Repeated exposure to novelty promotes resilience against the amyloid-beta effect through dopaminergic stimulation.

RATIONALE: The accumulation of beta-amyloid peptide (Aß) in the forebrain leads to cognitive dysfunction and neurodegeneration in Alzheimer's disease. Studies have shown that individuals with a consistently cognitively active lifestyle are less vulnerable to Aß toxicity. Recent research has demonstrated that intrahippocampal Aß can impact catecholaminergic release and spatial memory. Interestingly, exposure to novelty stimuli has been found to stimulate the release of catecholamines in the hippocampus. However, it remains uncertain whether repeated enhancing catecholamine activity can effectively alleviate cognitive impairment in individuals with Alzheimer's disease. OBJECTIVES: Our primary aim was to investigate whether repeated exposure to novelty could enable cognitive resilience against Aß. This protection could be achieved by modulating catecholaminergic activity within the hippocampus. METHODS: To investigate this hypothesis, we subjected mice to three different conditions-standard housing (SH), repeated novelty (Nov), or daily social interaction (Soc) for one month. We then infused saline solution (SS) or Aß (Aß1-42) oligomers intrahippocampally and measured spatial memory retrieval in a Morris Water Maze (MWM). Stereological analysis and extracellular baseline dopamine levels using in vivo microdialysis were assessed in independent groups of mice. RESULTS: The mice that received Aß1-42 intrahippocampal infusions and remained in SH or Soc conditions showed impaired spatial memory retrieval. In contrast, animals subjected to the Nov protocol demonstrated remarkable resilience, showing strong spatial memory expression even after Aß1-42 intrahippocampal infusion. The stereological analysis indicated that the Aß1-42 infusion reduced the tyrosine hydroxylase axonal length in SH or Soc mice compared to the Nov group. Accordingly, the hippocampal extracellular dopamine levels increased significantly in the Nov groups. CONCLUSIONS: These compelling results demonstrate the potential for repeated novelty exposure to strengthen the dopaminergic system and mitigate the toxic effects of Aß1-42. They also highlight new and promising therapeutic avenues for treating and preventing AD, especially in its early stages.

Cancer Stem Cell markers: Symphonic masters of chemoresistance and immune evasion.

Cancer Stem Cells (CSCs) are highly tumorigenic, chemoresistant, and immune evasive. They emerge as a central driver that gives rise to the bulk of tumoral mass, modifies the tumor microenvironment (TME), and exploits it, leading to poor clinical outcomes for patients with cancer. The existence of CSCs thus accounts for the failure of conventional therapies and immune surveillance. Identifying CSCs in solid tumors remains a significant challenge in modern oncology, with the use of cell surface markers being the primary strategy for studying, isolating, and enriching these cells. In this review, we explore CSC markers, focusing on the underlying signaling pathways that drive CSC self-renewal, which simultaneously makes them intrinsically chemoresistant and immune system evaders. We comprehensively discuss the autonomous and non-autonomous functions of CSCs, with particular emphasis on their interactions with the tumor microenvironment, especially immune cells. This reciprocal network enhances CSCs malignancy while compromising the surrounding niche, ultimately defining therapeutic vulnerabilities associated with each CSC marker. The most common CSCs surface markers addressed in this review-CD44, CD133, ICAM1/CD54, and LGR5-provide insights into the interplay between chemoresistance and immune evasion, two critically important phenomena in disease eradication. This new perspective on the state-of-the-art of CSCs will undoubtedly open new avenues for therapy.

ICAM1 (CD54) Contributes to the Metastatic Capacity of Gastric Cancer Stem Cells.

