We previously reported that reduced GPR183 expression in blood from tuberculosis (TB) patients with diabetes is associated with more severe TB.

To further elucidate the role of GPR183 and its oxysterol ligands in the lung, we studied dysglycemic mice infected with Mycobacterium tuberculosis (Mtb).

We found upregulation of the oxysterol-producing enzymes CH25H and CYP7B1 and increased concentrations of 25-hydroxycholesterol upon Mtb infection in the lungs of mice. This was associated with increased expression of GPR183 indicative of oxysterol-mediated recruitment of GPR183-expressing immune cells to the lung. CYP7B1 was predominantly expressed by macrophages in TB granulomas. CYP7B1 expression was significantly blunted in lungs from dysglycemic animals, which coincided with delayed macrophage infiltration. GPR183-deficient mice similarly had reduced macrophage recruitment during early infection.

Taken together, we demonstrate a requirement of the GPR183/oxysterol axis for positioning of macrophages to the site of infection and add an explanation to more severe TB in diabetes patients.

Taken together, we demonstrate a requirement of the GPR183/oxysterol axis for positioning of macrophages to the site of infection and add an explanation to more severe TB in diabetes patients.

The aim of this study was to examine whether maternal parenting behaviors (i.e., warmth, behavioral/psychological control) moderate the association between central nervous system (CNS)-directed treatment and adjustment among pediatric cancer survivors at 3 years post-diagnosis or relapse.

Three years after their child’s cancer diagnosis or relapse, mothers (N = 84) reported on their child’s academic and social competence, as well as their internalizing and externalizing problems. Children (N = 84; Mage = 13.21 years, 52.4% male) reported on maternal parenting behaviors. Using medical chart data, children were separated into CNS (i.e., received cranial radiation, intrathecal chemotherapy, and/or neurosurgery; N = 45) or non-CNS-directed treatment (N = 39) groups. Twelve moderation models were tested when examining two-way interactions between CNS treatment group and maternal parenting behaviors.

Children in the CNS-directed treatment group demonstrated significantly worse academic and social competence. ferent pattern of parenting during early cancer survivorship. Findings highlight the importance of considering the broader family context when conceptualizing the impact of illness-related factors on adjustment among pediatric cancer survivors.We have previously shown that Arabidopsis thaliana Prohibitin 3 (PHB3) controls auxin-stimulated lateral root (LR) formation; however, the underlying molecular mechanism is unknown. Here, we demonstrate that PHB3 regulates lateral root (LR) development mainly through influencing lateral root primordia (LRP) initiation, via affecting nitric oxide (NO) accumulation. The reduced LRP in phb3 mutant was largely rescued by treatment with a NO donor. The decreased NO accumulation in phb3 caused a lower expression of GATA TRANSCRIPTION FACTOR 23 (GATA23) and LATERAL ORGAN BOUNDARIES DOMAIN 16 (LBD16) through inhibiting the degradation of INDOLE-3-ACETIC ACID INDUCIBLE 14/28 (IAA14/28). Overexpression of either GATA23 or LBD16 in phb3 mutant background recovered the reduced density of LRP. These results indicate that PHB3 regulates LRP initiation via NO-mediated auxin signalling, by modulating the degradation of IAA14/28.

Nitrates and nitrites occur naturally in water and soil. They are also used as food additives (preservatives) in processed meats. They could play a role in the carcinogenicity of processed meat. The objective was to investigate the relationship between nitrate and nitrite intakes (natural food, water and food additive sources) and cancer risk in a large prospective cohort with detailed dietary assessment.

Overall, 101    056 adults from the French NutriNet-Santé cohort (2009-ongoing, median follow-up 6.7 years) were included. Nitrites/nitrates exposure was evaluated using repeated 24-h dietary records, linked to a comprehensive composition database and accounting for commercial names/brands of industrial products. Associations with cancer risk were assessed using multi-adjusted Cox hazard models.

In total, 3311 incident cancer cases were diagnosed. Compared with non-consumers, high consumers of food additive nitrates had higher breast cancer risk [hazard ratio (HR) = 1.24 (95% CI 1.03-1.48), P = 0.02], ively debate around the ban of these additives from the food industry.After 25 years of service to the American Medical Informatics Association (AMIA), Ms Karen Greenwood, the Executive Vice President and Chief Operating Officer, is leaving the organization. In this perspective, we reflect on her accomplishments and her effect on the organization and the field of informatics nationally and globally. We also express our appreciation and gratitude for Ms Greenwood’s role at AMIA.The aim is to examine the prognostic value of N-terminal pro-brain natriuretic peptide (NT-proBNP) in patients with major burns and sepsis. We collected the data of major burn patients who were admitted to our department. We compared the age, sex, burn area, burn depth, length of hospitalization, and mortality rate between the sepsis group and non-sepsis group and compared NT-proBNP, procalcitonin (PCT), platelet count, Sequential Organ Failure Assessment (SOFA) score, and quick SOFA (qSOFA) score between the survivors and nonsurvivors in the sepsis group. Receiver operating characteristic (ROC) curves were used in sepsis patients to evaluate the prognostic value of NT-proBNP, PCT, SOFA score, qSOFA score, et al.. Kaplan-Meier survival curves were used to compare the 90-day survival curves of patients. Logistic regression analysis was used to analyse the risk factors that affect the prognosis of sepsis patients. There were 90 major burn patients with sepsis and 114 major burn patients without sepsis. The mortality rate for the major burn sepsis group was significantly higher than that for the non-sepsis group. The NT-proBNP level in sepsis patients in the nonsurvivor group was 2900 pg/mL, which was significantly higher than that in patients in the survivor group. Survival analysis showed that the mean survival time for the NT-proBNP >2000 pg/mL group was 15.08 days. Multivariate regression analysis indicated that NT-proBNP was an independent risk factor for mortality in burn patients with sepsis. NT-proBNP can be used as a prognostic marker in patients with major burns and sepsis.

