Fc-gamma receptor expression and cytokine responses to intravenous human immunoglobulin in whole blood from non-pregnant and pregnant women and newborns.

BACKGROUND: Intravenous immunoglobulin (IVIG) can suppress the inflammatory response in adults, but its role in pregnant women and newborns is poorly studied. While the adult immune system is considered mature, it is immature in neonates and suppressed in pregnancy. Since the immune response differs in these 3 groups, the use of IVIG could differentially modulate the immune response. OBJECTIVES: We aimed to explore the effect of IVIG on myeloid blood cells from non-pregnant women, pregnant women and newborns. MATERIAL AND METHODS: Whole blood from healthy donors was incubated with lipopolysaccharide (LPS) and/or IVIG. After 0 h, 24 h and 48 h of culture, Fc-gamma receptor (CD16, CD32 and CD64) expression, monocyte and neutrophil bacterial phagocytosis, and cytokine and chemokine concentrations were determined in the supernatant. RESULTS: The baseline expression of monocyte CD16 was higher in newborns than in adult women, but the expression of CD32 and CD64 was similar between groups. Furthermore, LPS and IVIG stimulation, together or separately, did not change Fc-gamma receptor expression in monocytes or neutrophils and did not modify their phagocytosis capacity. On the other hand, IVIG did not downregulate the proinflammatory cytokine response induced by LPS in any group. Interestingly, IVIG induced a strong interleukin 8 (IL-8) response in neonates but not in non-pregnant or pregnant women. CONCLUSIONS: Our results show that IVIG did not induce changes in Fc-gamma receptor expression, phagocytic ability, or the cytokine response to LPS in blood cells from neonates, non-pregnant or pregnant women. However, IVIG induced a strong IL-8 response in neonates that could improve immunity.

Uterus infantilis: a novel phenotype associated with AARS2 new genetic variants. A case report.

Objectives: To report the first Mexican case with two novel AARS2 mutations causing primary ovarian failure, uterus infantilis, and early-onset dementia secondary to leukoencephalopathy. Methods: Detailed clinical, clinimetric, neuroimaging features, muscle biopsy with biochemical assays of the main oxidative phosphorylation complexes activities, and molecular studies were performed on samples from a Mexican female. Results: We present a 41-year-old female patient with learning difficulties since childhood and primary amenorrhea who developed severe cognitive, motor, and behavioral impairment in early adulthood. Neuroimaging studies revealed frontal leukoencephalopathy with hypometabolism at the fronto-cerebellar cortex and caudate nucleus. Uterus infantilis was detected on ultrasound study. Clinical exome sequencing identified two novel variants, NM_020745:c.2864G>A (p.W955*) and NM_020745:c.1036C>A (p.P346T, p.P346Wfs*18), in AARS2. Histopathological and biochemical studies on muscle biopsy revealed mitochondrial disorder with cytochrome C oxidase (COX) deficiency. Conclusions: Several adult-onset cases of leukoencephalopathy and ovarian failure associated with AARS2 variants have been reported. To our best knowledge, none of them showed uterus infantilis. Here we enlarge the genetic and phenotypic spectrum of AARS2-related dementia with leukoencephalopathy and ovarian failure and contribute with detailed clinical, clinometric, neuroimaging, and molecular studies to disease and novel molecular variants characterization.

The role of γδ T cells in the immunopathogenesis of inflammatory diseases: from basic biology to therapeutic targeting.

The γδ T cells are lymphocytes with an innate-like phenotype that can distribute to different tissues to reside and participate in homeostatic functions such as pathogen defense, tissue modeling, and response to stress. These cells originate during fetal development and migrate to the tissues in a TCR chain-dependent manner. Their unique manner to respond to danger signals facilitates the initiation of cytokine-mediated diseases such as spondyloarthritis and psoriasis, which are immune-mediated diseases with a very strong link with mucosal disturbances, either in the skin or the gut. In spondyloarthritis, γδ T cells are one of the main sources of IL-17 and, therefore, the main drivers of inflammation and probably new bone formation. Remarkably, this population can be the bridge between gut and joint inflammation.

Abnormal expression of H-Ras induces S-phase arrest and mitotic catastrophe in human T-lymphocyte leukemia.