Gastric cancer is the fourth leading cause of cancer deaths worldwide. The presence of chemoresistant cells has been used to explain this high mortality rate. These higher tumorigenic and chemoresistant cells involve cancer stem cells (CSCs), which have the potential for self-renewal, a cell differentiation capacity, and a greater tumorigenic capacity. Our research group identified gastric cancer stem cells (GCSCs) with the CD24+CD44+CD326+ICAM1+ immunophenotype isolated from gastric cancer patients. Interestingly, this GCSC immunophenotype was absent in cells isolated from healthy people, who presented a cell population with a CD24+CD44+CD326+ immunophenotype, lacking ICAM1. We aimed to explore the role of ICAM1 in these GCSCs; for this purpose, we isolated GCSCs from the AGS cell line and generated a GCSC line knockout for ICAM1 using CRISPR/iCas9, which we named GCSC-ICAM1KO. To assess the role of ICAM1 in the GCSCs, we analyzed the migration, invasion, and chemoresistance capabilities of the GCSCs using in vitro assays and evaluated the migratory, invasive, and tumorigenic properties in a zebrafish model. The in vitro analysis showed that ICAM1 regulated STAT3 activation (pSTAT3-ser727) in the GCSCs, which could contribute to the ability of GCSCs to migrate, invade, and metastasize. Interestingly, we demonstrated that the GCSC-ICAM1KO cells lost their capacity to migrate, invade, and metastasize, but they exhibited an increased resistance to a cisplatin treatment compared to their parental GCSCs; the GCSC-ICAM1KO cells also exhibited an increased tumorigenic capability in vivo.

Are there features that can predict the unresectability of pleural mesothelioma?

INTRODUCTION: The current clinical staging of pleural mesothelioma (PM) is often discordant with the pathologic staging. This study aimed to identify clinical and radiological features that could help predict unresectability in PM. METHODS: Twenty-two descriptive radiologic features were retrospectively evaluated on preoperative computed tomography (CT) and/or positron emission tomography/CT (PET/CT) performed in patients with presumably resectable PM who underwent surgery. Measurements of maximum and sum pleural thickness at three levels of the thorax (upper, middle, and lower) were taken and stratified based on the cutpoints provided by the International Association for the Study of Lung Cancer (IASLC). Clinical and radiological features, including clinical-stage, were compared between resectable and unresectable tumors by univariate analysis and logistic regression modeling. RESULTS: Of 133 patients, 69/133 (52%) had resectable and 64/133 (48%) had unresectable PM. Asbestos exposure (p = 0.005), neoadjuvant treatment (p = 0.001), clinical T-stage (p < 0.0001), all pleural thickness measurements (p < 0.05), pleural thickness pattern (p < 0.0001) and degree (p = 0.033), lung invasion (p = 0.004), extrapleural space obliteration (p < 0.0001), extension to subphrenic space (p = 0.0004), and two combination variables representing extensive diaphragmatic contact and/or chest wall involvement (p = 0.002) and mediastinal invasion (p < 0.0001) were significant predictors at univariate analysis. At multivariable analysis, all models achieved a strong diagnostic performance (area under the curve (AUC) > 0.8). The two best-performing models were one that included the upper-level maximum pleural thickness, extrapleural space obliteration, and mediastinal infiltration (AUC = 0.876), and another that integrated clinical variables and radiological assessment through the clinical T-stage (AUC = 0.879). CONCLUSION: Selected clinical and radiologic features, including pleural thickness measurements, appear to be strong predictors of unresectability in PM. CLINICAL RELEVANCE STATEMENT: A more accurate prediction of unresectability in the preoperative assessment of patients with pleural mesothelioma may avoid unnecessary surgery and prompt initiation of nonsurgical treatments. KEY POINTS: About half of pleural mesothelioma patients are reported to receive an incorrect disease stage preoperatively. Eleven features identified as predictors of unresectability were included in strongly performing predictive models. More accurate preoperative staging will help clinicians and patients choose the most appropriate treatments.

Metformin induces ZFP36 by mTORC1 inhibition in cervical cancer-derived cell lines.

