Comprehensive Characterization of Cancer Driver Genes and Mutations.

Identifying molecular cancer drivers is critical for precision oncology. Multiple advanced algorithms to identify drivers now exist, but systematic attempts to combine and optimize them on large datasets are few. We report a PanCancer and PanSoftware analysis spanning 9,423 tumor exomes (comprising all 33 of The Cancer Genome Atlas projects) and using 26 computational tools to catalog driver genes and mutations. We identify 299 driver genes with implications regarding their anatomical sites and cancer/cell types. Sequence- and structure-based analyses identified >3,400 putative missense driver mutations supported by multiple lines of evidence. Experimental validation confirmed 60%-85% of predicted mutations as likely drivers. We found that >300 MSI tumors are associated with high PD-1/PD-L1, and 57% of tumors analyzed harbor putative clinically actionable events. Our study represents the most comprehensive discovery of cancer genes and mutations to date and will serve as a blueprint for future biological and clinical endeavors.

Inflammation in HIV and Its Impact on Atherosclerotic Cardiovascular Disease.

People living with HIV have a 1.5- to 2-fold increased risk of developing cardiovascular disease. Despite treatment with highly effective antiretroviral therapy, people living with HIV have chronic inflammation that makes them susceptible to multiple comorbidities. Several factors, including the HIV reservoir, coinfections, clonal hematopoiesis of indeterminate potential (CHIP), microbial translocation, and antiretroviral therapy, may contribute to the chronic state of inflammation. Within the innate immune system, macrophages harbor latent HIV and are among the prominent immune cells present in atheroma during the progression of atherosclerosis. They secrete inflammatory cytokines such as IL (interleukin)-6 and tumor necrosis-α that stimulate the expression of adhesion molecules on the endothelium. This leads to the recruitment of other immune cells, including cluster of differentiation (CD)8+ and CD4+ T cells, also present in early and late atheroma. As such, cells of the innate and adaptive immune systems contribute to both systemic inflammation and vascular inflammation. On a molecular level, HIV-1 primes the NLRP3 (NLR family pyrin domain containing 3) inflammasome, leading to an increased expression of IL-1ß, which is important for cardiovascular outcomes. Moreover, activation of TLRs (toll-like receptors) by HIV, gut microbes, and substance abuse further activates the NLRP3 inflammasome pathway. Finally, HIV proteins such as Nef (negative regulatory factor) can inhibit cholesterol efflux in monocytes and macrophages through direct action on the cholesterol transporter ABCA1 (ATP-binding cassette transporter A1), which promotes the formation of foam cells and the progression of atherosclerotic plaque. Here, we summarize the stages of atherosclerosis in the context of HIV, highlighting the effects of HIV, coinfections, and antiretroviral therapy on cells of the innate and adaptive immune system and describe current and future interventions to reduce residual inflammation and improve cardiovascular outcomes among people living with HIV.

What Is a Meaningful Difference When Using Infarct Volume as the Primary Outcome?: Results From the HERMES Database.

BACKGROUND: Ischemic stroke lesion volume at follow-up is an important surrogate outcome for acute stroke trials. We aimed to assess which differences in 48-hour lesion volume translate into meaningful clinical differences. METHODS: We used pooled data from 7 trials investigating the efficacy of endovascular treatment for anterior circulation large vessel occlusion in acute ischemic stroke. We assessed 48-hour lesion volume follow-up computed tomography or magnetic resonance imaging. The primary outcome was a good functional outcome, defined as modified Rankin Scale (mRS) scores of 0 to 2. We performed multivariable logistic regression to predict the probability of achieving mRS scores of 0 to 2 and determined the differences in 48-hour lesion volume that correspond to a change of 1%, 5%, and 10% in the adjusted probability of achieving mRS scores of 0 to 2. RESULTS: In total, 1665/1766 (94.2%) patients (median age, 68 [interquartile range, 57-76] years, 781 [46.9%] female) had information on follow-up ischemic lesion volume. Computed tomography was used for follow-up imaging in 83% of patients. The median 48-hour lesion volume was 41 (interquartile range, 14-120) mL. We observed a linear relationship between 48-hour lesion volume and mRS scores of 0 to 2 for adjusted probabilities between 65% and 20%/volumes <80 mL, although the curve sloped off for lower mRS scores of 0-2 probabilities/higher volumes. The median differences in 48-hour lesion volume associated with a 1%, 5%, and 10% increase in the probability of mRS scores of 0 to 2 for volumes <80 mL were 2 (interquartile range, 2-3), 10 (9-11), and 20 (18-23) mL, respectively. We found comparable associations when assessing computed tomography and magnetic resonance imaging separately. CONCLUSIONS: A difference of 2, 10, and 20 mL in 48-hour lesion volume, respectively, is associated with a 1%, 5%, and 10% absolute increase in the probability of achieving good functional outcome. These results can inform the design of future stroke trials that use 48-hour lesion volume as the primary outcome.

