Repurposing crizotinib to target RIPK1-dependent cell death.

Receptor-interacting protein kinase 1 (RIPK1) has emerged as a key regulator of cell death and inflammation, which are implicated in the pathogenesis of many inflammatory and degenerative diseases. RIPK1 is therefore a putative therapeutic target in many of these diseases. However, no pharmacological inhibitor of RIPK1-mediated cell death is currently in clinical use. Recognizing that a repurposed drug has an expedited clinical development pipeline, here we performed a high-throughput drug screen of Food and Drug Administration (FDA)-approved compounds and identified a novel use for crizotinib as an inhibitor of RIPK1-dependent cell death. Furthermore, crizotinib rescued TNF-α-induced death in mice with systemic inflammatory response syndrome. RIPK1 kinase activity was directly inhibited by crizotinib. These findings identify a new use for an established compound and are expected to accelerate drug development for RIPK1-spectrum disorders.

SIRS epidemics with individual heterogeneity of immunity waning.

In the current paper we analyse an extended SIRS epidemic model in which immunity at the individual level wanes gradually at exponential rate, but where the waning rate may differ between individuals, for instance as an effect of differences in immune systems. The model also includes vaccination schemes aimed to reach and maintain herd immunity. We consider both the informed situation where the individual waning parameters are known, thus allowing selection of vaccinees being based on both time since last vaccination as well as on the individual waning rate, and the more likely uninformed situation where individual waning parameters are unobserved, thus only allowing vaccination schemes to depend on time since last vaccination. The optimal vaccination policies for both the informed and uniformed heterogeneous situation are derived and compared with the homogeneous waning model (meaning all individuals have the same immunity waning rate), as well as to the classic SIRS model where immunity at the individual level drops from complete immunity to complete susceptibility in one leap. It is shown that the classic SIRS model requires least vaccines, followed by the SIRS with homogeneous gradual waning, followed by the informed situation for the model with heterogeneous gradual waning. The situation requiring most vaccines for herd immunity is the most likely scenario, that immunity wanes gradually with unobserved individual heterogeneity. For parameter values chosen to mimic COVID-19 and assuming perfect initial immunity and cumulative immunity of 12 months, the classic homogeneous SIRS epidemic suggests that vaccinating individuals every 15 months is sufficient to reach and maintain herd immunity, whereas the uninformed case for exponential waning with rate heterogeneity corresponding to a coefficient of variation being 0.5, requires that individuals instead need to be vaccinated every 4.4 months.

KC-like chemokine as a biomarker of sepsis in dogs with pyometra.

BACKGROUND: Sepsis, defined as a dysregulated inflammatory response to infection inducing organ dysfunction, is a common cause of mortality in both humans and animals. Early detection and treatment is essential for survival, but accurate diagnosis is challenging due to the lack of specific biomarkers for sepsis. This study explored the potential of the keratinocyte-derived chemokine (KC)-like protein in dogs as a biomarker of sepsis in dogs with bacterial uterine infection (pyometra). The aim was to compare KC-like concentrations in dogs with pyometra with or without sepsis and to assess associations between KC-like and clinical variables, including days of hospitalization as an outcome. RESULTS: A mouse KC ELISA was validated and used to determine the concentrations of KC-like in serum from 34 dogs with pyometra and 18 healthy controls. Dogs with pyometra were classified as having sepsis based on two different criteria for systemic inflammatory response syndrome (SIRS), resulting in 74% and 30% sepsis-positive, respectively. The concentration of KC-like protein was higher in pyometra dogs with sepsis than in pyometra dogs without sepsis (p < 0.05) and in healthy controls (p < 0.0001) when using either of the two SIRS criteria. Moreover, KC-like was slightly increased in dogs with pyometra without sepsis compared with healthy controls when using the more stringent SIRS criteria (p < 0.05). Analyses of all dogs showed that KC-like concentrations correlated positively with hospitalization days, C-reactive protein (CRP) concentrations, white blood cells, and percentage of band neutrophils; however, KC-like correlated negatively with hemoglobin and did not correlate with circulating creatinine. CONCLUSIONS: Our results suggest that circulating KC-like protein increases in dogs with sepsis in pyometra and that KC-like is associated with more severe clinical illness. These findings support a potential role of KC-like as a biomarker of sepsis; however, the true identity of KC-like in dogs has yet to be uncovered.

