Integrating Genome-Wide Polygenic Risk Scores With Nongenetic Models to Predict Surgical Site Infection After Total Knee Arthroplasty Using United Kingdom Biobank Data.

BACKGROUND: Prediction of the risk of developing surgical site infection (SSI) in patients following total knee arthroplasty (TKA) is of clinical importance. Genetic susceptibility is involved in developing TKA-related SSI. Previously reported models for predicting SSI were constructed using nongenetic risk factors without incorporating genetic risk factors. To address this issue, we performed a genome-wide association study (GWAS) using the UK Biobank database. METHODS: Adult patients who underwent primary TKA (n = 19,767) were analyzed and divided into SSI (n = 269) and non-SSI (n = 19,498) cohorts. Nongenetic covariates, including demographic data and preoperative comorbidities, were recorded. Genetic variants associated with SSI were identified by GWAS and included to obtain standardized polygenic risk scores (zPRS, an estimate of genetic risk). Prediction models were established through analyses of multivariable logistic regression and the receiver operating characteristic curve. RESULTS: There were 4 variants (rs117896641, rs111686424, rs8101598, and rs74648298) achieving genome-wide significance that were identified. The logistic regression analysis revealed 7 significant risk factors: increasing zPRS, decreasing age, men, chronic obstructive pulmonary disease, diabetes mellitus, rheumatoid arthritis, and peripheral vascular disease. The areas under the receiver operating characteristic curve were 0.628 and 0.708 when zPRS (model 1) and nongenetic covariates (model 2) were used as predictors, respectively. The areas under the receiver operating characteristic curve increased to 0.76 when both zPRS and nongenetic covariates (model 3) were used as predictors. A risk-prediction nomogram was constructed based on model 3 to visualize the relative effect of statistically significant covariates on the risk of SSI and predict the probability of developing SSI. Age and zPRS were the top 2 covariates that contributed to the risk, with younger age and higher zPRS associated with higher risks. CONCLUSIONS: Our GWAS identified 4 novel variants that were significantly associated with susceptibility to SSI following TKA. Integrating genome-wide zPRS with nongenetic risk factors improved the performance of the model in predicting SSI.

Cytokine and epigenetic regulation of programmed death-ligand 1 in stem cell differentiation and cancer cell plasticity.

Programmed death-ligand 1 (PD-L1), an immune checkpoint ligand, is recognized as a potential target for cancer immunotherapy as well as for the induction of transplantation tolerance. However, how the crosstalk between stem cell programming and cytokine signaling regulates PD-L1 expression during stem cell differentiation and cancer cell plasticity remains unclear. Herein, we reported that PD-L1 expression was regulated by SOX2 during embryonic stem cell (ESC) differentiation and lung cancer cell plasticity. PD-L1 was induced during ESC differentiation to fibroblasts and was downregulated during SOX2-mediated reprogramming of fibroblasts to induced pluripotent stem cells (iPSCs). Furthermore, SOX2 activation affected cancer cell plasticity and inhibited PD-L1 expression in lung cancer cells. We discovered that the H3K27ac signal at the PD-L1 locus was enhanced during ESC differentiation to fibroblasts as well as during cancer plasticity of SOX2-positive lung cancer cells to SOX2-negative counterparts. Romidepsin, an epigenetic modifier, induced PD-L1 expression in lung cancer cells, whereas TGF-ß stimulation downregulated SOX2 but upregulated PD-L1 expression in lung cancer cells. Furthermore, in addition to PD-L1, the expressions of EGFR and its ligand HBEGF were downregulated by activation of endogenous SOX2 expression during lung cancer cell plasticity and iPSC reprogramming, and the activation of EGFR signaling by HBEGF upregulated PD-L1 expression in lung cancer cells. Together, our results reveal the crosstalk between SOX2 programming and cytokine stimulation influences PD-L1 expression, and these findings may provide insights into PD-L1-mediated therapeutics.

A versatile method for dorsal-approach plantar plate repair using standard operative instruments.

