Lymphomatoid Papulosis Type D in a Mestizo-Ancestry Man.

ABSTRACT: Lymphomatoid papulosis (LyP) belongs to the CD30+ skin lymphoproliferative disorders; it is defined as a chronic, recurrent, self-healing eruption of papules and small nodules with the histopathologic features of a cutaneous T-cell lymphoma. It is classified according to histopathology into subtypes A to F and with chromosomal rearrangement 6p25.3. Type D is characterized by epidermotropism of atypical CD8+ and CD30+ lymphocytes, small to medium size, forming papules and nodules with erosion and necrosis, which represents a formidable challenge in the differential diagnosis with aggressive cutaneous cytotoxic lymphomas. We present the clinical case of a 22-year-old man with subacute dermatosis, who underwent a skin biopsy with a report of LyP. Immunohistochemistry showed negative CD4, CD5, granzyme-B markers and positive CD3, CD30, CD8, CD56, and (T-cell intracellular antigen 1) TIA-1 markers, concluding the diagnosis of type D LyP. The course of the disease is recurrent; however, the prognosis is good with a 10-year survival of 100%. We present the case of a mestizo-ancestry patient who developed a type-D LyP, and, to the best of our knowledge, there are no publications of type D LyP from Latin-American authors or about mestizo-ancestry (or hispanic) patients; therefore, we consider of relevance to inform about these findings.

Primary cilia as a targetable node between biliary injury, senescence and regeneration in liver transplantation.

BACKGROUND & AIMS: Biliary complications are a major cause of morbidity and mortality in liver transplantation. Up to 25% of patients that develop biliary complications require additional surgical procedures, re-transplantation or die in the absence of a suitable regraft. Here, we investigate the role of the primary cilium, a highly specialised sensory organelle, in biliary injury leading to post-transplant biliary complications. METHODS: Human biopsies were used to study the structure and function of primary cilia in liver transplant recipients that develop biliary complications (n = 7) in comparison with recipients without biliary complications (n = 12). To study the biological effects of the primary cilia during transplantation, we generated murine models that recapitulate liver procurement and cold storage, and assessed the elimination of the primary cilia in biliary epithelial cells in the K19CreERTKif3afl/fl mouse model. To explore the molecular mechanisms responsible for the observed phenotypes we used in vitro models of ischemia, cellular senescence and primary cilia ablation. Finally, we used pharmacological and genetic approaches to target cellular senescence and the primary cilia, both in mouse models and discarded human donor livers. RESULTS: Prolonged ischemic periods before transplantation result in ciliary shortening and cellular senescence, an irreversible cell cycle arrest that blocks regeneration. Our results indicate that primary cilia damage results in biliary injury and a loss of regenerative potential. Senescence negatively impacts primary cilia structure and triggers a negative feedback loop that further impairs regeneration. Finally, we explore how targeted interventions for cellular senescence and/or the stabilisation of the primary cilia improve biliary regeneration following ischemic injury. CONCLUSIONS: Primary cilia play an essential role in biliary regeneration and we demonstrate that senolytics and cilia-stabilising treatments provide a potential therapeutic opportunity to reduce the rate of biliary complications and improve clinical outcomes in liver transplantation. IMPACT AND IMPLICATIONS: Up to 25% of liver transplants result in biliary complications, leading to additional surgery, retransplants, or death. We found that the incidence of biliary complications is increased by damage to the primary cilium, an antenna that protrudes from the cell and is key to regeneration. Here, we show that treatments that preserve the primary cilia during the transplant process provide a potential solution to reduce the rates of biliary complications.

Plant Protease Inhibitors as Emerging Antimicrobial Peptide Agents: A Comprehensive Review.

