Chromatin damage generated by DNA intercalators leads to degradation of RNA Polymerase II.

In cancer therapy, DNA intercalators are mainly known for their capacity to kill cells by inducing DNA damage. Recently, several DNA intercalators have attracted much interest given their ability to inhibit RNA Polymerase I transcription (BMH-21), evict histones (Aclarubicin) or induce chromatin trapping of FACT (Curaxin CBL0137). Interestingly, these DNA intercalators lack the capacity to induce DNA damage while still retaining cytotoxic effects and stabilize p53. Herein, we report that these DNA intercalators impact chromatin biology by interfering with the chromatin stability of RNA polymerases I, II and III. These three compounds have the capacity to induce degradation of RNA polymerase II and they simultaneously enable the trapping of Topoisomerases TOP2A and TOP2B on the chromatin. In addition, BMH-21 also acts as a catalytic inhibitor of Topoisomerase II, resembling Aclarubicin. Moreover, BMH-21 induces chromatin trapping of the histone chaperone FACT and propels accumulation of Z-DNA and histone eviction, similarly to Aclarubicin and CBL0137. These DNA intercalators have a cumulative impact on general transcription machinery by inducing accumulation of topological defects and impacting nuclear chromatin. Therefore, their cytotoxic capabilities may be the result of compounding deleterious effects on chromatin homeostasis.

Actionable cancer vulnerability due to translational arrest, p53 aggregation and ribosome biogenesis stress evoked by the disulfiram metabolite CuET.

Drug repurposing is a versatile strategy to improve current therapies. Disulfiram has long been used in the treatment of alcohol dependency and multiple clinical trials to evaluate its clinical value in oncology are ongoing. We have recently reported that the disulfiram metabolite diethyldithiocarbamate, when combined with copper (CuET), targets the NPL4 adapter of the p97VCP segregase to suppress the growth of a spectrum of cancer cell lines and xenograft models in vivo. CuET induces proteotoxic stress and genotoxic effects, however important issues concerning the full range of the CuET-evoked tumor cell phenotypes, their temporal order, and mechanistic basis have remained largely unexplored. Here, we have addressed these outstanding questions and show that in diverse human cancer cell models, CuET causes a very early translational arrest through the integrated stress response (ISR), later followed by features of nucleolar stress. Furthermore, we report that CuET entraps p53 in NPL4-rich aggregates leading to elevated p53 protein and its functional inhibition, consistent with the possibility of CuET-triggered cell death being p53-independent. Our transcriptomics profiling revealed activation of pro-survival adaptive pathways of ribosomal biogenesis (RiBi) and autophagy upon prolonged exposure to CuET, indicating potential feedback responses to CuET treatment. The latter concept was validated here by simultaneous pharmacological inhibition of RiBi and/or autophagy that further enhanced CuET's tumor cytotoxicity, using both cell culture and zebrafish in vivo preclinical models. Overall, these findings expand the mechanistic repertoire of CuET's anti-cancer activity, inform about the temporal order of responses and identify an unorthodox new mechanism of targeting p53. Our results are discussed in light of cancer-associated endogenous stresses as exploitable tumor vulnerabilities and may inspire future clinical applications of CuET in oncology, including combinatorial treatments and focus on potential advantages of using certain validated drug metabolites, rather than old, approved drugs with their, often complex, metabolic profiles.

Use of Cultivated Epidermal Allograft in Chronic Wounds: A Novel Therapeutic Alternative.

Introduction: Chronic wounds represent a frequent cause of consultation for plastic and reconstructive surgeons. The use of epidermal culture stands out because they provide complete epithelialization, adequate aesthetic-functional results, and no morbidity for the patient. Epifast® is a pre-manufactured cultured epidermal allograft derived from the amplification in vitro of human keratinocytes. Materials and Methods: A prospective longitudinal multicenter study was carried out in four chronic wound reference centers, which were in charge of plastic and reconstructive surgery services. For a standardized wound bed preparation, the protocol synthesized by the acronym "TIME" was used. At the end of the "TIME" protocol, the pre-fabricated allograft was applied and removed 7 days after its application. Results: A total of 133 patients with diagnosis of chronic wound were included in the study. The median age was 69.3 ± 13.6 years. The most common comorbidity found was diabetes mellitus type 2 in 71.4% of the patients (n = 95) and systemic arterial hypertension in 60.2% of the patients (n = 80). The most frequent location of chronic wounds was seen in the lower extremity with 45.1% (n = 60). The mean duration for it to close was 46 ± 14 days, in which they closed within the first 3 months in 93% (n = 125) of the cases. About 91.7% (n = 122) of the wounds achieved total closure. Conclusion: Cultured epidermal allograft, combined with a meticulous technique and an adequate selection of patients, represents a safe and effective tool for chronic wounds.