Oxidative stress plays an indispensable role in pathogenesis of Graves’ orbitopathy (GO). Ferroptosis is a newly discovered form of cell death resulting from lipid peroxidation. Little is known about the role of ferroptosis in GO.

We aimed to identify the divergent role of ferroptosis in the GO and control orbital fibroblasts (OFs).

Orbital fat/connective tissues and serum immunoglobulins (Igs) were collected from GO and control subjects. Cell viability and lipid peroxidation were measured to evaluate ferroptosis sensitivity. Pyruvate dehydrogenase kinase 2 (PDK2) level and oxygen consumption rate were quantified to assess glycolysis status.

Primary OFs were cultured from orbital tissues. Ferroptosis was induced by cystine deprivation and/or erastin treatment. The GO OFs possessed stronger resistance to ferroptosis than the control OFs. Selenium, a potential ferroptosis inhibitor, protected the control OFs from ferroptosis. Both transcriptomic and proteomic analyses indicated glycolytic shift in the GO OFs. Metabolic profiling, PDK2 quantification, and oxygen consumption assay confirmed enhanced glycolysis in the GO OFs. Inhibition of glycolysis by PDK2 knockdown and dichloroacetic acid (DCA) promoted ferroptosis sensitivity in the GO OFs. The ferroptosis-sensitizing effects of DCA were also observed when the GO OFs were treated with GO-Igs. IGF1R overexpression in the GO OFs contributed to glycolysis shift. IGF1R inhibitory antibodies facilitated ferroptosis induction in the GO OFs, but the effects were less remarkable under GO-Igs treatment.

These study findings establish that glycolysis facilitates ferroptosis resistance in the GO OFs, providing insights into the therapeutic role of glycolysis for GO treatment.

These study findings establish that glycolysis facilitates ferroptosis resistance in the GO OFs, providing insights into the therapeutic role of glycolysis for GO treatment.How quickly are different kinds of conceptual knowledge activated in action picture naming? Using a masked priming paradigm, we manipulated the prime category type (artificial vs. natural), prime action type (precision, power, vs. neutral grip), and target action type (precision vs. power grip) in action picture naming, while electrophysiological signals were measured concurrently. Naming latencies showed an inhibition effect in the congruent action type condition compared with the neutral condition. ERP results showed that artificial and natural category primes induced smaller waveforms in precision or power action primes than neutral primes in the time window of 100-200 msec. Time-frequency results consistently presented a power desynchronization of the mu rhythm in the time window of 0-210 msec with precision action type artificial objects compared with neutral primes, which localized at the supplementary motor, precentral and postcentral areas in the left hemisphere. These findings suggest an inhibitory effect of affordances arising at conceptual preparation in action picture naming and provide evidence for embodied cognition.

Anesthesia practitioners are at risk for percutaneous injuries by blood-contaminated needles and sharp objects that may result in the transmission of human immunodeficiency virus and hepatitis viruses. Reporting these injuries is important for the early prevention and management of blood-borne infections.

To investigate the occurrence, reporting, characteristics and outcome of contaminated percutaneous injuries (CPIs) in anesthesia residents, fellows and faculty.

A cross-sectional anonymous survey electronically distributed to all 214 anesthesia practitioners at a large academic multihospital-based anesthesia practice in Florida, USA.

The overall response rate was 51% (110/214) (60% (50/83) for residents, 50% (8/16) for fellows and 45% (52/115) for anesthesia faculty). Fifty-nine percent (65/110) (95% confidence interval (95% CI) 5068) of participants reported having one or more CPIs during their years of anesthesia practice (residents 42% (95% CI 2955), fellows 50% and faculty 77% (95% CI 6688)). Theins suboptimal among anesthesia residents. A fifth of injuries in the perioperative setting is from an infected source and requires postexposure prophylaxis. Although no infections were reported due to CPI exposure in this study, findings underscore the need for more education and interventions to reduce occupational blood exposures in anesthesia practitioners and improve reporting.

Based on our study results, most anesthesia practitioners will sustain a CPI during their years of practice. Despite some improvements compared to historic figures, the occurrence of CPIs continues to be high and reporting of percutaneous injuries remains suboptimal among anesthesia residents. A fifth of injuries in the perioperative setting is from an infected source and requires postexposure prophylaxis. Although no infections were reported due to CPI exposure in this study, findings underscore the need for more education and interventions to reduce occupational blood exposures in anesthesia practitioners and improve reporting.CX3CR1high myeloid cells in the small intestine mediate the induction of oral tolerance by driving regulatory T (Treg) cells. Bacterial metabolites, e.g. pyruvate and lactate, induce a dendrite extension of CX3CR1high myeloid cells into the intestinal lumen via GPR31. However, it remains unclear whether the pyruvate-GPR31 axis is involved in the induction of oral tolerance. Here, we show that pyruvate enhances oral tolerance in a GPR31-dependent manner. In ovalbumin (OVA)-fed Gpr31-deficient mice, an OVA-induced delayed-type hypersensitivity response was substantially induced, demonstrating the defective induction of oral tolerance in Gpr31-deficient mice. The percentage of RORγt+ Treg cells in the small intestine was reduced in Gpr31-deficient mice. In pyruvate-treated wild-type mice, a low dose of OVA efficiently induced oral tolerance. IL-10 production from intestinal CX3CR1high myeloid cells was increased by OVA ingestion in wild-type mice, but not in Gpr31-deficient mice. CX3CR1high myeloid cell-specific IL-10-deficient mice showed a defective induction of oral tolerance to OVA and a decreased accumulation of OVA-specific Treg cells in the small intestine. These findings demonstrate that pyruvate enhances oral tolerance through a GPR31-dependent effect on intestinal CX3CR1high myeloid cells.

