GNA13 suppresses proliferation of ER+ breast cancer cells via ERα dependent upregulation of the MYC oncogene.

GNA13 (Gα13) is one of two alpha subunit members of the G12/13 family of heterotrimeric G-proteins which mediate signaling downstream of GPCRs. It is known to be essential for embryonic development and vasculogenesis and has been increasingly shown to be involved in mediating several steps of cancer progression. Recent studies found that Gα13 can function as an oncogene and contributes to progression and metastasis of multiple tumor types, including ovarian, head and neck and prostate cancers. In most cases, Gα12 and Gα13, as closely related α-subunits in the subfamily, have similar cellular roles. However, in recent years their differences in signaling and function have started to emerge. We previously identified that Gα13 drives invasion of Triple Negative Breast Cancer (TNBC) cells in vitro. As a highly heterogenous disease with various well-defined molecular subtypes (ER+ /Her2-, ER+ /Her2+, Her2+, TNBC) and subtype associated outcomes, the function(s) of Gα13 beyond TNBC should be explored. Here, we report the finding that low expression of GNA13 is predictive of poorer survival in breast cancer, which challenges the conventional idea of Gα12/13 being universal oncogenes in solid tumors. Consistently, we found that Gα13 suppresses the proliferation in multiple ER+ breast cancer cell lines (MCF-7, ZR-75-1 and T47D). Loss of GNA13 expression drives cell proliferation, soft-agar colony formation and in vivo tumor formation in an orthotopic xenograft model. To evaluate the mechanism of Gα13 action, we performed RNA-sequencing analysis on these cell lines and found that loss of GNA13 results in the upregulation of MYC signaling pathways in ER+ breast cancer cells. Simultaneous silencing of MYC reversed the proliferative effect from the loss of GNA13, validating the role of MYC in Gα13 regulation of proliferation. Further, we found Gα13 regulates the expression of MYC, at both the transcript and protein level in an ERα dependent manner. Taken together, our study provides the first evidence for a tumor suppressive role for Gα13 in breast cancer cells and demonstrates for the first time the direct involvement of Gα13 in ER-dependent regulation of MYC signaling. With a few exceptions, elevated Gα13 levels are generally considered to be oncogenic, similar to Gα12. This study demonstrates an unexpected tumor suppressive role for Gα13 in ER+ breast cancer via regulation of MYC, suggesting that Gα13 can have subtype-dependent tumor suppressive roles in breast cancer.

Geriatric chronic recurrent multifocal osteomyelitis (CRMO) mimicking multifocal multiple myeloma: a first in an octogenarian.

Chronic recurrent multifocal osteomyelitis (CRMO), an autoinflammatory bone disorder characterized by non-bacterial osteomyelitis causing recurrent multifocal bone lesions, is a well-known, yet uncommon pediatric condition that rarely affects adults; to date, it has never been diagnosed over the age of 75. The following report will discuss the first octogenarian diagnosed with CRMO and therefore represents an exceptionally rare presentation of a rare disease. An 83-year-old woman presented with progressive right shoulder, forearm, and hip pain, with associated weight loss and global weakness, requiring a wheelchair for mobility. Imaging revealed a pathologic right ulna fracture in addition to lytic lesions of the right proximal humerus and proximal femur. The clinical picture was thus that of a patient with probable multiple myeloma versus metastatic disease. After an extensive workup, however, the lesions were not malignant; histologic findings were instead suggestive of chronic osteomyelitis with negative cultures. Given the multifocal nature of this condition, combined with a lack of clinical symptoms of infection, a diagnosis of CRMO was rendered. The patient underwent intramedullary nailing of the right femur and splinting of the ulna, with a subsequent remarkable recovery to painless ambulation, complete union of the right ulna fracture, and resolution of the lytic lesions without receiving any targeted medical treatment. This case highlights the importance of maintaining CRMO on the differential for multifocal skeletal lesions, regardless of age. Performing a thorough workup with necessary imaging, biopsy, and culture are critical to establishing this diagnosis, which can only made as a diagnosis of exclusion.

Sequencing analysis and efficient biodiesel production by lipase from Pseudomonas aeruginosa.

