bluuebunny/crossref_metadata_2025_split huggingface dataset:
Successful haploidentical hematopoietic stem cell transplantation for activated phosphoinositide 3-kinase δ syndrome: Case report and literature review
Authors: Yang Xiaolan , Xi Rui , Bai Jiaofeng , Pan Yaozhu 
Published: February 2023

Rationale:
Activated phosphoinositide 3-kinase δ syndrome (APDS), a recently described primary immunodeficiency,is caused by autosomal dominant mutation in the phosphatidylinositol-4,5-bisphosphate 3-kinase catalytic subunit delta(PIK3CD) gene encoding the p110δ catalytic subunit of PI3Kδ (APDS1) or the PIK3R1 gene that encodes the p85α regulatory subunit of PI3Kδ (APDS2). Gain-of-function mutation of PIK3CD in APDS1 leads to p110δ hyperactivity, with the result of the hyperphosphorylation of downstream mediators of Akt and mammalian target of rapamycin that cause a series of clinical symptoms. Few cases with APDS were reported in Asia.

Patient concerns:
We report a 6-year-old patient with a recurrent respiratory infection, cryptosporidium enteritis, lymphoproliferation, high serum immunoglobulin-M level, anemia, and inverted CD4+/CD8+ ratio. The whole exome sequencing confirmed a heterozygous missense mutation c.3061G>A（p.E1021K）in patient and her mother. Her mutant gene is inherited from her mother, but her mother has not any clinical symptoms.

Diagnoses:
Activated phosphoinositide 3-kinase δ syndrome.

Interventions:
The patient was received immunoglobulin (Ig) replacement therapy, antibiotics, and rapamycin treatment. Through effectively controlling infection and optimal timing of transplantation by adjusting the conditioning regimen, haploidentical Hematopoietic Stem Cell Transplantation(haplo-HSCT) from her brother was successfully performed.

Outcomes:
The patient is in good condiion with a good quality of life after 20 months of follow-up.

Lessons:
We reported a rare APDS1 case with PIK3CDE1021K gene mutation, Successfully treated with haplo-HSCT. This case provided a reference for treating APDS with haplo-HSCT.
Investigation of the efficacy and pharmacological mechanism of Danhong injections for treating chronic obstructive pulmonary disease: A PRISMA-compliant meta-analysis and network pharmacology analysis
Authors: Gao Xiaoyu , Gao Jinsong 
Published: February 2023

Background:
Accumulating evidence supported the clinical efficacy of Danhong injection (DHI) on chronic obstructive pulmonary disease (COPD). It is urgent to summarize the effects of DHI on various outcomes in COPD patients and to elucidate the molecular mechanisms of DHI in treating COPD.

Methods:
Eligible studies were retrieved from 6 databases including China national knowledge infrastructure, Wangfang, VIP, web of science, PubMed, and Embase. The heterogeneity across studies was tested using the I
2 statistic and the quality of studies was assessed. The pooled evaluation of outcomes was calculated using a fix- or random-effect model according to the heterogeneity. The underlying mechanism of DHI in treating COPD was analyzed using network pharmacology.

Results:
A total of 34 eligible studies with a general medium quality were included in the meta-analysis. The pooled data showed that DHI intervention significantly increased clinical efficacy as compared to routine treatment. Meanwhile, our data also revealed that the addition of DHI markedly improved hemorheological indicators, lung function index, arterial blood gas index, and as well as blood coagulation functions. However, the current meta-analysis lacked sufficient data to support the significant effect of DHI on prothrombin time and activated partial thromboplastin time. Network pharmacology found 59 candidate targets of DHI in treating COPD, and enrichment analysis found these targets were associated with lymphocyte proliferation and activation, glucocorticoid receptor signaling, TREM1 signaling, IL-12 signaling and production in macrophages, and aryl hydrocarbon receptor signaling. Multiple core targets including AKT1, TNF, and IL1B, etc. Were identified and might play an important role in the action of DHI against COPD.

