Long-Term Survival in Human Epidermal Growth Factor Receptor 2-Positive Bone-Only Metastatic Breast Cancer: Trastuzumab, Denosumab, and Potential Synergistic Effects.

Breast cancer is the second most common cancer worldwide. There are four main subtypes of breast cancer, one of which involves positivity for human epidermal growth factor receptor 2 (HER2). Here, we present a case series of unusually long survival in three patients with HER2-positive metastatic breast cancer. All cases involved post-menopausal women with bone-only metastases undergoing treatment with the HER2-targeted therapy trastuzumab and the receptor activator of nuclear factor kappa-Β ligand (RANK-L) inhibitor denosumab. Our three patients survived for 17, 13, and 11 years, respectively, from the time of metastasis. The patients who survived for 17 and 13 years both presented with metastatic disease at diagnosis, while the patient who survived for 11 years with metastatic disease was known to have non-metastatic breast cancer for four years prior. We also report the development of foot fractures from minor trauma, as low as walking, despite a bone density reported as normal in the patient with 17 years of treatment. These unusually long survival times and the unusual location of the fractures are questioned to be secondary to the long duration of treatment with HER2-targeted therapy and RANK-L inhibitor therapy. Our case series is the first to describe the use of trastuzumab and denosumab in HER2-positive metastatic breast cancer. All three reported cases had no clinical or radiographic disease progression at the time of reporting. Furthermore, our case of survival for 17 years represents the longest survival time reported yet, raising the possibility of a synergistic relationship between RANK-L inhibitors and HER2-targeted therapy in the long-term control of HER2-positive metastatic breast cancer. This manuscript discusses evidence from primary studies on HER2 and receptor activator of nuclear factor kappa-Β (RANK) signalling and drug responses and hypothesizes on possible mechanisms of synergism. Given that treatment of HER2-positive breast cancer has historically not involved RANK-L inhibition, this study may outline future areas of research in improving treatment algorithms, especially for bone-only metastatic disease.

Regulation of biological processes by ubiquitin ligases: a focus on the Pagano Lab's contribution.

Protein homeostasis depends on many fundamental processes including mRNA synthesis, translation, post-translational modifications, and proteolysis. In the late 70s and early 80s the discovery that the small 76 amino acid protein ubiquitin could be attached to target proteins via a multi-stage process involving ubiquitin-activating enzymes, ubiquitin conjugating enzymes, and ubiquitin ligases, revealed an exciting new post-translational mechanism to regulate protein degradation. This cellular system was uncovered using biochemical methods by Avram Hershko, who would later won the Nobel prize for this discovery; however, the biological functions of ubiquitin ligases remained unknown for many years. It was initially described that ubiquitin modifies proteins at one or more lysine residues and once a long ubiquitin chain was assembled, proteins were degraded by the proteasome. Now we know that proteins can be mono-, multimono-, homotypic poly-, or heterotypic poly-ubiquitylated, each of which confers a specific signal that goes beyond protein degradation regulating additional key cellular functions such as signal transduction, protein localization, recognition of damaged proteins, etc.

Atypical cell cycle regulation promotes mammary stem cell expansion during mammary development and tumourigenesis.

BACKGROUND: The cell cycle of mammary stem cells must be tightly regulated to ensure normal homeostasis of the mammary gland to prevent abnormal proliferation and susceptibility to tumorigenesis. The atypical cell cycle regulator, Spy1 can override cell cycle checkpoints, including those activated by the tumour suppressor p53 which mediates mammary stem cell homeostasis. Spy1 has also been shown to promote expansion of select stem cell populations in other developmental systems. Spy1 protein is elevated during proliferative stages of mammary gland development, is found at higher levels in human breast cancers, and promotes susceptibility to mammary tumourigenesis when combined with loss of p53. We hypothesized that Spy1 cooperates with loss of p53 to increase susceptibility to tumour initiation due to changes in susceptible mammary stem cell populations during development and drives the formation of more aggressive stem like tumours. METHODS: Using a transgenic mouse model driving expression of Spy1 within the mammary gland, mammary development and stemness were assessed. These mice were intercrossed with p53 null mice to study the tumourigenic properties of Spy1 driven p53 null tumours, as well as global changes in signaling via RNA sequencing analysis. RESULTS: We show that elevated levels of Spy1 leads to expansion of mammary stem cells, even in the presence of p53, and an increase in mammary tumour formation. Spy1-driven tumours have an increased cancer stem cell population, decreased checkpoint signaling, and demonstrate an increase in therapy resistance. Loss of Spy1 decreases tumor onset and reduces the cancer stem cell population. CONCLUSIONS: This data demonstrates the potential of Spy1 to expand mammary stem cell populations and contribute to the initiation and progression of aggressive, breast cancers with increased cancer stem cell populations.