Invaluable Benefits of 10 Years of the International Collaboration of Aphasia Trialists (CATs).

Aphasia research has traditionally been considered a (unidisciplinary) niche topic in medical science. The international Collaboration of Aphasia Trialists (CATs) is a global collaboration of multidisciplinary aphasia researchers. Over the past 10 years, CATs has collectively taken a rigorous approach to systematically address persistent challenges to aphasia research quality. This article summarizes the achievements over the past decade. CATs' achievements include: standardizing terminology, advancing aphasia research design by aphasia expert consensus recommendations, developing a core data set and intervention descriptors, facilitating the involvement of people with the language impairment aphasia in the research process, translating, and adapting assessment tools into global languages, encouraging data sharing, developing innovative secondary data analysis methodologies and promoting the transparency and accessibility of high quality aphasia research reports. CATs' educational and scientific achievements over the past 10 years far exceed what individual researchers in the field could have ever achieved.

Plasma Metabolites and Life's Simple 7 in REGARDS.

BACKGROUND: The American Heart Association's Life's Simple 7 (LS7) is a health metric that captures important factors associated with cardiovascular and cerebrovascular health. Previous studies highlight the potential of plasma metabolites to serve as a marker for lifestyle and health behavior that could be a target for stroke prevention. The objectives of this study were to identify metabolites that were associated with LS7 and incident ischemic stroke and mediate the relationship between the two. METHODS: Targeted metabolomic profiling of 162 metabolites by liquid chromatography-tandem mass spectrometry was used to identify candidate metabolites in a stroke case-cohort nested within the REGARDS study (Reasons for Geographic and Racial Differences in Stroke). Weighted linear regression and weighted Cox proportional hazard models were used to identify metabolites that were associated with LS7 and incident ischemic stroke, respectively. Effect measures were based on a 1-SD change in metabolite level. Metabolite mediators were examined using inverse odds ratio weighting mediation analysis. RESULTS: The study comprised 1075 ischemic stroke cases and 968 participants in the random cohort sample. Three out of 162 metabolites were associated with the overall LS7 score including guanosine (ß, -0.46 [95% CI, -0.65 to -0.27]; P=2.87×10-6), cotinine (ß, -0.49 [95% CI, -0.70 to -0.28]; P=7.74×10-6), and acetylneuraminic acid (ß, -0.59 [95% CI, -0.77 to -0.42]; P=4.29×10-11). Guanosine (hazard ratio, 1.47 [95% CI, 1.31-1.65]; P=6.97×10-11), cotinine (hazard ratio, 1.30 [95% CI, 1.16-1.44]; P=2.09×10-6), and acetylneuraminic acid (hazard ratio, 1.29 [95% CI, 1.15-1.45]; P=9.24×10-6) were associated with incident ischemic stroke. The mediation analysis identified guanosine (27% mediation, indirect effect; P=0.002), cotinine (30% mediation, indirect effect; P=0.004), and acetylneurminic acid (22% mediation, indirect effect; P=0.041) partially mediated the relationship between LS7 and ischemic stroke. CONCLUSIONS: We identified guanosine, cotinine, and acetylneuraminic acid that were associated with LS7, incident ischemic stroke, and mediated the relationship between LS7 and ischemic stroke.

