bluuebunny/crossref_metadata_2025_split huggingface dataset:
A truncated derivative of FGFR1 kinase cooperates with FLT3 and KIT to transform hematopoietic stem cells in syndromic and de novo AML
Authors: Cai Baohuan , Liu Yun , Chong Yating , Mori Stephanie Fay , Matsunaga Atsuko , Zhang Hualei , Fang Xuexiu , Chang Chang-Sheng , Cowell John K. , Hu Tianxiang 
Published: July 2022

Abstract
Background
Myeloid and lymphoid malignancies associated with chimeric FGFR1 kinases are the hallmark of stem cell leukemia and lymphoma syndrome (SCLL). In all cases, FGFR1 kinase is constitutively phosphoactivated as a result of chromosome translocations, which lead to acquisition of dimerization motifs in the chimeric proteins. Recently, we demonstrated that these chimeric kinases could be cleaved by granzyme B to generate a truncated derivative, tnFGFR1, which localized exclusively into the nucleus and was not phosphorylated.

Methods
Stem cell transduction and transplantation in syngeneic mice was used to assess the transforming ability of tnFGFR1 in bone marrow stem cells, and RPPA and RNA-Seq was used to examine the related signaling pathways and regulated target genes.

Results
For the first time, we show that this non-classical truncated form of FGFR1 can independently lead to oncogenic transformation of hematopoietic stem cells in an animal model in vivo. These leukemia cells show a mixed immunophenotype with a B-cell B220 + Igm- profile in the majority of cells and Kit+ in virtually all cells, suggesting a stem cell disease. tnFGFR1, however, does not activate classic FGFR1 downstream signaling pathways but induces a distinct profile of altered gene expression with significant upregulation of transmembrane signaling receptors including FLT3 and KIT. We further show that de novo human AML also express tnFGFR1 which correlates with upregulation of FLT3 and KIT as in mouse leukemia cells. ChIP analysis demonstrates tnFGFR1 occupancy at the Flt3 and Kit promoters, suggesting a direct transcriptional regulation. Cells transformed with tnFGFR1 are insensitive to FGFR1 inhibitors but treatment of these cells with the Quizartinib (AC220) FLT3 inhibitor, suppresses in vitro growth and development of leukemia in vivo. Combined treatment with FGFR1 and FLT3 inhibitors provides increased survival compared to FGFR1 inhibition alone.

Conclusions
This study demonstrates a novel model for transformation of hematopoietic stem cells by chimeric FGFR1 kinases with the combined effects of direct protein activation by the full-length kinases and transcriptional regulation by the truncated nuclear tnFGFR1 derivative, which is associated with GZMB expression levels. Genes significantly upregulated by tnFGFR1 include Flt3 and Kit which promote a leukemia stem cell phenotype. In human AML, tnFGFR1 activation leads to increased FLT3 and KIT expression, and higher FLT3 and GZMB expression levels are associated with an inferior prognosis. These observations provide insights into the relative therapeutic value of targeting FGFR1 and FLT3 in treating AML with this characteristic gene expression profile.
Oxygen regulates ILC3 antigen presentation potential and pregnancy-related hormone actions
Authors: Einenkel Rebekka , Ehrhardt Jens , Zygmunt Marek , Muzzio Damián Oscar 
Published: July 2022

AbstractEarly pregnancy is marked by placentation and embryogenesis, which take place under physiological low oxygen concentrations. This oxygen condition is crucial for many aspects of placentation, trophoblast function, vascularization and immune function. Recently, a new family of innate lymphoid cells has been found to be expressed at the fetomaternal interface. Among these, type 3 innate lymphoid cells (ILC3) are important antigen presenting cells in the context of MHC-II. The expression of MHC-II on ILC3s during pregnancy is reduced. We tested the hypothesis that low oxygen concentrations reduce the potential of ILC3s to present antigens promoting fetal tolerance.Using an in vitro approach, NCR+ILC3s generated from cord blood stem cell precursors were incubated under different O2concentrations in the presence or absence of the pregnancy-related hormones hCG and TGF-β1. The expression of MHC-II, accessory molecules and an activation marker were assessed by flow cytometry. We observed that 1% O2reduced the expression of the MHC-II molecule HLA-DR as compared to 21% O2and modulated the relative effects of hCG and TGF-β1.Our data indicate that low oxygen concentrations reduce the antigen presentation potential of NCR+ILC3s and suggest that it may promote fetal tolerance during the first trimester of pregnancy.
Dual contraceptives and associated predictors in HIV positive women: a case–control study
Authors: Ashore Alemu , Erkalo Desta , Prakash Ravi 
Published: July 2022

