Incidence and risk factors for shoulder stiffness after open and arthroscopic rotator cuff repair.

INTRODUCTION: The aim of this study was to estimate the incidence of stiffness during the first 6 months after rotator cuff repair and to evaluate postoperative stiffness with respect to its risk factors and its influence on the outcome at 6 months postoperatively. METHODS: In a prospective cohort of 117 patients (69 women, 48 men; average age 59) from our institutional rotator cuff registry, who underwent either arthroscopic (n = 77) or open (n = 40) rotator cuff repair, we measured shoulder range of motion (ROM) at 3 and 6 months post-surgery. We evaluated the incidence of stiffness and analyzed functional outcomes, comparing various preoperative and intraoperative factors in patients with stiffness to those without at the 6-month mark. RESULTS: Shoulder stiffness was observed in 31% of patients (36/117) at 3 months postoperatively, decreasing to 20% (23/117) at 6 months. No significant link was found between stiffness at 6 months and demographic factors, preoperative stiffness, tear characteristics, or the type of repair. Notably, patients undergoing arthroscopic repair exhibited a 4.3-fold higher risk (OR 4.3; 95% CI 1.2-15.6, p = 0.02) of developing stiffness at 6 months compared to those with mini-open repair. Despite these differences in stiffness rates, no significant variation was seen in the American Shoulder and Elbow Surgeons (ASES) score, Single Assessment Numeric Evaluation (SANE) score, or Visual Analog Scale (VAS) scores at 6 months between the groups. CONCLUSION: The incidence of postoperative shoulder stiffness following rotator cuff repair was substantial at 31% at 3 months, reducing to 20% by 6 months. Mini-open repair was associated with a lower 6-month stiffness incidence than arthroscopic repair, likely due to variations in rehabilitation protocols. However, the presence of stiffness at 6 months post-surgery did not significantly affect functional outcomes or pain levels.

Intestinal-specific Hdac3 deletion increases susceptibility to colitis and small intestinal tumor development in mice fed a high-fat diet.

High-fat (HF) diets (HFDs) and inflammation are risk factors for colon cancer; however, the underlying mechanisms remain to be fully elucidated. The transcriptional corepressor HDAC3 has recently emerged as a key regulator of intestinal epithelial responses to diet and inflammation with intestinal-specific Hdac3 deletion (Hdac3IKO) in mice increasing fatty acid oxidation genes and the rate of fatty acid oxidation in enterocytes. Hdac3IKO mice are also predisposed to experimentally induced colitis; however, whether this is driven by the intestinal metabolic reprogramming and whether this predisposes these mice to intestinal tumorigenesis is unknown. Herein, we examined the effects of intestinal-specific Hdac3 deletion on colitis-associated intestinal tumorigenesis in mice fed a standard (STD) or HFD. Hdac3IKO mice were highly prone to experimentally induced colitis, which was further enhanced by an HFD. Hdac3 deletion also accelerated intestinal tumor development, specifically when fed an HFD and most notably in the small intestine where lipid absorption is maximal. Expression of proteins involved in fatty acid metabolism and oxidation (SCD1, EHHADH) were elevated in the small intestine of Hdac3IKO mice fed an HFD, and these mice displayed increased levels of lipid peroxidation, DNA damage, and apoptosis in their villi, as well as extensive expansion of the stem cell and progenitor cell compartment. These findings reveal a novel role for Hdac3 in suppressing colitis and intestinal tumorigenesis, particularly in the context of consumption of an HFD, and reveal a potential mechanism by which HFDs may increase intestinal tumorigenesis by increasing fatty acid oxidation, DNA damage, and intestinal epithelial cell turnover.NEW & NOTEWORTHY We reveal a novel role for the transcriptional corepressor Hdac3 in suppressing colitis and intestinal tumorigenesis, particularly in the context of consumption of an HFD, and reveal a potential mechanism by which HFDs may increase intestinal tumorigenesis by increasing fatty acid oxidation, DNA damage, and intestinal epithelial cell turnover. We also identify a unique mouse model for investigating the complex interplay between diet, metabolic reprogramming, and tumor predisposition in the intestinal epithelium.

