Photodynamic Therapy: Agents and Mechanisms

Despite enormous efforts, cancer remains a leading cause of morbidity and mortality world-wide. The main challenges currently facing cancer therapy include lack of adequate tumor targeting, failure to treat hypoxic tumor cells, and induction therapy resistant tumors. A solution to these limitations can be found in photodynamic therapy (PDT) which combines light and light activatable compounds, photosensitizers (PSs), to produce cytotoxic reactive oxygen species (ROS) to damage tumor tissue. This creates a spatiotemporal therapeutic effect, where cell damage only occurs at the intersection of the PS and light. PDT can treat tumors through unique mechanisms which reduce induction of tumor resistance. Although PDT has had clinical success in treating skin cancer and macular degeneration, it has yet to be a widely adopted or accepted therapy. In this dissertation, we lay the groundwork for a new PDT strategy which systematically addresses and optimizes each aspect of PDT. To overcome the limitation of PDT to treat hypoxic tumors, we developed a novel nano-photosensitizer, TiO2-N3, that produces cytotoxic ROS even under hypoxic conditions. Next, to determine the optimal intracellular target for TiO2-N3, we compared the therapeutic outcome of ROS generated in endosomes, lysosomes, mitochondria, and ER. We identified the ER as the organelle most sensitive to ROS damage and therefore the optimal intracellular target for TiO2-N3. Finally, to deliver TiO2-N3 to tumors in vivo, we developed two tumor targeting agents, both of which are equipped with near-infrared fluorophores for whole body imaging. This work has laid the foundation for a novel PDT strategy by overcoming issues that have limited the clinical adoption of PDT

Looking for Dante: exploring the 'Divine Comedy' in print from the 15th century to today

When we pick up a book, we might forget that as well as reading a text we are looking at a physical object. This is not the case for the medieval poet Dante, whose famous poem, the ‘Divine Comedy’, was made into beautiful objects in the form of early printed books. The oldest of these books date back to the very beginning of the print revolution, over 550 years ago. In 2023, Rebecca Bowen and Simon Gilson – University of Oxford specialists in Dante Studies and Book History – invited artist-printmaker Wuon-Gean Ho to examine these books and make a contemporary response. The result is a body of work called ‘Looking for Dante’, a collection of artwork, flm, and essays that explores universal themes in Dante’s text and considers their relevance today. Moving from morality and condemnation through love and redemption, ‘Looking for Dante’ offers a modern reading of the ‘Divine Comedy’ and the historical books that preserve it, refecting on the universal appeal of ink on paper

Calibration-free structured-illumination photoacoustic flowgraphy of transverse flow in scattering media

We propose a calibration-free photoacoustic (PA) method for transverse flow measurements. In this method, a pulsed periodically structured (i.e., grating patterned) optical beam is used to illuminate flowing absorptive particles in an optically scattering medium. The PA signal amplitudes measured over consecutive laser pulses carry an imprint of the illumination structure. The modulation frequency of the imprint is proportional to the component of the flow speed projected onto the normal axis of the striped illumination pattern. This method can tolerate high particle density, and is insensitive to the particle size, thus calibration-free. Bovine blood and microsphere phantoms were used to validate the proposed method. Blood flow in a mouse ear was measured in vivo as well

Cloning, Purification, and Partial Characterization of the Halobacterium sp. NRC-1 Minichromosome Maintenance (MCM) Helicase

The MCM gene from the archaeon Halobacterium, with and without its intein, was cloned into an Escherichia coli expression vector, overexpressed and the protein was purified and antibodies were generated. The antibodies were used to demonstrate that in vivo only the processed enzyme, without the intein, could be detected

Calibration-free structured-illumination photoacoustic flowgraphy of transverse flow in scattering media

We propose a calibration-free photoacoustic (PA) method for transverse flow measurements. In this method, a pulsed periodically structured (i.e., grating patterned) optical beam is used to illuminate flowing absorptive particles in an optically scattering medium. The PA signal amplitudes measured over consecutive laser pulses carry an imprint of the illumination structure. The modulation frequency of the imprint is proportional to the component of the flow speed projected onto the normal axis of the striped illumination pattern. This method can tolerate high particle density, and is insensitive to the particle size, thus calibration-free. Bovine blood and microsphere phantoms were used to validate the proposed method. Blood flow in a mouse ear was measured in vivo as well

The 'Antiretrovirals, Sexual Transmission Risk and Attitudes' (ASTRA) study. Design, methods and participant characteristics.