Conclusion:
Taken together, this study suggested that DHI could ameliorate hemorheological indicators, lung function, arterial blood gas, and as well as coagulation functions of COPD patients and elucidate the underlying mechanism of DHI against COPD.
Antitumor activity of intraperitoneal paclitaxel in orthotopic patient-derived xenograft models of mucinous appendiceal adenocarcinoma
Authors: Ito Ichiaki , Yousef Abdelrahman MG , Dickson Princess N , Naini Zahra A , White Michael G , Fleten Karianne G , Flatmark Kjersti , Fournier Keith F , Fowlkes Natalie W , Shen John Paul 
Published: February 2023

AbstractAppendiceal adenocarcinomas (AAs) are a rare and heterogeneous mix of tumors for which few preclinical models exist. The rarity of AA has made performing prospective clinical trials difficult, and in part because of this AA remains an orphan disease with no chemotherapeutic agents approved by the FDA for its treatment. AA has a unique biology in which it frequently forms diffuse peritoneal metastases, but almost never spreads via a hematogenous route and rarely spreads to lymphatics. Given its localization to the peritoneal space we hypothesized that intraperitoneal (IP) delivery of chemotherapy could be an effective treatment strategy. Here we tested the efficacy paclitaxel given by IP administration using three orthotopic PDX models of AA established in NSG mice. Weekly treatment of 25.0 mg/kg of IP paclitaxel dramatically reduced AA tumor growth in TM00351 (81.9% reduction vs. control), PMP-2 (98.3% reduction vs. control), and PMCA-3 (71.4% reduction vs. control) PDX models. Comparing the safety and efficacy of intravenous (IV) to IP administration in PMCA-3, neither 6.25 nor 12.5 mg/kg of IV paclitaxel significantly reduced tumor growth. These results suggest that IP administration of paclitaxel is favorable to IV administration. Given the established safety record of IP paclitaxel in gastric and ovarian cancers, and lack of effective chemotherapeutics for AA, these data showing the activity of IP paclitaxel in orthotopic PDX models of mucinous AA support the evaluation of IP paclitaxel in a prospective clinical trial.
Safety, Virology, Pharmacokinetics, and Clinical Experience of High-dose Intravenous Sotrovimab for the Treatment of Mild to Moderate COVID-19: An Open-label Clinical Trial
Authors: Moya Jaynier , Temech Marisol , Parra Sergio , Juarez Erick , Hernandez-Loy Reinaldo , Moises Gutierrez Juan C. , Diaz Jorge , Hussain Rubaba , Segal Scott , Xu Claire , Skingsley Andrew , Schnell Gretja , El-Zailik Asma , Sager Jennifer E. , Aldinger Melissa , Alexander Elizabeth L. , Acloque Gerard 
Published: February 2023

ABSTRACTBackground500 mg intravenous (IV) sotrovimab has been shown to be well tolerated and efficacious against pre-Omicron strains in treating patients with mild to moderate coronavirus disease 2019 (COVID-19) at high risk for disease progression.MethodsThis was an open-label, single-arm substudy of phase 3 COMET-TAIL (NCT04913675) assessing the safety and tolerability of a 2000 mg IV dose of sotrovimab. Symptomatic patients (aged ≥18 years) with COVID-19 at high risk for progression were enrolled from June 30 through July 11, 2022, when Omicron BA.5, BA.2.12.1, and BA.4 were the predominant circulating variants in the United States. The primary endpoint was occurrence of adverse events (AEs), serious AEs (SAEs), AEs of special interest, and COVID-19 disease-related events (DREs) through Day 8. Safety, pharmacokinetics, viral load, and hospitalization >24 hours for acute management of illness or death through Day 29 were assessed.ResultsAll participants (n=81) were Hispanic, 58% were female, and 51% were aged ≥55 years. Through Day 8, no AEs, including infusion-related reactions or hypersensitivity, were reported; 2 participants reported DREs (mild cough, n=2). One SAE (acute myocardial infarction), which was considered unrelated to sotrovimab or COVID-19 by the investigator, occurred on Day 27 and was the only hospitalization reported. Maximum serum concentration (geometric mean) was 745.9 µg/mL. Viral load decreased from baseline through Day 29; only 2 participants (3%) had persistently high viral load (≥4.1 log10copies/mL) at Day 8.Conclusions2000 mg IV sotrovimab was well tolerated, with no new unanticipated safety signals observed.Key points summaryIn participants with mild to moderate coronavirus disease 2019 at risk for progression to severe disease, a 2000 mg intravenous dose of sotrovimab had a low frequency of adverse events, with no hypersensitivity, infusion-related reactions, or deaths observed.
Impacts of age on the gut microbiota in captive giant pandas
Authors: Li Huixin , Lu Kangning , Li Guo , Li Ti , Zhang Le , Li Chao , Xie Qingyang , Liu Huaiting , Zhang Xinxing , Gong Minghao , Liu Gang , Zhang Guiquan 
Published: February 2023

