Central Giant Cell Granuloma of the Mandible and Maxilla: A Clinicopathological Study of 21 Cases.

Background Central giant cell granuloma (CGCG) presents as a locally invasive, intraosseous lesion characterized by the accumulation of multinucleated giant cells amidst a matrix of hemorrhage and reactive fibrous tissue that infiltrates bone trabeculae. This idiopathic non-neoplastic proliferative lesion primarily affects the mandible, typically presenting as either unilocular or multilocular radiolucencies on X-rays. Although trauma or intraosseous hemorrhages are potential triggers, the precise histogenesis and etiology remain unclear. CGCG predominantly occurs in children and young adults, with a slight female predilection. Methods and materials A retrospective analysis of 21 cases of CGCG diagnosed at the Oral Pathology/Pathology department of Temple University Hospital between 2015 and 2022 was conducted. Each case was evaluated based on various parameters, including age, gender, presenting symptoms, radiographic findings, clinical differential diagnosis, and histological confirmation. The primary radiographic technique employed for diagnosis was X-ray imaging of the mandible and maxilla. The histological examination involved cutting paraffin-embedded tissue into 5-micrometer-thick sections, which were then stained using routine hematoxylin and eosin (H&E) stain. Notably, no specialized histochemical or immunohistochemical stains were utilized in the evaluation process. Results In our study, we reviewed 21 cases; 9 were male, 11 were female, and one had no available gender data. The age range was 15-76 years, with a mean of 50 years. The mandible was the most commonly affected location (17 cases; 81%) while the maxilla was less commonly involved (4 cases; 19%). Many CGCG lesions were asymptomatic (13 cases; 62%); eight cases (38%) were symptomatic, with pain and fullness of the affected dental region being the main manifestations. In a few cases, conditions such as brown tumor (severe hyperparathyroidism) and odontogenic neoplasms, such as ameloblastoma, were suspected clinically and radiographically. The diagnosis of CGCG with associated acute and chronic inflammation was confirmed in all the cases. Histological evaluation of routinely stained slides was the main diagnostic tool utilized. No special stains or molecular studies were required to establish the final diagnosis. Conclusions Our investigation has determined that CGCG exhibits a non-neoplastic nature, displaying a spectrum of behaviors ranging from non-aggressive to aggressive tendencies. While CGCG is predominantly observed in the mandible, rare instances of involvement in the maxilla have also been documented. Importantly, no confirmed association with neoplastic lesions was identified during our analysis. The clinical course of CGCG tends to be indolent, with some cases presenting in association with impacted teeth. It's noteworthy that CGCG can present features mimicking neoplastic conditions, such as ameloblastoma, or localized lesions linked to systemic disorders such as hyperparathyroidism (brown tumor).

Correction: Sugar-Sweetened Beverage Consumption and Its Association With Dental Caries Among Adolescents in Erbil, Iraq: A Cross-Sectional Study.

[This corrects the article DOI: 10.7759/cureus.58471.].

Structure of Aquifex aeolicus lumazine synthase by cryo-electron microscopy to 1.42†Šresolution.

Single-particle cryo-electron microscopy (cryo-EM) has become an essential structural determination technique with recent hardware developments making it possible to reach atomic resolution, at which individual atoms, including hydrogen atoms, can be resolved. In this study, we used the enzyme involved in the penultimate step of riboflavin biosynthesis as a test specimen to benchmark a recently installed microscope and determine if other protein complexes could reach a resolution of 1.5 Šor better, which so far has only been achieved for the iron carrier ferritin. Using state-of-the-art microscope and detector hardware as well as the latest software techniques to overcome microscope and sample limitations, a 1.42 Šmap of Aquifex aeolicus lumazine synthase (AaLS) was obtained from a 48 h microscope session. In addition to water molecules and ligands involved in the function of AaLS, we can observe positive density for ∼50% of the hydrogen atoms. A small improvement in the resolution was achieved by Ewald sphere correction which was expected to limit the resolution to ∼1.5 Šfor a molecule of this diameter. Our study confirms that other protein complexes can be solved to near-atomic resolution. Future improvements in specimen preparation and protein complex stabilization may allow more flexible macromolecules to reach this level of resolution and should become a priority of study in the field.