Functional Proteomic Profiling of Triple-Negative Breast Cancer.

Triple-negative breast cancer (TNBC) is a subtype of breast cancer that comprises various disease entities, all of which share a set of common features: a lack of expression of the estrogen receptor, progesterone receptor, and human epidermal growth factor receptor 2, respectively. Because of their receptor status, conventional chemotherapy remains the main therapeutic option for TNBC patients. We employed a reverse phase protein array approach (RPPA), complemented by immunohistochemistry, to quantitatively profile the activation state of 84 actionable key signaling intermediates and phosphoproteins in a set of 44 TNBC samples. We performed supervised and unsupervised approaches to proteomic data analysis to identify groups of samples sharing common characteristics that could be amenable to existing therapies. We found the heterogenous activation of multiple pathways, with PI3 K/AKT/mTOR signaling being the most common event. Some specific individualized therapeutic possibilities include the expression of oncogenic KIT in association with cytokeratin 15 and Erk1/2 positive tumors, both of which may have clinical value.

The exon-junction complex helicase eIF4A3 controls cell fate via coordinated regulation of ribosome biogenesis and translational output.

Eukaryotic initiation factor 4A-III (eIF4A3), a core helicase component of the exon junction complex, is essential for splicing, mRNA trafficking, and nonsense-mediated decay processes emerging as targets in cancer therapy. Here, we unravel eIF4A3's tumor-promoting function by demonstrating its role in ribosome biogenesis (RiBi) and p53 (de)regulation. Mechanistically, eIF4A3 resides in nucleoli within the small subunit processome and regulates rRNA processing via R-loop clearance. EIF4A3 depletion induces cell cycle arrest through impaired RiBi checkpoint-mediated p53 induction and reprogrammed translation of cell cycle regulators. Multilevel omics analysis following eIF4A3 depletion pinpoints pathways of cell death regulation and translation of alternative mouse double minute homolog 2 (MDM2) transcript isoforms that control p53. EIF4A3 expression and subnuclear localization among clinical cancer specimens correlate with the RiBi status rendering eIF4A3 an exploitable vulnerability in high-RiBi tumors. We propose a concept of eIF4A3's unexpected role in RiBi, with implications for cancer pathogenesis and treatment.

Evaluación del desempeño diagnóstico del Índice de Riesgo de Malignidad II en mujeres con diagnóstico de masa anexial en un hospital de tercer nivel.

OBJETIVO: Evaluar la exactitud diagnóstica del Índice de Riesgo de Malignidad II (IRM II) en 100 pacientes con diagnóstico de masa anexial. MÉTODO: En una muestra de 100 pacientes con diagnóstico de masa anexial se cuantificaron variables demográficas y se aplicó el IRM II. Mediante una tabla 2 × 2 se obtuvieron la sensibilidad, la especificidad, el valor predictivo positivo, el valor predictivo negativo y la exactitud diagnóstica, y se compararon con el resultado histopatológico. RESULTADOS: El IRM II con resultado positivo se presentó en el 73.1% (52 pacientes) de los casos con resultado histopatológico maligno y en el 26.9% de aquellos con resultado histopatológico benigno. Presenta una sensibilidad en la prueba del 73.1%, una especificidad del 70.8%, un valor predictivo positivo del 73.2% y un valor predictivo negativo del 70.8%. La exactitud diagnóstica es del 72%. CONCLUSIONES: El IRM II es una herramienta de cribaje con aceptable desempeño diagnóstico para normar la conducta, como referir a un centro especializado o solicitar estudios más específicos en pacientes con diagnóstico de masa anexial por sospecha de malignidad. OBJECTIVE: Evaluate the usefulness of the Malignancy Risk Index II (MRI II) using diagnostic accuracy variables in 100 patients diagnosed with adnexal mass. METHOD: In a sample of 100 patients with a diagnosis of adnexal mass, demographic variables were quantified and MRI II was applied. The sensitivity, specificity, positive predictive value, negative predictive value, and diagnostic accuracy were obtained using a 2 × 2 table and compared with the histopathological result. RESULTS: MRI II with positive result was presented in 73.1% (52 patients) with malignant histopathological result and in 26.9% of patients with benign histopathological result. It presents a sensitivity in the test of 73.1%, a specificity of 70.8%, positive and negative predictive value of 73.2 and 70.8%, respectively. Diagnostic accuracy of 72%. CONCLUSIONS: MRI II is a screening tool with acceptable diagnostic performance to regulate behavior, such as referring to a specialized center or requesting more specific studies in patients diagnosed with adnexal mass due to suspected malignancy.