Friendships and romantic relationships are important sources of support that contribute to well-being for youth across adolescence and emerging adulthood and may be especially important for those with a chronic illness. We examined gender differences in trajectories of peer relationships among those with type 1 diabetes (T1D) and how they differ from those without.

Individuals with T1D (N = 132) and controls (N = 131) completed questionnaires across 11 years (M age = 12 years at baseline). Trajectories of friend support, conflict, and companionship were estimated from ages 11 to 23. Romantic support and conflict trajectories were estimated from ages 17 to 23.

Females experienced more friend support than males, especially in comparison to males with T1D. Control females experienced highest levels of romantic support and lowest levels of romantic conflict. In comparison to control males, males with T1D experienced less friend support in early adolescence and less companionship in late adolescence and emerrelationships may be useful to clinicians as they assist individuals in garnering support in general and for their diabetes.Cognitive neuroscience currently conflates the study of serial responses (e.g., delay match to sample/nonsample, n-back) with the study of sequential operations. In this essay, our goal is to define and disentangle the latter, termed abstract cognitive task sequences (ACTS). Existing literatures address tasks requiring serial events, including procedural learning of implicit motor responses, statistical learning of predictive relationships, and judgments of attributes. These findings do not describe the behavior and underlying mechanism required to succeed at remembering to evaluate color, then shape; or to multiply, then add. A new literature is needed to characterize these sorts of second-order cognitive demands of studying a sequence of operations. Our second goal is to characterize gaps in knowledge related to ACTS that merit further investigation. In the following sections, we define more precisely what we mean by ACTS and suggest research questions that further investigation would be positioned to address.

The efficacy of irinotecan plus continuous trastuzumab beyond progression in patients with gastric cancer previously treated with trastuzumab plus standard first-line chemotherapy has not been reported.

Patients with human epidermal growth factor receptor 2 (HER2)-positive advanced gastric cancer who were previously treated with trastuzumab received trastuzumab every 3 weeks and irinotecan every 2 weeks. The primary endpoint was the overall response rate (ORR), and the secondary endpoints included progression-free survival (PFS), 6-month survival rates, safety, and subgroup analysis by HER2 status.

Sixteen patients were enrolled in a 3-year pre-planned registration period. This study was prematurely closed due to poor patient accrual. The ORR and disease control rate were 6.7% (95% CI, 0.2-32.0) and 53.3% (95% CI, 26.6-78.7). The median PFS and overall survival (OS) were 2.4 months (95% CI, 0.0-5.2) and 9.7 months (95% CI, 8.2-11.2), respectively. The most frequently reported grades 3-4 adverse events were neutropenia (40%), anemia (27%), anorexia (33%), and fatigue (33%).

With only 16 patients enrolled, the present study has very low power to detect any clinical benefit of trastuzumab plus irinotecan beyond disease progression in patients with HER2-positive advanced gastric cancer who previously received trastuzumab.Trial Identifier UMIN000007636.

With only 16 patients enrolled, the present study has very low power to detect any clinical benefit of trastuzumab plus irinotecan beyond disease progression in patients with HER2-positive advanced gastric cancer who previously received trastuzumab.Trial Identifier UMIN000007636.Prolonged chest tube drainage is one of the most common postoperative complications of pulmonary resections; it is related to complications such as residual pleural spaces or continuous alveolar air leaks. We retrospectively evaluated the efficacy of artificial intraoperative pneumoperitoneum in the treatment of such complications after lung resections. The presence of a residual space associated with prolonged air leaks can be difficult to treat, exposes the patient to a high risk of infection, prolongs hospitalization, and in some cases mandates reoperation. Between October 2016 and March 2020, four patients underwent pneumoperitoneum. The obliteration of the pleural cavity and the absence of air leaks were observed in 3 patients; only 1 patient was discharged with a Heimlich valve. Artificial intraoperative pneumoperitoneum is a safe and simple procedure. It decreases the duration of chest drainage and of the hospital stay; however, further studies are needed to corroborate our data. The learning curve for this technique may be relatively short.

Falling insulin requirements often lead to considerations of whether a pregnancy can continue safely or if delivery is indicated.

To evaluate prevalence and predictors of falling insulin requirements in pregnant women with preexisting diabetes delivering preterm and to explore the relationship to fetal asphyxia and neonatal morbidity.

A prospective cohort study of 101 consecutive singleton pregnant women with preexisting diabetes delivering preterm < 37 weeks (68 type 1 and 33 type 2 diabetes) where the prevalence of falling insulin requirements (≥20%) before delivery was recorded.

In total, 27% (27/101) experienced falling insulin requirements of median 30% (interquartile range 24-40) before delivery. In all women with type 1 diabetes, the prevalence was 37% (25/68), whereas it was 43% (24/56) in those with indicated preterm delivery and 6% (2/33) among women with type 2 diabetes. In women with type 1 diabetes and indicated preterm delivery, falling insulin requirements were first identified at 34nly reflects variations in normal physiology needs further investigation.

Diabetic kidney disease is a major burden among diabetic patients. Sodium-glucose cotransporter 2 inhibitors (SGLT2is) were shown to reduce renal outcomes in clinical trials and real-world studies. However, head-to-head comparisons with individual classes of glucose-lowering agents warranted further investigation.