Bloqueos supraescapular e interescalénico como analgesia después de la reparación artroscópica del manguito rotador: estudio de cohorte comparativo retrospectivo / Suprascapular and interscalene nerve block as analgesia after arthroscopic rotator cuff repair: a retrospective comparative cohort study

Introducción: El objetivo de este estudio fue comparar la eficacia de los bloqueos interescalénico y supraescapular, solos y combinados, como analgesia posoperatoria en las primeras 3 horas tras la reparación artroscópica del manguito rotador. Materiales y métodos: Estudio de cohorte comparativo retrospectivo, realizado entre 2019 y 2021. El criterio de valoración principal fue el puntaje del dolor de hombro en la sala de recuperación evaluado con una escala analógica visual por el paciente. Los criterios de valoración secundarios fueron el consumo de opioides en la sala de recuperación y las complicaciones de la anestesia locorregional. Resultados: Se incluyó a 175 pacientes, 13 en el grupo de bloqueo interescalénico, 61 en el grupo de bloqueos interescalénico más supraescapular y 101 en el grupo de bloqueo supraescapular. Los grupos de bloqueo interescalénico y de bloqueo interescalénico más supraescapular tuvieron significativamente menos dolor en la sala de recuperación y una tasa total menor de opioides consumidos en miligramos equivalentes de morfina que el grupo de bloqueo supraescapular (p = 0,001 y p <0,01, respectivamente). No hubo diferencias significativas en el dolor ni el consumo de opioides entre el bloqueo interescalénico solo o combinado con bloqueo supraescapular. Conclusiones: El bloqueo interescalénico fue más eficaz que el bloqueo supraescapular para aliviar el dolor y disminuir el consumo de opioides en la sala de recuperación tras la reparación artroscópica del manguito rotador. La combinación de bloqueo interescalénico más bloqueo supraescapular no resultó en un incremento de la eficacia, y se sugiere no combinar estas dos técnicas. Nivel de evidencia: III

Introduction: This study aimed to compare the efficacy of interscalene block (ISB) and suprascapular nerve block (SSNB), individually and in combination (ISB+SSNB), used as postoperative analgesia within the first 3 hours after arthroscopic rotator cuff repair. Materials and methods: Retrospective comparative cohort study, conducted between 2019 and 2021. The primary endpoint was shoulder pain score in the immediate postoperative period as reported on a visual analog scale (VAS) by the patient. Secondary endpoints were opioid use in the recovery room (first 3 hours) and locoregional anesthesia complications. Results:175 patients were included; 13 in the ISB group, 61 in the ISB+SSNB group, and 101 in the SSNB group. The ISB group and the ISB+SSNB group had significantly less pain in the recovery room than the SSNB group (p = 0.001 and p < 0.001, respectively). The percentage of patients who required at least one dose of opioid and the total number of opioids consumed in milligrams of morphine equivalent were significantly lower for the ISB and ISB+SSNB groups than for the SSNB group (p < 0.001). There were no significant differences in pain or opioid use between ISB alone or combined with SSNB (ISB+SSNB). Conclusions: In this retrospective comparative study, ISB was more effective in relieving pain and reducing opioid use in the recovery room after ar-throscopic rotator cuff repair than SSNB. The ISB+SSNB combination did not increase effectiveness, and therefore it is suggested not to combine these two techniques. .Level of Evidence: III

Reparación sistemática del manguito rotador: Clasificación de la Fundación Santa Fe de Bogotá / Standardized rotator cuff repair. Classification of Fundación Santa Fe de Bogotá

La cirugía de manguito rotador se ha popularizado en los últimos años y pasó de realizarse mediante una técnica abierta, en la mayoría de los casos, a la reparación artroscópica. Se han descrito múltiples técnicas para la fijación del hueso, pero no se han estandarizado el orden y los pasos para llevar a cabo esta reparación, lo que generó inconsistencias y heterogeneidad en los resultados de la reparación. En este artículo, se propone una nueva clasificación de las lesiones del manguito rotador que les permitirá a los cirujanos tomar decisiones durante la cirugía de reparación artroscópica del manguito rotador. Nivel de Evidencia: IV

