Clinical Outcomes of Breast-Conserving Surgery with Synchronous 50-kV X-ray Intraoperative Partial Breast Irradiation in Patients Aged 64 Years or Older with Low-Risk Breast Cancer.

Background: Breast-conserving surgery with synchronous 50-kV X-ray intraoperative radiation therapy (TARGIT-IORT) is a convenient form of partial breast irradiation; however, the existing literature supports a wide range of local control rates. Objectives: We investigated the treatment effectiveness and toxic effects of TARGIT-IORT in a patient cohort aged 64 years or older with low-risk breast cancer. Design: Retrospective analysis. Methods: Patients who received breast-conserving surgery with synchronous TARGIT-IORT at a single institution from 2016 to 2019 were reviewed. Additional whole breast irradiation was recommended at the discretion of the treating radiation oncologist. Baseline patient demographics and treatment details were recorded. Acute and chronic toxicities, measured using the Common Terminology Criteria for Adverse Events version 3.0 or 4.0 and breast cosmetic outcomes, using the Harvard Cosmesis score, were recorded. Locoregional recurrence, distant metastasis, and overall survival were recorded, and 5-year rates were estimated using the Kaplan-Meier method. Results: 61 patients were included with a median follow-up of 3.5 years and median age of 72 years. Eight (13%) patients received additional whole breast irradiation, and fifty-four (89%) received adjuvant hormone therapy. There were no local, regional, or distance recurrences. One patient died of complications from COVID-19 infection. Grade 2 + acute and chronic toxicities were observed in 6 (12%) and 7 (14%) patients, respectively. One patient experienced a grade 3 acute toxicity. Cosmetic outcome was "excellent" or "good" in 45 (92%) patients. Conclusions: Breast TARGIT-IORT was well tolerated and conferred excellent disease control in this cohort of patients with low-risk breast cancer. While continued follow-up is required, TARGIT-IORT may be an appropriate treatment option for this population.

Activin E-ACVR1C cross talk controls energy storage via suppression of adipose lipolysis in mice.

Body fat distribution is a heritable risk factor for cardiovascular and metabolic disease. In humans, rare Inhibin beta E (INHBE, activin E) loss-of-function variants are associated with a lower waist-to-hip ratio and protection from type 2 diabetes. Hepatic fatty acid sensing promotes INHBE expression during fasting and in obese individuals, yet it is unclear how the hepatokine activin E governs body shape and energy metabolism. Here, we uncover activin E as a regulator of adipose energy storage. By suppressing ß-agonist-induced lipolysis, activin E promotes fat accumulation and adipocyte hypertrophy and contributes to adipose dysfunction in mice. Mechanistically, we demonstrate that activin E elicits its effect on adipose tissue through ACVR1C, activating SMAD2/3 signaling and suppressing PPARG target genes. Conversely, loss of activin E or ACVR1C in mice increases fat utilization, lowers adiposity, and drives PPARG-regulated gene signatures indicative of healthy adipose function. Our studies identify activin E-ACVR1C as a metabolic rheostat promoting liver-adipose cross talk to restrain excessive fat breakdown and preserve fat mass during prolonged fasting, a mechanism that is maladaptive in obese individuals.

Biomechanical comparison of suture-button, bioabsorbable screw, and metal screw for ankle syndesmotic repair: A meta-analysis.

BACKGROUND: To compare biomechanically metal screw fixation to suture-button or bioabsorbable screw fixation for ankle syndesmotic injuries. METHODS: A literature search of the comparison studies in Pubmed and Google Scholar was conducted. The biomechanical outcomes of interest were syndesmotic stability in the coronal, sagittal, and axial planes as well as torque and rotation at failure. RESULTS: A total of 11 cadaveric studies were included. In the suture-button group, coronal displacement (MD 1.72mm, p = 0.02) and sagittal displacement (MD 2.65mm, p = 0.0003) were increased relative to the metal screw group. In contrast, no difference was found with axial rotation (MD 0.35 degrees, p = 0.57). Bioabsorbable screws exhibited equivalent failure torque (MD -3.04Nm, p = 0.53) and rotation at failure (MD 3.77 degrees, p = 0.48) in comparison to metal screws. CONCLUSIONS: Suture-button provide less rigidity when compared to metal screw fixation. They afford flexible syndesmotic micromotion which may more closely resemble a physiological state and be helpful for ligament healing. Bioabsorbable screws demonstrate similar mechanical strength properties to metal screws.