BACKGROUND: Recently, lipase processing for biodiesel production has shown a global increase as it is considered a potential alternative clean-fuel source. The current study's objective is to investigate of lipolytic activity of lipase produced from different strains of Pseudomonas aeruginosa (P. aeruginosa) in biodiesel production using edible plant oils. The goal is to develop an efficient and cost-effective method for producing inexpensive and environmentally friendly biodiesel. METHODS AND RESULTS: Four P. aeruginosa isolates were obtained from different environmental sources (soil), phenotypically identified, and it was confirmed by the PCR detection of the 16SrRNA gene. The isolated P. aeruginosa strains were screened for lipase production, and the recovered lipase was purified. Besides, the lipase (lip) gene was detected by PCR, and the purified PCR products were sequenced and analyzed. The production of biofuel was conducted using gas chromatography among tested oils. It was found that castor oil was the best one that enhances lipase production in-vitro.

The secrets of environmental Pseudomonas aeruginosa in slaughterhouses: Antibiogram profile, virulence, and antibiotic resistance genes.

Environmental pollution is a serious problem that can cause sicknesses, fatality, and biological contaminants such as bacteria, which can trigger allergic reactions and infectious illnesses. There is also evidence that environmental pollutants can have an impact on the gut microbiome and contribute to the development of various mental health and metabolic disorders. This study aimed to study the antibiotic resistance and virulence potential of environmental Pseudomonas aeruginosa (P. aeruginosa) isolates in slaughterhouses. A total of 100 samples were collected from different slaughterhouse tools. The samples were identified by cultural and biochemical tests and confirmed by the VITEK 2 system. P. aeruginosa isolates were further confirmed by CHROMagar™ Pseudomonas and genetically by rpsL gene analysis. Molecular screening of virulence genes (fimH, papC, lasB, rhlI, lasI, csgA, toxA, and hly) and antibiotic resistance genes (blaCTX-M, blaAmpC, blaSHV, blaNDM, IMP-1, aac(6')-Ib-, ant(4')IIb, mexY, TEM, tetA, and qnrB) by PCR and testing the antibiotic sensitivity, biofilm formation, and production of pigments, and hemolysin were carried out in all isolated strains. A total of 62 isolates were identified as P. aeruginosa. All P. aeruginosa isolates were multidrug-resistant and most of them have multiple resistant genes. blaCTX-M gene was detected in all strains; 23 (37.1%) strains have the ability for biofilm formation, 33 strains had virulence genes, and 26 isolates from them have more than one virulence genes. There should be probably 60 (96.8%) P. aeruginosa strains that produce pyocyanin pigment. Slaughterhouse tools are sources for multidrug-resistant and virulent pathogenic microorganisms which are a serious health problem. Low-hygienic slaughterhouses could be a reservoir for resistance and virulence genes which could then be transferred to other pathogens.

Association of consanguinity with neonatal asphyxia at birth: Evidence from Pakistan.

Consanguinity commonly known as inbreeding is a state of offspring borne to couple sharing same ancestors. It is a least researched non-obstetric determinant of adverse birth outcome in developing countries like Pakistan. This hospital based study was designed to investigate the association between consanguineous status and neonatal asphyxia measured measured as low APGAR scores after birth in 879 newborns.The data regarding consanguineous status was obtained retrospectively. Potential covariates were incorporated for finding confounding effects. Data was analyzed in SPSS version 26.0 as mean ± standard deviation, unadjusted & adjusted odds ratios by logistic regression at P-values ≤ 0.05 significance for associations. Over 36.1% newborns were consanguineous, delivered with APGAR < 6 at 1-minute compared to 5.2% born to non-consanguineous parents. Premature birth was the single most important factor associated with neonatal asphyxia and low APGAR at 1 & 5-minute after birth. After adjusting for confounding variables, first cousin couples' offsprings showed OR of 9.1 & 4.1 for APGAR score ≤ 6 at 1 & 5-minutes after birth, respectively (P < 0.001 & P =0.001). We conclude that consanguinity is a strong determinant for neonatal asphyxia reported as low APGAR scores in this population of new borns.

Anti-capsular activity of CuO nanoparticles against Acinetobacter baumannii produce efflux pump.