Antimicrobial peptides (AMPs) are important mediator molecules of the innate defense mechanisms in a wide range of living organisms, including bacteria, mammals, and plants. Among them, peptide protease inhibitors (PPIs) from plants play a central role in their defense mechanisms by directly attacking pathogens or by modulating the plant's defense response. The growing prevalence of microbial resistance to currently available antibiotics has intensified the interest concerning these molecules as novel antimicrobial agents. In this scenario, PPIs isolated from a variety of plants have shown potential in inhibiting the growth of pathogenic bacteria, protozoans, and fungal strains, either by interfering with essential biochemical or physiological processes or by altering the permeability of biological membranes of invading organisms. Moreover, these molecules are active inhibitors of a range of proteases, including aspartic, serine, and cysteine types, with some showing particular efficacy as trypsin and chymotrypsin inhibitors. In this review, we provide a comprehensive analysis of the potential of plant-derived PPIs as novel antimicrobial molecules, highlighting their broad-spectrum antimicrobial efficacy, specificity, and minimal toxicity. These natural compounds exhibit diverse mechanisms of action and often multifunctionality, positioning them as promising molecular scaffolds for developing new therapeutic antibacterial agents.

Funcionamiento, Discapacidad, Rehabilitación, Inclusión y Desempeño. Terminología Universal y Comunicación Efectiva, un Desafío de la Fisioterapia/Kinesiología

La comunicación efectiva en las intervenciones de fisioterapia/kinesiología tiene un impacto directo en los resultados y en la experiencia de los usuarios. Además, promover un lenguaje y una terminología universal en nuestra disciplina facilita la colaboración y la investigación nacional e internacional. El enfoque centrado en la Convención de las Naciones Unidas sobre los Derechos de las Personas con Discapacidad adoptado por la Confederación Mundial de Fisioterapia nos compromete a alinearnos con definiciones de conceptos acordados internacionalmente, lo que fortalece la profesión y promueve el profesionalismo en las acciones terapéuticas. Avanzar hacia reflexión y consensos en la comunidad de fisioterapia/kinesiología en torno a conceptos claves como discapacidad, rehabilitación, inclusión y desempeño, con la impronta del funcionamiento humano, optimizan la praxis profesional y su impacto en las intervenciones a lo largo del curso de vida en todos los niveles asistenciales.

Results of the transition from posterolateral to anterior minimally invasive approach for total hip arthroplasty.

BACKGROUND: The anterior minimally invasive (AMI) approach reduces soft tissue damage, risk of dislocation and enhances recovery, but it is associated with certain complications. The aim of this study is to compare the outcomes of patients who underwent total hip arthroplasty (THA) through posterolateral (PL) and AMI approaches performed by the same surgeon, in order to determine the learning curve associated with this new approach. METHODS: This retrospective cohort study included patients who underwent THA via PL and AMI approach between 2017 and 2022, with a minimum follow-up of 1 year. Hip fracture and oncologic patients were excluded. Demographic variables, functional scores and perioperative complications were assessed. A bivariate analysis was performed to identify differences between groups. RESULTS: Data of 124 AMI and 120 PL patients were analyzed. Demographic characteristics among groups were homogeneous. Functional outcomes at 3 months were superior for AMI (Oxford: 43 vs. 38; p < 0.05), no dislocations were identified (0% vs. 4.2%; p < 0.05) and no differences in the transfusion rate were found (6.5% AMI vs. 6.7% PL; p = 0.996). Infection rate was 4% for AMI and 3.4% for PL (p = 0.572). Surgical time was shorter for the PL approach, but the median surgical time of the last 25 AMI cases was shorter. CONCLUSIONS: The AMI approach is an excellent alternative for patients requiring THA. Although surgical time and perioperative bleeding were greater during the learning curve, this approach offers improved functional outcomes and a lower dislocation rate, without significant differences in transfusion and infection outcomes, demonstrating that responsible innovation and safe implementation of new techniques is possible.

Bilateral Variation of the Vertebral Artery: Report of a Case and its Clinical Implication / Variación Bilateral de la Arteria Vertebral; Reporte de un Caso y su Implicancia Clínica

SUMMARY: There are many reports on anatomical variations of the vertebral arteries, which may be related to origin, trajectory, caliber, and side. Bilateral variations are less frequent, however, and less common are bilateral variants that differ from each other. The aim of this work was to report the presence of a bilateral variation of the vertebral artery and its functional and clinical implications. Dissection of a female cadaver, fixed in 10 % buffered formaldehyde, which had not undergone any previous surgeries in the study area and had anatomical variations in both vertebral arteries. In each one, follow-up was done from its origin to its end, determining its trajectory, diameters, branching, and anatomical relations. A left vertebral artery was found, starting in the aortic arch and making a sinuous trajectory of 4 curvatures to enter the transverse foramen of C4. The right vertebral artery began as the first branch of the subclavian artery. Its initial trajectory was rectilinear, followed by a right concave curve, a 360° loop that included a second ascending curve, and ended straight before entering the transverse foramen of C6. The coexistence of bilateral variations in the vertebral arteries is possible. This atypical situation can potentially generate vascular and neurological pathologies, but with different symptoms and causes. Knowing these variations and deliberately searching for them will enable the specialist to make a suitable differential diagnosis.

