Transcriptomics of Besnoitia besnoiti-Infected Fibroblasts Reveals Hallmarks of Early Fibrosis and Cancer Progression.

Endothelial injury, inflammatory infiltrate and fibrosis are the predominant lesions in the testis of bulls with besnoitiosis that may result in sterility. Moreover, fibroblasts, which are key players in fibrosis, are parasite target cells in a Besnoitia besnoiti chronic infection. This study aimed to decipher the molecular basis that underlies a drift toward fibrosis during the disease progression. Transcriptomic analysis was developed at two times post-infection (p.i.), representative of invasion (12 h p.i.) and intracellular proliferation (32 h p.i.), in primary bovine aorta fibroblasts infected with B. besnoiti tachyzoites. Once the enriched host pathways were identified, we studied the expression of selected differentially expressed genes (DEGs) in the scrotal skin of sterile infected bulls. Functional enrichment analyses of DEGs revealed shared hallmarks of cancer and early fibrosis. Biomarkers of inflammation, angiogenesis, cancer, and MAPK signaling stood out at 12 h p.i. At 32 h p.i., again MAPK and cancer pathways were enriched together with the PI3K-AKT pathway related to cell proliferation. Some DEGs were also regulated in the skin samples of naturally infected bulls (PLAUR, TGFß1, FOSB). We have identified potential biomarkers and host pathways regulated during fibrosis that may hold prognostic significance and could emerge as potential therapeutic targets.

Inhibition of murine colorectal cancer metastasis by targeting M2-TAM through STAT3/NF-kB/AKT signaling using macrophage 1-derived extracellular vesicles loaded with oxaliplatin, retinoic acid, and Libidibia ferrea.

Colorectal cancer is still unmanageable despite advances in target therapy. However, extracellular vesicles (EVs) have shown potential in nanomedicine as drug delivery systems, especially for modulating the immune cells in the tumor microenvironment (TME). In this study, M1 Macrophage EVs (M1EVs) were used as nanocarriers of oxaliplatin (M1EV1) associated with retinoic acid (M1EV2) and Libidibia ferrea (M1EV3), alone or in combination (M1EV4) to evaluate their antiproliferative and immunomodulatory potential on CT-26 and MC-38 colorectal cancer cell lines and prevent metastasis in mice of allograft and peritoneal colorectal cancer models. Tumors were evaluated by qRT-PCR and immunohistochemistry. The cell death profile and epithelial-mesenchymal transition process (EMT) were analyzed in vitro in colorectal cancer cell lines. Polarization of murine macrophages (RAW264.7 cells) was also carried out. M1EV2 and M1EV3 used alone or particularly M1EV4 downregulated the tumor progression by TME immunomodulation, leading to a decrease in primary tumor size and metastasis in the peritoneum, liver, and lungs. STAT3, NF-kB, and AKT were the major genes downregulated by of M1EV systems. Tumor-associated macrophages (TAMs) shifted from an M2 phenotype (CD163) to an M1 phenotype (CD68) reducing levels of IL-10, TGF-ß and CCL22. Furthermore, malignant cells showed overexpression of FADD, APAF-1, caspase-3, and E-cadherin, and decreased expression of MDR1, survivin, vimentin, and PD-L1 after treatment with systems of M1EVs. The study shows that EVs from M1 antitumor macrophages can transport drugs and enhance their immunomodulatory and antitumor activity by modulating pathways associated with cell proliferation, migration, survival, and drug resistance.

Paraneoplastic or treatment-associated dermatomyositis: a diagnostic challenge.

Dermatomyositis (DM) is a systemic autoimmune disorder characterized by proximal myopathy and dermatological findings. Approximately 15-30% of DM cases emerge as a paraneoplastic syndrome caused by a concomitant malignancy. Although more rare, in cancer patients DM has also been reported as a possible result of toxicity of some antineoplastic agents, such as taxanes and monoclonal antibodies. Herein, we report a 35-year-old woman with metastatic breast cancer who presented with skin lesions after initiation of paclitaxel and anti-HER2 agents. Clinical, laboratory, and histological findings were consistent with the diagnosis of DM.

How Temporary/Permanent Employment Status and Mindfulness Redraw Employee Organizational Citizenship Responses to Person-Organization Fit / [Cómo redibujan el estatus de empleo temporal/permanente y el mindfulness las respuestas de ciudadanía organizacional de los empleados al ajuste personaorganización]

This paper analyzes the role of temporary/permanent employment in the way employees respond to person-organization fit (P-O Fit) with organizational citizenship behaviors (OCBs), and whether mindfulness redraws this relationship. Compared to permanent employees, temporary employees may have fewer future prospects in their organization, thus leading them to engage less in this type of behavior, the potential returns of which are typically unspecified in time and are likely beyond their temporary reach. However, the self-regulatory, present-moment awareness and non-judgmental acceptance functions of mindfulness could reverse this relationship. Structural equation modeling using data from 280 employees of 10 Spanish hotels revealed that temporary (permanent) employees reacted to P-O Fit with lower (higher) OCBs, unless they were mindful, in which case their OCBs increased (decreased). The findings show that employment status and mindfulness redraw the P-O Fit - OCB relationship and that mindfulness makes temporary (permanent) employees respond to P-O Fit with increased (decreased) OCBs.(AU)

