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Background/objectives: Ataxia telangiectasia (A-T) is an inherited multisystem disorder with increased sensitivity to ionising radiation and elevated cancer risk. Although other cancer predisposition syndromes have established cancer screening protocols, evidence-based guidelines for cancer screening in A-T are lacking. This study sought to assess feasibility of a cancer screening protocol based on whole-body MRI (WB-MRI) in children and young people with A-T., Design/methods: Children and young people with A-T were invited to undergo a one-off non-sedated 3-Tesla WB-MRI. Completion rate of WB-MRI was recorded and diagnostic image quality assessed by two experienced radiologists, with pre-specified success thresholds for scan completion of >50% participants and image quality between acceptable to excellent in 65% participants. Positive imaging findings were classified according to the ONCO-RADS system. Post-participation interviews were performed with recruited families to assess the experience of participating and feelings about waiting for, and communication of, the findings of the scan., Results: Forty-six children and young people with A-T were identified, of which 36 were eligible to participate, 18 were recruited and 16 underwent WB-MRI. Nineteen parents participated in interviews. Fifteen participants (83%) completed the full WB-MRI scan protocol. The pre-specified image quality criterion was achieved with diagnostic images obtained in at least 93% of each MRI sequence. Non-malignant scan findings were present in 4 (25%) participants. Six themes were identified from the interviews: (1) anxiety is a familiar feeling, (2) the process of MRI scanning is challenging for some children and families, (3) preparation is essential to reduce stress, (4) WB-MRI provides the reassurance about the physical health that families need, (5) WB-MRI experience turned out to be a positive experience and (6) WB-MRI allows families to be proactive., Conclusion: This study shows that WB-MRI for cancer screening is feasible and well-accepted by children and young people with A-T and their families., (© 2024 The Author(s). Cancer Medicine published by John Wiley & Sons Ltd.)

This study investigated the impacts of CCR5 promoter region polymorphisms on the development of systemic lupus erythematosus (SLE) by comparing CCR5 genotypes and haplotypes from SLE patients with ethnically matched controls. A total of 382 SLE patients (289 European-derived and 93 African-derived) and 375 controls (243 European-derived and 132 African-derived) were genotyped for the CCR2-64I G > A (rs1799864), CCR5-59353 C > T (rs1799988), CCR5-59356 C > T (rs41469351), CCR5-59402 A > G (rs1800023) and CCR5-59653 C > T (rs1800024) polymorphisms through polymerase chain reaction-restriction fragment length polymorphism and direct sequencing. Previous data from CCR5Δ32 analysis was included in the study to infer the CCR5 haplotypes and as a possible confounding factor in the binary logistic regression. European-derived patients showed a higher frequency of CCR5 wild-type genotype (conversely, a reduced frequency of Δ32 allele) and a reduced frequency of the HHG*2 haplotype compared to controls; both factors significantly affecting disease risk [p = .003 (OR 3.5, 95%CI 1.6-7.5) and 2.0% vs. 7.2% (residual p = 2.9E - 5), respectively]. Additionally, the HHA/HHB, HHC and HHG*2 haplotype frequencies differed between African-derived patients and controls [10% vs. 20.5% (residual p = .003), 29.4% vs. 17.4% (residual p = .003) and 3.9% vs. 0.8% (residual p = .023), respectively]. Considering the clinical manifestations of the disease, the CCR5Δ32 presence was confirmed as a susceptibility factor to class IV nephritis in the African-derived group and when all patients were grouped for comparison [p corrected  = .012 (OR 3.0; 95%CI 3.0-333.3) and p corrected  = .0006 (OR 6.8; 95%CI 1.9-24.8), respectively]. In conclusion, this study indicates that CCR5 promoter polymorphisms are important disease modifiers in SLE. Present data reinforces the CCR5Δ32 polymorphism as a protective factor for the development of the disease in European-derived patients and as a susceptibility factor for class IV nephritis in African-derived patients. Furthermore, we also described a reduced frequency of HHA/HHB and an increased frequency of HHC and HHG*2 haplotypes in African-derived patients, which could modify the CCR5 protein expression in specific cell subsets., (© 2023 John Wiley & Sons Ltd.)

