The Influence of Remnant Cholesterol on Cardiovascular Risk and Mortality in Patients with Non-Functional Adrenal Incidentalomas and Mild Autonomous Cortisol Secretion: A Retrospective Cohort Study.

Background: Increased cardiovascular risk has been described in individuals with adrenal incidentalomas. The aim of the present study is to assess the effect of remnant cholesterol (RC) on the cardiovascular risk and mortality of patients with adrenal incidentalomas. Methods: A retrospective cohort study was conducted with patients with adrenal incidentalomas between 2001 and 2024. One hundred thirty-seven patients (mean age of 61.2 ± 11.5 years; 56.6% women) with non-functioning adrenal incidentalomas and with mild autonomous cortisol secretion (MACS) (cortisol post-dexamethasone suppression test ≥1.8 µg/mL) were included. The patients were divided into two groups using 30 mg/dL as the cut-off for RC. Logistic regression models were used to study the impact of RC on major adverse cardiovascular events and mortality (MACEs). Results: Patients with RC ≥ 30 mg/dL exhibited a higher prevalence of type 2 diabetes mellitus (T2D) (p < 0.001), lower HDL-C (p < 0.001) and LDL-C (p = 0.025) levels, a higher frequency of treatment with statins (p = 0.032), and a higher rate of non-fatal major cardiovascular events (p = 0.038) and MACEs (p = 0.038). Patients with MACS showed no differences in RC or complications during the follow-up. The relative risk of high RC was 2.65 (1.04-6.77) for cardiovascular events and 2.27 (1.05-4.92) for MACEs, with p < 0.05 in both cases. The only variables independently affecting MACEs were age ([odds ratio] OR = 1.13 [p = 0.004]), female sex (OR = 0.20; p = 0.016), LDL-C (OR = 1.02; p = 0.029), and RC (OR = 1.06; p = 0.014). T2D and HDL-C were not independently associated with MACEs. Conclusions: RC ≥30 mg/dL in patients with adrenal incidentalomas was associated with a higher prevalence of T2D, lower HDL-C levels, and a higher risk of MACEs. MACS was not associated with RC or MACEs during the follow-up.

Flurbiprofen inhibits cAMP transport by MRP4/ABCC4 increasing the potency of gemcitabine treatment in PDAC cell models.

Pancreatic ductal adenocarcinoma (PDAC) remains a highly malignant cancer with a grim prognosis due to its early metastasis and resistance to current chemotherapies, such as Gemcitabine (GEM). We have previously demonstrated that cAMP exclusion by MRP4 is critical for PDAC cell proliferation, establishing this transporter as a promising prognostic marker and therapeutic target. In search for novel therapeutic options to improve GEM efficacy, we conducted a drug repositioning screening to identify potential inhibitors of cAMP transport by MRP4. Several non-steroidal anti-inflammatory drugs (NSAIDs) can inhibit the transport of certain MRP4 substrates. In this study, we assessed the efficacy of sixteen NSAIDs in inhibiting cAMP transport mediated by MRP4, identifying seven potent inhibitors based on their IC50 values. The most potent inhibitors were further tested for their effect on cell proliferation and migration. Flurbiprofen emerged as the most potent inhibitor of both MRP4-mediated cAMP transport and cell proliferation. Overexpression of MRP4 in BxPC-3 cells significantly increased GEM resistance, and co-administration of flurbiprofen with GEM markedly enhanced the latter's potency inhibiting PDAC cells proliferation. These findings position flurbiprofen as a potent inhibitor of cAMP transport by MRP4 and a promising adjunctive therapy to enhance GEM effectiveness in PDAC treatment.

Runt-related transcription factor 1 (RUNX1) is a mediator of acute kidney injury.