Background: Leukemia is a neoplasm with high incidence and mortality rates. Mitotic death has been observed in tumor cells treated with chemotherapeutic agents. Ras family proteins participate in the transduction of signals involved in different processes, such as proliferation, differentiation, survival, and paradoxically, initiation of cell death. Methods: This study investigated the effect of H-Ras expression on human T-cell acute lymphoblastic leukemia MOLT-4 cells. Cells were electroporated with either wild-type (Raswt) or oncogenic mutant in codon 12 exon 1 (Rasmut) versions of H-Ras gene and stained for morphological analysis. Cell viability was assessed using trypan blue staining and cell cycle analysis using flow cytometry. H-Ras gene expression was determined using quantitative real-time reverse transcription polymerase chain reaction. The t, ANOVA, and Scheffe tests were used for statistical analysis. Results: Human T-cell acute lymphoblastic leukemia MOLT-4 cells showed nuclear fragmentation and presence of multiple nuclei and micronuclei after transfection with either wt or mutant H-Ras genes. Cell cycle analysis revealed a statistically significant increase in cells in the S phase when transfected with either wt (83.67%, P<0.0005) or mutated (81.79%, P<0.0001) H-Ras genes. Although similar effects for both versions of H-Ras were found, cells transfected with the mutated version died at 120 h of mitotic catastrophe. Conclusion: Transfection of human T-cell acute lymphoblastic leukemia MOLT-4 cells with either normal or mutated H-Ras genes induced alterations in morphology, arrest in the S phase, and death by mitotic catastrophe.

Whole Genome Sequencing Links Mycobacterium bovis From Cattle, Cheese and Humans in Baja California, Mexico.

Mycobacterium bovis causes tuberculosis (TB) in cattle, which in turn can transmit the pathogen to humans. Tuberculosis in dairy cattle is of particular concern where the consumption of raw milk and dairy products is customary. Baja California (BCA), Mexico, presents high prevalence of TB in both cattle and humans, making it important to investigate the molecular epidemiology of the disease in the region. A long-term study was undertaken to fully characterize the diversity of M. bovis genotypes circulating in dairy cattle, cheese and humans in BCA by whole-genome sequencing (WGS). During a 2-year period, 412 granulomatous tissue samples were collected from local abattoirs and 314 cheese samples were purchased from local stores and vendors in BCA and sent to the laboratory for mycobacterial culture, histology, direct PCR and WGS. For tissue samples M. bovis was recovered from 86.8%, direct PCR detected 90% and histology confirmed 85.9% as mycobacteriosis-compatible. For cheese, M. bovis was recovered from 2.5% and direct PCR detected 6% of the samples. There was good agreement between diagnostic tests. Subsequently, a total of 345 whole-genome SNP sequences were obtained. Phylogenetic analysis grouped these isolates into 10 major clades. SNP analysis revealed putative transmission clusters where the pairwise SNP distance between isolates from different dairies was ≤3 SNP. Also, human and/or cheese isolates were within 8.45 (range 0-17) and 5.8 SNP (range 0-15), respectively, from cattle isolates. Finally, a comparison between the genotypes obtained in this study and those reported previously suggests that the genetic diversity of M. bovis in BCA is well-characterized, and can be used to determine if BCA is the likely source of M. bovis in humans and cattle in routine epidemiologic investigations and future studies. In conclusion, WGS provided evidence of ongoing local transmission of M. bovis among the dairies in this high-TB burden region of BCA, as well as show close relationships between isolates recovered from humans, cheese, and cattle. This confirms the need for a coordinated One Health approach in addressing the elimination of TB in animals and humans. Overall, the study contributes to the knowledge of the molecular epidemiology of M. bovis in BCA, providing insight into the pathogen's dynamics in a high prevalence setting.

Corrigendum: CXCL17 Is a Specific Diagnostic Biomarker for Severe Pandemic Influenza A(H1N1) That Predicts Poor Clinical Outcome.

[This corrects the article DOI: 10.3389/fimmu.2021.633297.].

Clinical and Immunological Factors That Distinguish COVID-19 From Pandemic Influenza A(H1N1).

The severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), the causative agent of coronavirus disease 2019 (COVID-19), is a global health threat with the potential to cause severe disease manifestations in the lungs. Although COVID-19 has been extensively characterized clinically, the factors distinguishing SARS-CoV-2 from other respiratory viruses are unknown. Here, we compared the clinical, histopathological, and immunological characteristics of patients with COVID-19 and pandemic influenza A(H1N1). We observed a higher frequency of respiratory symptoms, increased tissue injury markers, and a histological pattern of alveolar pneumonia in pandemic influenza A(H1N1) patients. Conversely, dry cough, gastrointestinal symptoms and interstitial lung pathology were observed in COVID-19 cases. Pandemic influenza A(H1N1) was characterized by higher levels of IL-1RA, TNF-α, CCL3, G-CSF, APRIL, sTNF-R1, sTNF-R2, sCD30, and sCD163. Meanwhile, COVID-19 displayed an immune profile distinguished by increased Th1 (IL-12, IFN-γ) and Th2 (IL-4, IL-5, IL-10, IL-13) cytokine levels, along with IL-1ß, IL-6, CCL11, VEGF, TWEAK, TSLP, MMP-1, and MMP-3. Our data suggest that SARS-CoV-2 induces a dysbalanced polyfunctional inflammatory response that is different from the immune response against pandemic influenza A(H1N1). Furthermore, we demonstrated the diagnostic potential of some clinical and immune factors to differentiate both diseases. These findings might be relevant for the ongoing and future influenza seasons in the Northern Hemisphere, which are historically unique due to their convergence with the COVID-19 pandemic.

Phenotype of Peripheral NK Cells in Latent, Active, and Meningeal Tuberculosis.

The mechanisms underlying the immunopathology of tuberculous meningitis (TBM), the most severe clinical form of extrapulmonary tuberculosis (TB), are not understood. It is currently believed that the spread of Mycobacterium tuberculosis (Mtb) from the lung is an early event that occurs before the establishment of adaptive immunity. Hence, several innate immune mechanisms may participate in the containment of Mtb infection and prevent extrapulmonary disease manifestations. Natural killer (NK) cells participate in defensive processes that distinguish latent TB infection (LTBI) from active pulmonary TB (PTB). However, their role in TBM is unknown. Here, we performed a cross-sectional analysis of circulating NK cellCID="C008" value="s" phenotype in a prospective cohort of TBM patients (n = 10) using flow cytometry. Also, we addressed the responses of memory-like NK cell subpopulations to the contact with Mtb antigens in vitro. Finally, we determined plasma levels of soluble NKG2D receptor ligands in our cohort of TBM patients by enzyme-linked immunosorbent assay (ELISA). Our comparative groups consisted of individuals with LTBI (n = 11) and PTB (n = 27) patients. We found that NK cells from TBM patients showed lower absolute frequencies, higher CD69 expression, and poor expansion of the CD45RO+ memory-like subpopulation upon Mtb exposure in vitro compared to LTBI individuals. In addition, a reduction in the frequency of CD56brightCD16- NK cells characterized TBM patients but not LTBI or PTB subjects. Our study expands on earlier reports about the role of NK cells in TBM showing a reduced frequency of cytokine-producing cells compared to LTBI and PTB.

CXCL17 Is a Specific Diagnostic Biomarker for Severe Pandemic Influenza A(H1N1) That Predicts Poor Clinical Outcome.

