Metallointercalator [Ru(dppz)2(PIP)]2+ Renders BRCA Wild-Type Triple-Negative Breast Cancer Cells Hypersensitive to PARP Inhibition

There is a need to improve and extend the use of clinically-approved poly(ADP-ribose) polymerase (PARP) inhibitors (PARPi), including for BRCA wild-type triple-negative breast cancer (TNBC). The demonstration that ruthenium(II) polypyridyl complex (RPC) metallo-intercalators can rapidly stall DNA replication fork progression provides the rationale for their combination alongside DNA damage response (DDR) inhibitors to achieve synergism in cancer cells. The aim of the present study was to evaluate use of the multi-intercalator [Ru(dppz)2(PIP)]2+ (dppz = dipyrido[3,2-a:2′,3′-c]phenazine, PIP = (2-(phenyl)imidazo[4,5-f][1,10]phenanthroline, Ru-PIP) alongside the PARP inhibitors (PARPi) olaparib and NU1025. Cell proliferation and clonogenic survival assays indicated a synergistic relationship between Ru-PIP and olaparib in MDA-MB-231 TNBC and MCF7 human breast cancer cells. Strikingly, low dose Ru-PIP renders both cell lines hypersensitive to olaparib, with a 300-fold increase in olaparib potency in TNBC; the largest non-genetic PARPi enhancement effect described to date. Negligible impact on the viability of normal human fibroblasts was observed for any combination tested. Increased levels of DNA double-strand break (DSB) damage and olaparib abrogation of Ru-PIP activated pChk1 signalling is consistent with PARPi-facilitated collapse of Ru-PIP-associated stalled replication forks. This results in enhanced G2/M cell-cycle arrest, apoptosis and decreased cell motility for the combination treatment compared to single-agent conditions. This work establishes that an RPC metallo-intercalator can be combined with PARPi for potent synergy in BRCA-proficient breast cancer cells, including TNBC

Pengaruh Water Hammer Terhadap Pipa dan Check Valve Pada Discharge Pump TPL 1-PM-002C (Studi Kasus PT. Pertamina TBBM Tuban)

In the pump discharge pipeline of TPL 1-PM-002C suffered disk damage at the check valve which serves to prevent backflow to the pump resulting in a considerable passing pressure running through the 1-8 "-PKS-CM-1019 pipeline even though the line has closed and diverted to another pipe line so that a major effect on the fuel distribution system. The simulation results show that the largest pressure increase due to a water hammer of 130 Bar from the pressure of 47 Bar and Pressure Relief Valve operation can reduce the pressure increase greater than Bladder Accumulator design to 3, which is equal to 60,5 bar while Bladder Accumulator design 3 reducing the maximum pressure increase of 76.4 Bars. So it can be concluded that the design using Pressure Relief Valve is a design with optimum operational results to overcome the influence of water hammer against pipes and check valve on pipeline 1-8 "-PKS-CM-1019

Investigating the biological properties of carbohydrate derived fulvic acid (CHD-FA) as a potential novel therapy for the management of oral biofilm infections.

Background: A number of oral diseases, including periodontitis, derive from microbial biofilms and are associated with increased antimicrobial resistance. Despite the widespread use of mouthwashes being used as adjunctive measures to control these biofilms, their prolonged use is not recommended due to various side effects. Therefore, alternative broad-spectrum antimicrobials that minimise these effects are highly sought after. Carbohydrate derived fulvic acid (CHD-FA) is an organic acid which has previously demonstrated to be microbiocidal against Candida albicans biofilms, therefore, the aims of this study were to evaluate the antibacterial activity of CHD-FA against orally derived biofilms and to investigate adjunctive biological effects.<p></p> Methods: Minimum inhibitory concentrations were evaluated for CHD-FA and chlorhexidine (CHX) against a range of oral bacteria using standardised microdilution testing for planktonic and sessile. Scanning electron microscopy was also employed to visualise changes in oral biofilms after antimicrobial treatment. Cytotoxicity of these compounds was assessed against oral epithelial cells, and the effect of CHD-FA on host inflammatory markers was assessed by measuring mRNA and protein expression.<p></p> Results: CHD-FA was highly active against all of the oral bacteria tested, including Porphyromonas gingivalis, with a sessile minimum inhibitory concentration of 0.5%. This concentration was shown to kill multi-species biofilms by approximately 90%, levels comparable to that of chlorhexidine (CHX). In a mammalian cell culture model, pretreatment of epithelial cells with buffered CHD-FA was shown to significantly down-regulate key inflammatory mediators, including interleukin-8 (IL-8), after stimulation with a multi-species biofilm.<p></p> Conclusions: Overall, CHD-FA was shown to possess broad-spectrum antibacterial activity, with a supplementary function of being able to down-regulate inflammation. These properties offer an attractive spectrum of function from a naturally derived compound, which could be used as an alternative topical treatment strategy for oral biofilm diseases. Further studies in vitro and in vivo are required to determine the precise mechanism by which CHD-FA modulates the host immune response.<p></p&gt