Treatment for acute kidney injury (AKI) is suboptimal. A better understanding of the pathogenesis of AKI may lead to new therapeutic approaches. Kidney transcriptomics of folic acid-induced AKI (FA-AKI) in mice identified Runx1 as the most upregulated RUNX family gene. We then examined the expression of RUNX1 in FA-AKI, in bacterial lipopolysaccharide (LPS)-induced cytokine storm-AKI (CS-AKI), and in human AKI. In cultured mouse tubule cells, we explored the expression and role of RUNX1 in response to the cytokine TWEAK or LPS. A chemical inhibitor of RUNX1 (Ro5-3335) was used in animal models of AKI to test its potential as a therapeutic target. RUNX1 overexpression in FA-AKI was validated at the mRNA and protein levels and localized mainly to tubule cell nuclei. CS-AKI also upregulated kidney RUNX1. Increased tubule and interstitial RUNX1 expression were also observed in human AKI. In cultured mouse tubule cells, the pro-inflammatory cytokine TWEAK and LPS increased RUNX1 and IL-6 expression. Mechanistically, RUNX1 bound to the Il6 gene promoter and RUNX1 targeting with the chemical inhibitor Ro5-3335, or a specific small interfering RNA (siRNA), prevented the TWEAK- and LPS-induced upregulation of IL6 through a RUNX1/NFκB1 p50 pathway. In vivo, preventive Ro5-3335 improved kidney function and reduced inflammation in FA-AKI and CS-AKI. However, Ro5-3335 administration after the insult only improved kidney function in CS-AKI. Kidney transcriptomics identified inflammatory genes and transcription factor mRNAs such as Yap1 and Trp53 as key targets of Ro5-3335 in CS-AKI. In conclusion, RUNX1 contributes to AKI by driving the expression of genes involved in inflammation and represents a novel therapeutic target in AKI. © 2024 The Author(s). The Journal of Pathology published by John Wiley & Sons Ltd on behalf of The Pathological Society of Great Britain and Ireland.

Predictive modeling of endocardial fibroelastosis recurrence in patients with congenital heart disease.

BACKGROUND: Endocardial fibroelastosis (EFE) is a major effector in the maldevelopment of the heart in patients with congenital heart disease. Despite successful surgical removal, EFE can redevelop, but the underlying cause of EFE recurrence remains unknown. This study aimed to identify hemodynamic predictors and genetic links to epithelial/endothelial-to-mesenchymal transition (EMT/EndMT) alterations for preoperative risk assessment. METHODS: We assessed the impact of preoperative hemodynamic parameters on EFE recurrence in a cohort of 92 patients with congenital heart disease who underwent left ventricular (LV) EFE resection between January 2010 and March 2021. Additionally, whole-exome sequencing in 18 patients was used to identify rare variants (minor allele frequency <10-5) in high-expression heart (HHE) genes related to cardiac EMT/EndMT and congenital heart disease. RESULTS: EFE recurred in 55.4% of patients, within a median of 2.2 years postsurgery. Multivariable analysis revealed specific hemodynamic parameters (mitral valve inflow and area, LV filling pressure, and aortic valve gradient and diameter) as predictors, forming a predictive model with an area under the receiver operating characteristic curve of 0.782. Furthermore, 89% of the patients exhibited damaging variants in HHE genes, with 38% linked to cardiac EMT/EndMT Gene Ontology processes and 22% associated with known congenital heart disease genes. Notably, HHE genes associated with cardiac EMT/EndMT were significantly associated with faster EFE recurrence in a multivariate analysis (hazard ratio, 3.56; 95% confidence interval, 1.24-10.17; P = .018). CONCLUSIONS: These findings established a predictive scoring system using preoperative hemodynamic parameters for EFE recurrence risk assessment. Alterations in HHE genes, particularly those linked to cardiac EMT/EndMT, exacerbate the risk of recurrence.

Multi-omic characterization of antibody-producing CHO cell lines elucidates metabolic reprogramming and nutrient uptake bottlenecks.