Clinical Application of CT Imaging Grading System in Upper Urinary Tract Calculi with Kidney Infection.

PURPOSE: This study aimed to establish a CT imaging grading system and explore its value in evaluating upper urinary tract calculi associated with kidney infections. METHODS: CT images of 126 patients with kidney infections caused by upper urinary tract calculi were retrospectively analyzed. The CT grading system was developed based on CT images. CT images were classified into 4 grades. General information, symptoms, and clinical findings of patients in different CT grades were analyzed. With the occurrence of systemic inflammatory response syndrome (SIRS) as the endpoint, univariate and multivariate analysis was conducted to analyze the risk factors of SIRS. RESULTS: Patients with fever or diabetes had higher CT grades, and the following examination data revealed significant differences across the various CT grades (P < 0.05): the white blood cell count, urine leucocytes count, CT1, CT2, maximum body temperature, duration of disease, the proportion of blood neutrophils, the size of stones, and levels of the C-reactive protein and procalcitonin. Only CT grading was statistically significant after multivariate analysis. According to the values of the partial regression coefficient (B), the higher the CT grade, the greater the risk of SIRS. The risk of SIRS was 4.472 times higher with each increment of the CT grade. CONCLUSIONS: The CT grade is directly associated with clinical symptoms and the risk of SIRS.

Urine oxygenation predicts COVID-19 risk.

Since February, 2023, the omicron variant has accounted for essentially all new coronavirus infections in Japan. If future infections involve mutant strains with the same level of infectivity and virulence as omicron, the government's basic policy will be to prevent the spread of infection, without compromising socioeconomic activities. Objectives include protecting pregnant women and elderly persons, and focusing on citizens requiring hospitalization and those at risk of serious illness, without imposing new social restrictions. Although the government tries to raise public awareness through education, most people affected by COVID-19 stay at home, and by the time patients become aware of the seriousness of their disease, it has often reached moderate or higher severity. In this review, we discuss why this situation persists even though the disease seems to have become milder with the shift from the delta variant to omicron. We also propose a pathophysiological method to determine the risk of severe illness. This assessment can be made at home in the early stages of COVID-19 infection, using urine analysis. Applicability of this method to drug discovery and development is also discussed.

Prolonged Systemic Inflammatory Response Syndrome After Cardiac Surgery.

OBJECTIVES: Cardiac surgery induces systemic inflammatory response syndrome (SIRS), leading to higher morbidity and mortality. There are no individualized predictors for worse outcomes or biomarkers for the multifactorial, excessive inflammatory response. The interest of this study was to evaluate whether a systematic use of the SIRS criteria could be used to predict postoperative outcomes beyond infection and sepsis, and if the development of an exaggerated inflammation response could be observed preoperatively. DESIGN: The study was observational, with prospectively enrolled patients. SETTING: This was a single institution study in a hospital setting combined with laboratory findings. PARTICIPANTS: The study included a cohort of 261 volunteer patients. INTERVENTIONS: Patients underwent cardiac surgery with cardiopulmonary bypass, and were followed up to 90 days. Biomarker profiling was run preoperatively. MEASUREMENTS AND MAIN RESULTS: Altogether, 17 of 261 (6.4%) patients had prolonged SIRS, defined as fulfilling at least 2 criteria on 4 consecutive postoperative days. During hospitalization, postoperative atrial fibrillation (POAF) was found in 42.2% of patients, and stroke and transient ischemic attack in 3.8% of patients. Prolonged SIRS was a significant predictor of POAF (odds ratio [OR] 4.5, 95% CI 1.2-17.3), 90-day stroke (OR 4.5, 95% CI 1.1-18.0), and mortality (OR 10.7, 95% CI 1.7-68.8). Biomarker assays showed that preoperative nerve growth factor and interleukin 5 levels were associated with prolonged SIRS (OR 5.6, 95%, CI 1.4-23.2 and OR 0.7, 95%, CI 0.4-1.0, respectively). CONCLUSIONS: Nerve growth factor and interleukin 5 can be used to predict prolonged systemic inflammatory response, which is associated with POAF, stroke, and mortality.

Development and validation of a machine learning-based model to assess probability of systemic inflammatory response syndrome in patients with severe multiple traumas.