The C-X-C motif chemokine ligand 17 (CXCL17) is chemotactic for myeloid cells, exhibits bactericidal activity, and exerts anti-viral functions. This chemokine is constitutively expressed in the respiratory tract, suggesting a role in lung defenses. However, little is known about the participation of CXCL17 against relevant respiratory pathogens in humans. Here, we evaluated the serum levels and lung tissue expression pattern of CXCL17 in a cohort of patients with severe pandemic influenza A(H1N1) from Mexico City. Peripheral blood samples obtained on admission and seven days after hospitalization were processed for determinations of serum CXCL17 levels by enzyme-linked immunosorbent assay (ELISA). The expression of CXCL17 was assessed by immunohistochemistry (IHQ) in lung autopsy specimens from patients that succumbed to the disease. Serum CXCL17 levels were also analyzed in two additional comparative cohorts of coronavirus disease 2019 (COVID-19) and pulmonary tuberculosis (TB) patients. Additionally, the expression of CXCL17 was tested in lung autopsy specimens from COVID-19 patients. A total of 122 patients were enrolled in the study, from which 68 had pandemic influenza A(H1N1), 24 had COVID-19, and 30 with PTB. CXCL17 was detected in post-mortem lung specimens from patients that died of pandemic influenza A(H1N1) and COVID-19. Interestingly, serum levels of CXCL17 were increased only in patients with pandemic influenza A(H1N1), but not COVID-19 and PTB. CXCL17 not only differentiated pandemic influenza A(H1N1) from other respiratory infections but showed prognostic value for influenza-associated mortality and renal failure in machine-learning algorithms and regression analyses. Using cell culture assays, we also identified that human alveolar A549 cells and peripheral blood monocyte-derived macrophages increase their CXCL17 production capacity after influenza A(H1N1) pdm09 virus infection. Our results for the first time demonstrate an induction of CXCL17 specifically during pandemic influenza A(H1N1), but not COVID-19 and PTB in humans. These findings could be of great utility to differentiate influenza and COVID-19 and to predict poor prognosis specially at settings of high incidence of pandemic A(H1N1). Future studies on the role of CXCL17 not only in severe pandemic influenza, but also in seasonal influenza, COVID-19, and PTB are required to validate our results.

Expression of Surfactant Protein D Distinguishes Severe Pandemic Influenza A(H1N1) from Coronavirus Disease 2019.

The differentiation between influenza and coronavirus disease 2019 (COVID-19) could constitute a diagnostic challenge during the ongoing winter owing to their clinical similitude. Thus, novel biomarkers are required to enable making this distinction. Here, we evaluated whether the surfactant protein D (SP-D), a collectin produced at the alveolar epithelium with known immune properties, was useful to differentiate pandemic influenza A(H1N1) from COVID-19 in critically ill patients. Our results revealed high serum SP-D levels in patients with severe pandemic influenza but not those with COVID-19. This finding was validated in a separate cohort of mechanically ventilated patients with COVID-19 who also showed low plasma SP-D levels. However, plasma SP-D levels did not distinguish seasonal influenza from COVID-19 in mild-to-moderate disease. Finally, we found that high serum SP-D levels were associated with death and renal failure among severe pandemic influenza cases. Thus, our studies have identified SP-D as a unique biomarker expressed during severe pandemic influenza but not COVID-19.

A bioinformatic prediction of antigen presentation from SARS-CoV-2 spike protein revealed a theoretical correlation of HLA-DRB1*01 with COVID-19 fatality in Mexican population: An ecological approach.

SARS-CoV-2 infection is causing a pandemic disease that is reflected in challenging public health problems worldwide. Human leukocyte antigen (HLA)-based epitope prediction and its association with disease outcomes provide an important base for treatment design. A bioinformatic prediction of T cell epitopes and their restricted HLA Class I and II alleles was performed to obtain immunogenic epitopes and HLA alleles from the spike protein of the severe acute respiratory syndrome coronavirus 2 virus. Also, a correlation with the predicted fatality rate of hospitalized patients in 28 states of Mexico was done. Here, we describe a set of 10 highly immunogenic epitopes, together with different HLA alleles that can efficiently present these epitopes to T cells. Most of these epitopes are located within the S1 subunit of the spike protein, suggesting that this area is highly immunogenic. A statistical negative correlation was found between the frequency of HLA-DRB1*01 and the fatality rate in hospitalized patients in Mexico.

The immune landscape in tuberculosis reveals populations linked to disease and latency.

Tuberculosis (TB), caused by Mycobacterium tuberculosis (Mtb) latently infects approximately one-fourth of the world's population. The immune mechanisms that govern progression from latent (LTBI) to active pulmonary TB (PTB) remain poorly defined. Experimentally Mtb-infected non-human primates (NHP) mirror the disease observed in humans and recapitulate both PTB and LTBI. We characterized the lung immune landscape in NHPs with LTBI and PTB using high-throughput technologies. Three defining features of PTB in macaque lungs include the influx of plasmacytoid dendritic cells (pDCs), an Interferon (IFN)-responsive macrophage population, and activated T cell responses. In contrast, a CD27+ Natural killer (NK) cell subset accumulated in the lungs of LTBI macaques. This NK cell population was also detected in the circulation of LTBI individuals. This comprehensive analysis of the lung immune landscape will improve the understanding of TB immunopathogenesis, providing potential targets for therapies and vaccines for TB control.

