The chromatin-associated lncREST ensures effective replication stress response by promoting the assembly of fork signaling factors.

Besides the well-characterized protein network involved in the replication stress response, several regulatory RNAs have been shown to play a role in this critical process. However, it has remained elusive whether they act locally at the stressed forks. Here, by investigating the RNAs localizing on chromatin upon replication stress induced by hydroxyurea, we identified a set of lncRNAs upregulated in S-phase and controlled by stress transcription factors. Among them, we demonstrate that the previously uncharacterized lncRNA lncREST (long non-coding RNA REplication STress) is transcriptionally controlled by p53 and localizes at stressed replication forks. LncREST-depleted cells experience sustained replication fork progression and accumulate un-signaled DNA damage. Under replication stress, lncREST interacts with the protein NCL and assists in engaging its interaction with RPA. The loss of lncREST is associated with a reduced NCL-RPA interaction and decreased RPA on chromatin, leading to defective replication stress signaling and accumulation of mitotic defects, resulting in apoptosis and a reduction in tumorigenic potential of cancer cells. These findings uncover the function of a lncRNA in favoring the recruitment of replication proteins to sites of DNA replication.

Autophagy-mediated control of ribosome homeostasis in oncogene-induced senescence.

Oncogene-induced senescence (OIS) is a persistent anti-proliferative response that acts as a barrier against malignant transformation. During OIS, cells undergo dynamic remodeling, which involves alterations in protein and organelle homeostasis through autophagy. Here, we show that ribosomes are selectively targeted for degradation by autophagy during OIS. By characterizing senescence-dependent alterations in the ribosomal interactome, we find that the deubiquitinase USP10 dissociates from the ribosome during the transition to OIS. This release of USP10 leads to an enhanced ribosome ubiquitination, particularly of small subunit proteins, including lysine 275 on RPS2. Both reinforcement of the USP10-ribosome interaction and mutation of RPS2 K275 abrogate ribosomal delivery to lysosomes without affecting bulk autophagy. We show that the selective recruitment of ubiquitinated ribosomes to autophagosomes is mediated by the p62 receptor. While ribophagy is not required for the establishment of senescence per se, it contributes to senescence-related metabolome alterations and facilitates the senescence-associated secretory phenotype.

Congenital Prepubic Sinus as a Variant of Incomplete Urethral Dorsal Duplication: A Case Report with New Insights into its Immunohistochemical Characterization and a Comprehensive Literature Review.

Congenital prepubic sinus (PS) is an extremely infrequent malformation consisting of a prepubic fistulous tract that classically does not communicate with the genitourinary system. Previous studies centered on its immunohistochemical characterization have shown inconsistent results, and the etiology has not been clarified. We present the case of a 2-year-old male who presented since birth with a fistulous orifice on the dorsum of the penis. He had no associated symptoms. Under general anesthesia, the fistulous tract was explored, and methylene blue was instilled through it. After cystoscopically verifying the absence of communication with the urethra, a complete resection of the lesion was performed. The immunohistochemical study showed positivity for low and high molecular weight keratins and a transitional pattern for keratin 7 and GATA3, with positivity at cul de sac level and negativity at proximal level. These findings suggest that this lesion is an incomplete dorsal duplication variant.

[Solitary dorsal paravertebral tumor: radiological and histopathological characterization of a pediatric case of nodular fasciitis].

Nodular fasciitis is a benign soft tissue lesion with rapid fibroblastic or myofibroblastic proliferation, rarely observed in pediatric patients. Here, we present the case of a seven-year-old boy with no relevant medical records, in whom an asymptomatic dorsal tumor was incidentally identified. Magnetic resonance imaging showed a left dorsal paravertebral lesion with hypointensity on T1, hyperintensity on T2, peripheral contrast enhancement, and the so-called fascial tail sign. Complete surgical resection of the lesion was achieved. The histopathological study showed a proliferation of spindle or stellate cells with nuclei without atypia in a myxoid or collagenized stroma. The immunohistochemical profile showed positivity for smooth muscle actin, muscle-specific actin antibody HHF35, and calponin. The lesion was diagnosed as nodular fasciitis, an entity with broad and complex differential diagnosis. Presence of specific radiological signs and adequate immunohistochemical characterization of the lesion help perform an accurate diagnosis.

