Asthma is the most prevalent pediatric chronic disease and affects more than 300 million people worldwide. Recent evidence in mice has identified a "critical window" early in life where gut microbial ...changes (dysbiosis) are most influential in experimental asthma. However, current research has yet to establish whether these changes precede or are involved in human asthma. We compared the gut microbiota of 319 subjects enrolled in the Canadian Healthy Infant Longitudinal Development (CHILD) Study, and show that infants at risk of asthma exhibited transient gut microbial dysbiosis during the first 100 days of life. The relative abundance of the bacterial genera Lachnospira, Veillonella, Faecalibacterium, and Rothia was significantly decreased in children at risk of asthma. This reduction in bacterial taxa was accompanied by reduced levels of fecal acetate and dysregulation of enterohepatic metabolites. Inoculation of germ-free mice with these four bacterial taxa ameliorated airway inflammation in their adult progeny, demonstrating a causal role of these bacterial taxa in averting asthma development. These results enhance the potential for future microbe-based diagnostics and therapies, potentially in the form of probiotics, to prevent the development of asthma and other related allergic diseases in children.
Our aim was to investigate whether molecular classification can be used to refine prognosis in grade 3 endometrial endometrioid carcinomas (EECs). Grade 3 EECs were classified into 4 subgroupsp53 ...abnormal, based on mutant-like immunostaining (p53abn); MMR deficient, based on loss of mismatch repair protein expression (MMRd); presence of POLE exonuclease domain hotspot mutation (POLE); no specific molecular profile (NSMP), in which none of these aberrations were present. Overall survival (OS) and recurrence-free survival (RFS) rates were compared using the Kaplan-Meier method (Log-rank test) and univariable and multivariable Cox proportional hazard models. In total, 381 patients were included. The median age was 66 years (range, 33 to 96 y). Federation Internationale de Gynecologie et dʼObstetrique stages (2009) were as followsIA, 171 (44.9%); IB, 120 (31.5%); II, 24 (6.3%); III, 50 (13.1%); IV, 11 (2.9%). There were 49 (12.9%) POLE, 79 (20.7%) p53abn, 115 (30.2%) NSMP, and 138 (36.2%) MMRd tumors. Median follow-up of patients was 6.1 years (range, 0.2 to 17.0 y). Compared to patients with NSMP, patients with POLE mutant grade 3 EEC (OShazard ratio HR, 0.36 95% confidence interval, 0.18-0.70; P=0.003; RFSHR, 0.17 0.05-0.54; P=0.003) had a significantly better prognosis; patients with p53abn tumors had a significantly worse RFS (HR, 1.73 1.09-2.74; P=0.021); patients with MMRd tumors showed a trend toward better RFS. Estimated 5-year OS rates were as followsPOLE 89%, MMRd 75%, NSMP 69%, p53abn 55% (Log rank P=0.001). Five-year RFS rates were as followsPOLE 96%, MMRd 77%, NSMP 64%, p53abn 47% (P=0.000001), respectively. In a multivariable Cox model that included age and Federation Internationale de Gynecologie et dʼObstetrique stage, POLE and MMRd status remained independent prognostic factors for better RFS; p53 status was an independent prognostic factor for worse RFS. Molecular classification of grade 3 EECs reveals that these tumors are a mixture of molecular subtypes of endometrial carcinoma, rather than a homogeneous group. The addition of molecular markers identifies prognostic subgroups, with potential therapeutic implications.
Our aim was to characterize the pathological, molecular and clinical outcomes of clear cell carcinoma of the endometrium (CCC).
CCC underwent ProMisE (Proactive Molecular Risk Classifier for ...Endometrial Cancer) classification identifying four molecular subtypes: i) ‘POLEmut’ for ECs with pathogenic POLE mutations, ii) ‘MMRd’, if there is loss of mismatch repair proteins by immunohistochemistry (IHC), iii) ‘p53wt’ or iv) ‘p53abn’ based on p53 IHC staining. Clinicopathologic parameters, immune markers (CD3, CD8, CD79a, CD138, PD-1), ER, L1CAM, and outcomes were assessed.
52 CCCs were classified, including 1 (2%) POLEmut, 5 (10%) MMRd, 28 (54%) p53wt and 18 (35%) p53abn. Women with p53abn and p53wt CCCs were older than women with MMRd and POLEmut subtypes. p53wt CCC were distinct from typical p53wt endometrioid carcinomas; more likely to arise in older, thinner women, with advanced stage disease, LVSI and lymph node involvement, and a higher proportion ER negative, L1CAM overexpressing tumors with markedly worse outcomes. High levels of immune infiltrates (TILhigh) were observed in 75% of the CCC cohort. L1CAM overexpression was highest within p53abn and p53wt subtypes of CCC.