Copper oxide nanoparticles are modern kinds of antimicrobials, which may get a lot of interest in the clinical application. This study aimed to detect the anti-capsular activity of CuO nanoparticles against Acinetobacter baumannii produce efflux pump. Thirty-four different clinical A. baumannii isolates were collected and identified by the phenotypic and genetic methods by the recA gene as housekeeping. Antibiotic sensitivity and biofilm-forming ability, capsular formation were carried out. The effect of CuO nanoparticles on capsular isolates was detected, the synergistic effects of a combination CuO nanoparticles and gentamicin against A. baumannii were determined by micro broth checkerboard method, and the effect of CuO nanoparticles on the expression of ptk, espA and mexX genes was analyzed. Results demonstrated that CuO nanoparticles with gentamicin revealed a synergistic effect. Gene expression results show reducing the expression of these capsular genes by CuO nanoparticles is major conduct over reducing A. baumannii capsular action. Furthermore, results proved that there was a relationship between the capsule-forming ability and the absence of biofilm-forming ability. As bacterial isolates which were negative biofilm formation were positive in capsule formation and vice versa. In conclusion, CuO nanoparticles have the potential to be used as an anti-capsular agent against A. baumannii, and their combination with gentamicin can enhance their antimicrobial effect. The study also suggests that the absence of biofilm formation may be associated with the presence of capsule formation in A. baumannii. These findings provide a basis for further research on the use of CuO nanoparticles as a novel antimicrobial agent against A. baumannii and other bacterial pathogens, also to investigate the potential of CuO nanoparticles to inhibit the production of efflux pumps in A. baumannii, which are a major mechanism of antibiotic resistance.

Effect of calcined clay and marble dust powder as cementitious material on the mechanical properties and embodied carbon of high strength concrete by using RSM-based modelling.

In the last decade, there has been an increase in research on ecologically benign, cost-effective, and socially useful cement alternative materials for concrete. Alternatives involve industrial and agriculture waste, the potential advantages of which may be recognized by recycling, repurposing, and recreating techniques. Important energy reserves and a decrease in Portland cement (PC) consumption may be attained by using these wastes as supplementary and substitute ingredients, contributing to a reduction in carbon dioxide (CO2) production. Consequently, the incorporation of marble dust powder (MDP) and calcined clay (CC) as supplementary cementitious material (SCM) in high strength concrete may lower the environmental effect and reduce the amount of PC in mixes. This study is conducted on concrete containing 0%, 5%, 10%, 15%, and 20% of MDP and CC as cementitious materials alone and in combination. The main objectives of this investigations are to examine the effect of MDP and CC as cementitious materials on the flowability and mechanical characteristics of high strength concrete. In order to examine the ecological effect of CC and MDP, the eco-strength efficiency and embodied carbon were considered. In this context, there are so many trial mixes were performed on cubical specimens for achieving targeted compressive strength about 60 MPa after 28 days. After getting it, a total of 273 concrete specimens (cubes, cylinders, and prisms) were used to test the compressive, splitting tensile, and flexural strength of high strength concrete correspondingly. Moreover, when the amount of MDP and CC as SCM in the mixture grows, the workability of green concrete decreases. In addition, the compressive strength, flexural strength, and splitting tensile strength are increased by 6.38 MPa, 67.66 MPa, and 4.88 MPa, respectively, at 10% SCM (5% MDP and 5% CC) over a period of 28 days. In addition, using ANOVA, response prediction models were generated and confirmed at a 95% level of significance. The R2 values of the models varied from 96 to 99%. Furthermore, increasing the amount of CC and MDP as SCM in concrete also reduces the amount of carbon embedded in the material. It is recommended that the utilization of 10% SCM (5% MDP and 5% CC) in high strength concrete is providing optimum outcomes for construction industry in the field of Civil Engineering.

Postpartum depression and its clinico-social correlates - A community-based study in aligarh.