BACKGROUND: Systemic inflammatory response syndrome (SIRS) is a predictor of serious infectious complications, organ failure, and death in patients with severe polytrauma and is one of the reasons for delaying early total surgical treatment. To determine the risk of SIRS within 24 h after hospitalization, we developed six machine learning models. MATERIALS AND METHODS: Using retrospective data about the patient, the nature of the injury, the results of general and standard biochemical blood tests, and coagulation tests, six models were developed: decision tree, random forest, logistic regression, support vector and gradient boosting classifiers, logistic regressor, and neural network. The effectiveness of the models was assessed through internal and external validation. RESULTS: Among the 439 selected patients with severe polytrauma in 230 (52.4%), SIRS was diagnosed within the first 24 h of hospitalization. The SIRS group was more strongly associated with class II bleeding (39.5% vs. 60.5%; OR 1.81 [95% CI: 1.23-2.65]; P = 0.0023), long-term vasopressor use (68.4% vs. 31.6%; OR 5.51 [95% CI: 2.37-5.23]; P < 0.0001), risk of acute coagulopathy (67.8% vs. 32.2%; OR 2.4 [95% CI: 1.55-3.77]; P < 0.0001), and greater risk of pneumonia (59.5% vs. 40.5%; OR 1.74 [95% CI: 1.19-2.54]; P = 0.0042), longer ICU length of stay (5 ± 6.3 vs. 2.7 ± 4.3 days; P < 0.0001) and mortality rate (64.5% vs. 35.5%; OR 10.87 [95% CI: 6.3-19.89]; P = 0.0391). Of all the models, the random forest classifier showed the best predictive ability in the internal (AUROC 0.89; 95% CI: 0.83-0.96) and external validation (AUROC 0.83; 95% CI: 0.75-0.91) datasets. CONCLUSIONS: The developed model made it possible to accurately predict the risk of developing SIRS in the early period after injury, allowing clinical specialists to predict patient management tactics and calculate medication and staffing needs for the patient. LEVEL OF EVIDENCE: Level 3. TRIAL REGISTRATION: The study was retrospectively registered in the ClinicalTrials.gov database of the National Library of Medicine (NCT06323096).

Primary Infection Site as a Predictor of Sepsis Development in Emergency Department Patients.

BACKGROUND: Sepsis is a life-threatening condition but predicting its development and progression remains a challenge. OBJECTIVE: This study aimed to assess the impact of infection site on sepsis development among emergency department (ED) patients. METHODS: Data were collected from a single-center ED between January 2016 and December 2019. Patient encounters with documented infections, as defined by the Systematized Nomenclature of Medicine-Clinical Terms for upper respiratory tract (URI), lower respiratory tract (LRI), urinary tract (UTI), or skin or soft-tissue infections were included. Primary outcome was the development of sepsis or septic shock, as defined by Sepsis-1/2 criteria. Secondary outcomes included hospital disposition and length of stay, blood and urine culture positivity, antibiotic administration, vasopressor use, in-hospital mortality, and 30-day mortality. Analysis of variance and various different logistic regression approaches were used for analysis with URI used as the reference variable. RESULTS: LRI was most associated with sepsis (relative risk ratio [RRR] 5.63; 95% CI 5.07-6.24) and septic shock (RRR 21.2; 95% CI 17.99-24.98) development, as well as hospital admission rates (odds ratio [OR] 8.23; 95% CI 7.41-9.14), intensive care unit admission (OR 4.27; 95% CI 3.84-4.74), in-hospital mortality (OR 6.93; 95% CI 5.60-8.57), and 30-day mortality (OR 7.34; 95% CI 5.86-9.19). UTIs were also associated with sepsis and septic shock development, but to a lesser degree than LRI. CONCLUSIONS: Primary infection sites including LRI and UTI were significantly associated with sepsis development, hospitalization, length of stay, and mortality among patients presenting with infections in the ED.

Prevalence of anterior uveitis in cases of systemic inflammatory response syndrome in dogs and cats.