BACKGROUND: The plantar plate is an important static stabilizer of the lesser metatarsophalangeal joints, and disruptions of the plantar plate can lead to significant instability and lesser toe deformities. In recent years, direct plantar plate repair has been proposed. Although direct repair via a dorsal approach is attractive, a torn plantar plate is small and difficult to access using regular instruments in a restricted operative field. METHODS: In this report, a unique method for plantar plate repairs was used to repair various configurations of plantar plate tears with standard operative instruments that are available in most operating rooms. RESULTS: Using this method, 10 patients underwent plantar plate repairs, and the mean follow-up period was 24 (range, 14-38) months. The mean visual analog scale score for pain preoperatively was 4.1 (range, 0-6) and decreased to 0.6 (range, 0-3) at last follow-up. Postoperatively, the mean visual analog scale score for satisfaction was 9.6 (range, 8-10) and the mean American Orthopedic Foot and Ankle Society forefoot score was 88.8 (range, 75-100). CONCLUSIONS: Our study proposes an inexpensive and versatile method for plantar plate repair via a dorsal approach that uses standard operative instruments. TRIAL REGISTRATION: ClinicalTrials.gov , NCT04949685 . July 2, 2021 - Retrospectively registered, LEVEL OF CLINICAL EVIDENCE: 4.

Predictive factors for glucocorticoid therapy in children with eosinophilic gastroenteritis. / å„¿ç«¥å—œé ¸æ€§ç²’ç»†èƒžæ€§èƒƒè‚ ç‚Žç³–çš®è´¨æ¿€ç´ æ²»ç–—çš„é¢„æµ‹å› ç´ åˆ†æž.

OBJECTIVES: To study the predictive factors for glucocorticoid therapy by analyzing the association between the clinical features and treatment regimens in children with eosinophilic gastroenteritis. METHODS: A retrospective analysis was performed on the medical data of 182 children with eosinophilic gastroenteritis who were admitted to Guangzhou Women and Children's Medical Center from January 2012 to December 2020. According to whether glucocorticoids were used, these children were divided into a glucocorticoid treatment group and a control group. The two groups were compared in terms of age, history of allergy, clinical symptoms, laboratory examination results, endoscopic findings, and pathological results of gastrointestinal mucosa. A multivariate logistic regression analysis was performed for the results with statistical significance. RESULTS: Of the 182 children, 36 (19.8%) received glucocorticoid therapy. The rates of hematochezia, anemia, and mucosal ulceration/luminal stenosis under endoscopy and the mucosal eosinophil infiltration count were significantly higher in the glucocorticoid treatment group than those in the control group (P<0.05). The serum albumin level in the glucocorticoid treatment group was significantly lower than that in the control group (P<0.05). The multivariate logistic regression analysis showed that mucosal ulceration/luminal stenosis under endoscopy (OR=10.830, 95%CI: 3.090-37.961, P<0.001) and the increased mucosal eosinophil infiltration count (OR=0.967, 95%CI: 0.941-0.993, P=0.015) were predictive factors for glucocorticoid therapy in children with eosinophil gastroenteritis. CONCLUSIONS: Mucosal ulceration/luminal stenosis under endoscopy or a significant increase in the mucosal eosinophil infiltration count based on pathology suggests that glucocorticoid therapy can be considered in children with eosinophil gastroenteritis.

Storage lipid studies in tuberculosis reveal that foam cell biogenesis is disease-specific.

Foam cells are lipid-laden macrophages that contribute to the inflammation and tissue damage associated with many chronic inflammatory disorders. Although foam cell biogenesis has been extensively studied in atherosclerosis, how these cells form during a chronic infectious disease such as tuberculosis is unknown. Here we report that, unlike the cholesterol-laden cells of atherosclerosis, foam cells in tuberculous lung lesions accumulate triglycerides. Consequently, the biogenesis of foam cells varies with the underlying disease. In vitro mechanistic studies showed that triglyceride accumulation in human macrophages infected with Mycobacterium tuberculosis is mediated by TNF receptor signaling through downstream activation of the caspase cascade and the mammalian target of rapamycin complex 1 (mTORC1). These features are distinct from the known biogenesis of atherogenic foam cells and establish a new paradigm for non-atherogenic foam cell formation. Moreover, they reveal novel targets for disease-specific pharmacological interventions against maladaptive macrophage responses.

Acute and Long-Term Effects of Mechanotherapy on the Outcome After an Achilles Repair: A Prospective Cohort Study With Historical Controls.

