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The ability to restrict gene expression to a relevant bacterial species in a complex microbiome is an unsolved problem. In the context of the human microbiome, one desirable target metabolic activity are glucuronide-utilization enzymes (GUS) that are implicated in the toxic re-activation of glucuronidated compounds in the human gastrointestinal (GI) tract, including the chemotherapeutic drug irinotecan. Here, we take advantage of the variable distribution of GUS enzymes in bacteria as a means to distinguish between bacteria with GUS activity, and re-purpose the glucuronide-responsive GusR transcription factor as a biosensor to regulate dCas9 expression in response to glucuronide inducers. We fused the Escherichia coli gusA regulatory region to the dCas9 gene to create pGreg-dCas9, and showed that dCas9 expression is induced by glucuronides, but not other carbon sources. When conjugated from E. coli to Gammaproteobacteria derived from human stool, dCas9 expression from pGreg-dCas9 was restricted to GUS-positive bacteria. dCas9-sgRNAs targeted to gusA specifically down-regulated gus operon transcription in Gammaproteobacteria, with a resulting ∼100-fold decrease in GusA activity. Our data outline a general strategy to re-purpose bacterial transcription factors responsive to exogenous metabolites for precise ligand-dependent expression of genetic tools such as dCas9 in diverse bacterial species.

Funding Acknowledgements Type of funding sources: None. Background Heart failure (HF) is the pandemic of our century and an estimated 64.3 million people are living with HF worldwide. New therapies alongside the old ones have been recently introduced in clinical practice with good results but the prognosis for a high percentage of patients remains poor with a high mortality rate and markedly reduced functional status. Purpose This study aims to investigate through two surveys what physicians think are the current needs in HF management to gain insight into the epidemiology and characteristics of patients followed by Italian HF outpatient clinics. In particular, we evaluated the gap that Cardiac Contractility Modulation (CCM) could fill in HF management in a real-world scenario. Methods a 20-question survey on HF management in different scenarios addressed to all physicians operating in Italian centers involved in HF care was published on the website Cardioinfo. A second survey was sent to Italian high-volume referral outpatient HF clinics. The participating centers were asked to collect the number of patients admitted during 4 weeks and to fill out a 19 items survey regarding some characteristics of these patients. Results A total of 105 physicians (77% cardiologists) and 14 high-volume referral outpatient HF clinics took part in the surveys. Despite regular clinical follow-up at 3-6 months in 94% of cases, the currently available medical therapy is considered insufficient in stabilizing HF patients in 30% of cases. 23% of physicians perceive to have a lack of treatment options in symptomatic patients with reduced ejection fraction and this percentage rises to 66% in patients without reduced ejection fraction (Figure 1). Cardiac contractility modulation is considered a valid option by 15% of physicians. According to Food and Drug Administration criteria, in the cohort of patients referred to HF clinics around 3% of patients are suitable for CCM implantation (2 patients a month per heart failure outpatient clinic), but considering additional selection criteria the percentage of patients eligible may increase to 5-6%. Conclusions The surveys confirm the significant attention paid to HF in Italian hospitals, however the lack of therapeutic options for a non-negligible number of patients, who are clinically evaluated regularly, but without associated substantial changes in therapy, leads to frustration for the patient and the physician, and an increase in costs for the health care system. A relatively small percentage of the total HF population fulfills the indication for immediate CCM treatment. Nevertheless, considering the size of the HF population, CCM, reducing hospitalizations, improving functional capacity and QoL may be of key importance for many HF patients, especially the elderly.

This paper examines infrared spectroscopic effects for the standoff detection of an explosive material, hexahydro-1,3,5-trinitro-1,3,5-triazine (RDX), inkjet printed on an aluminum surface. Results of a spectroscopic study are described, using multiple optical setups. These setups were selected to explore how variations in the angles of incidence and collection from the surface of the material result in corresponding variations in the spectral signatures. The goal of these studies is to provide an understanding of these spectral changes since it affects standoff detection of hazardous materials on a reflective substrate. We demonstrate that variations in spectral effects are dependent on the relative surface concentration of the deposited RDX. We also show that it is reasonable to use spectroscopic data collected in a standard laboratory infrared spectrometer outfitted with a variable angle reflectometer set at 0° as reference spectra for data collected in a standoff configuration. These results are important to provide a systematic approach to understanding infrared (IR) spectra collection using standoff systems in the field, and to allow for comparison between such data, and data collected in the laboratory. Although the precise results are constrained to a specific material system (thin layers on a reflective substrate), the approach and general discussion provided are applicable to a broad range of IR standoff sensing techniques and applications.