BACKGROUND: Metformin, a widely prescribed antidiabetic drug, has shown several promising effects for cancer treatment. These effects have been shown to be mediated by dual modulation of the AMPK-mTORC1 axis, where AMPK acts upstream of mTORC1 to decrease its activity. Nevertheless, alternative pathways have been recently discovered suggesting that metformin can act through of different targets regulation. METHODS: We performed a transcriptome screening analysis using HeLa xenograft tumors generated in NOD-SCID mice treated with or without metformin to examine genes regulated by metformin. Western Blot analysis, Immunohistochemical staining, and RT-qPCR were used to confirm alterations in gene expression. The TNMplot and GEPIA2 platform were used for in silico analysis of genes found up-regulated by metformin, in cervical cancer patients. We performed an AMPK knock-down using AMPK-targeted siRNAs and mTOR inhibition with rapamycin to investigate the molecular mechanisms underlying the effect of metformin in cervical cancer cell lines. RESULTS: We shown that metformin decreases tumor growth and increased the expression of a group of antitumoral genes involved in DNA-binding transcription activator activity, hormonal response, and Dcp1-Dcp2 mRNA-decapping complex. We demonstrated that ZFP36 could act as a new molecular target increased by metformin. mTORC1 inhibition using rapamycin induces ZFP36 expression, which could suggest that metformin increases ZFP36 expression and requires mTORC1 inhibition for such effect. Surprisingly, in HeLa cells AMPK inhibition did not affect ZFP36 expression, suggesting that additional signal transducers related to suppressing mTORC1 activity, could be involved. CONCLUSIONS: These results highlight the importance of ZFP36 activation in response to metformin treatment involving mTORC1 inhibition.

Body mass index and adiposity influence responses to immune checkpoint inhibition in endometrial cancer.

Background: Obesity is the foremost risk factor in the development of endometrial cancer (EC). However, the impact of obesity on the response to immune checkpoint inhibitors (ICI) in EC remains poorly understood. This retrospective study investigates the association between body mass index (BMI), body fat distribution, and clinical and molecular characteristics of EC patients treated with ICI. Methods: We analyzed progression-free survival (PFS) and overall survival (OS) in EC patients treated with ICI, categorized by BMI, fat mass distribution, and molecular subtypes. Incidence of immune-related adverse events (irAE) after ICI was also assessed based on BMI status. Results: 524 EC patients were included in the study. Overweight and obese patients exhibited a significantly prolonged PFS and OS compared to normal BMI patients after treatment with ICI. Multivariable Cox regression analysis confirmed the independent association of overweight and obesity with improved PFS and OS. Elevated visceral adipose tissue (VAT) was identified as a strong independent predictor for improved PFS to ICI. Associations between obesity and OS/PFS were particularly significant in the copy number-high/TP53abnormal (CN-H/TP53abn) EC molecular subtype. Finally, obese patients demonstrated a higher irAE rate compared to normal BMI individuals. Conclusion: Obesity is associated with improved outcomes to ICI in EC patients and a higher rate of irAEs. This association is more pronounced in the CN-H/TP53abn EC molecular subtype. Funding: NIH/NCI Cancer Center Support Grant P30CA008748 (MSK). K08CA266740 and MSK Gerstner Physician Scholars Program (J.C.O). RUCCTS Grant #UL1 TR001866 (N.G-B and C.S.J). Cycle for survival and Breast Cancer Research Foundation grants (B.W).

Body mass index and adiposity influence responses to immune checkpoint inhibition in endometrial cancer.

BACKGROUNDObesity is the foremost risk factor in the development of endometrial cancer (EC). However, the impact of obesity on the response to immune checkpoint inhibitors (ICI) in EC remains poorly understood. This retrospective study investigates the association among BMI, body fat distribution, and clinical and molecular characteristics of EC patients treated with ICI.METHODSWe analyzed progression-free survival (PFS) and overall survival (OS) in EC patients treated with ICI, categorized by BMI, fat-mass distribution, and molecular subtypes. Incidence of immune-related adverse events (irAEs) after ICI was also assessed based on BMI status.RESULTS524 EC patients were included in the study. Overweight and obese patients exhibited a significantly prolonged PFS and OS compared with normal BMI patients after treatment with ICI. Multivariable Cox's regression analysis confirmed the independent association of overweight and obesity with improved PFS and OS. Elevated visceral adipose tissue (VAT) was identified as a strong independent predictor for improved PFS to ICI. Associations between obesity and OS/PFS were particularly significant in the copy number-high/TP53abnormal (CN-H/TP53abn) EC molecular subtype. Finally, obese patients demonstrated a higher irAE rate compared with normal BMI individuals.CONCLUSIONObesity is associated with improved outcomes to ICI in EC patients and a higher rate of irAEs. This association is more pronounced in the CN-H/TP53abn EC molecular subtype.FUNDINGNIH/NCI Cancer Center; MSK Gerstner Physician Scholars Program; National Center for Advancing Translational Sciences (NCATS); Cycle for Survival; Breast Cancer Research Foundation.

