Handling Missing Data in COVID-19 Incidence Estimation: Secondary Data Analysis.

Background: The COVID-19 pandemic has revealed significant challenges in disease forecasting and in developing a public health response, emphasizing the need to manage missing data from various sources in making accurate forecasts. Objective: We aimed to show how handling missing data can affect estimates of the COVID-19 incidence rate (CIR) in different pandemic situations. Methods: This study used data from the COVID-19/SARS-CoV-2 surveillance system at the National Institute of Hygiene and Epidemiology, Vietnam. We separated the available data set into 3 distinct periods: zero COVID-19, transition, and new normal. We randomly removed 5% to 30% of data that were missing completely at random, with a break of 5% at each time point in the variable daily caseload of COVID-19. We selected 7 analytical methods to assess the effects of handling missing data and calculated statistical and epidemiological indices to measure the effectiveness of each method. Results: Our study examined missing data imputation performance across 3 study time periods: zero COVID-19 (n=3149), transition (n=1290), and new normal (n=9288). Imputation analyses showed that K-nearest neighbor (KNN) had the lowest mean absolute percentage change (APC) in CIR across the range (5% to 30%) of missing data. For instance, with 15% missing data, KNN resulted in 10.6%, 10.6%, and 9.7% average bias across the zero COVID-19, transition, and new normal periods, compared to 39.9%, 51.9%, and 289.7% with the maximum likelihood method. The autoregressive integrated moving average model showed the greatest mean APC in the mean number of confirmed cases of COVID-19 during each COVID-19 containment cycle (CCC) when we imputed the missing data in the zero COVID-19 period, rising from 226.3% at the 5% missing level to 6955.7% at the 30% missing level. Imputing missing data with median imputation methods had the lowest bias in the average number of confirmed cases in each CCC at all levels of missing data. In detail, in the 20% missing scenario, while median imputation had an average bias of 16.3% for confirmed cases in each CCC, which was lower than the KNN figure, maximum likelihood imputation showed a bias on average of 92.4% for confirmed cases in each CCC, which was the highest figure. During the new normal period in the 25% and 30% missing data scenarios, KNN imputation had average biases for CIR and confirmed cases in each CCC ranging from 21% to 32% for both, while maximum likelihood and moving average imputation showed biases on average above 250% for both CIR and confirmed cases in each CCC. Conclusions: Our study emphasizes the importance of understanding that the specific imputation method used by investigators should be tailored to the specific epidemiological context and data collection environment to ensure reliable estimates of the CIR.

Mental health stigma and health-seeking behaviors amongst pregnant women in Vietnam: a mixed-method realist study.

BACKGROUND: Approximately 15% of women in low-and middle-income countries experience common perinatal mental disorders. Yet, many women, even if diagnosed with mental health conditions, are untreated due to poor quality care, limited accessibility, limited knowledge, and stigma. This paper describes how mental health-related stigma influences pregnant women's decisions not to disclose their conditions and to seek treatment in Vietnam, all of which exacerbate inequitable access to maternal mental healthcare. METHODS: A mixed-method realist study was conducted, comprising 22 in-depth interviews, four focus group discussions (total participants n = 44), and a self-administered questionnaire completed by 639 pregnant women. A parallel convergent model for mixed methods analysis was employed. Data were analyzed using the realist logic of analysis, an iterative process aimed at refining identified theories. Survey data underwent analysis using SPSS 22 and descriptive analysis. Qualitative data were analyzed using configurations of context, mechanisms, and outcomes to elucidate causal links and provide explanations for complexity. RESULTS: Nearly half of pregnant women (43.5%) would try to hide their mental health issues and 38.3% avoid having help from a mental health professional, highlighting the substantial extent of stigma affecting health-seeking and accessing care. Four key areas highlight the role of stigma in maternal mental health: fear and stigmatizing language contribute to the concealment of mental illness, rendering it unnoticed; unconsciousness, normalization, and low literacy of maternal mental health; shame, household structure and gender roles during pregnancy; and the interplay of regulations, referral pathways, and access to mental health support services further compounds the challenges. CONCLUSION: Addressing mental health-related stigma could influence the decision of disclosure and health-seeking behaviors, which could in turn improve responsiveness of the local health system to the needs of pregnant women with mental health needs, by offering prompt attention, a wide range of choices, and improved communication. Potential interventions to decrease stigma and improve access to mental healthcare for pregnant women in Vietnam should target structural and organizational levels and may include improvements in screening and referrals for perinatal mental care screening, thus preventing complications.