North Carolina is the largest producer of sweetpotato (Ipomoea batatus L.) in the United States but only a small percentage of total production is organic. Transition to organic sweetpotato production has been limited, in part due to a lack of effective non-chemical strategies to control wireworms (Coleoptera: Elateridae). To help bridge this knowledge gap, this study focused on documenting the relationship between wireworm damage to sweetpotato roots and the use of cover crops, a common way to maintain soil health in organic production. This study also tested a wireworm-resistant variety (Monaco) against the widely cultivated susceptible variety (Covington). Two different field studies were used to test the interaction between cover crops and insect-resistant sweetpotato varieties. We first examined a reduced-till cover crop system where cover crop residue remained on the soil surface when transplanting sweetpotato. The following year, we tested a fully incorporated cover crop system with spring termination and intensive tillage before sweetpotato transplanting. To complement these field studies, a greenhouse experiment was conducted to compare the efficacy of the wireworm-resistant variety with two susceptible sweetpotato varieties. Results show that varietal resistance had a strong effect on the amount of wireworm damage observed, with susceptible sweetpotato having more direct wireworm damage than the resistant variety. The effect of the cover crop was not found to be significant in any trial. This study provides important context about the role of varietal resistance in organic production and relatively low risk of cover crop use.

Melanotus communis Gyllenhal (Coleoptera: Elateridae) larvae are a common soil-dwelling pest of many crops, including sweet potato, grains, and tobacco. Although many studies have focused on the larval stage of this pest, the seasonal activity and ecology of the adults (click beetles) are not well understood. The overarching goal of this study was to relate M. communis adult activity to host crops in the North Carolina row-crop agroecosystem. To do this, we conducted a two-year study documenting male M. communis activity, using a recently identified sex attractant pheromone, 13-tetradecenyl acetate. This project was divided into two parts: 1) a pheromone assessment study testing the efficacy and specificity of 13-tetradecenyl acetate, and two analogs, 13-tetradecenyl butyrate and 13-tetradecenyl hexanoate, and 2) a landscape survey using traps baited with 13-tetradecenyl acetate. Results of the efficacy study showed that 13-tetradecenyl acetate was the most effective M. communis lure when compared to non-baited control traps or traps baited with the two homologs. The landscape study documented a strong association between M. communis catch and the adjacent crop type. We found that adult M. communis abundance was greatest near corn, followed by sweet potato, and then cotton. Analysis of activity over time found that the peak activity occurred during July. Overall, this project demonstrates the usefulness of pheromone-baited traps in providing new information about M. communis activity.

Medium Earth orbit is subject to destabilizing resonances due to third body effects from the Moon and Sun. This behavior can be leveraged for debris mitigation in this regime. This paper will explore how feasible this technique is and whether satellites could be targeted into such impact trajectories at their end-of-life. In the paper, six targets are examined in detail to determine what level of uncertainty in targeting these satellites will achieve a reentry trajectory some decades in the future. This study will also characterize the sensitivity to initial conditions for this orbital regime and the feasibility of leveraging these naturally occurring dynamics.

This feature issue of Optics Express highlights contributions from authors who presented their latest research at the OPTICA Optical Sensors and Sensing Congress, held in Vancouver, British Columbia, Canada from 11–15 July 2022. The feature issue comprises 9 contributed papers, which expand upon their respective conference proceedings. The published papers introduced here cover a range of timely research topics in optics and photonics for chip-based sensing, open-path and remote sensing and fiber devices.

Funding Acknowledgements Type of funding sources: None. Background Left ventricular assist device (LVAD) implantation is increasingly used in patients with end-stage heart failure. Most patients already have an implantable defibrillator (ICD) at the time of L-VAD implantation. Studies on this patient population are limited by the small sample size and the short duration of follow-up. Purpose The aim of this study was to retrospectively describe the real-world management of patients implanted with both ICD and LVAD. The main objective was to evaluate the incidence and predictors of appropriate and inappropriate therapies of the ICD and the incidence and predictors of ICD related complications. Methods 212 patients were enrolled in four Centers in the period between July 2006 and November 2020. The inclusion criteria were age> 18 years, advanced heart failure, patients with ICD and concomitant or subsequent continuous flow LVAD implantation. ICD therapy was defined as antitachycardia pacing therapy or shock. The data available at the last visit with a median follow up of 21 months were analyzed. Outcome predictors were assessed by univariate logistic regression and the variables of interest included in a multivariate model. Results The rate of appropriate ICD therapies was 29.7%, while the incidence of inappropriate therapies was 10.4%; in the multivariate analysis the presence of a zone therapy with low detection rate (VT zone with median detection rate of 164.5 bpm) was found to be an independent predictor of the composite of appropriate and inappropriate therapies (OR = 19.05; CI = 2.19-165.21; p = 0.007). Interference between ICD and LVAD occurred in 7.5% of cases; the incidence of infectious complications related to the ICD was 7.1% and bleeding complications of 5.2%; in the multivariate analysis, ICD generator replacement was an independent predictor of total complications related to the ICD (interference, infectious and bleeding; OR = 4.45; IC = 1.60-12.36; p = 0.004). 103 patients had CRT defibrillator (48,6%). At follow up there was no statistically significant difference in the incidence of appropriate therapies between those who had CRT-on (n=74) and those who had CRT-off (n=29; p = 0.61). Conclusions Patients with LVAD implanted with an ICD experience a high rate of appropriate and inappropriate ICD therapies. An active VT zone at low heart rate was found to be an independent predictor of ICD therapies. Of more, ICD generator replacement was found to be an independent predictor of total complications related to the ICD. Our findings suggest the importance of tailoring device programming in order to minimize the incidence of ICD therapies, thus sparing the need for generator replacement in this population.

