Temporal relationship between sarcoidosis and malignancies in a nationwide cohort of 1942 patients.

PURPOSE: To investigate the phenotype of sarcoidosis according to the time when a malignancy is diagnosed (preexisting to the diagnosis of sarcoidosis, concomitant, or sequential) and to identify prognostic factors associated with malignancies in a large cohort of patients with sarcoidosis. METHODS: We searched for malignancies in the SARCOGEAS cohort, a multicenter nationwide database of consecutive patients diagnosed with sarcoidosis according to the ATS/ESC/WASOG criteria. Solid malignancies were classified using the International Statistical Classification of Diseases and Related Health Problems 10th Revision (ICD-10) nomenclature, and hematological malignancies using the 2016 WHO classification. We excluded patients with a biopsy-proven diagnosis of sarcoidosis based exclusively on demonstrating granulomas in tissues also involved by malignant cells. RESULTS: Out of 1942 patients with sarcoidosis, 233 (12%) developed 250 malignancies, including solid (n = 173), hematological (n = 57), and both types of malignancies (n = 3). Concerning the time interval between the diagnoses of both conditions, 83 (36%) patients were diagnosed with malignancy at least 1 year before sarcoidosis diagnosis, 22 (9%) had s synchronous diagnosis of both diseases, and 118 (51%) developed malignancies at least 1 year after the diagnosis of sarcoidosis (the remaining cases developed malignancies in different time intervals). The multivariate-adjusted model showed that individuals with sarcoidosis who developed a malignancy had an hazard ratio (HR) of 2.27 [95% confidence interval (CI), 1.62-3.17] for having an asymptomatic clinical phenotype at diagnosis of sarcoidosis and that spleen (presence vs. absence: HR = 2.06; 95% CI, 1.21-3.51) and bone marrow (presence vs. absence: HR = 3.04; 95% CI, 1.77-5.24) involvements were independent predictors for the development of all-type malignancies. No predictive factors were identified when the analysis was restricted to the development of solid malignancies. The analysis limited to the development of hematological malignancies confirmed the presence of involvement in the spleen (HR = 3.73; 95% CI, 1.38-10.06) and bone marrow (presence vs. absence: HR = 8.00; 95% CI, 3.15-20.35) at the time of sarcoidosis diagnosis as predictive factors. CONCLUSION: It is essential to consider the synchronous or metachronous timing of the diagnosis of malignancies in people with sarcoidosis. We found that half of the malignancies were diagnosed after a diagnosis of sarcoidosis, with spleen and bone marrow involvement associated with a four to eight times higher risk of developing hematological malignancies. Key messages What is already known on this topic Malignancies are one of the comorbidities more frequently encountered in people with sarcoidosis What this study adds Malignancies occur in 12% of patients with sarcoidosis Malignancy may precede, coincide with, or follow the diagnosis of sarcoidosis One-third were identified before sarcoidosis, and half were diagnosed after Spleen and bone marrow involvement are risk factors for developing hematological malignancies How this study might affect research, practice or policy Patients with sarcoidosis should be regularly monitored for neoplasms, informed of the increased risk, and educated on early detection. Those with spleen or bone marrow involvement must be closely followed.

Evaluating the Safety of the Intragastric Balloon: Spanish Multicenter Experience in 20,680 Cases and with 12 Different Balloon Models.