High-impact practices in cancer education and research: Undergraduate students' perceptions of skills and career development.

High-impact practices (HIPs) are educational practices that foster student success. HIPs have not been widely used in cancer education and research despite the need for students to develop key transferable skills and cultivate social responsibility. Our study addresses this need by implementing four community-based learning HIPs within the context of cancer education and research. Each HIP was classified as having low, moderate, or high alignment with the traits of effective HIPs. Undergraduate science students participated in one to four HIPs as a Feedback Participant, General Volunteer, Student Leader, or Cancer Undergraduate Research and Education (CURES) Class Student. We then studied the effect of these HIPs on students' development of knowledge and skills; career interest and preparedness; and social responsibility. Results from self-reported questionnaires showed that HIPs increased students' cancer knowledge and developed their transferable and technical skills. Many students reported that these HIPs strongly impacted their career preparedness; positively influenced their interest in pursuing careers in health or biomedical sciences; and encouraged them to participate in community service activities. Thus, these findings provide new insights into the perceived benefits of HIPs in cancer education and research by undergraduate students.

Presentation and Outcome of Patients with Multiple Myeloma (MM), Single Centre Experience from Windsor Essex Regional Cancer Centre.

Introduction: Outcomes for patients with multiple myeloma has significantly improved through the years. This is mainly related to the use of novel agents. Methods: This is a retrospective study that reviewed presentation and outcome of 139 patients with multiple myeloma at the Windsor Essex Regional Cancer Centre from Jan. 1, 2015 to Dec. 31, 2019. Median age was 71 years and most patients had higher risk disease (65.5% either R ISS stage II or III). 30% had high risk FISH for myeloma including del.17P, t (4:14), t (14:16) and Gain (1q21). In terms of presentation, 38.8% had anemia (hemoglobin <100g/L), 18.7% had hypercalcemia, 74.1% had skeletal lytic lesions, 38.8% had pathologic fracture and 17.3% had plasmacytoma. Results: Almost all (92%) of the patients were treated using at least one novel agent (proteasome inhibitor or immunomodulators [ImiDs]). Cyclophosphamide, bortezomib, and dexamethasone (CyBorD) was the most used treatment regimen (48.9%) followed by bortezomib, melphalan and prednisone (BMP) at 28.8% and lenalidomide, dexamethasone (LenDex) at 14.4%. With respect to response to therapy, 51.8% had at least Very good partial response (VGPR), while 9.4% had progressive disease. 33% had autologous stem cell transplant. After a median follow up of 2.4 years, median overall survival was 3.7 years. 2 years overall survival and relapse-free survival were 70% and 83%, respectively. Discussion: Our study showed comparable outcome for patients with multiple myeloma despite older age and higher risk disease. Outcome is expected to improve with the introduction of more novel agents.

Evaluating and optimizing Acid-pH and Direct Lysis RNA extraction for SARS-CoV-2 RNA detection in whole saliva.