Introduction Mitral regurgitation (MR) and tricuspid regurgitation (TR) are a known cause of morbidity and mortality in heart failure (HF) patients. Maximal up–titration of guideline–directed medical therapy (GDMT) for HF may not be enough to reduce the severity of the valve’s incompetence and patients’ symptoms. The development and successful results of transcatheter therapies for mitral/tricuspid disease have opened new therapeutic opportunities when surgery is not feasible. Accurate valve regurgitation’s mechanisms evaluation is essential to choose the best treatment option. This study aims at evaluating the prevalence and underlying mechanisms of at least moderate–to–severe (≥3+/4+) MR and/or TR in a cohort of HF outpatients. Methods We retrospectively analyzed the medical records of 1260 outpatients evaluated by our HF unit between January 2020 and June 2021. All patients with echocardiographic evidence of ≥ 3+/4+ MR and/or TR were included (treated ones were excluded), and a thorough echocardiographic images review was conducted. A full collection of patients’ clinical, laboratory and therapy regimens details was performed as well. Results Of the 1260 analyzed patients, 173 (13.7%) exhibited ≥3+/4+ MR and/or TR and were included in the registry. Table 1 shows the main clinical/echocardiographic characteristics. Mean age was 80±7 years, median ejection fraction was 45% (IQR=33–55). All patients were treated with maximal tolerated doses of GDMT and, if appropriate, with cardiac devices/myocardial revascularization. ≥3+/4+ MR and/or TR was observed in 92 (7.3%) and 117 (9.3%) patients, respectively. Patients with isolated significant MR were 56 (4.4%), with isolated significant TR were 81 (6.4%); the remaining 36 (2.8%) had both MR/TR. Among patients with significant MR, 50 (54%) had functional/secondary valvular defect (details in Figure 2): the majority (41,82%) presented a ventricular etiology (asymmetric tethering in 18/41) while 9 (18%) an atrial one (atriogenic tethering in 3/9). Conclusion Despite optimized GDMT, the prevalence of patients with hemodynamically significant valvular defects was considerably high in our HF population. This is the first registry to comprehensively detail atrioventricular valve regurgitations’ mechanisms in a wide real–life cohort of HF outpatients. Further studies are needed to identify reasons for potential undertreatment and patients who would benefit the most from percutaneous correction of their valvular defects.

Background Loop diuretics are the cornerstone of acutely decompensated heart failure (ADHF) treatment, but evidences on doses and administration modalities are still lacking. Veena S. et al have recently validated the Natriuretic Response Prediction Equation and applied it with the Yale Diuretic Protocol (YDP) in a clinical implementation cohort demonstrating its safety. Objectives Our purpose is to test the applicability and safety of YDP for titration of diuretic therapy in a real–world in–hospital setting, as compared to standard diuretic therapy. METHODS From 15th September 2021 patients hospitalized with ADHF, almost one sign of congestion and need of i.v. diuretics were enrolled. Patients with active bleeding, hematocrit Results Thirty patients were included. Median age was 76.4 [IQR 68.3; 82.7] years old; median EF and glomerular filtration rate were 40% [IQR 30; 55] and 57.2 ml/min/m2 [IQR 44.9; 79.9], respectively. Nineteen (63.3%) patients were on chronic loop diuretic treatment. Ten (33.3%) patients were treated according to YDP. Main results are shown in the Table attached. YDP patients were younger (p = 0.02) and received shorter treatment with i.v. diuretics (YDP 36 [IQR 27; 48] hours, controls 48 [IQRS 38; 88] hours; p = 0.03). No differences in terms of total diuresis, weight loss at the end of i.v. diuretic therapy and length of hospitalization were shown. YDP patients experienced significant lower increase in creatinine during i.v. diuretic therapy (p = 0.02). The incidence of adverse events was comparable between groups, with equal hypotension rate (10%), and similar plasma levels of electrolytes at the end of i.v. diuretic therapy; YDP patients required less potassium supplementation. Reasons for i.v. diuretic therapy suspension were comparable between groups; 7 (70%) YDP patients concluded i.v. diuretic therapy for satisfactory decongestion, while only one patient because of hypotension and none because of worsening of renal function. Conclusion In our reality the YDP appeared to be applicable, safe and comparable to the standard i.v. diuretic therapy in terms of in–hospital outcomes. These preliminary results need to be confirmed in a larger cohort and longer term outcomes still need to be explored.