Abstract
Background
People living with the human immune deficiency virus (PLHIV) are an important group to address HIV prevention. Mostly, 90% of the HIV cases in children are usually through mother-to-child transmission. Dual contraception (barrier condoms i.e., male, and female condoms) are one of the most effective ways to avoid HIV transmission. Thus, the present study was carried out to establish the predictors associated with the use of dual contraceptives in sexually active HIV positive women in Hossana, Southern Ethiopia.

Methods
An institution based unmatched case–control study among randomly selected 312 sexually active HIV positive women was conducted from February 2021 to May 2021. The data were collected through structured questionnaire and anti-retroviral treatment (ART) cards considering the case-to-control ratio of 1:3. The information was coded, entered into Epi-Info7.0 and exported to SPSS 20.0 for further analysis. A P-value < 0.25 in bi-variate analysis was further processed for multi-variate analysis and P-value < 0.05 was considered statistically significant.

Results
A response rate of 97.2% was recorded. A significant difference was observed towards the use of dual contraceptives in sexually active HIV positive women living in urban vs rural areas (AOR = 0.28; 95% CI = 0.09–0.84), having sexual intercourse with a regular partner (AOR = 3.77; 95% CI = 1.48–9.55) and taking first initiation to use (AOR = 0.05; 95% CI = 0.02–0.11).

Conclusion
The determinants associated with lower use of dual contraceptives were residing in rural areas, sexual intercourse with a regular partner and low initiation rate at first time for use of dual contraceptives. Therefore, we strongly recommend that open discussion about sexually transmitted infections like HIV and their prevention, providing adequate facilities in rural areas can help to prevent HIV transmission and reduce the disease burden. The health professionals are encouraged to organize awareness campaigns in rural areas for use of dual contraceptives among PLHIV.
Adjunct diagnostic value of radiological findings in mucopolysaccharidosis type IVa-related thoracic spinal abnormalities: a pilot study
Authors: Jan Ya-Ting , Tsai Pei-Shan , Huang Wen-Hui , Huang Shih-Chieh , Liu Yu-Peng , Cheng She-Meng , Huang Kun-Shuo 
Published: July 2022

Abstract
Background
In patients with mucopolysaccharidosis (MPS), systematic assessment and management of cervical instability, cervicomedullary and thoracolumbar junction spinal stenosis and spinal cord compression averts or arrests irreversible neurological damage, improving outcomes. However, few studies have assessed thoracic spinal involvement in MPS IVa patients. We aimed to evaluate thoracic spinal abnormalities in MPS IVa patients and identify associated image manifestations by CT and MRI study.

Results
Data of patients diagnosed and/or treated for MPS IVa at MacKay Memorial Hospital from January 2010 to December 2020 were extracted from medical records and evaluated retrospectively. Computed tomography (CT), plain radiography and magnetic resonance imaging (MRI) findings of MPS IVa-related spinal abnormalities were reviewed. Spine CT and plain radiography findings of 12 patients (6 males and 6 females with median age 7.5 years, range 1–28 years) revealed two subtypes of spinal abnormalities: thoracic kyphosis apex around T2 (subtype 1, n = 8) and thoracic kyphosis apex around T5 (subtype 2, n = 4). Spine CT and plain radiography clearly identified various degrees of thoracic kyphosis with apex around T2 or T5 in MPS IVa patients. Square-shaped to mild central beaking in middle thoracic vertebral bodies was observed in subtype 1 patients, while greater degrees of central beaking in middle thoracic vertebral bodies was observed in subtype 2 patients.