Existen múltiples reportes sobre variaciones anatómicas de las arterias vertebrales, las que se pueden relacionar con origen, trayecto, calibre y lateralidad. Sin embargo, las variaciones bilaterales son menos frecuentes, y menos común es que las variantes bilaterales sean diferentes entre ellas. El objetivo de este trabajo fue reportar la presencia de una variación bilateral de la arteria vertebral y su implicancia funcional y clínica. Disección en un cadáver de sexo femenino, fijado en formaldehido tamponado al 10 %, el cual no presentaba intervenciones quirúrgicas previas en la región de estudio y que tenía variaciones anatómicas en ambas arterias vertebrales. En cada una se realizó seguimiento desde su origen hasta su terminación, pudiendo determinar su trayecto, diámetros, ramificaciones y relaciones anatómicas. Se encontró una arteria vertebral izquierda originada en el arco aórtico, que realizaba un trayecto sinuoso de 4 curvaturas e ingresaba al foramen transverso de C4. La arteria vertebral derecha se originaba como primera rama de la arteria subclavia. Su trayecto inicial era rectilíneo seguido por una curva de concavidad derecha, un loop (giro) de 360° que incluía una segunda curva ascendente y terminaba en dirección recta antes de ingresar al foramen transverso de C6. La coexistencia de variaciones bilaterales en las arterias vertebrales es posible. Esta situación atípica, potencialmente puede generar en la persona patologías neurológicas de origen vascular, pero con sintomatología y causas diferentes. Conocer estas variaciones y realizar una búsqueda intencionada de ellas permitirá el especialista realizar un adecuado diagnóstico diferencial.

Clinical outcomes in patients with solid tumors living in rural and urban areas followed via telemedicine: experience in a highly complex latin american hospital.

BACKGROUND: Difficulties in cancer services access increase the burden of disease and mortality in rural areas, and telehealth can be a useful tool to address these inequalities. OBJECTIVE: We aimed to describe the outcomes of patients in rural and urban areas with solid tumors managed by oncologists through telemedicine. METHODS: We conducted a retrospective cohort study of patients with solid tumors from March to December 2020. A total of 1270 subjects with solid tumors were included, 704 living in urban areas and 566 in rural areas. RESULTS: The most frequent tumors were breast (51.8%) and prostate (12.4%). The trend of telemedicine care was similar for both populations; in-person care was more frequent in the urban population. There were no differences in referral to the emergency room, need for hospitalization, and mortality for both groups. CONCLUSION: Telemedicine is a care modality that reduces barriers in the care of patients with solid tumors, evidencing similar outcomes regardless of living in rural or urban areas.

Posterior hamstring harvest improves aesthetic satisfaction and decreases sensory complications as compared to the classic anterior approach in anterior cruciate ligament reconstruction surgery.