Angiopoietin-like protein 3 governs LDL-cholesterol levels through endothelial lipase-dependent VLDL clearance.

Angiopoietin-like protein (ANGPTL)3 regulates plasma lipids by inhibiting LPL and endothelial lipase (EL). ANGPTL3 inactivation lowers LDL-C independently of the classical LDLR-mediated pathway and represents a promising therapeutic approach for individuals with homozygous familial hypercholesterolemia due to LDLR mutations. Yet, how ANGPTL3 regulates LDL-C levels is unknown. Here, we demonstrate in hyperlipidemic humans and mice that ANGPTL3 controls VLDL catabolism upstream of LDL. Using kinetic, lipidomic, and biophysical studies, we show that ANGPTL3 inhibition reduces VLDL-lipid content and size, generating remnant particles that are efficiently removed from the circulation. This suggests that ANGPTL3 inhibition lowers LDL-C by limiting LDL particle production. Mechanistically, we discovered that EL is a key mediator of ANGPTL3's novel pathway. Our experiments revealed that, although dispensable in the presence of LDLR, EL-mediated processing of VLDL becomes critical for LDLR-independent particle clearance. In the absence of EL and LDLR, ANGPTL3 inhibition perturbed VLDL catabolism, promoted accumulation of atypical remnants, and failed to reduce LDL-C. Taken together, we uncover ANGPTL3 at the helm of a novel EL-dependent pathway that lowers LDL-C in the absence of LDLR.

ANGPTL8 Blockade With a Monoclonal Antibody Promotes Triglyceride Clearance, Energy Expenditure, and Weight Loss in Mice.

Angiopoietin-like protein (ANGPTL)8 is a negative regulator of lipoprotein lipase-mediated plasma triglyceride (TG) clearance. In this study, we describe a fully human monoclonal antibody (REGN3776) that binds monkey and human ANGPTL8 with high affinity. Inhibition of ANGPTL8 with REGN3776 in humanized ANGPTL8 mice decreased plasma TGs and increased lipoprotein lipase activity. Additionally, REGN3776 reduced body weight and fat content. The reduction in body weight was secondary to increased energy expenditure. Finally, single administration of REGN3776 normalized plasma TGs in dyslipidemic cynomolgus monkeys. In conclusion, we show that blockade of ANGPTL8 with monoclonal antibody strongly reduced plasma TGs in mice and monkeys. These data suggest that inhibition of ANGPTL8 may provide a new therapeutic avenue for the treatment of dyslipidemia with beneficial effects on body weight.

A Timely Intervention: Endoscopic Retrieval of a Swallowed Magnetized Activity Watch.

The accidental ingestion of a foreign object often presents a difficult scenario for the clinician. This includes not only the decision to retrieve the material but also the appropriate technique to use. We present the case of a young asymptomatic girl who swallowed a magnetic activity watch, which was then successfully retrieved with an endoscopic snare. To our knowledge, this is the first documented case of salvaging an operational watch from the stomach using an endoscopic technique.

TBX5 genetic testing validates strict clinical criteria for Holt-Oram syndrome.

Holt-Oram syndrome (HOS) is an autosomal dominant heart-hand syndrome characterized by congenital heart disease (CHD) and upper limb deformity, and caused by mutations in the TBX5 gene. To date, the sensitivity of TBX5 genetic testing for HOS has been unclear. We now report mutational analyses of a nongenetically selected population of 54 unrelated individuals who were consecutively referred to our center with a clinical diagnosis of HOS. TBX5 mutational analyses were performed in all individuals, and clinical histories and findings were reviewed for each patient without reference to the genotypes. Twenty-six percent of the complete cohort was shown to have mutations of the TBX5 gene. However, among those subjects for whom clinical review demonstrated that their presentations met strict diagnostic criteria for HOS, TBX5 mutations were identified in 74%. No mutations were identified in those subjects who did not meet these criteria. Thus, these studies validate our clinical diagnostic criteria for HOS including an absolute requirement for preaxial radial ray upper limb malformation. Accordingly, TBX5 genotyping has high sensitivity and specificity for HOS if stringent diagnostic criteria are used in assigning the clinical diagnosis.