Life expectancy for people diagnosed with HIV has improved dramatically however the number of new infections in the UK remains high. Understanding patterns of sexual behaviour among people living with diagnosed HIV, and the factors associated with having condom-less sex, is important for informing HIV prevention strategies and clinical care. In addition, in view of the current interest in a policy of early antiretroviral treatment (ART) for all people diagnosed with HIV in the UK, it is of particular importance to assess whether ART use is associated with increased levels of condom-less sex. In this context the ASTRA study was designed to investigate current sexual activity, and attitudes to HIV transmission risk, in a large unselected sample of HIV-infected patients under care in the UK. The study also gathered background information on demographic, socio-economic, lifestyle and disease-related characteristics, and physical and psychological symptoms, in order to identify other key factors impacting on HIV patients and the behaviours which underpin transmission. In this paper we describe the study rationale, design, methods, response rate and the demographic characteristics of the participants. People diagnosed with HIV infection attending 8 UK HIV out-patient clinics in 2011-2012 were invited to participate in the study. Those who agreed to participate completed a confidential, self-administered pen-and-paper questionnaire, and their latest CD4 count and viral load test results were recorded. During the study period, 5112 eligible patients were invited to take part in the study and 3258 completed questionnaires were obtained, representing a response rate of 64% of eligible patients. The study includes 2248 men who have sex with men (MSM), 373 heterosexual men and 637 women. Future results from ASTRA will be a key resource for understanding HIV transmission within the UK, targeting prevention efforts, and informing clinical care of individuals living with HIV

Expanding Rural Opioid Addictions Treatment: An Inter-institutional, Inter-professional Telehealth Case Study Simulation

Purpose: To determine if inter-institutional collaboration, using telehealth technology, inter-professional education techniques, and case study methodology is a feasible way to teach health professions students how to appropriately address opioid addictions, especially in rural populations with limited health care access. Study subjects: Ten health professions students from four Virginia universities participated. Professions represented included medicine, nursing, physical therapy, social work, nutrition, and psychology at the graduate and undergraduate levels. Methods: Inter-professional faculty from four Virginia universities developed an opioid addiction simulation case study using a standardized patient. Students from different regions engaged in a facilitated patient interview and care planning via secure virtual meeting platform. Faculty observation and feedback, student feedback, and inter-professional education assessments were used to assess this pilot study. Findings: Inter-institutional faculty collaboration and telehealth technology was successfully employed to convene multiple health professions students from different sites; simulation case study methodology using a standardized patient was effective and compelling; students effectively utilized interprofessional competencies and skills to develop a comprehensive and holistic care plan for opioid addiction treatment. Conclusions: Telehealth technology, inter-professional education, and simulation case study methodology can be successfully used to teach health professions students how to collaborate to address the opioid crisis, especially in resource-limited rural areas. Implications: Many resources are necessary to successfully treat opioid addictions. By using telehealth technology combined with inter-professional concepts and skills, resources can be shared between institutions and professions to successfully treat patients with opioid addictions in resource-limited areas

The Role and Mechanism of Erythrocyte Invasion by Francisella tularensis

Francisella tularensis is an extremely virulent bacterium that can be transmitted naturally by blood sucking arthropods. During mammalian infection, F. tularensis infects numerous types of host cells, including erythrocytes. As erythrocytes do not undergo phagocytosis or endocytosis, it remains unknown how F. tularensisinvades these cells. Furthermore, the consequence of inhabiting the intracellular space of red blood cells (RBCs) has not been determined. Here, we provide evidence indicating that residing within an erythrocyte enhances the ability of F. tularensis to colonize ticks following a blood meal. Erythrocyte residence protected F. tularensis from a low pH environment similar to that of gut cells of a feeding tick. Mechanistic studies revealed that the F. tularensis type VI secretion system (T6SS) was required for erythrocyte invasion as mutation of mglA (a transcriptional regulator of T6SS genes), dotU, or iglC (two genes encoding T6SS machinery) severely diminished bacterial entry into RBCs. Invasion was also inhibited upon treatment of erythrocytes with venom from the Blue-bellied black snake (Pseudechis guttatus), which aggregates spectrin in the cytoskeleton, but not inhibitors of actin polymerization and depolymerization. These data suggest that erythrocyte invasion by F. tularensis is dependent on spectrin utilization which is likely mediated by effectors delivered through the T6SS. Our results begin to elucidate the mechanism of a unique biological process facilitated by F. tularensis to invade erythrocytes, allowing for enhanced colonization of ticks