Tumor paravertebral dorsal solitario: caracterización radiológica e histopatológica de un caso pediátrico de fascitis nodular / Solitary dorsal paravertebral tumor: radiological and histopathological characterization of a pediatric case of nodular fasciitis

La fascitis nodular es una lesión benigna de tejidos blandos de rápida proliferación fibroblástica o miofibroblástica, excepcional en pediatría. Presentamos el caso de un varón de siete años, sin antecedentes, que debutó con una tumoración dorsal asintomática identificada incidentalmente. La resonancia magnética mostró una lesión paravertebral dorsal izquierda con hipointensidad en T1, hiperintensidad en T2, captación periférica de contraste y el denominado signo de la cola fascial. Se realizó una resección quirúrgica completa de la lesión. El estudio histopatológico mostró una proliferación de células fusiformes o estrelladas con núcleos sin atipia en un estroma mixoide o colagenizado. El perfil inmunohistoquímico mostró positividad para actina de músculo liso SMA, actina músculo específica HHF35 y calponina. Se diagnosticó fascitis nodular, entidad que presenta un diagnóstico diferencial amplio y complejo. La presencia de signos radiológicos específicos y la adecuada caracterización inmunohistoquímica de la lesión contribuyen a realizar un diagnóstico preciso.(AU)

Nodular fasciitis is a benign soft tissue lesion with rapid fibroblastic or myofibroblastic proliferation, rarely observed in pediatric patients. Here, we present the case of a seven-year-old boy with no relevant medical records, in whom an asymptomatic dorsal tumor was incidentally identified. Magnetic resonance imaging showed a left dorsal paravertebral lesion with hypointensity on T1, hyperintensity on T2, peripheral contrast enhancement, and the so-called fascial tail sign. Complete surgical resection of the lesion was achieved. The histopathological study showed a proliferation of spindle or stellate cells with nuclei without atypia in a myxoid or collagenized stroma. The immunohistochemical profile showed positivity for smooth muscle actin, muscle-specific actin antibody HHF35, and calponin. The lesion was diagnosed as nodular fasciitis, an entity with broad and complex differential diagnosis. Presence of specific radiological signs and adequate immunohistochemical characterization of the lesion help perform an accurate diagnosis.(AU)

Adrenal cortex ectopic tissue as an incidental finding in pediatric inguinal canal surgery: a case series.

The presence of ectopic adrenal remnants in the inguinal canal is an infrequent finding in pediatric patients. We performed a retrospective review of all pediatric patients diagnosed with ectopic adrenal tissue as an incidental finding during surgery of the inguinal canal at our center between 2000 and 2021. Six patients were included. The mean age was 3.83 ± 2.91 years. 3 (50%) were Arab and 3 (50%) were Caucasian. All patients were male. Five of the patients (83.3%) underwent surgery for testicular maldescent and one patient (16.6%) underwent surgery for a left hydrocele. 4 patients were operated on the right side (66%) and 2 on the left side (33%). Histologically, the presence of ectopic adrenal tissue was confirmed in all patients. All patients are healthy, discharged and under ambulatory follow-up. The existing literature suggests that ectopic adrenal remnants do not appear to have clinical or prognostic implications.

Implication of Different Tumor Biomarkers in Drug Resistance and Invasiveness in Primary and Metastatic Colorectal Cancer Cell Lines.

