The deficiency of hepcidin, the hormone that controls iron absorption and its tissue distribution, is the cause of iron overload in nearly all forms of hereditary hemochromatosis and in untransfused ...iron-loading anemias. In a recent study, we reported the development of minihepcidins, small drug-like hepcidin agonists. Here we explore the feasibility of using minihepcidins for the prevention and treatment of iron overload in hepcidin-deficient mice. An optimized minihepcidin (PR65) was developed that had superior potency and duration of action compared with natural hepcidin or other minihepcidins, and favorable cost of synthesis. PR65 was administered by subcutaneous injection daily for 2 weeks to iron-depleted or iron-loaded hepcidin knockout mice. PR65 administration to iron-depleted mice prevented liver iron loading, decreased heart iron levels, and caused the expected iron retention in the spleen and duodenum. At high doses, PR65 treatment also caused anemia because of profound iron restriction. PR65 administration to hepcidin knockout mice with pre-existing iron overload had a more moderate effect and caused partial redistribution of iron from the liver to the spleen. Our study demonstrates that minihepcidins could be beneficial in iron overload disorders either used alone for prevention or possibly as adjunctive therapy with phlebotomy or chelation.
Tradicionalmente se ha considerado el desarrollo como algo positivo que generaba una mayor riqueza y bienestar para las personas y las comunidades. Era una visión que partía del supuesto que el ...desarrollo, por sí mismo, impulsaba mayores cotas de bienestar y equidad. Este modelo, sustentado solo en la generación de riqueza económica, parece estar construyendo espacios de marginación y exclusión social. En el artículo quiero plantear, a partir de un caso concreto y sus consecuencias para unas personas concretas, como el desarrollo puede impulsar situaciones de abandono escolar y desarraigo social. Tras la presentación y discusión del caso, concluiré señalando como es preciso estudiar el desarrollo desde la perspectiva del cambio y repensarlo para que sea acompañado de propuestas educativas que garanticen a las personas la comprensión de los procesos en los que están inmersas y su participación en los mismos.
In response to iron loading, hepcidin synthesis is homeostatically increased to limit further absorption of dietary iron and its release from stores. Mutations in HFE, transferrin receptor 2 (Tfr2), ...hemojuvelin (HJV), or bone morphogenetic protein 6 (BMP6) prevent appropriate hepcidin response to iron, allowing increased absorption of dietary iron, and eventually iron overload. To understand the role each of these proteins plays in hepcidin regulation by iron, we analyzed hepcidin messenger RNA (mRNA) responsiveness to short and long‐term iron challenge in iron‐depleted Hfe, Tfr2, Hjv, and Bmp6 mutant mice. After 1‐day (acute) iron challenge, Hfe−/− mice showed a smaller hepcidin increase than their wild‐type strain‐matched controls, Bmp6−/− mice showed nearly no increase, and Tfr2 and Hjv mutant mice showed no increase in hepcidin expression, indicating that all four proteins participate in hepcidin regulation by acute iron changes. After a 21‐day (chronic) iron challenge, Hfe and Tfr2 mutant mice increased hepcidin expression to nearly wild‐type levels, but a blunted increase of hepcidin was seen in Bmp6−/− and Hjv−/− mice. BMP6, whose expression is also regulated by iron, may mediate hepcidin regulation by iron stores. None of the mutant strains (except Bmp6−/− mice) had impaired BMP6 mRNA response to chronic iron loading. Conclusion: TfR2, HJV, BMP6, and, to a lesser extent, HFE are required for the hepcidin response to acute iron loading, but are partially redundant for hepcidin regulation during chronic iron loading and are not involved in the regulation of BMP6 expression. Our findings support a model in which acute increases in holotransferrin concentrations transmitted through HFE, TfR2, and HJV augment BMP receptor sensitivity to BMPs. A distinct regulatory mechanism that senses hepatic iron may modulate hepcidin response to chronic iron loading. (HEPATOLOGY 2011;)
The myeloma surface proteome (surfaceome) determines tumor interaction with the microenvironment and serves as an emerging arena for therapeutic development. Here, we use glycoprotein capture ...proteomics to define the myeloma surfaceome at baseline, in drug resistance, and in response to acute drug treatment. We provide a scoring system for surface antigens and identify CCR10 as a promising target in this disease expressed widely on malignant plasma cells. We engineer proof-of-principle chimeric antigen receptor (CAR) T-cells targeting CCR10 using its natural ligand CCL27. In myeloma models we identify proteins that could serve as markers of resistance to bortezomib and lenalidomide, including CD53, CD10, EVI2B, and CD33. We find that acute lenalidomide treatment increases activity of MUC1-targeting CAR-T cells through antigen upregulation. Finally, we develop a miniaturized surface proteomic protocol for profiling primary plasma cell samples with low inputs. These approaches and datasets may contribute to the biological, therapeutic, and diagnostic understanding of myeloma.