COVID-19 has been a global public health and economic challenge. Screening for the SARS-CoV-2 virus has been a key part of disease mitigation while the world continues to move forward, and lessons learned will benefit disease detection beyond COVID-19. Saliva specimen collection offers a less invasive, time- and cost-effective alternative to standard nasopharyngeal swabs. We optimized two different methods of saliva sample processing for RT-qPCR testing. Two methods were optimized to provide two cost-efficient ways to do testing for a minimum of four samples by pooling in a 2.0 mL tube and decrease the need for more highly trained personnel. Acid-pH-based RNA extraction method can be done without the need for expensive kits. Direct Lysis is a quick one-step reaction that can be applied quickly. Our optimized Acid-pH and Direct Lysis protocols are reliable and reproducible, detecting the beta-2 microglobulin (B2M) mRNA in saliva as an internal control from 97 to 96.7% of samples, respectively. The cycle threshold (Ct) values for B2M were significantly higher in the Direct Lysis protocol than in the Acid-pH protocol. The limit of detection for N1 gene was higher in Direct Lysis at ≤ 5 copies/µL than Acid-pH. Saliva samples collected over the course of several days from two COVID-positive individuals demonstrated Ct values for N1 that were consistently higher from Direct Lysis compared to Acid-pH. Collectively, this work supports that each of these techniques can be used to screen for SARS-CoV-2 in saliva for a cost-effective screening platform.

E-learning and research experience exchange in the online setting of student peer mentor network during COVID-19 pandemic and beyond: A laboratory case study.

For close to 2 years, we have witnessed the impacts of the SARS-CoV-2 pandemic on research at several different levels. Among the list, limited access to laboratory-based training for undergraduate students prevented this cohort from gaining exposure to the realities of a research laboratory at a critical time in training when they may have found motivation in this area as a career. COVID exposed a weakness in our training pipeline; an extreme dependency on face-to-face training that threatened to create a void in the research talent needed to replenish the scientific community every year. In the classroom, we witnessed a revolution of e-learning based approaches that could be rapidly implemented based on existing footprints. Out of necessity, our laboratory developed and implemented an e-learning model of an undergraduate peer mentor network that provides a knowledge and experience exchange platform between students with different levels of research experience. Implementation of the platform was to aid students with gaining knowledge in multiple aspects of scientific research and hands-on work in a research laboratory. The collaboration between the students of the network was aimed at not only advancing the theoretical and practical research experience, but also at developing feedback implementation and practicing "soft skills" critical for teamwork and leadership. Herein, we present an overview of the model along with survey responses of the students participating in the peer mentor network. We have found that peer delivery of practical benchwork both via scientific presentations and visualized experiments, reduced the time of training and the amount of staff assistance needed when students returned to the bench. Furthermore, this model accelerated student independence in laboratory work and increased research interest overall. In summary, the model of a peer mentor network has the potential to serve as a training platform and as a customized tool, supplementing research laboratory training at the undergraduate level beyond the pandemic.

Adolescents' and Adults' Perceptions of Sensory-Based Interventions: A Qualitative Analysis.

IMPORTANCE: Adolescents and adults report that their sensory integration and processing differences affect their occupational performance and quality of life, thus requiring effective sensory-focused interventions. Researchers have yet to investigate this population's experience of occupational therapy interventions designed to remediate these challenges. OBJECTIVE: To explore the perceived experience of adolescents and adults with respect to (1) response to intervention, (2) strategies offered to manage sensory differences, and (3) need for services on completion of an intervention. DESIGN: Retrospective, qualitative study. SETTING: Zoom or phone call. PARTICIPANTS: Eleven adolescents and adults with sensory integration and processing differences who had previously completed occupational therapy interventions. INTERVENTION: Sensory-based intervention based on the principles of Ayres Sensory Integration® (ASI) and the Sensory Therapies and Research Frame of Reference. OUTCOMES AND MEASURES: A semistructured interview to obtain data, followed by an in-depth analysis using an inductive coding process to group initial open codes into themes and common subthemes Results: Open codes were grouped into three core themes: (1) therapist-related factors (what the therapist did in treatment); (2) client-related factors (what the client experienced); and (3) follow-up (future needs of the clients). Four main subthemes of the client-therapist relationship emerged: (1) therapeutic alliance; (2) education and knowledge; (3) strategies, tools, and resources; and (4) future needs. CONCLUSIONS AND RELEVANCE: This study provides a perspective on the experience of adolescents and adults specific to the impact of a sensory-focused occupational therapy intervention on their daily lives. This will help occupational therapists when designing interventions for current and future clients. What This Article Adds: This study highlights the need for further research addressing effective sensory-based interventions for adolescents and adults. It also captures which components of intervention clients deemed helpful and identifies potential targets for future intervention.