Single-molecule characterization of SV40 replisome and novel factors: human FPC and Mcm10.

The simian virus 40 (SV40) replisome only encodes for its helicase; large T-antigen (L-Tag), while relying on the host for the remaining proteins, making it an intriguing model system. Despite being one of the earliest reconstituted eukaryotic systems, the interactions coordinating its activities and the identification of new factors remain largely unexplored. Herein, we in vitro reconstituted the SV40 replisome activities at the single-molecule level, including DNA unwinding by L-Tag and the single-stranded DNA-binding protein Replication Protein A (RPA), primer extension by DNA polymerase δ, and their concerted leading-strand synthesis. We show that RPA stimulates the processivity of L-Tag without altering its rate and that DNA polymerase δ forms a stable complex with L-Tag during leading-strand synthesis. Furthermore, similar to human and budding yeast Cdc45-MCM-GINS helicase, L-Tag uses the fork protection complex (FPC) and the mini-chromosome maintenance protein 10 (Mcm10) during synthesis. Hereby, we demonstrate that FPC increases this rate, and both FPC and Mcm10 increase the processivity by stabilizing stalled replisomes and increasing their chances of restarting synthesis. The detailed kinetics and novel factors of the SV40 replisome establish it as a closer mimic of the host replisome and expand its application as a model replication system.

Whiteness and greenness assessments of a sensitive HPLC method with fluorimetric detection for dapagliflozin quantitation in human plasma: Application to a healthy human volunteer.

The evident ecological impact of human actions, like air pollution, global warming, and ozone depletion, underscores the need for environmentally friendly approaches across various domains, including analytical chemistry. This study aimed to establish a validated, eco-friendly, and sustainable approach utilizing a fluorescence detector coupled with high-performance liquid chromatography for quantifying the antihyperglycemic agent dapagliflozin (DAPA), in human plasma. This method employed a C18 Microsorb MV (4.5 × 250 mm, 5 µm [particle size]) column at 40°C, with 40:60% v/v isocratic elution of acetonitrile and (0.1%) orthophosphoric acid as the mobile phase at 1 mL/min flow rate. DAPA and the internal standard demonstrated their greatest response by performing excitation at 225 nm (λex) and recording chromatograms at an emission wavelength (λem) equal to 305 nm. The presented approach demonstrated high linearity between 50 and 2000 ng/mL and full adherence to the guidelines of the US Food and Drug Administration regarding the validation of bioanalytical methods. The described technique was effectively used for quantification of DAPA in human plasma samples from a healthy male participant who received a tablet of 10 mg DAPA. Analytical Eco-Scale, Analytical GREEnness metric, and the recently created ChlorTox Scale were utilized for greenness assessment. Additionally, the "Red, Green, and Blue 12" model was used in whiteness evaluation.

Severe Combined Immunodeficiency from a Homozygous DNA Ligase 1 Mutant with Reduced Catalytic Activity but Increased Ligation Fidelity.

