Abundance and distribution of cigarette butts on the sand of five touristic beaches in Latin America during the COVID-19 pandemic.

Cigarette butts (CB) and cigarette butt fibers (CBF) are highly abundant and frequent residues on beach sand. Also, they are hazardous waste due to their significant toxicity and potential risk to the ecosystems' biota and the health of beach tourists. This study aimed to determine the abundance and density of CB and CBF found on the active, rest, and service zones of five pilot beaches in Argentina, Colombia, Brazil, Ecuador, and Mexico. The methodology involved collecting CB and CBF in 500 m2 transects of urban tourist beaches using a citizen science-adapted methodology between June 2021 and May 2022, during the COVID-19 pandemic. The abundance and density of CB and CBF, and the Cigarette Butt Pollution Index (CBPI) were calculated. The highest proportion of CB was found in service and rest areas. Bocagrande (CO) reported the highest generation of CB and CBF and a severe CBPI.

Real-world safety and effectiveness of maintenance niraparib for platinum-sensitive recurrent ovarian cancer: A GEICO retrospective observational study within the Spanish expanded-access programme.

AIM: To describe patient characteristics, effectiveness and safety in a real-world population treated with niraparib in the Spanish expanded-access programme. PATIENTS AND METHODS: This retrospective observational study included women with platinum-sensitive recurrent high-grade serous ovarian cancer who received maintenance niraparib within the Spanish niraparib expanded-access programme. Eligible patients had received ≥2 previous lines of platinum-containing therapy, remained platinum-sensitive after the penultimate line of platinum and had responded to the most recent platinum-containing therapy. Niraparib dosing was at the treating physician's discretion (300 mg/day fixed starting dose or individualised starting dose [ISD] according to baseline body weight and platelet count). Safety, impact of dose adjustments, patient characteristics and effectiveness were analysed using data extracted from medical records. RESULTS: Among 316 eligible patients, 80% had BRCA wild-type tumours and 66% received an ISD. Median niraparib duration was 7.8 months. The most common adverse events typically occurred within 3 months of starting niraparib. Median progression-free survival was 8.6 (95% confidence interval [CI] 7.6-10.0) months. One- and 2-year overall survival rates were 86% (95% CI 81-89%) and 65% (95% CI 59-70%), respectively. Dose interruptions, dose reductions, haematological toxicities and asthenia/fatigue were less common with ISD than fixed starting dose niraparib, but progression-free survival was similar irrespective of dosing strategy. Subsequent therapy included platinum in 71% of patients who received further treatment. CONCLUSION: Outcomes in this large real-world dataset of niraparib-treated patients are consistent with phase III trials, providing reassuring evidence of the tolerability and activity of niraparib maintenance therapy for platinum-sensitive recurrent ovarian cancer. GOV REGISTRATION: NCT04546373.

PI3K-regulated Glycine N-methyltransferase is required for the development of prostate cancer.

Glycine N-Methyltransferase (GNMT) is a metabolic enzyme that integrates metabolism and epigenetic regulation. The product of GNMT, sarcosine, has been proposed as a prostate cancer biomarker. This enzyme is predominantly expressed in the liver, brain, pancreas, and prostate tissue, where it exhibits distinct regulation. Whereas genetic alterations in GNMT have been associated to prostate cancer risk, its causal contribution to the development of this disease is limited to cell line-based studies and correlative human analyses. Here we integrate human studies, genetic mouse modeling, and cellular systems to characterize the regulation and function of GNMT in prostate cancer. We report that this enzyme is repressed upon activation of the oncogenic Phosphoinositide-3-kinase (PI3K) pathway, which adds complexity to its reported dependency on androgen signaling. Importantly, we demonstrate that expression of GNMT is required for the onset of invasive prostate cancer in a genetic mouse model. Altogether, our results provide further support of the heavy oncogenic signal-dependent regulation of GNMT in prostate cancer.

Molecular phylogeny, historical biogeography and revised classification of andrenine bees (Hymenoptera: Andrenidae).

