Usefulness of the qSOFA score for predicting hospital mortality in cancer patients.

BACKGROUND: The quick Sequential Sepsis-related Organ Failure Assessment (qSOFA) is a score that has been proposed to quickly identify patients at higher risk of death. OBJECTIVE: To describe the usefulness of the qSOFA score to predict in-hospital mortality in cancer patients. MATERIAL AND METHODS: Cross-sectional study carried out between January 2021 and December 2022. Hospital mortality was the dependent variable. The area under the ROC curve (AUC) was calculated to determine the discriminative ability of qSOFA to predict in-hospital mortality. RESULTS: A total of 587 cancer patients were included. A qSOFA score higher than 1 obtained a sensitivity of 57.2%, specificity of 78.5%, a positive predictive value of 55.4% and negative predictive value of 79.7%. The AUC of qSOFA for predicting in-hospital mortality was 0.70. In-hospital mortality of patients with qSOFA scores of 2 and 3 points was 52.7 and 64.4%, respectively. In-hospital mortality was 31.9% (187/587). CONCLUSION: qSOFA showed acceptable discriminative ability for predicting in-hospital mortality in cancer patients.

ANTECEDENTES: El quick Sequential Sepsis-related Organ Failure Assessment (qSOFA) es una puntuación propuesta para identificar de forma rápida a pacientes con mayor probabilidad de morir. OBJETIVO: Describir la utilidad de la puntuación qSOFA para predecir mortalidad hospitalaria en pacientes con cáncer. MATERIAL Y MÉTODOS: Estudio transversal realizado entre enero de 2021 y diciembre de 2022. La mortalidad hospitalaria fue la variable dependiente. Se calculó el área bajo la curva ROC (ABC) para determinar la capacidad discriminativa de qSOFA para predecir mortalidad hospitalaria. RESULTADOS: Se incluyeron 587 pacientes con cáncer. La puntuación qSOFA < 1 obtuvo una sensibilidad de 57.2 %, una especificidad de 78.5 %, un valor predictivo positivo de 55.4 % y un valor predictivo negativo de 79.7 %. El ABC de qSOFA para predecir mortalidad hospitalaria fue de 0.70. La mortalidad hospitalaria de los pacientes con qSOFA de 2 y 3 puntos fue de 52.7 y 64.4 %, respectivamente. La mortalidad hospitalaria fue de 31.9 % (187/587). CONCLUSIÓN: qSOFA mostró capacidad discriminativa aceptable para predecir mortalidad hospitalaria en pacientes con cáncer.

Modulation of JAK-STAT Signaling by LNK: A Forgotten Oncogenic Pathway in Hormone Receptor-Positive Breast Cancer.

Breast cancer remains the most frequently diagnosed cancer in women worldwide. Tumors that express hormone receptors account for 75% of all cases. Understanding alternative signaling cascades is important for finding new therapeutic targets for hormone receptor-positive breast cancer patients. JAK-STAT signaling is commonly activated in hormone receptor-positive breast tumors, inducing inflammation, proliferation, migration, and treatment resistance in cancer cells. In hormone receptor-positive breast cancer, the JAK-STAT cascade is stimulated by hormones and cytokines, such as prolactin and IL-6. In normal cells, JAK-STAT is inhibited by the action of the adaptor protein, LNK. However, the role of LNK in breast tumors is not fully understood. This review compiles published reports on the expression and activation of the JAK-STAT pathway by IL-6 and prolactin and potential inhibition of the cascade by LNK in hormone receptor-positive breast cancer. Additionally, it includes analyses of available datasets to determine the level of expression of LNK and various members of the JAK-STAT family for the purpose of establishing associations between expression and clinical outcomes. Together, experimental evidence and in silico studies provide a better understanding of the potential implications of the JAK-STAT-LNK loop in hormone receptor-positive breast cancer progression.

Separation of the CaV 1.2-CaV 1.3 calcium channel duo prevents type 2 allergic airway inflammation.