Protein expression profiles are directly related to the different properties of cells and are conditioned by the cellular niche. As an example, they are the cause of the characteristic cell plasticity, epithelium-mesenchymal transition (EMT), and drug resistance of cancer cells. This article characterizes ten biomarkers related to these features in three human colorectal cancer cell lines: SW-480, SW-620, and DLD-1, evaluated by flow cytometry; and in turn, resistance to oxaliplatin is studied through dose-response trials. The main biomarkers present in the three studied lines correspond to EpCAM, CD-133, and AC-133, with the latter two in low proportions in the DLD-1 line. The biomarker CD166 is present in greater amounts in SW-620 and DLD-1 compared to SW-480. Finally, DLD-1 shows high values of Trop2, which may explain the aggressiveness and resistance of these cells to oxaliplatin treatments, as EpCAM is also highly expressed. Exposure to oxaliplatin slows cell growth but also helps generate resistance to the treatment. In conclusion, the response of the cell lines is variable, due to their genetic variability, which will condition protein expression and cell growth. Further analyses in this area will provide important information for better understanding of patients' cellular response and how to prevent resistance.

Adrenal cortex ectopic tissue as an incidental finding in pediatric inguinal canal surgery: a case series

The presence of ectopic adrenal remnants in the inguinal canal is an infrequent finding in pediatric patients. We performed aretrospective review of all pediatric patients diagnosed with ectopic adrenal tissue as an incidental finding during surgery of theinguinal canal at our center between 2000 and 2021. Six patients were included. The mean age was 3.83 ± 2.91 years. 3 (50%)were Arab and 3 (50%) were Caucasian. All patients were male. Five of the patients (83.3%) underwent surgery for testicularmaldescent and one patient (16.6%) underwent surgery for a left hydrocele. 4 patients were operated on the right side (66%)and 2 on the left side (33%). Histologically, the presence of ectopic adrenal tissue was confirmed in all patients. All patientsare healthy, discharged and under ambulatory follow-up. The existing literature suggests that ectopic adrenal remnants do notappear to have clinical or prognostic implications (AU)

Importance of Timely Treatment Initiation in Infantile-Onset Pompe Disease, a Single-Centre Experience.

Classic infantile Pompe disease (IPD) is a rare lysosomal storage disorder characterized by severe hypertrophic cardiomyopathy and profound muscle weakness. Without treatment, death occurs within the first 2 years of life. Although enzyme replacement therapy (ERT) with alglucosidase alfa has improved survival, treatment outcome is not good in many cases and is largely dependent on age at initiation. The objective of the study was (a) to analyse the different stages in the diagnosis and specific treatment initiation procedure in IPD patients, and (b) to compare clinical and biochemical outcomes depending on age at ERT initiation (<1 month of age vs. <3 months of age). Here, we show satisfactory clinical and biochemical outcomes in two IPD patients after early treatment initiation before 3 months of life with immunomodulatory therapy in the ERT-naïve setting, with a high ERT dose from the beginning. Despite the overall good evolution, the patient who initiated treatment <1 month of life presented even better outcomes than the patient who started treatment <3 months of life, with an earlier normalization of hypertrophic cardiomyopathy, along with CK normalization, highlighting the importance of early treatment initiation in this progressive disease before irreversible muscle damage has occurred.

The long non-coding RNA MIR31HG regulates the senescence associated secretory phenotype.

Oncogene-induced senescence provides a barrier against malignant transformation. However, it can also promote cancer through the secretion of a plethora of factors released by senescent cells, called the senescence associated secretory phenotype (SASP). We have previously shown that in proliferating cells, nuclear lncRNA MIR31HG inhibits p16/CDKN2A expression through interaction with polycomb repressor complexes and that during BRAF-induced senescence, MIR31HG is overexpressed and translocates to the cytoplasm. Here, we show that MIR31HG regulates the expression and secretion of a subset of SASP components during BRAF-induced senescence. The SASP secreted from senescent cells depleted for MIR31HG fails to induce paracrine invasion without affecting the growth inhibitory effect. Mechanistically, MIR31HG interacts with YBX1 facilitating its phosphorylation at serine 102 (p-YBX1S102) by the kinase RSK. p-YBX1S102 induces IL1A translation which activates the transcription of the other SASP mRNAs. Our results suggest a dual role for MIR31HG in senescence depending on its localization and points to the lncRNA as a potential therapeutic target in the treatment of senescence-related pathologies.

Impact of the COVID-19 pandemic during Spain's state of emergency on the diagnosis of colorectal cancer.