OBJECTIVES: To evaluate the effects of vibration on Achilles' tendon microcirculation and characteristics following surgical repair of Achilles' tendon rupture. DESIGN: Cohort study with historical controls. SETTING: A university institute. PARTICIPANTS: Participants (N=32), including 19 (16 men, 3 women; median [range] age: 43.0 [25.0-57.0] years) and 13 (10 men, 3 women; 44.00 [29.0-60.0] years) in the vibration (application to the ball of the foot, 30Hz, 2mm amplitude, 4kg pressure, and self-administration) and control groups, respectively, who underwent unilateral Achilles' tendon repairs were recruited. INTERVENTION: A 4-week vibration intervention in the vibration group. MAIN OUTCOME MEASUREMENTS: The tendon microcirculation was measured after the first session of vibration. The participants were evaluated repeatedly with bilateral follow-up measurements of tendon stiffness, 3 functional outcome tests, and a questionnaire survey. RESULTS: Acute effects of the vibration were observed immediately after the 5-minute vibration (P≤.001). Lower total hemoglobin and oxygen saturation were respectively observed (P=.043) in the repaired legs 3 and 6 months postsurgery in the vibration group as compared with the control group. The vibration group also showed greater tendon stiffness, heel raising height and hopping distance 3 or 6 months postoperation in both the repaired and noninjured legs (all P<.05). The microcirculatory characteristics 2 months postoperation were correlated with the outcomes at 6 months postoperation. CONCLUSIONS: Differences in microcirculatory characteristics and better rehabilitation outcomes were observed in the legs with an Achilles repair that underwent the early vibration intervention.

IMU Consensus Exception Detection with Dynamic Time Warping-A Comparative Approach.

A dynamic time warping (DTW) algorithm has been suggested for the purpose of devising a motion-sensitive microelectronic system for the realization of remote motion abnormality detection. In combination with an inertial measurement unit (IMU), the algorithm is potentially applicable for remotely monitoring patients who are at risk of certain exceptional motions. The fixed interval signal sampling mechanism has normally been adopted when devising motion detection systems; however, dynamically capturing the particular motion patterns from the IMU motion sensor can be difficult. To this end, the DTW algorithm, as a kind of nonlinear pattern-matching approach, is able to optimally align motion signal sequences tending towards time-varying or speed-varying expressions, which is especially suitable to capturing exceptional motions. Thus, this paper evaluated this kind of abnormality detection using the proposed DTW algorithm on the basis of its theoretical fundamentals to significantly enhance the viability of the methodology. To validate the methodological viability, an artificial neural network (ANN) framework was intentionally introduced for performance comparison. By incorporating two types of designated preprocessors, i.e., a DFT interpolation preprocessor and a convolutional preprocessor, to equalize the unequal lengths of the matching sequences, two kinds of ANN frameworks were enumerated to compare the potential applicability. The comparison eventually confirmed that the direct template-matching DTW is excellent in practical application for the detection of time-varying or speed-varying abnormality, and reliably captures the consensus exceptions.

Ultrasound-Guided Minimally Invasive Surgical Resection of Retrocalcaneal Bursitis: A Preliminary Comparison With Traditional Open Surgery.

Posterior heel pain is a common complaint that is often caused by overuse injuries. In such cases, the retrocalcaneal bursa is compressed and chafed repeatedly, leading to local inflammation. Sonography is a popular imaging tool used to study the pathology of soft tissues, and it can be used to assist in diagnosing bursitis because of its accuracy. Herein, we report an innovative method to treat retrocalcaneal bursitis under ultrasound guidance. Ten patients with posterior heel pain for >6 months who failed conservative treatment received this ultrasound-guided minimally invasive surgery. An endoscopic puncher and burr were inserted under ultrasound guidance via a stabbing wound, and the swollen retrocalcaneal bursa and bony prominence were resected. The patients were able to ambulate and undergo a rehabilitation program 2 weeks postoperatively. In the patients who underwent this ultrasound-guided minimally invasive surgery, both the average surgical time and average hospital stay were shorter than in those (n = 12) who underwent open surgery. In outcome rating assessment, the American Orthopaedic Foot & Ankle Society (AOFAS) pain score and total AOFAS ankle-hindfoot score were improved in the ultrasound-guided minimally invasive surgery group compared to the open surgery group at 2 months postoperatively. Other advantages included lesser wound pain, shorter hospital stay, faster recovery time, and minimal blood loss. Accordingly, ultrasound-guided surgery appears to be a good option for the treatment of retrocalcaneal bursitis.