Clinical relevance of double heterozygosity revealed by next-generation sequencing of homologous recombination repair pathway genes in South African breast cancer patients.

PURPOSE: Genetically predisposed breast cancer (BC) patients represent a minor but clinically meaningful subgroup of the disease, with 25% of all cases associated with actionable variants in BRCA1/2. Diagnostic implementation of next-generation sequencing (NGS) resulted in the rare identification of BC patients with double heterozygosity for deleterious variants in genes partaking in homologous recombination repair of DNA. As clinical heterogeneity poses challenges for genetic counseling, this study focused on the occurrence and clinical relevance of double heterozygous BC in South Africa. METHODS: DNA samples were diagnostically screened using the NGS-based Oncomine™ BRCA Expanded Research Assay. Data was generated on the Ion GeneStudio S5 system and analyzed using the Torrent Suite™ and reporter software. The clinical significance of the variants detected was determined using international variant classification guidelines and treatment implications. RESULTS: Six of 1600 BC patients (0.375%) tested were identified as being bi-allelic for two germline likely pathogenic or pathogenic variants. Most of the variants were present in BRCA1/2, including two founder-related small deletions in three cases, with family-specific variants detected in ATM, BARD1, FANCD2, NBN, and TP53. The scientific interpretation and clinical relevance were based on the clinical and tumor characteristics of each case. CONCLUSION: This study increased current knowledge of the risk implications associated with the co-occurrence of more than one pathogenic variant in the BC susceptibility genes, confirmed to be a rare condition in South Africa. Further molecular pathology-based studies are warranted to determine whether clinical decision-making is affected by the detection of a second pathogenic variant in BRCA1/2 and TP53 carriers.

Association of Hepatitis B Surface Antigen Levels With Long-Term Complications in Chronic Hepatitis B Virus Infection: A Systematic Literature Review.

Chronic hepatitis B virus (HBV) infection is a global issue and can lead to cirrhosis and hepatocellular carcinoma (HCC). Hepatitis B surface antigen (HBsAg) is an important marker of HBV infection and HBsAg quantification could be a useful tool in clinical practice. This systematic literature review aimed to explore the association between HBsAg titres and long-term disease outcomes and evaluate the relationship between HBsAg titres, or changes in HBsAg titres, and clinical and treatment characteristics in patients with chronic HBV infection. Structured searches were performed in MEDLINE and Embase (January 2000 to 31 March 2023). Eighty-two studies were included, comprising 51% retrospective cohort studies, mostly conducted in Asia (85%). HBsAg levels were shown to predict the long-term development of cirrhosis and HCC in patients who were untreated prior to and during follow-up; however, these data were inconclusive in mixed and treated populations. HBsAg titres were significantly associated with various virological markers including serum HBV DNA, HBcrAg, HBeAg, HBV RNA levels, intrahepatic covalently closed circular DNA (cccDNA) and intrahepatic HBsAg expression. HBsAg titres generally declined over time; this decline was more pronounced in early (HBeAg-positive) than later disease phases (HBeAg-negative). Higher decline in HBsAg levels was consistently associated with subsequent HBsAg seroclearance and a greater decline in total intrahepatic HBV DNA and cccDNA levels. In conclusion, this review showed that HBsAg levels and rates of decline could inform assessment, management and prediction of outcomes in chronic HBV infection. Further studies in broader, more diverse populations and treated patients are needed.

Triglyceride-glucose index as a suitable non-insulin-based insulin resistance marker to predict cardiovascular events in patients undergoing complex coronary artery intervention: a large-scale cohort study.