AbstractThe gut microbiota is the most complex and most abundant symbiotic microbial ecosystem in animals. Aging is one of the main factors that cause gut microbiota structure changes, and the relationship between age and the gut microbiota in the giant panda has been a key focus of attention. The giant panda has a specialized diet of bamboo, and it relies on the microbiota that colonizes its gut to complete digestion. However, there is no in-depth understanding of the changes in the gut microbiota across the lifespan of giant pandas. Here, we identified the differences in the gut microbiota between four age groups (cubs, juveniles, adults, and geriatrics) using 16S rRNA gene high-throughput sequencing on an Illumina MiSeq platform. The results revealed that Firmicutes (mean±SD: 65.45±30.21%; range: 0.91–99.62%) and Proteobacteria (mean±SD: 31.49±27.99%; range: 0.26–85.35%) were the dominant phyla. The relative abundance ofEscherichia-Shigellawas high in both the cubs and juveniles. It is interesting to note that the adults had the highest richness and lowest diversity, while the cubs had the opposite. In summary, our study indicates that the gut microbial community composition, abundance, and functional pathways differ across four age groups of giant pandas. Exploring the influence of age, an endogenous influencing factor, on gut microbes provides basic scientific data for monitoring gut microbial dynamics and formulating gut microbial health management approaches, thereby improving the protection of giant pandas.
Glycaemic control and associated factors among patients living with type 2 diabetes in Kinshasa, Democratic Republic of the Congo: a Cross-sectional study
Authors: Lubaki Jean-Pierre Fina , Omole Olufemi Babatunde , Francis Joel Msafiri 
Published: February 2023

ABSTRACTObjectivesTo assess the prevalence and factors associated with glycaemic control to inform potential interventions to improve glycaemic control in Kinshasa, Democratic Republic of the Congo.DesignThis was a cross-sectional study conducted between November 2011–September 2022. We conducted the selection of the participants through a two-stage sampling process. Participants were asked to complete a structured questionnaire and to provide two millilitres of blood for Hb1AC assay. We performed univariate and multivariable logistic regressions to identify factors associated with poor glycaemic control.SettingA total of 20 randomly selected primary care facilities in Kinshasa, Democratic Republic of the Congo.ParticipantsThe sample included 620 patients living with type 2 diabetes with a median age of 60 (IQR=53.5-69) years.ResultsMost of the study participants were female (66.1%), unemployed (67.8%), having income below the poverty line (76.4%), and without health insurance (92.1%). Two-thirds of the participants (420; 67.6%) had poor glycaemic control. Those participants having taken only insulin (AOR=1.64, 95%CI 1.10 to 2.45) and those on a treatment duration ≥7 years (AOR=1.45, 95%CI 1.01 to 2.08) were associated with increased odds of poor glycaemic control, while being overweight (AOR= 0.47, 95%CI 0.26 to 0.85) and those with uncontrolled blood pressure (AOR=0.65, 95% CI 0.48 to 0.90) were protective for poor glycaemic control.ConclusionsThis study confirms that poor glycaemic control is common among patients living with type 2 diabetes in Kinshasa, DRC. There is a need for targeted interventions to improve glycaemic control, including metabolic and clinical comorbidity control, lifestyle modifications, and health system factors.SIGNIFICANCE OF THE STUDYWhat is already known on this topicGlycaemic control is poor in most of the SSA settings, with glycaemic control ranging from 10–60%.Factors associated with glycaemic control are context specific; in the Democratic Republic of the Congo, few studies have investigated poor glycaemic control.What this study addsThe extent of poor glycaemic control among patients living with type 2 diabetes is determined in Kinshasa, Democratic Republic of the Congo.Identification of factors associated with poor glycaemic control in Kinshasa: taking only insulin and having a treatment duration ≥7 years increased the likelihood of poor glycaemic control, while being overweight and having uncontrolled blood pressure were protective.How this study might affect research, practice or policyThe study findings will inform potential interventions to improve glycaemic control in Kinshasa, DRC or similar settings elsewhere.
Dynamics of the MRSA Population in A Chilean Hospital: A Phylogenomic Analysis (2000-2016)
Authors: Martínez José RW , Planet Paul J. , Maria Spencer-Sandino , Lina Rivas , Lorena Díaz , Ana Quesille-Villalobos , Roberto Riquelme-Neira , Manuel Alcalde-Rico , Blake Hanson , Carvajal Lina P , Sandra Rincón , Jinnethe Reyes , Marusella Lam , Rafael Araos , Patricia García , Arias César A. , Munita José M. 
Published: February 2023