Light Bulb Procedure for the Treatment of Tarsal Navicular Osteonecrosis After Failed Percutaneous Decompression: A Case Report.

Tarsal navicular osteonecrosis in adults is a rare condition with unclear etiology, and the optimal treatment has not been established. Here we report a case of tarsal navicular osteonecrosis with a complete course of treatment and comprehensive imaging studies starting at an early stage. A 37-year-old female diagnosed with tarsal navicular osteonecrosis was first treated with percutaneous decompression, but her symptoms persisted postoperatively. The tarsal navicular showed no further collapse, but follow-up magnetic resonance imaging (MRI) at 6 months postoperatively revealed persistent osteonecrotic changes. Debridement of the necrotic bone with preservation of the cortical shell and bone substitute packing for the defect (light bulb procedure) were performed. The symptoms resolved by 3 months postoperatively, and the patient could return to work. At a 6-year follow-up visit, the patient was free of symptoms, and MRI showed remodeling of the tarsal navicular without further collapse.

Fibroblast growth factor-transforming growth factor beta dialogues, endothelial cell to mesenchymal transition, and atherosclerosis.

PURPOSE OF REVIEW: Despite much effort, atherosclerosis remains an important public health problem, leading to substantial morbidity and mortality worldwide. The purpose of this review is to provide an understanding of the role of endothelial cell fate change in atherosclerosis process. RECENT FINDINGS: Recent studies indicate that a process known as endothelial-to-mesenchymal transition (EndMT) may play an important role in atherosclerosis development. Transforming growth factor beta (TGFß) has been shown to be an important driver of the endothelial cell phenotype transition. SUMMARY: The current review deals with the current state of knowledge regarding EndMT's role in atherosclerosis and its regulation by fibroblast growth factor (FGF)-TGFß cross-talk. A better understanding of FGF-TGFß signaling in the regulation of endothelial cell phenotypes is key to the development of novel therapeutic agents.

High-Resolution Shear Wave Imaging of the Human Cornea Using a Dual-Element Transducer.

Estimating the corneal elasticity can provide valuable information for corneal pathologies and treatments. Ophthalmologic pathologies will invariably cause changes to the elasticity of the cornea. For example, keratoconus and the phototoxic effects of ultraviolet radiation usually increase the corneal elasticity. This makes a quantitative estimation of the elasticity of the human cornea important for ophthalmic diagnoses. The present study investigated the use of a proposed high-resolution shear wave imaging (HR-SWI) method based on a dual-element transducer (comprising an 8-MHz element for pushing and a 32-MHz element for imaging) for measuring the group shear wave velocity (GSWV) of the human cornea. An empirical Young's modulus formula was used to accurately convert the GSWV to Young's modulus. Four quantitative parameters, bias, resolution, contrast, and contrast-to-noise ratio (CNR), were measured in gelatin phantoms with two different concentrations (3% and 7%) to evaluate the performance of HR-SWI. The biases of gelatin phantoms (3% and 7%) were 5.88% and 0.78%, respectively. The contrast and CNR were 0.76, 1.31 and 3.22, 2.43 for the two-side and two-layer phantoms, respectively. The measured image resolutions of HR-SWI in the lateral and axial directions were 72 and 140 µm, respectively. The calculated phase SWV (PSWV) and their corresponding Young's modulus from six human donors were 2.45 ± 0.48 m/s (1600 Hz) and 11.52 ± 7.81 kPa, respectively. All the experimental results validated the concept of HR-SWI and its ability for measuring the human corneal elasticity.

Estrogen and cigarette sidestream smoke particulate matter exhibit ERα-dependent tumor-promoting effects in lung adenocarcinoma cells.