BACKGROUND: Insulin resistance (IR), a hallmark of proceeding diabetes and cardiovascular (CV) disease, has been shown to predict prognosis in patients undergoing percutaneous coronary intervention (PCI). The triglyceride-glucose (TyG) index, triglyceride to high-density lipoprotein cholesterol (TG/HDL-C) ratio and metabolic score for insulin resistance (METS-IR) have been shown to be simple and reliable non-insulin-based surrogates for IR. However, limited studies have determined the associations between distinct non-insulin-based IR markers and CV outcomes in patients undergoing complex PCI who are at higher risk of CV events after PCI. Therefore, this study aimed to investigate and compare the prognostic value of these markers in patients undergoing complex PCI. METHODS: This was a descriptive cohort study. From January 2017 to December 2018, a total of 9514 patients undergoing complex PCI at Fuwai Hospital were consecutively enrolled in this study. The 3 IR indices were estimated from the included patients. The primary study endpoint was CV events, defined as a composite of CV death, nonfatal myocardial infarction and nonfatal stroke. RESULTS: During a median follow-up of 3.1 years, 324 (3.5%) CV events occurred. Multivariable Cox regression models showed per-unit increase in the TyG index (hazard ratio [HR], 1.42; 95% confidence interval [CI] 1.13-1.77), rather than per-unit elevation in either Ln(TG/HDL-C ratio) (HR, 1.18; 95%CI 0.96-1.45) or METS-IR (HR, 1.00; 95%CI 0.98-1.02), was associated with increased risk of CV events. Meanwhile, adding the TyG index to the original model led to a significant improvement in C-statistics (0.618 vs. 0.627, P < 0.001), NRI (0.12, P = 0.031) and IDI (0.14%, P = 0.003), whereas no significant improvements were observed when adding Ln (TG/HDL-C ratio) or METS-IR (both P > 0.05) to the original model. CONCLUSIONS: The TyG index, not TG/HDL-C ratio and METS-IR, was positively associated with worse CV outcomes in patients undergoing complex PCI. Our study, for the first time, demonstrated that the TyG index can serve as the suitable non-insulin-based IR marker to help in risk stratification and prognosis in this population.

Clinical relevance of doubtful reactions in patch testing: A single-centre retrospective study.

BACKGROUND: Doubtful reactions in patch testing are infrequently reported in the literature; however, recent reports have suggested they be assessed with the same scrutiny as stronger reactions. OBJECTIVE: Assess the clinical relevance of doubtful reactions in patch testing. METHODS: Retrospective study of 1514 patients comprehensively patch tested via the NACDG standard series and additional allergens based on history. The clinical relevance of each reaction was graded based on the NACDG scale: definite, probable, possible, past, unknown and irritant. Reactions were considered 'unique' if an additional mild-to-strong reaction to the same chemical at a different concentration was not observed. RESULTS: 68.9% (1043) of patients demonstrated at least 1 doubtful reaction. Of 4453 total doubtful reactions, 92.2% (4106) were unique. Only 3.3% (137) and 12.2% (500) of these were determined to be of definite or probable clinical relevance respectively. 'Fragrance' was the most common allergen family present among the unique definite doubtful reactions (37). However, 24 (64.9%) of these also had a stronger reaction to another fragrance. Cocamidopropyl betaine was the second most frequent allergen demonstrating definite doubtful reactions (27) and unique in 85.2% (23) of cases. Methylchloroisothiazolinone/methylisothiazolinone (MCI/MI) was most prevalent (36) but less frequently unique (58.3%, 21). CONCLUSIONS: Doubtful reactions may not be as impactful to clinical decision making as theorised in the literature. Few demonstrate definite clinical significance, and many have related stronger reactions that capture them for clinical purposes. Identification of doubtful reactions to cocamidopropyl betaine and MCI/MI may be of greatest significance as they most frequently were not supported by stronger reactions.

Frequency and clinical relevance of contact allergy in dental patients.

BACKGROUND: While many studies have reported on occupational allergic contact dermatitis amongst dental personnel, studies on the relevance of patch testing in dental patients are scarce. OBJECTIVES: To determine the frequency and clinical relevance of contact allergy in patients with intra- and perioral complaints. METHODS: A total of 360 patients with intra- and perioral complaints suspected of having a contact allergy were patch-tested with the dental allergen series, European Baseline Series, and extended Amsterdam Baseline Series at Amsterdam University Medical Centers between January 2015 and November 2021. RESULTS: A total of 285 patients (79.2%) had a positive patch test reaction for either one (18.6%) or multiple allergens (60.6%). Sodium tetrachloropalladate was the most sensitising allergen with 98 patients (27.2%) testing positive, followed by nickel sulphate (23.3%), methylisothiazolinone (15.6%), and fragrance mix I (14.2%). Clinical relevance was found in 68 of 208 patients (32.7%), with patients having one (15.4%) or multiple (17.3%) patch test reactions clinically relevant to their (peri)oral complaints. CONCLUSIONS: Clinically relevant patch test reactions were frequently seen in dental patients. Although this study provides us with a better understanding on the frequency and clinical relevance of contact allergy in dental patients, further studies are needed to confirm our results.

