Bile salt hydrolase catalyses formation of amine-conjugated bile acids.

Bacteria in the gastrointestinal tract produce amino acid bile acid amidates that can affect host-mediated metabolic processes1-6; however, the bacterial gene(s) responsible for their production remain unknown. Herein, we report that bile salt hydrolase (BSH) possesses dual functions in bile acid metabolism. Specifically, we identified a previously unknown role for BSH as an amine N-acyltransferase that conjugates amines to bile acids, thus forming bacterial bile acid amidates (BBAAs). To characterize this amine N-acyltransferase BSH activity, we used pharmacological inhibition of BSH, heterologous expression of bsh and mutants in Escherichia coli and bsh knockout and complementation in Bacteroides fragilis to demonstrate that BSH generates BBAAs. We further show in a human infant cohort that BBAA production is positively correlated with the colonization of bsh-expressing bacteria. Lastly, we report that in cell culture models, BBAAs activate host ligand-activated transcription factors including the pregnane X receptor and the aryl hydrocarbon receptor. These findings enhance our understanding of how gut bacteria, through the promiscuous actions of BSH, have a significant role in regulating the bile acid metabolic network.

Rapid linkage of innate immunological signals to adaptive immunity by the brain-fat axis.

Innate immunological signals induced by pathogen- and/or damage-associated molecular patterns are essential for adaptive immune responses, but it is unclear if the brain has a role in this process. Here we found that while the abundance of tumor-necrosis factor (TNF) quickly increased in the brain of mice following bacterial infection, intra-brain delivery of TNF mimicked bacterial infection to rapidly increase the number of peripheral lymphocytes, especially in the spleen and fat. Studies of various mouse models revealed that hypothalamic responses to TNF were accountable for this increase in peripheral lymphocytes in response to bacterial infection. Finally, we found that hypothalamic induction of lipolysis mediated the brain's action in promoting this increase in the peripheral adaptive immune response. Thus, the brain-fat axis is important for rapid linkage of innate immunity to adaptive immunity.

Enteric Viruses Ameliorate Gut Inflammation via Toll-like Receptor 3 and Toll-like Receptor 7-Mediated Interferon-ß Production.

Metagenomic studies show that diverse resident viruses inhabit the healthy gut; however, little is known about the role of these viruses in the maintenance of gut homeostasis. We found that mice treated with antiviral cocktail displayed more severe dextran sulfate sodium (DSS)-induced colitis compared with untreated mice. DSS-induced colitis was associated with altered enteric viral abundance and composition. When wild-type mice were reconstituted with Toll-like receptor 3 (TLR3) or TLR7 agonists or inactivated rotavirus, colitis symptoms were significantly ameliorated. Mice deficient in both TLR3 and TLR7 were more susceptible to DSS-induced experimental colitis. In humans, combined TLR3 and TLR7 genetic variations significantly influenced the severity of ulcerative colitis. Plasmacytoid dendritic cells isolated from inflamed mouse colon produced interferon-ß in a TLR3 and TLR7-dependent manner. These results imply that recognition of resident viruses by TLR3 and TLR7 is required for protective immunity during gut inflammation.

A Review of Biodegradable Plastics: Chemistry, Applications, Properties, and Future Research Needs.

Environmental concerns over waste plastics' effect on the environment are leading to the creation of biodegradable plastics. Biodegradable plastics may serve as a promising approach to manage the issue of environmental accumulation of plastic waste in the ocean and soil. Biodegradable plastics are the type of polymers that can be degraded by microorganisms into small molecules (e.g., H2O, CO2, and CH4). However, there are misconceptions surrounding biodegradable plastics. For example, the term "biodegradable" on product labeling can be misconstrued by the public to imply that the product will degrade under any environmental conditions. Such misleading information leads to consumer encouragement of excessive consumption of certain goods and increased littering of products labeled as "biodegradable". This review not only provides a comprehensive overview of the state-of-the-art biodegradable plastics but also clarifies the definitions and various terms associated with biodegradable plastics, including oxo-degradable plastics, enzyme-mediated plastics, and biodegradation agents. Analytical techniques and standard test methods to evaluate the biodegradability of polymeric materials in alignment with international standards are summarized. The review summarizes the properties and industrial applications of previously developed biodegradable plastics and then discusses how biomass-derived monomers can create new types of biodegradable polymers by utilizing their unique chemical properties from oxygen-containing functional groups. The terminology and methodologies covered in the paper provide a perspective on directions for the design of new biodegradable polymers that possess not only advanced performance for practical applications but also environmental benefits.