AbstractThe global dissemination of methicillin-resistantStaphylococcus aureus(MRSA) is associated with the emergence and establishment of clones in specific geographic areas. The Chilean-Cordobes clone (ChC) (ST5-SCCmecI) has been the predominant MRSA clone in Chile since its first description in 1998, despite the report of other emerging MRSA clones in the last years. Here, we characterize the evolutionary history of MRSA from 2000 to 2016 in a Chilean tertiary healthcare center using phylogenomic analyses. We sequenced 469 MRSA isolates collected between 2000-2016 in a tertiary healthcare center in Chile. We evaluated the temporal trends of the circulating clones and performed a phylogenomic reconstruction to characterize the clonal dynamics. We found a significant increase in the diversity and richness of sequence types (STs; Spearman r=0.8748, p<0.0001) with a Shannon diversity index increasing from 0.221 in the year 2000 to 1.33 in 2016. The temporal trend analysis revealed that in the period 2000-2003 most of the isolates (94.2%; n=98) belonged to the ChC clone. However, since then, the frequency of the ChC clone has decreased over time, accounting for 52% of the collection in the 2013-2016 period. This decline was accompanied by the rise of two emerging MRSA lineages, ST105-SCCmecII and ST72-SCCmecVI. In conclusion, the ChC clone remains the most frequent MRSA lineage in Chile. However, this lineage is gradually being replaced by several emerging clones, the most important of which is clone ST105-SCCmecII. To the best of our knowledge, this is the largest study of MRSA clonal dynamics performed in South America.ImportanceMethicillin-resistantStaphylococcus aureus(MRSA) is a major public health pathogen that disseminates through the emergence of successful dominant clones in specific geographic regions. Knowledge of the dissemination and molecular epidemiology of MRSA in Latin America is scarce and is largely based on small studies or classical typing techniques with several limitations to depict an accurate description of their genomic landscape. We used whole-genome sequencing to study 469 MRSA isolates collected between 2000-2016 in Chile to provide the largest and most detailed study of clonal dynamics of MRSA carried out in South America to date. We found a significant increase in the diversity of MRSA clones circulating over the 17-year study period. Additionally, we describe the emergence of two novel clones (ST105-SCCmecII and ST72-SCCmecVI), which have been gradually increasing their frequency over time. Our results drastically improve our understanding of the dissemination and update our knowledge about MRSA in Latin America.
At least 10 genes on chromosome 5 ofCandida albicansare downregulated in concert to control cell wall and to confer adaptation to caspofungin
Authors: Sah Sudisht K. , Yadav Anshuman , Rustchenko Elena 
Published: February 2023

