Implications of chronic moderate protein-deficiency malnutrition on doxorubicin pharmacokinetics and cardiotoxicity in early post-weaning stage.

BACKGROUND: Malnutrition is a common problem in developing countries, and the impact of severe malnutrition on optimal treatment outcomes of chemotherapy in pediatric cancer patients is well documented. However, despite being a more prevalent and distinct entity, moderate malnutrition is until now unexplored for its effects on treatment outcomes. AIMS: In this study we aimed to investigate the molecular basis of altered pharmacokinetics and cardiotoxicity of doxorubicin observed in early-life chronic moderate protein deficiency malnutrition. MATERIALS AND METHODS: We developed an animal model of early-life moderate protein-deficiency malnutrition and validated it using clinical samples. This model was used to study pharmacokinetic and toxicity changes and was further utilized to study the molecular changes in liver and heart to get mechanistic insights. KEY FINDINGS: Here we show that moderate protein-deficiency malnutrition in weanling rats causes changes in drug disposition in the liver by modification of hepatic ABCC3 and MRP2 transporters through the TNFα signalling axis. Furthermore, malnourished rats in repeat-dose doxorubicin toxicity study showed higher toxicity and mortality. A higher accumulation of doxorubicin in the heart was observed which was associated with alterations in cardiac metabolic pathways and increased cardiotoxicity. SIGNIFICANCE: Our findings indicate that moderate malnutrition causes increased susceptibility towards toxic side effects of chemotherapy. These results may necessitate further investigations and new guidelines on the dosing of chemotherapy in moderately malnourished pediatric cancer patients.

Childhood opportunity and appropriate use of child safety restraints in motor vehicle collisions.

Objectives: Safety restraints reduce injuries from motor vehicle collisions (MVCs) but are often improperly applied or not used. The Childhood Opportunity Index (COI) reflects social determinants of health and its study in pediatric trauma is limited. We hypothesized that MVC patients from low-opportunity neighborhoods are less likely to be appropriately restrained. Methods: A retrospective cross-sectional study was performed on children/adolescents ≤18 years old in MVCs between January 1, 2011 and December 31, 2021. Patients were identified from the Children's Hospital Los Angeles trauma registry. The outcome was safety restraint use (appropriately restrained, not appropriately restrained). COI levels by home zip codes were stratified as very low, low, moderate, high, and very high. Multivariable regression controlling for age identified factors associated with safety restraint use. Results: Of 337 patients, 73.9% were appropriately restrained and 26.1% were not appropriately restrained. Compared with appropriately restrained patients, more not appropriately restrained patients were from low-COI (26.1% vs 20.9%), high-COI (14.8% vs 10.8%) and very high-COI (10.2% vs 3.6%) neighborhoods. Multivariable analysis demonstrated no significant associations in appropriate restraint use and COI. There was a non-significant trend that children/adolescents from moderate-COI neighborhoods were more likely than those from very low-COI neighborhoods to be appropriately restrained (OR=1.82, 95% CI 0.78, 4.28). Conclusion: Injury prevention initiatives focused on safety restraints should target families of children from all neighborhood types. Level of evidence: III.

Trends and Variation in Cervical Spine Imaging Utilization Across Children's Hospitals for Pediatric Trauma.

BACKGROUND: Cervical spine evaluation is a critical component in trauma evaluation, and though several pediatric cervical spine evaluation algorithms have been developed, none has been widely implemented. Here, we assess rates of cervical spine imaging use across children's hospitals, specifically temporal trends in imaging use, variation across hospitals in imaging used, and timing of magnetic resonance imaging in admitted patients. METHODS: Data from the Children's Hospital Associations Pediatric Health Information System was abstracted from 2015 to 2020. Patients less than 18 years of age seen in the emergency department with an International Classification of Diseases (ICD)-10 code indicative of trauma and cervical spine plain radiograph or computed tomography in the emergency department were included. Data visualization and descriptive statistics were used to assess rates of imaging use by age, year, hospital, injury severity, and day of service. Changes in rates of imaging use over time were evaluated via Chi-square test. RESULTS: Across 25,238 patient encounters at 35 children's hospitals, there was an increase in use of cervical spine computed tomography from 2015 to 2020 (28.5 to 36.5%). There was substantial inter-institutional variation in rates of use of plain radiographs versus computed tomography for initial evaluation of the cervical spine across all age groups and regardless of rates of severe injury across institutions. Magnetic resonance imaging was obtained more than three days after admission in 31.5% of intensive care patients who received this imaging. CONCLUSIONS: Increasing use of computed tomography, substantial inter-institutional variation in rates of use of plain radiographs versus computed tomography, and heterogenous timing of magnetic resonance imaging for evaluation of the pediatric cervical spine demonstrate the growing need for development and implementation of an age-specific cervical spine evaluation algorithm to guide judicious use of diagnostic resources. LEVEL OF EVIDENCE: Level III, Epidemiologic.