Myocardial Metabolomics of Human Heart Failure With Preserved Ejection Fraction.

BACKGROUND: The human heart primarily metabolizes fatty acids, and this decreases as alternative fuel use rises in heart failure with reduced ejection fraction (HFrEF). Patients with severe obesity and diabetes are thought to have increased myocardial fatty acid metabolism, but whether this is found in those who also have heart failure with preserved ejection fraction (HFpEF) is unknown. METHODS: Plasma and endomyocardial biopsies were obtained from HFpEF (n=38), HFrEF (n=30), and nonfailing donor controls (n=20). Quantitative targeted metabolomics measured organic acids, amino acids, and acylcarnitines in myocardium (72 metabolites) and plasma (69 metabolites). The results were integrated with reported RNA sequencing data. Metabolomics were analyzed using agnostic clustering tools, Kruskal-Wallis test with Dunn test, and machine learning. RESULTS: Agnostic clustering of myocardial but not plasma metabolites separated disease groups. Despite more obesity and diabetes in HFpEF versus HFrEF (body mass index, 39.8 kg/m2 versus 26.1 kg/m2; diabetes, 70% versus 30%; both P<0.0001), medium- and long-chain acylcarnitines (mostly metabolites of fatty acid oxidation) were markedly lower in myocardium from both heart failure groups versus control. In contrast, plasma levels were no different or higher than control. Gene expression linked to fatty acid metabolism was generally lower in HFpEF versus control. Myocardial pyruvate was higher in HFpEF whereas the tricarboxylic acid cycle intermediates succinate and fumarate were lower, as were several genes controlling glucose metabolism. Non-branched-chain and branched-chain amino acids (BCAA) were highest in HFpEF myocardium, yet downstream BCAA metabolites and genes controlling BCAA metabolism were lower. Ketone levels were higher in myocardium and plasma of patients with HFrEF but not HFpEF. HFpEF metabolomic-derived subgroups were differentiated by only a few differences in BCAA metabolites. CONCLUSIONS: Despite marked obesity and diabetes, HFpEF myocardium exhibited lower fatty acid metabolites compared with HFrEF. Ketones and metabolites of the tricarboxylic acid cycle and BCAA were also lower in HFpEF, suggesting insufficient use of alternative fuels. These differences were not detectable in plasma and challenge conventional views of myocardial fuel use in HFpEF with marked diabetes and obesity and suggest substantial fuel inflexibility in this syndrome.

Author Correction: Hypothalamic stem cells control ageing speed partly through exosomal miRNAs.

The microarray data generated and analysed in this Article have been uploaded to the Gene Expression Omnibus (GEO) under accession number GSE113383 . Accordingly, the 'Data availability' section of the Methods of the original Article has been rephrased online.

TrkB inhibition of DJ-1 degradation promotes the growth and maintenance of cancer stem cell characteristics in hepatocellular carcinoma.

Although TrkB may be associated with the pathogenesis of various cancer by upregulation, how upregulation of TrkB led to tumor progression in hepatocellular carcinoma (HCC) and the signaling mechanisms by which TrkB induces motility, invasion, metastasis, drug resistance, and acquisition of self-renewal traits has remained unclear. Here, we demonstrated that TrkB was significantly upregulated in highly metastatic HCC cells and HCC patients. Also, the increased TrkB levels were significantly correlated with tumor stages and poor survival of HCC patients. Furthermore, the upregulated TrkB expression enhances the metastatic ability of HCC cells through reduced anoikis sensitivity, induced migration, and colony formation. Most strikingly, TrkB markedly enhances the activation of STAT3 by preventing DJ-1 degradation through the formation of the TrkB/DJ-1 complex. This signaling mechanism is responsible for triggering cellular traits of highly aggressive HCC. The activation of the EMT program of HCC via increasing DJ-1 stability by TrkB induces the gain of cancer stem cell states and chemoresistance via the upregulation of stem cells cell markers and ABC transporters. Also, TrkB-mediated inhibition of DJ-1 degradation promotes tumor formation and metastasizes to other organs in vivo. Our observations illustrate that TrkB is a prognostic and therapeutic targeting in promoting aggressiveness and metastasis of HCC.