Background/objectives: Ataxia-telangiectasia (A-T) is a complex inherited disease associated with an increased risk of malignancy. Surveillance guidelines have demonstrated significant health benefits in other cancer predisposition syndromes. However, evidence-based guidelines for cancer screening are not currently used in the United Kingdom for people affected by A-T. This study aims to understand how people with A-T and their parents feel about cancer surveillance using whole-body magnetic resonance imaging (MRI) to inform the future development of cancer surveillance guidelines., Design/methods: We conducted semistructured interviews with people affected by A-T. Data were analysed inductively using thematic analysis., Results: Nine parents of children with A-T and four adults with A-T were interviewed. Five main themes emerged from the data, including (1) cancer screening was considered invaluable with the perceived value of early detection highlighted; (2) the cancer fear can increase anxiety; (3) the perceived limitations around current practice, with the responsibility for monitoring falling too strongly on parents and patients; (4) the need for effective preparation for cancer screening, including clear communication and (5) the challenges associated with MRI screening, where specific recommendations were made for improving the child's experience., Conclusion: This study suggests that stakeholders are positive about the perceived advantages of a cancer screening programme. Ongoing support and preparation techniques should be adopted to maximise adherence and minimise adverse psychosocial outcomes., Patient or Public Contribution: People with A-T and parents of people with A-T were actively involved in this study by giving their consent to be interviewed. An independent parent representative contributed to the study, supporting the research team in interpreting and commenting on the appropriateness of the language used in this report., (© 2023 The Authors. Health Expectations published by John Wiley & Sons Ltd.)

Well-characterized small molecules are essential tools for studying the biology and therapeutic relevance of a target protein. However, many compounds reported in the literature and routinely studied in biomedical research lack the potency and selectivity required for mechanistic cellular studies on the function of a given protein. Furthermore, commercially available compounds often do not include useful tools developed by industry as part of their research and development efforts, as they frequently remain proprietary. The freely available donated chemical probe (DCP) library, fueled by generous donations of compounds from industry and academia, enables easy access to a steadily growing collection of these valuable and well-characterized tools. Here, we provide a systematic description of the current DCP library collection and their associated comprehensive characterization data, including a variety of in vitro and cellular assays. Of note, we characterized the set in relevant human primary models by employing hepatotoxicity screening in primary human liver spheroids and viability screening in patient-derived colorectal cancer organoids and matched normal-adjacent epithelium. Taken together, the DCP library represents a well-annotated, openly available collection of tool compounds for studying a wide range of targets, including kinases, G-protein-coupled receptors, and ion channels. As such, it represents a unique resource for the biomedical research community.

Background: Ulcerative Colitis (UC) is an Inflammatory Bowel Disease (IBD) characterized by uncontrolled immune response, diarrhoea, weight loss and bloody stools, where sustained remission is not currently achievable. Dextran Sulphate Sodium (DSS)-induced colitis is an animal model that closely mimics human UC. Ultrasound (US) has been shown to prevent experimental acute kidney injury through vagus nerve (VN) stimulation and activation of the cholinergic anti-inflammatory pathway (CAIP). Since IBD patients may present dysfunctional VN activity, our aim was to determine the effects of therapeutic ultrasound (TUS) in DSS-induced colitis., Methods: Acute colitis was induced by 2% DSS in drinking water for 7 days and TUS was administered to the abdominal area for 7 min/day from days 4-10. Clinical symptoms were analysed, and biological samples were collected for proteomics, macroscopic and microscopic analysis, flow cytometry and immunohistochemistry., Findings: TUS attenuated colitis by reducing clinical scores, colon shortening and histological damage, inducing proteomic tolerogenic response in the gut during the injury phase and early recovery of experimental colitis. TUS did not improve clinical and pathological outcomes in splenectomised mice, while α7nAChR (α7 nicotinic acetylcholine receptor - indicator of CAIP involvement) knockout animals presented with disease worsening. Increased levels of colonic F4/80 + α7nAChR + macrophages in wild type mice suggest CAIP activation., Interpretation: These results indicate TUS improved DSS-induced colitis through stimulation of the splenic nerve along with possible contribution by VN with CAIP activation. FUND: Intramural Research Programs of the Clinical Centre, the National Institute of Biomedical Imaging and Bioengineering at the NIH and CAPES/Brazil., (Published by Elsevier B.V.)

