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Beta-adrenergic blockade has been associated with improved cancer survival in patients with triple-negative breast cancer (TNBC), but the mechanisms of these effects remain unclear. In clinical epidemiological analyses, we identified a relationship between beta-blocker use and anthracycline chemotherapy in protecting against TNBC progression, disease recurrence, and mortality. We recapitulated the effect of beta-blockade on anthracycline efficacy in xenograft mouse models of TNBC. In metastatic 4T1.2 and MDA-MB-231 mouse models of TNBC, beta-blockade improved the efficacy of the anthracycline doxorubicin by reducing metastatic development. We found that anthracycline chemotherapy alone, in the absence of beta-blockade, increased sympathetic nerve fiber activity and norepinephrine concentration in mammary tumors through the induction of nerve growth factor (NGF) by tumor cells. Moreover, using preclinical models and clinical samples, we found that anthracycline chemotherapy up-regulated β 2 -adrenoceptor expression and amplified receptor signaling in tumor cells. Neurotoxin inhibition of sympathetic neural signaling in mammary tumors using 6-hydroxydopamine or genetic deletion of NGF or β 2 -adrenoceptor in tumor cells enhanced the therapeutic effect of anthracycline chemotherapy by reducing metastasis in xenograft mouse models. These findings reveal a neuromodulatory effect of anthracycline chemotherapy that undermines its potential therapeutic impact, which can be overcome by inhibiting β 2 -adrenergic signaling in the tumor microenvironment. Supplementing anthracycline chemotherapy with adjunctive β 2 -adrenergic antagonists represents a potential therapeutic strategy for enhancing the clinical management of TNBC.

Nitrate signaling improves plant growth under limited nitrate availability and, hence, optimal resource use for crop production. Whereas several transcriptional regulators of nitrate signaling have been identified, including the Arabidopsis thaliana transcription factor NIN-LIKE PROTEIN7 (NLP7), additional regulators are expected to fine-tune this pivotal physiological response. Here, we characterized Arabidopsis NLP2 as a top-tier transcriptional regulator of the early nitrate response gene regulatory network. NLP2 interacts with NLP7 in vivo and shares key molecular features such as nitrate-dependent nuclear localization, DNA-binding motif, and some target genes with NLP7. Genetic, genomic, and metabolic approaches revealed a specific role for NLP2 in the nitrate-dependent regulation of carbon and energy-related processes that likely influence plant growth under distinct nitrogen environments. Our findings highlight the complementarity and specificity of NLP2 and NLP7 in orchestrating a multitiered nitrate regulatory network that links nitrate assimilation with carbon and energy metabolism for efficient nitrogen use and biomass production., Competing Interests: Conflict of interest statement. None declared., (© American Society of Plant Biologists 2023. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Removal of nitrogen and carbon from anaerobic digester (AD) effluents is challenging for currently available technologies. Herein, effective treatment for real AD effluents was achieved via the feammox process by using a Multistage Feammox Bioreactor (MSFB). The reactor achieved the best performance with AD effluent of a low carbon to nitrogen (C/N) ratio of 2.5. A 6-day retention time reached removal efficiencies for NH 4 + and COD at 99 % and 97 %, respectively, with a thorough conversion of NH 4 + to N 2 . Accordingly, the MSFB achieved removal rates for N and C of 14 and 34 mg L -1 d -1 , respectively. The C/N ratio of 2.5 is regarded to be the critical point above which the feammox is shifted to conventional iron reduction with organic carbon. Iron-reducing bacteria of the γ- Proteobacteria (Pseudomonas and Acinetobacter), and δ- Proteobacteria (Geobacter) were dominant in the MSFB and were supposed to drive the feammox process., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023 Elsevier Ltd. All rights reserved.)

