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Frontiers in Pharmacology 2024Niraparib, a poly ADP-ribose polymerase inhibitors (PARPi), has been widely applied in the intervention of epithelial ovarian, fallopian tube, or primary peritoneal...
BACKGROUND
Niraparib, a poly ADP-ribose polymerase inhibitors (PARPi), has been widely applied in the intervention of epithelial ovarian, fallopian tube, or primary peritoneal cancer. Nevertheless, as of the present moment, there are limited instances demonstrating favorable outcomes stemming from niraparib therapy in patients with clear cell renal cell carcinoma (ccRCC).
CASE PRESENTATION
Here, we report a case of a 50-year-old patient with ccRCC who subsequently developed distant metastasis. The patient received monotherapy with pazopanib and combination therapy with axitinib and tislelizumab, demonstrating limited efficacy. Liquid biopsy revealed missense mutations in the and of the homologous recombination repair (HRR) pathway, suggesting potential sensitivity to PARPi. Following niraparib treatment, the patient's condition improved, with no significant side effects.
CONCLUSION
In summary, patients with ccRCC harboring HRR pathway gene mutation may potentially benefit from niraparib. This will present more options for ccRCC patients with limited response to conventional treatments.
PubMed: 38953104
DOI: 10.3389/fphar.2024.1396606 -
The Lancet Regional Health. Western... Jun 2024In Australia the incidence of HIV has declined steadily, yet sustained reduction of HIV transmission in this setting requires improved public health responses. As...
BACKGROUND
In Australia the incidence of HIV has declined steadily, yet sustained reduction of HIV transmission in this setting requires improved public health responses. As enhanced public health responses and prioritisation of resources may be guided by molecular epidemiological data, here we aimed to assess the applicability of these approaches in Victoria, Australia.
METHODS
A comprehensive collection of HIV-1 sequences from individuals diagnosed with HIV in Victoria, Australia, between January 1st 2000 and December 31st 2020 were deidentified and used as the basis of our assessment. These sequences were subtyped and surveillance drug resistance mutations (SDRMs) identified, before definition of transmission groups was performed using HIV-TRACE (0.4.4). Phylodynamic methods were applied using BEAST (2.6.6), assessing effective reproductive numbers for large groups, and additional demographic data were integrated to provide a high resolution view of HIV transmission in Victoria on a decadal time scale.
FINDINGS
Based on standard settings for HIV-TRACE, 70% (2438/3507) of analysed HIV-1 sequences were readily assigned to a transmission group. Individuals in transmission groups were more commonly males (aOR 1.50), those born in Australia (aOR 2.13), those with probable place of acquisition as Victoria (aOR 6.73), and/or those reporting injectable drug use (aOR 2.13). SDRMs were identified in 375 patients (10.7%), with sustained transmission of these limited to a subset of smaller groups. Informative patterns of epidemic growth, stabilisation, and decline were observed; many transmission groups showed effective reproductive numbers ( ) values reaching greater than 4.0, representing considerable epidemic growth, while others maintained low values.
INTERPRETATION
This study provides a high resolution view of HIV transmission in Victoria, Australia, and highlights the potential of molecular epidemiology to guide and enhance public health responses in this setting. This informs ongoing discussions with community groups on the acceptability and place of molecular epidemiological approaches in Australia.
FUNDING
National Health and Medical Research Council, Australian Research Council.
PubMed: 38953059
DOI: 10.1016/j.lanwpc.2024.101103 -
Research and Practice in Thrombosis and... May 2024Congenital fibrinogen disorders (CFDs) are rare bleeding disorders (RBDs) caused by mutations in 1 of the 3 fibrinogen genes (, , and ).
BACKGROUND
Congenital fibrinogen disorders (CFDs) are rare bleeding disorders (RBDs) caused by mutations in 1 of the 3 fibrinogen genes (, , and ).
OBJECTIVES
To investigate the clinical phenotype, laboratory features, diagnosis, treatment, and prognosis of CFDs.
METHODS
Clinical data of 93 subjects with CFDs identified from June 2018 to December 2023 were retrospectively analyzed.