Understanding Parents' Experiences With Mainstream Schooling for Their Children With Autism Spectrum Disorder: A Meta-Analysis.

IMPORTANCE: Children with autism spectrum disorder (ASD) face school-related occupational challenges. Attending a mainstream school offers benefits for children's learning and their development of social skills; however, parents express frustration with ensuring their child's unique needs and preferences are met. OBJECTIVE: To gain insight into parents' experiences with the mainstream preschool and primary educational system for their children with ASD. DATA SOURCES: Eleven electronic databases were systematically searched, and processes were followed according to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses. STUDY SELECTION AND DATA COLLECTION: Study eligibility was determined through the use of selection criteria and paired independent reviewers. Critical appraisal was conducted using a qualitative research hierarchy and a modified version of the Critical Appraisal Skills Programme tool. Two reviewers synthesized the data into themes, following the Joanna Briggs Institute meta-aggregation process. Twenty-six qualitative studies, representing the voices of 397 parents, are presented in this review (spanning 2013-2021). Articles were set in Westernized and non-Westernized settings and represented culturally and linguistically diverse population groups. FINDINGS: Parents of children with ASD reported a lack of awareness and understanding of their children's unique learning needs in the mainstream school system at all levels. CONCLUSIONS AND RELEVANCE: This review has various occupational therapy practice implications for supporting school-age children with ASD, their parents, and school staff. These include adopting family-centered and ecological approaches, raising awareness, influencing policy, and facilitating collaboration. What This Article Adds: This review provides guidance for occupational therapists working in schools about their practice in working at the individual, targeted, and whole-school levels to address occupational barriers faced by children with ASD.

Actionable wastewater surveillance: application to a university residence hall during the transition between Delta and Omicron resurgences of COVID-19.

Wastewater surveillance has gained traction during the COVID-19 pandemic as an effective and non-biased means to track community infection. While most surveillance relies on samples collected at municipal wastewater treatment plants, surveillance is more actionable when samples are collected "upstream" where mitigation of transmission is tractable. This report describes the results of wastewater surveillance for SARS-CoV-2 at residence halls on a university campus aimed at preventing outbreak escalation by mitigating community spread. Another goal was to estimate fecal shedding rates of SARS-CoV-2 in a non-clinical setting. Passive sampling devices were deployed in sewer laterals originating from residence halls at a frequency of twice weekly during fall 2021 as the Delta variant of concern continued to circulate across North America. A positive detection as part of routine sampling in late November 2021 triggered daily monitoring and further isolated the signal to a single wing of one residence hall. Detection of SARS-CoV-2 within the wastewater over a period of 3 consecutive days led to a coordinated rapid antigen testing campaign targeting the residence hall occupants and the identification and isolation of infected individuals. With knowledge of the number of individuals testing positive for COVID-19, fecal shedding rates were estimated to range from 3.70 log10 gc ‧ g feces-1 to 5.94 log10 gc ‧ g feces-1. These results reinforce the efficacy of wastewater surveillance as an early indicator of infection in congregate living settings. Detections can trigger public health measures ranging from enhanced communications to targeted coordinated testing and quarantine.

Parents as Adult Learners in Occupational Therapy for Children With Sensory Challenges: A Scoping Review.

