Elevated rates of human papillomavirus (HPV)-related anal high-grade squamous intraepithelial lesions (HSIL) and anal cancer (AC) in populations like men who have sex with men (MSM) living with HIV ...underscore the need for effective screening. While high-resolution anoscopy-guided biopsy is the gold standard, limited provider availability poses a challenge. This has spurred interest in identifying biomarkers for improved AC prevention. Antibodies against HPV16 oncoprotein E6, known as markers for cervical and oropharyngeal cancers, are the focus of the current study. The systematic review and meta-analysis included six studies meeting inclusion criteria, assessing HPV16 E6 seroprevalence in individuals with anal HSIL or AC. A two-step meta-analysis estimated pooled odds ratios and 95% confidence intervals (CI) for HPV16 E6 seroprevalence and HSIL or AC. Pooled prevalence, sensitivity, specificity, and diagnostic odds ratios were also calculated. This meta-analysis revealed a 3.6-fold increased risk of HSIL for HPV16 E6 seropositive individuals, escalating to a 26.1-fold risk increase for AC. Pooled specificity and sensitivity indicated a high specificity (0.99; 95%CI: 0.99, 0.99) but lower sensitivity (0.19; 95%CI: 0.10, 0.34) for HPV16 E6 serostatus as an AC biomarker. In conclusion, while HPV16 E6 seroprevalence demonstrates specificity as a potential biomarker for HPV-related AC, its utility as a standalone screening tool may be limited. Instead, it could serve effectively as a confirmation test, particularly in high-risk populations, alongside other diagnostic methods. Further research is imperative to explore HPV16 E6 seroconversion dynamics and alternative screening algorithms.
is one of the most frequently reported causes of foodborne illness worldwide. Non-typhoidal serovars cause gastroenteritis in humans.
can grow on surfaces forming biofilms, contributing to its ...persistence since biofilms are difficult to eradicate due to the high resistance to antimicrobials and disinfectants. It has been described that there are two crucial biofilm promoting factors in
: curli and cellulose. The expression of both factors is coordinately regulated by the transcriptional regulator CsgD. Most biofilm studies of
have been performed by growing bacteria in low osmolarity rich medium and low temperature (25°C). In such conditions, the biofilm is formed at the air-liquid interface (pellicle biofilm). Remarkably, when
grow in minimal medium, biofilm formation switches from the air-liquid interface to the solid-liquid interface (bottom biofilm). In this report, the switching between pellicle and bottom biofilm has been characterized. Our data indicate that curli, but not cellulose, is crucial for the formation of both kinds of biofilms. In minimal medium, conditions promoting formation of bottom biofilm, a high transcriptional expression of
and consequently of the genes involved in the synthesis of curli and cellulose was detected. The nutritional status of the cells seems to be pivotal for the spatial distribution of the biofilms formed. When bacteria is growing in minimal medium the addition of amino acids downregulates the expression of
and causes the switch between bottom and pellicle biofilm. The crosstalk between general metabolism and biofilm formation is also highlighted by the fact that the metabolic sensor cAMP modulates the type of biofilm generated by
. Moreover, cAMP regulates transcriptional expression of
and stimulates pellicle biofilm formation, suggesting that the physiological conditions define the type of biofilm formed by
. The consequences of the switching between pellicle and bottom biofilm during either infection or survival in natural environments remain undercover.
Macrophages exert potent effector functions against invading microorganisms but constitute, paradoxically, a preferential niche for many bacterial strains to replicate. Using a model of infection by ...Salmonella Typhimurium, we have identified a molecular mechanism regulated by the nuclear receptor LXR that limits infection of host macrophages through transcriptional activation of the multifunctional enzyme CD38. LXR agonists reduced the intracellular levels of NAD+ in a CD38-dependent manner, counteracting pathogen-induced changes in macrophage morphology and the distribution of the F-actin cytoskeleton and reducing the capability of non-opsonized Salmonella to infect macrophages. Remarkably, pharmacological treatment with an LXR agonist ameliorated clinical signs associated with Salmonella infection in vivo, and these effects were dependent on CD38 expression in bone-marrow-derived cells. Altogether, this work reveals an unappreciated role for CD38 in bacterial-host cell interaction that can be pharmacologically exploited by activation of the LXR pathway.