Self-sealing atrio-oesophageal fistula as a complication of pulmonary vein isolation: a case report.

Background: Atrio-oesophageal fistulas (AEFs) are an uncommon complication of pulmonary vein ablation, and its diagnosis is challenging. Multidisciplinary interventions and diagnostic imaging are usually required and may play a role in the initial assessment. Case summary: A 69-year-old female with atrial fibrillation who had undergone recent pulmonary vein ablation consulted with unspecific symptoms and sudden hemiparesis. Brain imaging showed pneumocephalus and acute infarcts. Chest computed tomography (CT) was highly suspicious for AEF. Surgical exploration revealed a swollen mediastinum attached to the right inferior pulmonary vein. Discussion: Non-specific symptoms after pulmonary vein ablation should prompt the suspicion of complications. In the presence of fever or neurological deficit, AEF must be suspected and assessed with a contrast-enhanced chest CT, which has become the gold standard. In brain imaging, pneumocephalus and multiple punctate acute infarcts might also indicate the presence of this complication.

Paradoxical Boosting of Weak and Strong Spatial Memories by Hippocampal Dopamine Uncaging.

The ability to remember changes in the surroundings is fundamental for daily life. It has been proposed that novel events producing dopamine release in the hippocampal CA1 region could modulate spatial memory formation. However, the role of hippocampal dopamine increase on weak or strong spatial memories remains unclear. We show that male mice exploring two objects located in a familiar environment for 5 min created a short-term memory (weak) that cannot be retrieved 1 d later, whereas 10 min exploration created a long-term memory (strong) that can be retrieved 1 d later. Remarkably, hippocampal dopamine elevation during the encoding of weak object location memories (OLMs) allowed their retrieval 1 d later but dopamine elevation during the encoding of strong OLMs promoted the preference for a familiar object location over a novel object location after 24 h. Moreover, dopamine uncaging after the encoding of OLMs did not have effect on weak memories whereas on strong memories diminished the exploration of the novel object location. Additionally, hippocampal dopamine elevation during the retrieval of OLMs did not allow the recovery of weak memories and did not affect the retrieval of strong memory traces. Finally, dopamine elevation increased hippocampal theta oscillations, indicating that dopamine promotes the recurrent activation of specific groups of neurons. Our experiments demonstrate that hippocampal dopaminergic modulation during the encoding of OLMs depends on memory strength indicating that hyperdopaminergic levels that enhance weak experiences could compromise the normal storage of strong memories.

Characterization of Homicides in Mexico: Analysis of 2015-2022.

BACKGROUND: In Mexico, homicides are the leading cause of death among men aged 15 to 44 years; however, despite their increase in recent decades, the study of this issue is insufficient, given its magnitude and impact. Therefore, this study aimed to characterize the spatial and temporal patterns and associated factors of homicides in Mexico from 2015 to 2022. METHODS: An analytical cross-sectional study was conducted, analyzing death records from the National Institute of Statistics and Geography's general mortality databases. Simple frequencies and incidence rates per 100,000 inhabitants by sex, year, and state of the Mexican Republic were calculated. Mortality was evaluated by age groups and geographic areas, and bivariate logistic regression models with sociodemographic variables were performed. RESULTS: Records of 229,182 homicides in Mexico were analyzed, with a median age of 33 years, interquartile range 18. A total of 203,898 (88.96%) were men and 25,284 (11.04%) were women. The majority of deaths occurred in public places and were caused by firearms; women had a higher percentage of homicides at home. States with high incidence rates for both sexes were Chihuahua, Zacatecas, Michoacán, Colima, and Estado de México. The total years of life lost were 9.19 million years. The national incidence of homicides in men showed an upward trend from 2015 to 2019; however, in the case of women, this incidence increased in various age groups during the study period. Occupation, education, marital status, and place of occurrence had significant associations in the logistic regression models. CONCLUSIONS: This study provides a spatial-temporal characterization of homicides in Mexico between 2015 and 2022, highlighting the high incidence in men and the upward trend in certain age groups among women. These findings underscore the need for preventive measures and public policies to address this issue in a multisectoral manner.

Inhibition of Multifunctional Protein p32/C1QBP Promotes Cytostatic Effects in Colon Cancer Cells by Altering Mitogenic Signaling Pathways and Promoting Mitochondrial Damage.

