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Simple Summary: Breast cancer (BCa) is a pathology that affects the world population. Patients present risk factors for osteopenia and osteoporosis, such as chronic stress, estrogen deprivation due to hormonal treatment, a menopausal status, and decreased physical activity. An available alternative is the use of nonselective beta blockers (nsBBs) that have antitumoral properties, and in other diseases, antiresorptive and osteoforming effects. We demonstrated that BCa patients taking nsBBs had a greater bone mineral density and a lower incidence of osteoporosis and osteopenia than untreated patients. Although our study has several limitations, such as its retrospective design and single-center population, it revealed promising effects of nsBBs on the prevention and treatment of osteoporosis and osteopenia in patients with BCa. Breast cancer (BCa) is related to chronic stress and can reduce the bone mineral density (BMD) through neurochemicals related to beta-adrenergic receptor (ADRB) 1 and 2. Selective beta blockers (sBBs) and nonselective beta blockers (nsBBs) are used to treat systemic arterial hypertension (SAH) and may have osteoprotective effects, as they inhibit ADRBs. To evaluate the effects of sBBs and nsBBs on the BMD of Mexican patients with BCa. A retrospective study was conducted. We included 191 Mexican women with BCa without SAH and with SAH treated with nsBBs, sBBs, and diuretics. BMD was evaluated using a bone density scan (DEX scan). A greater average BMD (p < 0.05) was observed in patients with prior treatment with both nsBBs and sBBs (0.54 ± 0.94 and −0.44 ± 1.22, respectively) compared to patients treated with diuretics or without SAH (−1.73 ± 0.83 and −1.22 ± 0.98, respectively). Regarding the diagnosis of osteoporosis/osteopenia, no cases were observed in patients treated with nsBBs, whereas 5.6% of the patients treated with sBBs presented osteopenia. A total of 23.1% and 10.6% patients managed with diuretics or without treatment presented with osteoporosis and 61.5% and 48% patients managed with loop diuretics and without treatment presented with osteopenia, respectively (p < 0.05). Treatment with nsBBs is a promising option for the prevention and management of osteoporosis/osteopenia in Mexican patients with BCa; however, further prospective studies are needed. [ABSTRACT FROM AUTHOR]

Malaria transmission intensity affects the development of naturally acquired immunity to malaria. An absolute correlate measure of protection against malaria is lacking. However, antibody-mediated functions against Plasmodium falciparum correlate with protection against malaria. In children, antibody-mediated functions against P. falciparum decline with reduced exposure. It is unclear whether adults maintain antibody-mediated functions as malaria transmission declines. This study assessed antibody-dependent respiratory burst (ADRB) in individuals from an area with declining malaria transmission. In an age-matched analysis, we compare ADRB activity during high versus low malaria transmission periods. Age significantly predicted higher ADRB activity in the high (p < 0.001) and low (p < 0.001) malaria transmission periods. ADRB activity was higher during the high compared to the low malaria transmission period in older children and adults. Only older adults during the high malaria transmission period had their median ADRB activity above the ADRB cut-off. Ongoing P. falciparum infection influenced ADRB activity during the low (p = 0.01) but not the high (p = 0.29) malaria transmission period. These findings propose that naturally acquired immunity to P. falciparum is affected in children and adults as malaria transmission declines, implying that vaccines will be necessary to induce and maintain protection against malaria. [ABSTRACT FROM AUTHOR]

Malaria transmission intensity affects the development of naturally acquired immunity to malaria. An absolute correlate measure of protection against malaria is lacking. However, antibody-mediated functions against Plasmodium falciparum correlate with protection against malaria. In children, antibody-mediated functions against P. falciparum decline with reduced exposure. It is unclear whether adults maintain antibody-mediated functions as malaria transmission declines. This study assessed antibody-dependent respiratory burst (ADRB) in individuals from an area with declining malaria transmission. In an age-matched analysis, we compare ADRB activity during high versus low malaria transmission periods. Age significantly predicted higher ADRB activity in the high (p < 0.001) and low (p < 0.001) malaria transmission periods. ADRB activity was higher during the high compared to the low malaria transmission period in older children and adults. Only older adults during the high malaria transmission period had their median ADRB activity above the ADRB cut-off. Ongoing P. falciparum infection influenced ADRB activity during the low (p = 0.01) but not the high (p = 0.29) malaria transmission period. These findings propose that naturally acquired immunity to P. falciparum is affected in children and adults as malaria transmission declines, implying that vaccines will be necessary to induce and maintain protection against malaria.