Estrogen and secondhand smoke are key risk factors for nonsmoking female lung cancer patients who frequently have lung adenocarcinoma and show tumor estrogen receptor α (ERα) expression. We speculated that estrogen and secondhand smoke might cause harmful effects via ERα signaling. Our results showed that 17ß-estradiol (E2), the primary form of endogenous estrogen, exacerbated proliferation, migration, and granzyme B resistance of lung adenocarcinoma cells in an ERα-dependent manner. Cigarette sidestream smoke particulate matter (CSSP), the major component of secondhand smoke, could activate ERα activity dose dependently in human lung adenocarcinoma cells. The estrogenic activity of CSSP was abolished by an ERα-selective antagonist. CSSP regulated the nuclear entry, phosphorylation, and turnover of ERα similarly to E2. Furthermore, CSSP enhanced E2-stimulated ERα activity and Ser118 phosphorylation even when ERα became saturated with E2. Activation of ERα by CSSP required GSK3ß activity, but not involving polycyclic aromatic hydrocarbons, reactive oxygen species, calcium, epidermal growth factor receptor, and PI3K/Akt. Although CSSP possessed cytotoxicity, ERα-expressing cells grew and migrated faster than nonexpressing cells on recovery from CSSP exposure as observed in E2-pretreated cells. Knockdown of ERα by siRNA diminished E2- and CSSP-stimulated cell migration. Twenty-one genes, including SERPINB9, were identified to be upregulated by both E2 and CSSP via ERα. Increased SERPINB9 expression was accompanied with increased resistance to granzyme B-mediated apoptosis. This study demonstrates that estrogen has ERα-dependent tumor-promoting activity. CSSP acts like estrogen and shows a potential to enhance estrogen-induced ERα action.

Unraveling Drug Penetration of Echinocandin Antifungals at the Site of Infection in an Intra-abdominal Abscess Model.

Intra-abdominal candidiasis (IAC) is a prominent invasive fungal infection associated with high mortality. Prompt antifungal therapy and source control are crucial for successful treatment. Echinocandin antifungal drugs are first-line agents; however, their clinical effectiveness is highly variable, with known potential for breakthrough resistance, and little is known about drug exposure at the site of infection. Using matrix-assisted desorption ionization mass spectrometry imaging technology, we investigated the spatial and quantitative distribution in tissue lesions for two echinocandin drugs, micafungin and CD101, in a clinically relevant IAC mouse model. Drug accumulation within lesions was observed with both drugs at their humanized therapeutic doses. CD101, but not micafungin, accumulated in lesions at levels above the mutant prevention concentration of the infecting strain. These findings indicate that current echinocandin drugs are limited by penetration at the site of infection and have implications for clinical outcomes and emergence of resistance in patients with IAC.

Ethambutol Partitioning in Tuberculous Pulmonary Lesions Explains Its Clinical Efficacy.

Clinical trials and practice have shown that ethambutol is an important component of the first-line tuberculosis (TB) regime. This contrasts the drug's rather modest potency and lack of activity against nongrowing persister mycobacteria. The standard plasma-based pharmacokinetic-pharmacodynamic profile of ethambutol suggests that the drug may be of limited clinical value. Here, we hypothesized that this apparent contradiction may be explained by favorable penetration of the drug into TB lesions. First, we utilized novel in vitro lesion pharmacokinetic assays and predicted good penetration of the drug into lesions. We then employed mass spectrometry imaging and laser capture microdissection coupled to liquid chromatography and tandem mass spectrometry (LCM and LC/MS-MS, respectively) to show that ethambutol, indeed, accumulates in diseased tissues and penetrates the major human-like lesion types represented in the rabbit model of TB disease with a lesion-to-plasma exposure ratio ranging from 9 to 12. In addition, ethambutol exhibits slow but sustained passive diffusion into caseum to reach concentrations markedly higher than those measured in plasma at steady state. The results explain why ethambutol has retained its place in the first-line regimen, validate our in vitro lesion penetration assays, and demonstrate the critical importance of effective lesion penetration for anti-TB drugs. Our findings suggest that in vitro and in vivo lesion penetration evaluation should be included in TB drug discovery programs. Finally, this is the first time that LCM with LC-MS/MS has been used to quantify a small molecule at high spatial resolution in infected tissues, a method that can easily be extended to other infectious diseases.

Inhibition of the mTOR pathway in abdominal aortic aneurysm: implications of smooth muscle cell contractile phenotype, inflammation, and aneurysm expansion.