Rotator cuff surgery has become more popular in recent years, transitioning from an open technique to arthroscopic surgery. Although multiple techniques for bone fixation have been described, the steps to perform this repair have not been standardized, leading to inconsistencies and heterogeneity in the outcomes. This article proposes a new classification of rotator cuff injuries that will help surgeons make decisions during arthroscopic rotator cuff repair surgery. Level of Evidence: IV

Preoperative planning in reverse shoulder arthroplasty: plain radiographs vs. computed tomography scan vs. navigation vs. augmented reality.

Reverse shoulder arthroplasty (RSA) has become a highly successful treatment option for various shoulder conditions, leading to a significant increase in its utilization since its approval in 2003. However, postoperative complications, including scapular notching, prosthetic instability, and component loosening, remain a concern. These complications can often be attributed to technical errors during component implantation, emphasizing the importance of proper preoperative planning and accurate positioning of prosthetic components. Improper baseplate and glenosphere positioning in RSA have been linked to impingement, reduced range of motion, and increased scapular notching. Additionally, the relationship between component positioning and intrinsic stability of RSA has been established, with glenoid component retroversion exceeding 10° posing a risk to implant stability. Adequate initial glenoid baseplate fixation, achieved through optimal seating and the use of appropriate screws, is crucial for long-term success and prevention of early failure. Factors such as lateralization and distalization also influence outcomes and complications in RSA, yet standardized guidelines for preoperative planning in these parameters are still lacking. Despite the impact of component position on outcomes, glenoid component implantation remains challenging, with position errors being common even among experienced surgeons. Challenges arise due to factors such as deformity, bone defects, limited exposure, and the absence of reliable bony landmarks intraoperatively. With the evolving understanding of RSA biomechanics and the significance of implant configuration and positioning, advancements in preoperative planning and surgical aids have emerged. This review article explores the current evidence on preoperative planning techniques in RSA, including plain radiographs, three-dimensional imaging, computer planning software, intraoperative navigation, and augmented reality (AR), highlighting their potential benefits and advancements in improving implant position accuracy.

Giant cardiac hydatid cyst causing sustained ventricular tachycardia. Successful surgical treatment.

Cardiac involvement of hydatid disease is rare. In Peru, a country with a high prevalence of this infectious disease, few cases of cardiac hydatid disease have been reported. We present the case of a man with a cardiac hydatid cyst of more than 10 cm in diameter that debuted with malignant arrhythmia and successfully treated with surgery.

La afectación cardíaca de la enfermedad hidatídica es rara. En Perú, país con alta prevalencia de esta enfermedad infecciosa, se han reportado pocos casos de hidatidosis cardíaca. Presentamos el caso de un varón con un quiste hidatídico cardíaco de más de 10 cm de diámetro que debutó con arritmia maligna, tratado exitosamente con cirugía.

Transferencias tendinosas en hombro. Técnica quirúrgica y revisión de la literatura / Tendon transfers in shoulder. Surgical technique and literature review

En lesiones con criterios de irreparabilidad del manguito rotador en pacientes jóvenes y activos se considera realizar transferencia tendinosa como una opción de tratamiento; transferencia del trapecio inferior en lesiones irreparables posterosuperiores del manguito rotador; transferencia del dorsal ancho vía anterior en lesiones irreparables de supraespinoso y transferencia de dorsal ancho en lesiones irreparables del subescapular. En este trabajo realizamos una revisión narrativa de la técnica quirúrgica. Además, se puede observar el video de la experiencia anatómica de cada técnica descripta

In rotator cuff injuries with irreparable criteria in active and young patients, tendon transfer is considered as a treatment option. We describe our experience in performing lower trapezius transfer in irreparable posterosuperior rotator cuff injuries, anterior latissimus dorsi transfer in supraspinatus injuries, and latissimus dorsi transfer in subscapularis injuries. We carry out a narrative review of the surgical technique with the subsequent video of the anatomical experience of each technique described

An acetate-yielding diet imprints an immune and anti-microbial programme against enteric infection.