IMPORTANCE: Parent training is an essential part of occupational therapy intervention for children with sensory processing and sensory integration (SP-SI) challenges, and parents' learning needs should be considered. OBJECTIVE: To identify the extent to which adult learning needs are considered in occupational therapy literature addressing parent training as a part of intervention for children with SP-SI challenges. DATA SOURCES: Searches were performed of the following databases: MEDLINE, PsycINFO, CINAHL, Web of Science, EMBASE, and ERIC. The date range was limited to 1990 to 2019 to capture literature focused on family-centered care. STUDY SELECTION AND DATA COLLECTION: Using Arksey and O'Malley's framework for scoping reviews and the Preferred Reporting Items for Systematic Reviews and Meta-Analyses Extension for Scoping Reviews Checklist, the following criteria were used to guide the literature searches: population (parents and families of children with SP-SI challenges), intervention (parent training), outcomes (parent learning needs), and concept (parents as adult learners). FINDINGS: Searches produced 133 peer-reviewed articles, and 5 met the criteria for inclusion. Qualitative thematic analysis, including stakeholder interviews, revealed two themes: (1) Parents focus on children's needs, not their own, and (2) parents benefit from connection with peers and learn through shared experiences. CONCLUSIONS AND RELEVANCE: Parent training is an essential component of occupational therapy; however, there is limited occupational therapy evidence examining parents' learning needs, specifically parents of children with SP-SI challenges. Future studies should investigate parents' learning needs in relation to occupational therapy intervention for families of children with SP-SI challenges. What This Article Adds: Parents' learning needs are both rarely considered in the occupational therapy literature and important for best practice in pediatric therapy for children with SP-SI challenges. The results of this scoping review point to the need for further investigation of parent training programs specifically examining parents as adult learners.

Tuberin levels during cellular differentiation in brain development.

Tuberin is a member of a large protein complex, Tuberous Sclerosis Complex (TSC), and acts as a sensor for nutrient status regulating protein synthesis and cell cycle progression. Mutations in the Tuberin gene, TSC2, permits the formation of tumors that can lead to developmental defects in many organ systems, including the central nervous system. Tuberin is expressed in the brain throughout development and levels of Tuberin have been found to decrease during neuronal differentiation in cell lines in vitro. Our current work investigates the levels of Tuberin at two stages of embryonic development in vivo, and we study the mRNA and protein levels during a time course using immortalized cell lines in vitro. Our results show that total Tuberin levels are tightly regulated through developmental stages in the embryonic brain. At a cell biology level, we show that Tuberin levels are higher when cells are cultured as neurospheres, and knockdown of Tuberin results in a reduction in the number of neurospheres. This functional data supports the hypothesis that Tuberin is an important regulator of stemness and the reduction of Tuberin levels might support functional differentiation in the central nervous system. Understanding how Tuberin expression is regulated throughout neural development is essential to fully comprehend the role of this protein in several developmental and neural pathologies.

Frequently used antiemetic agent dexamethasone enhances the metastatic behaviour of select breast cancer cells.

Glucocorticoids, such as dexamethasone (Dex), are used to prevent common side effects induced by chemotherapy and are heavily prescribed for solid cancers such as breast cancer. There is substantial pre-clinical data to support that Dex activation of the glucocorticoid receptor overrides chemotherapy-induced apoptosis in breast cancer cell lines. These findings are compounded by a recent study demonstrating that increased glucocorticoid receptor activation by endogenous stress hormones increased breast cancer heterogeneity and metastasis. Our study is the first to use both in vitro and in vivo models to thoroughly compare the Dex response on the migration of multiple estrogen receptor negative (ER-) and ER+ cancer cell lines. ER+ and ER- breast cancer cell lines were studied to compare their endogenous glucocorticoid activity as well as their metastatic ability in response to Dex treatment. We show that in the ER- breast cancer lines, Dex increases cell numbers, invasiveness, and migration, while decreasing apoptotic ability. Furthermore, we show that following Dex treatment, ER- breast cancer lines migrate further in an in vivo zebrafish model in comparison to ER+ cell lines. The use of ROR1 antibody to block WNT signaling diminished the metastatic properties of ER- cells, however recombinant WNT5A alone was not sufficient to induce migration. Taken together, we demonstrate that Dex treatment exacerbates the metastatic potential of ER- but not ER+ cells. These findings add to the growing body of data stressing the potential adverse role of endogenous and synthetic glucocorticoids in breast cancer biology.

Dissecting the roles of the Tuberin protein in the subcellular localization of the G2/M Cyclin, Cyclin B1.

