Referred to as the "guardian of the genome", p53 is the most frequently mutated protein in cancer and almost all cancers exhibit malfunction along the p53 pathway. As an overexpressed and ...tumour-specific target, the past two decades have seen considerable dedication to the development of small molecules that aim to restore wild-type function in mutant p53. In this review we collect and communicate the chemical principles involved in small molecule drug design for misfolded proteins in anticancer therapy. While this approach has met with significant challenges including off-target mechanisms that induce cytotoxicity independent of p53 status, major technological advancements in gene sequencing capability and a shift towards personalized medicine holds significant promise for p53 reactivating compounds and could have widespread benefits for the field of cancer therapy.
Small molecules targeting various aspects of the p53 protein pathway have shown significant promise in the treatment of a number of cancer types.
BackgroundWe investigated work-related exposure to stressful and traumatic events in police officers, including repeated exposure to traumatic materials, and predicted that ICD-11 complex PTSD ...(CPTSD) would be more prevalent than posttraumatic stress disorder (PTSD). The effects of demographic variables on exposure and PTSD were examined, along with whether specific types of exposure were uniquely associated with PTSD or CPTSD.MethodsAn online survey covering issues about trauma management, wellbeing and working conditions was disseminated via social media and official policing channels throughout the UK. In total, 10 401 serving police officers self-identified as having been exposed to traumatic events. Measurement of PTSD and CPTSD utilised the International Trauma Questionnaire.ResultsThe prevalence of PTSD was 8.0% and of CPTSD was 12.6%. All exposures were associated with PTSD and CPTSD in bivariate analyses. Logistic regression indicated that both disorders were more common in male officers, and were associated independently with frequent exposure to traumatic incidents and traumatic visual material, and with exposure to humiliating behaviours and sexual harassment, but not to verbal abuse, threats or physical violence. Compared to PTSD, CPTSD was associated with exposure to humiliating behaviours and sexual harassment, and also with lower rank and more years of service.ConclusionsCPTSD was more common than PTSD in police officers, and the data supported a cumulative burden model of CPTSD. The inclusion in DSM-5 Criterion A of work-related exposure to traumatic materials was validated for the first time. Levels of PTSD and CPTSD mandate enhanced occupational mental health services.
IL-33 is a member of the IL-1 family and was first identified as an alarmin that acts at mucosal barrier sites. However, IL-33 is now understood to be a pleiotropic cytokine that acts on a variety of ...immune and non-immune cell types to promote type 2 T helper cell (TH2) inflammation as well as to regulate and suppress homeostatic processes. Of particular interest are group 2 innate lymphoid cells (ILC2s) which are activated by IL-33 and promote many IL-33-specific effects. Considerable investigation has surrounded the integral role of IL-33 and ILC2s in driving inflammation in asthma, allergy, atopic dermatitis, fibrotic diseases, microbial interactions, and more. However, IL-33 and ILC2s have also emerged as key components of a healthy pregnancy and fertility; when dysregulated, they can drastically drive female reproductive pathologies. We first summarize the presence of both IL-33 and ILC2s in the female reproductive tract (FRT) and in healthy pregnancy. We then provide insights into how IL-33 and ILC2s drive female reproductive pathologies and how this axis could be a potential therapeutic target in reproductive disorders including preterm birth, pre-eclampsia, recurrent spontaneous abortion, and endometriosis.
IL-33, an alarmin or danger signal that is normally released by damaged or necrotic cells, has emerged as a pleiotropic cytokine that can regulate physiological and pathological processes associated with chronic inflammation, homeostasis, infection, and cancer progression.IL-33 is considered to be a 'double-edged sword' cytokine that not only perpetuates type 2 inflammation (anti-inflammatory inflammation) but can also stimulate type 1, proinflammatory, antitumor, and antiviral responsesIn the female reproductive tract, both IL-33 and its receptor suppressor of tumorgenicity 2 (ST2) are present, but their expression varies across the menstrual or estrous cycle.Although the exact mechanism is not known, the IL-33–ST2/ group 2 innate lymphoid cell (ILC2) axis seems to contribute functionally not only to healthy pregnancy including embryo implantation and placental development but also to reproductive infections, pathologies, and malignancies.
Tsunami-driven rafting Carlton, James T.; Chapman, John W.; Geller, Jonathan B. ...
Science,
09/2017, Letnik:
357, Številka:
6358
Journal Article
Recenzirano
Odprti dostop
The 2011 East Japan earthquake generated a massive tsunami that launched an extraordinary transoceanic biological rafting event with no known historical precedent. We document 289 living Japanese ...coastal marine species from 16 phyla transported over 6 years on objects that traveled thousands of kilometers across the Pacific Ocean to the shores of North America and Hawai‘i. Most of this dispersal occurred on nonbiodegradable objects, resulting in the longest documented transoceanic survival and dispersal of coastal species by rafting. Expanding shoreline infrastructure has increased global sources of plastic materials available for biotic colonization and also interacts with climate change–induced storms of increasing severity to eject debris into the oceans. In turn, increased ocean rafting may intensify species invasions.
