Osteosarcoma is a malignant mesenchymal neoplasm that accounts for the majority of primary bone tumors in dogs and shares biological and clinical similarities with osteosarcoma in humans. Despite ...dose intensification with conventional cytotoxic therapies, survival times for dogs and humans diagnosed with high‐grade osteosarcoma have not changed in the past 20 years, with the principal cause of mortality being the development of pulmonary metastases. Given the therapeutic plateau reached for delaying metastatic progression with cytotoxic agents, exploration of alterative adjuvant therapies for improving management of osteosarcoma micrometastases is clinically justified. Evidence suggests that osteosarcoma is an immunogenic tumor, and development of immunotherapies for the treatment of microscopic lung metastases might improve long‐term outcomes. In this review, the history and foundational knowledge of immune interactions to canine osteosarcoma are highlighted. In parallel, immunotherapeutic strategies that have been explored for the treatment of canine osteosarcoma are summarized. With a greater understanding and awareness for how the immune system might be redirected toward combating osteosarcoma metastases, the rational development of diverse immune strategies for managing osteosarcoma holds substantial promise for transforming the therapeutic landscape and improving disease management in both dogs and human beings.
Background & Aims
Hepatocellular carcinoma (HCC) is one of the most common human cancers. Recently, emerging evidence has suggested the role of long non‐coding RNAs (lncRNAs) in human carcinogenesis. ...In this study, we aimed to investigate the expression and functional implications of lncRNAs in human HCC.
Methods
Eighty‐eight well‐annotated lncRNAs were profiled in primary HCC by quantitative RT‐PCR. Functional relevance of lncRNAs was elucidated in HCC cell lines and nude mice models. The regulatory relationship between miRNA and lncRNA was predicted in silico and further validated by luciferase reporter assay and expression analysis.
Results
In our profiling study, HOTTIP was identified as the most significantly up‐regulated lncRNA in human HCCs, even in early stage of HCC formation. Functionally, knock‐down of HOTTIP attenuated HCC cell proliferation in vitro and markedly abrogated tumourigenicity in vivo. In addition, knock‐down of HOTTIP also inhibited migratory ability of HCC cells and significantly abrogated lung metastasis in orthotopic implantation model in nude mice. HOTTIP is an antisense lncRNA mapped to the distal end of the HOXA gene cluster. Knock‐down of HOTTIP significantly suppressed the expression of a number of HOXA genes. Furthermore, we identified miR‐125b as a post‐transcriptional regulator of HOTTIP. Ectopic expression of miR‐125b reduced HOTTIP‐coupled luciferase activity and suppressed the endogenous level of HOTTIP. Moreover, in human HCCs, HOTTIP expression negatively correlated with that of miR‐125b.
Conclusions
HOTTIP is a novel oncogenic lncRNA, which negatively regulated by miR‐125b. Overexpression of HOTTIP contributes to hepatocarcinogenesis by regulating the expression of its neighbouring protein‐coding genes.
Endometriosis is a disease in which the lining of the uterus (endometrium), shed at the time of menstruation, becomes established at sites such as the peritoneum and ovaries. These explants develop a ...rich blood supply that enables them to survive and grow. We hypothesized that inhibitors of angiogenesis would prevent this growth by disrupting sensitive vessels supplying endometriotic lesions. Vessels sensitive to angiogenic antagonism have few associations with pericyte cells. The vessels supplying human endometriotic lesions were immunohistochemically characterized and found to be predominantly pericyte free. A model in which human endometrium is implanted into nude mice was used to test the effects of two antagonists of the angiogenic growth factor, vascular endothelial cell growth factor A. Soluble truncated receptor (flt-1; P = 0.002) and an affinity-purified antibody to human vascular endothelial cell growth factor A (P = 0.03) significantly inhibited the growth of nude mouse explants. Pericyte-free vessels were shown to supply endometrial lesions in nude mice and were disrupted in lesions taken from soluble flt-1-treated mice. In summary, antiangiogenic agents inhibited the growth of explants in an in vivo model of endometriosis by disrupting the vascular supply, and this effect is likely to apply to the human disease. These findings suggest that antiangiogenic agents may provide a novel therapeutic approach for the treatment of endometriosis.
Gas–liquid reactions form the basis of our everyday lives, yet they still suffer poor reaction efficiency and are difficult to monitor in situ, especially at ambient conditions. Now, an inert ...gas–liquid reaction between aniline and CO2 is driven at 1 atm and 298 K by selectively concentrating these immiscible reactants at the interface between metal–organic framework and solid nanoparticles (solid@MOF). Real‐time reaction SERS monitoring and simulations affirm the formation of phenylcarbamic acid, which was previously undetectable because they are unstable for post‐reaction treatments. The solid@MOF ensemble gives rise to a more than 28‐fold improvement to reaction efficiency as compared to ZIF‐only and solid‐only platforms, emphasizing that the interfacial nanocavities in solid@MOF are the key to enhance the gas–liquid reaction. Our strategy can be integrated with other functional materials, thus opening up new opportunities for ambient‐operated gas–liquid applications.