The mining bee subfamily Andreninae (Hymenoptera: Andrenidae) is a widely distributed and diverse group of ground-nesting solitary bees, including numerous species known to be important pollinators. Most of the species diversity of Andreninae is concentrated in the mainly Holarctic genus Andrena, comprising ca. 1550 described species. The subfamily and especially the genus have remained relatively neglected by recent molecular phylogenetic studies, with current classifications relying largely on morphological characters. We sampled ultraconserved element (UCE) sequences from 235 taxa, including all andrenine genera and 98 out of 104 currently recognized Andrena subgenera. Using 419,858 aligned nucleotide sites from 1009 UCE loci, we present a comprehensive molecular phylogenetic analysis of the subfamily. Our analysis supports the recognition of seven distinct genera in the Andreninae: Alocandrena, Ancylandrena, Andrena, Cubiandrena, Euherbstia, Megandrena, and Orphana. Within the genus Andrena, present-day subgeneric concepts revealed high degrees of paraphyly and polyphyly, due to strong homoplasy of morphological characters, necessitating a thorough, extensive revision of the higher classification of the genus. Based on our findings, we place the subgenus Calcarandrena in synonymy with Andrena (Lepidandrena); Hyperandrena, Nemandrena, Scoliandrena, Tylandrena and Zonandrena with A. (Melandrena); Distandrena, Fumandrena and Proxiandrena with A. (Micrandrena); Carandrena with A. (Notandrena); Agandrena with A. (Plastandrena); Geandrena and Xanthandrena with A. (Ptilandrena); Xiphandrena with A. (Scrapteropsis); and Platygalandrena and Poliandrena with A. (Ulandrena) (new synonymies). We additionally reestablish the groups known as Opandrena and Truncandrena as valid subgenera of Andrena. Our results also show that the MRCA of Andrena + Cubiandrena dispersed from the New World to the Palaearctic probably during the Eocene-early Oligocene, followed by 10-14 Neogene dispersal events from the Palaearctic to the Nearctic and 1-6 Neogene dispersals back into the Palaearctic, all within the genus Andrena.

A mutant form of ERα associated with estrogen insensitivity affects the coupling between ligand binding and coactivator recruitment.

A homozygous missense mutation in the gene encoding the estrogen receptor α (ERα) was previously identified in a female patient with estrogen insensitivity syndrome. We investigated the molecular features underlying the impaired transcriptional response of this mutant (ERα-Q375H) and four other missense mutations at this position designed to query alternative mechanisms. The identity of residue 375 greatly affected the sensitivity of the receptor to agonists without changing the ligand binding affinity. Instead, the mutations caused changes in the affinity of coactivator binding and alterations in the balance of coactivator and corepressor recruitment. Comparisons among the transcriptional regulatory responses of these six ERα genotypes to a set of ER agonists showed that both steric and electrostatic factors contributed to the functional deficits in gene regulatory activity of the mutant ERα proteins. ERα-coregulator peptide binding in vitro and RIME (rapid immunoprecipitation mass spectrometry of endogenous) analysis in cells showed that the degree of functional impairment paralleled changes in receptor-coregulator binding interactions. These findings uncover coupling between ligand binding and coregulator recruitment that affects the potency rather than the efficacy of the receptor response without substantially altering ligand binding affinity. This highlights a molecular mechanism for estrogen insensitivity syndrome involving mutations that perturb a bidirectional allosteric coupling between ligand binding and coregulator binding that determines receptor transcriptional output.

Physiologic Effects of Exogenous Dextrose in Murine Klebsiella pneumoniae Sepsis Vary by Route of Provision.

Sepsis is characterized by a dysregulated immune response to infection. Nutrition is important in the care of septic patients, but the effects of specific nutrients on inflammation in sepsis are not well defined. Our prior work has shown benefits from early enteral dextrose infusion in a preclinical endotoxemia model of sepsis. In the current study, we extend our initial work to examine the effects of dextrose infusions, varying by route of administration, on inflammation and glycemic control in a more clinically relevant and translational model of Klebsiella pneumoniae (KP) bacteremia. Ten-week old C57BL6/J male mice (n = 31) underwent the implantation of indwelling vascular catheters, followed by inoculation with oropharyngeal KP. The mice were randomized 24 h after inoculation to (1) intravenous (IV) dextrose, (2) enteral dextrose, or (3) enteral saline (control) to study the effects on systemic inflammation, hemodynamics, and glycemic control. At 72 h, 77% of the control mice died, whereas IV dextrose induced 100% mortality, associated with increased inflammation, hyperglycemia, and hypotension. Enteral dextrose reduced mortality to 27%, promoted euglycemia, and reduced inflammation compared to IV dextrose. We conclude, in a bacteremic model of sepsis, that enteral (but not IV) dextrose administration is protective, suggesting that the route of nutrient support influences inflammation in sepsis.

