Role of germinal center and CD39highCD73+ B cells in the age-related tonsillar involution.

BACKGROUND: The tonsils operate as a protection ring of mucosa at the gates of the upper aero-digestive tract. They show similarities with lymph nodes and participate as inductive organs of systemic and mucosal immunity. Based on the reduction of their size since puberty, they are thought to experience involution in adulthood. In this context, we have used tonsillar mononuclear cells (TMC) isolated from patients at different stages of life, to study the effect of ageing and the concomitant persistent inflammation on these immune cells. RESULTS: We found an age-dependent reduction in the proportion of germinal center B cell population (BGC) and its T cell counterpart (T follicular helper germinal center cells, TfhGC). Also, we demonstrated an increment in the percentage of local memory B cells and mantle zone T follicular helper cells (mTfh). Furthermore, younger tonsils rendered higher proportion of proliferative immune cells within the freshly isolated TMC fraction than those from older ones. We demonstrated the accumulation of a B cell subset (CD20+CD39highCD73+ cells) metabolically adapted to catabolize adenosine triphosphate (ATP) as patients get older. To finish, tonsillar B cells from patients at different ages did not show differences in their proliferative response to stimulation ex vivo, in bulk TMC cultures. CONCLUSIONS: This paper sheds light on the changing aspects of the immune cellular landscape, over the course of time and constant exposure, at the entrance of the respiratory and digestive systems. Our findings support the notion that there is a re-modelling of the immune functionality of the excised tonsils over time. They are indicative of a transition from an effector type of immune response, typically oriented to reduce pathogen burden early in life, to the development of an immunosuppressive microenvironment at later stages, when tissue damage control gets critical provided the time passed under immune attack. Noteworthy, when isolated from such histologic microenvironment, older tonsillar B cells seem to level their proliferation capacity with the younger ones. Understanding these features will not only contribute to comprehend the differences in susceptibility to pathogens among children and adults but would also impact on vaccine developments intended to target these relevant mucosal sites.

A common garden experiment supports a genetic component underlying the increased resilience of common cockle (Cerastoderma edule) to the parasite Marteilia cochillia.

The common cockle is a valuable bivalve species inhabiting the Atlantic European coasts. The parasite Marteilia cochillia has devastated cockle beds in the southern Galician (NW Spain) rias since 2012. Previous data suggested that cockles from Ría de Arousa acquired some resilience to this parasite through natural selection after consecutive annual marteiliosis outbreaks and candidate markers associated with marteiliosis resilience were identified using population genomics and transcriptomics approaches. Here, a common garden experiment was performed using a naïve stock (from Ría de Muros-Noia) and an affected stock (from Ría de Arousa) to test this hypothesis. Breeders from both stocks were used to produce seed cohorts at hatchery, which were pre-grown in a raft (outdoor nursery stage) and deployed in two shellfish beds affected by marteiliosis in Ría de Arousa (growing-out stage). In both beds, the naïve stock showed high marteiliosis prevalence and was fully depleted in a short period, while the affected stock barely showed evidence of marteiliosis. A set of 45 SNPs putatively associated with marteiliosis resilience were fitted for MassARRAY genotyping to check their role in the differential resilience detected between both stocks. Though no significant differentiation was found between the naïve and the affected stocks with neutral markers, 28 SNPs showed significant divergence between them, suggesting that these SNPs were involved in directional selection during eight generations (to the most) of marteiliosis pressure (long-term selection). Furthermore, signals of selection were also detected in the naïve stock along the marteiliosis outbreak in the growing-out stage (short-term selection) and six SNPs, all shared with the long-term evaluation, showed consistent signals of differentiation according to the infection severity. Some of these SNPs were located within immune genes pertaining to families such as proteasome, ubiquitin, tumor necrosis factor, and glutathione S-transferase. These resilience-associated markers will be useful to recover cockle production in Galicia.

Dll1-Mediated Notch Signaling Drives Tumor Cell Cross-talk with Cancer-Associated Fibroblasts to Promote Radioresistance in Breast Cancer.

SIGNIFICANCE: Dll1+ breast cancer cells activate Notch signaling in cancer-associated fibroblasts that increases Wnt ligand secretion and leads to ß-catenin-driven radioresistance and metastasis, opening new therapeutic avenues for breast cancer.

Targeting PARP11 to avert immunosuppression and improve CAR T therapy in solid tumors.