A Novel Artificial Intelligence-based Parameterization Approach of the Stromal Landscape in Merkel Cell Carcinoma: a Multi-Institutional Study.

BACKGROUND: Tumor-Stroma Ratio (TSR) has been recognized as a valuable prognostic indicator in various solid tumors. This study aimed to examine the clinicopathological relevance of TSR in Merkel cell carcinoma (MCC) using artificial intelligence (AI)-based parameterization of the stromal landscape and validate TSR scores generated by our AI model versus human-assessed. METHODS: 112 MCC cases with Whole Slide Images (WSIs) were collected from four different institutions. WSIs were first partitioned into 128x128-pixel "mini-patches" then classified by a novel framework, termed Pre-TumOr And STroma (Pre-TOAST) and TOAST, whose output equaled the probability of the mini-patch representing tumor cells rather than stroma. Hierarchical random samplings of 50 mini-patches per region were performed throughout 50 regions per slide. TSR and Tumor-Stromal Landscape (TSL) parameters were estimated by the maximum-likelihood algorithm. RESULTS: Receiver Operating Characteristic (ROC) curves showed the areas under the curve (AUCs) of Pre-TOAST in discriminating classed of interest (COI) including tumor cells, collagenous stroma, and lymphocytes from non-classes of interest (non-COI) including hemorrhage, space, and necrosis were 1.00. AUCs of TOAST in differentiating tumor cells from related stroma were 0.93. MCC stroma was categorized into TSR-high (TSR≥50%) and TSR-low (TSR<50%) using both AI- and human pathology-based methods. AI-based TSR-high subgroup exhibited notably shorter Metastasis-Free Survival (MFS) with a statistical significance of p=0.029. Interestingly, pathologist-determined TSR subgroups lacked statistical significance in Recurrence-Free Survival (RFS), MFS, and Overall Survival (OS) (p>0.05). Density-based spatial clustering of applications with noise (DBSCAN) analysis identified two distinct Tumor-Stroma Landscape (TSL) clusters: TSL1 and TSL2. TSL2 showed significantly shorter RFS (p=0.045) and markedly reduced MFS (p<0.001) compared to TSL1. CONCLUSION: TSL classification appears to offer better prognostic discrimination than traditional TSR evaluation in MCC. TSL can be reliably calculated using an AI-based classification framework and predict various prognostic features of MCC.

First record of a mixed species association between Hatinh langur (Trachypithecus hatinhensis) and red-shanked douc (Pygathrix nemaeus).

In primates, mixed species associations are not common occurrences, and have been linked to both ecological and anthropogenic factors. We present camera-trapping records of a mixed association between two primates, the Hatinh langur (Trachypithecus hatinhensis) and red-shanked douc (Pygathrix nemaeus) and discuss possible hypotheses for this occurrence. To our knowledge, this is the first evidence of such an association in the wild of these two threatened primates, and thus contributes to our limited ecological knowledge of the species.

Cold Storage of Human Femoral Arteries for 12 Months: Impact on Mechanical Properties.

OBJECTIVE: This biomechanical pre-clinical study aimed to assess the consequences on mechanical properties of long term cold storage (+2/+8 °C) of arterial allografts. METHODS: Femoropopliteal arterial segments were collected from multiorgan donors and stored at +2/+8 °C for 12 months in saline solution with added antibiotics. Mechanical characterisation was carried out using two different tests, with the aim of defining the physiological modulus and the maximum stress and strain borne by the sample before rupture. These characterisations were carried out after 0, 6, and 12 months of storage for each sample (T0, T6, and T12, respectively). For comparison, the same tests were performed on cryopreserved popliteal femoral segments after thawing. RESULTS: Twelve refrigerated allografts (RAs), each divided into three segments, and 10 cryopreserved allografts (CAs) were characterised. The median (interquartile range [IQR]) Young's modulus was not statistically significantly different between the storage times for cold stored allografts: RAT0, 164 (150, 188) kPa; RAT6, 178 (141, 185) kPa; RAT12, 177 (149, 185) kPa. The median (IQR) Young's modulus of the CA group (153 [141, 185] kPa) showed no significant differences from the RA groups, irrespective of storage time. Furthermore, median (IQR) maximum stress and strain values were not significantly different between the different groups: for maximum stress: RAT0, 1.58 (1.08, 2.09) MPa; RAT6, 1.74 (1.55, 2.36) MPa; RAT12, 2.25 (1.87, 2.53) MPa; CA, 2.25 (1.77, 2.61) MPa; and for maximum strain: RAT0, 64% (50, 90); RAT6, 79% (63, 84); RAT12, 72% (65, 86); CA, 67% (50, 95). CONCLUSION: Cold storage for up to 12 months appears to have no impact on the mechanical characteristics of human arterial allografts. Therefore, this preservation method, which would greatly simplify routine care, seems feasible. Other indicators are being studied to verify the safety of this preservation process before considering its use in vivo.