OBJECTIVES: During gastrointestinal infection, dysbiosis can result in decreased production of microbially derived short-chain fatty acids (SCFAs). In response to the presence of intestinal pathogens, we examined whether an engineered acetate- or butyrate-releasing diet can rectify the deficiency of SCFAs and lead to the resolution of enteric infection. METHODS: We tested whether a high acetate- or butyrate-producing diet (HAMSA or HAMSB, respectively) condition Citrobacter rodentium infection in mice and assess its impact on host-microbiota interactions. We analysed the adaptive and innate immune responses, changes in gut microbiome function, epithelial barrier function and the molecular mechanism via metabolite sensing G protein-coupled receptor 43 (GPR43) and IL-22 expression. RESULTS: HAMSA diet rectified the deficiency in acetate production and protected against enteric infection. Increased SCFAs affect the expression of pathogen virulence genes. HAMSA diet promoted compositional and functional changes in the gut microbiota during infection similar to healthy microbiota from non-infected mice. Bacterial changes were evidenced by the production of proteins involved in acetate utilisation, starch and sugar degradation, amino acid biosynthesis, carbohydrate transport and metabolism. HAMSA diet also induced changes in host proteins critical in glycolysis, wound healing such as GPX1 and epithelial architecture such as EZR1 and PFN1. Dietary acetate assisted in rapid epithelial repair, as shown by increased colonic Muc-2, Il-22, and anti-microbial peptides. We found that acetate increased numbers of colonic IL-22 producing TCRαß+CD8αß+ and TCRγδ+CD8αα+ intraepithelial lymphocytes expressing GPR43. CONCLUSION: HAMSA diet may be an effective therapeutic approach for fighting inflammation and enteric infections and offer a safe alternative that may impact on human health.

Transferencias tendinosas en escápula. Experiencia en cadáveres / Scapular tendon transfers. Experience in cadavers

Las transferencias tendinosas son consideradas para mejorar la función de la escápula y restablecer la biomecánica de la cintura escapular en aquellos pacientes con escápula alada que tienen alteración en la funcionalidad y que no han progresado con tratamiento conservador. Existen diferentes técnicas de transferencias tendinosas como parte del tratamiento. En este artículo realizamos una revisión narrativa, además, ilustramos con videos las siguientes técnicas: la triple transferencia tendinosa en parálisis del trapecio y la transferencia del pectoral mayor hacia la escápula en disfunción del serrato anterior

Tendon transfers are used in management of winged scapula refractory to conservative treatment to improve scapula function and reestablish adequate shoulder biomechanics. There are different techniques described for these tendon transfers. In this article we reviewed these techniques, in addition, we illustrate with videos on cadavers the following techniques: triple tendon transfer for trapezius paralysis and pectoralis mayor tendon transfer to scapula for serratus anterior disfunction

Molecular regulators of lipid metabolism in the intestine - Underestimated therapeutic targets for obesity?

The incidence of obesity and type 2 diabetes continues to rise across the globe necessitating the need to identify new therapeutic approaches to manage these diseases. In this review, we explore the potential for therapeutic interventions focussed on the intestinal epithelium, by targeting the role of this tissue in lipid uptake, lipid-mediated cross talk and lipid oxidation. We focus initially on ongoing strategies to manage obesity by targeting the essential role of the intestinal epithelium in lipid uptake, and in mediating tissue cross talk to regulate food intake. Subsequently, we explore a previously underestimated capacity of intestinal epithelial cells to oxidize fatty acids. In this context, we describe recent findings which have unveiled a key role for the peroxisome proliferator-activated receptor (PPAR) family of nuclear receptors and histone deacetylases (HDACs) in the regulation of lipid oxidation genes in enterocytes and how targeted genetic manipulation of these factors in enterocytes reduces weight gain, identifying intestinal PPARs and HDACs as potential therapeutic targets in the management of obesity.