INTRODUCTION: Intragastric balloon (IGB) is a minimally invasive and reversible option for obesity treatment. There is a worldwide growing number of different IGB models. The efficacy and safety profile for each model must be demonstrated. We aim to evaluate IGB safety profile according to the experience of the Spanish Bariatric Endoscopy Group (GETTEMO). METHODS: A survey of 37 IGBs safety-related questions was sent to all GETTEMO members, to retrospectively collect a multicenter Spanish registry. Incidence, causes, and resolution of both major and minor complications and adverse events (AEs), including legal consequences, differentiated for each balloon model were evaluated. Secondary outcome was weight loss data to confirm efficacy. RESULTS: Twenty-one Spanish hospitals experienced in IGBs responded. The overall data encompassed 20,680 IGBs, including 12 different models. Mean %TBWL of 17.66 ± 2.5% was observed. Early removal rate due to intolerance was 3.62%. Mean major complications rate was 0.70% (> 1% in Spatz2, HB, and Spatz3 models), mainly complicated gastric ulcer. Minor AEs rate was 6.37%, mainly esophagitis. Nine cases (0.04%) required surgery. A single case of mortality (0.0048%) occurred. Seven lawsuits (0.0034%) were received, all with favorable resolution. CONCLUSIONS: In the Spanish experience accumulating 20,680 IGBs and including 12 different balloon models, a low incidence rate of major complications and minor AEs are observed (0.70% and 6.37%, respectively), mostly resolved with medical/endoscopic management. IGB shows good tolerance and efficacy profile. These safety data are within the accepted quality standards.

SIRT7 promotes lung cancer progression by destabilizing the tumor suppressor ARF.

Sirtuin 7 (SIRT7) is a member of the mammalian family of nicotinamide adenine dinucleotide (NAD+)-dependent histone/protein deacetylases, known as sirtuins. It acts as a potent oncogene in numerous malignancies, but the molecular mechanisms employed by SIRT7 to sustain lung cancer progression remain largely uncharacterized. We demonstrate that SIRT7 exerts oncogenic functions in lung cancer cells by destabilizing the tumor suppressor alternative reading frame (ARF). SIRT7 directly interacts with ARF and prevents binding of ARF to nucleophosmin, thereby promoting proteasomal-dependent degradation of ARF. We show that SIRT7-mediated degradation of ARF increases expression of protumorigenic genes and stimulates proliferation of non-small-cell lung cancer (NSCLC) cells both in vitro and in vivo in a mouse xenograft model. Bioinformatics analysis of transcriptome data from human lung adenocarcinomas revealed a correlation between SIRT7 expression and increased activity of genes normally repressed by ARF. We propose that disruption of SIRT7-ARF signaling stabilizes ARF and thus attenuates cancer cell proliferation, offering a strategy to mitigate NSCLC progression.

Gelatin maleimide microgels for hematopoietic progenitor cell encapsulation.

Hematopoietic stem cells (HSCs) are the apical cells of the hematopoietic system, giving rise to cells of the blood and lymph lineages. HSCs reside primarily within bone marrow niches that contain matrix and cell-derived signals that help inform stem cell fate. Aspects of the bone marrow microenvironment have been captured in vitro by encapsulating cells within hydrogel matrices that mimic native mechanical and biochemical properties. Hydrogel microparticles, or microgels, are increasingly being used to assemble granular biomaterials for cell culture and noninvasive delivery applications. Here, we report the optimization of a gelatin maleimide hydrogel system to create monodisperse gelatin microgels via a flow-focusing microfluidic process. We report characteristic hydrogel stiffness, stability, and swelling characteristics as well as encapsulation of murine hematopoietic stem and progenitor cells, and mesenchymal stem cells within microgels. Microgels support cell viability, confirming compatibility of the microfluidic encapsulation process with these sensitive bone marrow cell populations. Overall, this work presents a microgel-based gelatin maleimide hydrogel as a foundation for future development of a multicellular artificial bone marrow culture system.

General Direct Anticancer Effects of Deer Growing Antler Extract in Several Tumour Cell Lines, and Immune System-Mediated Effects in Xenograft Glioblastoma.