Intraoral Ultrasound Imaging Using a Rotational Transducer with Periodontal Feature Identification by Machine Learning.

Innovative intraoral ultrasound devices with smart artificial intelligence-based identification for dento-anatomy could provide crucial information for oral health diagnosis and treatment and shed light on real-time detection of developmental dentistry. However, the grand challenge is that the current ultrasound technologies are meant for external use due to their bulkiness and low frequency. We report a compact versatile ultrasound intraoral device that consists of a rotational probe head robustly pivoted around a hand-held and portable handle for real-time imaging of intraoral anatomy using high-frequency ultrasonography (up to 25 MHz). The intraoral ultrasound device that could be adjusted for various orientations of the imaging planes by rotating the head provides real-time, high-resolution ultrasonograms of intraoral structures, including dento-periodontium of most tooth types and maxillary palate. Machine learning-based algorithms are integrated to automate the identification of important structures, including alveolar bone and cementum-enamel junction. The intraoral ultrasound device smartened with artificial intelligence could innovate oral health diagnosis and treatment plans toward precision health and patient care.

Toward Unveiling Putative Binding Sites of Interleukin-33: Insights from Mixed-Solvent Molecular Dynamics Simulations of the Interleukin-1 Family.

The interleukin (IL)-1 family is a major proinflammatory cytokine family, ranging from the well-studied IL-1s to the most recently discovered IL-33. As a new focus, IL-33 has attracted extensive research for its crucial immunoregulatory roles, leading to the development of notable monoclonal antibodies as clinical candidates. Efforts to develop small molecules disrupting IL-33/ST2 interaction remain highly desired but encounter challenges due to the shallow and featureless interfaces. The information from relative cytokines has shown that traditional binding site identification methods still struggle in mapping cryptic sites, necessitating dynamic approaches to uncover druggable pockets on IL-33. Here, we employed mixed-solvent molecular dynamics (MixMD) simulations with diverse-property probes to map the hotspots of IL-33 and identify potential binding sites. The protocol was first validated using the known binding sites of two IL-1 family members and then applied to the structure of IL-33. Our simulations revealed several binding sites and proposed side-chain rearrangements essential for the binding of a known inhibitor, aligning well with experimental NMR findings. Further microsecond-time scale simulations of this IL-33-protein complex unveiled distinct binding modes with varying occurrences. These results could facilitate future efforts in developing ligands to target challenging flexible pockets of IL-33 and IL-1 family cytokines in general.

A Brief Alcohol Intervention (BAI) to reduce alcohol use and improve PrEP outcomes among men who have sex with men in Vietnam: study protocol for a randomized controlled trial.

BACKGROUND: In Vietnam and other global settings, men who have sex with men (MSM) have become the population at greatest risk of HIV infection. Although HIV pre-exposure prophylaxis (PrEP) has been implemented as a prevention strategy, PrEP outcomes may be affected by low persistence and adherence among MSM with unhealthy alcohol use. MSM have a high prevalence of unhealthy alcohol use in Vietnam, which may affect PrEP outcomes. METHODS: Design: We will conduct a two-arm hybrid type 1 effectiveness-implementation randomized controlled trial of a brief alcohol intervention (BAI) compared to the standard of care (SOC) at the Sexual Health Promotion (SHP) clinic Hanoi, Vietnam. PARTICIPANTS: Sexually active MSM (n=564) who are newly initiating PrEP or re-initiating PrEP and have unhealthy alcohol use will be recruited and randomized 1:1 to the SOC or BAI arm. A subgroup of participants (n=20) in each arm will be selected for longitudinal qualitative interviews; an additional subset (n=48) in the BAI arm will complete brief quantitative and qualitative interviews after completion of the BAI to assess the acceptability of the intervention. Additional implementation outcomes will be assessed through interviews with clinic staff and stakeholders (n=35). INTERVENTION: Study participants in both arms will receive standard care for PrEP clients. In the BAI arm, each participant will receive two face-to-face intervention sessions and two brief booster phone sessions, based on cognitive behavioral therapy and delivered in motivational interviewing informed style, to address their unhealthy alcohol use. OUTCOMES: Effectiveness (PrEP and alcohol use) and cost-effectiveness outcomes will be compared between the two arms. Intervention implementation outcomes (acceptability, feasibility, adoption) will be assessed among MSM participants, clinic staff, and stakeholders. DISCUSSION: This proposed trial will assess an alcohol intervention for MSM with unhealthy alcohol use who initiate or re-initiate PrEP, while simultaneously preparing for subsequent implementation. The study will measure the effectiveness of the BAI for increasing PrEP persistence through reducing unhealthy alcohol use in a setting where excessive alcohol consumption is a normative behavior. If effective, implementation-focused results will inform future scale-up of the BAI in similar settings. TRIAL REGISTRATION: NCT06094634 on clinicaltrials.gov. Registered 16 October 2023.