Context: Postpartum depression (PPD) is onset of depressive symptoms in postpartum period from 2 weeks to 1 year. It causes maternal morbidity and long-term negative effects on growth and development of infant and child. It is often unreported and underdiagnosed. Aims: (1) To estimate the prevalence of PPD, (2) To determine socio-demographic, clinical, and obstetric correlates of the same. Settings and Design: A cross-sectional study was done in urban and rural areas of District Aligarh. Methods: A total of 304 females between 6 weeks and 6 months' postpartum period giving consent were included in this study. Sociodemographic, obstetric, and clinico-social factors were recorded using predesigned, pretested questionnaire. Edinburgh Postnatal Depression Scale (EPDS) score ≥10 was used to screen for PPD and International Classification of Disease (ICD-10) criteria for confirmation. Statistical Analysis Used: Correlates of PPD were determined using logistic regression analysis. Results: The prevalence of PPD was 9.5% using EPDS and was confirmed by ICD-10 criteria. History of abortion (adjusted odds ratio [AOR]: 6.0, 95% Confidence Interval [CI] 2.2-16.5), poor relationship with in-laws (AOR: 5.1; 95% CI 1.3-20.5), marital conflict (AOR: 13.3; 95% CI 2.2-77.6), and substance abuse in husband (AOR: 3.1; 95% CI 1.1-9.0) were found to be significant correlates for PPD. Conclusions: About one in every 10 postpartum females suffered from depression but did not seek health care for the same. Women facing social pathologies such as substance abuse in husband, marital conflict, and poor relationship with in-laws are more at risk of PPD. Screening for PPD should be included in the maternal and child health care programs to ensure early diagnosis and treatment.

The emerging roles of Gα12/13 proteins on the hallmarks of cancer in solid tumors.

G12 proteins comprise a subfamily of G-alpha subunits of heterotrimeric GTP-binding proteins (G proteins) that link specific cell surface G protein-coupled receptors (GPCRs) to downstream signaling molecules and play important roles in human physiology. The G12 subfamily contains two family members: Gα12 and Gα13 (encoded by the GNA12 and GNA13 genes, respectively) and, as with all G proteins, their activity is regulated by their ability to bind to guanine nucleotides. Increased expression of both Gα12 and Gα13, and their enhanced signaling, has been associated with tumorigenesis and tumor progression of multiple cancer types over the past decade. Despite these strong associations, Gα12/13 proteins are underappreciated in the field of cancer. As our understanding of G protein involvement in oncogenic signaling has evolved, it has become clear that Gα12/13 signaling is pleotropic and activates specific downstream effectors in different tumor types. Further, the expression of Gα12/13 proteins is regulated through a series of transcriptional and post-transcriptional mechanisms, several of which are frequently deregulated in cancer. With the ever-increasing understanding of tumorigenic processes driven by Gα12/13 proteins, it is becoming clear that targeting Gα12/13 signaling in a context-specific manner could provide a new strategy to improve therapeutic outcomes in a number of solid tumors. In this review, we detail how Gα12/13 proteins, which were first discovered as proto-oncogenes, are now known to drive several "classical" hallmarks, and also play important roles in the "emerging" hallmarks, of cancer.

Antibiofilm and antivirulence potential of silver nanoparticles against multidrug-resistant Acinetobacter baumannii.

We aimed to isolate Acinetobacter baumannii (A. baumannii) from wound infections, determine their resistance and virulence profile, and assess the impact of Silver nanoparticles (AgNPs) on the bacterial growth, virulence and biofilm-related gene expression. AgNPs were synthesized and characterized using TEM, XRD and FTIR spectroscopy. A. baumannii (n = 200) were isolated and identified. Resistance pattern was determined and virulence genes (afa/draBC, cnf1, cnf2, csgA, cvaC, fimH, fyuA, ibeA, iutA, kpsMT II, PAI, papC, PapG II, III, sfa/focDE and traT) were screened using PCR. Biofilm formation was evaluated using Microtiter plate method. Then, the antimicrobial activity of AgNPs was evaluated by the well-diffusion method, growth kinetics and MIC determination. Inhibition of biofilm formation and the ability to disperse biofilms in exposure to AgNPs were evaluated. The effect of AgNPs on the expression of virulence and biofilm-related genes (bap, OmpA, abaI, csuA/B, A1S_2091, A1S_1510, A1S_0690, A1S_0114) were estimated using QRT-PCR. In vitro infection model for analyzing the antibacterial activity of AgNPs was done using a co-culture infection model of A. baumannii with human fibroblast skin cell line HFF-1 or Vero cell lines. A. baumannii had high level of resistance to antibiotics. Most of the isolates harbored the fimH, afa/draBC, cnf1, csgA and cnf2, and the majority of A. baumannii produced strong biofilms. AgNPs inhibited the growth of A. baumannii efficiently with MIC ranging from 4 to 25 µg/ml. A. baumannii showed a reduced growth rate in the presence of AgNPs. The inhibitory activity and the anti-biofilm activity of AgNPs were more pronounced against the weak biofilm producers. Moreover, AgNPs decreased the expression of kpsMII , afa/draBC,bap, OmpA, and csuA/B genes. The in vitro infection model revealed a significant antibacterial activity of AgNPs against extracellular and intracellular A. baumannii. AgNPs highly interrupted bacterial multiplication and biofilm formation. AgNPs downregulated the transcription level of important virulence and biofilm-related genes. Our findings provide an additional step towards understanding the mechanisms by which sliver nanoparticles interfere with the microbial spread and persistence.