Deer antlers are the fastest growing tissue. Because they are based on proto-oncogenes, to avoid the risk of cancer, antlers evolved strong anticancer mechanisms, and thus their extract (DVA) is effective also against the few human tumours studied so far. We assessed whether DVA is a general anticancer compound by testing the direct effects in cells of different tumours: glioblastoma (GBM; lines U87MG and U251), colorectal (CRC; lines DLD-1, HT-29, SW480, and SW620), breast cancer (BRCA; lines MCF7, SKBR3, and PA00), and leukaemia (THP-1). DVA reduced the viability of tumours but not healthy cells (NHC; lines 293T and HaCaT). Mobility decreased at least for the longest test (72 h). Intraperitoneal/oral 200 mg DVA/kg administration in GBM xenograft mice for 28 d reduced tumour weight by 66.3% and 61.4% respectively, and it also reduced spleen weight (43.8%). In addition, tumours treated with DVA showed symptoms of liquefactive necrosis. Serum cytokines showed DVA up-regulated factors related to tumour fighting and down-regulated those related to inducing immune tolerance to the tumour. DVA shows general anticancer effects in the lines tested and, in GBM mice, also strong indirect effects apparently mediated by the immune system. DVA may contain a future anticancer medicine without secondary effects.

Efficacy and safety of biological treatment for inflammatory bowel disease in elderly patients: Results from a GETECCU cohort.

INTRODUCTION: Biological therapies used for the treatment of inflammatory bowel disease (IBD) have shown to be effective and safe, although these results were obtained from studies involving mostly a young population, who are generally included in clinical trials. The aim of our study was to determine the efficacy and safety of the different biological treatments in the elderly population. METHODS: Multicenter study was carried out in the GETECCU group. Patients diagnosed with IBD and aged over 65 years at the time of initiating biological therapy (infliximab, adalimumab, golimumab, ustekinumab or vedolizumab) were retrospectively included. Among the patients included, clinical response was assessed after drug induction (12 weeks of treatment) and at 52 weeks. Patients' colonoscopy data in week 52 were assessment, where available. Regarding complications, development of oncological events during follow-up and infectious processes occurring during biological treatment were collected (excluding bowel infection by cytomegalovirus). RESULTS: A total of 1090 patients were included. After induction, at approximately 12-14 weeks of treatment, 419 patients (39.6%) were in clinical remission, 502 patients (47.4%) had responded without remission and 137 patients (12.9%) had no response. At 52 weeks of treatment 442 patients (57.1%) had achieved clinical remission, 249 patients had responded without remission (32.2%) and 53 patients had no response to the treatment (6.8%). Before 52 weeks, 129 patients (14.8%) had discontinued treatment due to inefficacy, this being significantly higher (p<0.0001) for Golimumab - 9 patients (37.5%) - compared to the other biological treatments analyzed. With respect to tumor development, an oncological event was observed in 74 patients (6.9%): 30 patients (8%) on infliximab, 23 (7.14%) on adalimumab, 3 (11.1%) on golimumab, 10 (6.4%) on ustekinumab, and 8 (3.8%) on vedolizumab. The incidence was significantly lower (p=0.04) for the vedolizumab group compared to other treatments. As regards infections, these occurred in 160 patients during treatment (14.9%), with no differences between the different biologicals used (p=0.61): 61 patients (19.4%) on infliximab, 39 (12.5%) on adalimumab, 5 (17.8%) on golimumab, 22 (14.1%) on ustekinumab, and 34 (16.5%) on vedolizumab. CONCLUSIONS: Biological drug therapies have response rates in elderly patients similar to those described in the general population, Golimumab was the drug that was discontinued most frequently due to inefficacy. In our experience, tumor development was more frequent in patients who used anti-TNF therapies compared to other targets, although its incidence was generally low and that this is in line with younger patients based on previous literature.

Biomaterial-Based Therapeutic Delivery of Immune Cells.

Immune cell therapy (ICT) is a transformative approach used to treat a wide range of diseases including type 1 diabetes, sickle cell disease, disorders of the hematopoietic system, and certain forms of cancers. Despite excellent clinical successes, the scope of adoptively transferred immune cells is limited because of toxicities like cytokine release syndrome and immune effector cell-associated neurotoxicity in patients. Furthermore, reports suggest that such treatment can impact major organ systems including cardiac, renal, pulmonary, and hepatic systems in the long term. Additionally, adoptively transferred immune cells cannot achieve significant penetration into solid tissues, thus limiting their therapeutic potential. Recent studies suggest that biomaterial-assisted delivery of immune cells can address these challenges by reducing toxicity, improving localization, and maintaining desired phenotypes to eventually regain tissue function. In this review, recent efforts in the field of biomaterial-based immune cell delivery for the treatment of diseases, their pros and cons, and where these approaches stand in terms of clinical treatment are highlighted.