A cell's ability to survive and to evade cancer is contingent on its ability to retain genomic integrity, which can be seriously compromised when nucleic acid phosphodiester bonds are disrupted. DNA Ligase 1 (LIG1) plays a key role in genome maintenance by sealing single-stranded nicks that are produced during DNA replication and repair. Autosomal recessive mutations in a limited number of individuals have been previously described for this gene. Here we report a homozygous LIG1 mutation (p.A624T), affecting a universally conserved residue, in a patient presenting with leukopenia, neutropenia, lymphopenia, pan-hypogammaglobulinemia, and diminished in vitro response to mitogen stimulation. Patient fibroblasts expressed normal levels of LIG1 protein but exhibited impaired growth, poor viability, high baseline levels of gamma-H2AX foci, and an enhanced susceptibility to DNA-damaging agents. The mutation reduced LIG1 activity by lowering its affinity for magnesium 2.5-fold. Remarkably, it also increased LIG1 fidelity > 50-fold against 3' end 8-Oxoguanine mismatches, exhibiting a marked reduction in its ability to process such nicks. This is expected to yield increased ss- and dsDNA breaks. Molecular dynamic simulations, and Residue Interaction Network studies, predicted an allosteric effect for this mutation on the protein loops associated with the LIG1 high-fidelity magnesium, as well as on DNA binding within the adenylation domain. These dual alterations of suppressed activity and enhanced fidelity, arising from a single mutation, underscore the mechanistic picture of how a LIG1 defect can lead to severe immunological disease.

Sugar-Sweetened Beverage Consumption and Its Association With Dental Caries Among Adolescents in Erbil, Iraq: A Cross-Sectional Study.

Background Sugar-sweetened beverages are one of the most common sources of added sugar in the diet and have been associated with an increased risk of dental caries, obesity, major chronic diseases, and possibly cancer. Dental caries is a diet-related, highly prevalent, and preventable oral disease. The objective of this study was to assess the frequency of sugar-sweetened beverage consumption and its association with dental caries in adolescents in Erbil, Iraq. Methods This is a cross-sectional study that invited 11- to 16-year-old intermediate school students (n=380) in Erbil, Iraq. Data collection comprised a validated questionnaire and a clinical examination. In addition, dietary data were collected by using two non-consecutive 24-hour recalls. The mean of the daily consumption of sugar-sweetened beverages over a two-day period was calculated. Dental caries was diagnosed based on World Health Organization (WHO) criteria and was reported as a decayed, missing, and filled permanent tooth (DMFT). A multiple regression model was used to assess the influence of sugar-sweetened beverages on dental caries experience (DMFT). SPSS version 26 (Armonk, NY: IBM Corp) was used to analyze the data at the 5% significance level. Results Of the 380 students interviewed, one participant was excluded because of incomplete data. The participant's mean age and standard deviation (SD) were 13.3±1.2. A total of 54.1% of the students were female. The mean daily intake of sugar-sweetened beverages was 686.71±197.50 mL per day. Male students consumed more beverages than female students (p<0.001). The most frequently consumed sugar-sweetened beverages were sweetened tea and coffee, and the least frequently consumed beverages were milk and dairy products. The mean decayed, missing, and filled permanent tooth (DMFT) was 94.58±2.73. Results of multiple regression analysis showed that caries experience (DMFT) was associated with insufficient toothbrushing (p<0.001), plaque-affected sextants (p=0.001), and male sex (p=0.016). The model also showed a significant association between sugar-sweetened beverage consumption and dental caries experience (DMFT) (regression coefficient=0.008, CI: 0.006-0.009, p<0.001). Conclusions Adolescents in Erbil, Iraq, consumed sugar-sweetened beverages on a frequent basis, and male students consumed more sugary beverages than females. The higher frequency of these beverage consumptions was associated with a higher dental caries experience. Consequently, reducing sugar-sweetened beverage consumption could have a significant positive public health impact.

Hospice and palliative care utilization in 16 004 232 medicare claims: comparing trauma to surgical and medical inpatients.