BACKGROUND: Voltage-gated calcium (Cav 1) channels contribute to T-lymphocyte activation. Cav 1.2 and Cav 1.3 channels are expressed in Th2 cells but their respective roles are unknown, which is investigated herein. METHODS: We generated mice deleted for Cav 1.2 in T cells or Cav 1.3 and analyzed TCR-driven signaling. In this line, we developed original fast calcium imaging to measure early elementary calcium events (ECE). We also tested the impact of Cav 1.2 or Cav 1.3 deletion in models of type 2 airway inflammation. Finally, we checked whether the expression of both Cav 1.2 and Cav 1.3 in T cells from asthmatic children correlates with Th2-cytokine expression. RESULTS: We demonstrated non-redundant and synergistic functions of Cav 1.2 and Cav 1.3 in Th2 cells. Indeed, the deficiency of only one channel in Th2 cells triggers TCR-driven hyporesponsiveness with weakened tyrosine phosphorylation profile, a strong decrease in initial ECE and subsequent reduction in the global calcium response. Moreover, Cav 1.3 has a particular role in calcium homeostasis. In accordance with the singular roles of Cav 1.2 and Cav 1.3 in Th2 cells, deficiency in either one of these channels was sufficient to inhibit cardinal features of type 2 airway inflammation. Furthermore, Cav 1.2 and Cav 1.3 must be co-expressed within the same CD4+ T cell to trigger allergic airway inflammation. Accordingly with the concerted roles of Cav 1.2 and Cav 1.3, the expression of both channels by activated CD4+ T cells from asthmatic children was associated with increased Th2-cytokine transcription. CONCLUSIONS: Thus, Cav 1.2 and Cav 1.3 act as a duo, and targeting only one of these channels would be efficient in allergy treatment.

c-Kit Induces Migration of Triple-Negative Breast Cancer Cells and Is a Promising Target for Tyrosine Kinase Inhibitor Treatment.

Triple-negative breast cancer (TNBC) is associated with a poor prognosis and the absence of targeted therapy. c-Kit, a receptor tyrosine kinase (RTK), is considered a molecular target for anticancer drugs. Tyrosine kinase inhibitors (TKIs) recognizing c-Kit are used for the treatment of c-Kit-expressing tumors. However, the expression, function, and therapeutic potential of c-Kit have been little explored in TNBC. Here, we studied the expression and effects of c-Kit in TNBC through in vitro and in silico analysis, and evaluated the response to TKIs targeting c-Kit. Analysis of TNBC cells showed the expression of functional c-Kit at the cell membrane. The stimulation of c-Kit with its ligand induced the activation of STAT3, Akt, and ERK1/2, increasing cell migration, but had no effect on cell proliferation or response to Doxorubicin. Analysis of public datasets showed that the expression of c-Kit in tumors was not associated with patient survival. Finally, TNBC cells were susceptible to TKIs, in particular the effect of Nilotinib was stronger than Doxorubicin in all cell lines. In conclusion, TNBC cells express functional c-Kit, which is a targetable molecule, and show a strong response to Nilotinib that may be considered a candidate drug for the treatment of TNBC.

Reconstruction of PET Images Using Cross-Entropy and Field of Experts.

The reconstruction of positron emission tomography data is a difficult task, particularly at low count rates because Poisson noise has a significant influence on the statistical uncertainty of positron emission tomography (PET) measurements. Prior information is frequently used to improve image quality. In this paper, we propose the use of a field of experts to model a priori structure and capture anatomical spatial dependencies of the PET images to address the problems of noise and low count data, which make the reconstruction of the image difficult. We reconstruct PET images by using a modified MXE algorithm, which minimizes a objective function with the cross-entropy as a fidelity term, while the field of expert model is incorporated as a regularizing term. Comparisons with the expectation maximization algorithm and a iterative method with a prior penalizing relative differences showed that the proposed method can lead to accurate estimation of the image, especially with acquisitions at low count rate.

The Natural History of Post-Chikungunya Viral Arthritis Disease Activity and T-cell Immunology: A Cohort Study.