FAK, vinculin, and talin control mechanosensitive YAP nuclear localization.

Focal adhesions (FAs) are nanoscale complexes containing clustered integrin receptors and intracellular structural and signaling proteins that function as principal sites of mechanotransduction in part via promoting the nuclear translocation and activation of the transcriptional coactivator yes-associated protein (YAP). Knockdown of FA proteins such as focal adhesion kinase (FAK), talin, and vinculin can prevent YAP nuclear localization. However, the mechanism(s) of action remain poorly understood. Herein, we investigated the role of different functional domains in vinculin, talin, and FAK in regulating YAP nuclear localization. Using genetic or pharmacological inhibition of fibroblasts and human mesenchymal stem cells (hMSCs) adhering to deformable substrates, we find that disruption of vinculin-talin binding versus talin-FAK binding reduces YAP nuclear localization and transcriptional activity via different mechanisms. Disruption of vinculin-talin binding or knockdown of talin-1 reduces nuclear size, traction forces, and YAP nuclear localization. In contrast, disruption of the talin binding site on FAK or elimination of FAK catalytic activity did not alter nuclear size yet still prevented YAP nuclear localization and activity. These data support both nuclear tension-dependent and independent models for matrix stiffness-regulated YAP nuclear localization. Our results highlight the importance of vinculin-talin-FAK interactions at FAs of adherent cells, controlling YAP nuclear localization and activity.

Encapsulation and immune protection for type 1 diabetes cell therapy.

Type 1 Diabetes (T1D) involves the autoimmune destruction of insulin-producing ß-cells in the pancreas. Exogenous insulin injections are the current therapy but are user-dependent and cannot fully recapitulate physiological insulin secretion dynamics. Since the emergence of allogeneic cell therapy for T1D, the Edmonton Protocol has been the most promising immunosuppression protocol for cadaveric islet transplantation, but the lack of donor islets, poor cell engraftment, and required chronic immunosuppression have limited its application as a therapy for T1D. Encapsulation in biomaterials on the nano-, micro-, and macro-scale offers the potential to integrate islets with the host and protect them from immune responses. This method can be applied to different cell types, including cadaveric, porcine, and stem cell-derived islets, mitigating the issue of a lack of donor cells. This review covers progress in the efforts to integrate insulin-producing cells from multiple sources to T1D patients as a form of cell therapy.

VEGF-delivering PEG hydrogels promote vascularization in the porcine subcutaneous space.

For cell therapies, the subcutaneous space is an attractive transplant site due to its large surface area and accessibility for implantation, monitoring, biopsy, and retrieval. However, its poor vascularization has catalyzed research to induce blood vessel formation within the site to enhance cell revascularization and survival. Most studies focus on the subcutaneous space of rodents, which does not recapitulate important anatomical features and vascularization responses of humans. Herein, we evaluate biomaterial-driven vascularization in the porcine subcutaneous space. Additionally, we report the first use of cost-effective fluorescent microspheres to quantify perfusion in the porcine subcutaneous space. We investigate the vascularization-inducing efficacy of vascular endothelial growth factor (VEGF)-delivering synthetic hydrogels based on 4-arm poly(ethylene) glycol macromers with terminal maleimides (PEG-4MAL). We compare three groups: a non-degradable hydrogel with a VEGF-releasing PEG-4MAL gel coating (Core+VEGF gel); an uncoated, non-degradable hydrogel (Core-only); and naïve tissue. After 2 weeks, Core+VEGF gel has significantly higher tissue perfusion, blood vessel area, blood vessel density, and number of vessels compared to both Core-only and naïve tissue. Furthermore, healthy vital signs during surgery and post-procedure metrics demonstrate the safety of hydrogel delivery. We demonstrate that VEGF-delivering synthetic hydrogels induce robust vascularization and perfusion in the porcine subcutaneous space.

