Radiation nanomedicines for cancer treatment: a scientific journey and view of the landscape.

BACKGROUND: Radiation nanomedicines are nanoparticles labeled with radionuclides that emit α- or ß-particles or Auger electrons for cancer treatment. We describe here our 15 years scientific journey studying locally-administered radiation nanomedicines for cancer treatment. We further present a view of the radiation nanomedicine landscape by reviewing research reported by other groups. MAIN BODY: Gold nanoparticles were studied initially for radiosensitization of breast cancer to X-radiation therapy. These nanoparticles were labeled with 111In to assess their biodistribution after intratumoural vs. intravenous injection. Intravenous injection was limited by high liver and spleen uptake and low tumour uptake, while intratumoural injection provided high tumour uptake but low normal tissue uptake. Further, [111In]In-labeled gold nanoparticles modified with trastuzumab and injected iintratumourally exhibited strong tumour growth inhibition in mice with subcutaneous HER2-positive human breast cancer xenografts. In subsequent studies, strong tumour growth inhibition in mice was achieved without normal tissue toxicity in mice with human breast cancer xenografts injected intratumourally with gold nanoparticles labeled with ß-particle emitting 177Lu and modified with panitumumab or trastuzumab to specifically bind EGFR or HER2, respectively. A nanoparticle depot (nanodepot) was designed to incorporate and deliver radiolabeled gold nanoparticles to tumours using brachytherapy needle insertion techniques. Treatment of mice with s.c. 4T1 murine mammary carcinoma tumours with a nanodepot incorporating [90Y]Y-labeled gold nanoparticles inserted into one tumour arrested tumour growth and caused an abscopal growth-inhibitory effect on a distant second tumour. Convection-enhanced delivery of [177Lu]Lu-AuNPs to orthotopic human glioblastoma multiforme (GBM) tumours in mice arrested tumour growth without normal tissue toxicity. Other groups have explored radiation nanomedicines for cancer treatment in preclinical animal tumour xenograft models using gold nanoparticles, liposomes, block copolymer micelles, dendrimers, carbon nanotubes, cellulose nanocrystals or iron oxide nanoparticles. These nanoparticles were labeled with radionuclides emitting Auger electrons (111In, 99mTc, 125I, 103Pd, 193mPt, 195mPt), ß-particles (177Lu, 186Re, 188Re, 90Y, 198Au, 131I) or α-particles (225Ac, 213Bi, 212Pb, 211At, 223Ra). These studies employed intravenous or intratumoural injection or convection enhanced delivery. Local administration of these radiation nanomedicines was most effective and minimized normal tissue toxicity. CONCLUSIONS: Radiation nanomedicines have shown great promise for treating cancer in preclinical studies. Local intratumoural administration avoids sequestration by the liver and spleen and is most effective for treating tumours, while minimizing normal tissue toxicity.

Decreased air quality shows minimal influence on peak summer attendance at forested Pacific West national parks.

Wildfires are increasing in duration and intensity across the United States' Pacific West region, resulting in heightened particulate matter from smoke in the atmosphere. Levels of peak particulate matter are concurrent to peak visitor attendance at National Parks, given seasonal alignment with summer vacation travel and heightened forest fire conditions. Particulate matter threatens visitor health and safety and contributes to poor visibility and a deteriorated visitor experience. To assess visitation response to diminished air quality, we utilized wildfire-generated particulate matter (PM2.5) data in conjunction with monthly attendance records for three ecoregions containing eight national parks in Washington, Oregon, and California from 2009 to 2019. We analyzed daily PM2.5 levels from data gridded at the 10 km scale for National Park Service units by Level III forest ecoregions within the National Park Service's Pacific West Unit. Data were then compared to normalized monthly visitation trends for each of the ecoregions using two statistical methods Kendall's Tau and Analysis of Variance (ANOVA) with post-hoc Tukey tests. Results demonstrate that attendance at these national parks does not decrease in response to increased PM2.5 levels. Instead, we see several statistically significant increases in attendance across these ecoregions during periods of reduced air quality. Of 115 shifts between air quality categories during the busy season of July to September, there are no significant decreases in attendance as air quality worsens. These findings suggest that visitors are willing to tolerate reduced air quality compared to other factors such as temperature or precipitation. Given that park units within each ecoregion feature diverse historical contexts, varied built environments, and unique ecological systems, our discussion specifically addresses managerial concerns associated with maintained high levels of visitation during suboptimal, and potentially dangerous, conditions. There is substantial need for specific, scalable approaches to mitigate adverse health and experiential impacts as visitors are exposed to increased risks during a range of exertional activities associated with diverse settings.