Profiling FLT3 Mutations in Mexican Acute Myeloid Leukemia Pediatric Patients: Impact on Overall Survival.

Background: Acute myeloid leukemia (AML) is the second most frequent leukemia in childhood. The FLT3 gene participates in hematopoietic stem cell proliferation. FLT3 mutations are recurrent in AML and influence prognosis. In Mexican pediatric AML patients, FLT3 mutational profile, and their clinical impact have not been evaluated. Aim of the study: This study aimed to identify the profile of FLT3 mutations in pediatric patients with de novo AML and to assess their possible influence on overall survival (OS) and other clinical features. Methods: Massive parallel target sequencing of FLT3 was performed in 80 patients. Results: FLT3 mutations [internal tandem duplication (ITD) or tyrosine kinase domain (TKD)] were identified in 24% of them. OS was significantly lower in FLT3 POS cases than in FLT3 NEG (p = 0.03). The average OS for FLT3 POS was 1.2 vs. 2.2 years in FLT3 NEG. There were no significant differences in the children's sex, age, percentage of blasts in bone marrow aspirate, or white blood cell count in peripheral blood at diagnosis between both groups. No differences were identified stratifying by the mutational load (high > 0.4) or type of mutation. The negative effect of FLT3 mutations was also observed in patients with acute promyelocytic leukemia (APL). Conclusions: FLT3 mutational profile is described in Mexican pediatric AML patients for the first time. Mutated FLT3 negatively impacts the outcome of AML patients, even considering the APL group. The clinical benefit from treatment with tyrosine kinase inhibitors in the FLT3 POS pediatric patients needs to be assessed in clinical trials. FLT3 testing may contribute to better risk stratification in our pediatric AML patients.

Antigens of Mycobacterium tuberculosis Stimulate CXCR6+ Natural Killer Cells.

Natural killer (NK) cells participate in immunity against several pathogens by exerting cytotoxic and cytokine-production activities. Some NK cell subsets also mediate recall responses that resemble memory of adaptive lymphocytes against antigenic and non-antigenic stimuli. The C-X-C motif chemokine receptor 6 (CXCR6) is crucial for the development and maintenance of memory-like responses in murine NK cells. In humans, several subsets of tissue-resident and circulating NK cells with different functional properties express CXCR6. However, the role of CXCR6+ NK cells in immunity against relevant human pathogens is unknown. Here, we addressed whether murine and human CXCR6+ NK cells respond to antigens of Mycobacterium tuberculosis (Mtb). For this purpose, we evaluated the immunophenotype of hepatic and splenic CXCR6+ NK cells in mice exposed to a cell-wall (CW) extract of Mtb strain H37Rv. Also, we characterized the expression of CXCR6 in peripheral NK cells from active pulmonary tuberculosis (ATB) patients, individuals with latent TB infection (LTBI), and healthy volunteer donors (HD). Furthermore, we evaluated the responses of CXCR6+ NK cells from HD, LTBI, and ATB subjects to the in vitro exposure to CW preparations of Mtb H37Rv and Mtb HN878. Our results showed that murine hepatic CXCR6+ NK cells expand in vivo after consecutive administrations of Mtb H37Rv CW to mice. Remarkably, pooled hepatic and splenic, but not isolated splenic NK cells from treated mice, enhance their cytokine production capacity after an in vitro re-challenge with H37Rv CW. In humans, CXCR6+ NK cells were barely detected in the peripheral blood, although slightly significative increments in the percentage of CXCR6+, CXCR6+CD49a-, CXCR6+CD49a+, and CXCR6+CD69+ NK cells were observed in ATB patients as compared to HD and LTBI individuals. In contrast, the expansion of CXCR6+CD49a- and CXCR6+CD69+ NK cells in response to the in vitro stimulation with Mtb H37Rv was higher in LTBI individuals than in ATB patients. Finally, we found that Mtb HN878 CW generates IFN-γ-producing CXCR6+CD49a+ NK cells. Our results demonstrate that antigens of both laboratory-adapted and clinical Mtb strains are stimulating factors for murine and human CXCR6+ NK cells. Future studies evaluating the role of CXCR6+ NK cells during TB are warranted.

