Inflammatory cells, most especially neutrophils, can be a necessary component of the antitumor activity occurring after administration of photodynamic therapy. Generation of neutrophil responses has ...been suggested to be particularly important in instances when the delivered photodynamic therapy (PDT) dose is insufficient. In these cases, the release of neutrophil granules and engagement of antitumor immunity may play an important role in eliminating residual disease. Herein, we utilize in vivo imaging of luminol chemiluminescence to noninvasively monitor neutrophil activation after PDT administration. Studies were performed in the AB12 murine model of mesothelioma, treated with Photofrin‐PDT. Luminol‐generated chemiluminescence increased transiently 1 h after PDT, followed by a subsequent decrease at 4 h after PDT. The production of luminol signal was not associated with the influx of Ly6G+ cells, but was related to oxidative burst, as an indicator of neutrophil function. Most importantly, greater levels of luminol chemiluminescence 1 h after PDT were prognostic of a complete response at 90 days after PDT. Taken together, this research supports an important role for early activity by Ly6G+ cells in the generation of long‐term PDT responses in mesothelioma, and it points to luminol chemiluminescence as a potentially useful approach for preclinical monitoring of neutrophil activation by PDT.
As neutrophils can be necessary for antitumor activity after photodynamic therapy, we utilized in vivo imaging of luminol chemiluminescence to noninvasively monitor neutrophil activation after its administration. In murine mesothelioma, chemiluminescence increased at 1 h after photodynamic therapy (PDT) and subsequently decreased at 4 h after PDT. Luminol signal was not representative of neutrophil influx, but instead with neutrophil function (oxidative burst). Importantly, greater luminol signal 1 h after PDT predicted tumors with no regrowth after 90 days. This supports an important role for early neutrophil activity in optimal PDT response and highlights luminol chemiluminescence as a useful approach for preclinical studies.
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•3 endothermal transitions of galactomannans were observed in DSC thermograms.•Low ΔCp, wide ΔT and no typical wc dependence complicated Tg assignment.•An enthalpic relaxation-type ...transition around 50 °C was wc & frequency independent.•NMR T2 temperature dependence changed close to the low temperature transition.•Sinusoidal shape of FID NMR signals disappeared by increasing temperature or wc.
The thermal transitions of biopolymers were subject of great discussion in the 90s due to their relevance in structure development during processing and stability on storage. In the present work two galactomannans, vinal gum and guar gum, were evaluated by DSC, DMA and LF-1H NMR in order to compare them, establishing their potential operational application range and promoting the use of the non-conventional VG in foods or other products. Three endothermal transitions appeared when heating the samples in the DSC: one at temperatures −90 to −10 °C (LTT), other around 50 °C (MTT) and a third one between 50 and 100 °C (HTT). Both LTT and HTT showed water content dependence and low ΔCp values, which difficulted the assignment of a glass transition. MTT appeared as an enthalpic relaxation independent on frequency or on water content. This transition was related to changes in mechanical properties and with the stabilization of proton mobility.
Non-emergent clinical services were limited or suspended during the early stages of the coronavirus disease 2019 (COVID-19) pandemic in the United States (U.S.). This could adversely impact epidemics ...of public health importance, such as HIV, and access to testing, which is a cornerstone of prevention efforts.
In this observational study, we collected HIV testing and positivity rate clinical data from four geographically diverse U.S. healthcare systems in New Orleans, Louisiana; Minneapolis, Minnesota; Providence, Rhode Island; and, Seattle, Washington. Data from 2019 to 2020 were examined to assess changes in HIV testing in community-based, emergency department, and outpatient settings. Poisson regression was used to explore trends in HIV testing through phases of the COVID-19 pandemic.
In outpatient settings, there was a 68-97% reduction in the number of HIV tests per week during each state's stay-at-home order period, compared to during the pre-stay-at-home order period in early 2020. HIV testing remained reduced 11-54% after states transitioned to advisory phases. The HIV positivity rate increased slightly at outpatient settings, except in New Orleans where it fell.