WellNest: A Medical Student-Run Housing Support Program.

PROBLEM: Being unhoused and facing housing insecurity contribute to poor health outcomes. Medical school curricula may include social determinants of health (SDOH) topics. However, experiential learning opportunities allow students to better contextualize how SDOH impact patients. The WellNest Housing Support Program (WellNest) was conceived and developed by Duke University medical students to learn from and support community members with a history of housing insecurity. APPROACH: Under the supervision of community organizations providing housing assistance services, WellNest was created in April 2020. Medical student-volunteers (MSVs) call clients, who are referred to WellNest by the community organizations, to plan move-ins. Local experts provide trainings on topics relevant to health care for individuals experiencing loss of housing. MSVs source and move furniture and clients' belongings into the new homes. Following move-in, MSVs are paired with clients to provide longitudinal tenancy support for at least one year. Student-volunteers contemplate their experiences and learning takeaways through debriefing sessions and an optional online survey. OUTCOMES: From fall 2021 to spring 2023, 83 student-volunteers from across the university participated in WellNest. Student-volunteers were generally medical students (37, 45%), and 16 MSVs served on the leadership team. WellNest facilitated 29 move-ins, and 26 clients requested to be paired with MSVs for longitudinal tenancy support. Following participation in WellNest, student-volunteers reported increased comfort, awareness, knowledge, and motivation related to caring for, discussing, and advocating for individuals experiencing housing insecurity. NEXT STEPS: As students from other programs are also interested in WellNest, there is potential for interprofessional education. Student-volunteers will be encouraged to participate in additional opportunities for reflection and advocacy activities. The impact of WellNest on clients will be explored through a questionnaire and narrative interviews. Long-term financial support was secured from community donations and partnering community organizations.

Cutaneous Coccidiomycosis.

ABSTRACT: Coccidiomycosis is an infectious primary pulmonary disease caused by two highly virulent fungi, Coccidioides immitis and C. Posadasii. Coccidioides spp. are endemic to the southwestern USA, Central America, and South America with infection predominating in the summer and fall seasons. The disease commonly presents with flu-like symptoms. Cutaneous manifestations are rare and are a sign of a more serious infection with poorer outcomes. In this case, a 60-year-old female presented to the dermatology clinic with a 3-month history of a mild, non-pruritic, erythematous rash located on her proximal arms and legs. Two punch biopsies were obtained, and she was found to have a non-endemic case of disseminated coccidiomycosis.

A 10-Year Retrospective Review on the Use of Prophylactic Spinal Reconstruction in Spinal Surgery Involving High-Risk Patients.

BACKGROUND: Spinal surgeries are being offered to a broader patient population who are both medically and surgically complex. History of prior spinal surgery, advanced age, and presence of comorbidities, such as obesity, malnutrition, steroid use, and tobacco use, are risk factors for postoperative complications. Prophylactic spinal reconstruction at the time of spinal surgery has been shown to have improved outcomes and decreased wound complications; however, outcomes focusing specifically on complex patients with a history of previous spinal surgery (or surgeries) have not been well described. METHODS: This is a retrospective study performed at the University of Maryland Medical Center (Baltimore, MD) of high-risk patients who underwent complex spinal surgery with prophylactic spinal reconstruction from 2011 to 2022. One hundred forty-three consecutive surgeries from 136 patients were included in the study. Patients younger than 17 years or who had an incomplete medical record were excluded. RESULTS: Most patients were female (63.6%) versus male (31.5%). The average American Society of Anesthesiologists score was 3. All but 6 patients (11%) had a history of at least 1 spinal surgery, with nearly half of patients having had between 2 and 5 spinal surgeries. Reconstruction was performed with paraspinous flaps in most cases (n = 133 [93%]). The overall complication rate was 10.5%, with surgical site infection being the most common complication. Seventeen patients (12.5%) underwent reoperation within 90 days of initial surgery. Average length of follow-up was 4.18 months (range, 0.03-40.53 months). CONCLUSIONS: In appropriately selected patients, prophylactic spinal reconstruction offers improved outcomes with decreased wound complications compared with salvage. For large defects, paraspinous flaps are recommended over other reconstructive options. Prolonged drain placement is felt to be protective against complications.