Restricted Genetic Diversity of HIV-1 Subtype C Envelope Glycoprotein from Perinatally Infected Zambian Infants

Background: Mother-to-child transmission of HIV-1 remains a significant problem in the resource-constrained settings where anti-retroviral therapy is still not widely available. Understanding the earliest events during HIV-1 transmission and characterizing the newly transmitted or founder virus is central to intervention efforts. In this study, we analyzed the viral env quasispecies of six mother-infant transmission pairs (MIPs) and characterized the genetic features of envelope glycoprotein that could influence HIV-1 subtype C perinatal transmission. Methodology and Findings: The V1-V5 region of env was amplified from 6 MIPs baseline samples and 334 DNA sequences in total were analyzed. A comparison of the viral population derived from the mother and infant revealed a severe genetic bottleneck occurring during perinatal transmission, which was characterized by low sequence diversity in the infant. Phylogenetic analysis indicates that most likely in all our infant subjects a single founder virus was responsible for establishing infection. Furthermore, the newly transmitted viruses from the infant had significantly fewer potential N-linked glycosylation sites in Env V1-V5 region and showed a propensity to encode shorter variable loops compared to the nontransmitted viruses. In addition, a similar intensity of selection was seen between mothers and infants with a higher rate of synonymous (dS) compared to nonsynonymous (dN) substitutions evident (dN/dS\u3c1). Conclusions: Our results indicate that a strong genetic bottleneck occurs during perinatal transmission of HIV-1 subtype C. This is evident through population diversity and phylogenetic patterns where a single viral variant appears to be responsible for infection in the infants. As a result the newly transmitted viruses are less diverse and harbored significantly less glycosylated envelope. This suggests that viruses with the restricted glycosylation in envelope glycoprotein appeared to be preferentially transmitted during HIV-1 subtype C perinatal transmission. In addition, our findings also indicated that purifying selection appears to predominate in shaping the early intrahost evolution of HIV-1 subtype C envelope sequences

How does gender influence the recognition of cardiovascular risk and adherence to self-care recommendations? : a study in polish primary care

Background: Studies have shown a correlation between gender and an ability to change lifestyle to reduce the risk of disease. However, the results of these studies are ambiguous, especially where a healthy lifestyle is concerned. Additionally, health behaviors are strongly modified by culture and the environment. Psychological factors also substantially affect engagement with disease-related lifestyle interventions. This study aimed to examine whether there are differences between men and women in the frequency of health care behavior for the purpose of reducing cardiovascular risk (CVR), as well as cognitive appraisal of this type of risk. We also aimed to identify the psychological predictors of engaging in recommended behavior for reducing the risk of cardiovascular disease after providing information about this risk in men and women. Methods: A total of 134 consecutive eligible patients in a family practice entered a longitudinal study. At initial consultation, the individual’s CVR and associated health burden was examined, and preventive measures were recommended by the physician. Self-care behavior, cognitive appraisal of risk, and coping styles were then assessed using psychological questionnaires. Six months after the initial data collection, the frequency of subjects’ self-care behavior was examined. Results: We found an increase in health care behavior after providing information regarding the rate of CVR in both sexes; this increase was greater for women than for men. Women followed self-care guidelines more often than men, particularly for preventive measures and dietary advice. Women were more inclined to recognize their CVR as a challenge. Coping style, cognitive appraisal, age, level of health behaviors at baseline and CVR values accounted for 48% of the variance in adherence to self-care guidelines in women and it was 52% in men. In women, total risk of CVD values were most important, while in men, cognitive appraisal of harm/loss was most important. Conclusions: Different predictors of acquisition of health behavior are encountered in men and women. Our results suggest that gender-adjusted motivation models influencing the recognition process need to be considered to optimize compliance in patients with CVR

TFOS Lifestyle: Impact of nutrition on the ocular surface: TFOS Lifestyle Workshop: Nutrition report

Nutrients, required by human bodies to perform life-sustaining functions, are obtained from the diet. They are broadly classified into macronutrients (carbohydrates, lipids, and proteins), micronutrients (vitamins and minerals) and water. All nutrients serve as a source of energy, provide structural support to the body and/or regulate the chemical processes of the body. Food and drinks also consist of non-nutrients that may be beneficial (e.g., antioxidants) or harmful (e.g., dyes or preservatives added to processed foods) to the body and the ocular surface. There is also a complex interplay between systemic disorders and an individual's nutritional status. Changes in the gut microbiome may lead to alterations at the ocular surface. Poor nutrition may exacerbate select systemic conditions. Similarly, certain systemic conditions may affect the uptake, processing and distribution of nutrients by the body. These disorders may lead to deficiencies in micro- and macro-nutrients that are important in maintaining ocular surface health. Medications used to treat these conditions may also cause ocular surface changes. The prevalence of nutrition-related chronic diseases is climbing worldwide. This report sought to review the evidence supporting the impact of nutrition on the ocular surface, either directly or as a consequence of the chronic diseases that result. To address a key question, a systematic review investigated the effects of intentional food restriction on ocular surface health; of the 25 included studies, most investigated Ramadan fasting (56%), followed by bariatric surgery (16%), anorexia nervosa (16%), but none were judged to be of high quality, with no randomized-controlled trials