The study of the evolutionary history of genes related to human disease lies at the interface of evolution and medicine. These studies provide the evolutionary context on which medical researchers should work, and are also useful in providing information to suggest further genetic experiments, especially in model species where genetic manipulations can be made. Here we studied the evolution of the β-adrenoreceptor gene family in vertebrates with the aim of adding an evolutionary framework to the already abundant physiological information. Our results show that in addition to the three already described vertebrate β-adrenoreceptor genes there is an additional group containing cyclostome sequences. We suggest that β-adrenoreceptors diversified as a product of the two whole genome duplications that occurred in the ancestor of vertebrates. Gene expression patterns are in general consistent across species, suggesting that expression dynamics were established early in the evolutionary history of vertebrates, and have been maintained since then. Finally, amino acid polymorphisms that are associated to pathological conditions in humans appear to be common in non-human mammals, suggesting that the phenotypic effects of these mutations depend on epistatic interaction with other positions. The evolutionary analysis of the β-adrenoreceptors delivers new insights about the diversity of these receptors in vertebrates, the evolution of the expression patterns and a comparative perspective regarding the polymorphisms that in humans are linked to pathological conditions. [ABSTRACT FROM AUTHOR]

Background: The timing of infection is closely determined in controlled human malaria infection (CHMI) studies, and as such they provide a unique opportunity to dissect changes in immunological responses before and after a single infection. The first Kenyan Challenge Study (KCS) (Pan African Clinical Trial Registry: PACTR20121100033272) was performed in 2013 with the aim of establishing the CHMI model in Kenya. This study used aseptic, cryopreserved, attenuated Plasmodium falciparum sporozoites administered by needle and syringe (PfSPZ Challenge) and was the first to evaluate parasite dynamics post-CHMI in individuals with varying degrees of prior exposure to malaria. Methods: We describe detailed serological and functional immunological responses pre- and post-CHMI for participants in the KCS and compare these with those from malaria-naïve UK volunteers who also underwent CHMI (VAC049) (ClinicalTrials.gov NCT01465048) using PfSPZ Challenge. We assessed antibody responses to three key blood-stage merozoite antigens [merozoite surface protein 1 (MSP1), apical membrane protein 1 (AMA1), and reticulocyte-binding protein homolog 5 (RH5)] and functional activity using two candidate measures of anti-merozoite immunity; the growth inhibition activity (GIA) assay and the antibody-dependent respiratory burst activity (ADRB) assay. Results: Clear serological differences were observed pre- and post-CHMI by ELISA between malaria-naïve UK volunteers in VAC049, and Kenyan volunteers who had prior malaria exposure. Antibodies to AMA1 and schizont extract correlated with parasite multiplication rate (PMR) post-CHMI in KCS. Serum from volunteer 110 in KCS, who demonstrated a dramatically reduced PMR in vivo, had no in vitro GIA prior to CHMI but the highest level of ADRB activity. A significant difference in ADRB activity was seen between KCS volunteers with minimal and definite prior exposure to malaria and significant increases were seen in ADRB activity post-CHMI in Kenyan volunteers. Quinine and atovaquone/proguanil, previously assumed to be removed by IgG purification, were identified as likely giving rise to aberrantly high in vitro GIA results. Conclusions: The ADRB activity assay is a promising functional assay that warrants further investigation as a measure of prior exposure to malaria and predictor of control of parasite growth. The CHMI model can be used to evaluate potential measures of naturally-acquired immunity to malaria. [ABSTRACT FROM AUTHOR]