Gas–liquid reactions form the basis of our lives, yet they suffer from poor reaction efficiency and are difficult to monitor in situ, especially at ambient conditions. An inert gas–liquid reaction between aniline and CO2 is driven at 1 atm and 298 K. Real‐time reaction monitoring was performed by selectively concentrating these immiscible reactants at the interface between metal–organic framework and solid nanoparticles.
Peptide IRW is the first food-derived angiotensin-converting enzyme 2 (ACE2) upregulator. This study aimed to investigate the pharmacokinetic characteristics of IRW and identify the metabolites ...contributing to its antihypertensive activity in spontaneously hypertensive rats (SHRs). Rats were administered 100 mg of IRW/kg of the body weight via an intragastric or intravenous route. The bioavailability (F %) was determined to be 11.7%, and the half-lives were 7.9 ± 0.5 and 28.5 ± 6.8 min for gavage and injection, respectively. Interestingly, significant blood pressure reduction was not observed until 1.5 h post oral administration, or 2 h post injection, indicating that the peptide’s metabolites are likely responsible for the blood pressure-lowering activity. Time-course metabolomics revealed a significant increase in the level of kynurenine, a tryptophan metabolite, in blood after IRW administration. Kynurenine increased the level of ACE2 in cells. Oral administration of tryptophan (W), but not dipeptide IR, lowered the blood pressure and upregulated aortic ACE2 in SHRs. Our study supports the key role of tryptophan and its metabolite, kynurenine, in IRW’s blood pressure-lowering effects.
Human ear morphology, a complex anatomical structure represented by a multidimensional set of correlated and heritable phenotypes, has a poorly understood genetic architecture. In this study, we ...quantitatively assessed 136 ear morphology traits using deep learning analysis of digital face images in 14,921 individuals from five different cohorts in Europe, Asia, and Latin America. Through GWAS meta-analysis and C-GWASs, a recently introduced method to effectively combine GWASs of many traits, we identified 16 genetic loci involved in various ear phenotypes, eight of which have not been previously associated with human ear features. Our findings suggest that ear morphology shares genetic determinants with other surface ectoderm-derived traits such as facial variation, mono eyebrow, and male pattern baldness. Our results enhance the genetic understanding of human ear morphology and shed light on the shared genetic contributors of different surface ectoderm-derived phenotypes. Additionally, gene editing experiments in mice have demonstrated that knocking out the newly ear-associated gene (Intu) and a previously ear-associated gene (Tbx15) causes deviating mouse ear morphology.
ER-positive (ER+ ) breast cancer includes all of the intrinsic molecular subtypes, although the luminal A and B subtypes predominate. In this study, we evaluated the ability of six clinically ...relevant genomic signatures to predict relapse in patients with ER+ tumors treated with adjuvant tamoxifen only.
Four microarray datasets were combined and research-based versions of PAM50 intrinsic subtyping and risk of relapse (PAM50-ROR) score, 21-gene recurrence score (OncotypeDX), Mammaprint, Rotterdam 76 gene, index of sensitivity to endocrine therapy (SET) and an estrogen-induced gene set were evaluated. Distant relapse-free survival (DRFS) was estimated by Kaplan–Meier and log-rank tests, and multivariable analyses were done using Cox regression analysis. Harrell's C-index was also used to estimate performance.
All signatures were prognostic in patients with ER+ node-negative tumors, whereas most were prognostic in ER+ node-positive disease. Among the signatures evaluated, PAM50-ROR, OncotypeDX, Mammaprint and SET were consistently found to be independent predictors of relapse. A combination of all signatures significantly increased the performance prediction. Importantly, low-risk tumors (>90% DRFS at 8.5 years) were identified by the majority of signatures only within node-negative disease, and these tumors were mostly luminal A (78%–100%).
Most established genomic signatures were successful in outcome predictions in ER+ breast cancer and provided statistically independent information. From a clinical perspective, multiple signatures combined together most accurately predicted outcome, but a common finding was that each signature identified a subset of luminal A patients with node-negative disease who might be considered suitable candidates for adjuvant endocrine therapy alone.
Primary graft dysfunction (PGD) is the leading cause of morbidity and mortality early after heart transplantation (HT). The International Consortium on PGD is a multicenter collaboration dedicated to ...identifying the clinical risk factors for PGD in the contemporary era of HT. The objectives of the current report were (1) to assess the incidence of severe PGD in an international cohort; (2) to evaluate the performance of the most strongly validated PGD risk tool, the RADIAL score, in a contemporary cohort; and (3) to redefine clinical risk factors for severe PGD in the current era of HT.