Quality of life of patients with metastatic pancreatic adenocarcinoma initiating first-line chemotherapy in routine practice.

BACKGROUND: Despite advances in surgery, radiotherapy, and chemotherapy, pancreatic adenocarcinoma often progresses rapidly and causes death. The physical decline of these patients is expected to impact their quality of life (QoL). Therefore, in addition to objective measures of effectiveness, the evaluation of health-related QoL should be considered a matter of major concern when assessing therapy outcomes. METHODS: Observational, prospective, multicenter study including patients with metastatic pancreatic adenocarcinoma who started first-line chemotherapy in 12 Spanish centers. Treatment and clinical characteristics were recorded at baseline. Patients' health-related quality of life, ECOG, and Karnofsky index were measured at baseline, at Days 15 and 30, and every four weeks up to 6 months of chemotherapy. Health-related quality of life was measured using the EORTC-QLQ-C30 and EQ-5D questionnaires. Other endpoints included overall survival and progression-free survival. RESULTS: The study sample included 116 patients (median age of 65 years). Mean (SD) scores for the QLQ-C30 global health status scale showed a significant increasing trend throughout the treatment (p = 0.005). Patients with either a Karnofsky index of 70-80 or ECOG 2 showed greater improvement in the QLQ-C30 global health status score than the corresponding groups with better performance status (p ≤ 0.010). Pain, appetite, sleep disturbance, nausea, and constipation significantly improved throughout the treatment (p < 0.005). Patients with QLQ-C30 global health status scores ≥50 at baseline had significantly greater overall survival and progression-free survival (p = 0.005 and p = 0.021, respectively). No significant associations were observed regarding the EQ-5D score. CONCLUSIONS: Most metastatic pancreatic adenocarcinoma patients receiving first-line chemotherapy showed an increase in health-related quality of life scores throughout the treatment. Patients with lower performance status and health-related quality of life at baseline tended to greater improvement. The EORTC QLQ-C30 scale allowed us to measure the health-related quality of life of metastatic pancreatic adenocarcinoma patients receiving first-line chemotherapy.

Satisfaction of patients and primary care professionals with a teleophthalmology-based screening programme for diabetic retinopathy in a rural area in Castilla y León, Spain.

INTRODUCTION: Diabetic retinopathy (DR) is the leading cause of blindness in working-age adults in most developed countries. Early diagnosis and early treatment for retinopathy can reduce the incidence of severe loss of vision in a high percentage of sight-threatening DR. However, sight-threatening DR is asymptomatic in a high percentage of patients and no more than 50% of the diabetic patients are reviewed periodically in ophthalmology, mainly in rural areas. Telemedicine facilitates the exchange of information among professionals, reducing unnecessary journeys for patients who live in rural or remote areas. The survey of satisfaction is a highly useful quantitative instrument to obtain information directly from the users of a screening program. One aim of this study has been to determine the prevalence of DR in a sample of diabetic patients from a rural area of Spain and to classify DR patients according to the type and severity of this complication of the disease. The other main target was to evaluate the degree of satisfaction in both diabetic patients and professionals with a teleophthalmology-based screening program of DR. METHODS: A sample of 114 diabetic patients included in a new teleophthalmology program for the screening of DR in Castilla y León, Spain, were asked to take part in an in-person survey designed to evaluate the degree of satisfaction. This sample was obtained through a consecutive non-probability sampling technique, out of a total of 752 diabetic patients who underwent a retinography screening program in a distant rural healthcare center. The survey assessed aspects related to the information about the program the patients received, the organization of the center, the way the test was conducted and the reception of the results. All the included participants consented to participate in this study. Additionally, an anonymous survey was conducted via email. The sample was made up of 10 professionals responsible for taking the retinal images from the patients included in the study. This survey assessed their degree of satisfaction with their training, the way the test was carried out, the support from their managers and how this activity influenced their relationship with their patients. RESULTS: A high percentage of patients with DR in the study sample had a form of sight-threatening retinopathy (29.4%), which in this program is a criterion of referral to be assessed by an ophthalmologist. Of the surveyed patients, 93.8% scored eight points or higher for their degree of general satisfaction with the activity. All of them claimed they would prefer to continue their exploration at the healthcare center instead of going to the hospital. As regards the professionals, 70% scored eight points or more in terms of their degree of general satisfaction with the activity, whereas 20% scored between five and seven. One professional did not respond to the question. Finally, 90% stated that they would continue performing the activity, while the remaining 10% answered no. CONCLUSION: According to the high percentage of patients diagnosed with vision-threatening DR in this study, an early diagnosis of this complication of diabetes seems to be important. Teleophthalmology enhances patient accessibility to the healthcare system, making early diagnosis of DR easier, with a high degree of satisfaction among patients and healthcare professionals.