This work aimed to investigate the associations between SGLT2is use vs dipeptidyl peptidase-4 inhibitors (DPP4is) use and 4 renal outcomes end-stage renal disease (ESRD), albuminuria, acute renal failure (ARF), and the rate of estimated glomerular filtration rate (eGFR) change using a territory-wide electronic medical database in Hong Kong.

For this retrospective cohort study, the „prevalent new-user” design was adopted to account for previous exposure to study drugs. Propensity score matching was used to balance baseline characteristics. Electronic health data of type 2 diabetes patients using SGLT2is and DPP4is between 2015 and 2018 were collected.

The matched cohort consisted of 6333 SGLT2is users and 25 332 DPP4is users, with a median follow-up of 3.8 years. Compared to DPP4is, SGLT2is use was associated with lower risks of ESRD (hazard ratio [HR] 0.51; 95% CI, 0.42-0.62; P < .001) and ARF (HR 0.59; 95% CI, 0.48-0.73; P < .001), and a slower decline in eGFR. The associations remained statistically significant among patients with or without rapid eGFR decline and patients who added or switched to SGLT2is from DPP4is. The association with albuminuria was inconsistent across analyses.

Compared to DPP4is, SGLT2is use was associated with reduced risks of ESRD and ARF, and a slower eGFR decline in a real-world setting. The associations remained statistically significant in patients with or without preindex rapid eGFR decline.

Compared to DPP4is, SGLT2is use was associated with reduced risks of ESRD and ARF, and a slower eGFR decline in a real-world setting. The associations remained statistically significant in patients with or without preindex rapid eGFR decline.The hepatic transcription factor forkhead box O1 (FOXO1) is a critical regulator of hepatic and systemic insulin sensitivity. Previous work by our group and others demonstrated that genetic inhibition of FOXO1 improves insulin sensitivity both in genetic and dietary mouse models of metabolic disease. Mechanistically, this is due in part to cell nonautonomous control of adipose tissue insulin sensitivity. However, the mechanisms mediating this liver-adipose tissue crosstalk remain ill defined. One candidate hepatokine controlled by hepatic FOXO1 is fibroblast growth factor 21 (FGF21). Preclinical and clinical studies have explored the potential of pharmacological FGF21 as an antiobesity and antidiabetic therapy. In this manuscript, we performed acute loss-of-function experiments to determine the role of hepatocyte-derived FGF21 in glucose homeostasis and insulin tolerance both in control and mice lacking hepatic insulin signaling. Surprisingly, acute deletion of FGF21 did not alter glucose tolerance, insulin tolerance, or adipocyte lipolysis in either liver-specific FGF21KO mice or mice lacking hepatic AKT-FOXO1-FGF21, suggesting a permissive role for endogenous FGF21 in the regulation of systemic glucose homeostasis and insulin tolerance in mice. In addition, these data indicate that liver FOXO1 controls glucose homeostasis independently of liver-derived FGF21.

The purpose of this study was to develop and validate a cochlear implant (CI)-specific parenting stress measure using the FDA Guidance on Patient-Reported Outcomes (2009).

The development and psychometric validation of the Parenting Stress-CI module for both the Early Childhood (EC; 0-5 years) and School-Age (SA; 6-12 years) versions are reported in this article. Instrument development consisted of qualitative interviews with parents of children with CIs (EC N = 19; SA N = 21), content analysis, item development, and cognitive testing of the instrument. Last, we conducted the psychometric validation (EC N = 72; SA N = 64), including analyses of internal consistency, test-retest reliability (∼2 weeks between administrations; N = 24), and convergent validity with the Parenting Stress Index-4 (PSI-4).

The final EC version includes 15 questions, and the SA version includes 8 questions. Both the EC and SA versions had strong reliability (EC α = .88; SA α = .85), with all items significantly correlated with the overall module (r = .43-.80). Both versions also had strong test-retest reliability (r = .99, p < .001). Last, analyses of convergent validity demonstrated significant correlations with the PSI-4 Total Stress scale for both Parenting Stress-CI versions (EC r = .66, p < .00; SA r = .45, p < .001).

The Parenting Stress-CI modules are reliable and valid condition-specific parenting stress instruments for parents of children with CIs ages 0-12 years, filling a significant gap in the literature. These fully validated instruments can be used to assess parental needs for support and guide the development of targeted, family centered interventions.