Our Photonic Integrated Circuit (PIC) wearable biosensor platform is small (mm), easily mass-manufactured and has high sensitivity. Here we show a PIC platform for sensing biomarkers using streptavidin as a proof-of-concept.

Psoriasis is a chronic immune-mediated inflammatory skin disorder affecting children and adults. To date no approved biomarkers for diagnosis of this disease and follow up of patients have been translated into clinical practice. Recently, extracellular vesicles (EVs) secreted by all cells and present in almost all biological fluids are playing a crucial role in diagnosis and follow up of several diseases, including psoriasis. Since many psoriatic patients show altered plasma lipid profiles and since EVs have been involved in psoriasis pathogenesis, we studied the phospholipid profile of EVs, both microvesicles (MV) or exosomes (Exo), derived from plasma of psoriatic patients undergoing systemic biological treatment (secukinumab, ustekinumab, adalimumab), in comparison with EVs of untreated patients and healthy donors (HD). EVs were evaluated by immune electronmicroscopy for their morphology and by NanoSight for their amount and dimensions. EV phospholipid profiling was performed by High Resolution Liquid Chromatography-Mass Spectrometry and statistical Partial Least Squares Discriminant Analysis. Our results demonstrated that psoriatic patients showed a higher concentration of both MV and Exo in comparison to EVs from HD. The phospholipid profile of Exo from psoriatic patients showed increased levels of phosphatidylcholine (PC), phosphatidylethanolamine (PE), phosphatidylglycerol and lysoPC compared to Exo from HD. Sphingomyelin (SM) and phosphatidylinositol (PI) are the only phospholipid classes whose levels changed in MV. Moreover, the therapy with ustekinumab seemed to revert the PE and PC lipid composition of circulating Exo towards that of HD and it is the only one of the three biological drugs that did not alter SM expression in MV. Therefore, the determination of lipid alterations of circulating EVs could harbor useful information for the diagnosis and drug response in psoriatic patients.

The selective regulation of bacteria in complex microbial populations is key to controlling pathogenic bacteria. CRISPR nucleases can be programmed to kill bacteria, but require an efficient and broad-host range delivery system to be effective. Here, using an Escherichia coli and Salmonella enterica co-culture system, we show that plasmids based on the IncP RK2 conjugative system can be used as delivery vectors for a TevSpCas9 dual nuclease. Notably, a cis-acting plasmid that encodes the conjugation and CRISPR machinery conjugates from E. coli to S. enterica with high frequency compared to a trans system that separates conjugation and CRISPR machinery. In culture conditions that enhance cell-to-cell contact, conjugation rates approach 100% with the cis-acting plasmid. Targeting of single or multiplexed sgRNAs to non-essential genes results in high S. enterica killing efficiencies. Our data highlight the potential of cis-acting conjugative plasmids as a delivery system for CRISPR nucleases or other microbial-altering agents for targeted bacterial killing., CRISPR nucleases can be programmed to cleave sequences in specific bacteria to induce cell death. Here, Hamilton et al. present an optimized method for conjugative delivery of CRISPR nucleases, consisting of a single plasmid that encodes both the conjugative machinery and the nuclease.

Approaches to provide chip-scale aqueous chemical sensing for environmental and health monitoring via a photonic integrated circuit (PIC) technology are showing promise. To meet future U.S. Army demand, we have investigated waveguide structures compatible with feature sizes offered by modern mass-manufacturing PIC foundries. We have found that wide subwavelength grating (SWG) waveguide structures can maximally interact with an encapsulating analyte capture material with low propagation loss. We describe the analyte/light interaction component of our general integrated photonics chemical detector sensitivity model and use it to compare the effectiveness of waveguide geometries for sensing. The structures we have investigated afford superior detection to strip and slot waveguides. Finally, we introduce a novel tapered SWG waveguide geometry with improved transmission and similar sensitivity to nontapered SWG designs.