Deletion of intestinal Hdac3 remodels the lipidome of enterocytes and protects mice from diet-induced obesity.

Histone deacetylase 3 (Hdac3) regulates the expression of lipid metabolism genes in multiple tissues, however its role in regulating lipid metabolism in the intestinal epithelium is unknown. Here we demonstrate that intestine-specific deletion of Hdac3 (Hdac3IKO) protects mice from diet induced obesity. Intestinal epithelial cells (IECs) from Hdac3IKO mice display co-ordinate induction of genes and proteins involved in mitochondrial and peroxisomal ß-oxidation, have an increased rate of fatty acid oxidation, and undergo marked remodelling of their lipidome, particularly a reduction in long chain triglycerides. Many HDAC3-regulated fatty oxidation genes are transcriptional targets of the PPAR family of nuclear receptors, Hdac3 deletion enhances their induction by PPAR-agonists, and pharmacological HDAC3 inhibition induces their expression in enterocytes. These findings establish a central role for HDAC3 in co-ordinating PPAR-regulated lipid oxidation in the intestinal epithelium, and identify intestinal HDAC3 as a potential therapeutic target for preventing obesity and related diseases.

Enhanced Solubility, Permeability and Anticancer Activity of Vorinostat Using Tailored Mesoporous Silica Nanoparticles.

Suberoylanilide hydroxamic acid (SAHA) or vorinostat (VOR) is a potent inhibitor of class I histone deacetylases (HDACs) that is approved for the treatment of cutaneous T-cell lymphoma. However, it has the intrinsic limitations of low water solubility and low permeability which reduces its clinical potential especially when given orally. Packaging of drugs within ordered mesoporous silica nanoparticles (MSNs) is an emerging strategy for increasing drug solubility and permeability of BCS (Biopharmaceutical Classification System) class II and IV drugs. In this study, we encapsulated vorinostat within MSNs modified with different functional groups, and assessed its solubility, permeability and anti-cancer efficacy in vitro. Compared to free drug, the solubility of vorinostat was enhanced 2.6-fold upon encapsulation in pristine MSNs (MCM-41-VOR). Solubility was further enhanced when MSNs were modified with silanes having amino (3.9 fold) or phosphonate (4.3 fold) terminal functional groups. Moreover, permeability of vorinostat into Caco-2 human colon cancer cells was significantly enhanced for MSN-based formulations, particularly MSNs modified with amino functional group (MCM-41-NH2-VOR) where it was enhanced ~4 fold. Compared to free drug, vorinostat encapsulated within amino-modified MSNs robustly induced histone hyperacetylation and expression of established histone deacetylase inhibitor (HDACi)-target genes, and induced extensive apoptosis in HCT116 colon cancer cells. Similar effects were observed on apoptosis induction in HH cutaneous T-cell lymphoma cells. Thus, encapsulation of the BCS class IV molecule vorinostat within MSNs represents an effective strategy for improving its solubility, permeability and anti-tumour activity.

Interleukin 33 Signaling Restrains Sporadic Colon Cancer in an Interferon-γ-Dependent Manner.

Interleukin 33 (IL33) is an inflammatory cytokine released during necrotic cell death. The epithelium and stroma of the intestine express large amounts of IL33 and its receptor St2. IL33 is therefore continuously released during homeostatic turnover of the intestinal mucosa. Although IL33 can prevent colon cancer associated with inflammatory colitis, the contribution of IL33 signaling to sporadic colon cancer remains unknown. Here, we utilized a mouse model of sporadic colon cancer to investigate the contribution of IL33 signaling to tumorigenesis in the absence of preexisting inflammation. We demonstrated that genetic ablation of St2 enhanced colon tumor development. Conversely, administration of recombinant IL33 reduced growth of colon cancer cell allografts. In reciprocal bone marrow chimeras, the concurrent loss of IL33 signaling within radioresistant nonhematopoietic, and the radiosensitive hematopoietic, compartments was associated with increased tumor burden. We detected St2 expression within the radioresistant mesenchymal cell compartment of the colon whose stimulation with IL33 induced expression of bona fide NF-κB target genes. Mechanistically, we discovered that St2 deficiency within the nonhematopoietic compartment coincided with increased abundance of regulatory T cells and suppression of an IFNγ gene expression signature, whereas IL33 administration triggered IFNγ expression by tumor allograft-infiltrating T cells. The decrease of this IFNγ gene expression signature was associated with more aggressive disease in human colon cancer patients, suggesting that lack of IL33 signaling impaired the generation of a potent IFNγ-mediated antitumor immune response. Collectively, our data reveal that IL33 functions as a tumor suppressor in sporadic colon cancer. Cancer Immunol Res; 6(4); 409-21. ©2018 AACR.