A Label-Free DNA-Immunosensor Based on Aminated rGO Electrode for the Quantification of DNA Methylation.

In this work, we developed a sandwich DNA-immunosensor for quantification of the methylated tumour suppressor gene O-6-methylguanine-DNA methyltransferase (MGMT), which is a potential biomarker for brain tumours and breast cancer. The biosensor is based on aminated reduced graphene oxide electrode, which is achieved by ammonium hydroxide chemisorption and anti-5-methylcytosine (anti-5mC) as a methylation bioreceptor. The target single-strand (ss) MGMT oligonucleotide is first recognised by its hybridisation with complementary DNA to form double-stranded (ds) MGMT, which is then captured by anti-5mC on the electrode surface due to the presence of methylation. Raman spectroscopy, X-ray photoelectron spectroscopy (XPS) and Scanning electron microscopy (SEM) techniques were used to characterise the electrode surface. Cyclic voltammetry (CV) and differential pulse voltammetry (DPV) techniques were used for electrochemical measurements. Under optimised conditions, the proposed biosensor is able to quantify a linear range of concentrations of the MGMT gene from 50 fM to 100 pM with a limit of detection (LOD) of 12 fM. The sandwich design facilitates the simultaneous recognition and quantification of DNA methylation, and the amination significantly improves the sensitivity of the biosensor. This biosensor is label-, bisulfite- and PCR-free and has a simple design for cost-efficient production. It can also be tailor-made to detect other methylated genes, which makes it a promising detection platform for DNA methylation-related disease diagnosis and prognosis.

Biological assisted organic sulfur removal from low rank indigenous coal using airlift bioreactor.

Combustion of coal create many harmful gases which effect on human health as well as on environment. The sulfur in coal limits its own use, and bio-desulfurization (BDS) shows enormous development potential and the prospects for the application of coal desulfurization. Present study highlights the bioprocess strategies for reduction of sulfur content from coal before combustion. The bioprocess involved the use of Airlift Bioreactor along with Rhodococcus sp. ATCC55309 as biocatalyst. Different nutritional and operational parameters involved to promote sulfur reduction at maximum level. The parameters were investigated are different carbon source, temperature, pH, Agitation speed, and pulp density. The impact of these parameters shows that sulfur removal can be enhanced though optimized conditions. The amount of total sulfur and organic sulfur present in coal were reduced by 33 ± 1.7% and 71 ± 1.5%, respectively, compared to untreated coal at controlled condition of various parameters are 20% (w/v) pulp density, 30 °C, 170 rpm, glucose as carbon source and pH 7. Whereas organic sulfur degrades from coal using Rhodococcus sp. ATCC55309 about 0.36 mM DBT (Di-benzothiophene) within 8 days via 4S-pathway. The maximum conversion of DBT compound into 2-HBP(2-hydroxybiphenyl) by utilizing 30 °C, 170 rpm, 20 pulp density and glucose as carbon source.

Advanced microbial fuel cell for waste water treatment-a review.

Petroleum, coal, and natural gas reservoir were depleting continuously due to an increase in industrialization, which enforced study to identify alternative sources. The next option is the renewable resources which are most important for energy purpose coupled with environmental problem reduction. Microbial fuel cells (MFCs) have become a promising approach to generate cleaner and more sustainable electrical energy. The involvement of various disciplines had been contributing to enhancing the performance of the MFCs. This review covers the performance of MFC along with different wastewater as a substrate in terms of treatment efficiencies as well as for energy generation. Apart from this, effect of various parameters and use of different nanomaterials for performance of MFC were also studied. From the current study, it proves that the use of microbial fuel cell along with the use of nanomaterials could be the waste and energy-related problem-solving approach. MFC could be better in performances based on optimized process parameters for handling any wastewater from industrial process.