Association Between Hospital Arrival Time and Avoidable Transfer in Pediatric Trauma.

BACKGROUND: Avoidable transfers (AT) in pediatric trauma can increase strain on healthcare resources and families. We sought to identify characteristics of patients and their injuries that are associated with AT. METHODS: A multicenter retrospective cross-sectional study of the regional Trauma Registry was conducted from 1/1/10-12/31/21 of children <18 years-old who experienced an interfacility transfer. AT was defined as receiving hospital length of stay (LOS) < 48 hrs without procedure or intervention performed. Patient demographics, mechanism of injury, and arrival time were analyzed with descriptive statistics. A multivariable logistic regression was performed to analyze demographic and clinical factors associated with AT. RESULTS: We included 5438 trauma transfers, of which 2187 (40.2%) were AT. Patients experiencing AT had a median [IQR] age of 5 years [1-12] and most were male (67%) and Hispanic/Latino (46.3%). The odds of experiencing AT decreased as age increased and were less likely in females and Non-Hispanic Black children. Injuries from falls (ground level (OR = 2.48; 95%CI = 1.89-3.28) and >10 ft (OR = 3.20; 95%CI = 2.35-4.39)), sports/recreational activities (OR = 2.36; 95%CI = 1.78-3.16), MVCs (OR = 1.44; 95%CI = 1.05-1.98), and firearms (OR = 1.74; 95%CI = 1.15-2.62) were associated with an increased odds of AT. Time of arrival at the receiving facility in early hours (00:00-07:59) (OR = 1.48; 95%CI = 1.24-1.76) and evening hours (17:00-23:59) (OR = 1.75; 95%CI = 1.47-2.07) were associated with an increased odds of AT. CONCLUSION: Younger patients, injuries from falls, sports/recreational activities, MVCs, and firearms as well as arrival time outside of standard work hours are more likely to result in AT. Knowing these results, we can begin working with our referral centers to improve communication and strengthen institutional transfer criteria for pediatric trauma patients. Further investigation will then be needed to determine if the changes implemented have influenced care and lowered rates of avoidable transfer. LEVEL OF EVIDENCE: Level III.

Secretory phospholipase (sPLA2-IIA) regulates breast cancer stem cells differentiation and metastatic potential.

Breast cancer is the second most cancer worldwide in females. The primary factor responsible for tumor recurrence is the presence of breast cancer stem cells (BCSCs), which escape the chemo-radiotherapy. In this study, we have investigated the role of Secretory phospholipase-A2 Group 2A (sPLA2-IIA) that is overexpressed in BCSCs of MCF7 and MDA-MB-231 breast cancer cell lines. Further, overexpression of sPLA2-IIA revealed an increased EGFR/JNK/c-JUN/c-FOS signaling in BCSCs, while sPLA2-IIA knockdown significantly reduced the percentage of BCSCs and decreased signaling in both the cell lines. Importantly, sPLA2-IIA knockdown showed differentiation of BCSCs. Strikingly, PET imaging showed a decreased metastatic potential of BCSCs. Our study revealed a novel role of sPLA2-IIA in regulating BCSCs, which play a crucial role in regulating the differentiation and metastatic potential of BCSCs.

Pivotal role of AKR1B1 in pathogenesis of colitis associated colorectal carcinogenesis.