INTRODUCTION: We evaluate the impact of COVID-epidemic in colorectal cancer (CRC) diagnosis during Spain's state of emergency. METHODS: We compared newly diagnosed patients with patients diagnosed in the same period of 2019. RESULTS: A new diagnosis of CRC decreased 48% with a higher rate of patients diagnosed in the emergency setting (12.1% vs. 3.6%; p = .048) and a lower rate diagnosed in the screening program (5.2% vs. 33.3%; p = .000). CONCLUSIONS: Fewer patients have been diagnosed with CRC, with a higher rate of patients diagnosed in an emergency setting.

Aniline-Based Inhibitors of Influenza H1N1 Virus Acting on Hemagglutinin-Mediated Fusion.

Two series of easily accessible anilines were identified as inhibitors of influenza A virus subtype H1N1, and extensive chemical synthesis and analysis of the structure-activity relationship were performed. The compounds were shown to interfere with low pH-induced membrane fusion mediated by the H1 and H5 (group 1) hemagglutinin (HA) subtypes. A combination of virus resistance, HA interaction, and molecular dynamics simulation studies elucidated the binding site of these aniline-based influenza fusion inhibitors, which significantly overlaps with the pocket occupied by some H3 HA-specific inhibitors, indicating the high relevance of this cavity for drug design.

Signet ring cell carcinoma of the jejunum: an uncommon finding within the reach of capsule endoscopy.

An 80 year-old female presented with ductal breast carcinoma (stage II) three years ago, complained of asthenia and iron-deficiency anemia. No diagnosis was obtained after conventional endoscopy and iron supplements were indicated. Ten months later visible digestive hemorrhage was presented. Upper and lower endoscopy was repeated but non-diagnosis was obtained. Thus, video capsule endoscopy was indicated identifying a stenotic lesion arising in the mucosa of distal jejunum. Histopathological examination revealed a poorly mucinous differentiated signet-ring cell adenocarcinoma with an intense peri-tumoral lymphoid (Crohn´s-like lymphoid reaction) and lympho-vascular infiltration with no nodal metastases (pT3N0;7ª edition TNM classification). Immunochemistry revealed negative stained for estrogen and progesterone receptors in contrast with prior breast cancer. Thus, metastatic origin was rule out. Primary small-bowel malignancies are extremely rare. They account for 2% of all gastrointestinal tract malignancies. Carcinoid tumor (40%), adenocarcinoma (33%), lymphoma (17%) and sarcoma (8%) are most common histological types. Symptomatic lesions are rare, but when present: gastrointestinal bleeding, abdominal pain and weight loss are most common digestive symptoms. Primary signet ring cell adenocarcinoma is a rarely histopathological variety of adenocarcinoma with poor prognosis, usually identified in esophageal or gastric locations (95%). They are less commonly detected in remaining gastrointestinal tract, and when present, metastatic origin must always rule out. Nowadays, diagnostic delayed is common and leads to detected small bowel neoplasms at late stages with poor treatment outcomes. Thus, capsule endoscopy may help to improve this situation as it may identify them at early stages.

Signet ring cell carcinoma of the jejunum: an uncommon finding within the reach of capsule endoscopy

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Transcriptional Elongation Regulator 1 Affects Transcription and Splicing of Genes Associated with Cellular Morphology and Cytoskeleton Dynamics and Is Required for Neurite Outgrowth in Neuroblastoma Cells and Primary Neuronal Cultures.

TCERG1 is a highly conserved human protein implicated in interactions with the transcriptional and splicing machinery that is associated with neurodegenerative disorders. Biochemical, neuropathological, and genetic evidence suggests an important role for TCERG1 in Huntington's disease (HD) pathogenesis. At present, the molecular mechanism underlying TCERG1-mediated neuronal effects is unknown. Here, we show that TCERG1 depletion led to widespread alterations in mRNA processing that affected different types of alternative transcriptional or splicing events, indicating that TCERG1 plays a broad role in the regulation of alternative splicing. We observed considerable changes in the transcription and alternative splicing patterns of genes involved in cytoskeleton dynamics and neurite outgrowth. Accordingly, TCERG1 depletion in the neuroblastoma SH-SY5Y cell line and primary mouse neurons affected morphogenesis and resulted in reduced dendritic outgrowth, with a major effect on dendrite ramification and branching complexity. These defects could be rescued by ectopic expression of TCERG1. Our results indicate that TCERG1 affects expression of multiple mRNAs involved in neuron projection development, whose misregulation may be involved in TCERG1-linked neurological disorders.