One of the main limiting factors of plant yield is drought, and while the physiological responses to this environmental stress have been broadly described, research addressing its impact on mineral nutrition is scarce. Brassica napus and Triticum aestivum were subjected to moderate or severe water deficit, and their responses to drought were assessed by functional ionomic analysis, and derived calculation of the net uptake of 20 nutrients. While the uptake of most mineral nutrients decreased, Fe, Zn, Mn, and Mo uptake were impacted earlier and at a larger scale than most physiological parameters assessed (growth, ABA concentration, gas exchanges and photosynthetic activity). Additionally, in B. napus , the patterns of 183 differentially expressed genes in leaves related to the ionome (known ionomic genes, KIGs) or assumed to be involved in transport of a given nutrient were analyzed. This revealed three patterns of gene expression under drought consisting of up (transport of Cl and Co), down (transport of N, P, B, Mo, and Ni), or mixed levels (transport of S, Mg, K, Zn, Fe, Cu, or Mn) of regulation. The three patterns of gene regulations are discussed in relation to specific gene functions, changes of leaf ionomic composition and with consideration of the crosstalks that have been established between elements. It is suggested that the observed reduction in Fe uptake occurred via a specific response to drought, leading indirectly to reduced uptake of Zn and Mn, and these may be taken up by common transporters encoded by genes that were downregulated., Competing Interests: The authors declare that there are no conflicts of interest, (© 2022 The Authors. Plant Direct published by American Society of Plant Biologists and the Society for Experimental Biology and John Wiley & Sons Ltd.)

Background: Lignocellulose is a renewable and enormous biomass resource, which can be degraded efficiently by a range of cocktails of carbohydrate-active enzymes secreted by termite gut symbiotic bacteria. There is an urgent need to find enzymes with novel characteristics for improving the conversion processes in the production of lignocellulosic-based products. Although various studies dedicated to the genus Cellulosimicrobium as gut symbiont , genetic potential related to plant biomass-acting enzymes and exopolysaccharides production has been fully untapped to date., Methods: The cellulolytic bacterial strain MP1 was isolated from termite guts and identified to the species level by phenotypic, phylogenetic, and genomic analysis. To further explore genes related to cellulose and hemicellulose degradation, the draft genome of strain MP1 was obtained by using whole-genome sequencing, assembly, and annotation through the Illumina platform. Lignocellulose degrading enzymes and levan production in the liquid medium were also examined to shed light on bacterial activities., Results: Among 65 isolates obtained, the strain MP1 was the most efficient cellulase producer with cellulase activity of 0.65 ± 0.02 IU/ml. The whole genome analysis depicted that strain MP1 consists of a circular chromosome that contained 4,580,223 bp with an average GC content of 73.9%. The genome comprises 23 contigs including 67 rRNA genes, three tRNA genes, a single tmRNA gene, and 4,046 protein-coding sequences. In support of the phenotypic identification, the 16S rRNA gene sequence, average nucleotide identity, and whole-genome-based taxonomic analysis demonstrated that the strain MP1 belongs to the species Cellulosimicrobium cellulans . A total of 30 genes related to the degradation of cellulases and hemicellulases were identified in the C. cellulans MP1 genome. Of note, the presence of sacC1-levB-sacC2-ls operon responsible for levan and levan-type fructooligosaccharides biosynthesis was detected in strain MP1 genome, but not with closely related C. cellulans strains, proving this strain to be a potential candidate for further studies. Endoglucanases, exoglucanases, and xylanase were achieved by using cheaply available agro-residues such as rice bran and sugar cane bagasse. The maximum levan production by C. cellulans MP1 was 14.8 ± 1.2 g/l after 20 h of cultivation in media containing 200 g/l sucrose. To the best of our knowledge, the present study is the first genome-based analysis of a Cellulosimicrobium species which focuses on lignocellulosic enzymes and levan biosynthesis, illustrating that the C. cellulans MP1 has a great potential to be an efficient platform for basic research and industrial exploitation., Competing Interests: The authors declare there are no competing interests., (©2021 Vu et al.)