A pathogenic tau fragment compromises microtubules, disrupts insulin signaling and induces the unfolded protein response.

Human tauopathies including Alzheimer's disease, progressive supranuclear palsy and related disorders, are characterized by deposition of pathological forms of tau, synaptic dysfunction and neuronal loss. We have previously identified a pathogenic C-terminal tau fragment (Tau35) that is associated with human tauopathy. However, it is not known how tau fragmentation affects critical molecular processes in cells and contributes to impaired physiological function. Chinese hamster ovary (CHO) cells and new CHO cell lines stably expressing Tau35 or full-length human tau were used to compare the effects of disease-associated tau cleavage on tau function and signaling pathways. Western blots, microtubule-binding assays and immunofluorescence labeling were used to examine the effects of Tau35 on tau function and on signaling pathways in CHO cells. We show that Tau35 undergoes aberrant phosphorylation when expressed in cells. Although Tau35 contain the entire microtubule-binding region, the lack of the amino terminal half of tau results in a marked reduction in microtubule binding and defective microtubule organization in cells. Notably, Tau35 attenuates insulin-mediated activation of Akt and a selective inhibitory phosphorylation of glycogen synthase kinase-3. Moreover, Tau35 activates ribosomal protein S6 kinase beta-1 signaling and the unfolded protein response, leading to insulin resistance in cells. Tau35 has deleterious effects on signaling pathways that mediate pathological changes and insulin resistance, suggesting a mechanism through which N-terminal cleavage of tau leads to the development and progression of tau pathology in human tauopathy. Our findings highlight the importance of the N-terminal region of tau for its normal physiological function. Furthermore, we show that pathogenic tau cleavage induces tau phosphorylation, resulting in impaired microtubule binding, disruption of insulin signaling and activation of the unfolded protein response. Since insulin resistance is a feature of several tauopathies, this work suggests new potential targets for therapeutic intervention.

The SERM/SERD bazedoxifene disrupts ESR1 helix 12 to overcome acquired hormone resistance in breast cancer cells.

Acquired resistance to endocrine therapy remains a significant clinical burden for breast cancer patients. Somatic mutations in the ESR1 (estrogen receptor alpha (ERα)) gene ligand-binding domain (LBD) represent a recognized mechanism of acquired resistance. Antiestrogens with improved efficacy versus tamoxifen might overcome the resistant phenotype in ER +breast cancers. Bazedoxifene (BZA) is a potent antiestrogen that is clinically approved for use in hormone replacement therapies. We found that BZA possesses improved inhibitory potency against the Y537S and D538G ERα mutants compared to tamoxifen and has additional inhibitory activity in combination with the CDK4/6 inhibitor palbociclib. In addition, comprehensive biophysical and structural biology studies show BZA's selective estrogen receptor degrading (SERD) properties that override the stabilizing effects of the Y537S and D538G ERα mutations.

High fat diet blunts the effects of leptin on ventilation and on carotid body activity.