RESULTS
Among the 93 patients, there were 46 males (49.5%) and 47 females (50.5%), with a median age of 23 years. Fifty-three of 93 (57%) subjects experienced bleeding, 3/93 (3.2%) experienced thrombosis, and 37/93 (39.8%) were asymptomatic. Females were more prone to experience bleeding ( < .0001). The 93 patients exhibited prolonged thrombin time, significantly decreased fibrinogen activity (Fg:C), and normal or decreased fibrinogen antigen. The 93 patients included 3 with hypofibrinogenemia, 16 with hypodysfibrinogenemia, and 74 with dysfibrinogenemia. Among the 53 patients with bleeding, bleeding episodes were identified in 3.8% (2/53), 20.8% (11/53), and 75.5% (40/53) patients with hypofibrinogenemia, hypodysfibrinogenemia, and dysfibrinogenemia, respectively. Genetic analysis was performed on 22 cases from 8 pedigrees, revealing 10 mutations, including 1 novel splice mutation. Twenty-eight (30.1%) subjects received replacement therapy to treat or prevent bleeding, consisting of 8 fresh frozen plasma transfusions, 3 packing and suture treatment, and 61 fibrinogen infusions.
CONCLUSION
Most patients with CFDs have mild or no bleeding symptoms. Fg:C combined with fibrinogen antigen and pedigree investigation can improve the feasibility and accuracy of diagnosis of CFDs. The severity of bleeding symptoms was negatively correlated with Fg:C.
PubMed: 38953055
DOI: 10.1016/j.rpth.2024.102445 -
Frontiers in Immunology 2024Hereditary angioedema (HAE) is a rare disease characterized by localized and self-limited angioedema (AE) attacks. A local increase of bradykinin (BK) mediates AE...
BACKGROUND
Hereditary angioedema (HAE) is a rare disease characterized by localized and self-limited angioedema (AE) attacks. A local increase of bradykinin (BK) mediates AE attacks in HAE, however the role of inflammation in HAE has been poorly explored We aim to analyze the role of inflammatory mediators in HAE patients during AE attacks.
METHODS
Patients with a confirmed HAE diagnosis due to C1 inhibitor deficiency (HAE-C1INH) or patients gene mutations (HAE-FXII) attending to our outpatient clinic between November-2019 and May-2022 were included. Demographic and clinical characteristics were analyzed. Blood samples were collected both during symptom-free periods (baseline) and during HAE attacks, and acute phase reactants (APR), such as serum amyloid A (SAA), erythrocyte sedimentation rate (ESR), C-reactive protein (CRP), D-Dimer and white blood cells were measured.
RESULTS
Seventy-eight patients were enrolled in the study, with a predominant representation of women (76%, n=59), and a mean age of 47.8 years (range 6-88). Among them, 67% (n=52) of patients had HAE-C1INH (46 classified as type 1 and 6 as type 2) while 33% (n=26) had HAE-FXII. During attack-free periods, the majority of patients exhibited normal levels of SAA, ESR, D-dimer, ACE and WCC. However, in a subset of patients (16% for SAA, 18% for ESR, and 14.5% for D-dimer), elevations were noted at baseline. Importantly, during HAE attacks, significant increases were observed in SAA in 88% of patients (p< 0.0001 vs. baseline), in ESR in 65% (p= 0.003 baseline) and D-dimer in 71% (p=0.001 . baseline) of the patients. A comparison between baseline and acute attack levels in 17 patients revealed significant differences in SAA AA (p<0. 0001), ESR (p<0.0001) and D-dimer (p= 0.004). No significant differences were observed in CRP (p=0.7), ACE (p=0.67) and WCC (p=0.54). These findings remained consistent regardless of HAE type, disease activity or location of angioedema.
CONCLUSION
The systemic increase in APR observed during HAE attacks suggests that inflammation extends beyond the localized edematous area. This finding underscores the potential involvement of inflammatory pathways in HAE and highlights the need for further investigation into their role in the pathophysiology of HAE.
Topics: Humans; Female; Male; Adult; Angioedemas, Hereditary; Middle Aged; Biomarkers; Aged; Inflammation; Adolescent; Child; Young Adult; Aged, 80 and over; Complement C1 Inhibitor Protein; Serum Amyloid A Protein; Factor XII; Blood Sedimentation; Inflammation Mediators; Fibrin Fibrinogen Degradation Products
PubMed: 38953032
DOI: 10.3389/fimmu.2024.1400526 -
Frontiers in Immunology 2024Mast cell (MC) degranulation is a key process in allergic reactions and inflammatory responses. Aspartate aminotransferase 1 (AAT1)-derived endogenous sulfur dioxide...