Identifying the target linking inflammation and oxidative stress to aggravate the disease progression will help to prevent colitis associated carcinogenesis. Since AKR1B1 overexpression is observed in inflammatory diseases and various cancers, we have investigated the role of AKR1B1 in colitis-associated colon carcinogenesis with the aid of epalrestat and its potent analogue NARI-29 (investigational molecule) as pharmacological probes. A TNF-α inducible NF-κB reporter cell line (GloResponse™ NF-κB-RE-luc2P HEK293) and dextran sodium sulfate (DSS) and 1,2 dimethyl hydrazine (DMH))-induced mouse model was used to investigate our hypothesis in vitro and in vivo. Clinically, an increased expression of AKR1B1 was observed in patients with ulcerative colitis. Our in vitro and in vivo findings suggest that the AKR1B1 modulated inflammation and ROS generation for the progression of colitis to colon cancer. AKR1B1 overexpression was observed in DSS + DMH-treated mice colons. Moreover, we could observe histopathological changes like immune cell infiltration, aberrant crypt foci, and tumour formation in DC groups. Mechanistically, we have witnessed modulation of the IKK/IκB/NF-κB and Akt/FOXO-3a/DR axis, increased inflammatory cytokines, increased expression of proliferative markers, Ki-67 and PCNA, and accumulation of ß-catenin in the colon epithelium. However, pharmacological inhibition of AKR1B1 using NARI-29 or EPS has reversed the clinical, histopathological, and molecular alterations induced by DSS + DMH, confirming the obvious role of AKR1B1 in the promotion of colitis-associated carcinogenesis. In conclusion, our findings suggest that AKR1B1 targeted therapy could be a promising strategy for preventing CA-CRC and NARI-29 could be developed as a potent AKR1B1 inhibitor.

Design, characterization and evaluation of a new 99mTc-labeled folate derivative with affinity towards folate receptor.

Folate receptors (FRs) are known to be over-expressed in several human malignancies and therefore serve as an important target for small radiolabeled folate derivatives for non-invasive imaging of tumor, which is an important tool for future treatment recourse. In the present article, we report the synthesis of a new 99mTc-labeled radiotracer for the aforementioned application following the well-established 99mTc-'4+1' chemistry. Formation of the desired [99mTc]Tc-complex with >95% radiochemical purity was confirmed by radio-HPLC and its structure was ascertained by characterizing a natural rhenium analogue of the said complex. Although the ligand exhibited a weaker affinity towards FRs compared to native folic acid (IC50 8.09 µM vs 29.46 nM), the 99mTc-labeled complex was found to bind folate receptor-positive KB cells with high specificity (∼90%). Similar studies in a folate receptor negative cell line viz. A549 further corroborated the receptor-specificity of the synthesized complex. In vivo studies in KB tumor xenograft showed moderate uptake of ∼2.6% upto 3 h post-injection with high specificity (∼80%). The favorable features observed warrant further screening of the current design towards achieving an improved molecular probe for the said application.

Neighborhood deprivation and childhood opportunity indices are associated with violent injury among children in Los Angeles County.

BACKGROUND: Previous research has demonstrated mixed relationships between individual neighborhood socioeconomic factors and incidences of violence, such as poverty level, population density, and income inequality. We used the Childhood Opportunity Index and Area Disadvantage Index to evaluate the relationship between neighborhood characteristics and the number of incidents of violence among children across the zip codes of Los Angeles (LA) County. METHODS: We performed a retrospective cross-sectional study of children younger than 18 years from 2017 to 2019 who were entered in the LA County Trauma and Emergency Medicine Information System registry with violent mechanisms of injury, including gunshot, stabbing, or assault. Mechanisms classified as self-inflicted injuries were excluded from the study. The number of incidences of violent mechanism per 100,000 persons younger than 18 years for each zip code was calculated using population data from the US Census American Community Survey 5-Year estimates from 2019. The incidences of violence per capita younger than 18 years for each zip code was compared with the zip code Area Deprivation Index and Childhood Opportunity Index using logistic regression models. RESULTS: There were 6,791 trauma activations in LA County over the study period, 12.8% (n = 866) of which were due to violence. The mean prevalence of pediatric violent mechanism of injury per zip code was 4 cases per 100,000 persons younger than 18 years. Most injuries were the result of firearms (n = 345 [60.4%]) and occurred among Hispanic/Latino children (n = 362 [57.1%]). There were significantly greater rates of violent injury among children from highest disadvantage (odds ratio, 8.84) and lowest opportunity (odds ratio, 42.48) zip codes. CONCLUSION: Children living in high disadvantage or low opportunity zip codes had greater rates of violent injury. Further study of neighborhood factors is needed to develop targeted effective interventions to reduce violent injuries among children living in low opportunity areas. LEVEL OF EVIDENCE: Prognostic and Epidemiological; Level IV.