Mycology laboratory diagnostic capacity for invasive fungal diseases in public hospitals in Vietnam.

This was a cross-sectional study on the availability of laboratory infrastructure and capacity for the diagnosis of invasive fungal diseases in 24 public hospitals in Vietnam in 2023. Among the hospitals surveyed, 66.7% (14/21) had specialized personnel assigned for mycology testing, and 95.8% (23/24) had a separate microbiology laboratory space. Microscopy and culture methods are available in nearly all laboratories for isolate identification. Antifungal susceptibility testing is only performed for yeasts in 16/24 (66.7%) laboratories. Non-culture methods are hardly used in laboratories. Strengthening local laboratory capacities is essential to meeting health needs in these endemic regions.

There was a need for investment in fungal diagnostics to improve health services in the settings with a burden of endemic fungal infections.

Characteristics of Immunogenicity against SARS-CoV-2 in a Community-Based Model of Care during the Fourth Wave of COVID-19 Outbreak in Ho Chi Minh City.

PURPOSE: Although some immune protection from close contact with individuals who have coronavirus disease 2019 (COVID-19) has been documented, there is limited data on the seroprevalence of antibodies against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) in individuals who were in lockdown with confirmed COVID-19 cases. This study investigated immunogenicity against SARS-CoV-2 in household members and people who lived near home-quarantined patients with COVID-19. MATERIALS AND METHODS: This cross-sectional study was conducted during the community-based care that took place during lockdowns in District 10, Ho Chi Minh City, Vietnam from July to September 2021. SARS-CoV-2 antibody levels were determined in index cases of COVID-19, household contacts, and a no-contact group from the same area. RESULTS: A total of 770 participants were included (355 index cases, 103 household contacts, and 312 no contacts). All index cases were unvaccinated, but >90% of individuals in the household and no-contact groups had received ≥1 vaccine dose. SARS-CoV-2 neutralizing antibodies (Nabs) were present in >77% of unvaccinated index cases versus 64%/65.4% in the household/no-contact groups (p=0.001). Antibody concentrations in unvaccinated index cases were significantly higher than those in household contacts and no contacts, with no difference between the latter groups. In all cases, antibody levels declined markedly ≥6 weeks after infection, and failed to persist beyond this time in the household and no-contact groups. CONCLUSION: Community-based care may have helped to create community immunogenicity, but Nabs did not persist, highlighting a need for vaccination for all individuals before, or from 6 weeks after, infection with SARS-CoV-2.

IL-12 minicircle delivery via extracellular vesicles as immunotherapy for bladder cancer.

Interleukin-12 (IL-12) holds significant potential in cancer therapy; however, its clinical applicability is hindered by dose-limiting toxicity. Delivery of the IL-12 gene directly to tumours for constitutive IL-12 expression is a possible strategy to enhance its effectiveness while minimizing systemic toxicity. In this study, we investigate the potential of red blood cell-derived extracellular vesicles (RBCEVs) as a carrier for Il-12 plasmid delivery. We demonstrate that RBCEVs can be loaded with minicircle plasmid encoding IL-12 and delivered to MB49 bladder cancer cells for IL-12 expression. The expression of transgenes from minicircles was significantly higher than from the parental plasmids. RBCEV-mediated IL-12 expression stimulated immune responses in mouse splenocytes. Intratumoral delivery of Il-12 plasmid-loaded RBCEVs suppressed bladder cancer tumour growth, stimulated immune responses and promoted immune cell infiltration. In conclusion, our study demonstrates the promising potential of RBCEVs as an effective, safe and redosable nucleic acid drug delivery platform for IL-12.