OBJECTIVES
Mast cell (MC) degranulation is a key process in allergic reactions and inflammatory responses. Aspartate aminotransferase 1 (AAT1)-derived endogenous sulfur dioxide (SO) is an important regulator of MC function. However, the mechanism underlying its role in MC degranulation remains unclear. This study aimed to investigate the mechanism by which endogenous SO controlled MC degranulation.
METHODS
HMC-1 and Rat basophilic leukemia cell MC line (RBL-2H3) were used in the cell experiments. SO content was detected by fluorescent probe. MC degranulation represented by the release rate of MC β-hexosaminidase was determined using a colorimetric assay. Sulfenylation of galectin-9 (Gal-9) in MCs and purified protein was detected using a biotin switch assay. Liquid chromatography-tandem mass spectrometry (LC-MS/MS) was used to determine the exact sulfenylation sites of Gal-9 by SO. Animal models of passive cutaneous anaphylaxis (PCA) and hypoxia-driven pulmonary vascular remodeling were used to investigate the effect of SO on mast cell activation . Site-directed mutation of Gal-9 was conducted to confirm the exact site of SO and support the significance of SO/Gal-9 signal axis in the regulation of MC degranulation.
RESULTS
Degranulation was increased in AAT1-knockdowned MCs, and SO supplementation reversed the increase in MC degranulation. Furthermore, deficiency of endogenous SO contributed to IgE-mediated degranulation Besides, SO inhibited IgE-mediated and hypoxia-driven MC degranulation . Mechanistically, LC-MS/MS analysis and site-directed mutation results showed that SO sulfenylated Gal-9 at cysteine 74. Sulfenylation of the 74 cysteine of Gal-9 protein was required in the SO-inhibited MC degranulation under both physiological and pathophysiological conditions.
CONCLUSION
These findings elucidated that SO inhibited MC degranulation via sulfenylating Gal-9 under both physiological and pathophysiological conditions, which might provide a novel treatment approach for MC activation-related diseases.
Topics: Animals; Cell Degranulation; Mast Cells; Cysteine; Rats; Sulfur Dioxide; Humans; Galectins; Mice; Male; Passive Cutaneous Anaphylaxis; Cell Line
PubMed: 38953022
DOI: 10.3389/fimmu.2024.1369326 -
Pathology Oncology Research : POR 2024Lung cancer is a leading cause of cancer-related death worldwide in both men and women, however mortality in the US and EU are recently declining in parallel with the... (Review)
Review
Lung cancer is a leading cause of cancer-related death worldwide in both men and women, however mortality in the US and EU are recently declining in parallel with the gradual cut of smoking prevalence. Consequently, the relative frequency of adenocarcinoma increased while that of squamous and small cell carcinomas declined. During the last two decades a plethora of targeted drug therapies have appeared for the treatment of metastasizing non-small cell lung carcinomas (NSCLC). Personalized oncology aims to precisely match patients to treatments with the highest potential of success. Extensive research is done to introduce biomarkers which can predict the effectiveness of a specific targeted therapeutic approach. The EGFR signaling pathway includes several sufficient targets for the treatment of human cancers including NSCLC. Lung adenocarcinoma may harbor both activating and resistance mutations of the EGFR gene, and further, mutations of KRAS and BRAF oncogenes. Less frequent but targetable genetic alterations include ALK, ROS1, RET gene rearrangements, and various alterations of MET proto-oncogene. In addition, the importance of anti-tumor immunity and of tumor microenvironment has become evident recently. Accumulation of mutations generally trigger tumor specific immune defense, but immune protection may be upregulated as an aggressive feature. The blockade of immune checkpoints results in potential reactivation of tumor cell killing and induces significant tumor regression in various tumor types, such as lung carcinoma. Therapeutic responses to anti PD1-PD-L1 treatment may correlate with the expression of PD-L1 by tumor cells. Due to the wide range of diagnostic and predictive features in lung cancer a plenty of tests are required from a single small biopsy or cytology specimen, which is challenged by major issues of sample quantity and quality. Thus, the efficacy of biomarker testing should be warranted by standardized policy and optimal material usage. In this review we aim to discuss major targeted therapy-related biomarkers in NSCLC and testing possibilities comprehensively.