Knowledge and the behavioral patterns of photoprotection among Koreans with skin disease.

BACKGROUND: Photoprotection is crucial in preventing the development and progression of various skin diseases. However, patients with skin disease have limited awareness of photoprotection. We evaluated the knowledge and behavioral patterns of photoprotection among Koreans with skin diseases. METHODS: A cross-sectional study was conducted in 11 general hospitals across South Korea. The study population consisted of patients aged 19 years or older who visited dermatologic clinics for their skin diseases. A self-administered questionnaire was used to collect patient demographics, knowledge of photoprotection, and photoprotective habits. RESULTS: In this study, 1173 patients with skin cancer, hyperpigmentary disorders, hypopigmentary disorders, or other skin diseases participated. Females scored significantly higher in knowledge of photoprotection compared to males (mean score 8.4 vs. 7.8; p < .001), and younger patients (<50 years) scored higher than older patients (mean score 8.7 vs. 7.5; p < .001). Males also reported longer sun exposure times and lower usage of photoprotective measures (both p < .001). Patients with skin cancer had the lowest mean knowledge score (7.1 ± 2.6) and were less likely to use photoprotective measures compared to other groups (p < .001). In contrast, patients with hyperpigmentation actively avoided sun exposure compared with other groups (p < 0.001). CONCLUSIONS: Knowledge of photoprotection among Korean patients with skin diseases varied depending on the gender, age, and type of skin disease. Their photoprotective behaviors were inadequate, especially among males and those with skin cancer. These findings emphasize the importance of educating and tailoring photoprotection strategies for patients with skin diseases.

A protocolized five strategies in open repair for ruptured abdominal aortic aneurysm.

OBJECTIVES: Although the medical field has made significant progress, there has been little improvement in the survival rate of patients with ruptured abdominal aortic aneurysms (rAAAs). We implemented a protocol consisting of five strategies in the management of rAAA patients who underwent open repair surgery. METHODS: The protocol comprised the following strategies: intentional hypotension <70 mmHg, lung first and kidney last policy (restricted fluid resuscitation and permissive oligoanuria), immediate postoperative extubation, free-water intake with active ambulation, and open abdomen with the routine second-look operation. The study included 13 patients (11 male) with a mean age of 75.5 ± 7.4 (range: 58-87) years who underwent the procedure from 2016 to 2018, with a mean follow-up of 40.1 ± 9.04 months. Five deteriorating to hemodynamic shock and decreased consciousness requiring intubation and ventilation prior to surgery were observed. Two of these patients required preoperative cardiopulmonary resuscitation (CPR). RESULTS: All patients regained consciousness after surgery, including the two patients who required cardiopulmonary resuscitation. Immediate postoperative extubation was performed in nine patients, but two (22.2%) of them needed re-intubation due to ventilation/perfusion mismatch. Four patients underwent continuous renal replacement therapy, with three of them having anuria for up to 48 h after surgery. Two of these patients made a full recovery. Daily ambulation was carried out for a mean of 4.77 ± 3.5 (range 1-13) days with an open abdomen, during which no significant events were reported. Four cases of colon ischemia/necrosis were identified in the second-look operation, with two patients requiring Hartman's procedure and the other two undergoing left colon partial resection. There were two in-hospital mortalities (15.4%). CONCLUSIONS: A protocol-based approach, through multidisciplinary team consensus and the development of optimal surgical strategies, could improve clinical outcomes for patients undergoing emergency surgery for rAAA. Further studies with larger sample sizes are needed to refine the protocols.

Association between Perceived Activity Restriction Due to People's Perception of Aging and Unmet Medical Needs among Middle-Aged and Elderly People: A Population-Based Study.