Nitrification is the rate limiting step in the nitrogen removal processes since nitrifiers have high oxygen demand, but poorly compete with aerobic heterotrophs. In a laboratory-scaled system, we investigated a process of ammonium oxidation under ferric-iron reducing condition (feammox) in the presence of organic carbon using influents with high NH 4 + and COD contents, and ferrihydrite as the only electron acceptor. Batch incubations testing influents with different NH 4 + and COD concentrations revealed that the [COD]/[NH 4 + ] ratio of 1.4 and the influent redox potential ranging from - 20 to + 20 mV led to the highest removal efficiencies, i.e. 98.3% for NH 4 + and 58.8% for COD. N 2 was detected as the only product of NH 4 + conversion, whereas NO 2 - and NO 3 - were not detected. While operating continuously with influent having a [COD]/[NH 4 + ] ratio of 1.4, the system efficiently removed NH 4 + (> 91%) and COD (> 54%) within 6 day retention time. Fluorescence in situ hybridization analyses using Cy3-labeled 16S rRNA oligonucleotide probes revealed that gamma-proteobacteria dominated in the microbial community attaching to the matrix bed of the system. The iron-reduction dependent NH 4 + and COD co-removal with a thorough conversion of NH 4 + to N 2 demonstrated in this study would be a novel approach for nitrogen treatment.

Background: Recent literature on the differential role of genes within networks distinguishes core from peripheral genes. If previous works have shown contrasting features between them, whether such categorization matters for phenotype prediction remains to be studied., Results: We measured 17 phenotypic traits for 241 cloned genotypes from a Populus nigra collection, covering growth, phenology, chemical and physical properties. We also sequenced RNA for each genotype and built co-expression networks to define core and peripheral genes. We found that cores were more differentiated between populations than peripherals while being less variable, suggesting that they have been constrained through potentially divergent selection. We also showed that while cores were overrepresented in a subset of genes statistically selected for their capacity to predict the phenotypes (by Boruta algorithm), they did not systematically predict better than peripherals or even random genes., Conclusion: Our work is the first attempt to assess the importance of co-expression network connectivity in phenotype prediction. While highly connected core genes appear to be important, they do not bear enough information to systematically predict better quantitative traits than other gene sets.

This paper investigates the lateral pull-in effect of an in-plane overlap-varying transducer. The instability is induced by the translational and rotational displacements. Based on the principle of virtual work, the equilibrium conditions of force and moment in lateral directions are derived. The analytical solutions of the critical voltage, at which the pull-in phenomenon occurs, are developed when considering only the translational stiffness or only the rotational stiffness of the mechanical spring. The critical voltage in a general case is numerically determined by using nonlinear optimization techniques, taking into account the combined effect of translation and rotation. The influences of possible translational offsets and angular deviations to the critical voltage are modeled and numerically analyzed. The investigation is then expanded for the first time to anti-phase operation mode and Bennet's doubler configuration of the two transducers.

Objective: The aim of this study was to assess the impact of a urinary tract infection (UTI) management bundle to reduce the treatment of asymptomatic bacteriuria (AB) and to improve the management of symptomatic UTIs., Design: Before-and-after intervention study.SettingsTertiary-care hospital.PatientsConsecutive sample of inpatients with positive single or mixed-predominant urine cultures collected and reported while admitted to the hospital., Methods: The UTI management bundle consisted of nursing and prescriber education, modification of the reporting of positive urine cultures, and pharmacists' prospective audit and feedback. A retrospective chart review of consecutive inpatients with positive urinary cultures was performed before and after implementation of the management bundle., Results: Prior to the implementation of the management bundle, 276 patients were eligible criteria for chart review. Of these 276 patients, 165 (59·8%) were found to have AB; of these 165 patients with AB, 111 (67·3%) were treated with antimicrobials. Moreover, 268 patients met eligibility criteria for postintervention review. Of these 268, 133 patients (49·6%) were found to have AB; of these 133 with AB, 22 (16·5%) were treated with antimicrobials. Thus, a 75·5% reduction of AB treatment was achieved. Educational components of the bundle resulted in a substantial decrease in nonphysician-directed urine sample submission. Adherence to a UTI management algorithm improved substantially in the intervention period, with a notable decrease in fluoroquinolone prescription for empiric UTI treatment., Conclusions: A UTI management bundle resulted in a dramatic improvement in the management of urinary tract infection, particularly a reduction in the treatment of AB and improved management of symptomatic UTI.