Topics: Humans; Carcinoma, Non-Small-Cell Lung; Lung Neoplasms; Biomarkers, Tumor; Proto-Oncogene Mas
PubMed: 38953007
DOI: 10.3389/pore.2024.1611733 -
Leukemia Research Reports 2024Acute myeloid leukemia (AML) is a heterogeneous hematological malignancy associated with various combinations of gene mutations, epigenetic abnormalities, and chromosome...
Acute myeloid leukemia (AML) is a heterogeneous hematological malignancy associated with various combinations of gene mutations, epigenetic abnormalities, and chromosome rearrangement-related gene fusions. Despite the significant degree of heterogeneity in its pathogenesis, many gene fusions and point mutations are recurrent in AML and have been employed in risk stratification over the last several decades. Gene fusions have long been recognized for understanding tumorigenesis and their proven roles in clinical diagnosis and targeted therapies. Advances in DNA sequencing technologies and computational biology have contributed significantly to the detection of known fusion genes as well as for the discovery of novel ones. Several recurring gene fusions in AML have been linked to prognosis, treatment response, and disease progression. In this report, we present a case with a long history of essential thrombocythemia and hallmark mutation transforming to AML characterized by a previously unreported fusion gene. We propose mechanisms by which this fusion may contribute to the pathogenesis of AML and its potential as a molecular target for tyrosine kinase inhibitors.
PubMed: 38952949
DOI: 10.1016/j.lrr.2024.100465 -
Virus Evolution 2024Animal rotaviruses A (RVAs) are considered the source of emerging, novel RVA strains that have the potential to cause global spread in humans. A case in point was the...
Evolution of DS-1-like G8P[8] rotavirus A strains from Vietnamese children with acute gastroenteritis (2014-21): Adaptation and loss of animal rotavirus-derived during human-to-human spread.
Animal rotaviruses A (RVAs) are considered the source of emerging, novel RVA strains that have the potential to cause global spread in humans. A case in point was the emergence of G8 bovine RVA consisting of the P[8] VP4 and the DS-1-like backbone that appeared to have jumped into humans recently. However, it was not well documented what evolutionary changes occurred on the animal RVA-derived during circulation in humans. Rotavirus surveillance in Vietnam found that DS-1-like G8P[8] strains emerged in 2014, circulated in two prevalent waves, and disappeared in 2021. This surveillance provided us with a unique opportunity to investigate the whole process of evolutionary changes, which occurred in an animal RVA that had jumped the host species barrier. Of the 843 G8P[8] samples collected from children with acute diarrhoea in Vietnam between 2014 and 2021, fifty-eight strains were selected based on their distinctive electropherotypes of the genomic RNA identified using polyacrylamide gel electrophoresis. Whole-genome sequence analysis of those fifty-eight strains showed that the strains dominant during the first wave of prevalence (2014-17) carried animal RVA-derived VP1, NSP2, and NSP4 . However, the strains from the second wave of prevalence (2018-21) lost these , which were replaced with cognate human RVA-derived , thus creating strain with G8P[8] on a fully DS-1-like human RVA backbone. The G8 VP7 and P[8] VP4 s underwent some point mutations but the phylogenetic lineages to which they belonged remained unchanged. We, therefore, propose a hypothesis regarding the tendency for the animal RVA-derived to be expelled from the backbone of the progeny strains after crossing the host species barrier. This study underlines the importance of long-term surveillance of circulating wild-type strains in order to better understand the adaptation process and the fate of newly emerging, animal-derived RVA among the human population. Further studies are warranted to disclose the molecular mechanisms by which spillover animal RVAs become readily transmissible among humans, and the roles played by the expulsion of animal-derived and herd immunity formed in the local population.
PubMed: 38952820
DOI: 10.1093/ve/veae045 -
BioRxiv : the Preprint Server For... May 2024The microbiota can promote host health by inhibiting pathogen colonization, yet how host-resident fungi, or the mycobiota, contribute to this process remains unclear....