Evaluation of the chemopreventive potentials of ezetimibe and aspirin in a novel mouse model of gallbladder preneoplasia.

Gallbladder stones (cholecystolithiasis) are the main risk factor for gallbladder cancer (GBC), a lethal biliary malignancy with poor survival rates worldwide. Gallbladder stones are thought to damage the gallbladder epithelium and trigger chronic inflammation. Preneoplastic lesions that arise in such an inflammatory microenvironment can eventually develop into invasive carcinoma, through mechanisms that are not fully understood. Here, we developed a novel gallbladder preneoplasia mouse model through the administration of two lithogenic diets (a low- or a high-cholesterol diet) in wild-type C57BL/6 mice over a period of 9 months. Additionally, we evaluated the chemopreventive potentials of the anti-inflammatory drug aspirin and the cholesterol absorption inhibitor ezetimibe. Both lithogenic diets induced early formation of gallbladder stones, together with extensive inflammatory changes and widespread induction of metaplasia, an epithelial adaptation to tissue injury. Dysplastic lesions were presented only in mice fed with high-cholesterol diet (62.5%) in late stages (9th month), and no invasive carcinoma was observed at any stage. The cholesterol absorption inhibitor ezetimibe inhibited gallbladder stone formation and completely prevented the onset of metaplasia and dysplasia in both lithogenic diets, whereas aspirin partially reduced metaplasia development only in the low-cholesterol diet setting. This model recapitulates several of the structural and inflammatory findings observed in human cholecystolithiasic gallbladders, making it relevant for the study of gallbladder carcinogenesis. In addition, our results suggest that the use of cholesterol absorption inhibitors and anti-inflammatory drugs can be evaluated as chemopreventive strategies to reduce the burden of GBC among high-risk populations.

Diagnosis and Treatment of Carpal Tunnel Syndrome in A Tertiary Care Center in Mexico City.

BACKGROUND: Carpal tunnel syndrome is the most common peripheral neuropathy affecting patients at productive age and has an important economical impact on those who suffer it. This study assessed the diagnostic performance of carpal tunnel syndrome´s signs and described the epidemiology at a tertiary care center in Mexico City. METHODS: All patients diagnosed with carpal tunnel syndrome during a five-year period were included. Demographic data, electromyography results, positive clinical signs and the severity score according to the Italian scale were recorded. Diagnostic accuracy of Tinel and Phalen´s signs were calculated via odds ratio. RESULTS: Totally, 650 patients were diagnosed and treated during a five-year period, 84% were female and 16% male, and the mean age was 55.8 years. The associated comorbidities were trigger finger (36.1%), thyroid disease (25.6%) and diabetes (20%). Diagnosis yielded for Phalen and Tinel signs were variable in each of the study groups (males and females) and showed to be beneficial in diagnosis of the disease. CONCLUSION: Carpal tunnel syndrome is a complex disease in which clinical signs remain the cornerstone of diagnosis. Extension studies are useful to assess the severity of the disease.

High-Grade Patellar Chondral Defects: Promising Results From Management With Osteochondral Autografts.