We found a concerning trend of substantially decreased HIV testing across four geographically diverse sites. These findings suggest that new HIV infections within the U.S. may be undiagnosed and not yet linked to clinical care and services, as a consequence of the COVID-19 pandemic. Thus, augmented efforts to identify patients and link them to HIV services will be needed as healthcare settings return to full operation.
U.S. National Institute of Mental Health.
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► A binuclear mechanism for water oxidation is evaluated for transition metal oxides. ► Homonuclear transition metal oxides are classified. ► Improved electrocatalysis is obtained in ...suitable hetero-binuclear systems. ► Rationale for improved electrocatalytic performance in selectively mixed metal oxides is arrived at.
The energy profiles of the di-hydroxo – di-oxo – peroxo pathway are discussed for a set of 3d transition metal oxides comprising V(III–V), Cr(III–V), Mn(II–IV, Mn(III–V), Fe(II–IV), Co(II–IV) and Ni(II–IV) using density functional theory (DFT). Two classes of oxides were identified. The first class, comprising V(III–V), Cr(III–V) and Fe(II–IV), displays exothermicity for the oxidation of di-hydroxo to di-oxo versus the tyrosine/tyrosyl-radical (TyrOH/TyrO) couple and endothermicity for the subsequent OO bond formation (−/+ class), while the second class, comprising Mn(III–V), Co(II–IV) and Ni(II–IV), shows endothermicity with respect to the oxidation step and exothermicity for the OO bond formation (+/− class). The energetics of the endothermicity (exothermicity) for the oxidation step is reflected in the exothermicity (endothermicity) of the subsequent OO bond formation step. Mn(II–IV) is not part of any of the two classes. Instead it shows zero exothermicity with respect to TyrOH/TyrO for the oxidation step and a small endothermicity for the OO bond formation step. Despite the promising energy profile Mn(II–IV) is argued to be inactive due to a large activation barrier. A set of improved hetero-nuclear candidate catalysts is predicted by mixing −/+ with +/− transition metal oxides. A simple and efficient method to estimate the energy profile of mixed transition metal oxides from the homo-nuclear systems is demonstrated. The validity of this procedure is checked and agreement with the explicitly calculated values is found. All considered heteronuclear candidate catalysts display enhanced performance compared to the pure homonuclear systems.
Loss of employment contributes significantly to the burden of stroke on individuals and society. There is limited information on factors influencing return to work after stroke.
To investigate the ...frequency and determinants of return to paid work after stroke in a multi-ethnic urban population.
Patterns of return to work were examined among people with first ever stroke registered in the population based South London Stroke Register. Employment status and functional outcome (Barthel Index (BI), Frenchay Activity Index (FAI)) were assessed 1 year after stroke. Associations between baseline characteristics and return to paid work were analysed by multivariable logistic regression analysis.
Among 2874 patients with first ever strokes in 1995-2004, 400 (15%) were working before the stroke. At 1 year, 94 (35%) of 266 survivors had returned to paid work. Black ethnicity (OR 0.41; 95% CI 0.19 to 0.88), female sex (0.43; 0.21 to 0.91), older age (p<0.001), diabetes (0.25; 0.08 to 0.79) and dependence (BI < or = 19) in the acute phase (0.24; 0.11 to 0.49) were independently associated with lower odds of return to work in multivariable analysis. Better functional outcome at 1 year was associated with return to paid work (p<0.001) but 53% of 161 independent (BI > 19) and 39% of 96 very active (FAI > 30/45) individuals had not resumed work.
There were important sociodemographic differences in return to work after stroke that were independent of clinical and service use variables included in the analysis. A large proportion of patients did not resume work despite excellent functional outcome.