PURPOSE: The use of the posterior approach for harvesting hamstring grafts has recently become popular thanks to new all-inside techniques and retrograde drills. This study aims to compare the classic anterior approach with the posterior approach in the popliteal fossa. METHODS: Retrospective comparative study of 100 consecutive cases of primary ligamentoplasty performed using ipsilateral semitendinosus autograft with at least one year of follow-up. 50 patients with anterior approach (group A) and 50 patients with posterior approach (P). Ratio men/women: 9/1. Mean age: 32 ± 13 years. Mean operative time: 64.88 ± 12.28 min. STUDY VARIABLES: Graft harvest time; intraoperative complications (semitendinous [ST] tendon cut); postoperative neurological complications (allodynia, paresthesia, pain) or hematoma in the donor area; atrophy of the operated thigh compared to the contralateral thigh, postoperative VAS score, aesthetic satisfaction and overall satisfaction. RESULTS: Graft harvest time of 9.5 min in group A versus 5.25 min in group P (p < 0.05). Sensory complications: 16% in group A versus 2% in group P (p < 0.05). Regarding the patient's evaluation of the aesthetic result of the surgery, 80% in group A and 92% in group P were very satisfied, 16% in group A and 8% in group P were satisfied and 4% in group A and no patients in group P not very satisfied (p < 0.05). No significant differences were found in terms of total operative time, postoperative joint movement, atrophy of the operated thigh, postoperative VAS, or overall patient satisfaction. CONCLUSIONS: The posterior approach to harvesting the ipsilateral hamstring graft obtained better results than the anterior approach in terms of aesthetic satisfaction of the patient, lower rate of neurological complications (allodynia, paresthesias and hypoesthesia in the anterior region of the knee and leg) and shorter hamstring harvest time. LEVEL OF EVIDENCE: IV.

Human biliary epithelial cells from discarded donor livers rescue bile duct structure and function in a mouse model of biliary disease.

Biliary diseases can cause inflammation, fibrosis, bile duct destruction, and eventually liver failure. There are no curative treatments for biliary disease except for liver transplantation. New therapies are urgently required. We have therefore purified human biliary epithelial cells (hBECs) from human livers that were not used for liver transplantation. hBECs were tested as a cell therapy in a mouse model of biliary disease in which the conditional deletion of Mdm2 in cholangiocytes causes senescence, biliary strictures, and fibrosis. hBECs are expandable and phenotypically stable and help restore biliary structure and function, highlighting their regenerative capacity and a potential alternative to liver transplantation for biliary disease.

Deletion of kif3a in CK19 positive cells leads to primary cilia loss, biliary cell proliferation and cystic liver lesions in TAA-treated mice.

BACKGROUND & AIMS: Loss of primary cilia in epithelial cells is known to cause cystic diseases of the liver and kidney. We have previously shown that during experimental and human cirrhosis that primary cilia were predominantly expressed on biliary cells in the ductular reaction. However, the role of primary cilia in the pathogenesis of the ductular reaction is not fully understood. METHODS: Primary cilia were specifically removed in biliary epithelial cells (BECs) by the administration of tamoxifen to Kif3af/f;CK19CreERT mice at week 2 of a 20-week course of TAA treatment. Biliary progenitor cells were isolated and grown as organoids from gallbladders. Cells and tissue were analysed using histology, immunohistochemistry and Western blot assays. RESULTS: At the end of 20 weeks TAA administration, primary cilia loss in liver BECs resulted in multiple microscopic cystic lesions within an unaltered ductular reaction. These were not seen in control mice who did not receive TAA. There was no effect of biliary primary cilia loss on the development of cirrhosis. Increased cellular proliferation was seen within the cystic structures associated with a decrease in hepatocyte lobular proliferation. Loss of primary cilia within biliary organoids was initially associated with reduced cell passage survival but this inhibitory effect was diminished in later passages. ERK but not WNT signalling was enhanced in primary cilia loss-induced cystic lesions in vivo and its inhibition reduced the expansion of primary cilia deficient biliary progenitor cells in vitro. CONCLUSIONS: TAA-treated kif3a BEC-specific knockout mice had an unaltered progression to cirrhosis, but developed cystic lesions that showed increased proliferation.

Congenital hyperinsulinism in Gran Canaria, Canary Isles.