BACKGROUND: Patellar chondral defects represent up to 34.6% of defects found during routine arthroscopy. Surgical management has evolved during the past 20 years in an effort to develop techniques to replace hyaline cartilage. Currently, the only technique that achieves this is osteochondral autologous transfer (OAT). Although good and excellent results have often been reported at midterm and long-term follow-up for femoral lesions, little is known about isolated patellar defects. PURPOSE: To assess clinical and imaging results of patients treated with OAT for high-grade patellar defects. STUDY DESIGN: Case series; Level of evidence, 4. METHODS: This was a retrospective study on all patients who received OAT for high-grade symptomatic patellar chondral defects between 2010 and 2018 at our institution. The study included patients younger than 40 years of age with anterior knee pain and a grade 4 International Cartilage Repair Society patellar chondral defect between 1 and 2.5 cm2. Patients with surgery in other knee compartments, concomitant anterior cruciate ligament ruptures, infection, rheumatoid arthritis, and degenerative lesions were excluded. Six months postoperatively, all patients underwent magnetic resonance imaging (MRI) to allow assessment of graft integrity via the MOCART (Magnetic Resonance Observation of Cartilage Repair Tissue) score to evaluate morphologic features and integration. Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC) and Kujala scores were used to assess functional outcomes at final follow-up. RESULTS: A total of 26 patients who received a patellar OAT were included. Most patients were male (88.4%), and the mean ± SD age was 28.5 ± 9.7 years. Patellar chondral defects had a median size of 180 mm2 (range, 64-250 mm2), and patients received a median of 1 autograft (range, 1-3). Functional outcomes assessed at a minimum of 1 year after surgery showed a mean Kujala score of 90.42 ± 6.7 and a mean WOMAC score of 95 ± 3.6. MRI revealed a median MOCART score of 75 points (range, 20-90 points). CONCLUSION: To our knowledge, this is the largest series to date regarding isolated patellar OAT. At midterm follow-up, most patients reported good and excellent results regarding symptoms and activity levels. Most autografts showed good osseous integration and excellent filling of the chondral surface, as evidenced on MRI. OAT is a good alternative to treat high-grade patellar chondral defects, especially among young patients.

Functional and genomic characterization of three novel cell lines derived from a metastatic gallbladder cancer tumor.

BACKGROUND: Gallbladder cancer (GBC) is the most common tumor of the biliary tract. The incidence of GBC shows a large geographic variability, being particularly frequent in Native American populations. In Chile, GBC represents the second cause of cancer-related death among women. We describe here the establishment of three novel cell lines derived from the ascitic fluid of a Chilean GBC patient, who presented 46% European, 36% Mapuche, 12% Aymara and 6% African ancestry. RESULTS: After immunocytochemical staining of the primary cell culture, we isolated and comprehensively characterized three independent clones (PUC-GBC1, PUC-GBC2 and PUC-GBC3) by short tandem repeat DNA profiling and RNA sequencing as well as karyotype, doubling time, chemosensitivity, in vitro migration capability and in vivo tumorigenicity assay. Primary culture cells showed high expression of CK7, CK19, CA 19-9, MUC1 and MUC16, and negative expression of mesothelial markers. The three isolated clones displayed an epithelial phenotype and an abnormal structure and number of chromosomes. RNA sequencing confirmed the increased expression of cytokeratin and mucin genes, and also of TP53 and ERBB2 with some differences among the three cells lines, and revealed a novel exonic mutation in NF1. The PUC-GBC3 clone was the most aggressive according to histopathological features and the tumorigenic capacity in NSG mice. CONCLUSIONS: The first cell lines established from a Chilean GBC patient represent a new model for studying GBC in patients of Native American descent.

Hippo-YAP1 Is a Prognosis Marker and Potentially Targetable Pathway in Advanced Gallbladder Cancer.

Gallbladder cancer is an aggressive disease with late diagnosis and no efficacious treatment. The Hippo-Yes-associated protein 1 (YAP1) signaling pathway has emerged as a target for the development of new therapeutic interventions in cancers. However, the role of the Hippo-targeted therapy has not been addressed in advanced gallbladder cancer (GBC). This study aimed to evaluate the expression of the major Hippo pathway components mammalian Ste20-like protein kinase 1 (MST1), YAP1 and transcriptional coactivator with PDZ-binding motif (TAZ) and examined the effects of Verteporfin (VP), a small molecular inhibitor of YAP1-TEA domain transcription factor (TEAD) protein interaction, in metastatic GBC cell lines and patient-derived organoids (PDOs). Immunohistochemical analysis revealed that advanced GBC patients had high nuclear expression of YAP1. High nuclear expression of YAP1 was associated with poor survival in GBC patients with subserosal invasion (pT2). Additionally, advanced GBC cases showed reduced expression of MST1 compared to chronic cholecystitis. Both VP treatment and YAP1 siRNA inhibited the migration ability in GBC cell lines. Interestingly, gemcitabine resistant PDOs with high nuclear expression of YAP1 were sensitive to VP treatment. Taken together, our results suggest that key components of the Hippo-YAP1 signaling pathway are dysregulated in advanced gallbladder cancer and reveal that the inhibition YAP1 may be a candidate for targeted therapy.

