Using Light to Kill Cancer: Development of a Novel Photodynamic Therapy

Photodynamic therapy (PDT) is a treatment that uses special drugs called photosensitizing agents along with light to kill cancer cells. The specialized drugs only work after they have been activated or turned on by light. Photodynamic therapy may also be called photoradiation therapy, phototherapy, or photochemotherapy. In this research, I focused on the addition of four separate hydroxyl-amines to the unsubstituted porphyrin core, H2TPPC. The hydroxyl-amines attached to the porphyrin core were 5- amino-1-pentanol, 2-amino-2-ethyl-1, 3-propanediol, 3-amino-propanediol, and 5-aminovaleric acid. The novel water soluble PDT agents, H2TPP-A50H, H2TPP-2ET, H2TPP-3NH, and H2TPP-5AV, which were synthesized and purified, was structurally characterized by infrared spectroscopy (IR), nuclear magnetic resonance spectroscopy (NMR), and UV-vis spectroscopy. The purity of the compounds were confirmed through analyzing using high performance liquid chromatography (HPLC). Finally, the cytotoxicity of the novel PDT porphyrins were determined in the presence and absence of light using MTT assay on MDA-MB-231 triple negative breast cancer cells and Ewing\u27s Sarcoma cells

Challenges with Delivering Gender-Specific and Comprehensive Primary Care to Women Veterans

Background The growing presence of women veterans in Veterans Administration (VA) settings has prompted the need for greater attention to clinical proficiency related to women's health (WH) primary care needs. Instead of making appointments for multiple visits or referring patients to a WH clinic or alternate site for gender-specific care, a comprehensive primary care model now allows for women veteran patients be seen by primary care providers (PCPs) who have WH training/experience and can see patients for both primary and WH care in the context of a single visit. However, little is currently known about the barriers and facilitators WH-PCPs face in using this approach to incorporate gender-specific services into women veterans' primary care services. Methods We conducted qualitative in-depth interviews with 22 WH-PCPs at one Midwestern VA Medical Center. All participants were members of one of four outpatient primary care clinics within the main medical center, one off-site satellite clinic, or two off-site community-based outpatient clinics. Results Inductive thematic analysis identified six themes: 1) Time constraints, 2) importance of staff support, 3) necessity of sufficient space and equipment/supplies, 4) perceptions of discomfort among patients with trauma histories, 5) lack of education/training, and 6) challenges with scheduling/logistics. Conclusion Although adequate staff was a key facilitator, the findings suggest that there may be barriers that undermine the ability of VA WH-PCPs to provide high-quality, comprehensive primary and gender-specific care. The nature of these barriers is multifactorial and multilevel in nature, and may therefore require special policy and practice action

Exploring Student and Faculty Reactions to Smartphone Policies in the Classroom

The current studies examined attitudes about classroom cell phone usage and reactions to cell phone policies among students and faculty. Study 1 documented students’ and faculty’s perceptions of appropriateness of cell phones in the classroom and about what classroom policies should be. Students reported greater leniency regarding cell phone use in the classroom and suggested stricter penalties for inappropriate use. Study 2 surveyed faculty and students about four cell phone policies ranging in level of leniency. The results indicated as policy leniency increased, cell phone use increased and enforcement decreased. Study 3 evaluated students’ reactions to actual classroom cell phone policies. Students reported using their phones more than they anticipated and rated policy enforcement lower than expected, except under a prohibitive policy. These results indicate that differences remain between faculty and students and that there is a mismatch between what students prefer and perceive as effective cell phone policies

Differential Gene Expression in High- and Low-Active Inbred Mice

Numerous candidate genes have been suggested in the recent literature with proposed roles in regulation of voluntary physical activity, with little evidence of these genes' functional roles. This study compared the haplotype structure and expression profile in skeletal muscle and brain of inherently high- (C57L/J) and low- (C3H/HeJ) active mice. Expression of nine candidate genes [Actn2, Actn3, Casq1, Drd2, Lepr, Mc4r, Mstn, Papss2, and Glut4 (a.k.a. Slc2a4)] was evaluated via RT-qPCR. SNPs were observed in regions of Actn2, Casq1, Drd2, Lepr, and Papss2; however, no SNPs were located in coding sequences or associated with any known regulatory sequences. In mice exposed to a running wheel, Casq1 (P = 0.0003) and Mstn (P = 0.002) transcript levels in the soleus were higher in the low-active mice. However, when these genes were evaluated in naïve animals, differential expression was not observed, demonstrating a training effect. Among naïve mice, no genes in either tissue exhibited differential expression between strains. Considering that no obvious SNP mechanisms were determined or differential expression was observed, our results indicate that genomic structural variation or gene expression data alone is not adequate to establish any of these genes' candidacy or causality in relation to regulation of physical activity