INTRODUCTION: Congenital hyperinsulinism (CH) is a severe disorder characterised by the appearance of severe hypoglycaemia. Pathogenic mutations in the ABCC8 and KCNJ11 genes are the most frequent cause, although its appearance also been associated to mutations in other genes (GCK, GLUD1, HADH, HNF1A, HNF4A, SLC16A1, UCP2, HK1), and with different syndromes. MATERIALS AND METHODS: Retrospective review of patients diagnosed with CH in this unit during the last 18 years (2001-2018). Genetic analysis included screening for 11 genes in genomic DNA from peripheral blood (ABCC8, GCK, GLUD1, HADH, HNF1A, HNF4A, INSR, KCNJ11, SLC16A1, UCP2, and SLC25A15). OBJECTIVE: To carry out a clinical and genetic characterisation of the diagnosed cases of CH in Gran Canaria. RESULTS: There have been 10 cases of persistent HC since 2001. Seven of them had mutations in the ABCC8 gene, one in the HNF4α gene, and in two patients, no pathogenic mutations were found in the analysed genes. Four patients presented with previously undescribed mutations. Pancreatectomy was performed in two of the cases. The minimum insulin value detected in hypoglycaemia was 6.81 µIU/mL. The incidence of persistent CH for Gran Canaria and Lanzarote is 1/15,614. CONCLUSIONS: Four patients had previously undescribed mutations. The most frequently affected gene was ABCC8. Pancreatectomy was required in 20% of the patients. An insulin value of ≥6.81 µIU/mL was observed in all patients at the time of diagnosis. The incidence of CH in Gran Canaria is high.

Notch-IGF1 signaling during liver regeneration drives biliary epithelial cell expansion and inhibits hepatocyte differentiation.

In the adult liver, a population of facultative progenitor cells called biliary epithelial cells (BECs) proliferate and differentiate into cholangiocytes and hepatocytes after injury, thereby restoring liver function. In mammalian models of chronic liver injury, Notch signaling is essential for bile duct formation from these cells. However, the continual proliferation of BECs and differentiation of hepatocytes in these models have limited their use for determining whether Notch signaling is required for BECs to replenish hepatocytes after injury in the mammalian liver. Here, we used a temporally restricted model of hepatic repair in which large-scale hepatocyte injury and regeneration are initiated through the acute loss of Mdm2 in hepatocytes, resulting in the rapid, coordinated proliferation of BECs. We found that transient, early activation of Notch1- and Notch3-mediated signaling and entrance into the cell cycle preceded the phenotypic expansion of BECs into hepatocytes. Notch inhibition reduced BEC proliferation, which resulted in failure of BECs to differentiate into hepatocytes, indicating that Notch-dependent expansion of BECs is essential for hepatocyte regeneration. Notch signaling increased the abundance of the insulin-like growth factor 1 receptor (IGF1R) in BECs, and activating IGFR signaling increased BEC numbers but suppressed BEC differentiation into hepatocytes. These results suggest that different signaling mechanisms control BEC expansion and hepatocyte differentiation.

Impaired bone microarchitecture and strength in patients with tumor-induced osteomalacia.

Some studies based on bone biopsy have demonstrated that in patients with tumor-induced osteomalacia (TIO) the mineralization process of the bone matrix is profoundly disturbed. However, the interrelationship between clinical and biochemical features and bone microarchitecture in this disease needs further analysis. With this purpose in mind, we set out three objectives: (i) to determine bone microarchitecture and estimated bone strength in a group of patients with tumor-induced osteomalacia using high-resolution peripheral quantitative computed tomography (HR-pQCT) and finite element analysis (FEA), (ii) to investigate correlations between duration of disease, biochemical features, bone density, HR-pQCT and FEA parameters, and (iii) to compare HR-pQCT and FEA parameters with a healthy control group. Ten patients with TIO were included. All patients had non-resolved disease. At the distal radius, all bone microarchitecture parameters were significantly affected in patients with TIO in comparison with healthy controls. At the distal tibia, all parameters were significantly impaired, except for trabecular thickness. All the parameters were more affected in the distal tibia than in the distal radius. Women with TIO (n = 7) had significantly lower bone strength parameters than healthy controls. In men (n = 3), bone strength parameters were significantly lower than in the control group at the distal tibia. Alkaline phosphatase levels exhibited a negative correlation with microarchitecture parameters, failure load, and stiffness. Higher levels of parathyroid hormone correlated with poorer microarchitecture parameters. We believe that in TIO, hormonal disturbances and the lack of mechanical stimulus specially converge to generate an extremely harmful combination for bone health. © 2021 American Society for Bone and Mineral Research (ASBMR).

Cellular senescence inhibits renal regeneration after injury in mice, with senolytic treatment promoting repair.