Impact of covariate model building methods on their clinical relevance evaluation in population pharmacokinetic analyses: comparison of the full model, stepwise covariate model (SCM) and SCM+ approaches.

Covariate analysis in population pharmacokinetics is key for adjusting doses for patients. The main objective of this work was to compare the adequacy of various modeling approaches on covariate clinical relevance decision-making. The full model, stepwise covariate model (SCM) and SCM+ PsN algorithms were compared in a clinical trial simulation of a 383-patient population pharmacokinetic study mixing rich and sparse designs. A one-compartment model with first-order absorption was used. A base model including a body weight effect on CL/F and V/F and a covariate model including 4 additional covariates-parameters relationships were simulated. As for forest plots, ratios between covariates at a specific value and that of a typical individual were calculated with their 90% confidence interval (CI90) using standard errors. Covariates on CL, V and KA were considered relevant if their CI90 fell completely outside the reference area [0.8-1.2]. All approaches provided unbiased covariate ratio estimates. For covariates with a simulated effect, the 3 approaches correctly identify their clinical relevance. However, significant covariates were missed in up to 15% of cases with SCM/SCM+. For covariate with no simulated effects, the full model mainly identified them as non-relevant or with insufficient information while SCM/SCM+ mainly did not select them. SCM/SCM+ assume that non-selected covariates are non-relevant when it could be due to insufficient information, whereas the full model does not make this assumption and is faster. This study must be extended to other methods and completed by a more complex high-dimensional simulation framework.

Minimum clinically important difference and substantial clinical benefit in patients with chronic temporomandibular disorders.

BACKGROUND: Research on temporomandibular disorder (TMD) responsiveness is scarce and limited regarding patients' representativeness. OBJECTIVE(S): This study aimed to estimate minimum clinically important difference (MCID) and substantial clinical benefit (SCB) among a large and diverse patient population regarding sex and age. METHODS: In this study, 162 patients participated from five hospitals. MCID and SCB in pain, functional disability and quality of life were examined with anchor-based methods. Patients' global impression of change was used as the anchor. Area under the curve (AUC) values were determined for testing accuracy. Changes from baseline and coefficient of variation by responsiveness status were calculated to explain the results of accuracy. RESULTS: SCB was estimated to be 2.18 for the numeric rating scale (NRS) for pain (AUC: 0.80 [95% CI: 0.72-0.88]) in all patients and 2.50 in women (AUC: 0.81 [95% CI: 0.71-0.89]). The estimated SCB of NRS for discomfort (1.50) and Jaw Functional Limitation Scale for mastication (1.35) had wide CIs for AUCs. Likewise, the estimated MCIDs of NRS for pain (0.80) and NRS for discomfort (1.50) had wide CIs for AUCs. Among non-responders who did not achieve the MCID of NRS for pain, the coefficient of variation was very high for all outcomes other than the NRS for pain. CONCLUSION: This study investigated the responsiveness of patients with TMD using a large and diverse patient sample. SCB in pain decrease can be used to assess the responsiveness of patients with TMD. Composite outcomes should be developed to estimate MCID.

A comprehensive review on mango allergy: Clinical relevance, causative allergens, cross-reactivity, influence of processing techniques, and management strategies.