Commercially Available Mobile Apps With Family Behavioral Goal Setting and Tracking for Parents: Review and Quality Evaluation.

BACKGROUND: Goal setting and tracking are well established behavior change techniques. Little is known about the extent to which commercially available mobile apps are designed to guide parents in using these strategies, their evidence base, and their quality. OBJECTIVE: This study aims to review commercially available apps that target parents in relation to setting and tracking behavioral goals for their children. The objectives were to classify the apps' general characteristics, features, evidence base, and target behaviors and assess app quality overall and separately for apps that target health-related behaviors (HRBs) and apps without a health-related behavior (WHRB). METHODS: Apps were identified using keyword searches in the Apple App Store and Google Play in the United States. Apps were included if their primary purpose was to assist with setting goals, tracking goals, tracking behaviors, or giving feedback pertaining to goals for children by parents. App characteristics and common features were documented and summarized. Two reviewers assessed app quality using the Mobile App Rating Scale (MARS). Descriptive statistics summarized the MARS total score, 4 quality subscales, and 6 app-specific items that reflect the perceived impact of the app on goal setting and tracking, overall and with subgroup analysis for HRB and WHRB apps. RESULTS: Of the 21 apps identified, 16 (76%) met the review criteria. Overall, 9 apps defined and targeted the following HRBs: nutrition and mealtime (6/16, 38%), physical activity and screen time (5/16, 31%), sleep (7/16, 44%), and personal hygiene (6/16, 38%). Three apps targeted specific age groups (2 apps were for children aged 6-13 years and 1 app was for children aged ≥4 years). None of the apps provided tailored assessments or guidance for goal setting. None of the apps indicated that they were intended for the involvement of a health professional or had been tested for efficacy. The MARS total score indicated moderate app quality overall (mean 3.42, SD 0.49) and ranged from 2.5 to 4.2 out of 5 points. The Habitz app ranked highest on the MARS total score among HRB apps (score=4.2), whereas Thumsters ranked highest (score=3.9) among the WHRB apps. Subgroup analysis revealed a pattern of higher quality ratings in the HRB group than the WHRB group, including the mean MARS total score (mean 3.67, SD 0.34 vs mean 3.09, SD 0.46; P=.02); the engagement and information subscales; and the app-specific items about perceived impact on knowledge, attitudes, and behavior change. CONCLUSIONS: Several high-quality commercially available apps target parents to facilitate goal setting and tracking for child behavior change related to both health and nonhealth behaviors. However, the apps lack evidence of efficacy. Future research should address this gap, particularly targeting parents of young children, and consider individually tailored guided goal setting and involvement of health professionals.

The interplay of quaternary ammonium lipid structure and protein corona on lung-specific mRNA delivery by selective organ targeting (SORT) nanoparticles.

Messenger RNA (mRNA) can treat genetic disease using protein replacement or genome editing approaches but requires a suitable carrier to circumnavigate biological barriers and access the desired cell type within the target organ. Lipid nanoparticles (LNPs) are widely used in the clinic for mRNA delivery yet are limited in their applications due to significant hepatic accumulation because of the formation of a protein corona enriched in apolipoprotein E (ApoE). Our lab developed selective organ targeting (SORT) LNPs that incorporate a supplementary component, termed a SORT molecule, for tissue-specific mRNA delivery to the liver, spleen, and lungs of mice. Mechanistic work revealed that the biophysical class of SORT molecule added to the LNP forms a distinct protein corona that helps determine where in the body mRNA is delivered. To better understand which plasma proteins could drive tissue-specific mRNA delivery, we characterized a panel of quaternary ammonium lipids as SORT molecules to assess how chemical structure affects the organ-targeting outcomes and protein corona of lung-targeting SORT LNPs. We discovered that variations in the chemical structure of both the lipid alkyl tail and headgroup impact the potency and specificity of mRNA delivery to the lungs. Furthermore, changes to the chemical structure alter the quantities and identities of protein corona constituents in a manner that correlates with organ-targeting outcomes, with certain proteins appearing to promote lung targeting whereas others reduce delivery to off-target organs. These findings unveil a nuanced relationship between LNP chemistry and endogenous targeting, where the ensemble of proteins associated with an LNP can play various roles in determining the tissue-specificity of mRNA delivery, providing further design criteria for optimization of clinically-relevant nanoparticles for extrahepatic delivery of genetic payloads.