KEY POINTS: Leptin plays a role in the control of breathing, acting mainly on central nervous system; however, leptin receptors have been recently shown to be expressed in the carotid body (CB), and this finding suggests a physiological role for leptin in the regulation of CB function. Leptin increases minute ventilation in both basal and hypoxic conditions in rats. It increases the frequency of carotid sinus nerve discharge in basal conditions, as well as the release of adenosine from the CB. However, in a metabolic syndrome animal model, the effects of leptin in ventilatory control, carotid sinus nerve activity and adenosine release by the CB are blunted. Although leptin may be involved in triggering CB overactivation in initial stages of obesity and dysmetabolism, resistance to leptin signalling and blunting of responses develops in metabolic syndrome animal models. ABSTRACT: Leptin plays a role in the control of breathing, acting mainly on central nervous system structures. Leptin receptors are expressed in the carotid body (CB) and this finding has been associated with a putative physiological role of leptin in the regulation of CB function. Since, the CBs are implicated in energy metabolism, here we tested the effects of different concentrations of leptin administration on ventilatory parameters and on carotid sinus nerve (CSN) activity in control and high-fat (HF) diet fed rats, in order to clarify the role of leptin in ventilation control in metabolic disease states. We also investigated the expression of leptin receptors and the neurotransmitters involved in leptin signalling in the CBs. We found that in non-disease conditions, leptin increases minute ventilation in both basal and hypoxic conditions. However, in the HF model, the effect of leptin in ventilatory control is blunted. We also observed that HF rats display an increased frequency of CSN discharge in basal conditions that is not altered by leptin, in contrast to what is observed in control animals. Leptin did not modify intracellular Ca2+ in CB chemoreceptor cells, but it produced an increase in the release of adenosine from the whole CB. We conclude that CBs represent an important target for leptin signalling, not only to coordinate peripheral ventilatory chemoreflexive drive, but probably also to modulate metabolic variables. We also concluded that leptin signalling is mediated by adenosine release and that HF diets blunt leptin responses in the CB, compromising ventilatory adaptation.

Spontaneous nasal perforation in a bevacizumab-treated patient with metastatic breast cancer.

Nasal septum perforation in patients with cancer receiving systemic therapy is rare, and its association with bevacizumab use has described recently in the literature. Here, we report the case of a 34-year-old woman with hormone-sensitive, HER-2/neu negative, metastatic breast cancer who develope a nasal septum perforation during the treatment with paclitaxel and bevacizumab.

Activating ESR1 Mutations Differentially Affect the Efficacy of ER Antagonists.

Recent studies have identified somatic ESR1 mutations in patients with metastatic breast cancer and found some of them to promote estrogen-independent activation of the receptor. The degree to which all recurrent mutants can drive estrogen-independent activities and reduced sensitivity to ER antagonists like fulvestrant is not established. In this report, we characterize the spectrum of ESR1 mutations from more than 900 patients. ESR1 mutations were detected in 10%, with D538G being the most frequent (36%), followed by Y537S (14%). Several novel, activating mutations were also detected (e.g., L469V, V422del, and Y537D). Although many mutations lead to constitutive activity and reduced sensitivity to ER antagonists, only select mutants such as Y537S caused a magnitude of change associated with fulvestrant resistance in vivo Correspondingly, tumors driven by Y537S, but not D5358G, E380Q, or S463P, were less effectively inhibited by fulvestrant than more potent and bioavailable antagonists, including AZD9496. These data point to a need for antagonists with optimal pharmacokinetic properties to realize clinical efficacy against certain ESR1 mutants.Significance: A diversity of activating ESR1 mutations exist, only some of which confer resistance to existing ER antagonists that might be overcome by next-generation inhibitors such as AZD9496. Cancer Discov; 7(3); 277-87. ©2016 AACR.This article is highlighted in the In This Issue feature, p. 235.

Cyclic Ketoximes as Estrogen Receptorâ€ ß Selective Agonists.

The development of estrogen receptorâ€…ß (ERß)-selective agonists represents a therapeutic strategy against several kinds of cancers, but the high homology between the two receptor subtypes, ERα and ERß, makes the achievement of this goal very challenging. In the past, we developed salicylaldoxime- and salicylketoxime-based molecules that proved to bind well to ERß. In this paper, further structural evolution of the salicylketoximes is presented: two of the newly synthesized five-membered cyclic ketoximes bind with nanomolar affinities to ERß, and they show selectivity for this subtype over ERα. Their agonist character was confirmed by cell-free coactivator recruitment assays, in which we demonstrated the ability of these compounds to form an active complex with ERß capable of recruiting coactivator proteins; this indicated their efficacy as agonists. Finally, their potency and selectivity for ERß binding were rationalized by molecular-modeling studies.