Due to their sessile nature, plants have to cope with and adjust to their fluctuating environment. Temperature elevation stimulates the growth of Arabidopsis aerial parts. This process is mediated by increased biosynthesis of the growth-promoting hormone auxin. How plant roots respond to elevated ambient temperature is however still elusive. Here we present strong evidence that temperature elevation impinges on brassinosteroid hormone signaling to alter root growth. We show that elevated temperature leads to increased root elongation, independently of auxin or factors known to drive temperature-mediated shoot growth. We further demonstrate that brassinosteroid signaling regulates root responses to elevated ambient temperature. Increased growth temperature specifically impacts on the level of the brassinosteroid receptor BRI1 to downregulate brassinosteroid signaling and mediate root elongation. Our results establish that BRI1 integrates temperature and brassinosteroid signaling to regulate root growth upon long-term changes in environmental conditions associated with global warming.Moderate heat stimulates the growth of Arabidopsis shoots in an auxin-dependent manner. Here, Martins et al. show that elevated ambient temperature modifies root growth by reducing the BRI1 brassinosteroid-receptor protein level and downregulating brassinosteroid signaling.

Chronic stress accelerates metastasis - the main cause of death in cancer patients - through the activation of β-adrenoceptors (βARs). We have previously shown that β2AR signaling in MDA-MB-231(HM) breast cancer cells, facilitates invadopodia formation and invasion in vitro. However, in the tumor microenvironment where many stromal cells also express βAR, the role of β2AR signaling in tumor cells in metastasis is unclear. Therefore, to investigate the contribution of β2AR signaling in tumor cells to metastasis in vivo, we used RNA interference to generate MDA-MB-231(HM) breast cancer cells that are deficient in β2AR. β2AR knockdown in tumor cells reduced the proportion of cells with a mesenchymal-like morphology and, as expected, reduced tumor cell invasion in vitro. Conversely, overexpression of β2AR in low metastatic MCF-7 breast cancer cells induced an invasive phenotype. Importantly, we found that knockdown of β2AR in tumor cells significantly reduced the impact of stress on metastasis in vivo. These findings highlight a crucial role for β2AR tumor cell signaling in the adverse effects of stress on metastasis, and indicate that it may be necessary to block β2AR on tumor cells to fully control metastatic progression., Competing Interests: The authors declare that they have no conflict of interest., (Copyright © 2016 The Authors. Published by Elsevier Inc. All rights reserved.)

Chronic stress drives cancer progression, but the routes of metastasis are unclear. We recently demonstrated that chronic stress activates a neural-inflammatory signaling axis to remodel lymphatic vasculature and increase lymph flow. This unanticipated crosstalk between stress and the lymphatic system provides pathways of tumor cell dissemination and accelerates metastasis.

Chronic stress induces signalling from the sympathetic nervous system (SNS) and drives cancer progression, although the pathways of tumour cell dissemination are unclear. Here we show that chronic stress restructures lymphatic networks within and around tumours to provide pathways for tumour cell escape. We show that VEGFC derived from tumour cells is required for stress to induce lymphatic remodelling and that this depends on COX2 inflammatory signalling from macrophages. Pharmacological inhibition of SNS signalling blocks the effect of chronic stress on lymphatic remodelling in vivo and reduces lymphatic metastasis in preclinical cancer models and in patients with breast cancer. These findings reveal unanticipated communication between stress-induced neural signalling and inflammation, which regulates tumour lymphatic architecture and lymphogenous tumour cell dissemination. These findings suggest that limiting the effects of SNS signalling to prevent tumour cell dissemination through lymphatic routes may provide a strategy to improve cancer outcomes.