DUSP5 is methylated in CIMP-high colorectal cancer but is not a major regulator of intestinal cell proliferation and tumorigenesis.

The ERK signalling pathway regulates key cell fate decisions in the intestinal epithelium and is frequently dysregulated in colorectal cancers (CRCs). Variations in the dynamics of ERK activation can induce different biological outcomes and are regulated by multiple mechanisms, including activation of negative feedback loops involving transcriptional induction of dual-specificity phosphatases (DUSPs). We have found that the nuclear ERK-selective phosphatase DUSP5 is downregulated in colorectal tumours and cell lines, as previously observed in gastric and prostate cancer. The DUSP5 promoter is methylated in a subset of CRC cell lines and primary tumours, particularly those with a CpG island methylator phenotype (CIMP). However, this epigenetic change alone could not account for reduced DUSP5 expression in CRC cells. Functionally, DUSP5 depletion failed to alter ERK signalling or proliferation in CRC cell lines, and its transgenic overexpression in the mouse intestine had minimal impact on normal intestinal homeostasis or tumour development. Our results suggest that DUSP5 plays a limited role in regulating ERK signalling associated with the growth of colorectal tumours, but that methylation the DUSP5 gene promoter can serve as an additional means of identifying CIMP-high colorectal cancers.

ATF3 Repression of BCL-XL Determines Apoptotic Sensitivity to HDAC Inhibitors across Tumor Types.

Purpose: Histone deacetylase inhibitors (HDACi) are epigenome-targeting small molecules approved for the treatment of cutaneous T-cell lymphoma and multiple myeloma. They have also demonstrated clinical activity in acute myelogenous leukemia, non-small cell lung cancer, and estrogen receptor-positive breast cancer, and trials are underway assessing their activity in combination regimens including immunotherapy. However, there is currently no clear strategy to reliably predict HDACi sensitivity. In colon cancer cells, apoptotic sensitivity to HDACi is associated with transcriptional induction of multiple immediate-early (IE) genes. Here, we examined whether this transcriptional response predicts HDACi sensitivity across tumor type and investigated the mechanism by which it triggers apoptosis.Experimental Design: Fifty cancer cell lines from diverse tumor types were screened to establish the correlation between apoptotic sensitivity, induction of IE genes, and components of the intrinsic apoptotic pathway.Results: We show that sensitivity to HDACi across tumor types is predicted by induction of the IE genes FOS, JUN, and ATF3, but that only ATF3 is required for HDACi-induced apoptosis. We further demonstrate that the proapoptotic function of ATF3 is mediated through direct transcriptional repression of the prosurvival factor BCL-XL (BCL2L1) These findings provided the rationale for dual inhibition of HDAC and BCL-XL, which we show strongly cooperate to overcome inherent resistance to HDACi across diverse tumor cell types.Conclusions: These findings explain the heterogeneous responses of tumor cells to HDACi-induced apoptosis and suggest a framework for predicting response and expanding their therapeutic use in multiple cancer types. Clin Cancer Res; 23(18); 5573-84. ©2017 AACR.

Erratum to: "Monoallelic germline methylation and sequence variant in the promoter of the RB1 gene: a possible constitutive epimutation in hereditary retinoblastoma".

[This corrects the article DOI: 10.1186/s13148-015-0167-0.].