ABSTRACTCandida albicansis part of normal microbiota, however, can cause superficial and life threatening infection in immune-compromised individuals. Drugs from echinocandin (ECN) class that disrupt cell wall synthesis, are being used as a major treatment strategy against candidiasis. As the use of ECNs for the treatment of candidiasis is increasing, resistance against ECNs is also emerging. Previously, we reported involvement of 5 chromosome 2 (Ch2) genes in adaptation to ECN drugs. Here, we explored 22 candidate-genes on Ch5 that are consistently downregulated in independent mutants adapted to caspofungin (CAS), for their role in ECN adaptation. We also compared cell wall remodelling in CAS-adapted mutants and in 10 knockouts (KOs) from Ch5. Independent KO experiments as combined with broth microdilution assay, demonstrated that, as expected, 10 out of 22 Ch5 genes decrease ECN susceptibility by controlling the levels of three major components of the cell wall, glucan, mannan, and chitin. Some KOs decreased glucan or increased chitin or both. Similar cell wall remodelling, decreased glucan and increased chitin, was found in CAS-adapted mutants with no ploidy change. Some other KOs had no glucan change, but increased the level of either mannan or chitin. Our results identify the function of two uncharacterized genes, orf19.970 and orf19.4149.1, and expand the functions ofDUS4, RPS25B, UAP1, URA7, RPO26, HAS1, andCKS1. The function ofCHT2, as negative regulator of ECN susceptibility, has been previously established. Importantly, half of the above genes are essential indicating that essential processes are involved in cell wall remodelling for adaptation to ECNs. Also important, orf19.970 and orf19.4149.1 have no human orthologues. Finally, our work shows that multiple mechanisms are used byC. albicanscells to remodel cell wall in order to adapt to CAS. This work continues to identify common pathways that are involved in drug adaptation, as well as new genes controlling ECN susceptibility and reveals new targets for development of novel antifungal drugs.
Underlying driving forces of the SARS-CoV-2 evolution: immune evasion and ACE2 binding affinity
Authors: Ma Wentai , Fu Haoyi , Jian Fanchong , Cao Yunlong , Li Mingkun 
Published: February 2023

AbstractThe evolution of SARS-CoV-2 is characterized by the emergence of new variants with a sheer number of mutations compared to their predecessors, which conferred resistance to pre-existing antibodies and/or increased transmissibility. The recently emerged Omicron subvariants also exhibit a strong tendency for immune evasion, suggesting adaptive evolution. However, previous studies have been limited to specific lineages or subsets of mutations, the overall evolutionary trajectory of SARS-CoV-2 and the underlying driving forces are still not fully understood. In this study, we analyzed the mutations present in all open-access SARS-CoV-2 genomes (until November 2022) and correlated the mutation’s incidence and fitness change with its impact on immune evasion and ACE2 binding affinity. Our results showed that the Omicron lineage had an accelerated mutation rate in the RBD region, while the mutation incidence in other genomic regions did not change dramatically over time. Moreover, mutations in the RBD region (but not in any other genomic regions) exhibited a lineage-specific pattern and tended to become more aggregated over time, and the mutation incidence was positively correlated with the strength of antibody pressure on the specific position. Additionally, the incidence of mutation was also positively correlated with changes in ACE2 binding affinity, but with a lower correlation coefficient than with immune evasion. In contrast, the mutation’s effect on fitness was more closely correlated with changes in ACE2 binding affinity than immune evasion. In conclusion, our results suggest that immune evasion and ACE2 binding affinity play significant and diverse roles in the evolution of SARS-CoV-2.
Targeting Troponin C with Small Molecules Containing Diphenyl Moieties: Calcium Sensitivity Effects on Striated Muscle and Structure Activity Relationship
Authors: Hantz Eric R. , Tikunova Svetlana B. , Belevych Natalya , Davis Jonathan P. , Reiser Peter J. , Lindert Steffen 
Published: February 2023

AbstractDespite large investments from academia and industry, heart failure, which results from a disruption of the contractile apparatus, remains a leading cause of death. Cardiac muscle contraction is a calcium-dependent mechanism, which is regulated by the troponin protein complex (cTn) and specifically by the N-terminal domain of its calcium binding subunit (cNTnC). There is an increasing need for the development of small molecules that increase calcium sensitivity without altering systolic calcium concentration, thereby strengthening cardiac function. Here, we examined the effect of our previously identified calcium sensitizing small molecule, ChemBridge compound 7930079, in the context of several homologous muscle systems. The effect of this molecule on force generation in isolated cardiac trabeculae and slow skeletal muscle fibers was measured. Furthermore, we explored the use of Gaussian accelerated molecular dynamics in sampling highly predictive receptor conformations based on NMR derived starting structures. Additionally, we took a rational computational approach for lead optimization based on lipophilic diphenyl moieties. This led to the identification of three novel low affinity binders, which had similar binding affinities to known positive inotrope trifluoperazine. The most potent identified calcium sensitizer was compound 16 with an apparent affinity of 117 ± 17μM.