Background and Objectives: The older members of a population might experience unmet medical needs, despite desiring medical care due to activity limitations driven by their perception of aging. This study conducted a cross-sectional analysis of the association between perceived activity restriction (PAR) due to people's own perception of aging and unmet medical needs (UMN) in late middle-aged and older Koreans based on the Korean National Health and Nutrition Examination Survey (KNHANES). Materials and Methods: The 2016-2020 KNHANES was used to analyze a total of 2008 participants among groups aged 45 years or older by applying individual weights imposed from the raw data. The independent variable of PAR was assessed using self-reported questionnaires based on the global activity limitation indicator. Also, the dependent variable of UMN, referring to the state in which a patient's medical care or service was insufficient, inadequate, or lacking, was assessed using a single question. After excluding missing values, the data on 2008 individuals were analyzed using a chi-square test, weighted logistic regression, and a stratified analysis of gender, age, and the presence of chronic illnesses. Results: The group that experienced PAR had an OR 2.13 higher (odds ratio [OR]: 2.13; 95% confidence interval [CI]: 1.27-3.56) to present UMN than the group that did not experience PAR. Furthermore, the results of the stratified analysis indicated that, in the group of female participants with chronic illness and in the group of elderly people, experiencing PAR was associated with a higher experience of UMN. Conclusions: There was a close association between PAR and UMN. In particular, when PAR occurred in the group of female participants with chronic illness and in the group of elderly people, the incidence rate of UMN was also found to be high. This finding highlights the need for policies and institutional measures to reduce UMN within vulnerable groups with an increased risk of medical inaccessibility due to activity restriction.

Deep learning model integrating positron emission tomography and clinical data for prognosis prediction in non-small cell lung cancer patients.

BACKGROUND: Lung cancer is the leading cause of cancer-related deaths worldwide. The majority of lung cancers are non-small cell lung cancer (NSCLC), accounting for approximately 85% of all lung cancer types. The Cox proportional hazards model (CPH), which is the standard method for survival analysis, has several limitations. The purpose of our study was to improve survival prediction in patients with NSCLC by incorporating prognostic information from F-18 fluorodeoxyglucose positron emission tomography (FDG PET) images into a traditional survival prediction model using clinical data. RESULTS: The multimodal deep learning model showed the best performance, with a C-index and mean absolute error of 0.756 and 399 days under a five-fold cross-validation, respectively, followed by ResNet3D for PET (0.749 and 405 days) and CPH for clinical data (0.747 and 583 days). CONCLUSION: The proposed deep learning-based integrative model combining the two modalities improved the survival prediction in patients with NSCLC.

Predicting In Vivo Target Occupancy (TO) Profiles via Physiologically Based Pharmacokinetic-TO Modeling of Warfarin Pharmacokinetics in Blood: Importance of Low Dose Data and Prediction of Stereoselective Target Interactions.

Warfarin is well recognized for its high-affinity and capacity-limited binding to the pharmacological target and undergoes target-mediated drug disposition. Here, we developed a physiologically based pharmacokinetic (PBPK) model that incorporated saturable target binding and other reported hepatic disposition components of warfarin. The PBPK model parameters were optimized by fitting to the reported blood pharmacokinetic (PK) profiles of warfarin with no stereoisomeric separation after oral dosing of racemic warfarin (0.1, 2, 5, or 10 mg) using the Cluster Gauss-Newton method (CGNM). The CGNM-based analysis yielded multiple "accepted" sets for six optimized parameters, which were then used to simulate the warfarin blood PK and in vivo target occupancy (TO) profiles. When further analyses examined the impact of dose selection on uncertainty in parameter estimation by the PBPK modeling, the PK data from 0.1 mg dose (well below target saturation) was important in practically identifying the target binding-related parameters in vivo. When stereoselective differences were incorporated for both hepatic disposition and target interactions, our PBPK modeling predicted that R-warfarin (of slower clearance and lower target affinity than S-warfarin) contributes to TO prolongation after oral dosing of racemic warfarin. Our results extend the validity of the approach by which the PBPK-TO modeling of blood PK profiles can yield TO prediction in vivo (applicable to the drugs with targets of high affinity and abundance and limited distribution volume via nontarget interactions). Our findings support that model-informed dose selection and PBPK-TO modeling may aid in TO and efficacy assessment in preclinical and clinical phase 1 studies. SIGNIFICANCE STATEMENT: The current physiologically based pharmacokinetic modeling incorporated the reported hepatic disposition components and target binding of warfarin and analyzed the blood pharmacokinetic (PK) profiles from varying warfarin doses, practically identifying target binding-related parameters in vivo. By implementing the stereoselective differences between R- and S-warfarin, our analysis predicted the role of R-warfarin in prolonging overall target occupancy. Our results extend the validity of analyzing blood PK profiles to predict target occupancy in vivo, which may guide efficacy assessment.