The ability of the kidney to regenerate successfully after injury is lost with advancing age, chronic kidney disease, and after irradiation. The factors responsible for this reduced regenerative capacity remain incompletely understood, with increasing interest in a potential role for cellular senescence in determining outcomes after injury. Here, we demonstrated correlations between senescent cell load and functional loss in human aging and chronic kidney diseases including radiation nephropathy. We dissected the causative role of senescence in the augmented fibrosis occurring after injury in aged and irradiated murine kidneys. In vitro studies on human proximal tubular epithelial cells and in vivo mouse studies demonstrated that senescent renal epithelial cells produced multiple components of the senescence-associated secretory phenotype including transforming growth factor ß1, induced fibrosis, and inhibited tubular proliferative capacity after injury. Treatment of aged and irradiated mice with the B cell lymphoma 2/w/xL inhibitor ABT-263 reduced senescent cell numbers and restored a regenerative phenotype in the kidneys with increased tubular proliferation, improved function, and reduced fibrosis after subsequent ischemia-reperfusion injury. Senescent cells are key determinants of renal regenerative capacity in mice and represent emerging treatment targets to protect aging and vulnerable kidneys in man.

Downregulation of TGR5 (GPBAR1) in biliary epithelial cells contributes to the pathogenesis of sclerosing cholangitis.

BACKGROUND & AIMS: Primary sclerosing cholangitis (PSC) is characterized by chronic inflammation and progressive fibrosis of the biliary tree. The bile acid receptor TGR5 (GPBAR1) is found on biliary epithelial cells (BECs), where it promotes secretion, proliferation and tight junction integrity. Thus, we speculated that changes in TGR5-expression in BECs may contribute to PSC pathogenesis. METHODS: TGR5-expression and -localization were analyzed in PSC livers and liver tissue, isolated bile ducts and BECs from Abcb4-/-, Abcb4-/-/Tgr5Tg and ursodeoxycholic acid (UDCA)- or 24-norursodeoxycholic acid (norUDCA)-fed Abcb4-/- mice. The effects of IL8/IL8 homologues on TGR5 mRNA and protein levels were studied. BEC gene expression was analyzed by single-cell transcriptomics (scRNA-seq) from distinct mouse models. RESULTS: TGR5 mRNA expression and immunofluorescence staining intensity were reduced in BECs of PSC and Abcb4-/- livers, in Abcb4-/- extrahepatic bile ducts, but not in intrahepatic macrophages. No changes in TGR5 BEC fluorescence intensity were detected in liver tissue of other liver diseases, including primary biliary cholangitis. Incubation of BECs with IL8/IL8 homologues, but not with other cytokines, reduced TGR5 mRNA and protein levels. BECs from Abcb4-/- mice had lower levels of phosphorylated Erk and higher expression levels of Icam1, Vcam1 and Tgfß2. Overexpression of Tgr5 abolished the activated inflammatory phenotype characteristic of Abcb4-/- BECs. NorUDCA-feeding restored TGR5-expression levels in BECs in Abcb4-/- livers. CONCLUSIONS: Reduced TGR5 levels in BECs from patients with PSC and Abcb4-/- mice promote development of a reactive BEC phenotype, aggravate biliary injury and thus contribute to the pathogenesis of sclerosing cholangitis. Restoration of biliary TGR5-expression levels represents a previously unknown mechanism of action of norUDCA. LAY SUMMARY: Primary sclerosing cholangitis (PSC) is a chronic cholestatic liver disease-associated with progressive inflammation of the bile duct, leading to fibrosis and end-stage liver disease. Bile acid (BA) toxicity may contribute to the development and disease progression of PSC. TGR5 is a membrane-bound receptor for BAs, which is found on bile ducts and protects bile ducts from BA toxicity. In this study, we show that TGR5 levels were reduced in bile ducts from PSC livers and in bile ducts from a genetic mouse model of PSC. Our investigations indicate that lower levels of TGR5 in bile ducts may contribute to PSC development and progression. Furthermore, treatment with norUDCA, a drug currently being tested in a phase III trial for PSC, restored TGR5 levels in biliary epithelial cells.

Burden of Disease in Patients With Tumor-Induced Osteomalacia.