OBJECTIVE: To determine the prevalence of anterior uveitis in dogs and cats hospitalized with a diagnosis of systemic inflammatory response syndrome (SIRS). ANIMALS STUDIED: Dogs and cats hospitalized between May 2020 and January 2021 were prospectively included. PROCEDURES: Patients were categorized into two different groups: The first group included patients diagnosed with SIRS, and the second group included patients hospitalized without SIRS as a control group. Daily physical and ophthalmological examinations were conducted during hospitalization. Diagnosis of anterior uveitis was made based on the presence of aqueous flare, low intraocular pressure, and other associated ocular signs such as episcleral injection and miosis. A multinomial logistic regression analysis was conducted to investigate factors associated with SIRS and anterior uveitis development. RESULTS: The study comprised 42 patients with SIRS and 26 patients without SIRS. Among those with SIRS, 38% developed anterior uveitis, whereas only 7.7% of patients without SIRS showed signs of anterior uveitis. The prevalence of uveitis was significantly higher in animals with SIRS compared to those without SIRS (p < .05). CONCLUSION: Anterior uveitis is more prevalent in patients with SIRS than patients without SIRS. Therefore, complete ophthalmic examination is recommended in all patients presenting with this syndrome.

Prevalence of SIRS with primary epiploic appendagitis.

PURPOSE: Primary epiploic appendagitis (PEA) is not an uncommon cause of abdominal pain. The systemic inflammatory response syndrome (SIRS) criteria have high sensitivity for early detection of inflammation and infection. To date, there is limited data about the association between SIRS and PEA. The aims of this retrospective study were to evaluate the prevalence of SIRS response and its clinical relevance in patients diagnosed with PEA within a large tertiary hospital network. METHODS: A retrospective study was performed on all consecutive adult patients who presented to four major emergency departments with CT-confirmed PEA from 01 January 2022 to 27 March 2023. The fulfilment of SIRS criteria, hospital admission rate and treatments provided were analysed for these patients. RESULTS: Seventy-three patients had CT-confirmed PEA. Seventeen patients (23.2%) with PEA were SIRS positive. The hospital admission rate in the SIRS group trended higher than the non-SIRS group (odds ratio of 2.51, 95% CI (0.75, 8.39)). The odds of having an associated radiological comorbidity unrelated to PEA were 18.7 times higher in the SIRS positive group. Fifty-seven (78%) patients were discharged home, and 16 (22%) patients were admitted into hospital. Nearly all patients were treated conservatively (98.6%). CONCLUSION: PEA patients with SIRS response trend towards a higher hospital admission rate and are significantly more likely to have other radiological comorbidities than non-SIRS patients. It is important to look for other pathological conditions in a SIRS positive patient with a CT-diagnosis of PEA.

An overview of malingering and deception in neuropsychiatric cases.

Forensic practitioners must shoulder special responsibilities when evaluating over-stated pathology (e.g., malingering) as well as simulated adjustment. Such determinations may modify or even override other clinical findings. As a result, practitioners must be alert to their own misassumptions that may unintentionally bias their conclusions about response styles. Detection strategies for malingering-based on unlikely or markedly amplified presentations-are highlighted in this article. Given page constraints, assessment methods for feigning are succinctly presented with their applications to administrative, civil, and criminal referrals.

Early warning scores for sepsis identification and prediction of in-hospital mortality in adults with sepsis: A systematic review and meta-analysis.

AIM: The early warning scores (EWS), quick Sequential Organ Failure Assessment (qSOFA) and systemic inflammatory response syndrome (SIRS) criteria have been proposed as sepsis screening tools. This review aims to summarise and compare the performance of EWS with the qSOFA and SIRS criteria for predicting sepsis diagnosis and in-hospital mortality in patients with sepsis. DESIGN: A systematic review with meta-analysis. REVIEW METHODS: Seven databases were searched from January 1, 2016 until March 10, 2022. Study quality was assessed using the Quality Assessment of Diagnostic Accuracy Studies 2 tool. Sensitivity, specificity, likelihood ratios and diagnostic odd ratios were pooled by using the bivariate random effects model. Overall performance was summarised by using the hierarchical summary receiver-operating characteristics curve. This paper adhered to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses of Diagnostic Test Accuracy Studies (PRISMA-DTA) guidelines. RESULTS: Ten studies involving 52,474 subjects were included in the review. For predicting sepsis diagnosis, the pooled sensitivity of EWS (65%, 95% CI: 55, 75) was similar to SIRS ≥2 (70%, 95% CI: 49, 85) and higher than qSOFA ≥2 (37%, 95% CI: 20, 59). The pooled specificity of EWS (77%, 95% CI: 64, 86) was higher than SIRS ≥2 (62%, 95% CI: 41, 80) but lower than qSOFA ≥2 (94%, 95% CI: 86, 98). Results were similar for the secondary outcome of in-hospital mortality. CONCLUSIONS: Although no one scoring system had both high sensitivity and specificity, the EWS had at least equivalent values in most measures of diagnostic accuracy compared with SIRS or qSOFA. IMPLICATIONS FOR THE PROFESSION: Healthcare systems in which EWS is already in place should consider whether there is any clinical benefit in adopting qSOFA or SIRS. NO PATIENT OR PUBLIC CONTRIBUTION: This systematic review did not directly involve patient or public contribution to the manuscript.