The antimalarial drug amodiaquine stabilizes p53 through ribosome biogenesis stress, independently of its autophagy-inhibitory activity.

Pharmacological inhibition of ribosome biogenesis is a promising avenue for cancer therapy. Herein, we report a novel activity of the FDA-approved antimalarial drug amodiaquine which inhibits rRNA transcription, a rate-limiting step for ribosome biogenesis, in a dose-dependent manner. Amodiaquine triggers degradation of the catalytic subunit of RNA polymerase I (Pol I), with ensuing RPL5/RPL11-dependent stabilization of p53. Pol I shutdown occurs in the absence of DNA damage and without the subsequent ATM-dependent inhibition of rRNA transcription. RNAseq analysis revealed mechanistic similarities of amodiaquine with BMH-21, the first-in-class Pol I inhibitor, and with chloroquine, the antimalarial analog of amodiaquine, with well-established autophagy-inhibitory activity. Interestingly, autophagy inhibition caused by amodiaquine is not involved in the inhibition of rRNA transcription, suggesting two independent anticancer mechanisms. In vitro, amodiaquine is more efficient than chloroquine in restraining the proliferation of human cell lines derived from colorectal carcinomas, a cancer type with predicted susceptibility to ribosome biogenesis stress. Taken together, our data reveal an unsuspected activity of a drug approved and used in the clinics for over 30 years, and provide rationale for repurposing amodiaquine in cancer therapy.

Functional and genomic characterization of three novel cell lines derived from a metastatic gallbladder cancer tumor

BACKGROUND: Gallbladder cancer (GBC) is the most common tumor of the biliary tract. The incidence of GBC shows a large geographic variability, being particularly frequent in Native American populations. In Chile, GBC represents the second cause of cancer-related death among women. We describe here the establishment of three novel cell lines derived from the ascitic fluid of a Chilean GBC patient, who presented 46% European, 36% Mapuche, 12% Aymara and 6% African ancestry. RESULTS: After immunocytochemical staining of the primary cell culture, we isolated and comprehensively characterized three independent clones (PUC-GBC1, PUC-GBC2 and PUC-GBC3) by short tandem repeat DNA profiling and RNA sequencing as well as karyotype, doubling time, chemosensitivity, in vitro migration capability and in vivo tumorigenicity assay. Primary culture cells showed high expression of CK7, CK19, CA 19-9, MUC1 and MUC16, and negative expression of mesothelial markers. The three isolated clones displayed an epithelial phenotype and an abnormal structure and number of chromosomes. RNA sequencing confirmed the increased expression of cytokeratin and mucin genes, and also of TP53 and ERBB2 with some differences among the three cells lines, and revealed a novel exonic mutation in NF1. The PUC-GBC3 clone was the most aggressive according to histopathological features and the tumorigenic capacity in NSG mice. CONCLUSIONS: The first cell lines established from a Chilean GBC patient represent a new model for studying GBC in patients of Native American descent.

Osteochondral Autologous Transplantation for Treating Patellar High-Grade Chondral Defects: A Systematic Review.

BACKGROUND: Patellar cartilage defects account for 34.6% of defects found during routine arthroscopy. These defects pose a challenge in orthopaedic surgery because they have been associated with worse outcomes after surgical repair compared with other chondral lesions within the knee. PURPOSE: To systematically review the literature for evidence on results of osteochondral autologous transplantation (OAT) for the management of isolated patellar cartilage high-grade defects (International Cartilage Repair Society [ICRS] grade 3-4). STUDY DESIGN: Systematic review; Level of evidence, 4. METHODS: A systematic review of the literature was performed to find studies that addressed outcomes regarding OAT to treat patellar high-grade cartilage defects (ICRS grade 3-4). Studies addressing patient-reported outcomes, return to sports, or magnetic resonance imaging (MRI) at follow-up after isolated OAT procedures for patellar cartilage defects were included. RESULTS: A total of 5 studies were included in this review. We were not able to perform a meta-analysis as no studies had available data. A total of 102 patients who received an isolated OAT for a patellar chondral defect were included in these 5 studies. All patients showed significant improvement at final follow-up based on the following patient-reported outcome scores: Lysholm, International Knee Documentation Committee, Kujala, Tegner, and 36-Item Short Form Health Survey. We found that 4 studies used MRI during the first postoperative year to assess osteochondral plug integration and positioning. The results demonstrated that most plugs were integrated and correctly positioned when evaluated at follow-up, conducted on average after 12 months. Whether patients were able to return to sports was queried in 2 of the included studies, revealing that patients could return to their previous level in most cases (Tegner score, 5-9 at 2 years after surgery). CONCLUSION: Results indicate that OAT is a safe and reliable technique to treat patellar high-grade osteochondral defects, allowing for significant improvement in patient-reported outcomes and return to sports.