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•LXR agonists reduce intracellular NAD levels through induction of CD38•Activation of LXRs impairs cytoskeletal changes associated with bacterial infection•The LXR-CD38 circuit protects host macrophages from extensive bacterial infection•Activation of the LXR-CD38 circuit ameliorates clinical signs of infection in vivo
Macrophages constitute a preferential niche for intracellular bacteria to replicate. Matalonga et al. identified an antibacterial circuit mediated by pharmacological targeting of the liver X receptor (LXR) pathway that impacts intracellular NAD metabolism and interferes with macrophage cytoskeletal rearrangements subverted by invasive bacteria.
Due to the anatomical continuity of the uterine cavity with the cervix, genomic exploitation of material from routine Pap smears and other noninvasive sampling methods represent a unique opportunity ...to detect signs of disease using biological material shed from the upper genital tract. Recent research findings offer a promising perspective in the detection of endometrial cancer, but certain questions need to be addressed in order to accelerate the implementation of novel technologies in a routine screening or clinical setting. We discuss here new perspectives on detection of endometrial cancer using genomic and other biomarkers in minimally invasive sampling methods with a special focus on public health classic screening criteria, highlighting current gaps in knowledge.
Women with Lynch syndrome (LS) are at increased risk of endometrial cancer (EC), among other tumors, and are characterized by mismatch repair (MMR) deficiency and microsatellite instability (MSI). ...While risk-reducing gynecologic surgeries effectively decrease EC incidence, doubts arise regarding the appropriate timing of the surgery. We explored the usefulness of highly sensitive MSI (hs-MSI) assessment in endometrial aspirates for individualizing gynecologic surveillance in LS carriers. Ninety-three women with LS, 25 sporadic EC patients (9 MMR-proficient and 16 MMR-deficient), and 30 women with benign gynecologic disease were included in this study. hs-MSI was assessed in prospectively collected endometrial aspirates in 67 LS carriers, EC cases, and controls. MMR, PTEN, ARID1A, and PAX2 protein expression patterns were evaluated in the LS samples. Follow-up aspirates from 8 LS carriers were also analyzed. Elevated hs-MSI scores were detected in all aspirates from MMR-deficient EC cases (3 LS and 16 sporadic) and negative in aspirates from controls and MMR-proficient EC cases. Positive hs-MSI scores were also detected in all 4 LS aspirates reported as complex hyperplasia. High hs-MSI was also present in 10 of 49 aspirates (20%) from LS carriers presenting a morphologically normal endometrium, where MMR protein expression loss was detected in 69% of the samples. Interestingly, the hs-MSI score was positively correlated with MMR-deficient gland density and the presence of MMR-deficient clusters, colocalizing PTEN and ARID1A expression loss. High hs-MSI scores and clonality were evidenced in 2 samples collected up to 4 months before EC diagnosis; hs-MSI scores increased over time in 5 LS carriers, whereas they decreased in a patient with endometrial hyperplasia after progestin therapy. In LS carriers, elevated hs-MSI scores were detected in aspirates from premalignant and malignant lesions and normal endometrium, correlating with MMR protein loss. hs-MSI assessment and MMR immunohistochemistry may help individualize EC risk assessment in women with LS.
