Overcoming the challenges of cancer drug resistance through bacterial-mediated therapy.

Despite tremendous efforts to fight cancer, it remains a major public health problem and a leading cause of death worldwide. With increased knowledge of cancer pathways and improved technological platforms, precision therapeutics that specifically target aberrant cancer pathways have improved patient outcomes. Nevertheless, a primary cause of unsuccessful cancer therapy remains cancer drug resistance. In this review, we summarize the broad classes of resistance to cancer therapy, particularly pharmacokinetics, the tumor microenvironment, and drug resistance mechanisms. Furthermore, we describe how bacterial-mediated cancer therapy, a bygone mode of treatment, has been revitalized by synthetic biology and is uniquely suited to address the primary resistance mechanisms that confound traditional therapies. Through genetic engineering, we discuss how bacteria can be potent anticancer agents given their tumor targeting potential, anti-tumor activity, safety, and coordinated delivery of anti-cancer drugs

Modulated-laser source induction system for remote detection of infrared emissions of high explosives using laser-induced thermal emission

In a homeland security setting, the ability to detect explosives at a distance is a top security priority. Consequently, the development of remote, noncontact detection systems continues to represent a path forward. In this vein, a remote detection system for excitation of infrared emissions using a CO2 laser for generating laser-induced thermal emission (LITE) is a possible solution. However, a LITE system using a CO2 laser has certain limitations, such as the requirement of careful alignment, interference by the CO2 signal during detection, and the power density loss due to the increase of the laser image at the sample plane with the detection distance. A remote chopped-laser induction system for LITE detection using a CO2 laser source coupled to a focusing telescope was built to solve some of these limitations. Samples of fixed surface concentration (500 μg∕cm2) of 1,3,5-trinitroperhydro-1,3,5-triazine (RDX) were used for the remote detection experiments at distances ranging between 4 and 8 m. This system was capable of thermally exciting and capturing the thermal emissions (TEs) at different times in a cyclic manner by a Fourier transform infrared (FTIR) spectrometer coupled to a gold-coated reflection optics telescope (FTIR-GT). This was done using a wheel blocking the capture of TE by the FTIR-GT chopper while heating the sample with the CO2 laser. As the wheel moved, it blocked the CO2 laser and allowed the spectroscopic system to capture the TEs of RDX. Different periods (or frequencies) of wheel spin and FTIR-GT integration times were evaluated to find dependence with observation distance of the maximum intensity detection, minimum signal-to-noise ratio, CO2 laser spot size increase, and the induced temperature incremen

Mid-Infrared Laser Spectroscopy Applications I: Detection of Traces of High Explosives on Reflective and Matte Substrates

Mid-infrared (MIR) lasers have revolutionized infrared vibrational spectroscopy, converting an already dominant spectroscopic analysis technique into an even more powerful, easier to use, and quicker turn-around cadre of versatile spectroscopic tools. A selection of applications, revisited under the umbrella of MIR laser-based properties, very high brightness, collimated beams, polarized sources, highly monochromatic tunable sources, and coherent sources, is included. Applications discussed concern enhanced detection, discrimination, and quantification of high explosives (HEs). From reflectance measurements of chemical residues on highly reflective metallic substrates to reflectance measurements of HEs deposited on non-reflective, matte substrates is discussed. Coupling with multivariate analyses (MVA) techniques of Chemometrics allowed near trace detection of HEs, with sharp discrimination from highly MIR absorbing substrates

Mid-Infrared Laser Spectroscopy Applications in Process Analytical Technology: Cleaning Validation, Microorganisms, and Active Pharmaceutical Ingredients in Formulations

Mid-infrared (MIR) lasers are very high-brightness energy sources that are replacing conventional thermal sources (globars) in many infrared spectroscopy (IRS) techniques. Although not all laser properties have been exploited in depth, properties such as collimation, polarization, high brightness, and very high resolution have contributed to recast IRS tools. Applications of MIR laser spectroscopy to process analytical technology (PAT) are numerous and important. As an example, a compact grazing angle probe mount has allowed coupling to a MIR quantum cascade laser (QCL), enabling reflectance-absorbance infrared spectroscopy (RAIRS) measurements. This methodology, coupled to powerful multivariable analysis (MVA) routines of chemometrics and fast Fourier transform (FFT) preprocessing of the data resulted in very low limits of detection of active pharmaceutical ingredients (APIs) and high explosives (HEs) reaching trace levels. This methodology can be used to measure concentrations of surface contaminants for validation of cleanliness of pharmaceutical and biotechnology processing batch reactors and other manufacturing vessels. Another application discussed concerns the enhanced detection of microorganisms that can be encountered in pharmaceutical and biotechnology plants as contaminants and that could also be used as weapons of mass destruction in biological warfare. In the last application discussed, the concentration of APIs in formulations was determined by MIR laser spectroscopy and was cross validated with high-performance liquid chromatography

Blocking GM-CSF receptor α with mavrilimumab reduces infiltrating cells, pro-inflammatory markers and neoangiogenesis in ex vivo cultured arteries from patients with giant cell arteritis