Tuberin is a major component of the protein regulatory complex known as the Tuberous Sclerosis Complex and plays a crucial role in cell cycle progression and protein synthesis. Mutations in the Tuberin gene, TSC2, lead to the formation of benign tumors in many organ systems and causes the Tuberous Sclerosis Complex disorder. Genotypes ranging from point mutations to large deletions in the TSC2 gene have been clinically characterized with a wide range of phenotypes from skin tumors to large brain tumors. Our lab has previously demonstrated that Tuberin can directly bind and regulate the timing of nuclear transport of the G2/M cyclin, Cyclin B1. Herein we study the consequence of one clinically relevant truncation in the Tuberin protein on cell cycle function. We demonstrate that exogenous expression of a fragment of the N-term region of Tuberin alters the subcellular localization of Cyclin B1 and increases cell proliferation. This adds to our body of information about the residues within Tuberin responsible for regulating the cytoplasmic retention of Cyclin B1 and supports the phenotypic data seen in the clinic with Tuberous Sclerosis Complex patients harbouring similar large deletions in Tuberin.

Stabilization of c-Myc by the atypical cell cycle regulator, Spy1, decreases efficacy of breast cancer treatments.

PURPOSE: c-Myc is frequently upregulated in breast cancers, however, targeting c-Myc has proven to be a challenge. Targeting of downstream mediators of c-Myc, such as the 'cyclin-like' cell cycle regulator Spy1, may be a viable therapeutic option in a subset of breast cancer subtypes. METHODS: Mouse mammary tumor cells isolated from MMTV-Myc mice and human breast cancer cell lines were used to manipulate Spy1 levels followed by tamoxifen or chemotherapeutic treatment with a variety of endpoints. Patient samples from TNBC patients were obtained and constructed into a TMA and stained for c-Myc and Spy1 protein levels. RESULTS: Over time, MMTV-Myc cells show a decreased response to tamoxifen treatment with increasing levels of Spy1 in the tamoxifen-resistant cells. shRNA against Spy1 re-establishes tamoxifen sensitivity. Spy1 was found to be highly elevated in human TNBC cell and patient samples, correlating to c-Myc protein levels. c-Myc was found to be stabilized by Spy1 and knocking down Spy1 in TNBC cells shows a significant increase in response to chemotherapy treatments. CONCLUSION: Understanding the interplay between protein expression level and response to treatment is a critical factor in developing novel treatment options for breast cancer patients. These data have shown a connection between Spy1 and c-Myc protein levels in more aggressive breast cancer cells and patient samples. Furthermore, targeting c-Myc has proven difficult, these data suggest targeting Spy1 even when c-Myc is elevated can confer an advantage to current chemotherapies.

Impairing proliferation of glioblastoma multiforme with CD44+ selective conjugated polymer nanoparticles.

Glioblastoma is one of the most aggressive types of cancer with success of therapy being hampered by the existence of treatment resistant populations of stem-like Tumour Initiating Cells (TICs) and poor blood-brain barrier drug penetration. Therapies capable of effectively targeting the TIC population are in high demand. Here, we synthesize spherical diketopyrrolopyrrole-based Conjugated Polymer Nanoparticles (CPNs) with an average diameter of 109 nm. CPNs were designed to include fluorescein-conjugated Hyaluronic Acid (HA), a ligand for the CD44 receptor present on one population of TICs. We demonstrate blood-brain barrier permeability of this system and concentration and cell cycle phase-dependent selective uptake of HA-CPNs in CD44 positive GBM-patient derived cultures. Interestingly, we found that uptake alone regulated the levels and signaling activity of the CD44 receptor, decreasing stemness, invasive properties and proliferation of the CD44-TIC populations in vitro and in a patient-derived xenograft zebrafish model. This work proposes a novel, CPN- based, and surface moiety-driven selective way of targeting of TIC populations in brain cancer.

Fitted filtration efficiency and breathability of 2-ply cotton masks: Identification of cotton consumer categories acceptable for home-made cloth mask construction.