Access to medical monitoring in the field is primarily limited to physical or electrical measurements such as temperature, heart rate or respiration that readout a soldier’s immediate health. The ability to monitor biomarkers in combination with these measurement can uncover pathways leading to a health event and catch problems before the onset of symptoms. Our goal is to develop a fieldable, wearable PIC device for continuously monitoring small molecules and proteins. Continuous monitoring of biomarkers and physiological analytes is necessary for detecting abnormal fluctuations from baseline and provides real-time responses of human performance or injury. Wearable sensors for continuous monitoring require a combination of traits not seen in sample-based sensor systems including compact size, reversibility and sample replenishment. To accomplish this, we combine our expertise in sensors and photonic integrated circuits to generate a refractive index sensor platform. This approach takes advantage of sensing components and PIC devices to increase their sensitivity and selectivity for biomarkers while maintaining a small footprint required for practicality in the field. Here we report progress in striving to achieve a wearable sensor for continuously monitoring analytes in blood and sweat.

The use of antibiotics to prevent bovine mastitis is responsible for the emergence and selection of resistant strains. Lactic acid bacteria (LAB) could be introduced into animal feed as an alternative prevention method that would bypass the risk of resistance development. In previous research, we demonstrated that two probiotic LAB strains isolated from bovine milk were capable of stimulating the production of antibodies and the host’s immune cellular response in the udder. The present study aimed to elucidate whether the antibodies of animals inoculated with these strains were able to increase phagocytosis by neutrophils and inhibit the growth of different mastitis-causing pathogens. Moreover, the effect of LAB on the expression of pro-inflammatory cytokines was assessed. Ten animals were inoculated intramammarily with 106 cells of the two strains at dry-off. The blood serum was tested for its ability to opsonize bovine mastitis pathogens, the in vitro bactericidal activity of bovine blood and milk against these pathogens was determined, and cytokine mRNA expression was quantified in milk somatic cells. The inoculated animals did not show abnormal signs of sensitivity to the LAB. Their blood serum significantly enhanced the phagocytosis of Staphylococcus spp. and the LAB. Escherichia coli and Streptococcus uberis were inhibited by the milk serum but not the blood serum, whereas Staphylococcus aureus and Staphylococcus haemolyticus were inhibited by both. In regard to cytokine expression, interleukin (IL)-1β increased markedly for up to 4 h post-inoculation, and an increase in IL-8 was observed 4, 12 and 24 h after inoculation. Tumour necrosis factor-α mRNA increased 1 and 2 h after inoculation and a significant difference was registered at 6 h for interferon-γ. This rapid immunomodulatory response shows that inoculating animals with LAB at dry-off, when they are especially susceptible, could be a useful strategy for the prevention of bovine mastitis.

In this study we evaluated the effect of temperature and time storage on the quality parameters of mono cultivar olive oil drupes. In particular, analyses of total free phenols, fatty acids, lipophilic and hydrophilic antioxidant capacity, sensory analysis, at different temperatures and different times of post harvest storage, were performed. All data obtained have been singularly processed by Functional Mathematical Index (FMI).

Cultivated olive (Olea europaea L. subsp. europaea var. europaea) is the most ancient and spread tree crop in the Mediterranean basin. An important quality trait for the extra virgin olive oil is the fatty acid composition. In particular, a high content of oleic acid and low of linoleic, linolenic, and palmitic acid is considered very relevant in the health properties of the olive oil. The oleate desaturase enzyme encoding-gene (FAD2-2) is the main responsible for the linoleic acid content in the olive fruit mesocarp and, therefore, in the olive oil revealing to be the most important candidate gene for the linoleic acid biosynthesis. In this study, an in silico and structural analysis of the 5'UTR intron of the FAD2-2 gene was conducted with the aim to explore the natural sequence variability and its role in the gene expression regulation. In order to identify functional allele variants, the 5'UTR intron was isolated and partially sequenced in 97 olive cultivars. The sequence analysis allowed to find a 117-bp insertion including two long duplications never found before in FAD2-2 genes in olive and the existence of many intron-mediated enhancement (IME) elements. The sequence polymorphism analysis led to detect 39 SNPs. The candidate gene association study conducted for oleic and linoleic acids content revealed seven SNPs and one indel significantly associated able to explain a phenotypic variation ranging from 7% to 16% among the years. Our study highlighted new structural variants within the FAD2-2 gene in olive, putatively involved in the regulation mechanisms of gene expression associated with the variation of the content of oleic and linoleic acid.