Evasion of antitumor immunity and resistance to therapies in solid tumors are aided by an immunosuppressive tumor microenvironment (TME). We found that TME factors, such as regulatory T cells and adenosine, downregulated type I interferon receptor IFNAR1 on CD8+ cytotoxic T lymphocytes (CTLs). These events relied upon poly-ADP ribose polymerase-11 (PARP11), which was induced in intratumoral CTLs and acted as a key regulator of the immunosuppressive TME. Ablation of PARP11 prevented loss of IFNAR1, increased CTL tumoricidal activity and inhibited tumor growth in an IFNAR1-dependent manner. Accordingly, genetic or pharmacologic inactivation of PARP11 augmented the therapeutic benefits of chimeric antigen receptor T cells. Chimeric antigen receptor CTLs engineered to inactivate PARP11 demonstrated a superior efficacy against solid tumors. These findings highlight the role of PARP11 in the immunosuppressive TME and provide a proof of principle for targeting this pathway to optimize immune therapies.

Lengua negra pilosa asociada a carcinoma escamocelular de esófago / Black hairy tongue associated with squamous cell carcinoma of the esophagus

Resumen La lengua negra pilosa (LNP) es una alteración benigna caracterizada por coloración oscura e hipertrofia con hiperqueratosis en las papilas filiformes de la superficie de la lengua. Han sido implicados varios factores intrínsecos y extrínsecos como causales, entre ellos la pobre higiene dental, el tabaquismo, la ingesta de bebidas oscuras, el uso de antibióticos y algunas patologías malignas. Reportamos el caso de un paciente con carcinoma escamocelular avanzado de esófago medio conjunto con LNP, asociación no encontrada previamente en la literatura.

Abstract Black hairy tongue (BHT) is a benign disorder characterized by dark coloration and hypertrophy with hyperkeratosis in filiform papillae on the surface of the tongue. Several intrinsic and extrinsic factors, including poor dental hygiene, smoking, drinking dark beverages, indiscriminate use of antibiotics, and some malignant diseases, have been proposed as potential causes. This is the case of a patient with advanced squamous cell carcinoma of the mid esophagus in conjunction with BHT, a previously unknown association.

Epigenetic and Transcriptional Control of the Epidermal Growth Factor Receptor Regulates the Tumor Immune Microenvironment in Pancreatic Cancer.

Although immunotherapy has revolutionized cancer care, patients with pancreatic ductal adenocarcinoma (PDA) rarely respond to these treatments, a failure that is attributed to poor infiltration and activation of T cells in the tumor microenvironment (TME). We performed an in vivo CRISPR screen and identified lysine demethylase 3A (KDM3A) as a potent epigenetic regulator of immunotherapy response in PDA. Mechanistically, KDM3A acts through Krueppel-like factor 5 (KLF5) and SMAD family member 4 (SMAD4) to regulate the expression of the epidermal growth factor receptor (EGFR). Ablation of KDM3A, KLF5, SMAD4, or EGFR in tumor cells altered the immune TME and sensitized tumors to combination immunotherapy, whereas treatment of established tumors with an EGFR inhibitor, erlotinib, prompted a dose-dependent increase in intratumoral T cells. This study defines an epigenetic-transcriptional mechanism by which tumor cells modulate their immune microenvironment and highlights the potential of EGFR inhibitors as immunotherapy sensitizers in PDA. SIGNIFICANCE: PDA remains refractory to immunotherapies. Here, we performed an in vivo CRISPR screen and identified an epigenetic-transcriptional network that regulates antitumor immunity by converging on EGFR. Pharmacologic inhibition of EGFR is sufficient to rewire the immune microenvironment. These results offer a readily accessible immunotherapy-sensitizing strategy for PDA.This article is highlighted in the In This Issue feature, p. 521.

Immunologic characterization of COVID-19 patients with hematological cancer.

Not available.

Cell Cycle and DNA Repair Regulation in the Damage Response: Protein Phosphatases Take Over the Reins.

Cells are constantly suffering genotoxic stresses that affect the integrity of our genetic material. Genotoxic insults must be repaired to avoid the loss or inappropriate transmission of the genetic information, a situation that could lead to the appearance of developmental abnormalities and tumorigenesis. To combat this threat, eukaryotic cells have evolved a set of sophisticated molecular mechanisms that are collectively known as the DNA damage response (DDR). This surveillance system controls several aspects of the cellular response, including the detection of lesions, a temporary cell cycle arrest, and the repair of the broken DNA. While the regulation of the DDR by numerous kinases has been well documented over the last decade, the complex roles of protein dephosphorylation have only recently begun to be investigated. Here, we review recent progress in the characterization of DDR-related protein phosphatases during the response to a DNA lesion, focusing mainly on their ability to modulate the DNA damage checkpoint and the repair of the damaged DNA. We also discuss their protein composition and structure, target specificity, and biochemical regulation along the different stages encompassed in the DDR. The compilation of this information will allow us to better comprehend the physiological significance of protein dephosphorylation in the maintenance of genome integrity and cell viability in response to genotoxic stress.