Background: Identification of plasmodial antigens targeted by protective immune mechanisms is important for malaria vaccine development. Among functional assays, the neutrophil antibody-dependent respiratory burst (ADRB) induced by opsonized Plasmodium falciparum merozoites has been correlated with acquired immunity to clinical malaria in endemic areas, but the target merozoite antigens are unknown. Here, the contribution of antibodies to the conserved C-terminal domain of the P. falciparum merozoite surface protein-1 (PfMSP1p19) in mediating ADRB was investigated in sera from individuals living in two Senegalese villages with differing malaria endemicity. Methods: Anti-PfMSP1p19 antibody levels in sera from 233 villagers were investigated and the involvement of anti- PfMSP1p19 antibodies in ADRB was explored in a subset of samples using (1) isogenic P. falciparum parasite clones expressing P. falciparum or Plasmodium chabaudi MSP1p19; (2) PfMSP1p19-coated plaque ADRB; and, (3) ADRB triggering using sera depleted from PfMSP1p19 antibodies by absorption onto the baculovirus recombinant antigen. Results: ADRB activity correlated with anti-PfMSP1p19 IgG levels (P < 10−3). A substantial contribution of PfMSP1p19 antibody responses to ADRB was confirmed (P < 10−4) in an age-adjusted linear regression model. PfMSP1p19 antibodies accounted for 33.1 % (range 7–54 %) and 33.2 % (range 0–70 %) of ADRB activity evaluated using isogenic merozoites (P < 10−3) and depleted sera (P = 0.0017), respectively. Coating of PfMSP1p19 on plates induced strong ADRB in anti-PfMSP1p19-positive sera. Conclusion: These data show that naturally acquired P. falciparum MSP1p19 antibodies are potent inducers of neutrophil ADRB and support the development of PfMSP1p19-based malaria vaccine using ADRB assay as a functional surrogate for protection. [ABSTRACT FROM AUTHOR]

Background: Cluster analyses were previously performed to identify asthma phenotypes underlying asthma syndrome. Although a large number of patients with asthma develop the disease later in life, these previous cluster analyses focused mainly patients with younger-onset asthma. Methods: Cluster analysis examined the existence of distinct phenotypes of late-onset asthma in Japanese patients with adult asthma. We then associated genotypes at the CCL5, TSLP, IL4, and ADRB2 genes with the clusters of asthma identified. Results: Using the 8 variables of age, sex, age at onset of the disease, smoking status, total serum IgE, %FEVi, FEVi/FVC, and specific IgE responsiveness to common inhaled allergens, two-step cluster analysis of 880 Japanese adult asthma patients identified 6 phenotypes: cluster A (n = 155): older age at onset, no airflow obstruction; cluster B (n = 170): childhood onset, normal-to-mild airflow obstruction; cluster C (n = 119): childhood onset, the longest disease duration, and moderate-to-severe airflow obstruction; cluster D {n = 108): older age at onset, severe airflow obstruction; cluster E (n = 130): middle-age at onset, no airflow obstruction; and cluster F {n = 198): older age at onset, mild-to-moderate airflow obstruction. The CC/_5-28C>G genotype was significantly associated with clusters A, B and D (OR 1.65, p = 0.0021; 1.67, 0.018; and 1.74, 0.01, respectively). The ADRB2 Arg16Gly genotype was also associated with clusters B and D (OR 0.47, p = 0.0004; and 0.63, 0.034, respectively). Conclusions: The current cluster analysis identified meaningful adult asthma phenotypes linked to the functional CCL5 and ADRB2 genotypes. Genetic and phenotypic data have the potential to elucidate the pheno-typic heterogeneity and pathophysiology of asthma. [ABSTRACT FROM AUTHOR]

The full amino acid coding sequences of adrenergic receptor genes beta1, beta2, and beta3 (ADRB1, ADRB2, and ADRB3)were determined for Jinhua, Meishan, Duroc and Landrace pigs. Non-synonymous substitution of Arg458Pro was found in the porcine ADRB1 gene, resulting in a 469 amino acid sequence. Continuous substitutions of Asn29Asp and Glu30Gln were found in the porcine ADRB2 gene, resulting in a 418 amino acid sequence. Additionally, a Lys30 polymorphism of the ADRB2 gene was found in the Jinhua pigs. There were three non-synonymous substitutions of Asn24Thr, Arg264Gln and Asn398Asp on the porcine ADRB3 gene. A thymine insertion in the ADRB3 gene, resulting in a protein with two fewer amino acids, was found in the Jinhua and Meishan pigs. To assess the effect of ADRB polymorphisms on porcine subcutaneous fat layer thickness, we calculated the genetic frequency of the variants in fatty and lean groups, each consisting of 24 pigs that were crossbreds of Duroc and Jinhua pigs. The effect of the ADRB3 gene polymorphism was not evaluated, because there was insufficient variation on the ADRB3 gene in the examined groups. Although Fisher's exact test showed no significant difference in the frequency of ADRB1 and ADBR2 variants between the two groups, the Arg458 variant of ADRB1 was higher ( P = 0.11) in the lean group, and pigs in that group had a thinner fat layer than did those with the Pro458 variant. These results imply a possibility of ADRB1 polymorphism as a minor factor in porcine fat layer thickness. The Asp29 variant of ADRB2 was higher in the lean group ( P = 0.11), and the Glu30 variant was higher in the fatty group ( P = 0.15), but the Asp29 variant was found only in the Chinese pigs. Thus, the effect of ADRB2 polymorphisms was not clear in this study. [ABSTRACT FROM AUTHOR]