Sensors should exhibit many different characteristics which have to be provided all along their life time and that requires extensive experimental activity. But the world of sensors is very wide, covering different kind of materials and mechanisms of transduction, with a large variety of types and applications and it is hard to find either Standards or technical Specifications or Protocols these devices shall be complying to. As a consequence it is no one way for classifying sensors, to categorize them and to find either Standards or Technical Specifications suitable for all the sensors. So there are traditional sensors that must comply with applicable Standards (for instance the ASTM International, formerly known as American Society for Testing and Materials, is an international organization that develops and publishes voluntary consensus technical standards for a wide range of materials, products, such sensors) but other more innovative devices where Standards and Technical specifications can be hardly found. Laboratory PVSMART of CR ENEA in Portici, near Naples (I), has been active for so many years for quality and reliability of photovoltaic devices such as solar cells and modules and owns a very deep experience on laboratory artificial ageing processes and compliance to Standards. Although the field could seem quite different, nevertheless this competence might be useful for the world of sensors; in that way in the past the laboratory has already provided technical support to some customer by testing specific detectors. In this paper, the experience of this investigation is summarized and the potentials for a more general use is then proposed.

Aims: To assess reliability and validity of a two-minute wheeled mobility test (2MWMT) for older adults using manual wheelchairs living in long-term care communities. Methods: The distance wheeled ...

Fil: Pena, Gabriela Alejandra. Universidad Nacional de Rio Cuarto. Facultad de Ciencias Exactas, Fisicoquimicas y Naturales. Departamento de Microbiologia e Inmunologia; Argentina. Consejo Nacional de Investigaciones Cientificas y Tecnicas. Centro Cientifico Tecnologico Conicet - Cordoba; Argentina

Background Poly-ADP-ribose-polymerase is an essential nuclear enzyme, involved in base-excision repair of damaged DNA. Poly-ADP-ribose-polymerase inhibition sensitizes tumor cells to cytotoxic agents, which induce DNA damage, including cyclophosphamide (C), and metronomic dosing of C may optimize potential for synergy. Methods The primary objective of this phase I trial was to determine the safety and identify the recommended phase II dose of the combination of low-dose oral C (50, 75, 100, and 125 mg) once daily in combination with veliparib (V) (100, 200, and 300 mg) administered twice a day (BID) for 21-day cycles using a standard 3 + 3 design in patients with metastatic human epidermal growth factor receptor 2/neu-negative breast cancer. Dose-limiting toxicity was defined as any grade 3 non-hematologic toxicity or grade 4 thrombocytopenia/neutropenia occurring during cycle 1. Results A total of 31 patients were enrolled; 19 were treated with 50 mg of C and 12 were treated at higher doses (75, 100, or 125 mg), with V doses ranging from 50 to 300 mg BID. The recommended phase II dose of the combination was V 200 mg orally BID plus C 125 mg orally daily, with nausea and headache dose-limiting at higher V dose levels. Objective response or stable disease for at least 24 weeks occurred in 3 (43%) of 7 patients with known deleterious germline BRCA mutations and 2 (11%) of 19 patients with negative/unknown mutation status (P = .1). Conclusion The combination of oral continuous dosing of V (200 mg orally BID) with metronomic C (50, 75, 100, and 125 mg daily) is well-tolerated and shows antitumor activity in patients with BRCA–mutation-associated metastatic human epidermal growth factor receptor 2/neu-negative breast cancer.

Bovine mastitis causes economic losses on dairy farms worldwide. Lactic acid bacteria (LAB) in animal health are an alternative tool to avoid antibiotic therapy on the prevention of bovine mastitis. In previous studies, 12 LAB isolated from bovine milk were selected taking into account some of the following characteristics: hydrophobicity, auto aggregative capability, inhibition of indicator pathogens, hydrogen peroxide, and capsular polysaccharide production. These LAB were considered because of their beneficial properties. In this work, we also analyzed the antimicrobial activity and the co-aggregation against mastitis causing bacteria, auto-inhibition, adhesion to bovine teat canal epithelial cells (BTCEC), and growth kinetic curves for the 12 LAB. Two of them, Lactococcus lactis subsp. lactis CRL 1655 and Lactobacillus perolens CRL 1724, were selected because they had an interesting pattern of adhesion to BTEC, the inhibition of pathogens and the co-aggregation with the 100% of the assayed pathogens. They showed a predictable difference in the PFGE genomic pattern bands. The kinetic growth of these two strains was similar between them and with the rest of the assayed LAB. The strains selected in the present study showed indispensable characteristics for their inclusion in a probiotic formulation to be used at dry-off period for the prevention of bovine mastitis. Fil: Pellegrino, Matias Santiago. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Córdoba; Argentina. Universidad Nacional de Río Cuarto. Facultad de Ciencias Exactas, Fisicoquímicas y Naturales. Departamento de Microbiología e Inmunología; Argentina Fil: Frola, Ignacio Daniel. Universidad Nacional de Río Cuarto. Facultad de Ciencias Exactas, Fisicoquímicas y Naturales. Departamento de Microbiología e Inmunología; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Córdoba; Argentina Fil: Berardo, Natanael. Universidad Nacional de Río Cuarto. Facultad de Ciencias Exactas, Fisicoquímicas y Naturales. Departamento de Microbiología e Inmunología; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Córdoba; Argentina Fil: Gobelli, Dino Joaquin. Universidad Nacional de Río Cuarto. Facultad de Ciencias Exactas, Fisicoquímicas y Naturales. Departamento de Microbiología e Inmunología; Argentina Fil: Nader, Maria Elena Fatima. Consejo Nacional de Investigaciones Científicas y Técnicas; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Tucumán. Centro de Referencia para Lactobacilos; Argentina Fil: Bogni, Cristina Ines. Universidad Nacional de Río Cuarto. Facultad de Ciencias Exactas, Fisicoquímicas y Naturales. Departamento de Microbiología e Inmunología; Argentina