Response to Azacytidine in a Patient With Refractory Peripheral T-cell Lymphoma With TET2 Mutation.

Peripheral T-cell lymphomas (PTCLs) are an aggressive form of non-Hodgkin lymphomas. PTCLs have multiple subtypes, with PTCL not otherwise specified (PTCL-NOS) being the most common. This subtype usually has a high rate of relapse. Making an accurate diagnosis requires molecular genetic analyses, histopathological examination, and immunophenotyping. Treatment for PTCL traditionally starts with the CHOP regimen (cyclophosphamide, doxorubicin, vincristine, and prednisone). We present a case of a patient with PTCL-NOS who progressed despite multiple treatment regimens, including both traditional and novel therapeutic agents, and finally achieved good results with azacytidine, selected based on a TET2 mutation. This case proposes future research into Azacytidine's efficacy in this patient population and further exploration of the broader utility of epigenetic therapies in PTCL.

The spread of fake news: Disclosure willingness role.

The epidemic has had a profound negative impact on individuals worldwide, leading to pervasive anxiety, fear, and mental instability. Exploiting these fears, a significant amount of fake information proliferates and spreads rapidly on social networks. This study explores the factors that cause individuals to believe fake news under stressful and fearful conditions by applying the truth-default theory. Data was collected online in Vietnam, using Smart PLS software to analyze the research model. The findings indicated that risk perception, media trust, trust in celebrity posts, and stress were factors that urge users to believe news posted on social media, and even they actively share this news on their own channels. Disclosure willingness moderated the relationship between adoption fake news and sharing it. Both theoretical and practical implications were discussed.

Light Switchable Bioorthogonal Reaction Manifold for Modulation of Hydrogel Properties.

Chemical reaction systems that can occur via multiple pathways in a controllable fashion are highly attractive for advanced materials applications and biological research. In this report, we introduce a bioorthogonal reaction manifold based on a chalcone pyrene (CPyr) moiety that can undergo either red-shifted photoreversible [2 + 2] cycloaddition or thiol-Michael addition click reaction. By coupling the CPyr to a water-soluble poly(ethylene glycol) end group, we demonstrate the efficient polymer dimerization and cleavage by blue light (λ = 450 nm) and UV light (λ = 340 nm), respectively. In the absence of light, CPyr rapidly reacts with thiols in aqueous environments, enabling fast and efficient polymer end-group functionalization. The chemical reaction manifold was further employed in polymer cross-linking for the preparation of hydrogels whose stiffness and morphology can be modulated by different photonic fields or the addition of a thiol cross-linker. The photoreversible cycloaddition and thiol-Michael addition click reaction can be used in conjunction for spatial and temporal conjugation of a streptavidin protein. Both cross-linking conditions are nontoxic to various cell lines, highlighting their potential in biomaterials applications.

Deciphering tumour microenvironment and elucidating the origin of cancer cells in ovarian clear cell carcinoma.

Ovarian clear cell carcinoma (CCC) has an East Asian preponderance. It is associated with endometriosis, a benign condition where endometrial (inner lining of the uterus) tissue is found outside the uterus and on the peritoneal surface, in the abdominal or pelvic space. CCC is relatively more resistant to conventional chemotherapy compared to other ovarian cancer subtypes and is associated with a poorer prognosis. In this study, we recruited and obtained tumour tissues from seven patients across the four stages of CCC. The tumour and the tumour microenvironment (TME) from 7 CCC patients spanning clinical stages 1-4 were transcriptionally profiled using high-resolution scRNA-seq to gain insight into CCC's biological mechanisms. Firstly, we built a scRNA-seq resource for the CCC tumour microenvironment (TME). Secondly, we identified the different cell type proportions and found high levels of immune infiltration in CCC. Thirdly, since CCC is associated with endometriosis, we compared CCC with two publicly available endometriosis scRNA-seq datasets. The CCC malignant cells showed similarities with glandular secretory and ciliated epithelial cells found in endometriosis. Finally, we determined the differences in cell-cell communication between various cell types present in CCC TME and endometriosis conditions to gain insights into the transformations in CCC.

Exploring the Therapeutic Potential of Camellia longii Orel & Luu Leaf Extracts for Memory Loss in Alzheimer's Disease: Novel Findings and Functional Food Applications.