Background: Hospice and palliative care (PC) utilization is increasing in geriatric inpatients, but limited research exists comparing rates among trauma, surgical and medical specialties. The goal of this study was to determine whether there are differences among these three groups in rates of hospice and PC utilization. Methods: Patients from Centers for Medicare & Medicaid Services (CMS) Inpatient Standard Analytical Files for 2016-2020 aged ≥65 years were analyzed. Patients with a National Trauma Data Standard-qualifying ICD-10 injury code with abbreviated injury score ≥2 were classified as 'trauma'; the rest as 'surgical' or 'medical' using CMS MS-DRG definitions. Patients were classified as having PC if they had an ICD-10 diagnosis code for PC (Z51.5) and as hospice discharge (HD) if their hospital disposition was 'hospice' (home or inpatient). Use proportions for specialties were compared by group and by subgroups with increasing risk of poor outcome. Results: There were 16M hospitalizations from 1024 hospitals (9.3% trauma, 26.3% surgical and 64.4% medical) with 53.7% women, 84.5% white and 38.7% >80 years. Overall, 6.2% received PC and 4.1% a HD. Both rates were higher in trauma patients (HD: 3.6%, PC: 6.3%) versus surgical patients (HD: 1.5%, PC: 3.0%), but lower than in medical patients (HD: 5.2%, PC: 7.5%). PC rates increased in higher risk patient subgroups and were highest for inpatient HD. Conclusions: In this large study of Medicare patients, HD and PC rates varied significantly among specialties. Trauma patients had higher HD and PC utilization rates than surgical, but lower than medical. The presence of comorbidities, frailty and/or severe traumatic brain injury (in addition to advanced age) may be valuable criteria in selection of trauma patients for hospice and PC services. Further studies are needed to inform the most efficient use of hospice and PC resources, with particular focus on both timing and selection of subgroups most likely to benefit from these valuable yet limited resources. Level of evidence: Level III, therapeutic/care management.

Integrated management of groundwater quantity, physicochemical properties, and microbial quality in West Nile delta using a new MATLAB code and geographic information system mapping.

Groundwater is an excellent alternative to freshwater for drinking, irrigation, and developing arid regions. Agricultural, commercial, industrial, residential, and municipal activities may affect groundwater quantity and quality. Therefore, we aimed to use advanced methods/techniques to monitor the piezometric levels and collect groundwater samples to test their physicochemical and biological characteristics. Our results using software programs showed two main types of groundwater: the most prevalent was the Na-Cl type, which accounts for 94% of the groundwater samples, whereas the Mg-Cl type was found in 6% of samples only. In general, the hydraulic gradient values, ranging from medium to low, could be attributed to the slow movement of groundwater. Salinity distribution in groundwater maps varied between 238 and 1350 mg L-1. Although lower salinity values were observed in northwestern wells, higher values were recorded in southern ones. The collected seventeen water samples exhibited brackish characteristics and were subjected to microbial growth monitoring. Sample WD12 had the lowest total bacterial count (TBC) of 4.8 ± 0.9 colony forming unit (CFU mg L-1), while WD14 had the highest TBC (7.5 ± 0.5 CFU mg L-1). None of the tested water samples, however, contained pathogenic microorganisms. In conclusion, the current simulation models for groundwater drawdown of the Quaternary aquifer system predict a considerable drawdown of water levels over the next 10, 20, and 30 years with the continuous development of the region.

Synthesis of novel phthalazine-based derivatives with potent cytotoxicity against HCT-116 cells through apoptosis and VEGFR2 inhibition.

The parent ethyl 3-(4-benzyl-1-oxophthalazin-2(1H)-yl) propanoate (3) has 25 compounds. Their respective mono, dipeptides and hydrazones derivatives were produced by chemoselective N-alkylation via addition reaction of 4-benzylphthalazin-1(2H)-one (2) with ethyl acrylate and anhydrous potassium carbonate to give ethyl 3-(4-benzyl-1-oxophthalazin-2(1H)-yl) propanoate (3). The ester 3 was hydrazinolyzed to give the corresponding hydrazide 3-(4-benzyl-1-oxophthalazin-2(1H)-yl) propanehydrazide (5), then azide 6 coupled with amino acid ester hydrochloride and/or amines to afford several parent esters 8a-c, then a series of hydrazinolyzed reactions occurred to give corresponding hydrazides 9a-c. The hydrazide 9a was subjected to the azide coupling procedure, which resulted in the formation of various dipeptides. Subsequently, it was condensed with various aldehydes to yield hydrazone derivatives 13a-d. Interestingly, compounds 9c, 12b, and 13c exhibited potent cytotoxicity with IC50 values of 1.58, 0.32 and 0.64 µM compared to sorafenib (IC50 = 2.93 µM). Compound 12b exhibited potent VEGFR2 inhibition by 95.2% with an IC50 value of 17.8 µM compared to sorafenib (94.7% and IC50 of 32.1 µM). For apoptosis activity, 12b-treatment induced apoptosis in HCT-116 cells by 21.7-fold, arresting the cell proliferation at S-phase. Finally, it formed a good binding affinity towards VEGFR2 protein with a binding energy of -10.66 kcal mol-1, and it formed binding interactions with the key interactive amino acids.