AbstractObjectivesTo outline which infectious diseases in the pre-covid-19 era persist in children and adolescents in China and to describe recent trends and variations by age, sex, season, and ...province.DesignNational surveillance studies, 2008-17.Setting31 provinces in mainland China.Participants4 959 790 Chinese students aged 6 to 22 years with a diagnosis of any of 44 notifiable infectious diseases. The diseases were categorised into seven groups: quarantinable; vaccine preventable; gastrointestinal and enteroviral; vectorborne; zoonotic; bacterial; and sexually transmitted and bloodborne.Main outcome measuresDiagnosis of, and deaths from, 44 notifiable infectious diseases.ResultsFrom 2008 to 2017, 44 notifiable infectious diseases were diagnosed in 4 959 790 participants (3 045 905 males, 1 913 885 females) and there were 2532 deaths (1663 males, 869 females). The leading causes of death among infectious diseases shifted from rabies and tuberculosis to HIV/AIDS, particularly in males. Mortality from infectious diseases decreased steadily from 0.21 per 100 000 population in 2008 to 0.07 per 100 000 in 2017. Quarantinable conditions with high mortality have effectively disappeared. The incidence of notifiable infectious diseases in children and adolescents decreased from 280 per 100 000 in 2008 to 162 per 100 000 in 2015, but rose again to 242 per 100 000 in 2017, largely related to mumps and seasonal influenza. Excluding mumps and influenza, the incidence of vaccine preventable diseases fell from 96 per 100 000 in 2008 to 7 per 100 000 in 2017. The incidence of gastrointestinal and enterovirus diseases remained constant, but typhoid, paratyphoid, and dysentery continued to decline. Vectorborne diseases all declined, with a particularly noticeable reduction in malaria. Zoonotic infections remained at low incidence, but there were still unpredictable outbreaks, such as pandemic A/H1N1 2009 influenza. Tuberculosis remained the most common bacterial infection, although cases of scarlet fever doubled between 2008 and 2017. Sexually transmitted diseases and bloodborne infections increased significantly, particularly from 2011 to 2017, among which HIV/AIDS increased fivefold, particularly in males. Difference was noticeable between regions, with children and adolescents in western China continuing to carry a disproportionate burden from infectious diseases.ConclusionsChina’s success in infectious disease control in the pre-covid-19 era was notable, with deaths due to infectious diseases in children and adolescents aged 6-22 years becoming rare. Many challenges remain around reducing regional inequalities, scaling-up of vaccination, prevention of further escalation of HIV/AIDS, renewed efforts for persisting diseases, and undertaking early and effective response to highly transmissible seasonal and unpredictable diseases such as that caused by the novel SARS-CoV-2 virus.
In a small study involving 54 participants, omicron subvariants BA.2.12.1, BA.4, and BA.5 of SARS-CoV-2 were more likely to escape neutralizing antibodies induced by both vaccination and previous ...infection than were the prior omicron subvariants BA.1 and BA.2.
The Immunopathophysiology of Endometriosis Symons, Lindsey K.; Miller, Jessica E.; Kay, Vanessa R. ...
Trends in molecular medicine,
September 2018, 2018-09-00, 20180901, Letnik:
24, Številka:
9
Journal Article
Recenzirano
Endometriosis is a chronic, inflammatory, estrogen-dependent disease characterized by the growth of endometrial tissue outside of the uterine cavity. Although the etiology of endometriosis remains ...elusive, immunological dysfunction has been proposed as a critical facilitator of ectopic lesion growth following retrograde menstruation of endometrial debris. However, it is not clear whether this immune dysfunction is a cause or consequence of endometriosis. Thus, here we provide in-depth insights into our current understanding of the immunopathophysiology of endometriosis and highlight challenges and opportunities for future research. With the explosion of successful immune-based therapies targeting various chronic inflammatory conditions, it is crucial to determine whether immune dysfunction can be therapeutically targeted in endometriosis.
Immunological dysfunction, involving defective immunosurveillance against autologous tissue deposited in the peritoneal cavity, facilitates endometriotic lesion growth in endometriosis patients and ultimately perpetuates disease symptoms.
Conversely, innate and adaptive immune cells from endometriosis patients produce several proinflammatory and blood vessel growth-promoting factors that contribute to hallmarks of disease pathophysiology. Persistent and prolonged endometriosis-associated inflammation further contributes to comorbidities.
Recent studies suggest that endometriotic lesions harbor a unique microenvironment. The interplay between immune cells with stromal and epithelial compartments of lesions is regulated by hormonal pathways.
Targeting dysregulated immune pathways represents a potential avenue for novel therapeutic development that will hopefully not impact fertility.