Tumor Cell-Intrinsic USP22 Suppresses Antitumor Immunity in Pancreatic Cancer.

Although immune checkpoint blockade (ICB) improves clinical outcome in several types of malignancies, pancreatic ductal adenocarcinoma (PDA) remains refractory to this therapy. Preclinical studies have demonstrated that the relative abundance of suppressive myeloid cells versus cytotoxic T cells determines the efficacy of combination immunotherapies, which include ICB. Here, we evaluated the role of the ubiquitin-specific protease 22 (USP22) as a regulator of the immune tumor microenvironment (TME) in PDA. We report that deletion of USP22 in pancreatic tumor cells reduced the infiltration of myeloid cells and promoted the infiltration of T cells and natural killer (NK) cells, leading to an improved response to combination immunotherapy. We also showed that ablation of tumor cell-intrinsic USP22 suppressed metastasis of pancreatic tumor cells in a T-cell-dependent manner. Finally, we provide evidence that USP22 exerted its effects on the immune TME by reshaping the cancer cell transcriptome through its association with the deubiquitylase module of the SAGA/STAGA transcriptional coactivator complex. These results indicated that USP22 regulates immune infiltration and immunotherapy sensitivity in preclinical models of pancreatic cancer.

Retroclavicular vs Infraclavicular block for brachial plexus anesthesia: a multi-centric randomized trial.

BACKGROUND: The coracoid approach is a simple method to perform ultrasound-guided brachial plexus regional anesthesia (RA) but its simplicity is counterbalanced by a difficult needle visualization. We hypothesized that the retroclavicular (RCB) approach is not longer to perform when compared to the coracoid (ICB) approach, and improves needle visualization. METHODS: This randomized, controlled, non-inferiority trial conducted in two hospitals, included patients undergoing distal upper limb surgery. Patients were randomly assigned to a brachial plexus block (ICB or RCB). The primary outcome was performance time (sum of visualization and needling time), and was analyzed with a non-inferiority test of averages. Depth of sensory and motor blockade, surgical success, total anesthesia time, needle visualization, number of needle passes and complications were also evaluated. Subgroup analysis restricted to patients with higher body mass index was completed. RESULTS: We included 109 patients between September 2016 and May 2017. Mean RCB performance time was 4.8 ± 2.0 min while ICB was 5.2 ± 2.3 min (p = 0.06) with a 95% CI reaching up to 5.8% longer. RCB conferred an ultrasound-needle angle closer to 0° and significantly improved needle visibility after the clavicle was cleared and before local anesthetic administration. No differences were found in the secondary outcomes. Similar results were found in the subgroup analysis. CONCLUSION: RCB approach for brachial plexus anesthesia was similar to ICB approach in terms of time performance. Needle visibility, which represent an important clinical variable, was superior and angle between needle and ultrasound probe was close to 0° in the RCB group. CLINICAL TRIAL REGISTRATION: ClinicalTrials.gov (NCT02913625), registered 26 September 2016.

Role of protein phosphatases PP1, PP2A, PP4 and Cdc14 in the DNA damage response.

Maintenance of genome integrity is fundamental for cellular physiology. Our hereditary information encoded in the DNA is intrinsically susceptible to suffer variations, mostly due to the constant presence of endogenous and environmental genotoxic stresses. Genomic insults must be repaired to avoid loss or inappropriate transmission of the genetic information, a situation that could lead to the appearance of developmental anomalies and tumorigenesis. To safeguard our genome, cells have evolved a series of mechanisms collectively known as the DNA damage response (DDR). This surveillance system regulates multiple features of the cellular response, including the detection of the lesion, a transient cell cycle arrest and the restoration of the broken DNA molecule. While the role of multiple kinases in the DDR has been well documented over the last years, the intricate roles of protein dephosphorylation have only recently begun to be addressed. In this review, we have compiled recent information about the function of protein phosphatases PP1, PP2A, PP4 and Cdc14 in the DDR, focusing mainly on their capacity to regulate the DNA damage checkpoint and the repair mechanism encompassed in the restoration of a DNA lesion.

Author Correction: Hysteresis control of epithelial-mesenchymal transition dynamics conveys a distinct program with enhanced metastatic ability.