Characterizing the phenotypic diversity and metabolic capabilities of industrially relevant manufacturing cell lines is critical to bioprocess optimization and cell line development. Metabolic capabilities of production hosts limit nutrient and resource channeling into desired cellular processes and can have a profound impact on productivity. These limitations cannot be directly inferred from measured data such as spent media concentrations or transcriptomics. Here, we present an integrated multi-omic analysis pipeline combining exo-metabolomics, transcriptomics, and genome-scale metabolic network analysis and apply it to three antibody-producing Chinese Hamster Ovary cell lines to identify reprogramming features associated with high-producing clones and metabolic bottlenecks limiting product formation in an industrial bioprocess. Analysis of individual datatypes revealed a decreased nitrogenous byproduct secretion in high-producing clones and the topological changes in peripheral metabolic pathway expression associated with phase shifts. An integrated omics analysis in the context of the genome-scale metabolic model elucidated the differences in central metabolism and identified amino acid utilization bottlenecks limiting cell growth and antibody production that were not evident from exo-metabolomics or transcriptomics alone. Thus, we demonstrate the utility of a multi-omics characterization in providing an in-depth understanding of cellular metabolism, which is critical to efforts in cell engineering and bioprocess optimization.

TPX2 overexpression promotes sensitivity to dasatinib in breast cancer by activating YAP transcriptional signaling.

Chromosomal instability (CIN) is a hallmark of cancer aggressiveness, providing genetic plasticity and tumor heterogeneity that allows the tumor to evolve and adapt to stress conditions. CIN is considered a cancer therapeutic biomarker because healthy cells do not exhibit CIN. Despite recent efforts to identify therapeutic strategies related to CIN, the results obtained have been very limited. CIN is characterized by a genetic signature where a collection of genes, mostly mitotic regulators, are overexpressed in CIN-positive tumors, providing aggressiveness and poor prognosis. We attempted to identify new therapeutic strategies related to CIN genes by performing a drug screen, using cells that individually express CIN-associated genes in an inducible manner. We find that the overexpression of targeting protein for Xklp2 (TPX2) enhances sensitivity to the proto-oncogene c-Src (SRC) inhibitor dasatinib due to activation of the Yes-associated protein 1 (YAP) pathway. Furthermore, using breast cancer data from The Cancer Genome Atlas (TCGA) and a cohort of cancer-derived patient samples, we find that both TPX2 overexpression and YAP activation are present in a significant percentage of cancer tumor samples and are associated with poor prognosis; therefore, they are putative biomarkers for selection for dasatinib therapy.

Usefulness of Procalcitonin Levels for Predicting the Microbiological Orientation in Patients with Sepsis.

The main objective of the study was to verify whether levels of procalcitonin (PCT) could guide us toward determining the type of bacteria causing the sepsis and to identify the discriminatory cut-off point in the first urgent laboratory test. This study is a single center retrospective analysis that includes 371 patients with a mean age of 71.7 ± 15.6 years who were diagnosed with sepsis or septic shock. The yield of blood cultures in demonstrating the causative microbiological agent was 24.3% (90), and it was 57, 1% (212) when evaluating all types of cultures. Statistically significant positive differences were observed in the mean value of the PCT between the group that obtained positive cultures and the group that did not (p < 0.0001). The AUC-ROC of PCT values as a guide to the causal bacteria type was 0.68 (95%CI: 0.57-0.78, p < 0.0021). The PCT value that showed the best diagnostic characteristics for identifying Gram-negative rods (GNR) as the causative agent in blood cultures was 2.1 ng/mL. The positive predictive value (PPV) was 78, 9% (66.3-88.1%). The AUC-ROC of the PCT values for sepsis diagnosis, with any positive culture that could be assessed, was 0.67 (95%CI: 0.63-0.73, p < 0.0001). The PCT value that showed the best diagnostic characteristic for predicting sepsis was 3.6 ng/mL.

Nuclear VANGL2 Inhibits Lactogenic Differentiation.

Planar cell polarity (PCP) proteins coordinate tissue morphogenesis by governing cell patterning and polarity. Asymmetrically localized on the plasma membrane of cells, transmembrane PCP proteins are trafficked by endocytosis, suggesting they may have intracellular functions that are dependent or independent of their extracellular role, but whether these functions extend to transcriptional control remains unknown. Here, we show the nuclear localization of transmembrane, PCP protein, VANGL2, in the HCC1569 breast cancer cell line, and in undifferentiated, but not differentiated, HC11 cells that serve as a model for mammary lactogenic differentiation. The loss of Vangl2 function results in upregulation of pathways related to STAT5 signaling. We identify DNA binding sites and a nuclear localization signal in VANGL2, and use CUT&RUN to demonstrate recruitment of VANGL2 to specific DNA binding motifs, including one in the Stat5a promoter. Knockdown (KD) of Vangl2 in HC11 cells and primary mammary organoids results in upregulation of Stat5a, Ccnd1 and Csn2, larger acini and organoids, and precocious differentiation; phenotypes are rescued by overexpression of Vangl2, but not Vangl2ΔNLS. Together, these results advance a paradigm whereby PCP proteins coordinate tissue morphogenesis by keeping transcriptional programs governing differentiation in check.

