Although gastric cancer is a leading cause of cancer-related deaths, systemic treatment strategies remain scarce. Here, we report the pro-tumorigenic properties of the crosstalk between intestinal ...tuft cells and type 2 innate lymphoid cells (ILC2) that is evolutionarily optimized for epithelial remodeling in response to helminth infection. We demonstrate that tuft cell-derived interleukin 25 (IL25) drives ILC2 activation, inducing the release of IL13 and promoting epithelial tuft cell hyperplasia. While the resulting tuft cell - ILC2 feed-forward circuit promotes gastric metaplasia and tumor formation, genetic depletion of tuft cells or ILC2s, or therapeutic targeting of IL13 or IL25 alleviates these pathologies in mice. In gastric cancer patients, tuft cell and ILC2 gene signatures predict worsening survival in intestinal-type gastric cancer where ~40% of the corresponding cancers show enriched co-existence of tuft cells and ILC2s. Our findings suggest a role for ILC2 and tuft cells, along with their associated cytokine IL13 and IL25 as gatekeepers and enablers of metaplastic transformation and gastric tumorigenesis, thereby providing an opportunity to therapeutically inhibit early-stage gastric cancer through repurposing antibody-mediated therapies.
Hyperlactatemia often occurs in critically ill patients during severe sepsis/septic shock and is a powerful predictor of mortality. Lactate is the end product of glycolysis. While hypoxia due to ...inadequate oxygen delivery may result in anaerobic glycolysis, sepsis also enhances glycolysis under hyperdynamic circulation with adequate oxygen delivery. However, the molecular mechanisms involved are not fully understood. Mitogen-activated protein kinase (MAPK) families regulate many aspects of the immune response during microbial infections. MAPK phosphatase (MKP)-1 serves as a feedback control mechanism for p38 and JNK MAPK activities via dephosphorylation. Here, we found that mice deficient in Mkp-1 exhibited substantially enhanced expression and phosphorylation of 6-phosphofructo-2-kinase/fructose-2,6-biphosphatase (PFKFB) 3, a key enzyme that regulates glycolysis following systemic Escherichia coli infection. Enhanced PFKFB3 expression was observed in a variety of tissues and cell types, including hepatocytes, macrophages, and epithelial cells. In bone marrow–derived macrophages, Pfkfb3 was robustly induced by both E. coli and lipopolysaccharide, and Mkp-1 deficiency enhanced PFKFB3 expression with no effect on Pfkfb3 mRNA stability. PFKFB3 induction was correlated with lactate production in both WT and Mkp-1−/− bone marrow–derived macrophage following lipopolysaccharide stimulation. Furthermore, we determined that a PFKFB3 inhibitor markedly attenuated lactate production, highlighting the critical role of PFKFB3 in the glycolysis program. Finally, pharmacological inhibition of p38 MAPK, but not JNK, substantially attenuated PFKFB3 expression and lactate production. Taken together, our studies suggest a critical role of p38 MAPK and MKP-1 in the regulation of glycolysis during sepsis.
To investigate the timing for spontaneous repositioning of primary teeth with intrusive luxation in relation to degree of inclusion, gender and age of injured children.
This retrospective study ...analysed records of 1- to 6-year-old children referred to the Section of Paediatric Dentistry, C.I.R. Dental School, University of Turin (Italy) between January 2009 and December 2020 for traumatic intrusion of primary teeth. Time to the total re-eruption was calculated, and related factors were explored using Cox and Kaplan-Meier analyses.
Timing for spontaneous re-eruption seems to be associated to age, particularly as far as total intrusion of primary teeth is concerned. This observation could be related to the degree of bone mineralisation, which is modified during growth.
This study evaluates the prevalence of Interceptive Orthodontic Treatment Need (IOTN) in Italian school-children.
A prospective observational study was conducted to assess the prevalence of IOTN in ...patients undergoing a first visit at the Santa Chiara Hospital Paediatric Dentistry Unit in Pisa, Italy. Two thousand, one hundred ninetynine subjects met the inclusion criteria and were enrolled in the study; data on age, gender and concomitant systemic pathologies were collected from medical records. All participants were examined for individual IOTN: the presence of anterior and/or unilateral/bilateral crossbite with or without midline deviation, bad habits (finger, sucking habits, mouth breathing, and tongue thrust), overjet > 3 mm, lack of space for 1.2 and 2.2 eruption were investigated. The presence of one of the above mentioned parameters was considered positive for IOTN. Chi-square test was used to evaluate any statistically significant difference (p < 0.05).