The original version of this Article contained an error in the spelling of the author Daniel D. Liu, which was incorrectly given as Daniel Liu. This has now been corrected in both the PDF and HTML versions of the Article.

Hysteresis control of epithelial-mesenchymal transition dynamics conveys a distinct program with enhanced metastatic ability.

Epithelial-mesenchymal transition (EMT) have been extensively characterized in development and cancer, and its dynamics have been modeled as a non-linear process. However, less is known about how such dynamics may affect its biological impact. Here, we use mathematical modeling and experimental analysis of the TGF-ß-induced EMT to reveal a non-linear hysteretic response of E-cadherin repression tightly controlled by the strength of the miR-200s/ZEBs negative feedback loop. Hysteretic EMT conveys memory state, ensures rapid and robust cellular response and enables EMT to persist long after withdrawal of stimuli. Importantly, while both hysteretic and non-hysteretic EMT confer similar morphological changes and invasive potential of cancer cells, only hysteretic EMT enhances lung metastatic colonization efficiency. Cells that undergo hysteretic EMT differentially express subsets of stem cell and extracellular matrix related genes with significant clinical prognosis value. These findings illustrate distinct biological impact of EMT depending on the dynamics of the transition.

Herlyn-werner-wünderlich syndrome: case report

ABSTRACT Introduction: The Herlyn-Werner-Wünderlich (HWW) syndrome is the association of three urogenital anatomic alterations of low incidence. Müllerian alterations are rare and are usually incidental findings; consequently, they are underdiagnosed and their genesis and correlation with having a higher probability of expression on the right side are unknown. Case Report: This is the case of a 17-year-old patient who consulted for severe hypogastric abdominal pain linked to foul-smelling bleeding. On physical examination, a vaginal septum was found, while complementary images showed uterus didelphys and renal agenesis, leading to diagnose HWW syndrome. Furthermore, pyometra and hematocolpus were also documented and managed with antibiotic therapy. Given the adequate response to treatment, hospital discharge was authorized with follow-up by external consultation, since the definitive management could not be provided during hospital stay. Discussion: One of the causes of recurrent abortions is the presence of this syndrome; however, when properly diagnosed, definitive treatment can be provided to reduce con-ceptional losses and urogenital hematopuru-lent collections. Conclusions: HWW syndrome is a rare malformation that increases the risk of suffering from gynecological infectious diseases or blood collections. Surgical management of the vaginal septum is a definitive treatment that improves quality of life and reduces the risk of morbidities associated with the pathology.

RESUMEN Introducción. El síndrome de Herlyn-Werner-Wünderlich (HWW) es una asociación de tres alteraciones anatómicas urogenitales de baja incidencia. Las alteraciones müllerianas son poco comunes y suelen ser hallazgos incidentales, por lo que se encuentran subdiag-nosticadas y poco se conoce su génesis o su relación con tener más probabilidad de expresión en el lado derecho. Reporte de caso. Se trata de una paciente de 17 años quien consultó por dolor abdominal hipogástrico de fuerte intensidad ligado a sangrado fétido. En el examen físico se encontró tabique vaginal y en las imágenes complementarias se evidenció útero didelfo y agenesia renal, diagnosticando así síndrome HWW. Igualmente, se documentó piómetra y hematocolpos que se manejaron con terapia de antibióticos; dada la adecuada respuesta al tratamiento, se dio egreso hospitalario con seguimiento por consulta externa, pues el manejo definitivo no se pudo proporcionar durante la estancia hospitalaria. Discusión. Una causa de abortos a repetición es la presencia de síndrome HWW; sin embargo, al ser correctamente diagnosticado, se puede dar un tratamiento definitivo que disminuya las perdidas concepcionales y colecciones hematopurulentas urogenitales. Conclusiones. El síndrome HWW es una malformación poco común que aumenta el riesgo de padecer cuadros infecciosos ginecológicos o colecciones hemáticas. El tratamiento definitivo consiste en el manejo quirúrgico del tabique vaginal que mejora la calidad de vida y disminuye el riesgo de morbilidades asociadas a la patología.

Cdc14 and Chromosome Condensation: Evaluation of the Recruitment of Condensin to Genomic Regions.