Hybrid hydrogels support neural cell culture development under magnetic actuation at high frequency.

The combination of hydrogels and magnetic nanoparticles, scarcely explored to date, offers a wide range of possibilities for innovative therapies. Herein, we have designed hybrid 3D matrices integrating natural polymers, such as collagen, chitosan (CHI) and hyaluronic acid (HA), to provide soft and flexible 3D networks mimicking the extracellular matrix of natural tissues, and iron oxide nanoparticles (IONPs) that deliver localized heat when exposed to an alternating magnetic field (AMF). First, colloidally stable nanoparticles with a hydrodynamic radius of ∼20 nm were synthesized and coated with either CHI (NPCHI) or HA (NPHA). Then, collagen hydrogels were homogeneously loaded with these coated-IONPs resulting in soft (E0 ∼ 2.6 kPa), biodegradable and magnetically responsive matrices. Polymer-coated IONPs in suspension preserved primary neural cell viability and neural differentiation even at the highest dose (0.1 mg Fe/mL), regardless of the coating, even boosting neuronal interconnectivity at lower doses. Magnetic hydrogels maintained high neural cell viability and sustained the formation of highly interconnected and differentiated neuronal networks. Interestingly, those hydrogels loaded with the highest dose of NPHA (0.25 mgFe/mg polymer) significantly impaired non-neuronal differentiation with respect to those with NPCHI. When evaluated under AMF, cell viability slightly diminished in comparison with control hydrogels magnetically stimulated, but not compared to their counterparts without stimulation. Neuronal differentiation under AMF was only affected on collagen hydrogels with the highest dose of NPHA, while non-neuronal differentiation regained control values. Taken together, NPCHI-loaded hydrogels displayed a superior performance, maybe benefited from their higher nanomechanical fluidity. STATEMENT OF SIGNIFICANCE: Hydrogels and magnetic nanoparticles are undoubtedly useful biomaterials for biomedical applications. Nonetheless, the combination of both has been scarcely explored to date. In this study, we have designed hybrid 3D matrices integrating both components as promising magnetically responsive platforms for neural therapeutics. The resulting collagen scaffolds were soft (E0 ∼ 2.6 kPa) and biodegradable hydrogels with capacity to respond to external magnetic stimuli. Primary neural cells proved to grow on these substrates, preserving high viability and neuronal differentiation percentages even under the application of a high-frequency alternating magnetic field. Importantly, those hydrogels loaded with chitosan-coated iron oxide nanoparticles displayed a superior performance, likely related to their higher nanomechanical fluidity.

Immunomodulation with AM3 and antioxidants creates an adequate framework for skin repair and decreases the monocyte proinflammatory stage in smoker women.

Smoking has been considering a crucial factor in promoting skin and systemic aging that is associated with the development of a low-level, systemic, chronic inflammation known as "inflammaging" in which monocytes play a pivotal role. Our aim was to investigate the effects of AM3 plus antioxidants vs placebo in the activation status, function of monocytes and cutaneous aging parameters in healthy smoker middle-aged women. A total of 32 women were 1:1 randomly assigned to AM3 plus antioxidants or placebo for three months. Peripheral mononuclear blood cells and cutaneous biopsy were obtained and flow cytometry and immunohistological studies, respectively, were performed before and after the treatment. AM3 plus antioxidants treatment compared with placebo significantly reduced the monocyte production of the proinflammatory interleukin 1 (IL-1), tumor necrosis factor α (TNF-α) and interleukin 6 (IL-6) cytokines as well as increased the regulatory IL-10 in middle-aged smoker women. Furthermore, AM3 and antioxidants did not modify ROS production by monocytes and granulocytes but increased their phagocytic activity. The active combination also stimulated a significative increase in reticular dermis depth as well as an increase in the expression of CD117 and CD31. Thus, AM3 and antioxidants treatment reduces the systemic proinflammatory monocyte disturbance of heathy smoker middle-aged women and encourage skin repair mechanisms.