Correction to: A label-free biosensor based on graphene and reduced graphene oxide dual-layer for electrochemical determination of beta-amyloid biomarkers.

The published version of this article, unfortunately, contains errors. Corrections in references were incorrectly carried out. Also, the reduction of graphene oxide was carried out between the potential of -1.5 and 0.5 V, instead of 0.5 and 1.5 V.

A label-free biosensor based on graphene and reduced graphene oxide dual-layer for electrochemical determination of beta-amyloid biomarkers.

A label-free biosensor is developed for the determination of plasma-based Aß1-42 biomarker in Alzheimer's disease (AD). The platform is based on highly conductive dual-layer of graphene and electrochemically reduced graphene oxide (rGO). The modification of dual-layer with 1-pyrenebutyric acid N-hydroxysuccinimide ester (Pyr-NHS) is achieved to facilitate immobilization of H31L21 antibody. The effect of these modifications were studied with morphological, spectral and electrochemical techniques. The response of the biosensor was evaluated using differential pulse voltammetry (DPV). The data was acquired at a working potential of ~ 180 mV and a scan rate of 50 mV s-1. A low limit of detection (LOD) of 2.398 pM is achieved over a wide linear range from 11 pM to 55 nM. The biosensor exhibits excellent specificity over Aß1-40 and ApoE ε4 interfering species. Thus, it provides a viable tool for electrochemical determination of Aß1-42. Spiked human and mice plasmas were used for the successful validation of the sensing platform in bio-fluidic samples. The results obtained from mice plasma analysis concurred with the immunohistochemistry (IHC) and magnetic resonance imaging (MRI) data obtained from brain analysis. Graphical abstract Schematic representation of the electrochemical system proposed for Aß1-42 determination: (a) modification of graphene screen-printed electrode (SPE) with monolayer graphene oxide (GO) followed by its electrochemical reduction generating graphene/reduced graphene oxide (rGO) dual-layer (b), modification of dual-layer with linker (c), Aß1-42 antibody (H31L21) (d), bovine serum albumin (BSA) (e) and Aß1-42 peptide (f).

Effect of antidepressants on various periodontal parameters: A case-control study.

BACKGROUND: Various medications are used in the treatment of chronic systemic diseases that affect the periodontium. Antidepressants in mentally depressed patients are prescribed for a long term, but their effect on the periodontium has not been studied adequately. A case-control study was conducted to know the effect of two commonly prescribed antidepressants - venlafaxine (serotonin-norepinephrine reuptake inhibitor [SNRI]) and fluoxetine (selective serotonin reuptake inhibitor [SSRI]). These drugs have been shown to possess anti-inflammatory properties but do not protect the periodontium from insults caused by these medications, which are significantly associated with the presence of destruction of the periodontium. The aim of this study was to clinically evaluate the effect of antidepressants on various periodontal parameters. MATERIALS AND METHODS: The study sample consisted of 182 depressed patients divided into three study groups: Group I - the control group diagnosed as depressed on the first visit, Group II - depressed patients taking fluoxetine 20 mg/day, and Group III - patients taking venlafaxine 75 mg/day. Patients in Groups II and III were on isolated antidepressant medication at least for a period of 3 or more months. Mental depression in patients was assessed with the Patient Health Questionnaire-based Hamilton Depression Rating Scale with scoring of ≤16. All the depressed patients were assessed for periodontal health on the basis of the clinical periodontal parameters. RESULTS: The commonly prescribed antidepressants such as fluoxetine and venlafaxine do not protect the periodontium from destruction in spite of possessing anti-inflammatory properties; therefore, these drugs may be considered as a risk factor for periodontal health. The comparative periodontal indices on nonusers of antidepressants or control group (Group I), users of SSRI (fluoxetine) (Group II), and users of antidepressants-SNRI (venlafaxine) (Group III) showed increased periodontal parameters, especially debris index (DI), calculus index (CI), gingival index (GI), periodontal pocket depth (PD), and loss in clinical attachment level. There was no significant difference for CI and GI, probing PD, and clinical attachment levels except DI which was significantly different (P ≤ 0.001). CONCLUSION: The depressed patients receiving fluoxetine or venlafaxine should be regularly evaluated for periodontal health status as these drugs are risk factors for normal periodontal tissues. Further, these medications did not protect the periodontium from periodontal inflammation, although possessing anti-inflammatory properties.