Identification of delayed diagnosis of paediatric appendicitis in administrative data: a multicentre retrospective validation study.

OBJECTIVE: To derive and validate a tool that retrospectively identifies delayed diagnosis of appendicitis in administrative data with high accuracy. DESIGN: Cross-sectional study. SETTING: Five paediatric emergency departments (EDs). PARTICIPANTS: 669 patients under 21 years old with possible delayed diagnosis of appendicitis, defined as two ED encounters within 7 days, the second with appendicitis. OUTCOME: Delayed diagnosis was defined as appendicitis being present but not diagnosed at the first ED encounter based on standardised record review. The cohort was split into derivation (2/3) and validation (1/3) groups. We derived a prediction rule using logistic regression, with covariates including variables obtainable only from administrative data. The resulting trigger tool was applied to the validation group to determine area under the curve (AUC). Test characteristics were determined at two predicted probability thresholds. RESULTS: Delayed diagnosis occurred in 471 (70.4%) patients. The tool had an AUC of 0.892 (95% CI 0.858 to 0.925) in the derivation group and 0.859 (95% CI 0.806 to 0.912) in the validation group. The positive predictive value (PPV) for delay at a maximal accuracy threshold was 84.7% (95% CI 78.2% to 89.8%) and identified 87.3% of delayed cases. The PPV at a stricter threshold was 94.9% (95% CI 87.4% to 98.6%) and identified 46.8% of delayed cases. CONCLUSIONS: This tool accurately identified delayed diagnosis of appendicitis. It may be used to screen for potential missed diagnoses or to specifically identify a cohort of children with delayed diagnosis.

Targeted nano-delivery of chemotherapy via intranasal route suppresses in vivo glioblastoma growth and prolongs survival in the intracranial mouse model.

Nanotechnology-based drug delivery platforms have shown great potential in overcoming the limitations of conventional therapy for glioblastoma (GBM). However, permeation across the blood-brain barrier (BBB), physiological complexity of the brain, and glioma targeting strategies cannot entirely meet the challenging requirements of distinctive therapeutic delivery stages. The objective of this research is to fabricate lipid nanoparticles (LNPs) for the co-delivery of paclitaxel (PTX) and miltefosine (HePc) a proapoptotic agent decorated with transferrin (Tf-PTX-LNPs) and investigate its anti-glioma activity both in vitro and in vivo orthotopic NOD/SCID GBM mouse model. The present study demonstrates the anti-glioma effect of the dual drug combination of PTX and proapoptotic HePc lipid-based transferrin receptor (TfR) targeted alternative delivery (direct nose to brain transportation) of the nanoparticulate system (Tf-PTX-LNPs, 364 ± 5 nm, -43 ± 9 mV) to overcome the O6-methylguanine-DNA methyltransferase induce drug-resistant for improving the effectiveness of GBM therapy. The resulting nasally targeted LNPs present good biocompatibility, stability, high BBB transcytosis through selective TfR-mediated uptake by tumor cells, and effective tumor penetration in the brain of GBM induced mice. We observed markedly enhanced anti-proliferative efficacy of the targeted LNPs in U87MG cells compared to free drug. Nasal targeted LNPs had shown significantly improved brain concentration (Cmax fivefold and AUC0-24 4.9 fold) with early tmax (0.5 h) than the free drug. In vivo intracranial GBM-bearing targeted LNPs treated mice exhibited significantly prolonged survival with improved anti-tumor efficacy accompanied by reduced toxicity compared to systemic Taxol® and nasal free drug. These findings indicate that the nasal delivery of targeted synergistic nanocarrier holds great promise as a non-invasive adjuvant chemotherapy therapy of GBM.