Mangoes (Mangifera indica) are widely prized for their abundant nutritional content and variety of beneficial bioactive compounds and are popularly utilized in various foods, pharmaceuticals, and cosmetics industries. However, it is important to note that certain proteins present in mango can trigger various allergic reactions, ranging from mild oral allergy syndrome to severe life-threatening anaphylaxis. The immunoglobulin E-mediated hypersensitivity of mango is mainly associated with three major allergenic proteins: Man i 1 (class IV chitinase), Man i 2 (pathogenesis-related-10 protein; Bet v 1-related protein), and Man i 4 (profilin). Food processing techniques can significantly affect the structure of mango allergens, reducing their potential to cause allergies. However, it is worth mentioning that complete elimination of mango allergen immunoreactivity has not been achieved. The protection of individuals sensitized to mango should be carefully managed through an avoidance diet, immediate medical care, and long-term oral immunotherapy. This review covers various aspects related to mango allergy, including prevalence, pathogenesis, symptoms, and diagnosis. Furthermore, the characterization of mango allergens and their potential cross-reactivity with other fruits, vegetables, plant pollen, and seeds were discussed. The review also highlights the effects of food processing on mango and emphasizes the available strategies for managing mango allergy.

Revolutionizing Lung Cancer Treatment: Innovative CRISPR-Cas9 Delivery Strategies.

Lung carcinoma, including both non-small cell lung cancer (NSCLC) and small cell lung cancer (SCLC), remains a significant global health challenge due to its high morbidity and mortality rates. The objsective of this review is to meticulously examine the current advancements and strategies in the delivery of CRISPR-Cas9 gene-editing technology for the treatment of lung carcinoma. This technology heralds a new era in molecular biology, offering unprecedented precision in genomic modifications. However, its therapeutic potential is contingent upon the development of effective delivery mechanisms that ensure the efficient and specific transport of gene-editing tools to tumor cells. We explore a variety of delivery approaches, such as viral vectors, lipid-based nanoparticles, and physical methods, highlighting their respective advantages, limitations, and recent breakthroughs. This review also delves into the translational and clinical significance of these strategies, discussing preclinical and clinical studies that investigate the feasibility, efficacy, and safety of CRISPR-Cas9 delivery for lung carcinoma. By scrutinizing the landscape of ongoing clinical trials and offering translational perspectives, we aim to elucidate the current state and future directions of this rapidly evolving field. The review is structured to first introduce the problem and significance of lung carcinoma, followed by an overview of CRISPR-Cas9 technology, a detailed examination of delivery strategies, and an analysis of clinical applications and regulatory considerations. Our discussion concludes with future perspectives and challenges, such as optimizing delivery strategies, enhancing specificity, mitigating immunogenicity concerns, and addressing regulatory issues. This comprehensive overview seeks to provide insights into the potential of CRISPR-Cas9 as a revolutionary approach for targeted therapies and personalized medicine in lung carcinoma, emphasizing the importance of delivery strategy development in realizing the full potential of this groundbreaking technology.

Estrogen-related genes for thyroid cancer prognosis, immune infiltration, staging, and drug sensitivity.

BACKGROUND: Thyroid cancer (THCA) has become increasingly common in recent decades, and women are three to four times more likely to develop it than men. Evidence shows that estrogen has a significant impact on THCA proliferation and growth. Nevertheless, the effects of estrogen-related genes (ERGs) on THCA stages, immunological infiltration, and treatment susceptibility have not been well explored. METHODS: Clinicopathological and transcriptome data of patients with THCA from the Gene Expression Omnibus (GEO) and The Cancer Genome Atlas (TCGA) were cleaned before consensus clustering. Differential expression analysis was performed on the genes expressed between THCA and paraneoplastic tissues in TCGA, and Wayne analysis was performed on the ERGs obtained from the Gene Set Enrichment Analysis MsigDB and differentially expressed genes (DEGs). Univariate Cox and least absolute shrinkage and selection operator (LASSO) analyses were used to identify the set of estrogen-related differentially expressed genes (ERDEGs) associated with progression-free intervals (PFI) and to establish a prediction model. Receiver operating characteristic curves were plotted to calculate the risk scores and PFI status to validate the predictive effect of the model. Enrichment analyses and immune infiltration analyses were performed to analyze DEGs between the high- and low-risk groups, and a nomogram plot was used in the risk model to predict the PFI of THCA. RESULTS: The expression of 120 ERDEGs differed significantly between the two groups (P < 0.05). Five (CD24, CAV1, TACC1, TIPARP, and HSD17B10) of the eight ERDEGs identified using univariate Cox and LASSO regression were validated via RT-qPCR and immunohistochemistry analysis of clinical tissue samples and were used for clinical staging and drug sensitivity analysis. Risk-DEGs were shown to be associated with immune modulation and tumor immune evasion, as well as defense systems, signal transduction, the tumor microenvironment, and immunoregulation. In 19 of the 28 immune cells, infiltration levels differed between the high- and low-risk groups. High-risk patients in the immunotherapy dataset had considerably shorter survival times than low-risk patients. CONCLUSION: We identified and confirmed eight ERDEGs using a systematic analysis and screened sensitive drugs for ERDEGs. These results provide molecular evidence for the involvement of ERGs in controlling the immunological microenvironment and treatment response in THCA.