The aim of this article is to describe the surgical techniques for the treatment of hilar cholangiocarcinoma(HC).Resection with microscopically negative margin(R0) is the only way to cure patients ...with HC.Today,resection of the caudate lobe and part of segment Ⅳ,combined with a right or left hepatectomy,bile duct resection,lymphadenectomy of the hepatic hilum and sometimes vascular resection,is the standard surgical procedure for HC.Intraoperative frozen-section examination of proximal and distal biliary margins is necessary to confirm the suitability of resection.Although lymphadenectomy probably has little direct effect on survival,inaccurate staging information may influence post resection treatment recommendations.Aggressive venous and arterial resections should be undertaken in selected cases to achieve a R0 resection.The concept of "no-touch proposed" in 1999 by Neuhaus et al combine an extended right hepatectomy with systematic portal vein resection and caudate lobectomy avoiding hilar dissection and possible intraoperative microscopic dissemination of cancer cells.More recently minor liver resections have been proposed for treatment of HC.As the hilar bifurcation of the bile ducts is near to liver segments Ⅳ,Ⅴ and Ⅰ,adequate liver resection of these segments together with the bile ducts can result in cure.
Despite the advances in the pharmacological treatment of inflammatory bowel disease (IBD), the rate of surgical interventions remains high. These are typically associated with a high morbidity. The ...aims of the study were to assess the postoperative complications of emergency surgery in patients with IBD and to describe factors that may affect its occurrence. A case series analysis of consecutive patients who underwent emergency surgery due to inflammatory bowel disease from December 1991 and December 2020 was conducted. Sixty-five patients were included. The most common cause of surgery was intestinal perforation, and total colectomy was the most common procedure. Morbidity events occurred in 41 patients; twenty-six patients required staying in the intensive care unit, and the median length of stay was 20 days. Multivariate analysis identified the use of intraoperative vasopressors as a risk factor for perioperative morbidity, for length of stay (LOS) ≥ 14 days, and for postoperative mortality. The ROC analysis showed an intraoperative blood loss ≥ 275 mL with a sensitivity of 78.38% and specificity of 52.17% for LOS > 14 days and a platelet to lymphocyte ratio ≥ 289.93 with a sensitivity of 70.59% and specificity of 60.87% for the same outcome. Emergency surgery in IBD has a significant morbidity rate. Intraoperative vasopressor use was found as a risk factor for the development of morbid events, prolonged LOS, and postoperative mortality. Age and intraoperative blood loss, as well as the platelet to lymphocyte ratio, serve as significant categorical predictors for postoperative outcomes.
The purposes of our study were to describe the distribution of diagnoses in a series of 273 patients over 65 years of age who presented for neck masses and to identify semiological features ...associated with malignancy.
Neck masses were categorized as congenital lesions (n = 7, 3%, 95% CI: 1%- 5%), inflammatory masses (n = 67, 25%, 95% CI: 19%- 30%), benign neoplasms (n = 77, 28%, 95% CI: 23%- 34%), and malignant neoplasms (n = 87, 32%, 95% CI: 26%- 38%).
A group of patients had discontinued care and, consequently, a definitive diagnosis could not be reached (n = 35, 12%). Age (OR 1.06, 95% CI 1.00-1.12), male sex (OR 2.35, 95% CI 1.11-4.96), prior history of cancer (OR 2.66, 95% CI 1.02-6.92), mass fixation to skin or deep tissues (OR 4.87, 95% CI 2.20-10.76), and the involvement of multiple cervical lymph node levels (OR 4.15, 95% CI 1.64-10.51) were identified as semiological features associated with malignancy.
In the case of a neck mass in an elderly patient, its neoplastic origin should be strongly suspected.
PDF