The protein p32 (C1QBP) is a multifunctional and multicompartmental homotrimer that is overexpressed in many cancer types, including colon cancer. High expression levels of C1QBP are negatively correlated with the survival of patients. Previously, we demonstrated that C1QBP is an essential promoter of migration, chemoresistance, clonogenic, and tumorigenic capacity in colon cancer cells. However, the mechanisms underlying these functions and the effects of specific C1QBP protein inhibitors remain unexplored. Here, we show that the specific pharmacological inhibition of C1QBP with the small molecule M36 significantly decreased the viability rate, clonogenic capacity, and proliferation rate of different colon cancer cell lines in a dose-dependent manner. The effects of the inhibitor of C1QBP were cytostatic and non-cytotoxic, inducing a decreased activation rate of critical pro-malignant and mitogenic cellular pathways such as Akt-mTOR and MAPK in RKO colon cancer cells. Additionally, treatment with M36 significantly affected the mitochondrial integrity and dynamics of malignant cells, indicating that p32/C1QBP plays an essential role in maintaining mitochondrial homeostasis. Altogether, our results reinforce that C1QBP is an important oncogene target and that M36 may be a promising therapeutic drug for the treatment of colon cancer.

Top-down circuitry from the anterior insular cortex to VTA dopamine neurons modulates reward-related memory.

The insular cortex (IC) has been linked to the processing of interoceptive and exteroceptive signals associated with addictive behavior. However, whether the IC modulates the acquisition of drug-related affective states by direct top-down connectivity with ventral tegmental area (VTA) dopamine neurons is unknown. We found that photostimulation of VTA terminals of the anterior insular cortex (aIC) induces rewarding contextual memory, modulates VTA activity, and triggers dopamine release within the VTA. Employing neuronal recordings and neurochemical and transsynaptic tagging techniques, we disclose the functional top-down organization tagging the aIC pre-synaptic neuronal bodies and identifying VTA recipient neurons. Furthermore, systemic administration of amphetamine altered the VTA excitability of neurons modulated by the aIC projection, where photoactivation enhances, whereas photoinhibition impairs, a contextual rewarding behavior. Our study reveals a key circuit involved in developing and retaining drug reward-related contextual memory, providing insight into the neurobiological basis of addictive behavior and helping develop therapeutic addiction strategies.

Mutant p53 gain-of-function stimulates canonical Wnt signaling via PI3K/AKT pathway in colon cancer.

Aberrant canonical Wnt signaling is a hallmark of colon cancer. The TP53 tumor suppressor gene is altered in many solid tumors, including colorectal cancer, resulting in mutant versions of p53 (mut-p53) that lose their tumor suppressor capacities and acquire new-oncogenic functions (GOFs) critical for disease progression. Although the mechanisms related to mut-p53 GOF have been explored extensively, the relevance of mut-p53 in the canonical Wnt pathway is not well defined. This work investigated the influence of mut-p53 compared to wt-p53 in ß-catenin-dependent Wnt signaling. Using the TCGA public data from Pan-Cancer and the GEPIA2 platform, an in silico analysis of wt-p53 versus mut-p53 genotyped colorectal cancer patients showed that TP53 (p53) and CTNNB1 (ß-catenin) are significantly overexpressed in colorectal cancer, compared with normal tissue. Using p53 overexpression or p53 knockdown assays of wt-p53 or mut-p53, we found that while wt-p53 antagonizes canonical Wnt signaling, mut-p53 induces the opposite effect, improving the ß-catenin-dependent transcriptional activity and colony formation ability of colon cancer cells, which were both decreased by mut-p53 knockdown expression. The mechanism involved in mut-p53-induced activation of canonical Wnt appears to be via AKT-mediated phosphorylation of Ser 552 of ß-catenin, which is known to stabilize and enhance its transcriptional activity. We also found that while wt-p53 expression contributes to 5-FU sensitivity in colon cancer cells, the RITA p53 reactivating molecule counteracted the resistance against 5-FU in cells expressing mut-p53. Our results indicate that mut-p53 GOF acts as a positive regulator of canonical Wnt signaling and participates in the induction of resistance to 5-FU in colon cancer cells.