Conclusions
Spine CT findings clearly identify new radiological findings of thoracic kyphosis apex around T2 or T5 in MPS IVa patients. The degrees of central beaking at middle thoracic vertebral bodies may be a critical factor associated with different image presentations of thoracic kyphosis.
Salmonella serovars in sheep and goats and their probable zoonotic potential to humans in Suez Canal Area, Egypt
Authors: Hawwas Hanan Abd El-Halim , Aboueisha Abdel-Karim Mahmoud , Fadel Hanaa Mohamed , El-Mahallawy Heba Sayed 
Published: July 2022

Abstract
Background
Salmonella is one of the most common and economically important zoonotic pathogens. This study aimed to determine the occurrence of Salmonella serovars in sheep and goats and their probable zoonotic risk to humans in Suez Canal area in Egypt. A total of 320 fecal samples from sheep (n = 120), goats (n = 100), and humans (n = 100) were collected and examined for the presence of Salmonella based on cultural and biochemical characteristics, and serological analysis. Moreover, the virulence of the identified Salmonella isolates was assessed by molecular screening for invA, stn, spvC, and sopB virulence genes using PCR.

Results
Overall, the occurrence of Salmonella in sheep feces (23.3%) was higher than that in goat feces (7%) and human stool (13%) in the study area. The identified isolates belonged to 12 serotypes; ten, five, and eight from sheep, goats, and humans, respectively. The most frequently identified serotypes were S. Typhimurium from sheep feces, and S. Enteritidis from both goat feces and human stool, with four serotypes; S. Typhimurium, S. Enteritidis, S. Dublin and S. Saintpaul, were mutually shared between all of them. Demographic data revealed that diarrheic sheep (85.7%) and goats (25%) had a higher risk for Salmonella fecal carriage than non-diarrheic ones (19.5% and 6.25%, respectively). The prevalence of Salmonella infection in humans in contact with sheep and goats (28%) was significantly higher than its prevalence in people having a history of contact with animals other than sheep and goats (10%) and those having no history of animal contact (7.3%) (χ2 = 6.728, P ˂ 0.05). The stn, spvC, and sopB genes were detected in 98.1% of the isolates, with a significant, very strong positive correlation for their mutual presence (P < 0.05). Approximately 40.7% of isolates that carried the invA gene had a non-significant, very weak positive correlation with other virulence genes. The most common genotypic virulence profile for all isolates was stn, spvC, and sopB; however, invA, stn, spvC, and sopB was the frequent virulotype for S. Typhimurium, S. Tsevie, S. Apeyeme, and S. Infantis.

Conclusions
The present study highlights the role of apparently healthy and diarrheic sheep and goats as reservoirs and sources of human infection with virulent Salmonella serovars in the Suez Canal area.
Depression and suicidal behavior among adolescents living with HIV in Botswana: a cross-sectional study
Authors: Olashore Anthony A. , Paruk Saeeda , Tshume Ontibile , Chiliza Bonginkosi 
Published: July 2022

Abstract
Background
Depression and suicidal behavior are the main causes of disability and morbidity, especially in adolescents living with HIV (ALWHIV). Data regarding these are lacking in Botswana, a country with a predominantly youthful population and ranked among the top four in the world most affected by HIV. Therefore, the present study aimed to estimate the prevalence of depression and suicidal behavior and explore their associated factors in Botswana ALWHIV.

Methods
Responses were obtained from 622 ALWHIV using the DSM-5 and the Mini-International Neuropsychiatric Interview for Children and Adolescents.

Results
The mean age (SD) of the participants was 17.7 (1.60) years and more males (54.3%) participated than females. Depression and suicidal behavior rates among adolescents were 23% and 18.9%, respectively. Female participants were more likely to be depressed (AOR = 1.96; 95% CI 1.11–3.45) and have suicidal behaviour (AOR = 6.60; 95% CI 3.19–13.7). Loss of mother (AOR = 2.87; 95% CI 1.08–7.62) and viral load of 400 copies and above (AOR = 5.01; 95% CI 2.86–8.78) were associated with depression. Alcohol use disorder (AOR = 3.82; 95% CI 1.83–7.96) and negative feelings about status (AOR = 8.79; 95% CI 4.62–16.7) were associated with suicidal behavior. Good support (AOR = 0.42; 95% CI 0.23–0.76) and increased frequency of religious activities were protective (AOR = 0.33; 95% CI 0.14–0.79) against depression and suicidal behaviour, respectively.