Reduction of Erythema in Moderate-Severe Rosacea by a Low Molecular Weight Heparan Sulfate Analog (HSA).

Rosacea changes are a result of an immune mediated response and the angiogenic properties of the LL-37 peptide. This peptide induces an inflammatory signal that activates the NLRP3-mediated inflammasome, triggering rosacea pathogenesis. Research findings show that LL-37 peptide is inhibited by binding to a cell surface glycosaminoglycan, heparan sulfate. Heparan Sulfate Analog (HSA) is a proprietary low molecular weight analog of heparan sulfate that has been formulated into a Dermal Repair Cream (DRC), specifically to aid in such immune mediated responses. Herein, in vitro studies using human epidermal keratinocytes showed an increase in HSA decreased LL-37 toxicity and IL-8 cytokine release. A single-center, randomized double-blind trial included 16 subjects (Fitzpatrick skin types I-IV) with a clinical diagnosis of type 1 rosacea and moderate to severe facial erythema, who were undergoing Pulsed Dye Laser (PDL) treatment. The clinical improvements of their facial erythema were assessed at baseline, 2 weeks, 4 weeks, and 8 weeks. Results revealed that low molecular weight HSA significantly improves the clinical signs of rosacea during the 8 weeks of use likely resulting from inhibition of LL-37 induced IL-8 cytokine release. These findings support the use of DRC in rosacea topical treatment regimens as it demonstrates visible skin benefits and improves tolerability of PDL therapy in a shorter duration of time as compared with PDL alone.George R, Gallo RL, Cohen JL, et al. Reduction of erythema in moderate-severe rosacea by a low molecular weight Heparan Sulfate Analog (HSA). J Drugs Dermatol. 2023;22(6):546-553. doi:10.36849/JDD.7494.

Text Mining Oral Histories in Historical Archaeology.

Advances in text mining and natural language processing methodologies have the potential to productively inform historical archaeology and oral history research. However, text mining methods are largely developed in the context of contemporary big data and publicly available texts, limiting the applicability of these tools in the context of historical and archaeological interpretation. Given the ability of text analysis to efficiently process and analyze large volumes of data, the potential for such tools to meaningfully inform historical archaeological research is significant, particularly for working with digitized data repositories or lengthy texts. Using oral histories recorded about a half-century ago from the anthracite coal mining region of Pennsylvania, USA, we discuss recent methodological developments in text analysis methodologies. We suggest future pathways to bridge the gap between generalized text mining methods and the particular needs of working with historical and place-based texts.

Safety and Effectiveness of the Use of an Electronic Glucose Monitoring System Versus Weight-Based Dosing Nomogram for Treatment of Diabetic Ketoacidosis and Hyperglycemic Hyperosmolar Syndrome in a VA Hospital.

OBJECTIVE: The objective of this study is to assess the safety and effectiveness of an electronic glucose monitoring system (eGMS) versus paper-based protocols (PBPs) to manage diabetic ketoacidosis (DKA) and hyperglycemic hyperosmolar syndrome (HHS) within the VA setting. METHODS: This study is a retrospective chart review of patients on an insulin drip, treated in the emergency department (ED) or intensive care unit (ICU) at Veteran Health Indiana for DKA or HHS. The primary outcome was evaluating the percentage of patients with hypoglycemia (blood glucose [BG] level <70 mg/dL) in patients admitted with DKA and HHS comparing an eGMS versus a PBP. A total of 168 patients were included in the analysis, with 84 patients in each group. RESULTS: The primary outcome comparing rates of hypoglycemia in the eGMS group versus the PBP group showed a lower rate of hypoglycemia in the eGMS group (0.024%) compared with the PBP group (0.060%); however, this difference was not found to be statistically significant (P = .90). Statistically significant secondary outcomes include the percentage of glucose checks drawn within the protocol recommendation (80.7% vs 52.6%, P = .02). CONCLUSIONS: While the primary endpoint of decreased hypoglycemia was not found to be statistically significant, it did reduce the overall number of hypoglycemia events in the eGMS group compared with the PBP group which may be clinically significant. This demonstrates that eGMS use has the potential to minimize hypoglycemia and glycemic variability in a critically-ill Veteran population by individualizing insulin drip titration based on a variety of patient-specific factors and providing reminders for staff to obtain BG checks in a timely manner.