Regulated necrosis role in inflammation and repair in acute kidney injury.

Acute kidney injury (AKI) frequently occurs in patients with chronic kidney disease (CKD) and in turn, may cause or accelerate CKD. Therapeutic options in AKI are limited and mostly relate to replacement of kidney function until the kidneys recover spontaneously. Furthermore, there is no treatment that prevents the AKI-to-CKD transition. Regulated necrosis has recently emerged as key player in kidney injury. Specifically, there is functional evidence for a role of necroptosis, ferroptosis or pyroptosis in AKI and the AKI-to-CKD progression. Regulated necrosis may be proinflammatory and immunogenic, triggering subsequent waves of regulated necrosis. In a paradigmatic murine nephrotoxic AKI model, a first wave of ferroptosis was followed by recruitment of inflammatory cytokines such as TWEAK that, in turn, triggered a secondary wave of necroptosis which led to persistent kidney injury and decreased kidney function. A correct understanding of the specific forms of regulated necrosis, their timing and intracellular molecular pathways may help design novel therapeutic strategies to prevent or treat AKI at different stages of the condition, thus improving patient survival and the AKI-to-CKD transition. We now review key regulated necrosis pathways and their role in AKI and the AKI-to-CKD transition both at the time of the initial insult and during the repair phase following AKI.

Nuclear VANGL2 Inhibits Lactogenic Differentiation.

Planar cell polarity (PCP) proteins coordinate tissue morphogenesis by governing cell patterning and polarity. Asymmetrically localized on the plasma membrane of cells, PCP proteins are also trafficked by endocytosis, suggesting they may have intracellular functions that are dependent or independent of their extracellular role, but whether these functions extend to transcriptional control remains unknown. Here, we show the nuclear localization of transmembrane, PCP protein, VANGL2, in undifferentiated, but not differentiated, HC11 cells, which serve as a model for mammary lactogenic differentiation. Loss of Vangl2 function results in upregulation of pathways related to STAT5 signaling. We identify DNA binding sites and a nuclear localization signal in VANGL2, and use CUT&RUN to demonstrate direct binding of VANGL2 to specific DNA binding motifs, including one in the Stat5a promoter. Knockdown (KD) of Vangl2 in HC11 cells and primary mammary organoids results in upregulation of Stat5a , Ccnd1 and Csn2 , larger acini and organoids, and precocious differentiation; phenotypes rescued by overexpression of Vangl2 , but not Vangl2 ΔNLS . Together, these results advance a paradigm whereby PCP proteins coordinate tissue morphogenesis by keeping transcriptional programs governing differentiation in check.

Regular Exercise Improved Fatigue and Musculoskeletal Pain in Young Adult Psoriatic Patients without Psoriatic Arthritis.

Fatigue and musculoskeletal pain are also frequent in patients with psoriasis (PsO) without arthritis (PsA). The current study aimed to assess the impact of an intervention program based on aerobic training to reduce fatigue and musculoskeletal pain in patients with PsO without PsA. A total of 118 male patients with PsO volunteered in the current interventional study and were randomly allocated to the experimental (n = 59) or control group (n = 59). The intervention consisted of a 16-week aerobic training program on a treadmill, three sessions per week, consisting of a warm-up, 35-50 min treadmill exercise (increasing 5 min/4 weeks) at a work intensity of 50-65% of peak heart-rate (increasing 5%/4 weeks), and cooling-down. The functional assessment of chronic illness therapy fatigue scale (FACIT-Fatigue), health assessment questionnaire disability index (HAQ-DI), and visual analog scale (VAS) were compared pre and post intervention. Nutritional intake, maximal aerobic power, lipid profile, serum markers of muscle damage, and body composition were also assessed. When compared to baseline, FACIT-Fatigue, HAQ-DI, and VAS scores were significantly improved without increasing markers of muscle damage. Fat mass percentage, lipid profile, and maximal oxygen consumption were also improved. In conclusion, a 16-week aerobic training program at moderate intensity was safe, well tolerated, and effective in psoriatic patients without PsA. Long-term follow-up studies are required to examine whether these promising results may improve clinical outcomes.