Production of highly pure R,R-2,3-butanediol for biological plant growth promoting agent using carbon feeding control of Paenibacillus polymyxa MDBDO.

BACKGROUND: Chemical fertilizers have greatly contributed to the development of agriculture, but alternative fertilizers are needed for the sustainable development of agriculture. 2,3-butanediol (2,3-BDO) is a promising biological plant growth promoter. RESULTS: In this study, we attempted to develop an effective strategy for the biological production of highly pure R,R-2,3-butanediol (R,R-2,3-BDO) by Paenibacillus polymyxa fermentation. First, gamma-ray mutagenesis was performed to obtain P. polymyxa MDBDO, a strain that grew faster than the parent strain and had high production of R,R-2,3-BDO. The activities of R,R-2,3-butanediol dehydrogenase and diacetyl reductase of the mutant strain were increased by 33% and decreased by 60%, respectively. In addition, it was confirmed that the carbon source depletion of the fermentation broth affects the purity of R,R-2,3-BDO through batch fermentation. Fed-batch fermentation using controlled carbon feeding led to production of 77.3 g/L of R,R-2,3-BDO with high optical purity (> 99% of C4 products) at 48 h. Additionally, fed-batch culture using corn steep liquor as an alternative nitrogen source led to production of 70.3 g/L of R,R-2,3-BDO at 60 h. The fed-batch fermentation broth of P. polymyxa MDBDO, which contained highly pure R,R-2,3-BDO, significantly stimulated the growth of soybean and strawberry seedlings. CONCLUSIONS: This study suggests that P. polymyxa MDBDO has potential for use in biological plant growth promoting agent applications. In addition, our fermentation strategy demonstrated that high-purity R,R-2,3-BDO can be produced at high concentrations using P. polymyxa.

Hypothalamic stem cells control ageing speed partly through exosomal miRNAs.

It has been proposed that the hypothalamus helps to control ageing, but the mechanisms responsible remain unclear. Here we develop several mouse models in which hypothalamic stem/progenitor cells that co-express Sox2 and Bmi1 are ablated, as we observed that ageing in mice started with a substantial loss of these hypothalamic cells. Each mouse model consistently displayed acceleration of ageing-like physiological changes or a shortened lifespan. Conversely, ageing retardation and lifespan extension were achieved in mid-aged mice that were locally implanted with healthy hypothalamic stem/progenitor cells that had been genetically engineered to survive in the ageing-related hypothalamic inflammatory microenvironment. Mechanistically, hypothalamic stem/progenitor cells contributed greatly to exosomal microRNAs (miRNAs) in the cerebrospinal fluid, and these exosomal miRNAs declined during ageing, whereas central treatment with healthy hypothalamic stem/progenitor cell-secreted exosomes led to the slowing of ageing. In conclusion, ageing speed is substantially controlled by hypothalamic stem cells, partially through the release of exosomal miRNAs.

Pretreatment of rhesus monkeys with transdermal patches containing physostigmine and procyclidine: implications of the delivery system for the potential application against VX nerve agent intoxication in humans.