At present the olive oil industry produces large amounts of secondary products once considered waste or by-products. In this paper, we present, for the first time, a new interesting olive by-product named “dried destoned virgin olive pomace” (DDVOP), produced by the pomace oil industry. The production of DDVOP is possible thanks to the use of a new system that differs from the traditional ones by having the dryer set at a lower temperature value, 350 °C instead of 550 °C, and by avoiding the solvent extraction phase. In order to evaluate if DDVOP may be suitable as a new innovative feeding integrator for animal feed, its chemical characteristics were investigated. Results demonstrated that DDVOP is a good source of raw protein and precious fiber, that it is consistent in total phenols (6156 mg/kg), rich in oleic (72.29%), linoleic (8.37%) acids and tocopherols (8.80 mg/kg). A feeding trial was, therefore, carried out on sheep with the scope of investigating the influence of the diet on the quality of milk obtained from sheep fed with DDVOP-enriched feed. The resulting milk was enriched in polyunsaturated (0.21%) and unsaturated (2.42%) fatty acids, and had increased levels of phenols (10.35 mg/kg) and tocopherols (1.03 mg/kg).

How firms learn about foreign markets and internationalization processes is an important theme in the literature on SME internationalization, evidenced by the Uppsala model’s emphasis on experiential learning as an explanation for incremental internationalization, and attempts to explain how early and rapid internationalization can be facilitated by alternative modes of learning, especially congenital learning. Yet, the learning processes used, and the content and source of learning, have not been compared systematically, especially with respect to how these evolve as firms become increasingly internationalized. This paper reports the findings of a retrospective longitudinal analysis of the learning processes, sources and foci of four New Zealand-based SMEs that internationalized incrementally, and four that internationalized rapidly. The findings demonstrate that while experiential learning is important, both incrementally and rapidly internationalizing firms use other learning modes at different stages of their internationalization, and that there are differences in the content and source of learning. Thus, the relationship between internationalization and learning processes may be more complex than the literature currently suggests, inviting further exploration of the multiple ways that SMEs learn, and the contingent factors that might influence this.

Suberoylanilide hydroxamic acid (SAHA; vorinostat), a small molecule inhibitor of histone deacetylase, attenuates signaling pathways known to confer trastuzumab resistance. A combination of SAHA and trastuzumab may be a promising strategy to improve the efficacy of trastuzumab against breast cancer. In this Phase I/II study, we evaluated the toxicity and response rate after treatment with SAHA and trastuzumab in patients with HER2-overexpressing metastatic breast cancer with trastuzumab-resistant progressive disease. In Phase I, the SAHA dose was modified in cohorts of 3–6 patients to find the dose level at which 0 or 1 patients experienced a dose-limiting toxicity (DLT) during the first cycle of therapy. In the Phase II study, response to the recommended dose identified in Phase I was based on the response evaluation criteria in solid tumors. Overall survival and time to progression were also evaluated. The recommended dose was determined to be 200 mg twice a day on days 1–14 and IV trastuzumab 6 mg/kg on day 1 of a 21-day cycle (n = 6). The Phase II study (n = 10) was terminated when the pre-planned efficacy evaluation found that none of the patients in the primary analysis set responded to combination SAHA and trastuzumab treatment. In patients with HER2-positive metastatic breast cancer who had relapsed or progressed during trastuzumab therapy, we observed no DLTs with SAHA 200 mg twice daily combined with trastuzumab; however, there was insufficient statistical evidence that adding SAHA reversed trastuzumab resistance in these patients.

