Separating Actin-Dependent Chemokine Receptor Nanoclustering from Dimerization Indicates a Role for Clustering in CXCR4 Signaling and Function.

A current challenge in cell motility studies is to understand the molecular and physical mechanisms that govern chemokine receptor nanoscale organization at the cell membrane, and their influence on cell response. Using single-particle tracking and super-resolution microscopy, we found that the chemokine receptor CXCR4 forms basal nanoclusters in resting T cells, whose extent, dynamics, and signaling strength are modulated by the orchestrated action of the actin cytoskeleton, the co-receptor CD4, and its ligand CXCL12. We identified three CXCR4 structural residues that are crucial for nanoclustering and generated an oligomerization-defective mutant that dimerized but did not form nanoclusters in response to CXCL12, which severely impaired signaling. Overall, our data provide new insights to the field of chemokine biology by showing that receptor dimerization in the absence of nanoclustering is unable to fully support CXCL12-mediated responses, including signaling and cell function in vivo.

Altered CXCR4 dynamics at the cell membrane impairs directed cell migration in WHIM syndrome patients.

Chemokine receptor nanoscale organization at the cell membrane is orchestrated by the actin cytoskeleton and influences cell responses. Using single-particle tracking analysis we show that CXCR4R334X, a truncated mutant chemokine receptor linked to WHIM syndrome (warts, hypogammaglobulinemia, infections, myelokathexis), fails to nanoclusterize after CXCL12 stimulation, and alters the lateral mobility and spatial organization of CXCR4 when coexpressed. These findings correlate with multiple phalloidin-positive protrusions in cells expressing CXCR4R334X, and their inability to correctly sense chemokine gradients. The underlying mechanisms involve inappropriate actin cytoskeleton remodeling due to the inadequate ß-arrestin1 activation by CXCR4R334X, which disrupts the equilibrium between activated and deactivated cofilin. Overall, we provide insights into the molecular mechanisms governing CXCR4 nanoclustering, signaling and cell function, and highlight the essential scaffold role of ß-arrestin1 to support CXCL12-mediated actin reorganization and receptor clustering. These defects associated with CXCR4R334X expression might contribute to the severe immunological symptoms associated with WHIM syndrome.

The complex nature of CXCR4 mutations in WHIM syndrome.

Heterozygous autosomal dominant mutations in the CXCR4 gene cause WHIM syndrome, a severe combined immunodeficiency disorder. The mutations primarily affect the C-terminal region of the CXCR4 chemokine receptor, specifically several potential phosphorylation sites critical for agonist (CXCL12)-mediated receptor internalization and desensitization. Mutant receptors have a prolonged residence time on the cell surface, leading to hyperactive signaling that is responsible for some of the symptoms of WHIM syndrome. Recent studies have shown that the situation is more complex than originally thought, as mutant WHIM receptors and CXCR4 exhibit different dynamics at the cell membrane, which also influences their respective cellular functions. This review examines the functional mechanisms of CXCR4 and the impact of WHIM mutations in both physiological and pathological conditions.

The Role of the CXCL12/CXCR4/ACKR3 Axis in Autoimmune Diseases.

Chemokine receptors are members of the G protein-coupled receptor superfamily. These receptors are intimately involved in cell movement, and thus play a critical role in several physiological and pathological situations that require the precise regulation of cell positioning. CXCR4 is one of the most studied chemokine receptors and is involved in many functions beyond leukocyte recruitment. During embryogenesis, it plays essential roles in vascular development, hematopoiesis, cardiogenesis, and nervous system organization. It has been also implicated in tumor progression and autoimmune diseases and, together with CD4, is one of the co-receptors used by the HIV-1 virus to infect immune cells. In contrast to other chemokine receptors that are characterized by ligand promiscuity, CXCR4 has a unique ligand-stromal cell-derived factor-1 (SDF1, CXCL12). However, this ligand also binds ACKR3, an atypical chemokine receptor that modulates CXCR4 functions and is overexpressed in multiple cancer types. The CXCL12/CXCR4/ACKR3 axis constitutes a potential therapeutic target for a wide variety of inflammatory diseases, not only by interfering with cell migration but also by modulating immune responses. Thus far, only one antagonist directed against the ligand-binding site of CXCR4, AMD3100, has demonstrated clinical relevance. Here, we review the role of this ligand and its receptors in different autoimmune diseases.