Effect of the Addition of Fique Bagasse Cellulose Nanoparticles on the Mechanical and Structural Properties of Plastic Flexible Films from Cassava Starch.

One of the activities most representative of the agricultural sector in Colombia is the production of biodegradable fique fiber. The efficiency of the defiberization process of the fique leaves is very low since a mere 4% of the total weight of the leaf (cabuya) is used and marketed. The remaining 96%, composed of fique juice and bagasse, is considered to be waste and discarded, impacting the environment. The aim of this work was to study fique bagasse as a source of cellulose nanoparticles (CNCs). CNCs were obtained by acid hydrolysis and added at 10% to films made from cassava thermoplastic starch (TPS) by the casting method. Structural changes in the CNCs, TPS, and their mixtures were characterized by FTIR-ATR and their morphology and particle size by SEM and TEM microscopy, respectively. Thermal properties were analyzed using DSC and TGA, along with their effect on mechanical properties. Changes in the FTIR spectra indicated that the chemical method adequately removed hemicellulose and lignin from the fiber surface of fique bagasse. The CNCs showed a diameter and length of 7.5 ± 3.9 and 52.7 ± 18.1 nm, respectively, and TPS 10% CNC obtained an increase in mechanical strength of 116%. The obtainment of CNCs from lignocellulosic materials can thus be viewed as a favorable option for the subsequent reinforcement of a polymeric matrix.

Dietary Patterns of Children from the Amazon Region of Ecuador: A Descriptive, Qualitative Investigation.

Many young children in Ecuador suffer from high rates of malnutrition and stunting that affect their long-term growth and development. Little is known about the dietary patterns of children from the Amazon region who experience some of the highest rates of stunting (height-for-age) within Ecuador. Semi-structured interviews were conducted with 50 mothers of young children living in the Ecuadorian Amazon. In addition to descriptions of overall dietary patterns, three themes emerged from the interviews relating to strengths mothers have in feeding their children healthy diets: knowledge, autonomous and independent children, and supportive and responsive parenting. Five themes were found relating to barriers mothers have in feeding their children healthy diets. The first four themes concerned barriers (lack of knowledge of healthy foods, lack of access to healthy foods, not enough money, and child's health) related to multidimensional poverty. All these influenced the last theme found, namely, how difficult of an eater the child was. The implications of intervention efforts to reduce undernutrition and promote children's development by building on specific family and community strengths and identified barriers are also discussed in this paper.

Effectiveness of Virtual Reality in Balance Training for Fall Prevention in Older Adults: Systematic Review.

OBJECTIVE: The purpose of this study was to determine the effectiveness of virtual reality (VR) in balance training for the prevention of falls in older adults. METHODS: We included studies with experimental designs, cohort studies, and quasi-experimental studies of older adults who underwent balance training associated with the use of VR for the prevention of falls. The comparison of control and intervention groups in the studies reported statistically significant improvements in terms of balance for VR. RESULTS: The effects and benefits from the use of VR were seen by the fourth week of intervention, with significant improvements in balance and lower fall rates, the improvements became greater for groups using VR. CONCLUSIONS: The benefits presented by the studies were related not only to balance but also to fear of falling, reaction time, gait, physical fitness, independence in activities of daily living, muscle strength, and even quality of life.

Neutrophilic fixed drug eruption, a histopathologic variant or an expected finding?-A report of two cases and review of the literature.

Fixed drug eruption (FDE) is an adverse drug reaction characterized by recurrent circumscribed lesions at the same location upon re-exposure to the culprit medication, resulting in distinct postinflammatory hyperpigmentation. Histopathologically, FDE demonstrates a predominantly lymphocytic interface or lichenoid infiltrate with basal cell vacuolar changes and keratinocyte dyskeratosis/apoptosis. The term "neutrophilic fixed drug eruption" has been used to describe cases in which the inflammatory infiltrate is predominantly neutrophilic. The infiltrate can extend deeper in the dermis, potentially mimicking a neutrophilic dermatosis such as Sweet syndrome. We present two cases and review the literature to discuss the possibility that a neutrophilic inflammatory infiltrate may be an expected finding in FDE, rather than a histopathologic variant.

Non-canonical Wnt/Ca2+ signaling is essential to promote self-renewal and proliferation in colon cancer stem cells.