Fatty acid metabolism and brain mitochondrial performance of juvenile Nile tilapia (Oreochromis niloticus) exposed to the water-accommodated fraction of Maya crude oil.

Crude oil and its derivatives are still the primary source of energy for humankind. However, during its transportation and treatment, spills of this resource can occur in aquatic environments. Nile tilapia is one of the most globally widespread fish species. This species is even found in brackish water due to its tolerance to salinity and pollution. In this study, the performance of brain cells (mitochondrial membrane potential [ΔΨm], calcium [Ca2+] and O2 and H2O2 levels) exposed to crude oil was assessed. In addition, fatty acid metabolism (cholesterol concentration and fatty acid synthase [FAS], acyl CoA-oxidase [AOX] and catalase [CAT] activities) in the brain, heart, liver and intestine of Nile tilapia exposed to the water-accommodated fraction (WAF) of 0.01, 0.1 or 1 g/L Maya crude oil (MCO) for 96 h were evaluated. After exposure, in brain cells, there were only increases in ROS and slight reductions in ΔΨm. Exposure to WAF of MCO induced and increased the levels of cholesterol and altered FAS and AOX activities in all examined tissues. The brain is the most susceptible organ to alterations in the activity of fatty acid metabolic enzymes and cholesterol levels relative to the heart, liver and intestine. The correlation between inhibition of the activity of CAT and AOX suggests a possible reduction in the proliferation and size of peroxisomes. Most biomarkers were significantly altered in the brains of Nile tilapia exposed to the WAF containing 1 g/L MCO in comparison to the control.

Differential expression of TLR2 and TLR4 in α4ß7-positive leukocytes of patients with axial spondyloarthritis.

OBJECTIVES: Expression of α4ß7 integrin can identify gut-homing immune cells. This study aimed to determine the expression of Toll-like receptor 2 (TLR2) and TLR4 in α4ß7-positive leukocytes of patients with axial SpA (axSpA). METHODS: We analysed the frequencies of α4ß7-positive T cells, Tγδ cells and monocytes in 14 patients with axSpA and 14 healthy controls, together with the expression of TLR2 and TLR4 by flow cytometry. Also, the concentration of faecal calprotectin was measured in all patients and controls. RESULTS: We found significantly higher percentages of α4ß7-positive T (P = 0.026) and Tγδ cells (P = 0.0118) in the patients with axSpA than in controls; these cells showed differential expression of TLR2 and TLR4 when compared with α4ß7-negative cells. Such differences were not correlated with disease activity or faecal calprotectin concentration. CONCLUSION: There is an increase in circulating α4ß7-positive T and Tγδ cells in patients with axSpA. These cells differentially express TLR2 and TLR4.

Stress proteins in the pathogenesis of spondyloarthritis.

Spondyloarthritis is an autoinflammatory rheumatic disease in which arthritis and osteoproliferation lead the patients who suffer from it to chronic disability. This disease is associated with the expression of class I MHC molecule HLA-B27, which tends to be misfolded in the endoplasmic reticulum and, therefore, expressed in aberrant forms. This phenomena lead to endoplasmic reticulum stress, which in time, evokes a whole response to cellular injury. Under these conditions, the molecules involved in restoring cell homeostasis play a key role. Such is the case of the "heat-shock proteins", which usually regulate protein folding, but also have important immunomodulatory functions, as well as some roles in tissue modeling. In this review, we attempt to summarize the involvement of cell stress and heat-shock proteins in the homeostatic disturbances and pathological conditions associated with this disease.

Synergistic promoting effects of pentoxifylline and simvastatin on the apoptosis of triple-negative MDA-MB-231 breast cancer cells.