Tumor-induced osteomalacia (TIO) is a chronic condition associated with muscle weakness and long-term disability. We conducted a cross-sectional study of patients diagnosed with TIO who had been referred to our institution between May 2018 and December 2019. Our aim was to assess health-related quality of life (HRQoL), fatigue, pain, and muscle mass and strength in these patients. Detailed information was obtained regarding general characteristics, initial symptoms and biochemical parameters measured at diagnosis and on the first visit to our institution. Fatigue was assessed using the Functional Assessment of Chronic Illness Therapy-Fatigue (FACIT-Fatigue) scale, pain using the Brief Pain Inventory-Short Form (BPI-sf) scale and HRQoL by the 36-item Short Form survey (SF-36) questionnaire. Eight patients were included in the study: three without tumor localization, four with nonremission after surgery, and one with clinical recurrence 2 years after surgery. Fatigue experienced by patients with TIO was significantly higher compared to the general population (p ˂ .0001). The physical summary measure of the SF-36 showed significantly lower values than those of the Argentinean population with chronic conditions (mean 20.4 versus 45.9, p < .0001). According to the BPI-sf, patients with TIO have moderate average pain and the pain interferes severely with walking, general activities, work, and mood. Seven patients had a diagnosis of sarcopenia, four of which had severe sarcopenia. To our best knowledge, this is the first study aimed to quantify fatigue, pain, HRQoL, and muscle mass and strength in a group of patients with TIO. We hope our results contribute to a better understanding of the burden of disease and to establish a basis for future studies-with larger samples-which will make it possible to assess the efficacy of therapeutic interventions for these conditions. © 2020 American Society for Bone and Mineral Research © 2020 The Authors. JBMR Plus published by Wiley Periodicals LLC on behalf of American Society for Bone and Mineral Research.

Fibroblast growth factor 7 releasing particles enhance islet engraftment and improve metabolic control following islet transplantation in mice with diabetes.

Transplantation of islets in type 1 diabetes (T1D) is limited by poor islet engraftment into the liver, with two to three donor pancreases required per recipient. We aimed to condition the liver to enhance islet engraftment to improve long-term graft function. Diabetic mice received a non-curative islet transplant (n = 400 islets) via the hepatic portal vein (HPV) with fibroblast growth factor 7-loaded galactosylated poly(DL-lactide-co-glycolic acid) (FGF7-GAL-PLGA) particles; 26-µm diameter particles specifically targeted the liver, promoting hepatocyte proliferation in short-term experiments: in mice receiving 0.1-mg FGF7-GAL-PLGA particles (60-ng FGF7) vs vehicle, cell proliferation was induced specifically in the liver with greater efficacy and specificity than subcutaneous FGF7 (1.25 mg/kg ×2 doses; ~75-µg FGF7). Numbers of engrafted islets and vascularization were greater in liver sections of mice receiving islets and FGF7-GAL-PLGA particles vs mice receiving islets alone, 72 h posttransplant. More mice (six of eight) that received islets and FGF7-GAL-PLGA particles normalized blood glucose concentrations by 30-days posttransplant, versus zero of eight mice receiving islets alone with no evidence of increased proliferation of cells within the liver at this stage and normal liver function tests. This work shows that liver-targeted FGF7-GAL-PLGA particles achieve selective FGF7 delivery to the liver-promoting islet engraftment to help normalize blood glucose levels with a good safety profile.

TWEAK/Fn14 signalling promotes cholangiocarcinoma niche formation and progression.