Hha-like proteins are an evolutive trait of members of the family Enterobacteriaceae. These proteins mimic the oligomerization domain of the nucleoid-associated protein H-NS and interact with this ...latter protein to modulate gene expression. In this report, we provide evidence that, as has been shown for H-NS, Hha-like proteins play an essential role facilitating acquisition of horizontally transferred DNA in both Escherichia coli and Salmonella. Incorporation of conjugative plasmids such as pHly152 or R27 results in a fitness cost in E. coli or Salmonella strains that lack Hha-like proteins. E. coli spontaneous derivatives from double hha ydgT mutants that showed an increased growth rate and a restored fitness overexpressed the H-NS protein. In addition to reinforcing the role of H-NS/Hha-modulating xenogeneic DNA, the results obtained demonstrate that the Enterobacteriaceae display regulatory features not found in other bacteria that facilitate incorporation of horizontally transferred DNA.
Summary
Plasmids of the incompatibility group HI1 (IncHI1) have been isolated from several Gram‐negative pathogens and are associated with the spread of multidrug resistance. Their conjugation is ...tightly regulated and it is inhibited at temperatures higher than 30°C, indicating that conjugation occurs outside warm‐blooded hosts. Using R27, the prototype of IncHI1 plasmids, we report that plasmid transfer efficiency in E. coli strongly depends on the physiological state of the donor cells. Conjugation frequency is high when cells are actively growing, dropping sharply when cells enter the stationary phase of growth. Accordingly, our transcriptomic assays show significant downregulation of numerous R27 genes during the stationary phase, including several tra (transfer) genes. Growth phase‐dependent regulation of tra genes transcription is independent of H‐NS, a silencer of horizontal gene transfer, and ppGpp and RpoS, regulators of the stationary phase, but highly dependent on the plasmid‐encoded regulatory circuit TrhR/TrhY‐HtdA. The metabolic sensor cAMP, whose synthesis is chromosomally encoded, is also involved in the growth phase regulation of R27 conjugation by modulating htdA expression. Our data suggest that the involvement of regulators encoded by both chromosome and plasmid are required for efficient physiological control of IncHI1 plasmid conjugation.
Conjugation of R27 plasmid is thermoregulated, being promoted at 25°C and repressed at 37°C. Previous studies identified plasmid-encoded regulators, HtdA, TrhR and TrhY, that control expression of ...conjugation-related genes (
). Moreover, the nucleoid-associated protein H-NS represses conjugation at non-permissive temperature. A transcriptomic approach has been used to characterize the effect of temperature on the expression of the 205 R27 genes. Many of the 35
genes, directly involved in plasmid-conjugation, were upregulated at 25°C. However, the majority of the non-
R27 genes-many of them with unknown function-were more actively expressed at 37°C. The role of HtdA, a regulator that causes repression of the R27 conjugation by counteracting TrhR/TrhY mediated activation of
genes, has been investigated. Most of the R27 genes are severely derepressed at 25°C in an
mutant, suggesting that HtdA is involved also in the repression of R27 genes other than the
genes. Interestingly, the effect of
mutation was abolished at non-permissive temperature, indicating that the HtdA-TrhR/TrhY regulatory circuit mediates the environmental regulation of R27 gene expression. The role of H-NS in the proposed model is discussed.
Ovarian cancer is the most lethal gynaecological cancer in very-high-human-development-index regions. Ovarian cancer incidence and mortality rates are estimated to globally rise by 2035, although ...incidence and mortality rates depend on the region and prevalence of the associated risk factors. The aim of this study is to assess changes in incidence and mortality of ovarian cancer in Catalonia by 2030. Bayesian autoregressive age-period-cohort models were used to predict the burden of OC incidence and mortality rates for the 2015-2030 period. Incidence and mortality rates of ovarian cancer are expected to decline in Catalonia by 2030 in women ≥ 45 years of age. A decrease in ovarian-cancer risk was observed with increasing year of birth, with a rebound in women born in the 1980s. A decrease in mortality was observed for the period of diagnosis and period of death. Nevertheless, ovarian-cancer mortality remains higher among older women compared to other age groups. Our study summarizes the most plausible scenario for ovarian-cancer changes in terms of incidence and mortality in Catalonia by 2030, which may be of interest from a public health perspective for policy implementation.
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