Aim: To investigate the temporal clinical, proteomic, histological and cellular immune profiles of dextran sulfate sodium (DSS)-induced acute colitis., Methods: Acute colitis was induced in C57Bl/6 female mice by administration of 1%, 2% or 3% DSS in drinking water for 7 d. Animals were monitored daily for weight loss, stool consistency and blood in the stool, while spleens and colons were harvested on day 8. A time course analysis was performed in mice ingesting 3% DSS, which included colon proteomics through multiplex assay, colon histological scoring by a blinded investigator, and immune response through flow cytometry or immunohistochemistry of the spleen, mesenteric lymph node and colon., Results: Progressive worsening of clinical colitis was observed with increasing DSS from 1% to 3%. In mice ingesting 3% DSS, colon shortening and increase in pro-inflammatory factors starting at day 3 was observed, with increased spleen weights at day 6 and day 8. This coincided with cellular infiltration in the colon from day 2 to day 8, with progressive accumulation of macrophages F4/80 + , T helper CD4 + (Th), T cytotoxic CD8 + (Tcyt) and T regulatory CD25 + (Treg) cells, and progressive changes in colonic pathology including destruction of crypts, loss of goblet cells and depletion of the epithelial barrier. Starting on day 4, mesenteric lymph node and/or spleen presented with lower levels of Treg, Th and Tcyt cells, suggesting an immune cell tropism to the gut., Conclusion: These results demonstrate that the severity of experimental colitis is dependent on DSS concentration, correlated with clinical, proteomic, histological and cellular immune response on 3% DSS., Competing Interests: Conflict-of-interest statement: The authors declare that they have no conflict-of-interests.

Potent, selective and broadly characterized small molecule modulators of protein function (chemical probes) are powerful research reagents. The pharmaceutical industry has generated many high-quality chemical probes and several of these have been made available to academia. However, probe-associated data and control compounds, such as inactive structurally related molecules and their associated data, are generally not accessible. The lack of data and guidance makes it difficult for researchers to decide which chemical tools to choose. Several pharmaceutical companies (AbbVie, Bayer, Boehringer Ingelheim, Janssen, MSD, Pfizer, and Takeda) have therefore entered into a pre-competitive collaboration to make available a large number of innovative high-quality probes, including all probe-associated data, control compounds and recommendations on use (https://openscienceprobes.sgc-frankfurt.de/). Here we describe the chemical tools and target-related knowledge that have been made available, and encourage others to join the project., Competing Interests: SM, SA, CA, JB, CB, PB, DD, DD, AE, JE, SF, AI, TH, SL, BM, BR, NS, AS, PT, CW, TW, WZ, SK No competing interests declared, MB employee of Bayer AG, JB employee of Vertex Pharmaceuticals, JB employee of Boehringer Ingelheim, MB Mark E Bunnage: employee of Vertex Pharmaceuticals, AC Adrian J Carter: employee of Boehringer Ingelheim, VD Reviewing editor, eLife, JE employee of Janssen Pharmaceutical Research and Development LLC, CF employee of Merck & Co., Inc. AG Andreas Gollner: employee of Boehringer Ingelheim, CG employee of Ched Grimshaw Consulting, LLC, IH Ingo V Hartung: employee of Bayer AG, SH employee of Takeda California Inc. TH employee of J&J Innovation Centre, TH Terry V Hughes: employee of J&J Innovation Centre, VL Volkhart MJ Li: employee of Bayer AG, SL employee of Pfizer, HM employee of Takeda Pharmaceutical Company Ltd, JM John Mathias: employee of Pfizer, RO Ronan C O'Hagan: employee of Merck & Co., Inc.,, DO Dafydd R Owen: employee of Pfizer, VP employee of Janssen-Pharmaceutical Companies of Johnson & Johnson, DR Daniel Rauh received consulting and lecture fees (Sanofi-Aventis, Takeda, Novartis, Pfizer, LDC) as well as research support (Novartis, J&J, Bayer, Merck, MSD). SR employee of AbbVie, CS Cora Scholten: employee of Bayer AG, KS Kumar Singh Saikatendu: employee of Takeda California Inc, MT Masayuki Takizawa: employee of Takeda Pharmaceutical Company Ltd. CT Chris Tse: employee of AbbVie, DT employee of Eurofins DiscoverX, AV Amélia YI Viana: employee of Boehringer Ingelheim, AM Anke Mueller-Fahrnow: employee of Bayer AG, (© 2018, Müller et al.)