This study investigates the effect of fractionated (two-part) PDT on the long-term local control rate (LCR) using the concentration of reactive oxygen species (ROS
) as a dosimetry quantity. Groups ...with different fractionation schemes are examined, including a 2 h interval between light delivery sessions to cumulative fluences of 135, 180, and 225 J/cm
. While the total treatment time remains constant within each group, the division of treatment time between the first and second fractionations are explored to assess the impact on long-term survival at 90 days. In all preclinical studies, Photofrin is intravenously administered to mice at a concentration of 5 mg/kg, with an incubation period between 18 and 24 h before the first light delivery session. Fluence rate is fixed at 75 mW/cm
. Treatment ensues via a collimated laser beam, 1 cm in diameter, emitting light at 630 nm. Dosimetric quantities are assessed for all groups along with long-term (90 days) treatment outcomes. This study demonstrated a significant improvement in long-term survival after fractionated treatment schemes compared to single-fraction treatment, with the optimal 90-day survival increasing to 63%, 86%, and 100% vs. 20%, 25%, and 50%, respectively, for the three cumulative fluences. The threshold ROS
for the optimal scheme of fractionated Photofrin-mediated PDT, set at 0.78 mM, is significantly lower than that for the single-fraction PDT, at 1.08 mM.
Aberrant expression of the epidermal growth factor receptor (EGFR) is a common characteristic of many cancers, including non-small cell lung carcinoma (NSCLC), head and neck squamous cell carcinoma, ...and ovarian cancer. Although EGFR is currently a favorite molecular target for the treatment of these cancers, inhibition of the receptor with small-molecule inhibitors (i.e., erlotinib) or monoclonal antibodies (i.e., cetuximab) does not provide long-term therapeutic benefit as standalone treatment. Interestingly, we have found that addition of erlotinib to photodynamic therapy (PDT) can improve treatment response in typically erlotinib-resistant NSCLC tumor xenografts. Ninety-day complete response rates of 63% are achieved when erlotinib is administered in three doses before PDT of H460 human tumor xenografts, compared with 16% after PDT-alone. Similar benefit is found when erlotinib is added to PDT of A549 NCSLC xenografts. Improved response is accompanied by increased vascular shutdown, and erlotinib increases the in vitro cytotoxicity of PDT to endothelial cells. Tumor uptake of the photosensitizer (benzoporphyrin derivative monoacid ring A; BPD) is increased by the in vivo administration of erlotinib; nevertheless, this elevation of BPD levels only partially accounts for the benefit of erlotinib to PDT. Thus, pretreatment with erlotinib augments multiple mechanisms of PDT effect that collectively lead to large improvements in therapeutic efficacy. These data demonstrate that short-duration administration of erlotinib before PDT can greatly improve the responsiveness of even erlotinib-resistant tumors to treatment. Results will inform clinical investigation of EGFR-targeting therapeutics in conjunction with PDT.
Abstract Background Chagas disease has a long clinically silent period following Trypanosoma cruzi infection and before development of overt clinical pathology; detectable biomarkers of infection and ...pathogenesis are urgently needed. We tested 22 biomarkers known to be associated with cardiomyopathy to evaluate if a biomarker signature could successfully classify T. cruzi seropositive subjects into clinical Chagas disease stage groups. Methods This cross-sectional retrospective case–control study enrolled T. cruzi seropositive blood donors (BD) who were further characterized as having chronic Chagas cardiomyopathy (CC-BD) or not (nonCC-BD) and seronegative (SN) control donors; we also included clinically diagnosed Chagas cardiomyopathy patients (CC-P). All subjects underwent a health history questionnaire, medical examination, electro- and echocardiograms (ECG and Echo) and phlebotomy. Biomarkers were measured on blinded samples by luminex bead array and Ortho VITROS. Results A clear biomarker pattern was observed only in more severe cardiac disease; this pattern included significantly elevated levels of inflammatory cytokines IFN-γ, IL-6, IL-10 and TNF-α and soluble cardiovascular disease biomarkers CK-MB, troponin, myoglobin, VCAM and NTproBNP while there were lower levels of MPO, PAI-1, and MCP-1. The markers determined to be the most predictive of disease by ROC curve analysis were NTproBNP and T. cruzi PCR status. Conclusions Although many biomarkers demonstrated increased or decreased concentrations among the clinical forms of Chagas disease, NTproBNP and T. cruzi PCR were the only tests that would independently be of clinical value for disease staging, in concert with ECG, Echo and clinical assessments.
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