A Call to Action: Taking the Untenable out of Women Professors’ Pregnancy, Postpartum, and Caregiving Demands

Despite becoming increasingly represented in academic departments, women scholars face a critical lack of support as they navigate demands pertaining to pregnancy, motherhood, and child caregiving. In addition, cultural norms surrounding how faculty and academic leaders discuss and talk about tenure, promotion, and career success have created pressure for women who wish to grow their family and care for their children, leading to questions about whether it is possible for these women to have a family and an academic career. The current paper is a call to action for academia to build structures that support women professors as they navigate the complexities of pregnancy, the postpartum period, and the caregiving demands of their children. We specifically call on those of us in I-O psychology, management, and related departments to lead the way. In making this call, we first present the realistic, moral, and financial cases for why this issue needs to be at the forefront of discussions surrounding success in the academy. We then discuss how in the U.S. and elsewhere, an absence of policies supporting women places two groups of academics—department heads (as the leaders of departments who have discretion outside of formal policies to make work better for women) and other faculty members (as potential allies both in the department and within our professional organizations)—in a critical position to enact support and change. We conclude with our boldest call—to make a cultural shift that shatters the assumption that having a family is not compatible with academic success. Combined, we seek to launch a discussion that leads directly to necessary and overdue changes in how women scholars are supported in academia

An analysis of baseline data from the PROUD study: an open-label randomised trial of pre-exposure prophylaxis

Background: Pre-exposure prophylaxis (PrEP) has proven biological efficacy to reduce the sexual acquisition of the human immunodeficiency virus (HIV). The PROUD study found that PrEP conferred higher protection than in placebo-controlled trials, reducing HIV incidence by 86 % in a population with seven-fold higher HIV incidence than expected. We present the baseline characteristics of the PROUD study population and place the findings in the context of national sexual health clinic data. Methods: The PROUD study was designed to explore the real-world effectiveness of PrEP (tenofovir-emtricitabine) by randomising HIV-negative gay and other men who have sex with men (GMSM) to receive open-label PrEP immediately or after a deferral period of 12 months. At enrolment, participants self-completed two baseline questionnaires collecting information on demographics, sexual behaviour and lifestyle in the last 30 and 90 days. These data were compared to data from HIV-negative GMSM attending sexual health clinics in 2013, collated by Public Health England using the genitourinary medicine clinic activity database (GUMCAD). Results: The median age of participants was 35 (IQR: 29–43). Typically participants were white (81 %), educated at a university level (61 %) and in full-time employment (72 %). Of all participants, 217 (40 %) were born outside the UK. A sexually transmitted infection (STI) was reported to have been diagnosed in the previous 12 months in 330/515 (64 %) and 473/544 (87 %) participants reported ever having being diagnosed with an STI. At enrolment, 47/280 (17 %) participants were diagnosed with an STI. Participants reported a median (IQR) of 10 (5–20) partners in the last 90 days, a median (IQR) of 2 (1–5) were condomless sex acts where the participant was receptive and 2 (1–6) were condomless where the participant was insertive. Post-exposure prophylaxis had been prescribed to 184 (34 %) participants in the past 12 months. The number of STI diagnoses was high compared to those reported in GUMCAD attendees. Conclusions: The PROUD study population are at substantially higher risk of acquiring HIV infection sexually than the overall population of GMSM attending sexual health clinics in England. These findings contribute to explaining the extraordinary HIV incidence rate during follow-up and demonstrate that, despite broad eligibility criteria, the population interested in PrEP was highly selective. Trial registration: Current Controlled TrialsISRCTN94465371. Date of registration: 28 February 2013