The development of effective pharmacological treatment of abdominal aortic aneurysm (AAA) potentially offers great benefit to patients with preaneurysmal aortic dilation by slowing the expansion of aneurysms and reducing the need for surgery. To date, therapeutic targets for slowing aortic dilation have had low efficacy. Thus, in this study, we aim to elucidate possible mechanisms driving aneurysm progression to identify potential targets for pharmacological intervention. We demonstrate that mechanistic target of rapamycin (mTOR) signaling is overactivated in aortic smooth muscle cells (SMCs), which contributes to murine AAA. Rapamycin, a typical mTOR pathway inhibitor, dramatically limits the expansion of the abdominal aorta following intraluminal elastase perfusion. Furthermore, reduction of aortic diameter is achieved by inhibition of the mTOR pathway, which preserves and/or restores the contractile phenotype of SMCs and downregulates macrophage infiltration, matrix metalloproteinase expression, and inflammatory cytokine production. Taken together, these results highlight the important role of the mTOR cascade in aneurysm progression and the potential application of rapamycin as a therapeutic candidate for AAA.NEW & NOTEWORTHY This study provides novel observations that mechanistic target of rapamycin (mTOR) signaling is overactivated in aortic smooth muscle cells and contributes to mouse abdominal aortic aneurysm (AAA) and that rapamycin protects against aneurysm development. Our data highlight the importance of preservation and/or restoration of the smooth muscle cell contractile phenotype and reduction of inflammation by mTOR inhibition in AAA.

Cholest-4-en-3-one attenuates TGF-ß responsiveness by inducing TGF-ß receptors degradation in Mv1Lu cells and colorectal adenocarcinoma cells.

PURPOSE: The transforming growth factor-beta (TGF-ß) pathway is an important in the initiation and progression of cancer. Due to a strong association between an elevated colorectal cancer risk and increase fecal excretion of cholest-4-en-3-one, we aim to determine the effects of cholest-4-en-3-one on TGF-ß signaling in the mink lung epithelial cells (Mv1Lu) and colorectal cancer cells (HT29) in vitro. METHODS: The inhibitory effects of cholest-4-en-3-one on TGF-ß-induced Smad signaling, cell growth inhibition, and the subcellular localization of TGF-ß receptors were investigated in epithelial cells using a Western blot analysis, luciferase reporter assays, DNA synthesis assay, confocal microscopy, and subcellular fractionation. RESULTS: Cholest-4-en-3-one attenuated TGF-ß signaling in Mv1Lu cells and HT29 cells, as judged by a TGF-ß-specific reporter gene assay of plasminogen activator inhibitor-1 (PAI-1), Smad2/3 phosphorylation and nuclear translocation. We also discovered that cholest-4-en-3-one suppresses TGF-ß responsiveness by increasing lipid raft and/or caveolae accumulation of TGF-ß receptors and facilitating rapid degradation of TGF-ß and thus suppressing TGF-ß-induced signaling. CONCLUSIONS: Our results suggest that cholest-4-en-3-one inhibits TGF-ß signaling may be due, in part to the translocation of TGF-ß receptor from non-lipid raft to lipid raft microdomain in plasma membranes. Our findings also implicate that cholest-4-en-3-one may be further explored for its potential role in colorectal cancer correlate to TGF-ß deficiency.

Sclerosing mesenteritis in a 5-year-old Chinese boy: a case report.

BACKGROUND: Sclerosing mesenteritis is a rare fibroinflammatory disorder of unknown etiology that primarily affects the mesentery of the small intestine during late adult life. Only about twenty pediatric cases have been reported to date, but none has been reported in Chinese children. CASE PRESENTATION: A 5-year-old Chinese male presented with a 4-week history of recurrent bloating, abdominal pain, anorexia and vomiting. On admission, physical examination showed a severely distended abdomen. Biochemical investigations showed a slightly increased C-reactive protein, and normal serum levels of electrolytes and erythrocyte sedimentation rate. An abdominal film showed small intestine obstruction and massive ascites. An exploratory laparotomy revealed widespread inflammatory fibrotic adhesions between the bowel and the abdominal wall, thickening of the small bowel and massive ascites. During a prolonged hospital course, a 2nd surgery (4 months after 1st exploratory laparotomy) was performed in order to close the ileostomy and revealed that the bowel was still severely edematous, with very tight adhesions between the bowel and the abdominal wall. Histopathological examination of excised mesentery and nodules showed chronic inflammatory cell infiltration, fat necrosis and fibrosis. A diagnosis of sclerosing mesenteritis was finally established. Prednisolone at 2 mg/kg was started and he experienced rapid clinical improvement in 4 weeks. CONCLUSIONS: Sclerosing mesenteritis is extremely rare in children and often misdiagnosed due to its nonspecific clinical manifestation. It is important to be aware of sclerosing mesenteritis when evaluating a child with intractable abdominal pain, bloating, intestinal obstruction and massive ascites.