Conclusion
Therefore, routine psychologic screening, which includes identifying psychological stressors and maladaptive coping, family and caregiver support services, and psychosocial support platforms, should be integrated into the management package for ALWHIV in Botswana.
Congenital hypothyroidism after newborn screening program reorganization in the Apulia region
Authors: Simonetti Simonetta , D’Amato Gabriele , Esposito Benedetta , Chiarito Mariangela , Dentico Domenico , Lorè Tania , Cardinali Roberta , Russo Silvia , Laforgia Nicola , Faienza Maria Felicia 
Published: July 2022

Abstract
Background
Congenital hypothyroidism (CH) is the most frequent congenital endocrine disorder. The purpose of the present study was to evaluate the incidence and etiological classification of CH in Apulia in a three-year period according to the reorganization of the regional screening program in a single central laboratory, as well as to analyze the growth characteristics and the associated risk factors of the CH newborns diagnosed during the study period.

Methods
Data derived from the reorganization of the newborn screening program for CH in a single central laboratory that collects dried blood spot (DBS) from 27 Maternity Hospitals are analyzed over a three-year period. Birth weight and length, daily dose of L-T4 at specific key points (3, 6, 12 and 18 months, 2, 2.5 and 3 years) were also obtained from medical records of the CH newborns during the study period and calculated as standard deviation score (SDS).

Results
The screening program diagnosed 90 newborns with confirmed CH (incidence 1:990; recall rate: 3.6%). In detail, 75.6% newborns had an eutopic thyroid, and 24.4% had thyroid dysgenesis; 33 out of the 90 newborns (36.6%) had one or more risk factors. Among these, the multiple pregnancies are the most important because they tripled the risk of CH. At diagnosis, TSH levels were different between patients with dysgenesis and those with an eutopic thyroid (p = 0.005). Treatment was started at a mean of 18.5 ± 12.8 days of life. The mean starting dose of levothyroxine (L-T4) was 11.38 ± 2.46 μg/kg/day.

Conclusions
The results of these study show an increase of CH cases in newborns with an eutopic thyroid compared to the traditional classification. The centralization of the screening program allows a closer cooperation between laboratory and clinical centers and facilitates the implementation of appropriate diagnostic evaluations and timely initiation of treatment, with positive effects on the management of the condition.
Distal Arthrogryposis type 5 in an Italian family due to an autosomal dominant gain-of-function mutation of the PIEZO2 gene
Authors: Serra Gregorio , Antona Vincenzo , Cannata Chiara , Giuffrè Mario , Piro Ettore , Schierz Ingrid Anne Mandy , Corsello Giovanni 
Published: July 2022

AbstractBackgroundArthrogryposis multiplex congenita (AMC) is a group of clinically and etiologically heterogeneous conditions, characterized by prenatal onset contractures affecting two or more joints. Its incidence is about 1 in 3000 live births. AMC may be distinguished into amyoplasia, distal and syndromic arthrogryposis. Distal arthrogryposis (DA) predominantly affects hands and feet. It is currently divided into more than ten subtypes (DA1, DA2A/B, DA3–10), based on clinical manifestations, gene mutations and inheritance pattern. Among them, only a few patients with DA5 have been reported. It is associated to a gain-of-function pathogenic variant of thePIEZO2gene, encoding for an ion-channel necessary to convert mechanical stimulus to biological signals and crucial for the development of joints, neuromuscular and respiratory systems. Main clinical features include multiple distal contractures, short stature, ptosis, ophthalmoplegia and, in some cases, restrictive lung disease.Case presentationHereby, we report on a four-generation Italian family with DA5. Our first proband was a newborn with prenatal suspicion of AMC. At birth, clinical findings were compatible with a DA diagnosis. Family history was positive for the mother withshort stature,ophthalmoplegia, short neck, and contractures of the joints of distal extremities, and for three other relatives on the maternal side, including grandfather and great-grandmother, who all shared similar findings. Thus, we performed a next generation sequencing analysis (NGS) of the genes associated to AMC and of those involved in DA. The gain-of-function heterozygous mutation c.8181_8183delAGA (p.Glu2727del) ofPIEZO2was identified in the proband, and the same mutation was also found in the mother, confirming the autosomal dominant inheritance of the condition.ConclusionsOur patients contribute to the current DA5 genomic database, and to a better characterization of the disease. Clinicians may have suspicion of a DA diagnosis based on suggestive (also prenatal) clinical findings, which must be then confirmed by NGS analysis. Since natural history varies widely among different DA disorders, detection of the underlying causal variant is essential for the identification of the exact subtype, and to its adequate management, which must rely on a multidisciplinary and individualized approach.
Novel de novo missense mutation in the interferon regulatory factor 6 gene in an Italian infant with IRF6-related disorder
Authors: Schierz Ingrid Anne Mandy , Amoroso Salvatore , Antona Vincenzo , Giuffrè Mario , Piro Ettore , Serra Gregorio , Corsello Giovanni 
Published: July 2022