Background: Chikungunya virus (CHIKV) is an alphavirus spread by mosquitos that causes arthralgias and arthritis that may last for years. The objective of this study was to describe the arthritis progression and T cell immunology over a two-year period. Methods: A cohort of 40 cases of serologically confirmed CHIKV from Magdalena and Atlántico, Colombia were followed in 2019 and again in 2021. Arthritis disease severity, disability, pain, stiffness, physical function, mobility, fatigue, anxiety, sleep disturbances and depression were assessed. Serum cytokines and T-cell subsets were measured and tested for change. Correlations within each of the 2 time periods for laboratory parameters were also examined. Results: Although, arthritis disease severity, as measured by the Disease Activity Score-28 (DAS-28) did not change significantly over a two-year period, a new metric- the Chikungunya Disease Activity Score (CHIK-DAS)- was more sensitive to detect changes in disease severity than the Disease Activity Score-28 (DAS-28) and showed some improvement in average disease severity from moderate to mild over two years. Cases were characterized by moderate disability, pain, and stiffness with mild alterations of physical function, mobility, fatigue, anxiety, sleep disturbances and depression that did not change significantly over time. Small joints including the fingers and wrists were most affected without significant change over time. The percentage of effector T cells (Teffs) and regulatory T cells (Tregs) of CD4+ T cells both decreased over time. Teff percentages decreased more significantly resulting in a halving of the Teff/Treg ratio two years later. Furthermore, markers of Treg immunosuppressive function such as CTLA4, Helios, CD28, CD45RA and 41bb decreased over time. Cytokines did not change significantly over time. Conclusions: The presented data suggest that arthritis persists almost seven years after chikungunya infection in some patients with waning Teff and Treg numbers and activation markers over time. Treg activation may be a promising therapeutic target for further investigation.

A Novel Thermo-Alkaline Stable GDSL/SGNH Esterase with Broad Substrate Specificity from a Deep-Sea Pseudomonas sp.

Marine environments harbor a plethora of microorganisms that represent a valuable source of new biomolecules of biotechnological interest. In particular, enzymes from marine bacteria exhibit unique properties due to their high catalytic activity under various stressful and fluctuating conditions, such as temperature, pH, and salinity, fluctuations which are common during several industrial processes. In this study, we report a new esterase (EstGoM) from a marine Pseudomonas sp. isolated at a depth of 1000 m in the Gulf of Mexico. Bioinformatic analyses revealed that EstGoM is an autotransporter esterase (type Va) and belongs to the lipolytic family II, forming a new subgroup. The purified recombinant EstGoM, with a molecular mass of 67.4 kDa, showed the highest hydrolytic activity with p-nitrophenyl octanoate (p-NP C8), although it was also active against p-NP C4, C5, C10, and C12. The optimum pH and temperature for EstGoM were 9 and 60 °C, respectively, but it retained more than 50% of its activity over the pH range of 7-11 and temperature range of 10-75 °C. In addition, EstGoM was tolerant of up to 1 M NaCl and resistant to the presence of several metal ions, detergents, and chemical reagents, such as EDTA and ß-mercaptoethanol. The enzymatic properties of EstGoM make it a potential candidate for several industrial applications.

Cytokine and T cell responses in post-chikungunya viral arthritis: A cross-sectional study.

OBJECTIVE: To define the relationship between chronic chikungunya post-viral arthritis disease severity, cytokine response and T cell subsets in order to identify potential targets for therapy. METHODS: Participants with chikungunya arthritis were recruited from Colombia from 2019-2021. Arthritis disease severity was quantified using the Disease Activity Score-28 and an Arthritis-Flare Questionnaire adapted for chikungunya arthritis. Plasma cytokine concentrations (interleukin (IL)-1ß, IL-2, IL-4, IL-6, IL-8, IL-10, IL-12p70, IL-13, interferon-γ and tumor necrosis factor (TNF)) were measured using a Meso Scale Diagnostics assay. Peripheral blood T cell subsets were measured using flow cytometry. RESULTS: Among participants with chikungunya arthritis (N = 158), IL-2 levels and frequency of regulatory T cells (Tregs) were low. Increased arthritis disease activity was associated with higher levels of inflammatory cytokines (IL-6, TNF and CRP) and immunoregulatory cytokine IL-10 (p<0.05). Increased arthritis flare activity was associated with higher Treg frequencies (p<0.05) without affecting T effector (Teff) frequencies, Treg/Teff ratios and Treg subsets. Finally, elevated levels of IL-2 were correlated with increased Treg frequency, percent Tregs out of CD4+ T cells, and Treg subsets expressing immunosuppressive markers, while also correlating with an increased percent Teff out of live lymphocytes (p<0.05). CONCLUSION: Chikungunya arthritis is characterized by increased inflammatory cytokines and deficient IL-2 and Treg responses. Greater levels of IL-2 were associated with improved Treg numbers and immunosuppressive markers. Future research may consider targeting these pathways for therapy.