Usefulness of Preoperative Determination of Serum MR-ProAdrenomedullin Levels to Predict the Need for Postoperative Organ Support in Abdominal Oncological Surgery.

The need for postoperative organic support is associated with patient outcomes. Biomarkers may be useful for detecting patients at risk. MR-ProADM is a novel biomarker with an interesting profile that can be used in this context. The main objective of this study was to verify whether there was an association between the preoperative serum levels of MR-ProADM and the need for organic support after elective abdominal cancer surgery, and to determine the preoperative MR-ProADM value that predicts the need for postoperative organic support. This was a multicenter prospective observational study conducted by four tertiary hospitals in Spain between 2017 and 2018. Plasma samples were collected for the quantification of MR-ProADM from adults who underwent major abdominal surgery during 2017-2018. The primary outcome was the need for organic support in the first seven postoperative days and its association with the preoperative levels of MR-ProADM, and the secondary outcome was the preoperative levels of MR-ProADM in the study population. This study included 370 patients with a mean age of 67.4 ± 12.9 years. Seventeen percent (63 patients) required some postoperative organic support measures in the first week. The mean preoperative value of MR-ProADM in patients who required organic support was 1.16 ± 1.15 nmol/L. The AUC-ROC of the preoperative MR-ProADM values associated with the need for organic support was 0.67 (95% CI: 0.59-0.75). The preoperative MR-ProADM value, which showed the best compromise in sensitivity and specificity for predicting the need for organic support, was 0.70 nmol/L. The negative predictive value was 91%. A multivariate analysis confirmed that a preoperative level of MR-ProADM ≥ 0.70 nmol/L is an independent factor associated with risk of postoperative organic support (OR 2, 6). Elevated preoperative MR-ProADM levels are associated with the need for postoperative organic support. Therefore, MR-ProADM may be a useful biomarker for perioperative risk assessment.

Whole-Genome Doubling as a source of cancer: how, when, where, and why?

Chromosome instability is a well-known hallmark of cancer, leading to increased genetic plasticity of tumoral cells, which favors cancer aggressiveness, and poor prognosis. One of the main sources of chromosomal instability are events that lead to a Whole-Genome Duplication (WGD) and the subsequently generated cell polyploidy. In recent years, several studies showed that WGD occurs at the early stages of cell transformation, which allows cells to later become aneuploid, thus leading to cancer progression. On the other hand, other studies convey that polyploidy plays a tumor suppressor role, by inducing cell cycle arrest, cell senescence, apoptosis, and even prompting cell differentiation, depending on the tissue cell type. There is still a gap in understanding how cells that underwent WGD can overcome the deleterious effect on cell fitness and evolve to become tumoral. Some laboratories in the chromosomal instability field recently explored this paradox, finding biomarkers that modulate polyploid cells to become oncogenic. This review brings a historical view of how WGD and polyploidy impact cell fitness and cancer progression, and bring together the last studies that describe the genes helping cells to adapt to polyploidy.

Knowledge and practices about taeniasis/cysticercosis complex within the framework of the national plan for its elimination in Colombia, 2019.