Este trabajo analiza el papel del estatus laboral temporal/permanente en la forma en que los empleados responden al ajuste persona-organización con comportamientos de ciudadanía organizacional, y si el mindfulness redibuja esta relación. En comparación con los empleados fijos, los temporales pueden tener menos perspectivas de futuro en su organización, lo que les lleva a participar menos en este tipo de comportamientos, cuyos rendimientos potenciales suelen ser indeterminados en el tiempo y probablemente están fuera de su alcance temporal. Sin embargo, las funciones de autorregulación, conciencia del momento presente y aceptación sin prejuicios del mindfulness podrían invertir esta relación. La modelización de ecuaciones estructurales con datos de 280 empleados de 10 hoteles españoles reveló que los empleados temporales (fijos) reaccionaban al ajuste persona-organización con un menor (mayor) comportamiento de ciudadanía organizacional, a menos que tuvieran mindfulness, en cuyo caso su comportamiento de ciudadanía organizacional aumentaba (disminuía). Los resultados muestran que el estatus laboral y el mindfulness redibujan la relación entre ajuste persona-organización y comportamiento de ciudadanía organizacional y que el mindfulness hace que los empleados temporales (fijos) respondan a dicho ajuste con un mayor (menor) nivel de comportamiento de ciudadanía organizacional.(AU)

Lose at sunrise, but gain at sunset: Linking social cyberloafing to psychological detachment, personal life enhancement of work, and mental health.

BACKGROUND: Previous research has demonstrated that the personal use of social media, i.e., social cyberloafing, is associated with employee mental health. However, the underlying mechanism through which social cyberloafing is related to mental health has received limited attention. OBJECTIVE: Drawing on conservation of resource theory and work/nonwork enhancement literatures, we developed and tested a model that examines health effect of social cyberloafing. As such, employees' social cyberloafing is posited as positively related to psychological detachment and personal life enhancement of work, which in turn would act as mediators that explain why social cyberloafing improves mental health. METHODS: Data from 375 Chinese employees were analyzed to test research hypotheses using the structural equation modeling and bias-corrected bootstrap method with Mplus 7.4. RESULTS: The results found that social cyberloafing is positively related to psychological detachment, but not with personal life enhancement of work. Social cyberloafing was positively related to employees' mental health through both psychological detachment and through psychological detachment and personal life enhancement of work serially. CONCLUSION: Psychological detachment alone and alongside personal life enhancement of work form part of the mechanisms explaining how and why engaging in social cyberloafing is positively associated with employees' mental health. These mechanisms offer insights to organizations into how the mental health of employees can be improved in the digital workplace.

Design and Validation of a Food Frequency Questionnaire to Evaluate the Consumption of Trans Fatty Acids in the Adult Population (FFQ-TFA).

Instruments for estimating the intake of food components can be useful in the prevention and/or treatment of diseases related to improper diet. There is, at present, no scientifically validated instrument for estimating consumption of trans fatty acids (TFA) in the Mexican population. The objective of this study was to design and validate such an instrument: a questionnaire that can be used to estimate consumption of TFA from food products. The questionnaire was applied to 162 students from the Autonomous University of Querétaro (UAQ). There were two phases to the study: (1) design of a food frequency questionnaire to assess consumption of trans fatty acids (FFQ-TFA) and an eating practices questionnaire (EPQ-TFA); (2) validation of the instrument. Content validity was measured by expert review and by Aiken's V method, obtaining an overall score of 0.895. As final tests for the FFQ-TFA analysis, criterion validity was measured using Spearman's correlation (r = 0.717, p < 0.01) and a linear regression (B = 0.668), considering the results of the 24-h dietary recall (24 HR); and reproducibility or temporal stability was measured using Pearson's correlation (r = 0.406, p < 0.01). Subsequently, a Pearson correlation was applied between TFA consumption estimated by the FFQ-TFA-2 and the global score from the EPQ-TFA-2 (r = 0.351, p < 0.01). A Pearson correlation was applied between the EPQ-TFA-1 and the EPQ-TFA-2 (r = 0.575, p < 0.01). TFA consumption per day was 2.49 ± 1.32 g in the participating population, which was 1.04 ± 0.51% of their total kcal consumption.

M1-derived extracellular vesicles enhance photodynamic therapy and promote immunological memory in preclinical models of colon cancer.