Trends in digestive cancer mortality, Cuba 1987-2008.

BACKGROUND: Gastrointestinal malignancies are among the most common cancers suffered by Cubans. The purpose of our study is to analyse the evolution of digestive cancer mortality in Cuba. METHODS: Mortality data for this study were obtained from the National Medical Records and Health Statistic Bureau. Trends (1987-2008) in age-standardized cancer mortality were described using joinpoint regression. RESULTS: In the data set of digestive cancer mortality, in the period 1987-2008, colorectal/anal cancer was the most frequent cause of cancer mortality in males and females. In men, a rise in mortality was observed for cancer of the oesophagus between 2001 and 2008, and pancreatic cancer showed a slight mortality rise for the period 1987-2008. In women, colorectal/anal cancer increased from 1989 to 2001. A mortality increase was observed for oesophageal cancer in the period 2005-08. The result of the joinpoint analysis for the age group of 35-64 years was consistent with those for overall mortality. CONCLUSION: The trend in mortality from digestive cancer in Cuba shows differences depending on sex, age and type of tumour. The Cuban health system has seen improvements in diagnostic systems, which has contributed even better diagnoses of digestive diseases.

Adaptive filter with Riemannian manifold constraint.

The adaptive filtering theory has been extensively developed, and most of the proposed algorithms work under the assumption of Euclidean space. However, in many applications, the data to be processed comes from a non-linear manifold. In this article, we propose an alternative adaptive filter that works on a manifold, thus generalizing the filtering task to non-Euclidean spaces. To this end, we generalized the least-mean-squared algorithm to work on a manifold using an exponential map. Our experiments showed that the proposed method outperforms other state-of-the-art algorithms in several filtering tasks.

The Importance of Clinical Reasoning in Pancreatic Insufficiency: A Case Report.

Evidence-based medicine has demonstrated an extensive list of etiologies for exocrine pancreatic insufficiency (EPI). EPI is defined as inadequate pancreatic enzyme efficacy in digestion due to insufficient enzyme production, activation, or early enzyme degradation. Among the etiologies, acute pancreatitis secondary to chronic and excessive consumption of alcohol has been found to be one of the most common causes. In 2022, a 43-year-old male patient with a past medical history of polysubstance abuse, acute on chronic pancreatitis, alcohol dependence, pulmonary embolism, hypertension, hyperlipidemia and diabetes mellitus type 2 presented to the Emergency Department with three days of epigastric abdominal pain, nausea and non-bloody, non-bilious vomiting. Proper imaging confirmed the diagnosis of acute pancreatitis. The key to treatment and surveillance relies on proper identification of risk factors, pertinent imaging for diagnostic evaluation and appropriate treatment with electrolyte repletion. The patient developed persistent electrolyte deficiencies despite appropriate repletion, indicating high suspicion of pancreatic insufficiency. The treatment most importantly relies on a combination of repletion of electrolytes as well as pancreatic enzymes with a clear patient understanding of their chronic condition, the importance of reducing modifiable risk factors and compliance with medical therapy.

TLR8 escapes X chromosome inactivation in human monocytes and CD4+ T cells.

BACKGROUND: Human endosomal Toll-like receptors TLR7 and TLR8 recognize self and non-self RNA ligands, and are important mediators of innate immunity and autoimmune pathogenesis. TLR7 and TLR8 are, respectively, encoded by adjacent X-linked genes. We previously established that TLR7 evades X chromosome inactivation (XCI) in female immune cells. Whether TLR8 also evades XCI, however, has not yet been explored. METHOD: In the current study, we used RNA fluorescence in situ hybridization (RNA FISH) to directly visualize, on a single-cell basis, primary transcripts of TLR7 and TLR8 relative to X chromosome territories in CD14+ monocytes and CD4+ T lymphocytes from women, Klinefelter syndrome (KS) men, and euploid men. To assign X chromosome territories in cells lacking robust expression of a XIST compartment, we designed probes specific for X-linked genes that do not escape XCI and therefore robustly label the active X chromosome. We also assessed whether XCI escape of TLR8 was associated with sexual dimorphism in TLR8 protein expression by western blot and flow cytometry. RESULTS: Using RNA FISH, we show that TLR8, like TLR7, evades XCI in immune cells, and that cells harboring simultaneously TLR7 and TLR8 transcript foci are more frequent in women and KS men than in euploid men, resulting in a sevenfold difference in frequency. This transcriptional bias was again observable when comparing the single X of XY males with the active X of cells from females or KS males. Interestingly, TLR8 protein expression was significantly higher in female mononuclear blood cells, including all monocyte subsets, than in male cells. CONCLUSIONS: TLR8, mirroring TLR7, escapes XCI in human monocytes and CD4+ T cells. Co-dependent transcription from the active X chromosome and escape from XCI could both contribute to higher TLR8 protein abundance in female cells, which may have implications for the response to viruses and bacteria, and the risk of developing inflammatory and autoimmune diseases.