Noninvasive profiling of serum cytokines in breast cancer patients and clinicopathological characteristics.

Cancers elicit an immune response by modifying the microenvironment. The immune system plays a pivotal role in cancer recognition and eradication. While the potential clinical value of infiltrating lymphocytes at the tumor site has been assessed in breast cancer, circulating cytokines - the molecules coordinating and fine-tuning immune response - are still poorly characterized. Using two breast cancer cohorts (MicMa, n = 131, DCTB, n = 28) and the multiplex Luminex platform, we measured the levels of 27 cytokines in the serum of breast cancer patients prior to treatment. We investigated the cytokine levels in relation to clinicopathological characteristics and in perspective of the tumor infiltrating immune cells predicted from the bulk mRNA expression data. Unsupervised clustering analysis of the serum cytokine levels in the MicMa cohort identified a cluster of pro-inflammatory, pro-angiogenic, and Th2-related cytokines which was associated with poor prognosis. Notably high levels of platelet derived growth factor BB (PDGF) reflected a more aggressive tumor phenotype and larger tumor size. A significant positive correlation between serum levels of interferon gamma-induced protein 10 (IP10) and its mRNA expression at the tumor site suggested that tumor-IP10-production may outflow to the bloodstream. High IP10 serum levels were associated with a worse prognosis. Finally, we found serum levels of both PDGF and IP10 associated with enrichment scores of specific tumor infiltrating immune cells. Our study suggests that monitoring cytokine circulating levels in breast cancer could be used to characterize breast cancers and the immune composition of their microenvironment through readily available biological material.

Mucin 5B, carbonic anhydrase 9 and claudin 18 are potential theranostic markers of gallbladder carcinoma.

AIMS: Gallbladder cancer (GBC) is an aggressive tumour that is usually diagnosed at advanced stages and is characterised by a poor prognosis. Using public data of normal human tissues, we found that mRNA and protein levels of mucin 5B (MUC5B) and carbonic anhydrase 9 (CA9) were highly increased in gallbladder tissues. In addition, previous evidence has shown that claudin 18 (CLDN18) protein expression is higher in GBC. The aim of this study was to perform an analysis of these cell surface proteins during the histological progression of GBC in order to identify their theranostic potential. METHODS AND RESULTS: MUC5B expression, CA9 expression and CLDN18 expression were examined by immunohistochemistry in a series of 179 chronic cholecystitis (including 16 metaplastic tissues), 15 dysplasia and 217 GBC samples by the use of tissue microarray analysis. A composite staining score was calculated from staining intensity and percentage of positive cells. Immunohistochemical analysis showed high expression of MUC5B and CA9 among normal epithelium, metaplastic tissues, and dysplastic tissues. However, expression of both proteins was observed in roughly 50% of GBC samples. In contrast, CLDN18 was absent in normal epithelium, but its expression was higher in metaplastic cells. Among GBC cases, approximately half showed high CLDN18 expression. No associations were found between MUC5B, CA9 and CLDN18 expression and any clinicopathological features. CONCLUSIONS: CLDN18 is a new metaplasia marker in gallbladder tissues, and is conserved in approximately half of GBC cases. MUC5B and CA9 are highly conserved during GBC histological progression. The three markers are potential theranostic markers, in particular CA9 and CLDN18, for which there are already targeted therapies available.