Transketolase-like 1 ectopic expression is associated with DNA hypomethylation and induces the Warburg effect in melanoma cells.

BACKGROUND: The metabolism of cancer cells is often reprogrammed by dysregulation of metabolic enzymes. Transketolase-like 1 (TKTL1) is a homodimeric transketolase linking the pentose-phosphate pathway with the glycolytic pathway. It is generally silenced at a transcriptional level in somatic tissues. However, in human cancers its expression is associated with the acquisition of a glycolytic phenotype (the Warburg effect) by cancer cells that contributes to the progression of malignant tumors. In melanoma, defective promoter methylation results in the expression of genes and their products that can affect the tumor cell's phenotype including the modification of immune and functional characteristics. The present study evaluates the role of TKTL1 as a mediator of disease progression in melanoma associated with a defective methylation phenotype. METHODS: The expression of TKTL1 in metastatic melanoma tumors and cell lines was analysed by qRT-PCR and immunohistochemistry. The promoter methylation status of TKTL1 in melanoma cells was evaluated by quantitative methylation specific PCR. Using qRT-PCR, the effect of a DNA demethylating agent 5-aza-2'-deoxycytidine (5aza) on the expression of TKTL1 was examined. Biochemical and molecular analyses such as glucose consumption, lactate production, invasion, proliferation and cell cycle progression together with ectopic expression and siRNA mediated knockdown were used to investigate the role of TKTL1 in melanoma cells. RESULTS: Expression of TKTL1 was highly restricted in normal adult tissues and was overexpressed in a subset of metastatic melanoma tumors and derived cell lines. The TKTL1 promoter was activated by hypomethylation and treatment with 5aza induced TKTL1 expression in melanoma cells. Augmented expression of TKTL1 in melanoma cells was associated with a glycolytic phenotype. Loss and gain of function studies revealed that TKTL1 contributed to enhanced invasion of melanoma cells. CONCLUSIONS: Our data provide evidence for an important role of TKTL1 in aerobic glycolysis and tumor promotion in melanoma that may result from defective promoter methylation. This epigenetic change may enable the natural selection of tumor cells with a metabolic phenotype and thereby provide a potential therapeutic target for a subset of melanoma tumors with elevated TKTL1 expression.

"Monoallelic germline methylation and sequence variant in the promoter of the RB1 gene: a possible constitutive epimutation in hereditary retinoblastoma".

BACKGROUND: Retinoblastoma is a malignant tumor of the retina in children <5 years of age and occurs after two mutations in the RB1 gene. The first mutation (M1) is germinal and confers predisposition to the hereditary type, which is transmitted as an autosomal dominant highly penetrant trait, so 90 % of carriers develop retinoblastoma; however, 10 % of carriers either do not develop the tumor or develop it unilaterally. Most mutations are point mutations. Inactivation of the RB1 gene is usually caused by mutations affecting the coding region. Silencing by methylation of the RB1 promoter has been observed in retinoblastoma tumors as a second mutation (M2) and is classified as somatic epimutation. Germline methylation of the RB1 gene promoter was studied in a particular pedigree of six generations from the paternal side, with incomplete penetrance and bias towards healthy male carriers and those affected with unilateral retinoblastoma. RESULTS: The methylation status of the 27 CpGs dinucleotides that constitute the core of the RB1 gene promoter, analyzed by cloning and genomic sequencing after DNA sodium bisulfite conversion, demonstrated a monoallelic methylation pattern which coincides with a c. [-187T > G; -188T > G] sequence variant that is found in peripheral blood lymphocytes and tumor DNA. Unexpectedly, it was the mother who transmitted this variant to two more generations. Microsatellite markers of D chromosome showed a biparental contribution of both D13 chromosomes to the retinoblastoma phenotype, conferring double heterozygosity in the affected cases. CONCLUSIONS: The monoallelic genetic-epigenetic finding, the sequence variant, and methylation suggest a constitutive epimutation and probably a genetic-epigenetic hereditary predisposition for retinoblastoma in this family.