To assess the risk of severe childhood infections within families, we conducted a sibling analysis in a population-based cohort study with genealogical linkage. We investigated the sibling risk of ...hospitalization with common infections, a marker of severity. We hypothesized that having siblings hospitalized for infection would increase the proband's risk of admission with infection.
We used population data on Western Australian live-born singletons and their siblings between 1980 and 2014. Measures of infection were infection-related hospitalizations from discharge diagnostic codes. Exposure was having a sibling who had an infection-related hospitalization. Outcomes were infection-related hospitalizations in the child/proband. Probands were followed until an infection-related hospitalization admission (up to the first three), death, 18th birthday, or end of 2014, whichever occurred first. Infection risks were estimated by adjusted Cox proportional hazard models for multiple events.
Of 512,279 probands, 142,915 (27.9%) had infection-related hospitalizations; 133,322 (26.0%) had a sibling with a previous infection-related hospitalization (i.e. exposed). Median interval between sibling and proband infection-related hospitalizations was 1.4 years (inter-quartile range 0.5-3.7). Probands had a dose-dependent increase in risk if sibling/s had 1, 2, or 3+ infection-related hospitalizations (adjusted hazard ratio, aHR 1.41, 95% CI 1.39-1.43; aHR 1.65, 1.61-1.69; aHR 1.83, 1.77-1.90, respectively). Among siblings with the same clinical infection type, highest sibling risks were for genitourinary (aHR 2.06, 1.68-2.53), gastrointestinal (aHR 2.07, 1.94-2.19), and skin/soft tissue infections (aHR 2.34, 2.15-2.54). Overall risk of infection-related hospitalization was higher in children with more siblings and with older siblings.
In this population-based study, we observed an increased risk of infection-related hospitalization in children whose siblings were previously hospitalized for infection. Public health interventions may be particularly relevant in families of children hospitalized with infection.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
To perform real-time whole genome sequencing (WGS) and RNA sequencing (RNASeq) of advanced pancreatic ductal adenocarcinoma (PDAC) to identify predictive mutational and transcriptional features for ...better treatment selection.
Patients with advanced PDAC were prospectively recruited prior to first-line combination chemotherapy. Fresh tumor tissue was acquired by image-guided percutaneous core biopsy for WGS and RNASeq. Laser capture microdissection was performed for all cases. Primary endpoint was feasibility to report WGS results prior to first disease assessment CT scan at 8 weeks. The main secondary endpoint was discovery of patient subsets with predictive mutational and transcriptional signatures.
Sixty-three patients underwent a tumor biopsy between December 2015 and June 2017. WGS and RNASeq were successful in 62 (98%) and 60 (95%), respectively. Genomic results were reported at a median of 35 days (range, 19-52 days) from biopsy, meeting the primary feasibility endpoint. Objective responses to first-line chemotherapy were significantly better in patients with the classical PDAC RNA subtype compared with those with the basal-like subtype (
= 0.004). The best progression-free survival was observed in those with classical subtype treated with m-FOLFIRINOX.
expression in tumor measured by RNA
hybridization was found to be a robust surrogate biomarker for differentiating classical and basal-like PDAC subtypes. Potentially actionable genetic alterations were found in 30% of patients.
Prospective genomic profiling of advanced PDAC is feasible, and our early data indicate that chemotherapy response differs among patients with different genomic/transcriptomic subtypes.
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Mosquito-transmitted malaria parasites infect hepatocytes and asymptomatically replicate as liver stages. Using RNA sequencing, we show that a rodent malaria liver-stage infection stimulates a robust ...innate immune response including type I interferon (IFN) and IFNγ pathways. Liver-stage infection is suppressed by these infection-engendered innate responses. This suppression was abrogated in mice deficient in IFNγ, the type I IFN α/β receptor (IFNAR), and interferon regulatory factor 3. Natural killer and CD49b+CD3+ natural killer T (NKT) cells increased in the liver after a primary infection, and CD1d-restricted NKT cells, which secrete IFNγ, were critical in reducing liver-stage burden of a secondary infection. Lack of IFNAR signaling abrogated the increase in NKT cell numbers in the liver, showing a link between type I IFN signaling, cell recruitment, and subsequent parasite elimination. Our findings demonstrate innate immune sensing of malaria parasite liver-stage infection and that the ensuing innate responses can eliminate the parasite.
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•Plasmodium liver stages induce an interferon-mediated innate immune response•The impact of innate immune responses can be assayed using a unique infection model•NKT cells increase in the liver and are required for eliminating an infection•The increase of NKT cells in infected livers is dependent upon type I IFN signaling
Malaria is a devastating infectious disease caused by Plasmodium parasites. The parasites first infect the liver and replicate, yet little is known about the innate immune responses to this obligate stage of infection. Miller et al. demonstrate that malaria liver infection induces a pronounced type I IFN-mediated innate immune response. This causes IFNγ-secreting NKT cells to enter the liver, which can limit subsequent infection. The results demonstrate a link between liver infection, type I IFN signaling, cell recruitment, and subsequent parasite elimination.
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