UNLABELLED
The microbiota can promote host health by inhibiting pathogen colonization, yet how host-resident fungi, or the mycobiota, contribute to this process remains unclear. The human skin mycobiota is uniquely stable compared to other body sites and dominated by yeasts of the genus . We observe that colonization of human skin by significantly reduces subsequent colonization by the prominent bacterial pathogen . secreted products possess potent bactericidal activity against and are sufficient to impair skin colonization. This bactericidal activity requires an acidic environment and is exacerbated by free fatty acids, demonstrating a unique synergy with host-derived epidermal defenses. Leveraging experimental evolution to pinpoint mechanisms of adaptation in response to the skin mycobiota, we identified multiple mutations in the stringent response regulator Rel that promote survival against . Similar Rel alleles have been reported in clinical isolates, and natural Rel variants are sufficient for tolerance to antagonism. Partial stringent response activation underlies tolerance to clinical antibiotics, with both laboratory-evolved and natural Rel variants conferring multidrug tolerance. These findings demonstrate the ability of the mycobiota to mediate pathogen colonization resistance, identify new mechanisms of bacterial adaptation in response to fungal antagonism, and reveal the potential for microbiota-driven evolution to shape pathogen antibiotic susceptibility.
HIGHLIGHTS
- reduces colonization of human skin by - Bactericidal activity of is exacerbated by features of the skin niche - Rel variants are sufficient for tolerance to antagonism - Evolved tolerance to yeast antagonism coincides with multidrug tolerance.
PubMed: 38952794
DOI: 10.1101/2024.05.03.592489 -
MedRxiv : the Preprint Server For... May 2024HIV drug resistance poses a challenge to the United Nation's goal of ending the HIV/AIDS epidemic. The integrase strand transfer inhibitor (InSTI) dolutegravir, which...
INTRODUCTION
HIV drug resistance poses a challenge to the United Nation's goal of ending the HIV/AIDS epidemic. The integrase strand transfer inhibitor (InSTI) dolutegravir, which has a higher resistance barrier, was endorsed by the World Health Organization in 2019 for first-, second-, and third-line antiretroviral therapy (ART). This multiplicity of roles of dolutegravir in ART may facilitate the emergence of dolutegravir resistance.
METHODS AND ANALYSIS
DTG RESIST is a multicentre longitudinal study of adults and adolescents living with HIV in sub-Saharan Africa, Asia, and South and Central America who experienced virologic failure on dolutegravir-based ART. At the time of virologic failure whole blood will be collected and processed to prepare plasma or dried blood spots. Laboratories in Durban, Mexico City and Bangkok will perform genotyping. Analyses will focus on (i) individuals who experienced virologic failure on dolutegravir, and (ii) on those who started or switched to such a regimen and were at risk of virologic failure. For population (i), the outcome will be any InSTI drug resistance mutations, and for population (ii) virologic failure defined as a viral load >1000 copies/mL. Phenotypic testing will focus on non-B subtype viruses with major InSTI resistance mutations. Bayesian evolutionary models will explore and predict treatment failure genotypes. The study will have intermediate statistical power to detect differences in resistance mutation prevalence between major HIV-1 subtypes; ample power to identify risk factors for virologic failure and limited power for analysing factors associated with individual InSTI drug resistance mutations.
ETHICS AND DISSEMINATION
The research protocol was approved by the Biomedical Research Ethics Committee at the University of KwaZulu-Natal, South Africa, and the Ethics Committee of the Canton of Bern, Switzerland. All sites participate in IeDEA and have obtained ethics approval from their local ethics committee to conduct the additional data collection.
REGISTRATION
NCT06285110.
STRENGTHS AND LIMITATIONS OF THIS STUDY
- DTG RESIST is a large international study to prospectively examine emergent dolutegravir resistance in diverse settings characterised by different HIV-1 subtypes, provision of ART, and guidelines on resistance testing. - Embedded within the International epidemiology Databases to Evaluate AIDS (IeDEA), DTG RESIST will benefit from harmonized clinical data across participating sites and expertise in clinical, epidemiological, biological, and computational fields. - Procedures for sequencing and assembling genomes from different HIV-1 strains will be developed at the heart of the HIV epidemic, by the KwaZulu-Natal Research Innovation and Sequencing Platform (KRISP), in Durban, South Africa. Phenotypic testing, Genome Wide Association Study (GWAS) methods and Bayesian evolutionary models will explore and predict treatment failure genotypes. - A significant limitation is the absence of genotypic resistance data from participants before they started dolutegravir treatment, as collecting and bio-banking pre-treatment samples was not feasible at most IeDEA sites. Consistent and harmonized data on adherence to treatment are also lacking. - The distribution of HIV-1 subtypes across different sites is uncertain, which may limit the statistical power of the study in analysing patterns and risk factors for dolutegravir resistance. The results from GWAS and Bayesian modelling analyses will be preliminary and hypothesis-generating.
PubMed: 38952780
DOI: 10.1101/2024.05.23.24307850