Prognostic accuracy of SOFA, MEWS, and SIRS criteria in predicting the mortality rate of patients with sepsis: A meta-analysis.

BACKGROUND: In recent years, some studies classified patients with sepsis and predicted their mortality by using some evaluation scales. Several studies reported significant differences in the predictive values of several tools, and the non-uniformity of the cut-off value. AIM: To determine and compare the prognostic accuracy of Sequential Organ Failure Assessment (SOFA) score, Modified Early Warning Score (MEWS), and Systemic Inflammatory Response Syndrome (SIRS) criteria in predicting the mortality of patients with sepsis. METHODS: This study comprised of systematic literature review and meta-analysis according to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses. We searched PubMed, Embase, Web of Science and Cochrane Library databases from their establishment to July 31, 2022. The research articles published in the index journals provide sufficient data (true positive, false positive, true negative, and false negative results) for patients with sepsis. The combined sensitivity and specificity of the 95% confidence interval (CI) were calculated using the bivariate random effect model (BRM). The hierarchical overall subject working characteristics (HSROC) curve was drawn to evaluate the accuracy of the overall prognosis. RESULTS: Data of 55 088 patients from 32 studies were included in this meta-analysis. SOFA had an intermediate sensitivity of 0.73 (95% CI: 0.67-0.78) and a specificity of 0.70 (0.63-0.76). SIRS criteria had the highest sensitivity of 0.75 (0.66-0.82) and the lowest specificity of 0.40 (0.29-0.52). MEWS had the lowest sensitivity of 0.49 (0.40-0.59) and the highest specificity of 0.82 (0.78-0.86). CONCLUSIONS: Among SOFA, MEWS, and SIRS criteria, SOFA showed moderate sensitivity and specificity for predicting mortality in patients with sepsis, the highest sensitivity of SIRS and the strongest specificity of MEWS for predicting mortality in patients with sepsis. The future research direction is to combine the relevant indicators of MEWS and SIRS to develop a measurement tool with high reliability and validity. RELEVANCE TO CLINICAL PRACTICE: The review provides useful insights into the prognostic accuracy of different assessment tools in predicting mortality in sepsis patients, which will help clinicians choose the most appropriate tool for early identification and treatment of sepsis. The findings may also contribute to the development of more accurate and reliable prognostic models for sepsis.

Coronavirus infection and systemic inflammatory reaction syndrome.

OBJECTIVE: Aim: The purpose of this study was a clinical approbation of the Kometad drug (international non-proprietary name sodium colistimethate), an antibiotic from the polymyxin group in patients with severe course of confirmed сoronavirus infection in the intensive care unit of the Branch of the I. Zhekenova Municipal Clinical Infectious Diseases Hospital.. PATIENTS AND METHODS: Materials and Methods: The methodology is based on both theoretical and empirical methods of scientific cognition. During the study, the features of the Coronavirus infection and the inflammatory reaction syndrome were considered, which became quite a big problem during the pandemic. RESULTS: Results: The main indications for the tested drug and the consequences of its use for one age group were also determined. CONCLUSION: Conclusions: The conclusion was made about the positive dynamics of the patients' health status, and recommendations were given for further research in this area. The practical significance of this study lies in the first clinical approbation of the Kometad drug, which can be used in medicine to reduce the severity of the systemic inflammatory reaction syndrome and improve the patient's health as a result of the disease of Coronavirus infection, after further clinical trials of the drug with different age groups of patients.

RNA m6A methylation regulators in sepsis.