Validation of Prediction Rules for Computed Tomography Use in Children With Blunt Abdominal or Blunt Head Trauma: Protocol for a Prospective Multicenter Observational Cohort Study.

BACKGROUND: Traumatic brain injuries (TBIs) and intra-abdominal injuries (IAIs) are 2 leading causes of traumatic death and disability in children. To avoid missed or delayed diagnoses leading to increased morbidity, computed tomography (CT) is used liberally. However, the overuse of CT leads to inefficient care and radiation-induced malignancies. Therefore, to maximize precision and minimize the overuse of CT, the Pediatric Emergency Care Applied Research Network (PECARN) previously derived clinical prediction rules for identifying children at high risk and very low risk for IAIs undergoing acute intervention and clinically important TBIs after blunt trauma in large cohorts of children who are injured. OBJECTIVE: This study aimed to validate the IAI and age-based TBI clinical prediction rules for identifying children at high risk and very low risk for IAIs undergoing acute intervention and clinically important TBIs after blunt trauma. METHODS: This was a prospective 6-center observational study of children aged <18 years with blunt torso or head trauma. Consistent with the original derivation studies, enrolled children underwent routine history and physical examinations, and the treating clinicians completed case report forms prior to knowledge of CT results (if performed). Medical records were reviewed to determine clinical courses and outcomes for all patients, and for those who were discharged from the emergency department, a follow-up survey via a telephone call or SMS text message was performed to identify any patients with missed IAIs or TBIs. The primary outcomes were IAI undergoing acute intervention (therapeutic laparotomy, angiographic embolization, blood transfusion, or intravenous fluid for ≥2 days for pancreatic or gastrointestinal injuries) and clinically important TBI (death from TBI, neurosurgical procedure, intubation for >24 hours for TBI, or hospital admission of ≥2 nights due to a TBI on CT). Prediction rule accuracy was assessed by measuring rule classification performance, using standard point and 95% CI estimates of the operational characteristics of each prediction rule (sensitivity, specificity, positive and negative predictive values, and diagnostic likelihood ratios). RESULTS: The project was funded in 2016, and enrollment was completed on September 1, 2021. Data analyses are expected to be completed by December 2022, and the primary study results are expected to be submitted for publication in 2023. CONCLUSIONS: This study will attempt to validate previously derived clinical prediction rules to accurately identify children at high and very low risk for clinically important IAIs and TBIs. Assuming successful validation, widespread implementation is then indicated, which will optimize the care of children who are injured by better aligning CT use with need. INTERNATIONAL REGISTERED REPORT IDENTIFIER (IRRID): RR1-10.2196/43027.

Bio-polymeric transferrin-targeted temozolomide nanoparticles in gel for synergistic post-surgical GBM therapy.

Spatiotemporal targeting of anti-glioma drugs remains a pressing issue in glioblastoma (GBM) treatment. We challenge this issue by developing a minimally invasive in situ implantable hydrogel implant comprising transferrin-targeted temozolomide-miltefosine nanovesicles in the surgically resected GBM cavity (tumour bed). Injection of the "nanovesicle in hydrogel system" in orthotopic GBM-bearing mice improved drug penetration into the peri-cavitary region (∼4.5 mm in depth) with the potential to act as a bridge therapy in the immediate postoperative period, before the initiation of adjuvant radiotherapy. The controlled and sustained release of temozolomide over a month in the surgical cavity eradicated the microscopic GBM cells present within the tumour bed, thereby augmenting the efficacy of adjuvant therapy. The drug (temozolomide and miltefosine) combination was tolerable and efficiently inhibited tumour growth, causing significant prolongation of the survival of tumour-bearing mice compared to that with the free drug. Direct implantation at the target site in the brain resulted in spatiotemporal anti-glioma activity with minimal extracranial and systemic distribution. Nanovesicle in flexible hydrogel systems can be used as potential platforms for the post-surgical management of GBM before initiating adjuvant radiation therapy.

ARID2 suppression promotes tumor progression and upregulates cytokeratin 8, 18 and ß-4 integrin expression in TP53-mutated tobacco-related oral cancer and has prognostic implications.