Standard- versus intermediate-dose enoxaparin for anti-factor Xa guided thromboprophylaxis in critically ill patients with COVID-19

Abstract The prevalence of venous thromboembolism (VTE) is high in critically ill patients with COVID-19. Dosing of Low Molecular Weight Heparin (LMWH) for thromboprophylaxis in patients with severe COVID-19 is subject to ongoing debate. In this brief report, we describe our study where we retrospectively examined the efficacy of standard- versus intermediate-dosing of enoxaparin in attaining and maintaining accepted prophylactic levels of anti-Factor Xa (anti-FXa) in critically ill patients with COVID-19. We collected data for all patients with confirmed COVID-19 who were treated with enoxaparin for thromboprophylaxis in a single Intensive Care Unit (ICU) in the United Kingdom between 31st March and 16th November 2020. Standard-dose of enoxaparin was 40 mg subcutaneously once daily for patients with normal renal function and body weight between 50 and 100 kg; the intermediate-dose was 40 mg subcutaneously twice daily. Anti-FXa peak concentrations between 0.2-0.4 IU/ml were considered appropriate for thromboprophylaxis. Age, sex, weight, Body Mass Index, APACHE II score, ICU length of stay, initial P/F ratio and creatinine were not statistically significantly different between standard- and intermediate-dose thromboprophylaxis cohorts. In the standard-dose group, the median initial anti-FXa level was 0.13 (interquartile range 0.06-0.18) compared to 0.26 (0.21-0.33) in the intermediate-dose cohort (p < 0.001). On repeated measurement, in the standard dose cohort, 44 of 95 (46%) anti-FXa levels were < 0.2 IU/ml compared with 24 of 132 (18%) levels in the intermediate-dose cohort even after dose-adjustment. There was one radiologically confirmed pulmonary embolism (PE) on computed tomography pulmonary angiogram during hospital admission in each cohort. Our study supports starting intermediate-dose thromboprophylaxis for critically ill patients with COVID-19 to achieve anti-FXa levels in the accepted thromboprophylactic range although further study is required to investigate whether anti-FXa guided thromboprophylaxis is safe and effective in reducing the incidence of VTEs in critically ill patients with COVID-19

A parametrization of the growth index of matter perturbations in various Dark Energy models and observational prospects using a Euclid-like survey

We provide exact solutions to the cosmological matter perturbation equation in a homogeneous FLRW universe with a vacuum energy that can be parametrized by a constant equation of state parameter $w$ and a very accurate approximation for the Ansatz $w(a)=w_0+w_a(1-a)$. We compute the growth index \gamma=\log f(a)/\log\Om_m(a), and its redshift dependence, using the exact and approximate solutions in terms of Legendre polynomials and show that it can be parametrized as $\gamma(a)=\gamma_0+\gamma_a(1-a)$ in most cases. We then compare four different types of dark energy (DE) models: $w\Lambda$CDM, DGP, $f(R)$ and a LTB-large-void model, which have very different behaviors at z\gsim1. This allows us to study the possibility to differentiate between different DE alternatives using wide and deep surveys like Euclid, which will measure both photometric and spectroscopic redshifts for several hundreds of millions of galaxies up to redshift $z\simeq 2$. We do a Fisher matrix analysis for the prospects of differentiating among the different DE models in terms of the growth index, taken as a given function of redshift or with a principal component analysis, with a value for each redshift bin for a Euclid-like survey. We use as observables the complete and marginalized power spectrum of galaxies $P(k)$ and the Weak Lensing (WL) power spectrum. We find that, using $P(k)$, one can reach (2%, 5%) errors in $(w_0, w_a)$, and (4%, 12%) errors in $(\gamma_0, \gamma_a)$, while using WL we get errors at least twice as large. These estimates allow us to differentiate easily between DGP, $f(R)$ models and $\Lambda$CDM, while it would be more difficult to distinguish the latter from a variable equation of state parameter or LTB models using only the growth index.}Comment: 29 pages, 7 figures, 6 table

Differential Gene Expression in High- and Low-Active Inbred Mice

Numerous candidate genes have been suggested in the recent literature with proposed roles in regulation of voluntary physical activity, with little evidence of these genes’ functional roles. This study compared the haplotype structure and expression profile in skeletal muscle and brain of inherently high- (C57L/J) and low- (C3H/HeJ) active mice. Expression of nine candidate genes [Actn2, Actn3, Casq1, Drd2, Lepr, Mc4r, Mstn, Papss2, and Glut4 (a.k.a. Slc2a4)] was evaluated via RT-qPCR. SNPs were observed in regions of Actn2, Casq1, Drd2, Lepr, and Papss2; however, no SNPs were located in coding sequences or associated with any known regulatory sequences. In mice exposed to a running wheel, Casq1 (P=0.0003) and Mstn (P=0.002) transcript levels in the soleus were higher in the low-active mice. However, when these genes were evaluated in naïve animals, differential expression was not observed, demonstrating a training effect. Among naïve mice, no genes in either tissue exhibited differential expression between strains. Considering that no obvious SNP mechanisms were determined or differential expression was observed, our results indicate that genomic structural variation or gene expression data alone is not adequate to establish any of these genes’ candidacy or causality in relation to regulation of physical activity

