A mouse-human phase 1 co-clinical trial of a protease-activated fluorescent probe for imaging cancer

Local recurrence is a common cause of treatment failure for patients with solid tumors. Intraoperative detection of microscopic residual cancer in the tumor bed could be used to decrease the risk of a positive surgical margin, reduce rates of reexcision, and tailor adjuvant therapy. We used a protease-activated fluorescent imaging probe, LUM015, to detect cancer in vivo in a mouse model of soft tissue sarcoma (STS) and ex vivo in a first-in-human phase 1 clinical trial. In mice, intravenous injection of LUM015 labeled tumor cells, and residual fluorescence within the tumor bed predicted local recurrence. In 15 patients with STS or breast cancer, intravenous injection of LUM015 before surgery was well tolerated. Imaging of resected human tissues showed that fluorescence from tumor was significantly higher than fluorescence from normal tissues. LUM015 biodistribution, pharmacokinetic profiles, and metabolism were similar in mouse and human subjects. Tissue concentrations of LUM015 and its metabolites, including fluorescently labeled lysine, demonstrated that LUM015 is selectively distributed to tumors where it is activated by proteases. Experiments in mice with a constitutively active PEGylated fluorescent imaging probe support a model where tumor-selective probe distribution is a determinant of increased fluorescence in cancer. These co-clinical studies suggest that the tumor specificity of protease-activated imaging probes, such as LUM015, is dependent on both biodistribution and enzyme activity. Our first-in-human data support future clinical trials of LUM015 and other protease-sensitive probes

THE ROLE OF STIGMA IN THE GLOBAL MENTAL HEALTH CRISIS: A LITERATURE REVIEW

“This oppressive darkness is too much for me to bear alone, but my family and community tells me that nothing’s wrong with me. They say if I would only pray more, or if I would reach out and help others, then I would be fine.” This statement negates the depressive symptoms of the individual and attributes the “oppressive darkness” to the personhood of the individual in a negative light. Underlying those statements are erroneous beliefs, negative attitudes, and discriminatory behaviors related to mental illness. Stigma plays a large role in this. This is prevalent in many Low and Middle Income Countries as well as in High Income Countries. Across the globe, people with mental illness, either common mental health disorders or chronic mental illnesses, are not valued as equally nor treated as respectfully as persons who do not have mental illness. This article addresses the global mental health crisis and the continued need to make it a global health priority.</jats:p

Mouse embryonic stem cells carrying one or two defective <i>Msh2</i> alleles respond abnormally to oxidative stress inflicted by low-level radiation

Chronic oxidative stress may play a critical role in the pathogenesis of many human cancers. Here, we report that mouse embryonic stem (ES) cells deficient in DNA mismatch repair responded abnormally when exposed to low levels of ionizing radiation, a stress known to generate oxidative DNA damage. ES cells derived from mice carrying either one or two disrupted Msh2 alleles displayed an increased survival following protracted exposures to low-level ionizing radiation as compared with wild-type ES cells. The increases in survival exhibited by ES cells deficient in DNA mismatch repair appeared to have resulted from a failure to efficiently execute cell death (apoptosis) in response to radiation exposure. For each of the ES cell types, prolonged low-level radiation treatment generated oxidative genome damage that manifested as an accumulation of oxidized bases in genomic DNA. However, ES cells from Msh2 +/− and Msh2 −/− mice accumulated more oxidized bases as a consequence of low-level radiation exposure than ES cells from Msh2 +/+ mice. The propensity for normal cells with mismatch repair enzyme deficiencies, including cells heterozygous for inactivating mismatch repair enzyme gene mutations, to survive promutagenic genome insults accompanying oxidative stresses may contribute to the increased cancer risk characteristic of the hereditary nonpolyposis colorectal cancer syndrome. </jats:p

Development and validation of a 6-plex Luminex-based assay for measuring human serum antibodies to group B streptococcus capsular polysaccharides

ABSTRACTSix serotypes (Ia, Ib, II, III, IV, and V) cause nearly all group B streptococcal (GBS) disease globally. Capsular polysaccharide (CPS) conjugate vaccines aim to prevent GBS disease, however, licensure of a vaccine would depend on a standardized serological assay for measuring anti-CPS IgG responses. A multiplex direct Luminex-based immunoassay (dLIA) has been developed to simultaneously measure the concentration of serum IgG specific for the six prevalent GBS CPS serotypes. Assay validation was performed using serum samples obtained from human subjects vaccinated with an investigational 6-valent GBS CPS conjugate vaccine. Results for the assay are expressed as IgG concentrations (µg/mL) using a human serum reference standard composed of pooled sera from vaccinated subjects. The lower limits of quantitation (LLOQ) for all serotypes covered in the 6-plex GBS IgG dLIA fell within the range of 0.002-0.022 µg/mL IgG. Taken together, the 6-plex GBS IgG dLIA platform is specific for the six GBS serotypes included in Pfizer’s investigational vaccine, has a wide dilution adjusted assay range, and is precise (<18.5% relative standard deviation) for all serotypes, and, therefore, is suitable for quantitatively measuring vaccine-induced or naturally acquired serotype-specific anti-CPS IgG responses against GBS

External Beam Radiation Therapy for Palliation of Symptomatic Bone Metastases: An ASTRO Clinical Practice Guideline

PURPOSE: This guideline provides evidence-based recommendations for palliative external beam radiation therapy (RT) in symptomatic bone metastases. METHODS: The ASTRO convened a task force to address 5 key questions regarding palliative RT in symptomatic bone metastases. Based on a systematic review by the Agency for Health Research and Quality, recommendations using predefined consensus-building methodology were established; evidence quality and recommendation strength were also assessed. RESULTS: For palliative RT for symptomatic bone metastases, RT is recommended for managing pain from bone metastases and spine metastases with or without spinal cord or cauda equina compression. Regarding other modalities with RT, for patients with spine metastases causing spinal cord or cauda equina compression, surgery and postoperative RT are conditionally recommended over RT alone. Furthermore, dexamethasone is recommended for spine metastases with spinal cord or cauda equina compression. Patients with nonspine bone metastases requiring surgery are recommended postoperative RT. Symptomatic bone metastases treated with conventional RT are recommended 800 cGy in 1 fraction (800 cGy/1 fx), 2000 cGy/5 fx, 2400 cGy/6 fx, or 3000 cGy/10 fx. Spinal cord or cauda equina compression in patients who are ineligible for surgery and receiving conventional RT are recommended 800 cGy/1 fx, 1600 cGy/2 fx, 2000 cGy/5 fx, or 3000 cGy/10 fx. Symptomatic bone metastases in selected patients with good performance status without surgery or neurologic symptoms/signs are conditionally recommended stereotactic body RT over conventional palliative RT. Spine bone metastases reirradiated with conventional RT are recommended 800 cGy/1 fx, 2000 cGy/5 fx, 2400 cGy/6 fx, or 2000 cGy/8 fx; nonspine bone metastases reirradiated with conventional RT are recommended 800 cGy/1 fx, 2000 cGy/5 fx, or 2400 cGy/6 fx. Determination of an optimal RT approach/regimen requires whole person assessment, including prognosis, previous RT dose if applicable, risks to normal tissues, quality of life, cost implications, and patient goals and values. Relatedly, for patient-centered optimization of treatment-related toxicities and quality of life, shared decision making is recommended. CONCLUSIONS: Based on published data, the ASTRO task force\u27s recommendations inform best clinical practices on palliative RT for symptomatic bone metastases