The docking protein FRS2α is a critical regulator of VEGF receptors signaling.

Vascular endothelial growth factors (VEGFs) signal via their cognate receptor tyrosine kinases designated VEGFR1-3. We report that the docking protein fibroblast growth factor receptor substrate 2 (FRS2α) plays a critical role in cell signaling via these receptors. In vitro FRS2α regulates VEGF-A and VEGF-C-dependent activation of extracellular signal-regulated receptor kinase signaling and blood and lymphatic endothelial cells migration and proliferation. In vivo endothelial-specific deletion of FRS2α results in the profound impairment of postnatal vascular development and adult angiogenesis, lymphangiogenesis, and arteriogenesis. We conclude that FRS2α is a previously unidentified component of VEGF receptors signaling.

Protective effect of Co-enzyme Q10 On doxorubicin-induced cardiomyopathy of rat hearts.

Q10 is a powerful antioxidant often used in medical nutritional supplements for cancer treatment. This study determined whether Q10 could effectively prevent cardio-toxicity caused by doxorubicin treatment. Four week old SD rats were segregated into groups namely control, doxorubicin group (challenged with doxorubicin), Dox + Q10 group (with doxorubicin challenge and oral Q10 treatment), and Q10 group (with oral Q10 treatment). Doxorubicin groups received IP doxorubicin (2.5 mg/kg) every 3 days and Q10 groups received Q10 (10 mg/kg) every day. Three weeks of doxorubicin challenge caused significant reduction in heart weight, disarray in cardiomyocyte arrangement, elevation of collagen accumulation, enhancement of fibrosis and cell death associated proteins, and inhibition of survival proteins. However, Q10 effectively protected cardiomyocytes and ameliorated fibrosis and cell death induced by doxorubicin. Q10 is, therefore, evidently a potential drug to prevent heart damage caused by doxorubicin. © 2016 Wiley Periodicals, Inc. Environ Toxicol 32: 679-689, 2017.

A Small Dibromotyrosine Derivative Purified From Pseudoceratina Sp. Suppresses TGF-ß Responsiveness by Inhibiting TGF-ß Type I Receptor Serine/Threonine Kinase Activity.

For clinical application, there is a great need for small-molecule inhibitors (SMIs) that could control pathogenic effects of transforming growth factor (TGF-ß) and/or modulate effects of TGF-ß in normal responses. Selective SMIs of the TGF-ß signaling pathway developed for therapeutics will also be powerful tools in experimentally dissecting this complex pathway, especially its cross-talk with other signaling pathways. In this study, we characterized (1'R,5'S,6'S)-2-(3',5'-dibromo-1',6'-dihydroxy-4'-oxocyclohex-2'-enyl) acetonitrile (DT), a member of a new class of small-molecule inhibitors related to bromotyrosine derivate from Pseudoceratina sp., which inhibits the TGF-ß type I receptor serine/threonine kinase known as activin receptor-like kinase (ALK) 5. The inhibitory effects of DT on TGF-ß-induced Smad signaling and epithelial-to-mesenchymal transition (EMT) were investigated in epithelial cells using in vitro kinase assay, luciferase reporter assays, immunoblotting, confocal microscopy, and wound healing assays. The novel ALK5 inhibitor, DT, inhibited the TGF-ß-stimulated transcriptional activations of 3TP-Lux. In addition, DT decreased phosphorylated Smad2/3 levels and the nuclear translocation of Smad2/3 increased by TGF-ß. In addition, DT inhibited TGF-ß-induced EMT and wound healing of A549 cells. Our results suggest that DT is a potential therapeutic agent for fibrotic disease and cancer treatment. J. Cell. Biochem. 117: 2800-2814, 2016. © 2016 Wiley Periodicals, Inc.