Chromosome condensation is an essential morphological event required for successful DNA segregation during mitosis. The high level of genome compaction achieved during this process is attained by the evolutionary conserved condensin complex. Recently, several lines of evidences have demonstrated that the mitotic phosphatase Cdc14 is required to ensure condensin loading onto chromosomes. To date several approaches have been used in order to characterize condensin activity and regulation, however these techniques are time-consuming and require complex equipment. In this chapter we described an easy and reliable protocol to analyze Cdc14-dependent condensin loading onto specific genomic DNA regions by using a chromatin immunoprecipitation (ChIP) technique.

Hemicorea vascular: caso clínico y revisión / Vascular hemichorea: case report and review

La corea es una rara complicación de las lesiones vasculares cerebrales isquémicas o hemorrágicas y aunque las manifestaciones clínicas son variables, habitualmente se afecta un único hemicuerpo, en cuyos casos la lesión se encuentra en el hemisferio cerebral contralateral. A pesar de que la remisión espontánea es la norma, el tratamiento sintomático en ocasiones es requerido. El caso es un paciente masculino de 58 años de edad, con hipertensión arterial sin tratamiento, obesidad tipo II, consumo de 6 cajetillas de cigarrillos al año e ingesta moderada de alcohol. El paciente inició enfermedad actual tres días previos a acudir al servicio de emergencias, cuando presentó movimientos involuntarios incesantes en miembro superior izquierdo y pie ipsilateral, persistiendo durante el día y observables durante la noche, sin limitación del movimiento voluntario. El examen físico no presentó alteraciones adicionales a los movimientos coreiformes; exámenes pertinentes de laboratorio no alterados. Se realizó resonancia magnética de cerebro revelando hiperintensidad en región talámica posterolateral derecha consistente con enfermedad cerebrovascular isquémica. Se indicó tratamiento sintomático y para patologías de base. El caso es importante por la baja prevalencia y escasos estudios publicados actualizados inherentes al origen vascular de la hemicorea para diagnóstico, pronóstico y tratamiento.

Chorea rarely complicates ischemic or hemorrhagic cerebral vascular lesions. Clinical symptoms usually involve one side of the body while the injury is situated on the contralateral cerebral hemisphere. Spontaneous remission is the norm, but sometimes symptomatic treatment is required. A 58-year-old male patient who suffers from untreated high blood pressure, type II obesity, smokes 6 packs of cigarettes per year and has a moderate intake of alcohol is presented. The patient’s recent history began three days before he appeared at the Emergency Department. His symptoms were ceaseless, involuntary movements in his left arm and foot during day and night with no restriction of voluntary movements. Physical examination and laboratory tests revealed no other findings. Magnetic resonance imaging of the brain showed hyperintensity in the right posterolateral thalamic region consistent with ischemic cerebrovascular disease. Symptomatic therapy was indicated and his underlying conditions were addressed. The importance of this case lies on the low prevalence as well as the scarcity of publications regarding vascular causes of hemichorea, including diagnosis, therapy and prognosis.

Cdc14 inhibits transcription by RNA polymerase I during anaphase.

Chromosome condensation and the global repression of gene transcription are features of mitosis in most eukaryotes. The logic behind this phenomenon is that chromosome condensation prevents the activity of RNA polymerases. In budding yeast, however, transcription was proposed to be continuous during mitosis. Here we show that Cdc14, a protein phosphatase required for nucleolar segregation and mitotic exit, inhibits transcription of yeast ribosomal genes (rDNA) during anaphase. The phosphatase activity of Cdc14 is required for RNA polymerase I (Pol I) inhibition in vitro and in vivo. Moreover Cdc14-dependent inhibition involves nucleolar exclusion of Pol I subunits. We demonstrate that transcription inhibition is necessary for complete chromosome disjunction, because ribosomal RNA (rRNA) transcripts block condensin binding to rDNA, and show that bypassing the role of Cdc14 in nucleolar segregation requires in vivo degradation of nascent transcripts. Our results show that transcription interferes with chromosome condensation, not the reverse. We conclude that budding yeast, like most eukaryotes, inhibit Pol I transcription before segregation as a prerequisite for chromosome condensation and faithful genome separation.

La comunidad terapéutica psicoanalítica como tratamiento de un paciente con el diagnóstico de esquizofrenia / Psychoanalitic terapeutic community as the treatment of a patient with schizophrenia diagnosis

En estre trabajo describimos el tratamiento psicoterapéutico institucional efectuado con un paciente diagnósticado como esquizofrénico. Enunciamos brevemente los basamentos teóricos tanto de la comunidad terapéutica como los del psicoanálisis del self. Se realiza una presentación del paciente y se muestra la evolución clínica del mismo en la comunidad terapéutica de Hospital de día, por medio de escenas dramáticas originadas y dirigidas por el paciente