Human endosomal Toll-like receptors TLR7 and TLR8, encoded by two adjacent X-linked genes, recognize self and non-self RNA ligands, and are important mediators of innate immunity and autoimmune pathogenesis. We previously reported that TLR7 evades X chromosome inactivation (XCI) in female immune cells, correlating with enhanced functional properties in B cells harboring biallelic expression of this gene. Here, we conducted a comprehensive single-cell resolution analysis of the transcriptional regulation of both TLR7 and TLR8, in CD14⁺ monocytes and CD4⁺ T lymphocytes. We unequivocally demonstrated that TLR8, like TLR7, escapes XCI in immune cells from female and Klinefelter syndrome males. When we analyzed TLR7 and TLR8 transcripts together, cells from women and KS men exhibited higher frequencies of cells co-transcribing the two genes. Surprisingly, these differences were attributable not only to the ability of TLR7 and TLR8 to be expressed on the Xi, but also to the joint transcriptional behavior of the TLR7­TLR8 gene pair on the active X chromosome specifically. This contrasted with a striking pattern of mutually exclusive transcription on the single X of euploid men. Corroborating our RNA FISH results, we found higher TLR8 protein expression in female than in male leukocytes, including all monocyte subpopulations. In summary, our data suggest that sex-biased co-regulation of the Toll-like receptor locus and XCI escape of TLR8 contribute to the sexual dimorphism in TLR8 expression, which may have important consequences for the functional make-up of monocyte and T cell populations.

A Case Report and Literature Review of Adrenal Myelolipoma.

Adrenal myelolipoma is considered a benign neoplasm that accounts for 6% to 16% of adrenal incidentalomas, and it is the second most common incidental adrenal tumor after adrenal adenomas. They are usually asymptomatic; however, in the presence of symptoms, significant growth, or complications, open surgical resection is indicated. We present the case of a 46-year-old woman with obesity and diabetes who experienced five years of left hemiabdominal pain, which was unsuccessfully treated symptomatically. A computed tomography scan revealed findings suggestive of pancreatic lipoma and a suggestive image of left adrenal myelolipoma. Resection of the tumor was performed using an anterior midline approach, and histopathological examination confirmed left adrenal myelolipoma. The presented case represents the typical presentation of these tumors in a patient in the fifth decade of life with obesity, diabetes, and nonspecific abdominal pain possibly related to the size of the lesion found. Surgical intervention was indicated due to the presence of symptoms, lesion size, contiguity with abdominal organs, and the absence of a precise diagnosis. An anterior midline approach was chosen, and histopathological examination provided a definitive diagnosis. Adrenal myelolipoma is a rare entity that is often asymptomatic and incidentally diagnosed through imaging studies. However, they should be resected when symptomatic to prevent complications. Open surgical resection is the preferred approach.

Germ cell cancer presenting as gastrointestinal bleeding and developing brain metastases: case report and review of the literature.