The study confirms the presence of a significant percentage of paediatric patients who need IOTN; early treatment is highly recommended to reduce malocclusion outcomes in the adult population.
MicroRNA-21 (miR-21) is a small, non-coding RNA overexpressed in gastric cancer and many other solid malignancies, where it exhibits both pro-and anti-tumourigenic properties. However, the pathways ...regulating miR-21 and the consequences of its inhibition in gastric cancer remain incompletely understood. By exploiting the spontaneous Stat3-dependent formation of inflammation-associated gastric tumors in
mice, we functionally established miR-21 as a Stat3-controlled driver of tumor growth and progression. We reconciled our discoveries by identifying several conserved Stat3 binding motifs upstream of the miR-21 gene promoter, and showed that the systemic administration of a miR-21-specific antisense oligonucleotide antagomir reduced the established gastric tumor burden in
mice. We molecularly delineated the therapeutic benefits of miR-21 inhibition with the functional restoration of PTEN in vitro and in vivo, alongside an attenuated epithelial-to-mesenchymal transition and the extracellular matrix remodeling phenotype of tumors. We corroborated our preclinical findings by correlating high STAT3 and miR-21 expression with the reduced survival probability of gastric cancer patients. Collectively, our results provide a molecular framework by which miR-21 mediates inflammation-associated gastric cancer progression, and establish miR-21 as a robust therapeutic target for solid malignancies characterized by excessive Stat3 activity.
The detection of low-mass transiting exoplanets in multiple systems brings new constraints to planetary formation and evolution processes and challenges the current planet formation theories. ...Nevertheless, only a mere fraction of the small planets detected by Kepler and K2 have precise mass measurements, which are mandatory to constrain their composition. We aim to characterise the planets that orbit the relatively bright star K2-138. This system is dynamically particular as it presents the longest chain known to date of planets close to the 3:2 resonance. We obtained 215 HARPS spectra from which we derived the radial-velocity variations of K2-138. Via a joint Bayesian analysis of both the K2 photometry and HARPS radial-velocities (RVs), we constrained the parameters of the six planets in orbit. The masses of the four inner planets, from b to e, are 3.1, 6.3, 7.9, and 13.0 M⊕ with a precision of 34, 20, 18, and 15%, respectively. The bulk densities are 4.9, 2.8, 3.2, and 1.8 g cm−3, ranging from Earth to Neptune-like values. For planets f and g, we report upper limits. Finally, we predict transit timing variations of the order two to six minutes from the masses derived. Given its peculiar dynamics, K2-138 is an ideal target for transit timing variation (TTV) measurements from space with the upcoming CHaracterizing ExOPlanet Satellite (CHEOPS) to study this highly-packed system and compare TTV and RV masses.
ABSTRACT We present the description and initial results of the TRAPUM (TRAnsients And PUlsars with MeerKAT) search for pulsars associated with supernova remnants (SNRs), pulsar wind nebulae, and ...unidentified TeV emission. The list of sources to be targeted includes a large number of well-known candidate pulsar locations but also new candidate SNRs identified using a range of criteria. Using the 64-dish MeerKAT radio telescope, we use an interferometric beamforming technique to tile the potential pulsar locations with coherent beams which we search for radio pulsations, above a signal-to-noise of 9, down to an average flux density upper limit of 30 μJy. This limit is target-dependent due to the contribution of the sky and nebula to the system temperature. Coherent beams are arranged to overlap at their 50 per cent power radius, so the sensitivity to pulsars is not degraded by more than this amount, though realistically averages around 65 per cent if every location in the beam is considered. We report the discovery of two new pulsars; PSR J1831−0941 is an adolescent pulsar likely to be the plerionic engine of the candidate PWN G20.0+0.0, and PSR J1818−1502 appears to be an old and faint pulsar that we serendipitously discovered near the centre of a SNR already hosting a compact central object. The survey holds importance for better understanding of neutron star birth rates and the energetics of young pulsars.