Pragmatic Trial of Hospitalization Rate in Chronic Kidney Disease.

BACKGROUND: Despite the availability of effective therapies for patients with chronic kidney disease, type 2 diabetes, and hypertension (the kidney-dysfunction triad), the results of large-scale trials examining the implementation of guideline-directed therapy to reduce the risk of death and complications in this population are lacking. METHODS: In this open-label, cluster-randomized trial, we assigned 11,182 patients with the kidney-dysfunction triad who were being treated at 141 primary care clinics either to receive an intervention that used a personalized algorithm (based on the patient's electronic health record [EHR]) to identify patients and practice facilitators to assist providers in delivering guideline-based interventions or to receive usual care. The primary outcome was hospitalization for any cause at 1 year. Secondary outcomes included emergency department visits, readmissions, cardiovascular events, dialysis, and death. RESULTS: We assigned 71 practices (enrolling 5690 patients) to the intervention group and 70 practices (enrolling 5492 patients) to the usual-care group. The hospitalization rate at 1 year was 20.7% (95% confidence interval [CI], 19.7 to 21.8) in the intervention group and 21.1% (95% CI, 20.1 to 22.2) in the usual-care group (between-group difference, 0.4 percentage points; P = 0.58). The risks of emergency department visits, readmissions, cardiovascular events, dialysis, or death from any cause were similar in the two groups. The risk of adverse events was also similar in the trial groups, except for acute kidney injury, which was observed in more patients in the intervention group (12.7% vs. 11.3%). CONCLUSIONS: In this pragmatic trial involving patients with the triad of chronic kidney disease, type 2 diabetes, and hypertension, the use of an EHR-based algorithm and practice facilitators embedded in primary care clinics did not translate into reduced hospitalization at 1 year. (Funded by the National Institutes of Health and others; ICD-Pieces ClinicalTrials.gov number, NCT02587936.).

Intrinsic endothelial hyperresponsiveness to inflammatory mediators drives acute episodes in models of Clarkson disease.

Clarkson disease, or monoclonal gammopathy-associated idiopathic systemic capillary leak syndrome (ISCLS), is a rare, relapsing-remitting disorder featuring the abrupt extravasation of fluids and proteins into peripheral tissues, which in turn leads to hypotensive shock, severe hemoconcentration, and hypoalbuminemia. The specific leakage factor(s) and pathways in ISCLS are unknown, and there is no effective treatment for acute flares. Here, we characterize an autonomous vascular endothelial defect in ISCLS that was recapitulated in patient-derived endothelial cells (ECs) in culture and in a mouse model of disease. ISCLS-derived ECs were functionally hyperresponsive to permeability-inducing factors like VEGF and histamine, in part due to increased endothelial nitric oxide synthase (eNOS) activity. eNOS blockade by administration of N(γ)-nitro-l-arginine methyl ester (l-NAME) ameliorated vascular leakage in an SJL/J mouse model of ISCLS induced by histamine or VEGF challenge. eNOS mislocalization and decreased protein phosphatase 2A (PP2A) expression may contribute to eNOS hyperactivation in ISCLS-derived ECs. Our findings provide mechanistic insights into microvascular barrier dysfunction in ISCLS and highlight a potential therapeutic approach.

Circulating microRNA Panel for Prediction of Recurrence and Survival in Early-Stage Lung Adenocarcinoma.