Mutations in ARID2 and TP53 genes are found to be implicated in the tobacco related tumorigeneses. However, the effect of loss of ARID2 in the TP53 mutated background in tobacco related cancer including oral cancer has not been investigated yet. Hence, in this study we knockdown ARID2 using shRNA mediated knockdown strategy in TP53 mutated oral squamous cell carcinoma (OSCC) cell line and studied its tumorigenic role. Our study revealed that suppression of ARID2 in TP53 mutated oral cancer cells increases cell motility and invasion, induces drastic morphological changes and leads to a marked increase in the expression levels of cytokeratins, and integrins, CK8, CK18 and ß4-Integrin, markers of cell migration/invasion in oral cancer. ARID2 suppression also showed early onset and increased tumorigenicity in-vivo. Interestingly, transcriptome profiling revealed differentially expressed genes associated with migration and invasion in oral cancer cells including AKR1C2, NCAM2, NOS1, ADAM23 and genes of S100A family in ARID2 knockdown TP53 mutated oral cancer cells. Pathway analysis of differentially regulated genes identified "cancer pathways" and "PI3K/AKT Pathway" to be significantly dysregulated upon suppression of ARID2 in TP53 mutated OSCC cells. Notably, decreased ARID2 expression and increased CK8, CK18 expression leads to poor prognosis in Head and Neck cancer (HNSC) patients as revealed by Pan-Cancer TCGA data analysis. To conclude, our study is the first to demonstrate tumor suppressor role of ARID2 in TP53 mutated background indicating their cooperative role in OSCC, and also highlights its prognostic implications suggesting ARID2 as an important therapeutic target in OSCC.

Epidemiology and management of abdominal injuries in children.

BACKGROUND: Although more guideline-adherent care has been described in pediatric compared to adult trauma centers, we aimed to provide a more detailed characterization of management and resource utilization of children with intra-abdominal injury (IAI) within pediatric centers. Our primary objective was to describe the epidemiology, diagnostic evaluation, and management of children with IAI across U.S. children's hospitals. Our secondary objective was to describe the interhospital variation in surgical management of children with IAI. METHODS: We conducted a cross-sectional study of 33 hospitals in the Pediatric Health Information System. We included children aged <18 years evaluated in the emergency department from 2010 to 2019 with IAI, as defined by ICD coding, and who underwent an abdominal computed tomography (CT). Our primary outcome was abdominal surgery. We categorized IAI by organ system and described resource utilization data. We used generalized linear regression to calculate adjusted hospital-level proportions of abdominal surgery, with a random effect for hospital. RESULTS: We studied 9265 children with IAI. Median (IQR) age was 9.0 (6.0-13.0) years. Abdominal surgery was performed in 16% (n = 1479) of children, with the lowest proportion of abdominal surgery observed in children aged <5 years. Liver (38.6%) and spleen (32.1%) were the most common organs injured. A total of 3.1% of children with liver injuries and 2.8% with splenic injuries underwent abdominal surgery. Although there was variation in rates of surgery across hospitals (p < 0.001), only three of 33 hospitals had rates that were statistically different from the aggregate mean of 16%. CONCLUSIONS: Most children with IAI are managed nonoperatively, and most children's hospitals manage children with IAI similarly. These data can be used to inform future benchmarking efforts across hospitals to assess concordance with guidelines for the management of children with IAI.

Combinatorial cetuximab targeted polymeric nanocomplexes reduce PRC1 level and abrogate growth of metastatic hepatocellular carcinoma in vivo with efficient radionuclide uptake.

Hepatocellular carcinoma (HCC) is the most aggressive form of cancer with poor drug responses. Developing an effective drug treatment remains a major unmet clinical need for HCC. We report a comprehensive study of combinatorial Cetuximab (Cet) targeted polymeric poly(D, L-lactide-co-glycolide)-b-poly(ethylene glycol) nanocomplexes delivery of Combretastatin A4 (CA4) and 2-Methoxyestradiol (2ME) (Cet-PLGA-b-PEG-CA4 NP + Cet-PLGA-b-PEG-2ME NP) against metastatic HCC in SCID mice. 125I-Cet-PLGA-b-PEG NP showed potent accumulation and retention in HCC tumors with longer circulation time up to 48 h (18 ±â€¯1.0% ID/g, P < .0001). Combinatorial treatment with targeted polymeric nanocomplexes presented significant tumor growth inhibition (85%, P < .0001) than the free drug combinatorial counterpart, effectively inhibited orthotopic HCC and prevented lung metastasis. Combinatorial nanocomplexes treatment significantly blocked PRC1, a novel target of therapeutic response against HCC. Thus, the combinatorial cetuximab-targeted polymeric nanocomplexes possess superior antitumor activity against metastatic HCC and provide supports for the clinical translation ahead.