N6-methyladenosine (m6A) modification is a class of epitope modifications that has received significant attention in recent years, particularly in relation to its role in various diseases, including sepsis. Epigenetic research has increasingly focused on m6A modifications, which is influenced by the dynamic regulation of three protein types: ?Writers" (such as METTL3/METTL14/WTAP)-responsible for m6A modification; ?Erasers" (FTO and ALKBH5)-involved in m6A de-modification; and ?Readers" (YTHDC1/2, YTHDF1/2/3)-responsible for m6A recognition. Sepsis, a severe and fatal infectious disease, has garnered attention regarding the crucial effect of m6A modifications on its development. In this review, we attempted to summarize the recent studies on the involvement of m6A and its regulators in sepsis, as well as the significance of m6A modifications and their regulators in the development of novel drugs and clinical treatment. The potential value of m6A modifications and modulators in the diagnosis, treatment, and prognosis of sepsis has also been discussed.

Combination of GM CSF and carbapenem is superior to carbapenem monotherapy in difficult-to-treat spontaneous bacterial peritonitis: A randomized controlled trial.

BACKGROUND: Patients with cirrhosis and treatment non-responsive spontaneous bacterial peritonitis (SBP) have high mortality. We aimed to investigate whether GM-CSF can improve SBP response rates. PATIENTS AND METHODS: In this open-label RCT, 131 cirrhosis patients with difficult-to-treat SBP (DTT SBP) were randomized to receive meropenem alone (1 g IV thrice daily for 5 days) (MERO Group, n = 66) or in combination with GM-CSF (1.5 mcg/Kg daily IV till resolution or till 5d) (MEROGM Group, n = 65). The primary end-point was SBP early-response (reduction in absolute neutrophil count (ANC) by >25% after 48 h). Secondary end-points included SBP resolution at day 5. RESULTS: Patients in MEROGM group in comparison to MERO group had higher SBP early-response (60% vs. 31.8%; p = .001) and SBP resolution rates (55.4% vs. 24.2%; p = .0003). Patients in the combination arm also had better resolution of pneumonia {8/17 (47.05%) vs. 2/19 (10.5%), p = .02} and lower incidence of new-onset AKI (15.4% vs. 31.8%, p = .02), HE (18.5% vs. 34.8%, p = .04) and infections (21.5% vs. 37.9%, p = .05). In comparison to MERO group, 7-day survival was higher in MEROGM group (89.2% vs. 78.7%, p = .03), though the 28-day survival was comparable (78.4% vs. 71.2%; p = .66). None of the patients developed treatment-related severe adverse effects requiring discontinuation of therapy. CONCLUSIONS: The addition of GM-CSF to meropenem significantly improves response rates in DTT SBP patients within 48 h. Early use of GMCSF modulates host immune response, and enhances antibiotic response with higher SBP resolution. The use of GMCSF needs to be considered in combating difficult SBP in cirrhosis patients.

Scaffold hopping derived novel benzoxazepinone RIPK1 inhibitors as anti-necroptosis agents.

Receptor-interacting protein kinase 1 (RIPK1)-mediated necroptosis is believed to have a significant role in contributing to inflammatory diseases. Inhibiting RIPK1 has shown promise in effectively alleviating the inflammation process. In our current study, we employed scaffold hopping to develop a series of novel benzoxazepinone derivatives. Among these derivatives, compound o1 displayed the most potent antinecroptosis activity (EC50=16.17±1.878nM) in cellular assays and exhibited the strongest binding affinity to the target site. Molecular docking analyses further elucidated the mechanism of action of o1, revealing its ability to fully occupy the protein pocket and form hydrogen bonds with the amino acid residue Asp156. Our findings highlight that o1 specifically inhibits necroptosis, rather than apoptosis, by impeding the RIPK1/Receptor-interacting protein kinase 3 (RIPK3)/mixed-lineage kinase domain-like (MLKL) pathway's phosphorylation, triggered by TNFα, Smac mimetic, and z-VAD (TSZ). Additionally, o1 demonstrated dose-dependent improvements in the survival rate of mice with Systemic Inflammatory Response Syndrome (SIRS), surpassing the protective effect observed with GSK'772.

Risk of second primary malignancies in survivors of pancreatic neuroendocrine neoplasms from 2000 to 2018.