Angiotensin II stimulates alpha3(IV) collagen production in mouse podocytes via TGF-beta and VEGF signalling: implications for diabetic glomerulopathy.

BACKGROUND: The podocyte is bathed in an angiotensin II (AngII)-rich ultrafiltrate, but the impact of AngII on podocyte pathobiology is not well known. Because podocytes play a direct role in the glomerular basement membrane (GBM) thickening of diabetes, the alpha3(IV) collagen chain was examined. Podocyte expression of alpha3(IV) collagen may involve the transforming growth factor-beta (TGF-beta) and vascular endothelial growth factor (VEGF) systems. METHODS: Cultured mouse podocytes were treated with various doses of AngII for selected periods of time, with or without inhibitors of TGF-beta and VEGF signalling, SB-431542 and SU5416, respectively. TGF-beta1 and VEGF were assayed by enzyme-linked immunosorbent assay (ELISA); alpha3(IV) collagen, TGF-beta type II receptor and phospho-Smad2 were assayed by immunoblotting. RESULTS: AngII >or=10(-10) M was found to stimulate the production of alpha3(IV) collagen significantly in as short a time as 3 h. The expression of alpha3(IV) collagen was influenced by the TGF-beta system, but AngII did not increase the podocyte's production of TGF-beta1 ligand; rather, it increased the expression of the TGF-beta type II receptor and activated the TGF-beta signalling system through Smad2. Despite the TGF-beta receptor upregulation, synergy between AngII and TGF-beta1 to boost alpha3(IV) collagen production was not observed. However, blockade of TGF-beta signalling with SB-431542 prevented AngII from stimulating alpha3(IV) collagen production. Podocyte expression of alpha3(IV) collagen was also increased by the autocrine activity of VEGF. Podocytes were stimulated to secrete VEGF by 10(-10) M or higher AngII after 48 h. Blockade of the endogenous VEGF activity by SU5416 prevented AngII-stimulated alpha3(IV) collagen production. CONCLUSIONS: AngII stimulates the podocyte to produce alpha3(IV) collagen protein via mechanisms involving TGF-beta and VEGF signalling. Alterations in alpha3(IV) collagen production may contribute to GBM thickening and perhaps proteinuria in diabetes.

Podocyte-derived vascular endothelial growth factor mediates the stimulation of alpha3(IV) collagen production by transforming growth factor-beta1 in mouse podocytes.

Podocyte-derived vascular endothelial growth factor (VEGF) is upregulated in diabetes and may contribute to albuminuria. Although believed to act upon the glomerular endothelium, VEGF may have pronounced effects on the podocyte itself. The functionality of this VEGF autocrine loop was investigated in conditionally immortalized mouse podocytes. Exogenous VEGF(164) increased the production of alpha3(IV) collagen, an integral component of the glomerular basement membrane (GBM); this effect was completely prevented by SU5416, a pan-VEGF receptor inhibitor. The VEGF inhibitor also partially prevented the stimulation of alpha3(IV) collagen by transforming growth factor (TGF)-beta1, establishing a novel role for endogenous VEGF. However, VEGF did not influence the production of another novel chain of collagen IV, alpha5(IV) collagen, and SU5416 failed to reverse the known inhibitory effect of TGF-beta1 on alpha5(IV) collagen production. Cultured mouse podocytes possess at least the VEGFR-1 receptor, confirmed by RT-PCR, immunoblotting, and immunocytochemistry. By these techniques, however, VEGFR-2 is absent. VEGF signaling proceeds via autophosphorylation of VEGFR-1 and activation of the phosphatidylinositol 3-kinase (PI3K) pathway. Thus, podocyte-derived VEGF operates in an autocrine loop, likely through VEGFR-1 and PI3K, to stimulate alpha3(IV) collagen production. The TGF-beta1-stimulated endogenous VEGF may have significant implications for podocyte dysfunction in diabetic glomerulopathy, manifesting as GBM thickening and altered macromolecular permeability.