Introduction: For efficient metastatic dissemination, tumor cells form invadopodia to degrade and move through three-dimensional extracellular matrix. However, little is known about the conditions that favor invadopodia formation. Here, we investigated the effect of β-adrenoceptor signaling - which allows cells to respond to stress neurotransmitters - on the formation of invadopodia and examined the effect on tumor cell invasion., Methods: To characterize the molecular and cellular mechanisms of β-adrenergic signaling on the invasive properties of breast cancer cells, we used functional cellular assays to quantify invadopodia formation and to evaluate cell invasion in two-dimensional and three-dimensional environments. The functional significance of β-adrenergic regulation of invadopodia was investigated in an orthotopic mouse model of spontaneous breast cancer metastasis., Results: β-adrenoceptor activation increased the frequency of invadopodia-positive tumor cells and the number of invadopodia per cell. The effects were selectively mediated by the β2-adrenoceptor subtype, which signaled through the canonical Src pathway to regulate invadopodia formation. Increased invadopodia occurred at the expense of focal adhesion formation, resulting in a switch to increased tumor cell invasion through three-dimensional extracellular matrix. β2-adrenoceptor signaling increased invasion of tumor cells from explanted primary tumors through surrounding extracellular matrix, suggesting a possible mechanism for the observed increased spontaneous tumor cell dissemination in vivo. Selective antagonism of β2-adrenoceptors blocked invadopodia formation, suggesting a pharmacological strategy to prevent tumor cell dissemination., Conclusion: These findings provide insight into conditions that control tumor cell invasion by identifying signaling through β2-adrenoceptors as a regulator of invadopodia formation. These findings suggest novel pharmacological strategies for intervention, by using β-blockers to target β2-adrenoceptors to limit tumor cell dissemination and metastasis.

The tumor microenvironment is known to play a pivotal role in driving cancer progression and governing response to therapy. This is of significance in pancreatic cancer where the unique pancreatic tumor microenvironment, characterized by its pronounced desmoplasia and fibrosis, drives early stages of tumor progression and dissemination, and contributes to its associated low survival rates. Several molecular factors that regulate interactions between pancreatic tumors and their surrounding stroma are beginning to be identified. Yet broader physiological factors that influence these interactions remain unclear. Here, we discuss a series of preclinical and mechanistic studies that highlight the important role chronic stress plays as a physiological regulator of neural-tumor interactions in driving the progression of pancreatic cancer. These studies propose several approaches to target stress signaling via the β-adrenergic signaling pathway in order to slow pancreatic tumor growth and metastasis. They also provide evidence to support the use of β-blockers as a novel therapeutic intervention to complement current clinical strategies to improve cancer outcome in patients with pancreatic cancer.

Pancreatic cancer cells intimately interact with a complex microenvironment that influences pancreatic cancer progression. The pancreas is innervated by fibers of the sympathetic nervous system (SNS) and pancreatic cancer cells have receptors for SNS neurotransmitters which suggests that pancreatic cancer may be sensitive to neural signaling. In vitro and non-orthotopic in vivo studies showed that neural signaling modulates tumour cell behavior. However the effect of SNS signaling on tumor progression within the pancreatic microenvironment has not previously been investigated. To address this, we used in vivo optical imaging to non-invasively track growth and dissemination of primary pancreatic cancer using an orthotopic mouse model that replicates the complex interaction between pancreatic tumor cells and their microenvironment. Stress-induced neural activation increased primary tumor growth and tumor cell dissemination to normal adjacent pancreas. These effects were associated with increased expression of invasion genes by tumor cells and pancreatic stromal cells. Pharmacological activation of β-adrenergic signaling induced similar effects to chronic stress, and pharmacological β-blockade reversed the effects of chronic stress on pancreatic cancer progression. These findings indicate that neural β-adrenergic signaling regulates pancreatic cancer progression and suggest β-blockade as a novel strategy to complement existing therapies for pancreatic cancer., (Copyright © 2014 Elsevier Inc. All rights reserved.)