Naturally acquired immunity against malaria is largely mediated by serum antibodies controlling levels of blood-stage parasites. A limited understanding of the antigenic targets and functional mechanisms of protective antibodies has hampered the development of efficient malaria vaccines. Besides directly inhibiting the growth of Plasmodium parasites, antibodies can opsonize merozoites and recruit immune effector cells such as monocytes and neutrophils. Antibodies against the vaccine candidate merozoite surface protein 1 (MSP-1) are acquired during natural infections and have been associated with protection against malaria in several epidemiological studies. Here we analyzed serum antibodies from semi-immune individuals from Burkina Faso for their potential (i) to directly inhibit the growth of P. falciparum blood stages in vitro and (ii) to opsonize merozoites and to induce the antibody-dependent respiratory burst (ADRB) activity of neutrophils. While a few sera that directly inhibited the growth of P. falciparum blood stages were identified, immunoglobulin G (IgG) from all individuals clearly mediated the activation of neutrophils. The level of neutrophil activation correlated with levels of antibodies to MSP-1, and affinity-purified MSP-1-specific antibodies elicited ADRB activity. Furthermore, immunization of nonhuman primates with recombinant full-size MSP-1 induced antibodies that efficiently opsonized P. falciparum merozoites. Reversing the function by preincubation with recombinant antigens allowed us to quantify the contribution of MSP-1 to the antiparasitic effect of serum antibodies. Our data suggest that MSP-1, especially the partially conserved subunit MSP-1 83 , is a major target of opsonizing antibodies acquired during natural exposure to malaria. Induction of opsonizing antibodies might be a crucial effector mechanism for MSP-1-based malaria vaccines., (Copyright © 2017 American Society for Microbiology.)

Unlabelled: The advancement of breast cancer therapy is limited by the biologic behaviors of cancer cells, such as metastasis and recurrence. β-adrenoceptors (ADRB) are reported to be associated with the biologic behaviors of breast cancer and may influence glucose metabolism. Here, we sought to investigate the relationship between the activation of ADRB and the expression of glucose transporter (GLUT)-1 and hexokinase (HK)-2 and to clarify the impact of ADRB on (18)F-FDG PET imaging in breast cancer., Methods: ADRB1/2 expression in 4T1, MDA-MB-231, and MCF-7 breast cancer cell lines was detected by Western blotting and immunofluorescence. ADRB-dependent regulation of GLUT-1 and HK-2 was determined by in vitro pharmacologic intervention. 4T1 breast cancer cells were treated with phosphate-buffered saline, isoproterenol, or propranolol, and the transcription and expression of GLUT-1 and HK-2 were measured by quantitative real-time polymerase chain reaction (RT-PCR) and Western blotting, respectively. ADRB1/2 was, respectively, blocked by small-interfering RNA to investigate the direct relationship between ADRB1/2 and HK-2. To evaluate the impact of ADRB on (18)F-FDG PET imaging, BALB/c mice bearing 4T1 tumors were injected with phosphate-buffered saline, isoproterenol, or propranolol, and (18)F-FDG PET imaging was performed. The tumor-to-nontumor (T/NT) values of tumors and brown adipose tissue were calculated by defining the liver as a reference. The in vivo expression of GLUT-1 and HK-2 was observed by immunohistochemical analysis and Western blotting., Results: MDA-MB-231, MCF-7, and 4T1 breast cancer cells were positive for ADRB1/2 expression. The protein expression and posttranscriptional level of HK-2 were significantly decreased by treatment with propranolol in vitro, whereas GLUT-1 expression was not significantly altered by pharmacologic intervention. The expression of HK-2 could be reduced in ADRB2-blocked 4T1 cells. Mice in the propranolol-treated group exhibited lower T/NT values for the tumors and brown adipose tissue than the control group. Immunohistochemical analysis and Western blotting revealed reduced HK-2 expression in the tumors of propranolol-treated mice., Conclusion: The expression of HK-2 was regulated by the activation of ADRB2 in 4T1 breast cancer cells primarily at the posttranscriptional level. Additionally, propranolol prevented glucose metabolism and (18)F-FDG PET imaging of 4T1 breast cancer tumors.