This paper describes a rare case of germ cell cancer with duodenum, brain and lung metastases. The patient presented with melena and left testicle enlargement. Orchiectomy revealed mixed germ cell cancer, enteroscopy revealed duodenal choriocarcinoma, and chest x-ray and computed tomography (CT) showed bilateral lung metastases. The patient received and tolerated cisplatinum-based chemotherapy, and responded well. However, he developed seizures 3 months later. MRI showed brain metastases and he was treated with whole-brain radiation. One month later, he developed progressive dyspnea. Chest CT showed worsening lung metastases. He received second-line chemotherapy, but died due to multiorgan failure. Germ cell cancer with nonpulmonary metastases has poor prognosis and the management of these patients requires a multimodal approach. Head CT should be considered as routine screening for all germ cell cancer patients on initial diagnosis and brain MRI should be considered for high-risk patients (with an embryo- or choriocarcinoma histology, dramatically elevated ß-human chorionic gonadotropin and lung involvement).

Estimation of systolic blood pressure by Random Forest using heart sounds and a ballistocardiogram.

Cuffless blood pressure measurement enables unobtrusive and continuous monitoring that can be integrated with wearable devices to extend healthcare to non-hospital settings. Most of the current research has focused on the estimation of blood pressure based on pulse transit time or pulse arrival time using ECG or peripheral cardiac pulse signals as proximal time references. This study proposed the use of a phonocardiogram (PCG) and ballistocardiogram (BCG), two signals detected noninvasively, to estimate systolic blood pressure (SBP). For this, the PCG and the BCG were simultaneously measured in 21 volunteers in the rest, activity, and post-activity conditions. Different features were considered based on the relationships between these signals. The intervals between S1 and S2 of the PCG and the I, J, and K waves of the BCG were statistically analyzed. The IJ and JK slopes were also estimated as additional features to train the machine-learning algorithm. The intervals S1-J, S1-K, S1-I, J-S2, and I-S2 were negatively correlated with changes in SBP (p-val < 0.01). The features were used as explanatory variables for a regressor based on the Random Forest. It was possible to estimate the systolic blood pressure with a mean error of 3.3 mmHg with a standard deviation of ± 5 mmHg. Therefore, we foresee that this proposal has potential applications for wearable devices that use low-cost embedded systems.

COVID-19 Exposure Unmasking Systemic Amyloidosis With Hepatic Predominance.

Amyloidosis is characterized by depositing insoluble fibrillar proteins that misfold into beta-pleated sheets. This phenomenon occurs on a systemic or local level and may interfere with the function of various organs, including the heart, kidneys, and liver. Among those presenting with amyloidosis, hepatic, gastrointestinal, renal, cardiac, vitreous, and immunological involvement may occur. These manifestations are linked to several clinical presentations, varying from abdominal pain and hepatomegaly to restrictive cardiomyopathy and chronic renal failure. The two most common types of amyloid proteins are amyloid light chain (AL) and serum amyloid A (AA) proteins. AL produced by immunoglobulin light chains kappa and lambda (κ, λ) circulate systemically and accumulate in organs. At the same time, serum AA proteins are acute-phase reactants seen in infectious, chronic inflammatory states. In an immune-mediated infection such as COVID-19, serum AA levels may be a predictive factor of disease severity and a valuable biomarker to monitor the clinical course of COVID-19 patients. This report highlights a case in which infection with COVID-19 provoked an effective immune response that may have contributed to the accelerated progression of systemic amyloidosis with hepatic involvement. The study further investigates the involvement of AL and AA proteins in COVID-19 infections, including their role in synergistically exacerbating an already grueling clinical course.

Chronic urticaria associated with lung adenocarcinoma - a paraneoplastic manifestation: A case report and literature review.