Gα-13 induces CXC motif chemokine ligand 5 expression in prostate cancer cells by transactivating NF-κB.

GNA13, the α subunit of a heterotrimeric G protein, mediates signaling through G-protein-coupled receptors (GPCRs). GNA13 is up-regulated in many solid tumors, including prostate cancer, where it contributes to tumor initiation, drug resistance, and metastasis. To better understand how GNA13 contributes to tumorigenesis and tumor progression, we compared the entire transcriptome of PC3 prostate cancer cells with those cells in which GNA13 expression had been silenced. This analysis revealed that GNA13 levels affected multiple CXC-family chemokines. Further investigation in three different prostate cancer cell lines singled out pro-tumorigenic CXC motif chemokine ligand 5 (CXCL5) as a target of GNA13 signaling. Elevation of GNA13 levels consistently induced CXCL5 RNA and protein expression in all three cell lines. Analysis of the CXCL5 promoter revealed that the -505/+62 region was both highly active and influenced by GNA13, and a single NF-κB site within this region of the promoter was critical for GNA13-dependent promoter activity. ChIP experiments revealed that, upon induction of GNA13 expression, occupancy at the CXCL5 promoter was significantly enriched for the p65 component of NF-κB. GNA13 knockdown suppressed both p65 phosphorylation and the activity of a specific NF-κB reporter, and p65 silencing impaired the GNA13-enhanced expression of CXCL5. Finally, blockade of Rho GTPase activity eliminated the impact of GNA13 on NF-κB transcriptional activity and CXCL5 expression. Together, these findings suggest that GNA13 drives CXCL5 expression by transactivating NF-κB in a Rho-dependent manner in prostate cancer cells.

Thymidylate synthase maintains the de-differentiated state of triple negative breast cancers.

Cancer cells frequently boost nucleotide metabolism (NM) to support their increased proliferation, but the consequences of elevated NM on tumor de-differentiation are mostly unexplored. Here, we identified a role for thymidylate synthase (TS), a NM enzyme and established drug target, in cancer cell de-differentiation and investigated its clinical significance in breast cancer (BC). In vitro, TS knockdown increased the population of CD24+ differentiated cells, and attenuated migration and sphere-formation. RNA-seq profiling indicated repression of epithelial-to-mesenchymal transition (EMT) signature genes upon TS knockdown, and TS-deficient cells showed an increased ability to invade and metastasize in vivo, consistent with the occurrence of a partial EMT phenotype. Mechanistically, TS enzymatic activity was found essential for maintenance of the EMT/stem-like state by fueling a dihydropyrimidine dehydrogenase-dependent pyrimidine catabolism. In patient tissues, TS levels were found significantly higher in poorly differentiated and in triple negative BC, and strongly correlated with worse prognosis. The present study provides the rationale to study in-depth the role of NM at the crossroads of proliferation and differentiation, and depicts new avenues for the design of novel drug combinations for the treatment of BC.

Polyol Pathway Links Glucose Metabolism to the Aggressiveness of Cancer Cells.

Cancer cells alter their metabolism to support their malignant properties. In this study, we report that the glucose-transforming polyol pathway (PP) gene aldo-keto-reductase-1-member-B1 (AKR1B1) strongly correlates with epithelial-to-mesenchymal transition (EMT). This association was confirmed in samples from lung cancer patients and from an EMT-driven colon cancer mouse model with p53 deletion. In vitro, mesenchymal-like cancer cells showed increased AKR1B1 levels, and AKR1B1 knockdown was sufficient to revert EMT. An equivalent level of EMT suppression was measured by targeting the downstream enzyme sorbitol-dehydrogenase (SORD), further pointing at the involvement of the PP. Comparative RNA sequencing confirmed a profound alteration of EMT in PP-deficient cells, revealing a strong repression of TGFß signature genes. Excess glucose was found to promote EMT through autocrine TGFß stimulation, while PP-deficient cells were refractory to glucose-induced EMT. These data show that PP represents a molecular link between glucose metabolism, cancer differentiation, and aggressiveness, and may serve as a novel therapeutic target.Significance: A glucose-transforming pathway in TGFß-driven epithelial-to-mesenchymal transition provides novel mechanistic insights into the metabolic control of cancer differentiation. Cancer Res; 78(7); 1604-18. ©2018 AACR.