Rosaceae food allergy: a review.

This review provides a global overview on Rosaceae allergy and details the particularities of each fruit allergy induced by ten Rosaceae species: almond/peach/cherry/apricot/plum (Amygdaleae), apple/pear (Maleae), and raspberry/blackberry/strawberry (Rosoideae). Data on clinical symptoms, prevalence, diagnosis, and immunotherapies for the treatment of Rosaceae allergy are herein stated. Allergen molecular characterization, cross-reactivity/co-sensitization phenomena, the impact of food processing and digestibility, and the methods currently available for the Rosaceae detection/quantification in foods are also described. Rosaceae allergy has a major impact in context to pollen-food allergy syndrome (PFAS) and lipid transfer protein (LTP) allergies, being greatly influenced by geography, environment, and presence of cofactors. Peach, apple, and almond allergies are probably the ones most affecting the quality of life of the allergic-patients, although allergies to other Rosaceae fruits cannot be overlooked. From patients' perspective, self-allergy management and an efficient avoidance of multiple fruits are often difficult to achieve, which might raise the risk for cross-reactivity and co-sensitization phenomena and increase the severity of the induced allergic responses with time. At this point, the absence of effective allergy diagnosis (lack of specific molecular markers) and studies advancing potential immunotherapies are some gaps that certainly will prompt the progress on novel strategies to manage Rosaceae food allergies.

Physiologically Based Biopharmaceutics Model for Selumetinib Food Effect Investigation and Capsule Dissolution Safe Space - Part I: Adults.

OBJECTIVE: A physiologically based biopharmaceutics model (PBBM) was developed to mechanistically investigate the effect of formulation and food on selumetinib pharmacokinetics. METHODS: Selumetinib is presented as a hydrogen sulfate salt, and in vitro and in vivo data were used to verify the precipitation rate to apply to simulations. Dissolution profiles observed for capsules and granules were used to derive product-particle size distributions for model input. The PBBM incorporated gut efflux and first-pass gut metabolism, based on intravenous and oral pharmacokinetic data, alongside in vitro data for the main enzyme isoform and P-glycoprotein efflux. The PBBM was validated across eight clinical scenarios. RESULTS: The quality-control dissolution method for selumetinib capsules was found to be clinically relevant through PBBM validation. A safe space for capsule dissolution was established using a virtual batch. The effect of food (low fat vs high fat) on capsules and granules was elucidated by the PBBM. For capsules, a lower amount was dissolved in the fed state due to a pH increase in the stomach followed by higher precipitation in the small intestine. First-pass gut extraction is higher for capsules in the fed state due to drug dilution in the stomach chyme and reduced concentration in the lumen. The enteric-coated granules dissolve more slowly than capsules after stomach emptying, attenuating the difference in first-pass gut extraction between prandial states. CONCLUSIONS: The PBBM was instrumental in understanding and explaining the different behaviors of the selumetinib formulations. The model can be used to predict the impact of food in humans.

High Expression of CD300A Predicts Poor Survival in Acute Myeloid Leukemia.