Perichondritis and auricular cellulitis related to piercings as first manifestation of monkeypox.

INTRODUCTION: Pinna infections are usually due to Staphylococcus aureus infection. It is common for the patient to have had an earring in the area of infection. Monkeypox infection has gone from being an endemic infection to a worldwide health emergency. CASE SUMMARY: In this article we present five cases of monkeypox earring infection of the pinna and what common features we have seen that differentiate them from Staphylococcus aureus infection. DISCUSSION: Symptoms of monkeypox include general malaise, fever with uni- or bilateral lymphadenopathy, and then the appearance within one or two days of skin lesions, we want to alert he otolaryngologist and the medical society to the possibility the diagnostic possibility of monkeypox in patients with an auricular perichondritis.

Lagrangian modelling of oil concentrations at sea: A sensitivity analysis to the grid resolution and number of Lagrangian elements.

This paper presents a novel method to select the optimal combination of grid resolution and number of Lagrangian elements (LEs) required in numerical modelling of oil concentrations at sea. A sensitivity analysis in terms of grid resolution and the number of LEs, was carried out to understand the uncertainty that these user-dependent parameters introduce in the numerical results. A dataset of 211,200 simulations performed under 400 metocean patterns, 6 initial volumes, 11 grid resolutions, and different numbers of LEs (100 to 500,000), was used to analyze the sensitivity of the model along different Thresholds of Concern. Results show the importance of a correct selection of the number of LEs and the grid resolution in Lagrangian modelling of surface oil concentrations. The method proposed will allow selecting the optimal combination of these parameters to find an optimal balance between the accuracy and the computational cost of the simulation.

Gene expression changes in conjunctival cells associated with contact lens wear and discomfort.

PURPOSE: This study aimed to analyze the differences in the expression of pain-related genes in conjunctival epithelial cells among symptomatic contact lens (CL) wearers (SCLWs), asymptomatic CL wearers (ACLWs), and non-CL wearers (non-CLWs). METHODS: For this study, 60 participants (20 non-CLWs, 40 CLWs) were enrolled. The CLW group comprised 20 ACLWs and 20 SCLWs according to the Contact Lens Dry Eye Questionnaire short form©. Conjunctival cells were collected using impression cytology, and RNA was isolated and used to determine the expression levels of 85 human genes involved in neuropathic and inflammatory pain. The effects of CL wear and discomfort were evaluated using mixed-effects ANOVA with partially nested fixed-effects model. Gene set enrichment analysis was performed to assign biological meaning to sets of differentially expressed genes. RESULTS: Six genes (CD200, EDN1, GRIN1, PTGS1, P2RX7, and TNF) were significantly upregulated in CLWs compared to non-CLWs. Eleven genes (ADORA1, BDKRB1, CACNA1B, DBH, GRIN1, GRM1, HTR1A, PDYN, PTGS1, P2RX3, and TNF) were downregulated in SCLWs compared to ACLWs. These genes were mainly related to pain, synaptic transmission and signaling, ion transport, calcium transport and concentration, and cell-cell signaling. CONCLUSIONS: CL wear modified the expression of pain- and inflammation-related genes in conjunctival epithelial cells. These changes may be in part, along with other mechanisms, responsible for CL discomfort in SCLWs.

In vitro characterization of a novel resin-based restorative material containing alkaline fillers