BACKGROUND & AIMS: Cholangiocarcinoma (CCA) is a cancer of the hepatic bile ducts that is rarely resectable and is associated with poor prognosis. Tumour necrosis factor-like weak inducer of apoptosis (TWEAK) is known to signal via its receptor fibroblast growth factor-inducible 14 (Fn14) and induce cholangiocyte and myofibroblast proliferation in liver injury. We aimed to characterise its role in CCA. METHODS: The expression of the TWEAK ligand and Fn14 receptor was assessed immunohistochemically and by bulk RNA and single cell transcriptomics of human liver tissue. Spatiotemporal dynamics of pathway regulation were comprehensively analysed in rat and mouse models of thioacetamide (TAA)-mediated CCA. Flow cytometry, qPCR and proteomic analyses of CCA cell lines and conditioned medium experiments with primary macrophages were performed to evaluate the downstream functions of TWEAK/Fn14. In vivo pathway manipulation was assessed via TWEAK overexpression in NICD/AKT-induced CCA or genetic Fn14 knockout during TAA-mediated carcinogenesis. RESULTS: Our data reveal TWEAK and Fn14 overexpression in multiple human CCA cohorts, and Fn14 upregulation in early TAA-induced carcinogenesis. TWEAK regulated the secretion of factors from CC-SW-1 and SNU-1079 CCA cells, inducing polarisation of proinflammatory CD206+ macrophages. Pharmacological blocking of the TWEAK downstream target chemokine monocyte chemoattractant protein 1 (MCP-1 or CCL2) significantly reduced CCA xenograft growth, while TWEAK overexpression drove cancer-associated fibroblast proliferation and collagen deposition in the tumour niche. Genetic Fn14 ablation significantly reduced inflammatory, fibrogenic and ductular responses during carcinogenic TAA-mediated injury. CONCLUSION: These novel data provide evidence for the action of TWEAK/Fn14 on macrophage recruitment and phenotype, and cancer-associated fibroblast proliferation in CCA. Targeting TWEAK/Fn14 and its downstream signals may provide a means to inhibit CCA niche development and tumour growth. LAY SUMMARY: Cholangiocarcinoma is an aggressive, chemotherapy-resistant liver cancer. Interactions between tumour cells and cells that form a supportive environment for the tumour to grow are a source of this aggressiveness and resistance to chemotherapy. Herein, we describe interactions between tumour cells and their supportive environment via a chemical messenger, TWEAK and its receptor Fn14. TWEAK/Fn14 alters the recruitment and type of immune cells in tumours, increases the growth of cancer-associated fibroblasts in the tumour environment, and is a potential target to reduce tumour formation.

[Noonan syndrome: genetic and clinical update and treatment options]. / Síndrome de Noonan: actualización genética, clínica y de opciones terapéuticas.

Noonan syndrome (NS) is a relatively common genetic condition characterised by short stature, congenital heart defects, and distinctive facial features. NS and other clinically overlapping conditions such as NS with multiple lentigines (formerly called LEOPARD syndrome), cardiofaciocutaneous syndrome, or Costello syndrome, are caused by mutations in genes encoding proteins of the RAS-MAPKinases pathway. Because of this shared mechanism, these conditions have been collectively termed «RASopathies¼. Despite the recent advances in molecular genetics, nearly 20% of patients still lack a genetic cause, and diagnosis is still made mainly on clinical grounds. NS is a clinically and genetically heterogeneous condition, with variable expressivity and a changing phenotype with age, and affects multiple organs and systems. Therefore, it is essential that physicians involved in the care of these patients are familiarised with their manifestations and the management recommendations, including management of growth and development. Data on growth hormone treatment efficacy are sparse, and show a modest response in height gains, similar to that observed in Turner syndrome. The role of RAS/MAPK hyper-activation in the pathophysiology of this group of disorders offers a unique opportunity for the development of targeted approaches.

Krüppel-Like Factor 6 Is Required for Oxidative and Oncogene-Induced Cellular Senescence.

Krüppel-like factor 6 (KLF6) is a transcription factor involved in the regulation of several cellular processes. Regarding its role in tumorigenesis, KLF6 is considered a tumor suppressor. Numerous reports demonstrate its frequent genomic loss or down-regulation, implying a functional inactivation in a broad range of human cancers. Previous work from our laboratory showed that the down-regulation of KLF6 expression in normal fibroblasts leads to cellular transformation, while its ectopic expression interferes with the oncogenic transformation triggered by activated Ras through a cell cycle arrest. We hypothesize that the growth suppressor activity of KLF6 may involve the induction of cellular senescence thereby helping to prevent the proliferation of cells at risk of neoplastic transformation. Here, we explored the association of KLF6 up-regulation in two different cellular senescence scenarios. We found that KLF6 silencing bypasses both oxidative and oncogene-induced senescence. In this context, KLF6 expression per se was capable to trigger cellular senescence in both normal and tumoral contexts. As such, the findings presented in this report provide insights into a potential mechanism by which KLF6 may play a suppressing role of uncontrolled or damaged cell proliferation.