Early-stage lung adenocarcinoma (LUAD) patients remain at substantial risk for recurrence and disease-related death, highlighting the unmet need of biomarkers for the assessment and identification of those in an early stage who would likely benefit from adjuvant chemotherapy. To identify circulating miRNAs useful for predicting recurrence in early-stage LUAD, we performed miRNA microarray analysis with pools of pretreatment plasma samples from patients with stage I LUAD who developed recurrence or remained recurrence-free during the follow-up period. Subsequent validation in 85 patients with stage I LUAD resulted in the development of a circulating miRNA panel comprising miR-23a-3p, miR-320c, and miR-125b-5p and yielding an area under the curve (AUC) of 0.776 in predicting recurrence. Furthermore, the three-miRNA panel yielded an AUC of 0.804, with a sensitivity of 45.8% at 95% specificity in the independent test set of 57 stage I and II LUAD patients. The miRNA panel score was a significant and independent factor for predicting disease-free survival (p < 0.001, hazard ratio [HR] = 1.64, 95% confidence interval [CI] = 1.51-4.22) and overall survival (p = 0.001, HR = 1.51, 95% CI = 1.17-1.94). This circulating miRNA panel is a useful noninvasive tool to stratify early-stage LUAD patients and determine an appropriate treatment plan with maximal efficacy.

Mitochondrial genetic variation and risk of chronic kidney disease and acute kidney injury in UK Biobank participants.

Experimental models suggest an important role for mitochondrial dysfunction in the pathogenesis of chronic kidney disease (CKD) and acute kidney injury (AKI), but little is known regarding the impact of common mitochondrial genetic variation on kidney health. We sought to evaluate associations of inherited mitochondrial DNA (mtDNA) variation with risk of CKD and AKI in a large population-based cohort. We categorized UK Biobank participants who self-identified as white into eight distinct mtDNA haplotypes, which were previously identified based on their associations with phenotypes associated with mitochondrial DNA copy number, a measure of mitochondrial function. We used linear and logistic regression models to evaluate associations of these mtDNA haplotypes with estimated glomerular filtration rate by serum creatinine and cystatin C (eGFRCr-CysC, N = 362,802), prevalent (N = 416 cases) and incident (N = 405 cases) end-stage kidney disease (ESKD), AKI defined by diagnostic codes (N = 14,170 cases), and urine albumin/creatinine ratio (ACR, N = 114,662). The mean age was 57 ± 8 years and the mean eGFR was 90 ± 14 ml/min/1.73 m2. MtDNA haplotype was significantly associated with eGFR (p = 2.8E-12), but not with prevalent ESKD (p = 5.9E-2), incident ESKD (p = 0.93), AKI (p = 0.26), or urine ACR (p = 0.54). The association of mtDNA haplotype with eGFR remained significant after adjustment for diabetes mellitus and hypertension (p = 1.2E-10). When compared to the reference haplotype, mtDNA haplotypes I (ß = 0.402, standard error (SE) = 0.111; p = 2.7E-4), IV (ß = 0.430, SE = 0.073; p = 4.2E-9), and V (ß = 0.233, SE = 0.050; p = 2.7E-6) were each associated with higher eGFR. Among self-identified white UK Biobank participants, mtDNA haplotype was associated with eGFR, but not with ESKD, AKI or albuminuria.

Design, synthesis, molecular modelling and biological evaluation of novel 6-amino-5-cyano-2-thiopyrimidine derivatives as potent anticancer agents against leukemia and apoptotic inducers.