CCC is a heterogeneous disease encompassing all four molecular subtypes and a wide range of clinical outcomes. Outcomes of patients with POLEmut, MMRd and p53abn CCC are not distinguishable from those of other patients with these respective subtypes of EC; p53wt CCC, however, differ from endometrioid p53wt EC in clinical, pathological, molecular features and outcomes. Thus, p53wt CCC of endometrium appear to be a distinct clinicopathological entity within the larger group of p53wt ECs.
•There is molecular heterogeneity within clear cell carcinoma (CCC) of the endometrium.•P53wt CCC of endometrium show aggressive features and are distinct from other p53wt endometrial cancers.•Molecular classification of CCC of endometrium elicits prognostic parameters that are not apparent with histology alone.
Coagulation factor XIIIa (FXIIIa) is a transglutaminase that covalently cross-links fibrin and other proteins to fibrin to stabilize blood clots and reduce blood loss. A clear mechanism to describe ...the physiological inactivation of FXIIIa has been elusive. Here, we show that plasmin can cleave FXIIIa in purified systems and in blood. Whereas zymogen FXIII was not readily cleaved by plasmin, FXIIIa was rapidly cleaved and inactivated by plasmin in solution (catalytic efficiency = 8.3 × 103 M−1s−1). The primary cleavage site identified by mass spectrometry was between K468 and Q469. Both plasma- and platelet-derived FXIIIa were susceptible to plasmin-mediated degradation. Inactivation of FXIIIa occurred during clot lysis and was enhanced both in plasma deficient in fibrinogen and in plasma treated with therapeutic levels of tissue plasminogen activator. These results indicate that FXIIIa activity can be modulated by fibrinolytic enzymes, and suggest that changes in fibrinolytic activity may influence cross-linking of blood proteins.
•Plasmin inactivates the enzyme FXIIIa, but not the zymogen FXIII.•FXIIIa is inactivated during clot lysis.
Leptin signaling in the central nervous system, and particularly the arcuate hypothalamic nucleus, is important for regulating energy and glucose homeostasis. However, the roles of extra-arcuate ...leptin responsive neurons are less defined. In the current study, we generated mice with widespread inactivation of the long leptin receptor isoform in the central nervous system via Synapsin promoter-driven Cre (Leprflox/flox Syn-cre mice). Within the hypothalamus, leptin signaling was disrupted in the lateral hypothalamic area (LHA) and ventral premammillary nucleus (PMV) but remained intact in the arcuate hypothalamic nucleus and ventromedial hypothalamic nucleus, dorsomedial hypothalamic nucleus, and nucleus of the tractus solitarius. To investigate the role of LHA/PMV neuronal leptin signaling, we examined glucose and energy homeostasis in Leprflox/flox Syn-cre mice and Leprflox/flox littermates under basal and diet-induced obese conditions and tested the role of LHA/PMV neurons in leptin-mediated glucose lowering in streptozotocin-induced diabetes. Leprflox/flox Syn-cre mice did not have altered body weight or blood glucose levels but were hyperinsulinemic and had enhanced glucagon secretion in response to experimental hypoglycemia. Surprisingly, when placed on a high-fat diet, Leprflox/flox Syn-cre mice were protected from weight gain, glucose intolerance, and diet-induced hyperinsulinemia. Peripheral leptin administration lowered blood glucose in streptozotocin-induced diabetic Leprflox/flox Syn-cre mice as effectively as in Leprflox/flox littermate controls. Collectively these findings suggest that leptin signaling in LHA/PMV neurons is not critical for regulating glucose levels but has an indispensable role in the regulation of insulin and glucagon levels and, may promote the development of diet-induced hyperinsulinemia and weight gain.
This is the first report of a NACC2‐NTRK2 fusion in a histological glioblastoma. Oncogenomic analysis revealed this actionable fusion oncogene in a pediatric cerebellar glioblastoma, which would not ...have been identified through routine diagnostics, demonstrating the value of clinical genome profiling in cancer care.
This is the first report of a NACC2‐NTRK2 fusion in a histological glioblastoma. Oncogenomic analysis revealed this actionable fusion oncogene in a pediatric cerebellar glioblastoma, which would not have been identified through routine diagnostics, demonstrating the value of clinical genome profiling in cancer care.