Abstract Objective: In this study, a comparative evaluation of the physicochemical properties of Cention N and other direct restorative materials was performed. Three restorative materials—a resin-modified glass ionomer (Fuji II LC), an alkasite-based resinous material (Cention N), and a resin composite (Tetric N Ceram)—were characterized in terms of degree of conversion, Knoop hardness number (KHN) ratio, flexural strength, elastic modulus, water sorption, water solubility, microshear bond strength to dentin, immediate microleakage, and radiopacity. Methodology: The microshear bond strength to dentin and microleakage of Cention N were evaluated with and without the application of an adhesive system (Tetric N Bond Universal). A one-way ANOVA test was used to analyze the data in terms of degree of conversion, KHN ratio, water sorption, water solubility, microshear bond strength to dentin, and radiopacity. A two-way ANOVA test (carried out considering the material type and ethanol aging as factors) was used to analyze the data in terms of flexural strength and elastic modulus. The Kruskal-Wallis test was used to statistically analyze the data on microleakage. A significance level of α=0.05 was used for all tests. Results: Fuji II LC was found to have the highest degree of conversion, water sorption, and microleakage, as well as the lowest flexural strength. Cention N had the highest solubility; when used with an adhesive system, it achieved bond strength and microleakage similar to those of the Tetric N Ceram composite. Tetric N Ceram had the highest degree of conversion, KHN ratio, and radiopacity. Conclusion: The properties of Cention N validate its efficacy as an alternative direct restorative material when used in conjunction with an adhesive system.

Estabilidad dimensional de hidrocoloides irreversibles de vaciado convencional y de vaciado de tiempo extendido disponibles en el mercado uruguayo

Objetivo. Comparar la estabilidad dimensional de un hidrocoloide irreversible de vaciado convencional con hidrocoloides irreversibles de vaciado extendido. Metodología. Fueron evaluados cuatro productos con indicación de vaciado extendido: Jeltrate Plus (Denstply Sirona), Hydrogum 5 (Zhermack SpA), Algimax (Major), Kromopan (Lascod) y un producto de vaciado convencional (Tropicalgin; Zhermack SpA). Con cada producto se realizaron 10 impresiones y se vaciaron en yeso tipo III en cinco tiempos de almacenamiento diferentes (0, 24, 96, 120 y 168 horas). Un escáner para modelos tridimensionales se utilizó para digitalizar los modelos de yeso y realizar las mediciones correspondientes: sumatoria de las longitudes, variabilidad dimensional, porcentaje de variabilidad. Resultados. Las cinco marcas comerciales presentaron una sumatoria de longitudes mayor al grupo control (p<0,033). A las 0, 24 y 96h Tropicalgin e Hydrogum 5 presentaron significativamente menor variación dimensional en comparación con el modelo maestro (p<0,001). Los porcentajes de variabilidad oscilaron entre un 0.24 a 0.91%. Conclusiones. La estabilidad dimensional depende del producto utilizado. Almacenado correctamente, el hidrocoloide irreversible de vaciado convencional parece no sufrir alteraciones significativas hasta 96h, mientras que en el caso de Hydrogum 5 parece mantener su estabilidad dimensional hasta 168h.

Objetivo. Comparar a estabilidade dimensional de um hidrocolóide irreversível de vazamento convencional com hidrocolóides irreversíveis de vazamento prolongado. Metodologia. Foram avaliados quatro produtos com indicação de vazamento estendido: Jeltrate Plus (Denstply Sirona), Hydrogum 5 (Zhermack SpA), Algimax (Major), Kromopan (Lascod) e um produto de vaziamento convencional (Tropicalgin; Zhermack SpA). Para cada produto foram feitas 10 impressões e vazadas em gesso tipo III em cinco tempos de armazenamento diferentes (0, 24, 96, 120 e 168 horas). Um scanner de modelos tridimensionais foi utilizado para digitalizar os modelos de gesso e fazer as medições correspondentes: soma dos comprimentos, variabilidade dimensional, percentagem de variabilidade. Resultados. As cinco marcas comerciais apresentaram somatório de comprimentos maior que o grupo controle (p<0,033). Nos tempos 0, 24 e 96h Tropicalgin e Hydrogum 5 apresentaram variação dimensional significativamente menor em comparação ao modelo Mestre (p<0,001). Os percentuais de variabilidade variaram de 0,24 a 0,91%. Conclusões. A estabilidade dimensional depende do produto utilizado. Armazenado corretamente, o hidrocolóide irreversível de vaziamento convencional convencionalmente parece não sofrer alterações significativas até 96h, enquanto no caso do Hydrogum 5 parece manter sua estabilidade dimensional até 168h.