Physostigmine (Phs) is a reversible inhibitor of acetylcholinesterase (AChE) that penetrates the blood-brain barrier (BBB) and could be used to protect the central nervous system (CNS) against the effects of nerve agents. For prophylactic effectiveness, long, steady, and adequate inhibition of AChE activity by Phs is needed to broadly protect against the CNS effects of nerve agents. Here, we evaluated the efficacy of transdermal patches containing Phs and procyclidine (PC) as prophylactic agents. Patches (25 cm2) containing 4.4 mg Phs and 17.8 mg PC had a protective ratio of approximately 78.6-fold in rhesus monkeys challenged with VX nerve agent and given an antidote. Physiologically based pharmacokinetic model in conjunction with an indirect pharmacodynamic (PBPK/PD) was developed for Phs and scaled to rhesus monkeys. The model was able to reproduce the concentration profile and inhibitory effect on AChE of Phs in monkeys, as evidenced by correlation coefficients of 0.994 and 0.992 for 25 cm2 and 49 cm2 patches, respectively (i.e., kinetic data), and 0.989 and 0.968 for 25 cm2 and 49 cm2 patches, respectively (i.e., dynamic data). By extending the monkey PBPK/ PD model to humans, the effective human dose was predicted to be five applications of a 25 cm2 patch (i.e., 22 mg Phs), and two applications of a 49 cm2 patch (i.e., 17.4 mg Phs). Therefore, given that patch application of Phs in rhesus monkeys has a prolonged effect (namely, AChE inhibition of 19.6% for the 25 cm2 patch and 23.0% for the 49 cm2 patch) for up to 216 h, patch formulation of Phs may provide similar protection against nerve agent intoxication in humans.

Comparison of preoxygenation efficiency measured by the oxygen reserve index between high-flow nasal oxygenation and facemask ventilation: a randomised controlled trial.

BACKGROUND: High-flow nasal oxygenation and the oxygen reserve index (ORI), which is a non-invasive and innovative modality that reflects the arterial oxygen content, are used in general anaesthesia. This study compares the preoxygenation efficiency (measured by the ORI) of high-flow nasal oxygenation and facemask ventilation during the induction process. METHODS: This single-centre, two-group, randomised controlled trial included 197 patients aged ≥ 20 years who underwent orotracheal intubation for general anaesthesia for elective surgery. The patients were randomly allocated to receive preoxygenation via facemask ventilation or high-flow nasal oxygenation. The ORI was measured and compared between both groups. RESULTS: The ORI increased during preoxygenation in all patients. At 1 min of preoxygenation, the ORI was significantly higher in the high-flow nasal oxygenation group (0.34 ± 0.33) than in the facemask ventilation group (0.21 ± 0.28; P = 0.003). The highest ORI was not significantly different between the two groups (0.68 ± 0.25 in the high-flow nasal oxygenation group vs. 0.70 ± 0.28 in the facemask ventilation group; P = 0.505). CONCLUSIONS: High-flow nasal oxygenation results in an oxygenation status similar to that provided by facemask ventilation during the induction process of general anaesthesia; therefore, high-flow nasal oxygenation is a feasible preoxygenation method. TRIAL REGISTRATION: Clinicaltrials.gov (NCT04291339).

A Colon-Targeted Prodrug of Riluzole Improves Therapeutic Effectiveness and Safety upon Drug Repositioning of Riluzole to an Anti-Colitic Drug.

Riluzole (RLZ) is a neuroprotective drug indicated for amyotrophic lateral sclerosis. To examine the feasibility of RLZ for repositioning as an anti-inflammatory bowel disease (IBD) drug, RLZ (2, 5, and 10 mg/kg) was administered orally to rats with colitis induced by 2,4-dinitrobenzenesulfonic acid. Oral RLZ was effective against rat colitis in a dose-dependent manner, which was statistically significant at doses over 5 mg/kg. To address safety issues upon repositioning and further improve anti-colitic effectiveness, RLZ was coupled with salicylic acid (SA) via an azo-bond to yield RLZ-azo-SA (RAS) for the targeted colonic delivery of RLZ. Upon oral gavage, RAS (oral RAS) was efficiently delivered to and activated to RLZ in the large intestine, and systemic absorption of RLZ was substantially reduced. Oral RAS ameliorated colonic damage and inflammation in rat colitis and was more effective than oral RLZ and sulfasalazine, a current anti-IBD drug. Moreover, oral RAS potently inhibited glycogen synthase kinase 3ß (GSK3ß) in the inflamed distal colon, leading to the suppression of NFκB activity and an increase in the level of the anti-inflammatory cytokine interleukin-10. Taken together, RAS, which enables RLZ to be delivered to and inhibit GSK3ß in the inflamed colon, may facilitate repositioning of RLZ as an anti-IBD drug.