Pentoxifylline (PTX), a xanthine family molecule and simvastatin (SIM), an anti-hypercholesterolemic agent, have recently been considered as sensitizers to chemotherapy and radiotherapy. The present in vitro study evaluated their antitumor synergistic effects on MDA­MB­231 breast cancer cells characterized by the triple­negative phenotype (TNP). The anti-proliferative effects of these two agents were evaluated by MTT and clonogenic assays. Cell cycle progression was examined using propidium iodide staining. Apoptosis was investigated by Annexin V labeling, and by examining caspase 3 activity and DNA fragmentation. Autophagic vesicles and reactive oxygen species (ROS) levels were monitored by flow cytometry. Western blot analysis was performed to evaluate molecular targets. Our results revealed that when used alone, PTX and SIM exerted antitumor effects. Nevertheless, used in combination, the inhibition of cell proliferation was synergistically superior (80% vs 42%) than that observed following treatment with each agent alone after 48 h. PTX alone (0.5 mM) induced both apoptosis (25%) and autophagy (25%); however, when used in combination with SIM (0.5 µM), the balance between these processes was disrupted and the cells underwent apoptosis (>65%) as opposed to autophagy (<13%). This imbalance was associated with an increase in ERK1/2 and AKT activation, but not with an increase in mTOR phosphorylation, and with the suppression of the NF-κB pathway. In addition, in the cells treated with both agents, almost 78% of the cells were arrested at the G0/G1 phase and lost their colony-forming ability (38±5%) compared to the cells treated with PTX alone (115±5%). On the whole, these results suggest that the induction of autophagy may be a protective mechanism preventing MDA­MB­231 cancer cell death. The combined use of PTX and SIM may drive dormant autophagic cancer cells to undergo apoptosis and thus this may be a novel treatment strategy for breast cancer characterized by the TNP.

Similar to Adiponectin, Serum Levels of Osteocalcin are Associated with Mammographic Breast Density in Postmenopausal Women.

OBJECTIVE: Breast cancer is the most common type of cancer in Canadian women and worldwide. Mammographic density is a well-established breast cancer risk. Recent evidence suggested inverse correlations among adiponectin, osteocalcin, and the risk developing breast cancer. The objective of the study was to evaluate the relationship between breast density and adiponectin and osteocalcin concentrations. METHODS: A cross-sectional study was performed in 239 women, age range 40 to 60. Mammographic density, serum adiponectin, and osteocalcin levels were measured. According to the Wolfe method, participants were divided into those with low-risk and high-risk pattern mammograms. RESULTS: The study population included 107 premenopausal and 132 postmenopausal women. Parameters were no different between women with low-risk and high-risk patterns. In obese postmenopausal women, the high-risk pattern mammogram group had significantly higher values of adiponectin and osteocalcin compared with the low-risk pattern group. Multiple linear regression analyses showed that adiponectin and osteocalcin levels were associated with high-risk pattern mammograms. CONCLUSION: Adiponectin and osteocalcin levels were directly associated with high-risk pattern mammograms in obese postmenopausal women. These results do not support the use of adipokines as biomarkers; nevertheless, the most important factor is to assess the risk through breast density.

Key Clinical Factors Predicting Adipokine and Oxidative Stress Marker Concentrations among Normal, Overweight and Obese Pregnant Women Using Artificial Neural Networks.

Maternal obesity has been related to adverse neonatal outcomes and fetal programming. Oxidative stress and adipokines are potential biomarkers in such pregnancies; thus, the measurement of these molecules has been considered critical. Therefore, we developed artificial neural network (ANN) models based on maternal weight status and clinical data to predict reliable maternal blood concentrations of these biomarkers at the end of pregnancy. Adipokines (adiponectin, leptin, and resistin), and DNA, lipid and protein oxidative markers (8-oxo-2'-deoxyguanosine, malondialdehyde and carbonylated proteins, respectively) were assessed in blood of normal weight, overweight and obese women in the third trimester of pregnancy. A Back-propagation algorithm was used to train ANN models with four input variables (age, pre-gestational body mass index (p-BMI), weight status and gestational age). ANN models were able to accurately predict all biomarkers with regression coefficients greater than R² = 0.945. P-BMI was the most significant variable for estimating adiponectin and carbonylated proteins concentrations (37%), while gestational age was the most relevant variable to predict resistin and malondialdehyde (34%). Age, gestational age and p-BMI had the same significance for leptin values. Finally, for 8-oxo-2'-deoxyguanosine prediction, the most significant variable was age (37%). These models become relevant to improve clinical and nutrition interventions in prenatal care.