Effective and safe therapies are needed for the treatment of patients with giant cell arteritis (GCA). Emerging as a key cytokine in inflammation, granulocyte-macrophage colony stimulating factor (GM-CSF) may play a role in promoting inflammation in GCA.To investigate expression of GM-CSF and its receptor in arterial lesions from patients with GCA. To analyse activation of GM-CSF receptor-associated signalling pathways and expression of target genes. To evaluate the effects of blocking GM-CSF receptor α with mavrilimumab in ex vivo cultured arteries from patients with GCA.Quantitative real time PCR, in situ RNA hybridisation, immunohistochemistry, immunofluorescence and confocal microscopy, immunoassay, western blot and ex vivo temporal artery culture.GM-CSF and GM-CSF receptor α mRNA and protein were increased in GCA lesions; enhanced JAK2/STAT5A expression/phosphorylation as well as increased expression of target genes CD83 and Spi1/PU.1 were observed. Treatment of ex vivo cultured GCA arteries with mavrilimumab resulted in decreased transcripts of CD3ε, CD20, CD14 and CD16 cell markers, and reduction of infiltrating CD16 and CD3ε cells was observed by immunofluorescence. Mavrilimumab reduced expression of molecules relevant to T cell activation (human leukocyte antigen-DR [HLA-DR]) and Th1 differentiation (interferon-γ), the pro-inflammatory cytokines: interleukin 6 (IL-6), tumour necrosis factor α (TNFα) and IL-1β, as well as molecules related to vascular injury (matrix metalloprotease 9, lipid peroxidation products and inducible nitric oxide synthase [iNOS]). Mavrilimumab reduced CD34 + cells and neoangiogenesis in GCA lesions.The inhibitory effects of mavrilimumab on multiple steps in the GCA pathogenesis cascade in vitro are consistent with the clinical observation of reduced GCA flares in a phase 2 trial and support its development as a therapeutic option for patients with GCA.© Author(s) (or their employer(s)) 2022. Re-use permitted under CC BY. Published by BMJ

Taxonomical over splitting in the Rhodnius prolixus (Insecta: Hemiptera: Reduviidae) clade: Are R. taquarussuensis (da Rosa et al., 2017) and R. neglectus (Lent, 1954) the same species?

El uso de características sutiles como características de diagnóstico de especies en taxones con una gran similitud morfológica a veces falla en discriminar la variación intraespecífica de las diferencias interespecíficas, lo que lleva a una delimitación incorrecta de la especie. Una evaluación clara de los límites de las especies es particularmente relevante en los organismos vectores de enfermedades para comprender los procesos epidemiológicos y evolutivos que afectan la capacidad de transmisión. Aquí, evaluamos la validez del Rhodnius taquarussuensis recientemente descrito (da Rosa et al., 2017) utilizando cruces interespecíficos y marcadores moleculares. No detectamos diferencias en las tasas de eclosión en cruces interespecíficos entre R. taquarussuensis y R. negligencias (Lent, 1954). Además, los análisis de divergencia genética y delimitación de especies muestran que R. taquarussuensis no es un linaje independiente en el grupo R. prolixus. Estos resultados sugieren que R. taquarussuensis es una forma fenotípica de R. negligenciaus en lugar de una especie distinta. Nos gustaría enfatizar que se necesitan diferentes fuentes de evidencia para delimitar correctamente las especies. Consideramos que este es un paso importante en la comprensión de la propagación y transmisión vectorial de la enfermedad de Chagas.The use of subtle features as species diagnostic traits in taxa with high morphological similarity sometimes fails in discriminating intraspecific variation from interspecific differences, leading to an incorrect species delimitation. A clear assessment of species boundaries is particularly relevant in disease vector organisms in order to understand epidemiological and evolutionary processes that affect transmission capacity. Here, we assess the validity of the recently described Rhodnius taquarussuensis (da Rosa et al., 2017) using interspecific crosses and molecular markers. We did not detect differences in hatching rates in interspecific crosses between R. taquarussuensis and R. neglectus (Lent, 1954). Furthermore, genetic divergence and species delimitation analyses show that R. taquarussuensis is not an independent lineage in the R. prolixus group. These results suggest that R. taquarussuensis is a phenotypic form of R. neglectus instead of a distinct species. We would like to stress that different sources of evidence are needed to correctly delimit species. We consider this is an important step in understanding vectorial Chagas disease spread and transmission

Taxonomical over splitting in the Rhodnius prolixus (Insecta: Hemiptera: Reduviidae) clade: Are R. Taquarussuensis (da Rosa et al., 2017) and R. Neglectus (Lent, 1954) the same species?