Targeting renal cell carcinoma with a HIF-2 antagonist.

Clear cell renal cell carcinoma (ccRCC) is characterized by inactivation of the von Hippel-Lindau tumour suppressor gene (VHL). Because no other gene is mutated as frequently in ccRCC and VHL mutations are truncal, VHL inactivation is regarded as the governing event. VHL loss activates the HIF-2 transcription factor, and constitutive HIF-2 activity restores tumorigenesis in VHL-reconstituted ccRCC cells. HIF-2 has been implicated in angiogenesis and multiple other processes, but angiogenesis is the main target of drugs such as the tyrosine kinase inhibitor sunitinib. HIF-2 has been regarded as undruggable. Here we use a tumourgraft/patient-derived xenograft platform to evaluate PT2399, a selective HIF-2 antagonist that was identified using a structure-based design approach. PT2399 dissociated HIF-2 (an obligatory heterodimer of HIF-2α-HIF-1ß) in human ccRCC cells and suppressed tumorigenesis in 56% (10 out of 18) of such lines. PT2399 had greater activity than sunitinib, was active in sunitinib-progressing tumours, and was better tolerated. Unexpectedly, some VHL-mutant ccRCCs were resistant to PT2399. Resistance occurred despite HIF-2 dissociation in tumours and evidence of Hif-2 inhibition in the mouse, as determined by suppression of circulating erythropoietin, a HIF-2 target and possible pharmacodynamic marker. We identified a HIF-2-dependent gene signature in sensitive tumours. Gene expression was largely unaffected by PT2399 in resistant tumours, illustrating the specificity of the drug. Sensitive tumours exhibited a distinguishing gene expression signature and generally higher levels of HIF-2α. Prolonged PT2399 treatment led to resistance. We identified binding site and second site suppressor mutations in HIF-2α and HIF-1ß, respectively. Both mutations preserved HIF-2 dimers despite treatment with PT2399. Finally, an extensively pretreated patient whose tumour had given rise to a sensitive tumourgraft showed disease control for more than 11 months when treated with a close analogue of PT2399, PT2385. We validate HIF-2 as a target in ccRCC, show that some ccRCCs are HIF-2 independent, and set the stage for biomarker-driven clinical trials.

Feasibility of the Ultrasound-Guided Insertion of the Peripherally Inserted Central Catheter (PICC) by the Vascular Surgeon at the Bedside in the Trauma Intensive Care Unit.

BACKGROUND: This study analyzed the outcomes of the ultrasound-guided insertion of the peripherally inserted central venous catheter (PICC) by experienced vascular surgeons at the bedside of the trauma intensive care unit (ICU) and compared the outcomes with those of fluoroscopy-guided PICC performed by radiologists in the interventional suite. METHODS: Between May 1, 2016, and April 30, 2021, 97 patients who were hospitalized in the trauma ICU and underwent PICC insertion were enrolled in the study. Forty-two out of the 97 patients underwent PICC insertion by interventional radiologists in the interventional radiology suite under fluoroscopy guidance, while the remaining 55 cases underwent ultrasound-guided PICC insertion by the vascular surgeon at the trauma ICU bedside. RESULTS: The technical failure (P = 0.504) and malposition (P = 0.127) rates were not significantly different between the 2 groups. However, it took significantly less time for the vascular surgeon to complete the PICC insertion procedure (P < 0.001). Significantly more patients of the ultrasound-guided group required inotropes (P = 0.012) and mechanical ventilation (P = 0.003) at the time of the procedure. In addition, the ultrasound-guided group appeared to be in critical condition in terms of kidney function according to laboratory data (P = 0.014). Meanwhile, the ultrasound-guided group maintained the central line catheter for a shorter time (P < 0.001). CONCLUSIONS: In trauma patients, ultrasound-guided PICC insertion at the bedside by experienced vascular surgeons at the trauma ICU was feasible compared to fluoroscopy-guided insertion performed by interventional radiologists.