INTRODUCTION: Recent studies have suggested that CD300A was an oncogene in acute myeloid leukemia (AML) development. However, the clinical relevance and biological insight into CD300A expression in AML are still not well understood. The present study aimed to examine the expression characteristics of CD300A in AML and confirmed its clinical significance for AML. METHODS: Quantification of the CD300A transcript was performed in 119 AML patients by real-time quantitative PCR in bone marrow blasts. The predictive significance of CD300A expression on the clinical outcomes of AML was assessed using overall survival (OS) and relapse-free survival (RFS). The published Cancer Genome Atlas (TCGA) data were used as an external validation for survival analysis and pathway analyses. RESULTS: In comparison with monocytes from healthy peripheral blood cells, the expression levels of CD300A in AML cells were higher. Patients in the intermediate and adverse risk categories by WHO criteria (2018) had higher CD300A expression levels than those in the favorable risk category (p < 0.001). AML patients with high expression of CD300A had a higher early death rate (p = 0.029), lower complete remission rate (p = 0.042), higher death rate (p < 0.001) and relapse rate (p = 0.002), and shorter OS (p < 0.0001) and RFS (p < 0.0001). Through multivariable analysis, high CD300A expression in AML was also an independent poor prognostic factor. The CAMP and CGMP-PKG signaling pathways may be stimulated by increased CD300A expression levels, which may be important for the development of AML. CONCLUSIONS: The expression levels of CD300A were associated with risk stratification and the clinical relevance of AML. High CD300A expression may act as an independent adverse prognostic factor for OS and RFS in AML.

Imaging findings and clinical relevance of 68Ga-Pentixafor PET in atherosclerosis: a systematic review.

OBJECTIVE: We aimed to perform a qualitative synthesis of evidence on the role of 68Ga-Pentixafor PET in atherosclerosis. METHODS: A systematic search of the PubMed and Embase databases for studies reporting the evaluation of atherosclerotic lesions by 68Ga-Pentixafor PET was performed with a search time frame from database creation to 2022-12-26. The diagnostic test evaluation tool QUADAS-2 was used to evaluate the quality of the included literature and to perform descriptive analyses of relevant outcome indicators. RESULTS: A total of 6 studies with 280 patients were included. One study reported only imaging outcome metrics, while the other five studies reported imaging outcome metrics and clinical correlation metrics. For imaging outcomes, three studies reported imaging results for 68Ga-Pentixafor PET only, and the other three studies reported imaging results for comparative analysis of 68Ga-Pentixafor PET with 18F-FDG PET. For clinical correlation, three studies reported the correlation between tracer uptake and cardiovascular risk factors, one study reported the correlation between tracer uptake and plaque calcification, and one study reported the correlation between all three: tracer uptake, cardiovascular risk factors, and plaque calcification. CONCLUSION: 68Ga-Pentixafor PET has a good imaging effect on atherosclerotic lesions, and it is a promising imaging modality that may replace 18F-FDG PET for atherosclerosis imaging in the future. In patients with atherosclerosis, there is a clear clinical correlation between cardiovascular risk factors, tracer uptake, and plaque calcification.

Using ChatGPT to Generate Research Ideas in Dysphagia: A Pilot Study.

Current research in dysphagia faces challenges due to the rapid growth of scientific literature and the interdisciplinary nature of the field. To address this, the study evaluates ChatGPT, an AI language model, as a supplementary resource to assist clinicians and researchers in generating research ideas for dysphagia, utilizing recent advancements in natural language processing and machine learning. The research ideas were generated through ChatGPT's command to explore diverse aspects of dysphagia. A web-based survey was conducted, 45 dysphagia experts were asked to rank each study on a scale of 1 to 5 according to feasibility, novelty, clinical implications, and relevance to current practice. A total of 26 experts (58%) completed the survey. The mean (± sd) rankings of research ideas were 4.03 (± 0.17) for feasibility, 3.5 (± 0.17) for potential impact on the field, 3.84 (± 0.12) for clinical relevance, and 3.08 (± 0.36) for novelty and innovation. Results of this study suggest that ChatGPT offers a promising approach to generating research ideas in dysphagia. While its current capability to generate innovative ideas appears limited, it can serve as a supplementary resource for researchers.