Objective: To investigate the effects of oxidative stress injury in dextran sulfate sodium (DSS)-induced colitis in mice treated with mesenchymal stem cells (MSC)., Results: Mice exposed to oral administration of 2% DSS over 7 days presented a high disease activity index and an intense colonic inflammation. Systemic infusion of MSC protected from severe colitis, reducing weight loss and diarrhea while lowering the infiltration of inflammatory cells. Moreover, toxic colitis injury increased oxidative stress. Administration of DSS decreased reduced glutathione (GSH) and superoxide dismutase (SOD) activity, and increased thiobarbituric acid-reactive substances levels in the colon. No alteration was found in catalase (CAT) and glutathione peroxidase (GPx) activity. Otherwise, MSC transplantation was able to prevent the decrease of GSH levels and SOD activity suggestive of an antioxidant property of MSC., Conclusion: The oxidative stress is a pathomechanism underlying the pathophysiology of colitis and MSC play an important role in preventing the impairment of antioxidants defenses in inflamed colon.

Although the highly conserved Ca(2+)/calmodulin-dependent protein kinase II (CaMKII) is known to play an essential role in cardiac myocytes, its involvement in the frequency-dependent acceleration of relaxation is still controversial. To investigate the functional significance of CaMKII autophosphorylation and its regulation by protein phosphatases (PPs) in heart, we developed a new mathematical model for the CaMKIIdelta isoform. Due to better availability of experimental data, the model was first adjusted to the kinetics of the neuronal CaMKIIalpha isoform and then converted to a CaMKIIdelta model by fitting to kinetic data of the delta isoform. Both models satisfactorily reproduced experimental data of the CaMKII-calmodulin interaction, the autophosphorylation rate, and the frequency dependence of activation. The level of autophosphorylated CaMKII cumulatively increased upon starting the Ca(2+) stimulation at 3 Hz in the delta model. Variations in PP concentration remarkably affected the frequency-dependent activation of CaMKIIdelta, suggesting that cellular PP activity plays a key role in adjusting CaMKII activation in heart. The inhibitory effect of PP was stronger for CaMKIIalpha compared to CaMKIIdelta. Simulation results revealed a potential involvement of CaMKIIdelta autophosphorylation in the frequency-dependent acceleration of relaxation at physiological heart rates and PP concentrations.

Background: Spontaneous bacterial peritonitis is a serious complication in cirrhotic patients, and the changes in the microbiological characteristics reported in the last years are impacting the choice of antibiotic used in the treatment., Aim: To evaluate the change in the epidemiology and antibiotic resistance of the bacteria causing spontaneous bacterial peritonitis in a 7 years period., Methods: All the cases of cirrhotic patients with spontaneous bacterial peritonitis with positive cultural examination were retrospectively studied. Two periods were evaluated: 1997-1998 and 2002-2003. The most frequent infecting organisms and the sensitivity in vitro to antibiotics were registered., Results: In the first period (1997-1998) there were 33 cases, 3 (9%) with polymicrobial infection. The most common were: E.coli in 13 (36,11%), Staphylococcus coagulase-negative in 6 (16,66%), K. pneumoniae in 5 (13,88%), S. aureus in 4 (11,11%) and S. faecalis in 3 (8,33%). In 2003-2004, there were 43 cases, 2 (5%) with polymicrobial infection. The most frequent were: Staphylococus coagulase-negative in 16 (35,55%), S. aureus in 8 (17,77%), E. coli in 7 (15,55%) and K. pneumoniae in 3 (6,66%). No one was using antibiotic prophilaxys. The prevalence of S. aureus methicillin-resitant to quinolone and trimethoprim-sulfamethoxazole changed from 25% to 50%, and vancomicin was the only one with absolute activity during all the period. In the same way, the prevalence of E. coli resistant to third generation cephalosporin and to quinolone changed from 0% to 16%., Conclusion: There was a modification of the bacterial population causing spontaneous bacterial peritonitis, with high frequency of gram-positive organisms, as well as an increase in the resistance to the traditionally recommended antibiotics. This study suggests a probable imminent inclusion of a drug against gram-positive organisms in the empiric treatment of spontaneous bacterial peritonitis.