This is a retrospective, observational study of consecutive adult HT recipients between 2010 and 2020 in 10 centers in the United States, Canada and Europe. Patients with severe PGD were compared to those without severe PGD (comprising those with no, mild and moderate PGD). The RADIAL score was calculated for each transplant recipient. The discriminatory power of the RADIAL score was evaluated using receiver operating characteristic (ROC) analysis, and its calibration was assessed by plotting the percentage of PGD predicted vs that which was observed. To identify clinical risk factors associated with severe PGD, we performed multivariable mixed-effects logistic regression modeling to account for among-center variability.
A total of 2746 patients have been enrolled in the registry to date, including 2015 (73.4%) from North America, and 731 (26.6%) from Europe; 215 participants (7.8%) met the criteria for severe PGD. There was an increase in the incidence of severe PGD over the study period (P value for trend by difference sign test = 0.004). The Kaplan-Meier estimate for 1-year survival was 75.7% (95% CI 69.4–80.9%) in patients with severe PGD as compared to 94.4% (95% CI 93.5–95.2%) in those without severe PGD (log-rank P value < 0.001). The RADIAL score performed poorly in our contemporary cohort and was not associated with severe PGD; it had an AUC of 0.53 (95% CI 0.48–0.58). In the multivariable regression model, acute preoperative dialysis (OR 2.41, 95% CI 1.31–4.43), durable left ventricular assist device support (OR 1.77, 95% CI 1.13–2.77), and total ischemic time (OR 1.20 for each additional hour, 95% CI 1.02–1.41) were associated with an increased risk of severe PGD.
Our consortium has identified an increasing incidence of PGD in the modern transplant era. We identified contemporary risk factors for this early post-transplant complication, which confers a high mortality risk. These results may enable the identification of patients at high risk for developing severe PGD in order to inform peri-transplant donor and recipient management practices.
Background
The community prevalence of eating disorders among Chinese young women may now be similar to their western counterparts.
Aim
To investigate the prevalence of eating disorders (ED) in ...female university students in Wuhan, China, using a two-stage design.
Method
In stage one, 99.1 % (
N
= 8,444) of eligible students (
N
= 8,521) completed the eating disorder inventory-1 (EDI-1) and a survey of relevant anthropomorphic data. A total of 421 women scored above the cut-off for EDE-1, as defined by a set of criteria similar to those of Keski-Rahkonen (Int J Eat Disord 39:754–762,
2006
). 257 (61 %) of these case-positive women and a random sample of case-negative women (312 out of 8,023, 4 %) whose scores did not exceed the defined cut-off were interviewed using the eating disorder examination (EDE) and the structured clinical interview for DSM-IV axis I disorders (SCID-I).
Results
On interview with the SCID-I, 79 women were diagnosed with an ED. Among them, 10 had anorexia nervosa (AN), 21 bulimia nervosa (BN), and 48 binge eating disorder (BED) The results showed a prevalence rate of 1.05 % (95 % CI = 0.02–2.08) for AN, 2.98 % (95 % CI = 1.21–4.74) for BN, and 3.53 % (95 % CI = 1.75–5.30) for BED.
Conclusion
The prevalence of ED among female university students in China is now similar to that of their western counterparts, and BED is the most common ED followed by BN and AN similarly.
Drawing is a powerful tool that can be used to convey rich perceptual information about objects in the world. What are the neural mechanisms that enable us to produce a recognizable drawing of an ...object, and how does this visual production experience influence how this object is represented in the brain? Here we evaluate the hypothesis that producing and recognizing an object recruit a shared neural representation, such that repeatedly drawing the object can enhance its perceptual discriminability in the brain. We scanned human participants (
= 31; 11 male) using fMRI across three phases of a training study: during training, participants repeatedly drew two objects in an alternating sequence on an MR-compatible tablet; before and after training, they viewed these and two other control objects, allowing us to measure the neural representation of each object in visual cortex. We found that: (1) stimulus-evoked representations of objects in visual cortex are recruited during visually cued production of drawings of these objects, even throughout the period when the object cue is no longer present; (2) the object currently being drawn is prioritized in visual cortex during drawing production, while other repeatedly drawn objects are suppressed; and (3) patterns of connectivity between regions in occipital and parietal cortex supported enhanced decoding of the currently drawn object across the training phase, suggesting a potential neural substrate for learning how to transform perceptual representations into representational actions. Together, our study provides novel insight into the functional relationship between visual production and recognition in the brain.
Humans can produce simple line drawings that capture rich information about their perceptual experiences. However, the mechanisms that support this behavior are not well understood. Here we investigate how regions in visual cortex participate in the recognition of an object and the production of a drawing of it. We find that these regions carry diagnostic information about an object in a similar format both during recognition and production, and that practice drawing an object enhances transmission of information about it to downstream regions. Together, our study provides novel insight into the functional relationship between visual production and recognition in the brain.
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