ABSTRACT
The TRAPUM collaboration has used the MeerKAT telescope to conduct a search for pulsed radio emission from the young Small Magellanic Cloud pulsar J0058−7218 located in the supernova remnant ...IKT 16, following its discovery in X-rays with XMM–Newton. We report no significant detection of dispersed, pulsed radio emission from this source in three 2-h L-band observations using the core dishes of MeerKAT, setting an upper limit of 7.0 $\mu$Jy on its mean flux density at 1284 MHz. This is nearly seven times deeper than previous radio searches for this pulsar in Parkes L-band observations. This suggests that the radio emission of PSR J0058−7218 is not beamed towards Earth or that PSR J0058−7218 is similar to a handful of Pulsar Wind Nebulae systems that have a very low radio efficiency, such as PSR B0540−6919, the Large Magellanic Cloud Crab pulsar analogue. We have also searched for bright, dispersed, single radio pulses and found no candidates above a fluence of 93 mJy ms at 1284 MHz.
ABSTRACT The sensitivity of the MeerKAT radio interferometer is an opportunity to probe deeper into the population of rare and faint extragalactic pulsars. The TRAPUM (TRAnsients and PUlsars with ...MeerKAT) collaboration has conducted a radio-domain search for accelerated pulsars and transients in the Small Magellanic Cloud (SMC). This partially targeted survey, performed at L band (856–1712 MHz) with the core array of the MeerKAT telescope in 2-h integrations, is twice as sensitive as the latest SMC radio pulsar survey. We report the discovery of seven new SMC pulsars, doubling this galaxy’s radio pulsar population and increasing the total extragalactic population by nearly a quarter. We also carried out a search for accelerated millisecond pulsars in the SMC globular cluster NGC 121 using the full array of MeerKAT. This improved the previous upper limit on pulsed radio emission from this cluster by a factor of 6. Our discoveries reveal the first radio pulsar-PWN systems in the SMC, with only one such system previously known outside our Galaxy (the ‘Crab pulsar twin’ in the Large Magellanic Cloud, PSR J0540−6919). We associate the 59 ms pulsar discovery PSR J0040−7337, now the fastest spinning radio pulsar in the SMC, with the bow-shock Pulsar Wind Nebula (PWN) of supernova remnant DEM S5. We also present a new young pulsar with a 79 ms period, PSR J0048−7317, in a PWN recently discovered in a MeerKAT radio continuum image. Using the multibeam capability of MeerKAT, we localized our pulsar discoveries, and two previous Murriyang discoveries, to a positional uncertainty of a few arcseconds.
Purpose
This study aimed to evaluate the effect and individual responsiveness after 12 (12wk) and 24 weeks (24wk) of physical exercise (PE) and nutritional guidance (NG) on metabolic syndrome (MetS) ...criteria and hepatic parameters in overweight adolescents.
Methods
The study comprised 94 overweight adolescents, aged between 10 and 16 years old, from both sexes, allocated into groups: PE and NG (PENGG,
n
= 64) and control with NG (NGCG,
n
= 30). Variables were collected at baseline, 12wk, and 24wk. Weight, height, abdominal circumference (AC), blood pressure, and peak oxygen consumption (VO
2peak
), as well as insulin, triglycerides (TAG), high-density lipoprotein (HDL-c), aspartate aminotransferase (AST) and alanine aminotransferase (ALT) were evaluated. HOMA-IR and QUICKI were calculated. PE session consisted of 45 min of indoor cycling, 45 min of walking, and 20 min of stretching, three times a week. The NG consisted of three collective sessions in the first 12wk. Anova, effect size, and prevalence of responders were used for statistical analysis.
Results
The PENGG12wk reduced anthropometric and metabolic measurements, while increased VO
2peak
and HDL-c. The PEG24wk promoted anthropometric, blood pressure, metabolic, and VO
2peak
improvements, but participants without PE returned to pre-exercise status and presented worsening AST and ALT concentrations. Frequencies of respondents in PENGG12wk versus (vs) NGCG12wk were, respectively, AC (69.1% vs 17.6%,
p
< 0.01), HDL-c (87.2% vs 23.5%,
p
< 0.01), TAG (67.3% vs 41.7%,
p
= 0.05) and ALT (45.5% vs 5,9%;
p
= 0.003).
Conclusion
Interventions with PE were effective to reduce MetS components in 12wk and maintenance in 24wk, showing anthropometric, metabolic, and VO
2peak
improvements. Higher individual responses were observed in 12wk and in 24wk, important changes in overweight adolescent’s therapy.
Level of evidence
Level I, evidence obtained from well-designed controlled trials randomization.
Trial registration number and date of registration
Brazilian Registry of Clinical Trials (RBR-4v6h7b) and date of registration April 4th, 2020.
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