The Parenting Stress-CI modules are reliable and valid condition-specific parenting stress instruments for parents of children with CIs ages 0-12 years, filling a significant gap in the literature. These fully validated instruments can be used to assess parental needs for support and guide the development of targeted, family centered interventions.Neutrophils are key players during host defense and sterile inflammation. Neutrophil dysfunction is a characteristic feature of the acquired immunodeficiency during kidney disease. We speculated that the impaired renal clearance of the intrinsic purine metabolite soluble uric acid (sUA) may account for neutrophil dysfunction. Indeed, hyperuricemia (HU, serum UA of 9-12 mg/dL) related or unrelated to kidney dysfunction significantly diminished neutrophil adhesion and extravasation in mice with crystal- and coronavirus-related sterile inflammation using intravital microscopy and an air pouch model. This impaired neutrophil recruitment was partially reversible by depleting UA with rasburicase. We validated these findings in vitro using either neutrophils or serum from patients with kidney dysfunction-related HU with or without UA depletion, which partially normalized the defective migration of neutrophils. Mechanistically, sUA impaired β2 integrin activity and internalization/recycling by regulating intracellular pH and cytoskeletal dynamics, physiological processes that are known to alter the migratory and phagocytic capability of neutrophils. This effect was fully reversible by blocking intracellular uptake of sUA via urate transporters. In contrast, sUA had no effect on neutrophil extracellular trap formation in neutrophils from healthy subjects or patients with kidney dysfunction. Our results identify an unexpected immunoregulatory role of the intrinsic purine metabolite sUA, which contrasts the well-known immunostimulatory effects of crystalline UA. Specifically targeting UA may help to overcome certain forms of immunodeficiency, for example in kidney dysfunction, but may enhance sterile forms of inflammation.Bruton tyrosine kinase (BTK) inhibitor is an established treatment for relapsed/refractory (R/R) mantle cell lymphoma (MCL). Zanubrutinib, a highly selective BTK inhibitor, is approved for patients with MCL who have received ≥1 prior therapy. We report the long-term safety and efficacy results from the multicenter, open-label, phase 2 registration trial of zanubrutinib. Patients (n = 86) received oral zanubrutinib 160 mg twice daily. The primary endpoint was the overall response rate (ORR), assessed per Lugano 2014. After a median follow-up of 35.3 months, the ORR was 83.7%, with 77.9% achieving complete response (CR); the median duration of response was not reached. Median progression-free survival (PFS) was 33.0 months (95% confidence interval [CI], 19.4-NE). The 36-month PFS and overall survival (OS) rates were 47.6% (95% CI, 36.2-58.1) and 74.8% (95% CI, 63.7-83.0), respectively. The safety profile was largely unchanged with extended follow-up. Most common (≥20%) all-grade adverse events (AEs) were neutrophil count decreased (46.5%), upper respiratory tract infection (38.4%), rash (36.0%), white blood cell count decreased (33.7%), and platelet count decreased (32.6%); most were grade 1/2 events. Most common (≥10%) grade ≥3 AEs were neutrophil count decreased (18.6%) and pneumonia (12.8%). Rates of infection, neutropenia, and bleeding were highest in the first 6 months of therapy and decreased thereafter. No cases of atrial fibrillation/flutter, grade ≥3 cardiac AEs, second primary malignancies, or tumor lysis syndrome were reported. After extended follow-up, zanubrutinib demonstrated durable responses and a favorable safety profile in R/R MCL. The trial is registered at ClinicalTrials.gov as NCT03206970.

The conservation of pathways and genes across species has allowed scientists to use non-human model organisms to gain a deeper understanding of human biology. However, the use of traditional model systems such as mice, rats, and zebrafish is costly, time-consuming and increasingly raises ethical concerns, which highlights the need to search for less complex model organisms. Existing tools only focus on the few well-studied model systems, most of which are complex animals. To address these issues, we have developed Orthologous Matrix and Alternative Model Organisms, a software and a web service that provide the user with the best non-complex organism for research into a biological process of interest based on orthologous relationships between human and the species. The outputs provided by OMAMO were supported by a systematic literature review.

https//omabrowser.org/omamo/, https//github.com/DessimozLab/omamo.

Supplementary data are available at Bioinformatics online.

Supplementary data are available at Bioinformatics online.

The goal of this study was to investigate the overall survival between open and thoracoscopic oesophagectomy in patients with oesophageal squamous cell carcinoma (ESCC) undergoing neoadjuvant chemoradiotherapy (NCRT).

The Taiwan Cancer Registry was queried for ESCC from 2008 to 2016. We enrolled 2250 patients with ESCC receiving NCRT plus open (n = 487) or thoracoscopic (n = 1763) oesophagectomy. One-to-two propensity score matching between open and thoracoscopic oesophagectomy was performed. Overall survival was compared between the 2 groups before and after propensity score matching. Univariable analysis and multivariable analysis were performed to identify prognostic factors.

After one-to-two propensity score matching, 353 patients were in the open group and 706 patients were in the thoracoscopic group. The 3-year overall survival rates for matched patients treated with open or thoracoscopic oesophagectomy were similar (39.18% vs 44.33%, p = 0.11). Better overall survival was associated with thoracosm survival in patients with ESCC undergoing NCRT. Stage-specific comparisons showed that thoracoscopic oesophagectomy is associated with better survival than open oesophagectomy in patients with the pathological complete response, y-pathological III and y-pathological T0N+ stages and with similar survival in y-pathological I/II patients.

Hundreds of gene expression signatures have been developed during the last two decades. However, due to the multitude of development procedures and sometimes a lack of explanation for their implementation, it can become challenging to apply the original method on custom data. Moreover, at present there is no unified and tidy interface to compute signature scores with different single sample enrichment methods. For these reasons, we developed hacksig, an R package intended as a unified framework to obtain single sample scores with a tidy output as well as a collection of manually curated gene signatures and methods from cancer transcriptomics literature.

The hacksig R package is freely available on CRAN (https//CRAN.R-project.org/package=hacksig) under the MIT license. The source code can be found on GitHub at https//github.com/Acare/hacksig.

Supplementary data are available at Bioinformatics online.

Supplementary data are available at Bioinformatics online.Immune-checkpoint inhibitors have had impressive efficacy in some patients with cancer, reinvigorating long-term durable immune responses against tumors. Despite the clinical success of these therapies, most patients with cancer continue to be unresponsive to these treatments, highlighting the need for novel therapeutic options. Although P-selectin glycoprotein ligand-1 (PSGL-1) has been shown to inhibit immune responses in a variety of disease models, previous work has yet to address whether PSGL-1 can be targeted therapeutically to promote antitumor immunity. Using an aggressive melanoma tumor model, we targeted PSGL-1 in tumor-bearing mice and found increased effector CD4+ and CD8+ T-cell responses and decreased regulatory T cells (Treg) in tumors. T cells exhibited increased effector function, activation, and proliferation, which delayed tumor growth in mice after anti-PSGL-1 treatment. Targeting PD-1 in PSGL-1-deficient, tumor-bearing mice led to an increased frequency of mice with complete tumor eradication. Targeting both PSGL-1 and PD-1 in wild-type tumor-bearing mice also showed enhanced antitumor immunity and slowed melanoma tumor growth. Our findings showed that therapeutically targeting the PSGL-1 immune checkpoint can reinvigorate antitumor immunity and suggest that targeting PSGL-1 may represent a new therapeutic strategy for cancer treatment.