Abstract
Background
Congenital maxillomandibular syngnathia is a rare craniofacial anomaly leading to difficulties in feeding, breathing and ability to thrive. The fusion may consist of soft tissue union (synechiae) to hard tissue union. Isolated cases of maxillomandibular fusion are extremely rare, it is most often syndromic in etiology.

Case presentation
Clinical management of a female newborn with oromaxillofacial abnormities (synechiae, cleft palate, craniofacial dysmorphisms, dental anomaly) and extraoral malformations (skinfold overlying the nails of both halluces, syndactyly, abnormal external genitalia) is presented. The associated malformations addressed to molecular genetic investigations revealing an interferon regulatory factor 6 (IRF6)-related disorder (van der Woude syndrome/popliteal pterygium syndrome). A novel de novo heterozygous mutation in exon 4 of IRF6 gene on chromosome 1q32.2, precisely c.262A > G (p.Asn88Asp), was found. Similarities are discussed with known asparagine missense mutations in the same codon, which may alter IRF6 gene function by reduced DNA-binding ability. A concomitant maternal Xp11.22 duplication involving two microRNA genes could contribute to possible epigenetic effects.

Conclusions
Our reported case carrying a novel mutation can contribute to expand understandings of molecular mechanisms underlying synechiae and orofacial clefting and to correct diagnosing of incomplete or overlapping features in IRF6-related disorders. Additional multidisciplinary evaluations to establish the phenotypical extent of the IRF6-related disorder and to address family counseling should not only be focused on the surgical corrections of syngnathia and cleft palate, but also involve comprehensive otolaryngologic, audiologic, logopedic, dental, orthopedic, urological and psychological evaluations.
A longitudinal assessment of trial protocols approved by research ethics committees: The Adherance to SPIrit REcommendations in the UK (ASPIRE-UK) study
Authors: Speich Benjamin , Odutayo Ayodele , Peckham Nicholas , Ooms Alexander , Stokes Jamie R. , Saccilotto Ramon , Gryaznov Dmitry , von Niederhäusern Belinda , Copsey Bethan , Altman Douglas G. , Briel Matthias , Hopewell Sally 
Published: July 2022

Abstract
Background
To assess the quality of reporting of RCT protocols approved by UK research ethics committees before and after the publication of the Standard Protocol Items: Recommendations for Interventional Trials (SPIRIT) guideline.

Methods
We had access to RCT study protocols that received ethical approval in the UK in 2012 (n=103) and 2016 (n=108). From those, we assessed the adherence to the 33 SPIRIT items (i.e. a total of 64 components of the 33 SPIRIT items). We descriptively analysed the adherence to SPIRIT guidelines as proportion of adequately reported items (median and interquartile range [IQR]) and stratified the results by year of approval and sponsor.

Results
The proportion of reported SPIRIT items increased from a median of 64.9% (IQR, 57.6–69.2%) in 2012 to a median of 72.5% (IQR, 65.3–78.3%) in 2016. Industry-sponsored RCTs reported more SPIRIT items in 2012 (median 67.4%; IQR, 64.1–69.4%) compared to non-industry-sponsored trials (median 59.8%; IQR, 46.5–67.7%). This gap between industry- and non-industry-sponsored trials increased in 2016 (industry-sponsored: median 75.6%; IQR, 71.2–79.0% vs non-industry-sponsored: median 65.3%; IQR, 51.6–76.3%).

Conclusions
The adherence to SPIRIT guidelines has improved in the UK from 2012 to 2016 but remains on a modest level, especially for non-industry-sponsored RCTs.