Rigidez en cirugía de reconstrucción del ligamento cruzado anterior / Knee stiffness in anterior cruciate ligament reconstruction

La rigidez de rodilla en cirugía de Reconstrucción del Ligamento Cruzado Anterior (R-LCA) es una complicación devastadora, alcanzando una incidencia variable entre el 4% y el 38%. La definición de artrofibrosis es aún poco clara, lo que ha llevado a distintos esquemas terapéuticos. Conocer la etiopatogenia es clave para entender los procesos y las posibles alternativas de tratamiento. Distintas clasificaciones han sido descritas, siendo la de Shelbourne la más usada, debido a su valor pronóstico asociado. El objetivo del tratamiento en una rodilla estable es mejorar la movilidad articular, la satisfacción del paciente, y disminuir el riesgo de artrosis a largo plazo. El tratamiento se puede dividir en quirúrgico y conservador. Ese último, se enfoca principalmente en buscar la causa y lograr una prevención e intervención temprana, siendo el manejo que con mayor frecuencia se realiza. El tratamiento quirúrgico es una opción cuando el tratamiento conservador falla. Se realizó una revisión de la literatura y de 150 pacientes sometidos a R-LCA, de los cuales 4 presentaron artrofibrosis a un seguimiento de 2 años. Además, presentamos nuestro algoritmo de manejo terapéutico.

Knee stiffness in Anterior Cruciate Ligament Reconstruction (ACL-R) is a devastating complication, with a variable incidence of 4% to 38%. The definition of arthrofibrosis is still unclear, which has led to different therapeutic schemes. Knowing the etiopathogenesis is key to understanding the processes and possible treatment alternatives. Different classifications have been described, with Shelbourne being the most used, due to its associated prognostic value. The aim of treatment in a stable knee is to improve joint mobility, patient satisfaction, and decrease the risk of long-term osteoarthritis. The treatment can be divided into operative and non-operative. The latter focuses mainly on finding the cause and achieving prevention and early intervention, being the management that is most frequently performed. Surgical treatment is an option when conservative treatment fails. A review of the literature and of 150 patients undergoing R-LCA was performed, of which 4 presented arthrofibrosis at a 2-year follow-up. In addition, we present our therapeutic management algorithm.

Primary leiomyosarcoma of kidney with metastasis to contralateral kidney. Case report.

INTRODUCTION: Renal leiomyosarcoma is a rare entity in the world and its understanding is based on reports and various cases; however, the prognosis is bleak for its malignant potential and an average survival of 18 months. CLINICAL CASE: A 54-year-old woman with a clinical picture of 6 months of pain in the right flank and a tomographic image of a bilateral renal lesion underwent right radical nephrectomy and left conservative surgery. The definitive histopathological study reported right primary renal leiomyosarcoma with left metastasis. CONCLUSION: Renal leiomyosarcoma is an entity of low incidence and high mortality; however, our case represents the minority of patients with contralateral kidney metastasis reported in the literature.

Reduced Expression of PROX1 Transitions Glioblastoma Cells into a Mesenchymal Gene Expression Subtype.

The homeodomain transcription factor PROX1 has been linked to several cancer types, including gliomas, but its functions remain to be further elucidated. Here we describe a functional role and the prognostic value of PROX1 in glioblastoma. Low expression of PROX1 correlated with poor overall survival and the mesenchymal glioblastoma subtype signature. The latter finding was recapitulated in vitro, where suppression or overexpression of PROX1 in glioma cell cultures transitioned cells to a mesenchymal or to a nonmesenchymal glioblastoma gene expression signature, respectively. PROX1 modulation affected proliferation rates that coincided with changes in protein levels of CCNA1 and CCNE1 as well as the cyclin inhibitors CDKN1A, CDKN1B, and CDKN1C. Overexpression of SOX2 increased PROX1 expression, but treatment with a CDK2 inhibitor subsequently decreased PROX1 expression, which was paralleled by decreased SOX2 levels. The THRAP3 protein was a novel binding partner for PROX1, and suppression of THRAP3 increased both transcript and protein levels of PROX1. Together, these findings highlight the prognostic value of PROX1 and its role as a regulator of glioblastoma gene expression subtypes, intratumoral heterogeneity, proliferation, and cell-cycle control.Significance: These findings demonstrate the role and prognostic value of PROX1 in glioblastomas; low PROX1 levels correlate with a mesenchymal gene expression subtype and shorter survival in glioblastoma tumors. Cancer Res; 78(20); 5901-16. ©2018 AACR.