Both methotrexate and tioguanine can be considered as treatment options in patients with Crohn’s disease after failure of conventional thiopurines. This study aimed to compare tolerability and drug survival of methotrexate and tioguanine therapy after failure of conventional thiopurines in patients with Crohn’s disease.

We conducted a retrospective, multi-centre study, including patients with Crohn’s disease initiating monotherapy methotrexate or tioguanine after failure (all causes) of conventional thiopurines. Follow-up duration was 104 weeks or until treatment discontinuation. The primary outcome was cumulative therapy discontinuation incidence due to adverse events. Secondary outcomes included total number of (serious) adverse events, and ongoing monotherapy.

In total, 219 patients starting either methotrexate (n=105) or tioguanine (n=114) were included. Sixty-five (29.7%) patients (methotrexate 43.8% [46/105 people]; tioguanine 16.7% [19/114 people], p<0.001) discontinued their treatment due to tioguanine (17%) in Crohn’s disease patients after failure of conventional thiopurines. The total adverse events incidence during methotrexate use was higher, while serious adverse events incidence was similar. These favourable results for tioguanine treatment may guide the selection of immunosuppressive therapy after failure of conventional thiopurines.

Interactions between ecological factors and seed physiological responses during the establishment phase shape the distribution of plants. Yet, our understanding of the functions and evolution of early-life traits has been limited by the scarcity of large-scale datasets. Here, we tested the hypothesis that the germination niche of temperate plants is shaped by their climatic requirements and phylogenetic relatedness, using germination data sourced from a comprehensive seed conservation database of the European flora (ENSCOBASE).

We performed a phylogenetically informed Bayesian meta-analysis of primary data, considering 18 762 germination tests of 2418 species from laboratory experiments conducted across all European geographical regions. We tested for the interaction between species’ climatic requirements and germination responses to experimental conditions including temperature, alternating temperature, light and dormancy-breaking treatments, while accounting for between-study variation related to seed s addition, our methodological approach highlighted how large datasets generated by conservation seed banking can be valuable sources to address questions in plant macroecology and evolution.

This is the first quantitative meta-analysis of the germination niche at a continental scale. Our findings showed that the germination niches of European plants exhibit evolutionary convergence mediated by strong pressures at the macroclimatic level. In addition, our methodological approach highlighted how large datasets generated by conservation seed banking can be valuable sources to address questions in plant macroecology and evolution.

We pooled ambulatory blood pressure monitoring data from 5 US studies, including the Jackson Heart Study (JHS), the Coronary Artery Risk Development in Young Adults (CARDIA) study, the Masked Hypertension Study, the Improving the Detection of Hypertension Study, and the North Carolina Masked Hypertension Study. Using a cross-sectional study design, we estimated differences in the prevalence of masked hypertension by race/ethnicity when out-of-office blood pressure (BP) included awake, asleep, and 24-hour BP vs. awake BP alone.

We restricted the analyses to participants with office systolic BP (SBP) <130 mm Hg and diastolic BP (DBP) <80 mm Hg. High awake BP was defined as mean SBP/DBP ≥130/80 mm Hg, high asleep BP as mean SBP/DBP ≥110/65 mm Hg, and high 24-hour BP as mean SBP/DBP ≥125/75 mm Hg.

Among participants not taking antihypertensive medication (n = 1,292), the prevalence of masked hypertension with out-of-office BP defined by awake BP alone or by awake, asleep, or 24-hour BP was 34.5% and 48.7%, respectively, among non-Hispanic White, 39.7% and 67.6% among non-Hispanic Black, and 19.4% and 35.1% among Hispanic participants. After multivariable adjustment, non-Hispanic Black were more likely than non-Hispanic White participants to have masked hypertension by asleep or 24-hour BP but not awake BP (adjusted odds ratio [OR] 2.14 95% confidence interval [CI] 1.45-3.15) and by asleep or 24-hour BP and awake BP (OR 1.61; 95% CI 1.12-2.32) vs. not having masked hypertension.

Assessing asleep and 24-hour BP measures increases the prevalence of masked hypertension more among non-Hispanic Black vs. non-Hispanic White individuals.