Aim . Compare the dimensional stability of a conventional pouring irreversible hydrocolloid with extended pouring irreversible hydrocolloids. Methodology. Four products with extended emptying indication were evaluated: Jeltrate Plus (Denstply Sirona), Hydrogum 5 (Zhermack SpA), Algimax (Major), Kromopan (Lascod) and a conventional emptying product (Tropicalgin; Zhermack SpA). For each product, 10 impressions were made and cast in type III plaster at five different storage times (0, 24, 96, 120 and 168 hours). A three-dimensional model scanner was used to digitize the plaster models and make the corresponding measurements: sum of lengths, dimensional variability, percentage of variability. Results . The five commercial brands presented a greater sum of lengths than the control group (p<0,033). At 0, 24 and 96h Tropicalgin and Hydrogum 5 presented significantly less dimensional variation compared to the master model (p<0,001). The variability percentages ranged from 0.24 to 0.91%. Conclusions. Dimensional stability depends on the product used. Stored correctly, the conventionally cast irreversible hydrocolloid appears not to undergo significant alterations up to 96h, while in the case of Hydrogum 5 it appears to maintain its dimensional stability up to 168h.

Cuerpo extraño en espacio paraglótico

Los cuerpos extraños en la vía aérea son una urgencia muy común en la práctica de la otorrinolaringología. La mayoría suelen encontrarse en población pediátrica donde la gravedad es mayor. En adultos estos episodios suelen ser accidentales, siendo la exploración física fundamental para su diagnóstico. Exponemos aquí el caso de un varón qué presentó una espina de pescado en el área interaritenoidea.

Foreign bodies in the airway are a very common emergency in the practice of otorhinolaryngology, the majority of which are usually found in the pediatric population. In adults, these episodes are usually accidental, and physical examination is fundamental for its diagnosis. We report a case of fish bone impaction in the interarytenoid area.

MAP kinase ERK5 modulates cancer cell sensitivity to extrinsic apoptosis induced by death-receptor agonists.

Death receptor ligand TRAIL is a promising cancer therapy due to its ability to selectively trigger extrinsic apoptosis in cancer cells. However, TRAIL-based therapies in humans have shown limitations, mainly due inherent or acquired resistance of tumor cells. To address this issue, current efforts are focussed on dissecting the intracellular signaling pathways involved in resistance to TRAIL, to identify strategies that sensitize cancer cells to TRAIL-induced cytotoxicity. In this work, we describe the oncogenic MEK5-ERK5 pathway as a critical regulator of cancer cell resistance to the apoptosis induced by death receptor ligands. Using 2D and 3D cell cultures and transcriptomic analyses, we show that ERK5 controls the proteostasis of TP53INP2, a protein necessary for full activation of caspase-8 in response to TNFα, FasL or TRAIL. Mechanistically, ERK5 phosphorylates and induces ubiquitylation and proteasomal degradation of TP53INP2, resulting in cancer cell resistance to TRAIL. Concordantly, ERK5 inhibition or genetic deletion, by stabilizing TP53INP2, sensitizes cancer cells to the apoptosis induced by recombinant TRAIL and TRAIL/FasL expressed by Natural Killer cells. The MEK5-ERK5 pathway regulates cancer cell proliferation and survival, and ERK5 inhibitors have shown anticancer activity in preclinical models of solid tumors. Using endometrial cancer patient-derived xenograft organoids, we propose ERK5 inhibition as an effective strategy to sensitize cancer cells to TRAIL-based therapies.

Ulcerative colitis induced by obinutuzumab in a patient treated for a folicular lymphoma.

An increasing use of immunomodulatory drugs has led to a corresponding increase in treatment-related pathologies such as inflammatory bowel disease. Here, we present a case of ulcerative colitis due to Obinutuzumab, an antiCD20 monoclonal approved for the treatment of Non-Hodgkin lymphomas.