Estrogen receptor alpha somatic mutations Y537S and D538G confer breast cancer endocrine resistance by stabilizing the activating function-2 binding conformation.

Somatic mutations in the estrogen receptor alpha (ERα) gene (ESR1), especially Y537S and D538G, have been linked to acquired resistance to endocrine therapies. Cell-based studies demonstrated that these mutants confer ERα constitutive activity and antiestrogen resistance and suggest that ligand-binding domain dysfunction leads to endocrine therapy resistance. Here, we integrate biophysical and structural biology data to reveal how these mutations lead to a constitutively active and antiestrogen-resistant ERα. We show that these mutant ERs recruit coactivator in the absence of hormone while their affinities for estrogen agonist (estradiol) and antagonist (4-hydroxytamoxifen) are reduced. Further, they confer antiestrogen resistance by altering the conformational dynamics of the loop connecting Helix 11 and Helix 12 in the ligand-binding domain of ERα, which leads to a stabilized agonist state and an altered antagonist state that resists inhibition.

Selective Human Estrogen Receptor Partial Agonists (ShERPAs) for Tamoxifen-Resistant Breast Cancer.

Almost 70% of breast cancers are estrogen receptor α (ERα) positive. Tamoxifen, a selective estrogen receptor modulator (SERM), represents the standard of care for many patients; however, 30-50% develop resistance, underlining the need for alternative therapeutics. Paradoxically, agonists at ERα such as estradiol (E2) have demonstrated clinical efficacy in patients with heavily treated breast cancer, although side effects in gynecological tissues are unacceptable. A drug that selectively mimics the actions of E2 in breast cancer therapy but minimizes estrogenic effects in other tissues is a novel, therapeutic alternative. We hypothesized that a selective human estrogen receptor partial agonist (ShERPA) at ERα would provide such an agent. Novel benzothiophene derivatives with nanomolar potency in breast cancer cell cultures were designed. Several showed partial agonist activity, with potency of 0.8-76 nM, mimicking E2 in inhibiting growth of tamoxifen-resistant breast cancer cell lines. Three ShERPAs were tested and validated in xenograft models of endocrine-independent and tamoxifen-resistant breast cancer, and in contrast to E2, ShERPAs did not cause significant uterine growth.

Licorice root components in dietary supplements are selective estrogen receptor modulators with a spectrum of estrogenic and anti-estrogenic activities.

Licorice root extracts are often consumed as botanical dietary supplements by menopausal women as a natural alternative to pharmaceutical hormone replacement therapy. In addition to their components liquiritigenin (Liq) and isoliquiritigenin (Iso-Liq), known to have estrogenic activity, licorice root extracts also contain a number of other flavonoids, isoflavonoids, and chalcones. We have investigated the estrogenic activity of 7 of these components, obtained from an extract of Glycyrrhiza glabra powder, namely Glabridin (L1), Calycosin (L2), Methoxychalcone (L3), Vestitol (L4), Glyasperin C (L5), Glycycoumarin (L6), and Glicoricone (L7), and compared them with Liq, Iso-Liq, and estradiol (E2). All components, including Liq and Iso-Liq, have low binding affinity for estrogen receptors (ERs). Their potency and efficacy in stimulating the expression of estrogen-regulated genes reveal that Liq and Iso-Liq and L2, L3, L4, and L6 are estrogen agonists. Interestingly, L3 and L4 have an efficacy nearly equivalent to E2 but with a potency ca. 10,000-fold less. The other components, L1, L5 and L7, acted as partial estrogen antagonists. All agonist activities were reversed by the antiestrogen, ICI 182,780, or by knockdown of ERα with siRNA, indicating that they are ER dependent. In HepG2 hepatoma cells stably expressing ERα, only Liq, Iso-Liq, and L3 stimulated estrogen-regulated gene expression, and in all cases gene stimulation did not occur in HepG2 cells lacking ERα. Collectively, these findings classify the components of licorice root extracts as low potency, mixed ER agonists and antagonists, having a character akin to that of selective estrogen receptor modulators or SERMs.