Assessing asleep and 24-hour BP measures increases the prevalence of masked hypertension more among non-Hispanic Black vs. non-Hispanic White individuals.Ribosomes are a complex ensemble of rRNA and ribosomal proteins that function as mRNA translation machines. Ribosome biogenesis is a multistep process that begins in the nucleolus and concludes in the cytoplasm. The process is tightly controlled by multiple checkpoint and surveillance pathways. Perturbations in these checkpoints and pathways can lead to hyperactivation of ribosome biogenesis. Emerging evidence suggests that cancer cells harbor a specialized class of ribosomes (onco-ribosomes) that facilitates the oncogenic translation program, modulates cellular functions, and promotes metabolic rewiring. Mutations in ribosomal proteins, rRNA processing, and ribosome assembly factors result in ribosomopathies that are associated with an increased risk of developing malignancies. Recent studies have linked mutations in ribosomal proteins and aberrant ribosomes with poor prognosis, highlighting ribosome-targeted therapy as a promising approach for treating patients with cancer. Here, we summarize various aspects of dysregulation of ribosome biogenesis and the impact of resultant onco-ribosomes on malignant tumor behavior, therapeutic resistance, and clinical outcome. Ribosome biogenesis is a promising therapeutic target, and understanding the important determinants of this process will allow for improved and perhaps selective therapeutic strategies to target ribosome biosynthesis.MicroRNA childhood Cancer Catalog (M3Cs) is a high-quality curated collection of published miRNA research studies on 16 pediatric cancer diseases. M3Cs scope was based on two approaches data-driven clinical significance and data-driven human pediatric cell line models. Based on the translational bioinformatics spectrum, the main objective of this study is to bring miRNA research into clinical significance in both pediatric cancer patient care and drug discovery toward health informatics in childhood cancer. M3Cs development passed through three phases 1. Literature Mining It includes external database search and screening. 2. Data processing that includes three steps (a) Data Extraction, (b) Data Curation and annotation, (c) Web Development. 3. Publishing Shinyapps.io was used as a web interface for the deployment of M3Cs. M3Cs is now available online and can be accessed through https//m3cs.shinyapps.io/M3Cs/. For data-driven clinical significance approach, 538 miRNAs from 268 publications were reported in the clinical domain while 7 miRNAs from 5 publications were reported in the clinical & drug domain. For data-driven human pediatric cell line models approach, 538 miRNAs from 1268 publications were reported in the cell line domain while 211 miRNAs from 177 publications in the cell line & drug domain. M3Cs acted to fill the gap by applying translational bioinformatics general pathway to transfer data-driven research toward data-driven clinical care and/or hypothesis generation. Aggregated and well-curated data of M3Cs will enable stakeholders in health care to incorporate miRNA in the clinical policy. Database URLhttps//m3cs.shinyapps.io/M3Cs/.

Vigorous spontaneous effort can potentially worsen lung injury. This study hypothesized that the prone position would diminish a maldistribution of lung stress and inflation after diaphragmatic contraction and reduce spontaneous effort, resulting in less lung injury.

A severe acute respiratory distress syndrome model was established by depleting surfactant and injurious mechanical ventilation in 6 male pigs („mechanism” protocol) and 12 male rabbits („lung injury” protocol). In the mechanism protocol, regional inspiratory negative pleural pressure swing (intrabronchial balloon manometry) and the corresponding lung inflation (electrical impedance tomography) were measured with a combination of position (supine or prone) and positive end-expiratory pressure (high or low) matching the intensity of spontaneous effort. In the lung injury protocol, the intensities of spontaneous effort (esophageal manometry) and regional lung injury were compared in the supine position versus prone position.

The mechanism proy was less without regional difference (lung myeloperoxidase activity in ventral vs. dorsal lung, 74.0 ± 30.9 μm · min-1 · mg-1 protein vs. 61.0 ± 23.0 μm · min-1 · mg-1 protein, P = 0.951). In the supine position, stronger spontaneous effort increased dorsal lung injury (lung myeloperoxidase activity in ventral vs. dorsal lung, 67.5 ± 38.1 μm · min-1 · mg-1 protein vs. 167.7 ± 65.5 μm · min-1 · mg-1 protein, P = 0.003).

Prone position, independent of positive end-expiratory pressure levels, diminishes a maldistribution of lung stress and inflation imposed by spontaneous effort and mitigates spontaneous effort, resulting in less effort-dependent lung injury.

The epitranscriptome represents the more than 140 types of chemically varying and reversable RNA modifications affecting RNA fate. Among these, the most relevant for this review are the mRNA modifications N6-methyladenosine and N6,2′-O-dimethyladenosine. Epitranscriptomic mRNA biology involves RNA methyltransferases (so-called „writers”), RNA demethylases („erasers”), and RNA-binding proteins („readers”) that interact with methylation sites to determine the functional outcome of the modification. In this review, we discuss the role of a specific RNA demethylase encoded by the fat mass and obesity-associated gene (FTO) in cancer. FTO initially became known as the strongest genetic link for human obesity. Only in 2010, 16 years after its discovery, was its enzymatic function as a demethylase clarified, and only recently has its role in the development of cancer been revealed. FTO functions are challenging to study and interpret because of its genome-wide effects on transcript turnover and translation. We review the discovery of FTO and its enzymatic function, the tumor-promoting and suppressive roles of FTO in selected cancer types, and its potential as a therapeutic target.

Slick, a sodium-activated potassium channel, has been recently identified in somatosensory pathways, but its functional role is poorly understood. The authors of this study hypothesized that Slick is involved in processing sensations of pain and itch.

Immunostaining, in situ hybridization, Western blot, and real-time quantitative reverse transcription polymerase chain reaction were used to investigate the expression of Slick in dorsal root ganglia and the spinal cord. Mice lacking Slick globally (Slick-/-) or conditionally in neurons of the spinal dorsal horn (Lbx1-Slick-/-) were assessed in behavioral models.

The authors found Slick to be enriched in nociceptive Aδ-fibers and in populations of interneurons in the spinal dorsal horn. Slick-/- mice, but not Lbx1-Slick-/- mice, showed enhanced responses to noxious heat in the hot plate and tail-immersion tests. Both Slick-/- and Lbx1-Slick-/- mice demonstrated prolonged paw licking after capsaicin injection (mean ± SD, 45.6 ± 30.1 s [95% CI, 19.8 to 71.4]; and 13.1 ± 16.1 s [95% CI, 1.8 to 28.0]; P = 0.006 [Slick-/- n = 8 and wild-type n = 7, respectively]), which was paralleled by increased phosphorylation of the neuronal activity marker extracellular signal-regulated kinase in the spinal cord. In the spinal dorsal horn, Slick is colocalized with somatostatin receptor 2 (SSTR2), and intrathecal preadministration of the SSTR2 antagonist CYN-154806 prevented increased capsaicin-induced licking in Slick-/- and Lbx1-Slick-/- mice. Moreover, scratching after intrathecal delivery of the somatostatin analog octreotide was considerably reduced in Slick-/- and Lbx1-Slick-/- mice (Slick-/- [n = 8] 6.1 ± 6.7 bouts [95% CI, 0.6 to 11.7]; wild-type [n =8] 47.4 ± 51.1 bouts [95% CI, 4.8 to 90.2]; P = 0.039).