Loco-regional radiosensitizing nanoparticles-in-gel augments head and neck cancer chemoradiotherapy.

The therapeutic gain in loco-regionally advanced unresectable head and neck squamous cell carcinoma (HNSCC) is limited with the traditional use of concurrent chemoradiotherapy (CRT) owing to dose-limiting toxicities of systemic clinical radiosensitizers. Delivery through regional platforms is challenging due to limited drug permeation but allows spatio-temporal control of combinatorial regimens locally to overcome drug resistance. We address these challenges by developing biodegradable gellan- and lipid-based dual nanocarriers-in-ion-triggered porous mucoadhesive hydrogels for enhanced site-specific delivery of clinically relevant radiosensitizers i.e. cisplatin and paclitaxel. Interestingly, the nanoparticle-in-gel prolonged the tumor bioaccumulation of both the chemotherapeutic drugs with reduced systemic absorption, thereby improving in vivo efficacy which was confirmed by PET-CT imaging and safety as compared to systemic commercial formulations approved for HNSCC chemoradiotherapy. The nanoparticles facilitated intracellular radiosensitizer uptake and cell arrest to synergistically enhance radiation-induced DNA nicks and apoptosis. Our findings suggest the clinical potential of the present platform in the loco-regional management of HNSCC requiring curative CRT.

Epidemiology of pediatric trauma during the coronavirus disease-2019 pandemic.

BACKGROUND/PURPOSE: We aimed to describe the epidemiology of trauma activations and variations in injury patterns, injury severity, and hospital length-of-stay for injured children in Los Angeles (LA) County during the coronavirus-disease-19 (COVID-19) pandemic. METHODS: We conducted a retrospective cross-sectional study of children aged < 18-years evaluated in 15 trauma centers from 2019 to 2020 and entered in the LA County trauma registry. We defined 01/01/2019-03/18/2020 as pre-pandemic and 03/19/2020-12/31/2020 as the pandemic period. Our primary outcome was pediatric trauma activations. We analyzed demographic and clinical data, including types and severity of injuries sustained. We conducted unadjusted bivariate analyzes of injury patterns between periods. Segmented linear regression models were used to test rates (per 100,000 LA County children) of trauma activations pre-pandemic versus the pandemic period. RESULTS: We studied 4399 children with trauma activations, 2695 of which occurred pre-pandemic and 1701 in the pandemic period. Motor vehicle collisions, gunshot wounds, and burns increased during the pandemic (all p-values< 0.05), while sports injuries decreased (p < 0.001). Median injury severity scores (p = 0.323) and Glasgow Coma Scales (p = 0.558) did not differ between periods, however mortality (p = 0.023) decreased during the pandemic. Segmented linear regression estimates demonstrated that rates of trauma activations pre-pandemic were similar to the pandemic period (p = 0.384). CONCLUSION: Pediatric trauma activations in LA County did not significantly differ during the COVID-19 pandemic, but types and severity of injuries varied between pre-pandemic and pandemic periods. With lockdown restrictions being lifted and novel SARS-CoV-2 variants circulating, our investigation describes this recent epidemiologic phenomenon to aid future preparation for healthcare systems. LEVEL OF EVIDENCE: Level III TYPE OF STUDY: Retrospective cross-sectional study.

Non-invasive transferrin targeted nanovesicles sensitize resistant glioblastoma multiforme tumors and improve survival in orthotopic mouse models.