Cultured tubule cells from TGF-beta1 null mice exhibit impaired hypertrophy and fibronectin expression in high glucose.

BACKGROUND: To firmly establish the role of the transforming growth factor-beta1 (TGF-beta1) isoform in the pathophysiology of diabetic tubulointerstitial hypertrophy and fibrosis, we examined how the total absence of TGF-beta1 would alter the effect of high glucose on cellular hypertrophy and matrix expression in tubuloepithelial cells cultured from TGF-beta1 null mice. METHODS: Primary tubule cell cultures, obtained from kidneys of TGF-beta1 knockout mice and their wild-type littermates, were treated with exogenous TGF-beta1 or high glucose. The TGF-beta system was characterized at the ligand and receptor levels using Northern and Western blotting. Cellular hypertrophy and growth were assessed by thymidine incorporation, cell counting, leucine incorporation, and protein content. Fibronectin expression was assessed by Northern analysis and enzyme-linked immunosorbent assay (ELISA). RESULTS: Knockout cells did not express TGF-beta1 but did express TGF-beta2, TGF-beta3, and TGF-beta type I and type II receptors. Exogenous TGF-beta1 down-regulated the ligand-binding type II receptor but up-regulated type I receptor expression. Knockout cells proliferated more rapidly than wild-type cells, but restoring TGF-beta1 to knockout cells slowed their proliferation. In wild-type cells, high glucose caused cellular hypertrophy, evidenced by greater leucine incorporation and protein content along with decreased thymidine incorporation. High glucose also increased fibronectin message and protein. However, in knockout cells, high glucose failed to induce hypertrophy and was severely limited in its capacity to stimulate fibronectin. CONCLUSION: In tubular epithelial cells, TGF-beta1 mediates the hypertrophic and fibronectin-stimulatory effects of high glucose, confirming the role of the TGF-beta1 isoform in the pathogenesis of diabetic tubular hypertrophy and fibronectin overexpression.

Diltiazem co-treatment in renal transplant patients receiving microemulsion cyclosporin.

BACKGROUND: Usage of cyclosporin (the Hong Kong Hospital Authority's single largest item of drug expenditure) continues to increase, mainly due to increasing numbers of renal allograft patients taking it as long-term antirejection therapy. Diltiazem, an antihypertensive agent, interferes with the first pass extraction of oral cyclosporin, thus serving to conserve its dosage. AIMS: In renal transplant patients, to assess whether diltiazem co-treatment could achieve worthwhile dosage conservation of Neoral (a relatively new microemulsified cyclosporin formulation), safely. METHODS: A randomized, placebo-controlled, double-blind clinical trial was undertaken at three local hospitals. Renal transplant recipients receiving Neoral as prophylactic immunosuppression were randomized to two treatment arms. Active treatment consisted of diltiazem tablets 30 or 60 mg twice daily for patients weighing < 60 or >or= 60 kg, respectively. One hundred and ten eligible patients gave their informed consent, and were followed up for at least six months. The mean difference in the dollar cost in the sixth month was the primary outcome. Secondary/ancillary outcomes included changes in cyclosporin dosage and blood level, and untoward clinical events including rejection. Outcomes were evaluated by intention to treat analyses. RESULTS: During weeks 23-26 (sixth month) post randomization, diltiazem co-treatment yielded an estimated average cost saving per patient on drugs of 15%[the 95% confidence interval (CI) of the difference being HK dollars 609 +/- 517 or pound 50 +/- 42], with no apparent excess of untoward or adverse events, complications, hospitalization, outpatient visits, or inferior quality of life. CONCLUSIONS: This diltiazem co-treatment regime applied to the nearly 1800 surviving renal allograft patients followed up in Hospital Authority hospitals could have saved approximately HK dollars 14.3 million ( pound 1.17 million) annually, without adverse sequelae.