Introduction: Cancer Stem Cells (CSC) are responsible for maintaining tumor growth, chemoresistance, and metastasis. Therefore, understanding their characteristics is critical to progress in cancer therapy. While the contribution of the canonical Wnt/b-catenin signaling in both normal and CSCs had been well established, the function of non-canonical Wnt signaling cascades in stem cells is unclear. Recently, we reported that Wnt ligands trigger complex signaling in which the canonical and non-canonical responses can be simultaneously activated by one ligand in colon cancer cells, suggesting, therefore, that noncanonical Wnt pathways may also be important in CSCs. Methods: The present work aimed to know the role of the Wnt/Ca2+ pathway in colon CSCs. We used tumorspheres as a model of CSCs enrichment of CRC cell lines with different Wnt/b-catenin contexts. Results: Using Wnt3a and Wnt5a as prototype ligands to activate the canonical or the non-canonical pathways, respectively, we found that both Wnt3a and Wnt5a promote sphere-formation capacity and proliferation without stimulating b-catenin-dependent transcription. Upregulation of sphere formation by Wnt5a or Wnt3a requires the downstream activation of Phospholipase C and transcriptional factor NFAT. Moreover, the single specific inhibition of PLC or NFAT, using U73122 and 11R-VIVIT, respectively, leads to impaired sphere formation. Discussion: Our results indicate that both types of ligands activate the Wnt/Ca2+ signaling axis to induce/maintain the self-renewal efficiency of CSCs, demonstrating to be essential for the functions of CSC in colon cancer.

Salience to remember: VTA-IC dopaminergic pathway activity is necessary for object recognition memory formation.

Previous studies have shown that dopaminergic activity modulates the salience of novel stimuli enabling the formation of recognition memories. In this work, we hypothesize that dopamine released into the insular cortex (IC) from the ventral tegmental area (VTA) inputs enables the acquisition to consolidate object recognition memory. It has been reported that short training produces weak recognition memories; on the contrary, longer training produces lasting and robust recognition memories. Using a Cre-recombinase under the tyrosine hydroxylase (TH+) promoter mouse model, we photostimulated the VTA-IC dopaminergic pathway during short training or photoinhibited the same pathway during long training while mice explored objects. Our results showed that the photostimulation of the VTA-IC pathway during a short training enables the acquisition of recognition memory. Conversely, photoinhibition of the same pathway during a long training prevents the acquisition of recognition memory. Interestingly, the exploration time of the objects under photoinhibition or photostimulation of the dopaminergic VTA-IC pathway was not altered. Significantly, this enhancement of acquisition of the object recognition memory through the photostimulation of the VTA dopaminergic neurons could be impaired by the blockage of the D1-like receptors into the IC, either before or after the photostimulation. Altogether, our results suggest that dopamine released by the VTA is required during the acquisition to consolidate the object recognition memory through D1-like receptors into the IC without affecting the activity or the motivation to explore objects.

Reactive infectious mucocutaneous eruption due to COVID-19 with erythema-multiforme-like lesions and myeloid cells.

Reactive infectious mucocutaneous eruption (RIME) is a recently described entity in which there is prominent mucositis, most commonly involving the oral and urogenital mucosa, secondary to a variety of pathogens. There is typically minimal cutaneous involvement in RIME. This contrasts with erythema multiforme (EM) in which characteristic targetoid lesions predominate, usually in isolation (EM minor), but in a subset of cases, with severe mucositis (EM major). While the histopathologic features of RIME have not been as well defined, those of EM are characterized by epidermal apoptosis and interface dermatitis with lymphocytes making up the predominant cell type. We report a unique case of RIME in a 16-year-old male with COVID-19 characterized by significant mucositis involving the oral and genital mucosa, as well as numerous targetoid lesions on the trunk and extremities. Histopathologically, there was an inflammatory infiltrate obscuring and disrupting the epidermal interface, associated with epidermal necrosis, and blister formation. The infiltrate was composed of cells with irregular, non-segmented and elongate nuclei, with myeloid and histiocytoid cytomorphology. The cells were positive for myeloperoxidase, CD68, and CD163 (subset) suggesting myeloid lineage. RIME is a rarely reported COVID-19-related eruption, and targetoid lesions and myeloid interface reactions have not been described with RIME.