The taeniasis/cysticercosis complex (TCC) belongs to the group of neglected infectious diseases with a multifactorial transmission that includes hosts such as humans and pigs of the parasitic tapeworm (Taenia solium) and environmental factors. This study represents the first phase of the National and Cross-sectoral Plan for TCC Elimination. OBJECTIVES: To obtain data about knowledge and practices in relation to the TCC from knowledge, attitudes, and practices (KAP) surveys applied in two pilot localities for building a baseline of the potential risk factors related to identification, prevention, and control of TCC in Colombia. METHODS: A descriptive cross-sectional survey from October to November in 2019 was carried out using a structured questionnaire and random sampling by single-stage conglomerates in the municipalities of Mahates, Bolívar (n = 152) (Atlantic Region) and Mercaderes, Cauca (n = 152) (Andean Region). RESULTS: Respondents in Mahates showed moderate knowledge about TCC compared to those in Mercaderes, however, risky practices were identified in both places (consumption of pork with cysts and defecation in places other than the bathroom or latrine). Deficiency in infrastructure and failure in basic services were observed as potential risk factors for TCC transmission in both municipalities. CONCLUSION: Based on the framework of the National and Cross-sectoral Plan for TCC Elimination, adequate knowledge on identification, prevention, and control of the disease must be reinforced; cultural and ecological differences should be considered when designing communication and knowledge transmission tools. We consider that major investment should be made in improving basic services and creating sustainable modernized pig farming in Mahates and Mercaderes.

Ceefourin-1, a MRP4/ABCC4 inhibitor, induces apoptosis in AML cells enhanced by histamine.

BACKGROUND: Ceefourin-1 is a specific MRP4/ABCC4 inhibitor with potential antileukemic activity. In this study, we evaluate the ability of ceefourin-1 alone or in combination with histamine, an approved antileukemic agent, to induce cell differentiation or apoptosis in human acute myeloid leukemic cells. We also examine ceefourin-1 toxicity in mice. METHODS: U937, HL-60, and KG1a cells were used as models for human acute myeloid leukemia. Cyclic AMP efflux was estimated by measuring intracellular and extracellular cAMP levels. Cell differentiation was assessed by levels of CD14 and CD11b by FACS, and CD88 by western blot, and by cell morphology. Apoptosis was evaluated by cleavage of caspase-3 and PARP by western blot, and by annexin V binding assay. Subacute toxicity study of ceefourin-1 was carried out in BALB/c mice. RESULTS: Ceefourin-1 inhibits cAMP exclusion in AML cells and promotes intracellular signaling via CREB. Ceefourin-1 leads AML cells to apoptosis and histamine potentiates this effect, without evidence of cell differentiation. Intraperitoneal administration of ceefourin-1 shows no important alterations in mice blood parameters, hepatic, and renal functions, nor signs of histologic damage. CONCLUSIONS: These results show that ceefourin-1 promotes apoptosis in AML cells that is enhanced by histamine. GENERAL SIGNIFICANCE: This work indicates that ceefourin-1 represents a promising molecule that could be used alone or in combination with histamine for in vivo evaluation in acute myeloid leukemia malignancies.

DNA damage triggers squamous metaplasia in human lung and mammary cells via mitotic checkpoints.

Epithelial transdifferentiation is frequent in tissue hyperplasia and contributes to disease in various degrees. Squamous metaplasia (SQM) precedes epidermoid lung cancer, an aggressive and frequent malignancy, but it is rare in the epithelium of the mammary gland. The mechanisms leading to SQM in the lung have been very poorly investigated. We have studied this issue on human freshly isolated cells and organoids. Here we show that human lung or mammary cells strikingly undergo SQM with polyploidisation when they are exposed to genotoxic or mitotic drugs, such as Doxorubicin or the cigarette carcinogen DMBA, Nocodazole, Taxol or inhibitors of Aurora-B kinase or Polo-like kinase. To note, the epidermoid response was attenuated when DNA repair was enhanced by Enoxacin or when mitotic checkpoints where abrogated by inhibition of Chk1 and Chk2. The results show that DNA damage has the potential to drive SQM via mitotic checkpoints, thus providing novel molecular candidate targets to tackle lung SCC. Our findings might also explain why SCC is frequent in the lung, but not in the mammary gland and why chemotherapy often causes complicating skin toxicity.

Assessment of clinical and ultrasonographic parameters as indicators for buccal fat pad excision by esthetic reasons.