BACKGROUND AND AIM: As a result of improved survival, cancer survivors continue to remain at risk of developing second primary malignancies (SPMs). However, the association between first primary pancreatic neuroendocrine neoplasms (PanNENs) and SPMs has not been thoroughly investigated. METHODS: Using the Surveillance, Epidemiology, and End Results-18 database, patients histologically diagnosed with PanNENs as their first malignancy between 2000 and 2018 were identified. Standardized incidence ratios (SIRs) with 95% confidence intervals (CIs) and excess absolute risks per 10 000 person-years of SPMs were calculated to estimate the risk of being diagnosed with subsequent cancers compared with the general population. RESULTS: A total of 489 (5.7%) PanNENs survivors developed an SPM during the follow up, with a median latency between first and second cancer diagnoses of 32.0 months. The overall SIR of SPMs was 1.30 (95% CI: 1.19, 1.42) and the excess absolute risk was 35.67 cases per 10 000 person-years in comparison with the general population. Age 25-64 years at PanNENs diagnosis was associated with statistically higher risks for SPMs of all cancers combined. Latency stratification was significant for elevated SPMs risk between 2-23 and 84+ months after diagnosis. White patients were found to have a significantly increased incidence of SPMs (SIR: 1.23, 95% CI: 1.11, 1.35), mainly owing to the higher risk of stomach, small intestine, pancreas, kidney and renal pelvis, and thyroid cancers. CONCLUSION: Pancreatic neuroendocrine neoplasms survivors experience a significant increase in the burden of SPMs compared with the reference population. The heightened relative risk calls for careful long-term scrutiny as part of survivorship care plans.

Repurposing of the FGFR inhibitor AZD4547 as a potent inhibitor of necroptosis by selectively targeting RIPK1.

Necroptosis is a form of regulated necrosis involved in various pathological diseases. The process of necroptosis is controlled by receptor-interacting kinase 1 (RIPK1), RIPK3, and pseudokinase mixed lineage kinase domain-like protein (MLKL), and pharmacological inhibition of these kinases has been shown to have therapeutic potentials in a variety of diseases. In this study, using drug repurposing strategy combined with high-throughput screening (HTS), we discovered that AZD4547, a previously reported FGFR inhibitor, is able to interfere with necroptosis through direct targeting of RIPK1 kinase. In both human and mouse cell models, AZD4547 blocked RIPK1-dependent necroptosis. In addition, AZD4547 rescued animals from TNF-induced lethal shock and inflammatory responses. Together, our study demonstrates that AZD4547 is a potent and selective inhibitor of RIPK1 with therapeutic potential for the treatment of inflammatory disorders that involve necroptosis.

Abdominal perfusion in canine patients with pyometra and sepsis evaluated by Doppler and contrast-enhanced ultrasound.

BACKGROUND: Sepsis is a condition characterized by organic dysfunction, leading to hemodynamic instability and high morbidity and mortality rates in humans and animals. Early identification of perfusion changes and appropriate management of sepsis are crucial for improving patient prognosis. Currently, the Systemic Inflammatory Response Syndrome (SIRS) and Sequential Organ Failure Assessment (SOFA) scores are widely studied for sepsis identification and evaluation of organ dysfunction. However, these scores do not assess gastrointestinal involvement, which is common in this condition. Contrast-enhanced ultrasound (CEUS) and Doppler have been considered promising diagnostic techniques for detecting changes in vascularization and microcirculation in a non-invasive and safe manner, particularly in the gastrointestinal system. This study aimed to evaluate duodenal perfusion using CEUS, as well as abdominal aortic and cranial mesenteric artery blood flow using Doppler ultrasound, and systolic arterial pressure (SAP) in 17 bitches with pyometra and in 10 healthy animals. RESULTS: The variables were compared between the pyometra and control groups, as well between patients with and without sepsis determined by the SOFA or SIRS scores. Pyometra was found to cause a reduction in abdominal aortic blood flow volume, aortic peak systolic velocity, and resistivity index as evaluated by Doppler ultrasound. Patients with sepsis according to the SOFA criteria only presented lower SAP. In contrast, sepsis animals identified by the SIRS score exhibited lower SAP, aortic peak systolic velocity, aortic blood flow volume, and aortic resistivity index and additionally, higher peak intensity of contrast in the duodenal wall. CONCLUSIONS: Pyometra causes a reduction in abdominal aortic blood flow, which is more pronounced in animals with sepsis identified by the SIRS criteria. These animals also exhibited a decrease in systolic blood pressure and an increase in duodenal perfusion, as evident by CEUS. However, these changes were not observed in patients with sepsis identified by the SOFA criteria. The alterations in intestinal perfusion observed in animals with sepsis indicate the presence of inflammation or dysfunction. In this regard, CEUS proves to be a valuable technique for detecting subtle changes in tissue hemodynamics that may not be apparent in conventional exams.