Extracellular vesicles (EVs) are promising drug carriers of photosensitizers for photodynamic therapy (PDT) in cancer treatment, due to their ability to circulate in blood and enter cells efficiently. The therapeutic potential of EVs has been suggested to depend on the type and physiological state of their cell of origin. However, the effects of deriving EVs from various cells in different physiological states on their antitumor capacity are rarely evaluated. In the present study, we compared the antitumor efficacy of EV-mediated PDT by incorporating the photosensitizer Zinc Phthalocyanine (ZnPc) into EVs from multiple cells sources. ZnPc was incorporated by a direct incubation strategy into EVs derived from immune cells (M1-like macrophages and M2-like macrophages), cancer cells (B16F10 melanoma cancer cells) and external sources (milk). Our data show that all EVs are suitable carriers for ZnPc and enable efficient PDT in vitro in co-culture models and in vivo. We observed that EV-mediated PDT initiates immunogenic cell death through the release and exposure of damage associated molecular patterns (DAMPs) on cancer cells, which subsequently induced dendritic cell (DC) maturation. Importantly, of all ZnPc-EVs tested, in absence of light only M1-ZnPc displayed toxicity to MC38, but not to DC, in monoculture and in co-culture, indicating specificity for cancer over immune cells. In MC38 tumor-bearing mice, only M1-ZnPc induced a tumor growth delay compared to control in absence of light. Interestingly, M1- but not M2-mediated PDT, induced complete responses against MC38 tumors in murine models (100% versus 38% of cases, respectively), with survival of all animals up to at least 60 days post inoculation. Finally, we show that all cured animals are protected from a rechallenge with MC38 cells, suggesting the induction of immunological memory after EV-mediated PDT. Together, our data show the importance of the cell type from which the EVs are obtained and highlight the impact of the immunological state of these cells on the antitumor efficacy of EV-mediated PDT.

Myopericytoma presenting as a painful dark subungual discoloration.

Myopericytoma is an uncommon benign neoplasm that arises from the perivascular myoid cells. It typically presents as a painless well-circumscribed cutaneous or soft-tissue nodule, most commonly on the extremities of adults. Histologically, it is characterized by spindle-shaped myoid-appearing cells with a concentric arrangement in vessel walls, that are immunoreactive to alpha-smooth muscle actin and often for h-caldesmon, but negative for other smooth muscle markers. Herein, we present an unusual case of a painful subungual myopericytoma presenting as a dark subungual discoloration.

Extracellular Vesicles from M1-Polarized Macrophages Combined with Hyaluronic Acid and a ß-Blocker Potentiate Doxorubicin's Antitumor Activity by Downregulating Tumor-Associated Macrophages in Breast Cancer.

One of the main reasons for cancer's low clinical response to chemotherapeutics is the highly immunosuppressive tumor microenvironment (TME). Tumor-ass ociated M2 macrophages (M2-TAMs) orchestrate the immunosuppression, which favors tumor progression. Extracellular vesicles (EVs) have shown great potential for targeted therapies as, depending on their biological origin, they can present different therapeutic properties, such as enhanced accumulation in the target tissue or modulation of the immune system. In the current study, EVs were isolated from M1-macrophages (M1-EVs) pre-treated with hyaluronic acid (HA) and the ß-blocker carvedilol (CV). The resulting modulated-M1 EVs (MM1-EVs) were further loaded with doxorubicin (MM1-DOX) to assess their effect in a mouse model of metastatic tumor growth. The cell death and cell migration profile were evaluated in vitro in 4T1 cells. The polarization of the RAW 264.7 murine macrophage cell line was also analyzed to evaluate the effects on the TME. Tumors were investigated by qRT-PCR and immunohistochemistry. MM1-DOX reduced the primary tumor size and metastases. NF-κB was the major gene downregulated by MM1-DOX. Furthermore, MM1-DOX reduced the expression of M2-TAM (CD-163) in tumors, which resulted in increased apoptosis (FADD) as well as decreased expression of MMP-2 and TGF-ß. These results suggest a direct effect in tumors and an upregulation in the TME immunomodulation, which corroborate with our in vitro data that showed increased apoptosis, modulation of macrophage polarization, and reduced cell migration after treatment with M1-EVs combined with HA and CV. Our results indicate that the M1-EVs enhanced the antitumor effects of DOX, especially if combined with HA and CV in an animal model of metastatic cancer.

Toxic erythema of chemotherapy induced by liposomal doxorubicin, a clinical case.

A 76-year-old woman presented to the medical oncology outpatient clinic with painful, burning, pruritic erythematous plaques involving both palms and axillae that had suddenly appeared five days before. Examination revealed no additional relevant findings and laboratory studies did not show any alteration. The patient had been recently diagnosed with a high-grade angiosarcoma of the breast (probably radiation induced) and after frequent local recurrences, was being treated with liposomal doxorubicin (three cycles were administered, the last of which was seven days before the appearance of the mentioned lesions). Oral corticosteroids were started, treatment with liposomal doxorubicin was stopped, and cutaneous biopsies performed that revealed features compatible with toxic erythema of chemotherapy induced by liposomal doxorubicin. Complete resolution of the cutaneous lesions was verified one month after. No signs of recurrence of angiosarcoma were documented at follow-up three months later.