Pólipos serrados y su asociación con neoplasia avanzada de colon / Serrated polyps and their association with synchronous advanced colorectal neoplasia

INTRODUCCIÓN: Los pólipos serrados (PS) grandes, PS proximales, PS con displasia y la presencia de múltiples adenomas sésiles serrados (P/ASS), que englobamos bajo el término PS con riesgo aumentado de lesiones metacrónicas (PSRALM), se asocian a un mayor riesgo de presentar dichas lesiones, pero desconocemos si también se asocian a un mayor riesgo de neoplasia avanzada de colon (NA) sincrónica. OBJETIVO: Estimar la prevalencia de PSRALM y evaluar la asociación con NA sincrónica. MÉTODOS: Se trata de un estudio transversal de base poblacional que incluyó a todos los pacientes (1.538) con diagnostico histológico de PS de muestras procedentes de colonoscopias, rectosigmoidoscopias e intervenciones quirúrgicas de los hospitales públicos del Servicio Navarro de Salud durante el año 2011. Se analizaron parámetros demográficos y presencia de lesiones sincrónicas de colon (adenomas, adenomas avanzados [AA] y NA) RESULTADOS: La cuarta parte de los pacientes (384) presentaron PSRALM, con una edad media más avanzada, un ligero predominio en mujeres y sin diferencias en cuanto al IMC respecto a los pacientes sin PSRALM. En el análisis multivariante el grupo PSRALM presentó un mayor riesgo de AA y NA sincrónicos (OR: 2,38 [1,77-3,21] y OR: 2,29 [1,72-3,05] respectivamente) y en el caso de NA, este riesgo fue estadísticamente significativo en ambas localizaciones (proximal y distal), con OR superior para la proximal. Los distintos subtipos de PSRALM presentaron un mayor riesgo de AA y NA sincrónicos. CONCLUSIÓN: Los PSRALM fueron frecuentes entre los pacientes con PS y se asociaron a un mayor riesgo de presentar NA sincrónica

INTRODUCTION: Large serrated polyps (SP), proximal SP, SP with dysplasia and the presence of multiple sessile serrated adenomas/polyps (SSA/P), which we refer to as SP with increased risk of metachronous lesions (SPIRML), have been associated with an increased risk of advanced colon lesions on follow-up. It is unclear, however, whether SPIRML are also associated with an increased risk of synchronous advanced colorectal neoplasia (ACN). AIM: The aim of this study was to estimate the prevalence of SPIRML and to evaluate the association between SPIRML and synchronous ACN. METHODS: A cross-sectional population-based study in all patients (1,538) with histological diagnosis of SP obtained from colonoscopies, sigmoidoscopies and colonic surgery performed in Navarra Health Service hospitals (Spain) in 2011. Demographic parameters and synchronous colonic lesions (adenomas, advanced adenomas [AA] and ACN) were analyzed. RESULTS: One fourth of the sample (384 patients) presented SPIRML. These were older patients, with a slight predominance of women, and with no differences in body mass index (BMI) compared to patients without SPIRML. In the univariate analysis, patients with SPIRML showed an increased risk of adenoma, AA and ACN. In the multivariate analysis, the SPIRML group had a higher risk of synchronous AA and ACN (odds ratio [OR]: 2.38 [1.77-3.21] and OR: 2.29 [1.72-3.05], respectively); in the case of ACN, this risk was statistically significant in both locations (proximal or distal), with OR slightly higher for the proximal location. Different subtypes of SPIRML had a higher risk of AA and synchronous NA. CONCLUSION: SPIRML were common in patients with SP, and their presence was associated with an increased risk of synchronous CAN