Elbow medial collateral ligament injuries

Elbow medial collateral ligament sprain occurs when the elbow is subjected to a valgus force exceeding the tensile properties of the medial collateral ligament (MCL). This is an injury seen more often in throwing athletes. Understanding the differential diagnosis of medial elbow pain is paramount to diagnose MCL injury as well as addressing other medial elbow pathology. A natural evolution regarding MCL injury has occurred over the past 20 years, with modifications of the original surgical procedure, specificity and sensitivity analysis of imaging modalities, and physical exam maneuvers to diagnose MCL pathology. In order for the MCL literature to advance further, more biomechanical and long-term clinical outcome data for the respective surgical modifications are needed. This review describes MCL injury pathophysiology, patient evaluation, reconstruction indications/contraindications, and current and evolving surgical techniques

Exploring novel correlations in trilepton channels at the LHC for the minimal supersymmetric inverse seesaw model

We investigate signatures of the minimal supersymmetric inverse seesaw model at the large hadron collider (LHC) with three isolated leptons and large missing energy (3\ell + \mET or 2\ell + 1\tau + \mET, with \ell=e,\mu) in the final state. This signal has its origin in the decay of chargino-neutralino (\chpm1\ntrl2) pair, produced in pp collisions. The two body decays of the lighter chargino into a charged lepton and a singlet sneutrino has a characteristic decay pattern which is correlated with the observed large atmospheric neutrino mixing angle. This correlation is potentially observable at the LHC by looking at the ratios of cross sections of the trilepton + \mET channels in certain flavour specific modes. We show that even after considering possible leading standard model backgrounds these final states can lead to reasonable discovery significance at the LHC with both 7 TeV and 14 TeV center-of-mass energy.Comment: 28 pages, 9 .eps figures. 3 new figures and discussions on LHC observables added, minor modifications in text and in the abstract, 23 new references added, matches with the published version in JHE

The effect of Piper betle on wound healing in male Sprague Dawley rats

Piper betle (PB) leaves have been traditionally used in many Asian countries for the healing of wounds and other ailments. The aim of this study was to examine the wound healing effect of PB on skin injury-inflicted Sprague-Dawley rats. Eighteen male Sprague-Dawley rats were inflicted with wounds and then divided into three groups consisting of a control (normal wound healing without dressing), saline (wound healing aided by gauze soaked in saline) and PB (gauze impregnated with PB paste) dressings. Wounds were created on the back of rats with 6-mm sterilized punch biopsy needle. Wounds were examined on days 3, 5, 7, 9, 11 and 13 for dryness, exudation, and scar formation. Rats were sacrificed on day 14 and the granulation tissue formed on the wound was then excised for histological examination using Hematoxylin and Eosin staining. The formation of granulation tissue in rats treated with PB showed higher progress to wound closure with shorter days (on day 3) compared to the control and saline group (on day 5). PB dressing minimized the formation of scar tissue significantly (p<0.05) compared to the control and saline groups. In conclusion, our results suggest that PB has good wound healing effect with less scarring and perhaps it can be used to treat wound complementary to the present method

LHC and lepton flavour violation phenomenology of a left-right extension of the MSSM

We study the phenomenology of a supersymmetric left-right model, assuming minimal supergravity boundary conditions. Both left-right and (B-L) symmetries are broken at an energy scale close to, but significantly below the GUT scale. Neutrino data is explained via a seesaw mechanism. We calculate the RGEs for superpotential and soft parameters complete at 2-loop order. At low energies lepton flavour violation (LFV) and small, but potentially measurable mass splittings in the charged scalar lepton sector appear, due to the RGE running. Different from the supersymmetric 'pure seesaw' models, both, LFV and slepton mass splittings, occur not only in the left- but also in the right slepton sector. Especially, ratios of LFV slepton decays, such as Br(${\tilde\tau}_R \to \mu \chi^0_1$)/Br(${\tilde\tau}_L \to \mu \chi^0_1$) are sensitive to the ratio of (B-L) and left-right symmetry breaking scales. Also the model predicts a polarization asymmetry of the outgoing positrons in the decay $\mu^+ \to e^+ \gamma$, A ~ [0,1], which differs from the pure seesaw 'prediction' A=1$. Observation of any of these signals allows to distinguish this model from any of the three standard, pure (mSugra) seesaw setups.Comment: 43 pages, 17 figure