Herein, a novel series of 6-amino-5-cyano-2-thiopyrimidines and condensed pyrimidines analogues were prepared. All the synthesized compounds (1a-c, 2a-c, 3a-c, 4a-r and 5a-c) were evaluated for in vitro anticancer activity by the National Cancer Institute (NCI; MD, USA) against 60 cell lines. Compound 1c showed promising anticancer activity and was selected for the five-dose testing. Results demonstrated that compound 1c possessed broad spectrum anti-cancer activity against the nine cancerous subpanels tested with selectivity ratio ranging from 0.7 to 39 at the GI50 level with high selectivity towards leukaemia. Mechanistic studies showed that Compound 1c showed comparable activity to Duvelisib against PI3Kδ (IC50 = 0.0034 and 0.0025 µM, respectively) and arrested cell cycle at the S phase and displayed significant increase in the early and late apoptosis in HL60 and leukaemia SR cells. The necrosis percentage showed a significant increase from 1.13% to 3.41% in compound 1c treated HL60 cells as well as from 1.51% to 4.72% in compound 1c treated leukaemia SR cells. Also, compound 1c triggered apoptosis by activating caspase 3, Bax, P53 and suppressing Bcl2. Moreover, 1c revealed a good safety profile against human normal lung fibroblast cell line (WI-38 cells). Molecular analysis of Duvelisib and compound 1c in PI3K was performed. Finally, these results suggest that 2-thiopyrimidine derivative 1c might serve as a model for designing novel anticancer drugs in the future.

Designer high-density lipoprotein particles enhance endothelial barrier function and suppress inflammation.

High-density lipoprotein (HDL) nanoparticles promote endothelial cell (EC) function and suppress inflammation, but their utility in treating EC dysfunction has not been fully explored. Here, we describe a fusion protein named ApoA1-ApoM (A1M) consisting of apolipoprotein A1 (ApoA1), the principal structural protein of HDL that forms lipid nanoparticles, and ApoM, a chaperone for the bioactive lipid sphingosine 1-phosphate (S1P). A1M forms HDL-like particles, binds to S1P, and is signaling competent. Molecular dynamics simulations showed that the S1P-bound ApoM moiety in A1M efficiently activated EC surface receptors. Treatment of human umbilical vein ECs with A1M-S1P stimulated barrier function either alone or cooperatively with other barrier-enhancing molecules, including the stable prostacyclin analog iloprost, and suppressed cytokine-induced inflammation. A1M-S1P injection into mice during sterile inflammation suppressed neutrophil influx and inflammatory mediator secretion. Moreover, systemic A1M administration led to a sustained increase in circulating HDL-bound S1P and suppressed inflammation in a murine model of LPS-induced endotoxemia. We propose that A1M administration may enhance vascular endothelial barrier function, suppress cytokine storm, and promote resilience of the vascular endothelium.

Citrus clementine Peel Essential Oil Ameliorates Potassium Dichromate-Induced Lung Injury: Insights into the PI3K/AKT Pathway.

Acute Lung Injury (ALI) is a life-threatening syndrome that has been identified as a potential complication of COVID-19. There is a critical need to shed light on the underlying mechanistic pathways and explore novel therapeutic strategies. This study aimed to examine the potential therapeutic effects of Citrus clementine essential oil (CCEO) in treating potassium dichromate (PDC)-induced ALI. The chemical profile of CCEO was created through GC-MS analysis. An in vivo study in rats was conducted to evaluate the effect of CCEO administrated via two different delivery systems (oral/inhalation) in mitigating acute lung injury (ALI) induced by intranasal instillation of PDC. Eight volatile compounds were identified, with monoterpene hydrocarbons accounting for 97.03% of the identified constituents, including 88.84% of D-limonene. CCEO at doses of 100 and 200 mg/kg bw exhibited antioxidant and anti-inflammatory properties. These significant antioxidant properties were revealed through the reduction of malondialdehyde (MDA) and the restoration of reduced glutathione (GSH). In addition, inflammation reduction was observed by decreasing levels of cytokines tumor necrosis factor-α and tumor growth factor-ß (TNF-α and TGF-ß), along with an increase in phosphatidylinositide-3-kinase (PI3K) and Akt overexpression in lung tissue homogenate, in both oral and inhalation routes, compared to the PDC-induced group. These results were supported by histopathological studies and immunohistochemical assessment of TGF-ß levels in lung tissues. These findings revealed that CCEO plays an integral role in relieving ALI induced by intranasal PDC and suggests it as a promising remedy.