BACKGROUND: PARP, an essential nuclear enzyme, is involved in the recognition of DNA damage and facilitation of DNA base-excision repair (BER). PARP inhibition sensitizes tumor cells to cytotoxic agents which induce DNA damage, including C. Metronomic dosing of C may optimize potential for synergy with PARP inhibitors, and also inhibits angiogenesis (Kerbel et al, Nat Rev Cancer, 4:423-36, 2004) and may enhance anti-tumor immunity (Ghiringhelli et al. Cancer Immunol Immunother 56:641–648, 2007) V is an oral small molecule inhibitor of PARP which potentiates the antineoplastic activity of DNA damaging agents such as C in MX-1 breast xenograft model (Donawho et al Clin Cancer Res 13:2728-37, 2007). We performed a phase I trial of metronomic dose oral C plus V in patients with MBC. METHODS: The primary objective was to determine the safety and identify the recommended phase II dose (RPTD) of the combination of low-dose oral C once daily in combination with V (100, 200, 300 mg) administered BID for 21 days using a standard 3+3 design. Eligibility included HER2/neu negative MBC, ECOG PS 0-1, and at least 1 prior chemotherapy regimen for MBC. Dose limiting toxicity (DLT) was defined as any Grade 3 non-hematological toxicity or Grade 4 thrombocytopenia/neutropenia occurring during cycle 1. After the RPTD of V was shown to be 200 mg BID with C 50 mg daily, the trial was amended to increase the C dose to 75, 100 and then 125 mg daily until hematologic toxicity was dose-limiting. RESULTS: 31 patients were enrolled, 19 treated with 50 mg of C and 12 treated at higher doses (75-125 mg), with V doses ranging from 50 mg-300 mg BID (see table);5 patients with not evaluable due to rapid disease progression (N=2), non-compliance (N=2), or tumor pain that was not a DLT (N=1). Median age was 52 years (28-72 years), 14 (45 %) had triple negative disease, all had at least 1 prior chemotherapy regimen for metastasis (median 2, range 1-8), and, 7 had germline BRCA mutations, (3 BRCA1 and 4 BRCA2). When combined with 50 mg C daily, RPTD of V was 200 mg PO BID, with nausea being DLT at 300 mg BID. DLT was not observed in any of the 9 additional patients. The median number of cycles given was 3 (range 1-14). Clinical benefit (response or stable disease for at least 24 weeks) occurred in 3/7 (43%), 1/3 (33%) and 1/16(6%) for BRCA mutated, BRCA negative and BRCA unknown, respectively. Median progression-free survival was 4.3 months (1.2-10.9 months) for BRCA mutated patients and 2 months (0.7-10 months) for non-mutated. CONCLUSIONS: The combination of oral continuous dosing of V (200 mg PO BID) with metronomic C (50, 75, 100 and 125 mg daily) is well tolerated and shows antitumor activity in patients with BRCA mutation associated MBC. The RPTD is C 125 mg daily plus V 200 mg BID, although further escalation of the C dose may be feasible since DLT was not seen at this dose level. Dose LevelsDose Level# Patients/Evaluable# DLTType of DLTDL 1 :V 50mg , C 50mg3/30 DL 2 :V 100 mg, C 50mg4/30 DL 3 :V 200 mg, C 50mg6/61HeadacheDL 4 :V 300 mg, C 50mg6/52Nausea (N=2)DL 3A :V 200 mg; C 75mg3/30 DL 3B :V 200 mg, C 100mg6/30 DL 3C :V 200 mg, C 125mg3/30 Citation Format: Anampa JD, Patel M, Pellegrino C, Fehn K, Makower D, Oh S-y, Noah K, Chen A, Sparano JA, Andreopoulou E. Phase I study of low dose oral cyclophosphamide (C) plus the poly-ADP-ribose- polymerase (PARP) inhibitor veliparib (V) in women with HER2/neu-negative inoperable locally advanced/metastatic breast cancer (MBC): NCI P8853 [abstract]. In: Proceedings of the 2016 San Antonio Breast Cancer Symposium; 2016 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2017;77(4 Suppl):Abstract nr P6-12-08.

Color vision results from the interaction of retinal photopigments with reflected or transmitted visible light. The International Commission on Illumination (CIE) developed the CIE color-matching chart, which separates colors on the basis of the interaction of their spectral profiles with three retinal photopigments in the human eye. We report the development of an infrared chromaticity (CIE-IR) chart, which mimics the CIE chart, in order to discriminate between different chemicals on the basis of the interactions of their IR signatures with three different IR optical filters, instead of the retinal photopigments in the human eye. Our results demonstrate that the CIE-IR chart enables separation of different classes of chemicals, as the visible CIE chart does with color, except for those in the IR spectral region. Such results clearly show that the biomimetic sensing method based on human color vision is in fact a true analogue to color vision and that the proposed CIE-IR chart can be used as a classification method unique to this biomimetic sensing modality.