The blood-brain barrier (BBB) and tumor heterogeneity have resulted in abysmally poor clinical outcomes in glioblastoma (GBM) with the standard therapeutic regimen. Despite several anti-glioma drug delivery strategies, the lack of adequate chemotherapeutic bioavailability in gliomas has led to a suboptimal therapeutic gain in terms of improvement in survival and increased systemic toxicities. This has paved the way for designing highly specific and non-invasive drug delivery approaches for treating GBM. The intranasal (IN) route is one such delivery strategy that has the potential to reach the brain parenchyma by circumventing the BBB. We recently showed that in situ hydrogel embedded with miltefosine (HePc, proapoptotic anti-tumor agent) and temozolomide (TMZ, DNA methylating agent) loaded targeted nanovesicles prevented tumor relapses in orthotopic GBM mouse models. In this study, we specifically investigated the potential of a non-invasive IN route of TMZ delivered from lipid nanovesicles (LNs) decorated with surface transferrin (Tf) and co-encapsulated with HePc to reach the brain by circumventing the BBB in glioma bearing mice. The targeted nanovesicles (228.3 ± 10 nm, -41.7 ± 4 mV) exhibited mucoadhesiveness with 2% w/v mucin suggesting their potential to increase brain drug bioavailability after IN administration. The optimized TLNs had controlled, tunable and significantly different release kinetics in simulated cerebrospinal fluid and simulated nasal fluid demonstrating efficient release of the payload upon reaching the brain. Drug synergy (combination index, 0.7) showed a 6.4-fold enhanced cytotoxicity against resistant U87MG cells compared to free drugs. In vivo gamma scintigraphy of 99mTc labeled LNs showed 500- and 280-fold increased brain concentration post 18 h of treatment. The efficacy of the TLNs increased by 1.8-fold in terms of survival of tumor-bearing mice compared to free drugs. These findings suggested that targeted drug synergy has the potential to intranasally deliver a high therapeutic dose of the chemotherapy agent (TMZ) and could serve as a platform for future clinical application.

Ultrasound augments on-demand breast tumor radiosensitization and apoptosis through a tri-responsive combinatorial delivery theranostic platform.

Advanced inoperable triple-negative breast cancer (TNBC) comprises aggressive tumors with a modest pathological response to neoadjuvant chemotherapy. The concomitant use of chemoradiotherapy improves the pathological response rates. However, the dose-dependent systemic toxicity of clinical radiosensitizers with poor circulation half-life and limited passive bioavailability limits their clinical utility. We address these challenges by rationally designing a stealth and tumor microenvironment responsive nano-conjugate platform for the ultrasound-mediated on-demand spatio-temporal delivery of plant flavonoid curcumin as a combinatorial regimen with clinically approved paclitaxel for the neoadjuvant chemoradiotherapy of locally advanced triple-negative breast cancer (TNBC). Interestingly, the focused application of ultrasound at the orthotopic TNBC xenograft of NOD-SCID mice facilitated the immediate infiltration of nano-conjugates at the tumor interstitium, and conferred in vivo safety over marketed paclitaxel formulation. In addition, curcumin significantly potentiated the in vivo chemoradiotherapeutic efficacy of paclitaxel upon loading into nano-conjugates. This gets further enhanced by the concurrent pulse of ultrasound, as confirmed by PET-CT imaging, along with a significant improvement in the mice survival. The quadrapeutic apoptotic effect by the combination of paclitaxel, curcumin, radiation, and ultrasound, along with a reduction in the tumor microvessel density and cell proliferation marker, confers the broad chemo-radiotherapeutic potential of this regimen for radio-responsive solid tumors, as well as metastatic niches.

Direct evidence of cellular transformation by prion-like p53 amyloid infection.

Tumor suppressor p53 mutations are associated with more than 50% of cancers. Aggregation and amyloid formation of p53 is also implicated in cancer pathogenesis, but direct evidence for aggregated p53 amyloids acting as an oncogene is lacking. Here, we conclusively demonstrate that wild-type p53 amyloid formation imparts oncogenic properties to non-cancerous cells. p53 amyloid aggregates were transferred through cell generations, contributing to enhanced survival, apoptotic resistance with increased proliferation and migration. The tumorigenic potential of p53 amyloid-transformed cells was further confirmed in mouse xenografts, wherein the tumors showed p53 amyloids. p53 disaggregation rescued the cellular transformation and inhibited tumor development in mice. We propose that wild-type p53 amyloid formation contributes to tumorigenesis and can be a potential target for therapeutic intervention. This article has an associated First Person interview with the first author of the paper.