PURPOSE: The selection of candidates for buccal fat pad (BFP) removal depends on the patient's requirements, the subjective surgeons' evaluation, and objective clinical factors. This cross-sectional observational study aimed to identify objective clinical and ultrasonographic parameters as indicators of cheek contouring with BFP excision. METHODS: Sixty-six patients with cheek fullness complaints were examined by two experienced surgeons to determine if they were good candidates for the procedure. Thereafter, participants underwent clinical and ultrasonographic assessments in a separate session to aid in the surgical decision-making. The association between the clinical judgment for BFP excision and the study variables was analyzed individually and adjusted for confounders using binary logistic regression and grouping analyses. RESULTS: Forty-nine participants were regarded as suitable and 17 as non-suitable for the procedure. After regression analysis, cheek skin-fold thickness > 6.00 mm, midfacial contour > 2.20 mm, ovoid/triangular facial form, and ultrasonographic BFP volume > 2.05 mL remained as robust individual indicators for the suitability for the procedure. However, the grouping analysis showed that patients having three-to-four significant criteria synchronously had significantly higher odds for eligibility with excellent discrimination capability. CONCLUSION: Although high values of cheek skin-fold thickness, midfacial contour, and ultrasonographic BFP volume, as well as an ovoid/triangular facial form, might be robust indicators for the suitability for BFP excision, the surgical decision-making should not be based on isolated parameters. Instead, those patients possessing a combination of at least three of these specific eligibility criteria above the threshold value might be considered the best candidates for the procedure.

Caracterización y factores asociados con la atención de embarazadas con dengue en Cali, Colombia / Characterization and factors associated with the care of pregnant women with dengue in Cali, Colombia

Resumen OBJETIVO: Describir las características sociodemográficas y clínicas y determinar los factores asociados con la hospitalización y la oportunidad de consulta en embarazadas notificadas con dengue en Cali, Colombia. MATERIALES Y MÉTODOS: Estudio observacional, analítico y retrospectivo de base poblacional. Descripción de las características sociodemográficas y clínicas de las embarazadas con dengue que se notificaron al Sistema de Vigilancia en Salud Pública (SIVIGILA). Para identificar los factores asociados con la hospitalización se aplicó un modelo de regresión logística y para el procesamiento estadístico se utilizó SPSS versión 26. RESULTADOS: Se estudiaron 674 embarazadas con dengue, 63.9% (n = 431) sin signos de alarma, 36.1% (n = 243) con signos de alarma y ningún caso de dengue grave. En cuanto a la conducta, el 42.3% ( n = 285) se trató de manera ambulatoria, 39.5% (n = 266) en el hospital;12.5% (n = 84) permaneció en observación, 1.9% (n = 13) requirió el envío a otro centro de salud para su hospitalización y el 3.9% (n = 26) requirió atención en cuidados intensivos. CONCLUSIONES: En las embarazadas, la infección por dengue aumenta la morbilidad; los principales factores asociados con la hospitalización fueron: trombocitopenia, hipotensión, dolor abdominal, erupción cutánea y vómito. Por parte de las entidades de salud y la comunidad se requieren intervenciones efectivas enfocadas a la manipulación de residuos y educación e insistencia en los principales signos de alarma por los que deben solicitar la consulta médica.

Abstract OBJECTIVE: To describe the sociodemographic and clinical characteristics and to determine the factors associated with hospitalization and timeliness of consultation in pregnant women notified with dengue fever in Cali, Colombia. MATERIALS AND METHODS: Observational, analytical and retrospective population-based study. Description of the sociodemographic and clinical characteristics of pregnant women with dengue reported to the Public Health Surveillance System (SIVIGILA). A logistic regression model was applied to identify factors associated with hospitalization and SPSS version 26 was used for statistical processing. RESULTS: A total of 674 pregnant women with dengue were studied, 63.9% (n = 431) without alarm signs, 36.1% (n = 243) with alarm signs and no cases of severe dengue. In terms of behavior, 42.3% ( n = 285) were treated on an outpatient basis, 39.5% (n = 266) in hospital;12.5% (n = 84) remained under observation, 1.9% (n = 13) required referral to another health center for hospitalization and 3.9% (n = 26) required intensive care. CONCLUSIONS: In pregnant women, dengue infection increases morbidity; the main factors associated with hospitalization were: thrombocytopenia, hypotension, abdominal pain, rash, and vomiting. On the part of the health entities and the community, effective interventions focused on waste handling and education and insistence on the main warning signs for which they should seek medical consultation are required.