Integration of Two Diploid Potato Linkage Maps with the Potato Genome Sequence

To facilitate genome-guided breeding in potato, we developed an 8303 Single Nucleotide Polymorphism (SNP) marker array using potato genome and transcriptome resources. To validate the Infinium 8303 Potato Array, we developed linkage maps from two diploid populations (DRH and D84) and compared these maps with the assembled potato genome sequence. Both populations used the doubled monoploid reference genotype DM1-3 516 R44 as the female parent but had different heterozygous diploid male parents (RH89-039-16 and 84SD22). Over 4,400 markers were mapped (1,960 in DRH and 2,454 in D84, 787 in common) resulting in map sizes of 965 (DRH) and 792 (D84) cM, covering 87% (DRH) and 88% (D84) of genome sequence length. Of the mapped markers, 33.5% were in candidate genes selected for the array, 4.5% were markers from existing genetic maps, and 61% were selected based on distribution across the genome. Markers with distorted segregation ratios occurred in blocks in both linkage maps, accounting for 4% (DRH) and 9% (D84) of mapped markers. Markers with distorted segregation ratios were unique to each population with blocks on chromosomes 9 and 12 in DRH and 3, 4, 6 and 8 in D84. Chromosome assignment of markers based on linkage mapping differed from sequence alignment with the Potato Genome Sequencing Consortium (PGSC) pseudomolecules for 1% of the mapped markers with some disconcordant markers attributable to paralogs. In total, 126 (DRH) and 226 (D84) mapped markers were not anchored to the pseudomolecules and provide new scaffold anchoring data to improve the potato genome assembly. The high degree of concordance between the linkage maps and the pseudomolecules demonstrates both the quality of the potato genome sequence and the functionality of the Infinium 8303 Potato Array. The broad genome coverage of the Infinium 8303 Potato Array compared to other marker sets will enable numerous downstream applications

Emissions and Energy Impacts of the Inflation Reduction Act

If goals set under the Paris Agreement are met, the world may hold warming well below 2 C; however, parties are not on track to deliver these commitments, increasing focus on policy implementation to close the gap between ambition and action. Recently, the US government passed its most prominent piece of climate legislation to date, the Inflation Reduction Act of 2022 (IRA), designed to invest in a wide range of programs that, among other provisions, incentivize clean energy and carbon management, encourage electrification and efficiency measures, reduce methane emissions, promote domestic supply chains, and address environmental justice concerns. IRA's scope and complexity make modeling important to understand impacts on emissions and energy systems. We leverage results from nine independent, state-of-the-art models to examine potential implications of key IRA provisions, showing economy wide emissions reductions between 43-48% below 2005 by 2035

Intracranial Efficacy and Survival With Tucatinib Plus Trastuzumab and Capecitabine for Previously Treated HER2-Positive Breast Cancer With Brain Metastases in the HER2CLIMB Trial

PURPOSE: In the HER2CLIMB study, patients with human epidermal growth factor receptor 2 (HER2)-positive breast cancer with brain metastases (BMs) showed statistically significant improvement in progression-free survival (PFS) with tucatinib. We describe exploratory analyses of intracranial efficacy and survival in participants with BMs. PATIENTS AND METHODS: Patients were randomly assigned 2:1 to tucatinib or placebo, in combination with trastuzumab and capecitabine. All patients underwent baseline brain magnetic resonance imaging; those with BMs were classified as active or stable. Efficacy analyses were performed by applying RECIST 1.1 criteria to CNS target lesions by investigator assessment. CNS-PFS (intracranial progression or death) and overall survival (OS) were evaluated in all patients with BMs. Confirmed intracranial objective response rate (ORR-IC) was evaluated in patients with measurable intracranial disease. RESULTS: There were 291 patients with BMs: 198 (48%) in the tucatinib arm and 93 (46%) in the control arm. The risk of intracranial progression or death was reduced by 68% in the tucatinib arm (hazard ratio [HR], 0.32; 95% CI, 0.22 to 0.48; CONCLUSION: In patients with HER2-positive breast cancer with BMs, the addition of tucatinib to trastuzumab and capecitabine doubled ORR-IC, reduced risk of intracranial progression or death by two thirds, and reduced risk of death by nearly half. To our knowledge, this is the first regimen to demonstrate improved antitumor activity against BMs in patients with HER2-positive breast cancer in a randomized, controlled trial