The objective of this study was to characterize commercially-available cotton fabrics to determine their suitability as materials for construction of cloth masks for personal and public use to reduce infectious disease spread. The study focused on cottons because of their widespread availability, moderate performance and they are recommended for inclusion in home-made masks by international health authorities. Fifty-two cottons were analyzed by electron microscopy to determine fabric characteristics and fabric weights. Sixteen fabrics were selected to test for breathability and to construct 2-ply cotton masks of a standard design to use in quantitative fit testing on a human participant. Cotton mask fitted filtration efficiencies (FFEs) for 0.02-1 µm ambient and aerosolized sodium chloride particles ranged from 40 to 66% compared with the mean medical mask FFE of 55±2%. Pressure differentials across 2-ply materials ranged from 0.57 to > 12 mm H2O/cm2 on samples of equal surface area with 6 of 16 materials exceeding the recommended medical mask limit. Models were calibrated to predict 2-ply cotton mask FFEs and differential pressures for each fabric based on pore characteristics and fabric weight. Models indicated cotton fabrics from 6 of 9 consumer categories can produce cloth masks with adequate breathability and FFEs equivalent to a medical mask: T-shirt, fashion fabric, mass-market quilting cotton, home décor fabric, bed sheets and high-quality quilting cotton. Masks from one cloth mask and the medical mask were re-tested with a mask fitter to distinguish filtration from leakage. The fabric and medical masks had 3.7% and 41.8% leakage, respectively. These results indicate a well fitted 2-ply cotton mask with overhead ties can perform similarly to a disposable 3-ply medical mask on ear loops due primarily to the superior fit of the cloth mask which compensates for its lower material filtration efficiency.

A prospective phase II clinical trial identifying the optimal regimen for carboplatin plus standard backbone of anthracycline and taxane-based chemotherapy in triple negative breast cancer.

Addition of platinums to combination chemotherapy for triple negative breast cancer (TNBC) has shown efficacy and is increasingly accepted in the clinic, yet optimal delivery is unknown. A prospective clinical trial with TNBC patients was conducted to determine the optimal chemotherapy regimen to deliver carboplatin with standard dose dense ACT. Tissue microarray was conducted to isolate markers indicative of response to treatment. 90 TNBC patients were enrolled onto our trial. The most successful version placed the carboplatin on the second and final paclitaxel treatment with liberal hematological parameters. Our final regimen had the lowest grade 3 or 4 toxicities, no delays, no dose reductions of carboplatin, and 32% reduction in paclitaxel doses. Stage I (AJCC7) patients did well with carboplatin-based chemotherapy with zero relapse rate. Reduction in protein levels of androgen receptor and PD-L1 were found to be potential indicators of patient relapse. We have optimized a protocol for the addition of carboplatin to standard of care chemotherapy in TNBC patients. Early data indicates reduced protein levels of androgen receptor and PD-L1 as indicators of response to treatment.Trial registration This trial was registered at Canadian Cancer Trials. http://www.canadiancancertrials.ca/.

Identification of alternative protein targets of glutamate-ureido-lysine associated with PSMA tracer uptake in prostate cancer cells.

Prostate-specific membrane antigen (PSMA) is highly overexpressed in most prostate cancers and is clinically visualized using PSMA-specific probes incorporating glutamate-ureido-lysine (GUL). PSMA is effectively absent from certain high-mortality, treatment-resistant subsets of prostate cancers, such as neuroendocrine prostate cancer (NEPC); however, GUL-based PSMA tracers are still reported to have the potential to identify NEPC metastatic tumors. These probes may bind unknown proteins associated with PSMA-suppressed cancers. We have identified the up-regulation of PSMA-like aminopeptidase NAALADaseL and the metabotropic glutamate receptors (mGluRs) in PSMA-suppressed prostate cancers and find that their expression levels inversely correlate with PSMA expression and are associated with GUL-based radiotracer uptake. Furthermore, we identify that NAALADaseL and mGluR expression correlates with a unique cell cycle signature. This provides an opportunity for the future study of the biology of NEPC and potential therapeutic directions. Computationally predicting that GUL-based probes bind well to these targets, we designed and synthesized a fluorescent PSMA tracer to investigate these proteins in vitro, where it shows excellent affinity for PSMA, NAALADaseL, and specific mGluRs associated with poor prognosis.