BACKGROUND: Urticaria is one of the most common causes of emergency room visits. It is defined as an acute inflammatory dermatosis, characterized by localized degranulation of mast cells, with consequent dermal microvascular and formation of edematous and pruritic plaques called hives. Urticaria affects the skin and tissues of the superficial mucosa. Sometimes it is accompanied by angioedema, which is characterized by deeper edema of the dermis and subcutaneous cellular tissue known as the urticarial-angioedema syndrome. About 15%-25% of the general population has suffered at least one type of urticaria at some point during their lifetime and hyperpermeability estimated at 7.6%-16% and has experienced acute urticaria that is usually self-limited and spontaneously resolves without requiring medical attention. CASE SUMMARY: We present the case of a young male patient who was referred to our department with a clinical picture of 4 mo of pruritus associated with hives of variable sizes, irregular borders, with interlesional confluence, that were non-painful, without involvement of the palms and soles of the feet but with a tendency to progression in a generalized manner. He had multiple emergency room visits and poor response to antihistamines and systemic corticosteroids. Imaging studies demonstrated nodules in the lower lingula segment, at the level of the greater fissure and in the anterior contour of the left anterior basal segment associated with parahiliar adenopathies in the absence of findings suggestive of infectious or autoimmune etiology. Segmental lobectomy was performed by thoracoscopy with resection of a lung nodule in the lingula and biopsy of the para-aortic mediastinal ganglion. The histopathological report showed the presence of poorly differentiated invasive adenocarcinoma with a solid morphological and acinar pattern with immunohistochemical description of lung tissue that expresses strong positive and diffuse reaction for thyroid transcription factor 1 (TTF-1) with negativity to P40 for a histopathological diagnosis of malignant epithelial neoplasia with expression of infiltrating adenocarcinoma. Spontaneous chronic urticaria is considered possibly secondary to lung adenocarcinoma. CONCLUSION: Chronic spontaneous urticaria is considered a paraneoplastic dermatosis with a controversial association in the literature. In the presented case, a young patient presented with chronic refractory urticaria and after an exhaustive clinical work-up was found to have a diagnosis of poorly differentiated lung adenocarcinoma with high expression of TTF-1. According to the Curth criteria, the urticaria presented by the patient is related to the oncological diagnosis. In addition, the high expression of TTF-1 documented in this case could be acting as an autoantigen that would cause chronic spontaneous urticaria. Further research evaluating a causal relationship between the TFF-1 protein and urticaria in lung cancer is needed.

Histamine promotes the expression of receptors TLR2 and TLR4 and amplifies sensitivity to lipopolysaccharide and lipoteichoic acid treatment in human gingival fibroblasts.

The vasoactive hydrophilic amine histamine is the most important molecule released by mast cells. However, histamine's role in activating intracellular responses in HGFs (human gingival fibroblasts) has not been evaluated to date. In the present study, we investigated the effect of histamine and of Gram-negative [LPS (lipopolysaccharide)] and Gram-positive [LTA (lipoteichoic acid)] bacterial components on the modulation of the inflammatory response of HGFs. We incubated HGFs with histamine to determine whether this hydrophilic amine regulates overexpression of TLR2 (Toll-like receptor 2) and TLR4, which recognize LTA and LPS respectively. Our experiments demonstrated that histamine increases transcription and translation of TLR2 and TLR4. Incubation with LTA or LPS in the presence of histamine markedly increased expression of COX2 (cyclo-oxygenase 2) and synthesis of prostaglandin E2. These results suggest that histamine plays an important role in modulating the innate immune response, and likewise, that LTA and LPS regulate the adaptive immune response. The present study provides information about the regulation and expression of molecules that promote chronic inflammatory processes leading to the emergence of periodontitis and the consequent loss of the dental organ.

SIN retroviral vectors expressing COL7A1 under human promoters for ex vivo gene therapy of recessive dystrophic epidermolysis bullosa.

Recessive dystrophic epidermolysis bullosa (RDEB) is caused by loss-of-function mutations in COL7A1 encoding type VII collagen which forms key structures (anchoring fibrils) for dermal-epidermal adherence. Patients suffer since birth from skin blistering, and develop severe local and systemic complications resulting in poor prognosis. We lack a specific treatment for RDEB, but ex vivo gene transfer to epidermal stem cells shows a therapeutic potential. To minimize the risk of oncogenic events, we have developed new minimal self-inactivating (SIN) retroviral vectors in which the COL7A1 complementary DNA (cDNA) is under the control of the human elongation factor 1alpha (EF1alpha) or COL7A1 promoters. We show efficient ex vivo genetic correction of primary RDEB keratinocytes and fibroblasts without antibiotic selection, and use either of these genetically corrected cells to generate human skin equivalents (SEs) which were grafted onto immunodeficient mice. We achieved long-term expression of recombinant type VII collagen with restored dermal-epidermal adherence and anchoring fibril formation, demonstrating in vivo functional correction. In few cases, rearranged proviruses were detected, which were probably generated during the retrotranscription process. Despite this observation which should be taken under consideration for clinical application, this preclinical study paves the way for a therapy based on grafting the most severely affected skin areas of patients with fully autologous SEs genetically corrected using a SIN COL7A1 retroviral vector.