Effects of intraoperative dexmedetomidine infusion on renal function in elective living donor kidney transplantation: a randomized controlled trial.

PURPOSE: Ischemia-reperfusion injury is inevitable during donor organ harvest and recipient allograft reperfusion in kidney transplantation, and affects graft outcomes. Dexmedetomidine, an α2-adrenoreceptor agonist, has renoprotective effects against ischemia-reperfusion injury. We investigated the effects of intraoperative dexmedetomidine infusion on renal function and the development of delayed graft function after elective living donor kidney transplantation in a randomized controlled trial. METHODS: A total of 104 patients were randomly assigned to receive either an intraoperative infusion of dexmedetomidine 0.4 µg·kg-1·hr-1 or 0.9% saline. The primary outcome was the serum creatinine level on postoperative day (POD) 7. Secondary outcomes were renal function and the degree of inflammation and included the following variables: serum creatinine level and estimated glomerular filtration rate up to six months; incidence of delayed graft function; and levels of serum cystatin C, plasma interleukin (IL)-1ß, and IL-18 during the perioperative period. RESULTS: The mean (standard deviation) serum creatinine level on POD 7 was comparable between the groups (dexmedetomidine vs control: 1.11 [0.87] mg·dL-1 vs 1.06 [0.73] mg·dL-1; mean difference, 0.05; 95% confidence interval, -0.27 to 0.36; P = 0.77). Delayed graft function occurred in one patient in each group (odds ratio, 1.020; P > 0.99). There were no significant differences in the secondary outcomes between the groups (all P > 0.05). CONCLUSIONS: Intraoperative dexmedetomidine infusion did not produce any beneficial effects on renal function or delayed graft function in patients undergoing elective living donor kidney transplantation. STUDY REGISTRATION: www. CLINICALTRIALS: gov (NCT03327389); registered 31 October 2017.

RéSUMé: OBJECTIF: Les lésions d'ischémie-reperfusion sont inévitables lors du prélèvement d'organes du donneur et de la reperfusion de l'allogreffe chez le receveur pour une transplantation rénale, et affectent le devenir du greffon. La dexmédétomidine, un agoniste des adrénorécepteurs de type α2, a des effets néphroprotecteurs sur les lésions d'ischémie-reperfusion. Nous avons réalisé une étude randomisée contrôlée afin d'examiner les effets d'une perfusion peropératoire de dexmédétomidine sur la fonction rénale et l'apparition d'un retard de fonctionnement du greffon après une transplantation rénale élective issue de donneurs vivants. MéTHODE: Au total, 104 patients ont été aléatoirement répartis pour recevoir une perfusion peropératoire de 0,4 µg·kg-1·r-1 de dexmédétomidine ou une solution saline à 0,9 %. Le critère d'évaluation principal était la créatininémie au jour postopératoire (JPO) 7. Les critères d'évaluation secondaires étaient la fonction rénale et le degré d'inflammation et comprenaient les variables suivantes : créatininémie et infiltration glomérulaire estimée jusqu'à six mois; incidence de retard de fonctionnement du greffon; et taux sériques de cystatine C, d'interleukine plasmatique (IL)-1ß et d'IL-18 pendant la période périopératoire. RéSULTATS: Le taux moyen (écart type) de créatinine sérique au JPO 7 était comparable entre les groupes (dexmédétomidine vs témoin : 1,11 [0,87] mg·dL-1 vs 1,06 [0,73] mg·dL-1; différence moyenne, 0,05; intervalle de confiance à 95 %, -0,27 à 0,36; P = 0,77). Un patient de chaque groupe a subi un retard de fonctionnement du greffon (rapport de cotes, 1,020; P > 0.99). Aucune différence intergroupe significative n'a été observée en ce qui concerne les critères d'évaluation secondaires. CONCLUSION: La perfusion peropératoire de dexmédétomidine n'a produit aucun effet bénéfique sur la fonction rénale ou le retard de fonctionnement du greffon chez les patients bénéficiant d'une transplantation rénale élective issue de donneur vivant. ENREGISTREMENT DE L'éTUDE: www.ClinicalTrials.gov (NCT03327389); enregistrée le 31 octobre 2017.