Baseline Serum Inflammatory Proteins Predict Poor CAR T Outcomes in Diffuse Large B-cell Lymphoma.

A subset of patients with diffuse large B-cell lymphoma (DLBCL) treated with CD19 chimeric antigen receptor (CAR) T-cell therapy have poor clinical outcomes. We report serum proteins associated with severe immune-mediated toxicities and inferior clinical responses in 146 patients with DLBCL treated with axicabtagene ciloleucel. We develop a simple stratification based on pre-lymphodepletion C reactive protein (CRP) and ferritin to classify patients into low-, intermediate-, and high-risk groups. We observe that patients in the high-risk category were more likely to develop grade ≥3 toxicities and had inferior overall and progression-free survival. We sought to validate our findings with two independent international cohorts demonstrating that patients classified as low-risk have excellent efficacy and safety outcomes. Based on routine and readily available laboratory tests that can be obtained prior to lymphodepleting chemotherapy, this simple risk stratification can inform patient selection for CAR T-cell therapy. SIGNIFICANCE: CAR T-cell therapy has changed the treatment paradigm for patients with relapsed/refractory hematologic malignancies. Despite encouraging efficacy, a subset of patients have poor clinical outcomes. We show that a simple clinically applicable model using pre-lymphodepletion CRP and ferritin can identify patients at high risk of poor outcomes. This article is featured in Selected Articles from This Issue, p. 80.

Patient-Reported Financial Burden of Treatment for Colon or Rectal Cancer.

Importance: The longitudinal experience of patients is critical to the development of interventions to identify and reduce financial hardship. Objective: To evaluate financial hardship over 12 months in patients with newly diagnosed colorectal cancer (CRC) undergoing curative-intent therapy. Design, Setting, and Participants: This prospective, longitudinal cohort study was conducted between May 2018 and July 2020, with time points over 12 months. Participants included patients at National Cance Institute Community Oncology Research Program sites. Eligibility criteria included age at least 18 years, newly diagnosed stage I to III CRC, not started chemotherapy and/or radiation, treated with curative intent, and able to speak English. Data were analyzed from December 2022 through April 2023. Main Outcomes and Measures: The primary end point was financial hardship, measured using the Comprehensive Score for Financial Toxicity (COST), which assesses the psychological domain of financial hardship (range, 0-44; higher score indicates better financial well-being). Participants completed 30-minute surveys (online or paper) at baseline and 3, 6, and 12 months. Results: A total of 450 participants (mean [SD] age, 61.0 [12.0] years; 240 [53.3%] male) completed the baseline survey; 33 participants (7.3%) were Black and 379 participants (84.2%) were White, and 14 participants (3.1%) identified as Hispanic or Latino and 424 participants (94.2%) identified as neither Hispanic nor Latino. There were 192 participants (42.7%) with an annual household income of $60 000 or greater. There was an improvement in financial hardship from diagnosis to 12 months of 0.3 (95% CI, 0.2 to 0.3) points per month (P < .001). Patients with better quality of life and greater self-efficacy had less financial toxicity. Each 1-unit increase in Functional Assessment of Cancer Therapy-General (rapid version) score was associated with an increase of 0.7 (95% CI, 0.5 to 0.9) points in COST score (P < .001); each 1-unit increase in self-efficacy associated with an increase of 0.6 (95% CI, 0.2 to 1.0) points in COST score (P = .006). Patients who lived in areas with lower neighborhood socioeconomic status had greater financial toxicity. Neighborhood deprivation index was associated with a decrease of 0.3 (95% CI, -0.5 to -0.1) points in COST score (P = .009). Conclusions and Relevance: These findings suggest that interventions for financial toxicity in cancer care should focus on counseling to improve self-efficacy and mitigate financial worry and screening for these interventions should include patients at higher risk of financial burden.