Burden and Risk Factors of Brain Metastases in Melanoma: A Systematic Literature Review.

Melanoma can frequently metastasize to the brain with severe consequences. However, variation of melanoma brain metastases (MBM) development among populations is not well studied, and underlying mechanisms and risk factors for MBM development are not consistently documented. We conducted a systematic literature review (SLR) including a total of 39 articles to evaluate the proportion of melanoma patients who are diagnosed with, or develop, brain metastases, and summarize the risk factors of MBM. The average proportion of MBM was calculated and weighted by the sample size of each study. Meta-analyses were conducted for the selected risk factors using a random-effects model. The proportion of MBM at diagnosis was 33% (975 with MBM out of 2948 patients) among patients with cutaneous melanoma (excluding acral) and 23% (651/2875) among patients with cutaneous mixed with other types of melanoma. The proportion at diagnosis was lower among populations with mucosal (9/96, 9%) or uveal (4/184, 2%) melanoma and among populations outside the United States and Europe. Meta-analysis demonstrated that male vs. female gender and left-sided tumors vs. right-sided were significantly associated with increased risk of melanoma brain metastases. These data may help clinicians to assess an individual patient's risk of developing melanoma brain metastases.

A comprehensive literature review and meta-analysis of the prevalence of pan-cancer BRCA mutations, homologous recombination repair gene mutations, and homologous recombination deficiencies.

There is significant improvement in the outcomes following treatment with PARP inhibitors among patients with certain tumors that have BRCA mutations (BRCAm), homologous recombination repair (HRR) gene mutations, or homologous recombination deficiency (HRD) positivity. We performed a literature review and meta-analysis to evaluate the prevalence of BRCA1/2m, HRR gene mutations, and HRD positivity across multiple cancers. There were 265 publications on BRCA1/2 mutation prevalence, 189 on HRR gene mutation prevalence, and 7 on HRD positivity prevalence. The prevalences of germline BRCA1m and BRCA2m were 7.8% and 5.7% for breast cancer, 13.5% and 6.6% for ovarian cancer, 0.5% and 3.5% for prostate cancer, and 1.1% and 4.1% for pancreatic cancer, respectively. The prevalences of somatic BRCA1m and BRCA2m were 3.4% and 2.7% for breast cancer, 4.7% and 2.9% for ovarian cancer, 5.7% and 3.2% for prostate cancer, and 1.2% and 2.9% for pancreatic cancer, respectively. We identified 189 studies with over 418,649 samples across 25 tumor types that examined mutations in one or more HRR genes other than BRCA1/2. The prevalence of mutations among HRR genes remained low (less than 1%), with ATM (5.2%), CHEK2 (1.6%), and PALB2 (0.9%) exhibiting the highest prevalence. Seven studies evaluated HRD positivity in breast, ovarian, and prostate cancer patients. The prevalence of HRD positivity was 56% overall (95% CI = 48%-64%). The understanding of biomarker prevalence across tumor types and standardization of biomarker assays could have important clinical implications.

A Systematic Review and Meta-Analysis on the Prognostic Value of BRCA Mutations, Homologous Recombination Gene Mutations, and Homologous Recombination Deficiencies in Cancer.

