.000) were less likely to be mistreated compared to women aged 18 years or younger. Women from a relatively disadvantaged (Dalit) ethnic group were more likely to be mistreated (β, 0.29596; p-value, 0.000) compared to a relatively advantaged (Chettri) ethnic group. Newborns who were born preterm (β, − 0.05988; p-value, 0.000) were less likely to be mistreated than those born at term.

Conclusion

The study reports high rate of some categories of mistreatment of women during childbirth. Women from disadvantaged ethnic group, young women, and term newborns are at higher risk of mistreatment. Strengthening health system and improving health workers’ readiness and response will be key in experience respectful care during childbirth.