El uso de características sutiles como características de diagnóstico de especies en taxones con una gran similitud morfológica a veces falla en discriminar la variación intraespecífica de las diferencias interespecíficas, lo que lleva a una delimitación incorrecta de la especie. Una evaluación clara de los límites de las especies es particularmente relevante en los organismos vectores de enfermedades para comprender los procesos epidemiológicos y evolutivos que afectan la capacidad de transmisión. Aquí, evaluamos la validez del Rhodnius taquarussuensis recientemente descrito (da Rosa et al., 2017) utilizando cruces interespecíficos y marcadores moleculares. No detectamos diferencias en las tasas de eclosión en cruces interespecíficos entre R. taquarussuensis y R. negligencias (Lent, 1954). Además, los análisis de divergencia genética y delimitación de especies muestran que R. taquarussuensis no es un linaje independiente en el grupo R. prolixus. Estos resultados sugieren que R. taquarussuensis es una forma fenotípica de R. negligenciaus en lugar de una especie distinta. Nos gustaría enfatizar que se necesitan diferentes fuentes de evidencia para delimitar correctamente las especies. Consideramos que este es un paso importante en la comprensión de la propagación y transmisión vectorial de la enfermedad de Chagas.The use of subtle features as species diagnostic traits in taxa with high morphological similarity sometimes fails in discriminating intraspecific variation from interspecific differences, leading to an incorrect species delimitation. A clear assessment of species boundaries is particularly relevant in disease vector organisms in order to understand epidemiological and evolutionary processes that affect transmission capacity. Here, we assess the validity of the recently described Rhodnius taquarussuensis (da Rosa et al., 2017) using interspecific crosses and molecular markers. We did not detect differences in hatching rates in interspecific crosses between R. taquarussuensis and R. neglectus (Lent, 1954). Furthermore, genetic divergence and species delimitation analyses show that R. taquarussuensis is not an independent lineage in the R. prolixus group. These results suggest that R. taquarussuensis is a phenotypic form of R. neglectus instead of a distinct species. We would like to stress that different sources of evidence are needed to correctly delimit species. We consider this is an important step in understanding vectorial Chagas disease spread and transmission. © 2019 Nascimento et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited

Association of oxidative stress and inflammatory metabolites with Alzheimer’s disease cerebrospinal fluid biomarkers in mild cognitive impairment

Background: Isoprostanes and prostaglandins are biomarkers for oxidative stress and inflammation. Their role in Alzheimer's disease (AD) pathophysiology is yet unknown. In the current study, we aim to identify the association of isoprostanes and prostaglandins with the Amyloid, Tau, Neurodegeneration (ATN) biomarkers (Aβ-42, p-tau, and t-tau) of AD pathophysiology in mild cognitive impairment (MCI) subjects. Methods: Targeted metabolomics profiling was performed using liquid chromatography-mass spectrometry (LCMS) in 147 paired plasma-CSF samples from the Ace Alzheimer Center Barcelona and 58 CSF samples of MCI patients from the Mannheim/Heidelberg cohort. Linear regression was used to evaluate the association of metabolites with CSF levels of ATN biomarkers in the overall sample and stratified by Aβ-42 pathology and APOE genotype. We further evaluated the role of metabolites in MCI to AD dementia progression. Results: Increased CSF levels of PGF2α, 8,12-iso-iPF2α VI, and 5-iPF2α VI were significantly associated (False discovery rate (FDR) < 0.05) with higher p-tau levels. Additionally, 8,12-iso-iPF2α VI was associated with increased total tau levels in CSF. In MCI due to AD, PGF2α was associated with both p-tau and total tau, whereases 8,12-iso-iPF2α VI was specifically associated with p-tau levels. In APOE stratified analysis, association of PGF2α with p-tau and t-tau was observed in only APOE ε4 carriers while 5-iPF2α VI showed association with both p-tau and t-tau in APOE ε33 carriers. CSF levels of 8,12- iso-iPF2α VI showed association with p-tau and t-tau in APOE ε33/APOE ε4 carriers and with t-tau in APOE ε3 carriers. None of the metabolites showed evidence of association with MCI to AD progression. Conclusions: Oxidative stress (8,12-iso-iPF2α VI) and inflammatory (PGF2α) biomarkers are correlated with biomarkers of AD pathology during the prodromal stage of AD and relation of PGF2α with tau pathology markers may be influenced by APOE genotype

Stellar Astrophysics and Exoplanet Science with the Maunakea Spectroscopic Explorer (MSE)

The Maunakea Spectroscopic Explorer (MSE) is a planned 11.25-m aperture facility with a 1.5 square degree field of view that will be fully dedicated to multi-object spectroscopy. A rebirth of the 3.6m Canada-France-Hawaii Telescope on Maunakea, MSE will use 4332 fibers operating at three different resolving powers (R ~ 2500, 6000, 40000) across a wavelength range of 0.36-1.8mum, with dynamical fiber positioning that allows fibers to match the exposure times of individual objects. MSE will enable spectroscopic surveys with unprecedented scale and sensitivity by collecting millions of spectra per year down to limiting magnitudes of g ~ 20-24 mag, with a nominal velocity precision of ~100 m/s in high-resolution mode. This white paper describes science cases for stellar astrophysics and exoplanet science using MSE, including the discovery and atmospheric characterization of exoplanets and substellar objects, stellar physics with star clusters, asteroseismology of solar-like oscillators and opacity-driven pulsators, studies of stellar rotation, activity, and multiplicity, as well as the chemical characterization of AGB and extremely metal-poor stars.Comment: 31 pages, 11 figures; To appear as a chapter for the Detailed Science Case of the Maunakea Spectroscopic Explore