Endoscopic subfascial perforator vein surgery for patients with severe, chronic venous insufficiency.

Before 1985, surgery on incompetent perforator veins in patients with severe, chronic, venous insufficiency and venous ulcerations was generally performed utilizing long skin incisions through diseased skin and subcutaneous tissues. Known as "the Linton operation," wound infections and poor healing complicated this procedure. In 1985 G. Hauer demonstrated a new surgical technique for identifying and ligating incompetent perforator veins using an endoscopic approach in the limbs' subfascial space. This seminal contribution marked the advent of subfascial endoscopic perforator surgery (SEPS). From 1996 to 2003 our group prospectively collected data on 86 patients with chronic venous insufficiency (CVI) who underwent a SEPS procedure. Preoperative assessment consisted of color-flow duplex ultrasound scanning and ascending and descending phlebography. The patient's ages ranged from 42 to 82 years (mean 60). A total of 98 limbs underwent the SEPS procedure from the cohort group of 86 patients. The CHEAP classification of the limb disease was used: 45 limbs were classified as group C5, 53 limbs group C6. Ninety-eight SEPS procedures were performed without significant morbidity on 86 patients. Of the 53 limbs in class C6, 41 had ulcer healing within 12 weeks. The remaining 12 limbs in class C6 had ulcer healing within 6 months. In this latter group, 9 had ulcers greater than 4 cm in widest diameter. These patients underwent a split-thickness skin graft at the time the SEPS procedure was performed. The grafts have remained intact after 2 years in this cohort group. The results of this study demonstrate that the SEPS procedure incorporated into the overall treatment plan for patients with CVI produces excellent healing with minimal postoperative complications. The study also underscores the important role incompetent perforator veins have in the formation of venous ulcers.

Reoperation for recurrent colorectal cancer.

Recurrence of colorectal carcinoma represents a significant challenge. As the majority of recurrences involve more than just the anastomosis, surgical resection is ordinarily a major undertaking. Curative resection may require resection of other organs and structures, resulting in complex reconstructive procedures and substantial morbidity. In addition, carefully selected patients with distant metastases to sites such as the liver and lungs may also undergo potentially curative resection. Long-term survival following curative surgery for recurrence, however, ranges from only 15 to 40%. In addition to resection for curative intent, some patients may benefit from palliative procedures designed to relieve symptoms. Surgery alone is not usually sufficient therapy in these patients. Chemotherapy and radiation therapy play a vital adjunctive role in the management of recurrent disease. This article strives to review the risk factors and patterns of recurrence, selection of individuals for resection of recurrent disease, and outcomes of surgical procedures.

Estudio retrospectivo de 39 pacientes con síndrome de fibromialgia reumática / Retrospectic study of 39 patients with the rheumatic fibromyalgia syndrome

El síndrome de fibromialgia reumática, se está diagnosticando más frecuentemente, ya que ocupa un importante porcentaje del que hacer cotidiano del médico internista, del reumatólogo, del psicólogo clínico y del psiquiatria. Este trabajo presenta el reporte preliminar de 39 pacientes con ese diagnóstico, seguidos durante 18 meses (de enero de 1995 hasta junio de 1996) en un consultorio de reumatología privado. Se analizaron dichos casos por edad-sexo-raza-proveniencia-ocupación u oficio síntomas referidos en la primera entrevista-signos del examen físico- exámenes complementarios-normas del tratamiento y evolución de los mismos. El estudio fue retrospectivo, analizando los registros médicos de los pacientes y a pesar de no seguir un protocolo doble ciego, se deja entrever que los mayores éxitos terapéuticos se encontraron en los pacientes tratados con antiinflamatorios no esteroideos asociados a fármacos antidepresivos, dedicarles mayor tiempo en sus consultas, haciendo psicoterapia de apoyo y/o psicoterapia de enlace con psiquiatras, así como un adecuado programa de ejercicios y fisiatría cotidiana. Aunque ninguno de los pacientes requirió hospitalización se considera que la severidad de sus molestias disminuyó importantemente su rendimiento en el trabajo, los estudios y en el mismo hogar, por lo cual estos pacientes deben ser atendidos tempranamente y de manera holística, no restando prioridad a su soma y a su psiquis. Se revisó la bibliografía médica publicada sobre este tema