Background
This study virtually compares patient‐specific fibular and scapular reconstructions for maxillectomies.
Methods
Nine maxillectomy defects were created on 10 maxillas and virtually ...reconstructed with patient‐specific fibulas and scapulas. Reconstructions were compared for restoring midface cephalometrics, dental implantability, and pedicle length.
Results
Of 90 maxillectomy defects, the vertically oriented scapula provided improved orbital floor and maxillary height reconstructions (p < 0.001), albeit at the cost of dental implantability compared to the fibula (p < 0.001). In two defects crossing the midline, the fibula, allowing for more osteotomies, provided improved maxillary projection. In the remaining three defects crossing the midline, the horizontally oriented scapula was comparable to the fibula. Fibular and scapular reconstructions were amenable for dental implantation and had similar pedicle lengths, although favoring scapula in extensive defects.
Conclusion
Fibular and scapular reconstructions of maxillectomy defects provide unique strengths. This virtual analysis can guide a goal‐oriented reconstruction based on defect type and patient‐specific goals.
Approximately 15% of endometrial carcinomas (ECs) arise in young women who may wish to avoid surgical menopause and/or preserve fertility. Our aim was to evaluate the prognostic significance of ...Proactive Molecular risk classifier for Endometrial Carcinoma (ProMisE) in young (<50 yo) women with EC.
ProMisE was applied to a retrospective cohort of women with ECs <50 yo at diagnosis, and associations between the four ProMisE molecular subtypes (MMR deficient (MMRd), POLE mutated (POLE), p53 wild type (p53wt), and p53 abnormal (p53abn)) and clinicopathological parameters, including outcomes, were assessed.
Of 257 ECs, there were 48 (19%) MMRd, 34 (13%) POLE, 164 (64%) p53wt and 11 (4%) p53abn. ProMisE subtypes were associated with differences in all measured clinicopathological parameters except for presence of synchronous ovarian tumours and fertility. Age at diagnosis was youngest and BMI highest in women with p53wt ECs. MMRd and p53abn tumours were more likely to be advanced stage (III/IV), high-risk (ESMO), and receive chemotherapy. ProMisE subtypes were strongly associated with outcomes (overall, disease-specific, and progression-free survival (p < 0.0001 for all)). Advanced stage, grade, LVSI, myometrial invasion and ESMO risk groups showed associations with some but not all survival parameters. ProMisE maintained a strong association with OS and DSS on multivariable analysis.
ProMisE molecular classification is prognostic in young women with EC, enabling early stratification and risk assignment to direct care. Further studies can assess response to therapy, fertility, and cancer-related outcomes within the framework of molecular subtype.
•Management of young women with endometrial carcinoma (EC) presents unique challenges, impacting fertility and menopause.•Better tools are needed to help direct management, identifying patients for whom conservative management is safe.•Molecular classification enables consistent categorization of ECs and biologically relevant information to guide care.•Molecular subtype is prognostic in young women with EC and achievable on biopsies enabling risk stratification from first diagnosis.
This study's objective was to evaluate the utility of intraoperative frozen section (IFS) performed during parathyroidectomy for treatment of primary hyperparathyroidism (PHP), and to identify ...patients for whom it is most helpful.
A retrospective chart review was carried out for all patients who underwent parathyroidectomy for treatment of PHP between January 2013 and June 2018.
262 patients made up the final study population. Overall, IFS provided information that influenced the operative plan in 46 patients (17.6%). IFS altered the operative plan in 10.2% of cases that were correctly preoperatively localized, and in 41.5% of cases that were either incorrectly or not preoperatively localized.
IFS did not provide information that influenced the operative plan during parathyroidectomy for treatment of PHP for the majority of patients. Patients that present with normal PTH and hypercalcemia, or those who do not localize preoperatively, are most likely to benefit from IFS.
•Intraoperative frozen section rarely influenced the plan during parathyroidectomy.•It altered the plan in 10.2% of cases correctly localized.•It also altered the plan in 41.5% of cases that were incorrectly or not localized.•It most likely benefits patients that present with normal PTH and hypercalcemia.
This study's objective was to evaluate the utility of intraoperative frozen section (IFS) performed during parathyroidectomy for treatment of primary hyperparathyroidism, and to identify patients for whom it is most helpful. IFS did not provide information that influenced the operative plan for the majority of patients. Patients that present with normal PTH and hypercalcemia, or those who do not localize preoperatively, are most likely to benefit from IFS.
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