Slick expressed in a subset of sensory neurons modulates heat-induced pain, while Slick expressed in spinal cord interneurons inhibits capsaicin-induced pain but facilitates somatostatin-induced itch.

The clinical predictors and outcomes of patients with cardiogenic shock (CS) requiring renal replacement therapy (RRT) have not been studied previously. This study assesses the impact of RRT on mortality in patients with CS and aims to identify clinical factors that contribute to the need of RRT.

Consecutive patients presenting with CS were included from a prospective registry of cardiac intensive care unit admissions at a single institution between 2014 and 2020. Of the 1030 patients admitted with CS, 123 (11.9%) received RRT. RRT was associated with higher 1-year mortality [adjusted hazard ratio = 1.62, 95% confidence interval (CI) 1.02-2.14], and a higher in-hospital incidence of sepsis [risk ratio = 2.76, P < 0.001], and pneumonia (risk ratio = 2.9, P = 0.001). Those who received RRT were less likely to receive guideline-directed medical treatment at time of discharge, undergo heart transplantation (2.4% vs. 11.5%, P = 0.002) or receive a durable left ventricular assist device (0.0% vs. 11.6%, P < 0.001). Five variables at admission best predicted the need for RRT (age, lactate, haemoglobin, use of pre-admission loop diuretics, and admission estimated glomerular filtration rate) and were used to generate the CALL-K 9-point risk score, with better discrimination than creatinine alone (P = 0.008). The score was internally validated (area under the curve = 0.815, 95% CI 0.739-0.835) with good calibration (Hosmer-Lemeshow P = 0.827).

RRT is associated with worse outcomes, including a lower likelihood to receive advanced heart failure therapies in patients with CS. A risk score comprising five variables routinely collected at admission can accurately estimate the risk of needing RRT.

RRT is associated with worse outcomes, including a lower likelihood to receive advanced heart failure therapies in patients with CS. A risk score comprising five variables routinely collected at admission can accurately estimate the risk of needing RRT.Osteosarcoma is the most common malignancy of the bone, yet the survival for patients with osteosarcoma is virtually unchanged over the past 30 years. This is principally because development of new therapies is hampered by a lack of recurrent mutations that can be targeted in osteosarcoma. Here, we report that epigenetic changes via mRNA methylation holds great promise to better understand the mechanisms of osteosarcoma growth and to develop targeted therapeutics. In patients with osteosarcoma, the RNA demethylase ALKBH5 was amplified and higher expression correlated with copy-number changes. ALKBH5 was critical for promoting osteosarcoma growth and metastasis, yet it was dispensable for normal cell survival. Methyl RNA immunoprecipitation sequencing analysis and functional studies showed that ALKBH5 mediates its protumorigenic function by regulating m6A levels of histone deubiquitinase USP22 and the ubiquitin ligase RNF40. ALKBH5-mediated m6A deficiency in osteosarcoma led to increased expression of USP22 anassociated genes, driving osteosarcoma progression.Cemiplimab is a novel programmed death-1 inhibitor recently approved for advanced cutaneous squamous cell carcinoma. Immune-related adverse events derived from cemiplimab are similar to other anti-PD-1 drugs, including gastrointestinal and cutaneous toxicities. Oral immune-related adverse events were not reported with cemiplimab in previous studies; thus this case report warns of the fact that the oral cavity may be a site of immune-related adverse events during programmed death-1 block therapy and that this can lead to significant limitations when not properly treated. The present report describes the case of a patient with locally advanced cutaneous squamous cell carcinoma metastatic to cervical lymph nodes who developed dysphagia due to large and painful oral ulcers after a single dose of cemiplimab. The patient also exhibited a sarcoid-like reaction in mediastinal lymph nodes. No immune-related adverse events were found in any other organs. The oral lesions showed significant improvement after topical and short-course systemic corticosteroids, and low-level laser therapy was also performed in the oral lesions. The patient achieved a near-complete response and treatment was discontinued. This article discusses in detail the clinical outcomes and oral toxicity management of cemiplimab therapy for cutaneous squamous cell carcinoma.Despite advances in understanding of carcinogenesis and of treatment of acute myeloid leukemia, this neoplasm still has a lethality of at least 30%. The search for biomarkers that can predict the response to treatment in the early stages of the disease is still necessary. In recent years, a new form of cellular communication between tumor and non-neoplastic cells has been discovered the exchange of information through extracellular vesicles. These are small vesicles released by membrane-coated cells that carry proteins, lipids, messenger RNAs, microRNA and DNA, which can be internalized and promote biological changes in target cells. Exosomes are qualified as a type of extracellular vesicle and, in tumors, carry immunoinhibitory signals that promote the escape of immune control. Recent studies have showed their involvement in communication with the cells of the tumor microenvironment and with chemoresistance in several tumors. To date, there is no information about immunoregulatory microRNAs transported by exosomes and their correlation with clinical evolution during chemotherapy for acute myeloid leukemia. Knowledge about immunomodulatory microRNAs obtained by leukemic cells and transported by exosomes can direct us towards the design of new diagnostic and treatment tools in this type of leukemia.