A stretch-induced increase of active tension is one of the most important properties of the heart, known as the Frank-Starling law. Although a variation of myofilament Ca(2+) sensitivity with sarcomere length (SL) change was found to be involved, the underlying molecular mechanisms are not fully clarified. Some recent experimental studies indicate that a reduction of the lattice spacing between thin and thick filaments, through the increase of passive tension caused by the sarcomeric protein titin with an increase in SL within the physiological range, promotes formation of force-generating crossbridges (Xbs). However, the mechanism by which the Xb concentration determines the degree of cooperativity for a given SL has so far evaded experimental elucidation. In this simulation study, a novel, rather simple molecular-based cardiac contraction model, appropriate for integration into a ventricular cell model, was designed, being the first model to introduce experimental data on titin-based radial tension to account for the SL-dependent modulation of the interfilament lattice spacing and to include a conformational change of troponin I (TnI). Simulation results for the isometric twitch contraction time course, the length-tension and the force-[Ca(2+)] relationships are comparable to experimental data. A complete potential Frank-Starling mechanism was analyzed by this simulation study. The SL-dependent modulation of the myosin binding rate through titin's passive tension determines the Xb concentration which then alters the degree of positive cooperativity affecting the rate of the TnI conformation change and causing the Hill coefficient to be SL-dependent.

The efficiency of heart pump function greatly depends on synchronized contraction of myocardial muscle. In this work, contraction simulation of an excitable ventricular tissue cable was constructed to study the influence of excitation patterns on tissue contraction. The tissue cable is composed of elements which contract when excited by an external stimulus. In each calculation step, contraction force of each element is determined by a ventricular cell model. The mechanical deformation is then solved by finite element method and states of cells are updated accordingly. Several factors such as the starting position of the stimulation signal and the conduction velocity of gap-junctions affect contraction behavior. Simulation results show that the activation time, i.e. the time period the stimulation signal needs to spread over the tissue, is a dominant parameter for determining tissue contraction force. Contraction force of myocardial tissue increases monotonically with a decrease in activation time. This result suggests that minimization of activation time might be important for achieving effective tissue contraction.

A 27-year-old man who habitually smoked marihuana developed clinical, laboratory, and radiologic findings consistent with allergic bronchopulmonary aspergillosis. Culture of the marihuana obtained from the patient's source yielded heavy mixed growths of Aspergillus. Treatment with corticosteroids was effective.

The ability of short-term furosemide administration to alter intrarenal hemodynamics and to modify the clinical course of acute renal failure was assessed in six patients 2 to 9 days after the onset of acute renal failure. Following renal arterial catheterization, the intraarterial administration of furosemide at a dose of 9.6 mg/min for 30 minutes failed to improve renal function as assessed either by an increase in urine output or a decrease in serum creatinine during the 4 days after administration in the five oliguric patients. In a sixth patient with nonoliguric acute renal failure, urine volume increased with a gradual decrease in blood urea nitrogen and creatinine during the week after study. Furosemide failed to alter either mean renal blood flow or its intrarenal distribution as determined at intervals of 3 to 40 minutes after its infusion. These studies demonstrate that the short-term administration of furosemide in large doses does not improve renal hemodynamics or alter the clinical course of patients with established acute oliguric renal failure.