Purpose: To report the clinical features, patient demographics, management, and outcomes of a series of patients with orbital solitary fibrous tumors (OSFTs) and provide a review of the English literature describing this rare entity., Design: A review of patient demographics, clinical presentations, imaging, histopathology, surgical management, and outcomes were analyzed., Methods: A non-comparative retrospective chart review of the demographics, clinical presentations, imaging, histopathological features, management, and disease outcomes of patients presenting to a tertiary orbital center with a tissue diagnosis of OSFT between 2007-2012 was performed along with a review of the English-language literature., Results: Our study included four male patients, with a mean age of 48 years at referral. The most common presentations included a slowly growing mass, globe displacement, diplopia on extreme gazes, and/or facial disfiguration. All tumors were analyzed with histopathology and immunohistochemistry. Treatment involved the complete surgical excision of the lesion, obtaining clear margins. All patients remain alive and well with no evidence of recurrence after a minimum follow-up of 15 months (range 15 months-5 years)., Conclusion: SFTs should be considered when confronting a painless slowly growing orbital mass that induces globe displacement and/or facial deformity. Imaging will show a well-defined lesion that enhances with contrast. A careful initial surgical excision with clear margins is required for adequate local control of the tumor, avoiding recurrence and potential malignant transformation.

Isolated sphenoid sinus disease is a rare entity with severe and potentially life threatening sequela. Because of the proximity of the sinus to the orbit, anatomical defects within the surrounding bony structures can facilitate communication with orbital content, predisposing the patient to substantial visual consequences. We report a case of a 51-year-old immunocompromised male who presented with headache and gradual unilateral decreases in vision. Computed tomography revealed opacification of the left sphenoid sinus accompanied by unusual bony dehiscence of the proximal optic canal. Early recognition and treatment of sphenoid sinusitis requires urgent surgical intervention with delay of treatment potentially leading to irreversible blindness or other devastating consequences. Bony dehiscence of the sphenoid sinus overlying the optic nerve has only been found in 4% of cadavers. It is associated with increased risk of orbital complications and predicts a poor prognosis. Immediate intervention is particularly important in immunocompromised individuals who are at greater risk of these severe complications.

The progression of cancer is supported by a wide variety of non-neoplastic cell types which make up the tumour stroma, including immune cells, endothelial cells, cancer-associated fibroblasts and nerve fibres. These host cells contribute molecular signals that enhance primary tumour growth and provide physical avenues for metastatic dissemination. This article provides an overview of the role of blood vessels, lymphatic vessels and nerve fibres in the tumour microenvironment and highlights the interconnected molecular signalling pathways that control their development and activation in cancer. Further, this article highlights the known pharmacological agents which target these pathways and discusses the potential therapeutic uses of drugs that target angiogenesis, lymphangiogenesis and stress-response pathways in the different stages of cancer care., (Copyright © 2013. Published by Elsevier Ltd.)

The efficacy of protein-based therapeutics with indications in the treatment of lymphatic diseases is expected to be improved by enhancing lymphatic disposition. This study was therefore aimed at examining whether PEGylation can usefully be applied to improve the lymphatic uptake of interferon α2 and whether this ultimately translates into improved therapeutic efficacy against lymph-resident cancer. The lymphatic pharmacokinetics of interferon α2b (IFN, 19kDa) and PEGylated interferon α2b (IFN-PEG12, 31kDa) or α2a (IFN-PEG40, 60kDa) was examined in thoracic lymph duct cannulated rats. IFN was poorly absorbed from the SC injection site (Fabs 36%) and showed little uptake into lymph after SC or IV administration (≤1%). In contrast, IFN-PEG12 was efficiently absorbed from the SC injection site (Fabs 82%) and approximately 20% and 8% of the injected dose was recovered in thoracic lymph over 30h after SC or IV administration respectively. IFN-PEG40, however, was incompletely absorbed from the SC injection site (Fabs 23%) and showed similar lymphatic access after SC administration to IFN-PEG12 (21%). The recovery of IFN-PEG40 in thoracic lymph after IV administration, however, was significantly greater (29%) when compared to IV IFN-PEG12. The anti-tumour efficacy of interferon against axillary metastases of a highly lymph-metastatic variant of human breast MDA-MB-231 carcinoma was significantly increased by SC administration of lymph-targeted IFN-PEG12 when compared to the administration of IFN on the ipsilateral side to the axillary metastasis. Optimal PEGylation may therefore represent a viable approach to improving the lymphatic disposition and efficacy of therapeutic proteins against lymphatic diseases., (Crown Copyright © 2013. Published by Elsevier B.V. All rights reserved.)