Patients with BRCA1/2 mutations (BRCAm), loss-of-function mutations in other homologous recombination repair (HRRm) genes, or tumors that are homologous recombination deficiency positivity (HRD+) demonstrate a robust response to PARPi therapy. We conducted a systematic literature review and meta-analysis to evaluate the prognostic value of BRCAm, HRRm, and HRD+ on overall survival (OS) among those treated by chemotherapy or targeted therapy other than PARPi across tumor types. A total of 135 eligible studies were included. Breast cancer (BC) patients with BRCA1/2m had a similar overall survival (OS) to those with wild-type BRCA1/2 (BRCA1/2 wt) across 18 studies. Ovarian cancer (OC) patients with BRCA1/2m had a significantly longer OS than those with BRCA1/2 wt across 24 studies reporting BRCA1m and BRCA2m, with an HR of 0.7 (0.6-0.8). Less OS data were reported for other tumors: 6 studies for BRCA2m compared with BRCA2 wt in prostate cancer with an HR of 1.9 (1.1-3.2) and 2 studies for BRCA1/2m compared with BRCA1/2 wt in pancreatic cancer with an HR of 1.5 (0.8-3.1). Only 4 studies reported HRD+ by either BRCA m or genomic instability score (GIS) ≥ 42 and OS by HRD status. The HR was 0.67 (0.43-1.02) for OS with HRD+ vs. HRD-. A total of 15 studies reported the association between HRRm and OS of cancers in which one or more HRR genes were examined. The HR was 1.0 (0.7-1.4) comparing patients with HRRm to those with HRR wild-type across tumors. Our findings are useful in improving the precision and efficacy of treatment selection in clinical oncology.

Insurance Coverage of Dermabrasion and Chemical Peel Procedures: A Critical Analysis of 58 American Insurance Companies.

Introduction Dermabrasion and chemical peels are infrequently utilized methods of treatment for medical-grade conditions despite demonstrations of favorable outcomes. Insurance coverage status has previously been shown to impact availability and accessibility to specific treatments. The purpose of this study is to evaluate the rate of insurance coverage provided for dermabrasion and chemical peel procedures in the treatment of acne, acne scarring, and non-melanoma skin cancers (NMSC). Methods A cross-sectional analysis of 58 insurance companies by web-based search or phone interview determined the number of insurers with a publicly available policy on dermabrasion or chemical peels. Coverage status and any corresponding criteria were extracted from existing company policies. Results Thirteen (22%) and 22 (38%) policies discussed dermabrasion in the treatment of basal cell carcinoma and actinic keratosis, with 62% and 73% of these policies providing coverage. Acne scarring was discussed in significantly more dermabrasion policies than basal cell carcinoma (45% vs 22%; p=0.018). However, significantly more insurers denied coverage of dermabrasion for active acne and acne scarring when compared to dermabrasion to treat basal cell carcinoma or actinic keratosis (p<0.001). Eighty-seven percent of companies (n=20) with a chemical peel policy for premalignant lesions would provide coverage, with required criteria present in 95% (n=19) of the policies that would cover chemical peels for actinic keratosis specifically. Of the 25 companies (43%) that discussed the treatment of acne with chemical peel procedures, 14 (56%) provided coverage, and 11 (44%) denied coverage. Coverage was denied by significantly less insurers for the treatment of active acne with chemical peel procedures compared to treatment with dermabrasion (44% vs 83%; p<0.006). Conclusion Significant discrepancies were noted in both the presence of a public policy and the coverage status of dermabrasion or chemical peel procedures among the United States health insurance companies. These inconsistencies, along with multiple criteria required for coverage, may create an artificial barrier to receiving care for specific medical-grade conditions.

Applied Mycology Can Contribute to Sustainable Rural Livelihoods: Building upon China's Matsutake Management Initiatives.

Matsutake mushrooms are an important part of rural livelihoods and forest ecosystems across large parts of China, as well as elsewhere in East Asia, Northern Europe and North America. Mushroom harvesters have developed sophisticated understandings of matsutake ecology and production, and are applying this knowledge in various innovative management strategies. At the same time, Chinese government agencies and scientists are promoting matsutake-based livelihoods to support development and conservation goals. We collaborated with matsutake harvesters in one Yunnan community to carry out a systematic experiment on a popular shiro-level management technique: covering matsutake shiros with either plastic or leaf litter. Our experimental results suggest that although leaf litter coverings are superior to plastic coverings, shiros that are left uncovered may produce the highest yields. Complementing our experimental work is a multi-sited household survey of existing matsutake management practices across Yunnan, which shows that a high proportion of harvesters are already engaged in a broad range of potentially beneficial management strategies. Though both findings highlight limitations of previous initiatives led by government and research actors in China, this existing body of work is an important foundation and opportunity for developing applied mycology in the region. In and beyond China, working with communities to develop site-specific management strategies through rigorous and participatory scientific inquiry can provide salient benefits for both scientists and resource users.