Novel research on the chemical compositions and biochemical activities of Camellia longii Orel and Luu leaf extracts revealed valuable resources with potential applications in Alzheimer's disease treatment. Qualitative phytochemicals detected various compound groups, including polyphenols, saponins, tannins, flavonoids, alkaloids, amino acids, coumarins, and polysaccharides. HPLC-MS identified 23 compounds in C. longii leaves with compounds found at significant levels, including epicatechin gallate (17.12%), tryptophan (13.73%), isovitexin (12.91%), gallic acid (3.06%), and quercetin (3.06%). Interestingly, the ethanol extract (CLL-Ew) exhibited the highest extraction yield (26.6%) and potent antioxidant and acetylcholinesterase (AChE) inhibitory effects in vitro. In the Drosophila melanogaster model, CLL-Ew improved longevity, movement, and memory by reducing malondialdehyde and increasing glutathione levels. Docking simulations suggested that the above compounds bind tightly to AChE's active site, potentially contributing to memory enhancement. Interestingly, observations of male and female mice after administration of a dose of 5000 mg/kg C. longii leaf extract were recorded normally throughout the 14 day experiment. These findings highlight the potential of C. longii leaf extracts in functional foods and therapeutic interventions for memory impairment prevention and treatment.

Prognosticating global functional outcome in the recurrent ischemic stroke using baseline clinical and pre-clinical features: A machine learning study.

BACKGROUND AND PURPOSE: Recurrent ischemic stroke (RIS) induces additional functional limitations in patients. Prognosticating globally functional outcome (GFO) in RIS patients is thereby important to plan a suitable rehabilitation programme. This study sought to investigate the ability of baseline features for classifying the patients with and without improving GFO (task 1) and identifying patients with poor GFO (task 2) at the third month after discharging from RIS. METHODS: A total of 86 RIS patients were recruited and divided into the training set and testing set (50:50). The clinical and pre-clinical data were recorded. The outcome was the changes in Modified Rankin Scale (mRS) (task 1) and the mRS score at the third month (mRS 0-2: good GFO, mRS >2: poor GFO) (task 2). The permutation importance ranking method selected features. Four algorithms were trained on the training set with five-fold cross-validation. The best model was tested on the testing set. RESULTS: In task 1, the support vector machine (SVM) model outperformed the other models, with the high performance matrix on the training set (sensitivity = 0.80; specificity = 1.00) and the testing set (sensitivity = 0.80; specificity = 0.95). In task 2, the SVM model with selected features also performed well on both datasets (training set: sensitivity = 0.76; specificity = 0.92; testing set: sensitivity = 0.72; specificity = 0.88). CONCLUSION: A machine learning model could be used to classify GFO responses to treatment and identify the third-month poor GFO in RIS patients, supporting physicians in clinical practice.

Clinical implication of PRAME immunohistochemistry in differentiating melanoma in situ and dysplastic nevus in non-acral nevus-associated melanoma in situ: An institutional experience and meta-analysis.

INTRODUCTION: PReferentially expressed Antigen in MElanoma (PRAME) has shown utility in differentiating benign from malignant melanocytic neoplasms. In this study, we investigated the clinical significance of PRAME expression in dysplastic nevi (DN) and nevus-associated melanoma in situ (MIS). METHODS: We included 172 DN and 38 nevus-associated MIS from our institutional archive. PRAME positive expression was defined as nuclear staining in at least 75% of melanocytes. In addition, relevant studies from PubMed and Web of Science were incorporated into a meta-analysis using the random-effects model to assess PRAME expression in MIS and DN. RESULTS: Our institutional data revealed that 71.1% of nevus-associated MIS cases exhibited positive PRAME expression in the MIS components, whereas all DN components were negative for PRAME. 5.7% of cases diagnosed as DN in our cohort demonstrated diffuse positivity for PRAME. Notably, MIS associated with DN displaying epidermal and dermal components displayed a higher likelihood of PRAME positivity compared to those arising on a background of DN with solely epidermal (junctional) components (84% vs. 46%, p = 0.024). The meta-analysis indicated that the pooled PRAME positivity in MIS and DN was 54.5% and 1.9%, respectively. CONCLUSION: PRAME is a valuable immunohistochemical marker for differentiating MIS from DN, particularly in the context of nevus-associated MIS.

Extracellular vesicle surface display enhances the therapeutic efficacy and safety profile of cancer immunotherapy.

Immunotherapy has emerged as a mainstay in cancer therapy, yet its efficacy is constrained by the risk of immune-related adverse events. In this study, we present a nanoparticle-based delivery system that enhances the therapeutic efficacy of immunomodulatory ligands while concurrently limiting systemic toxicity. We demonstrate that extracellular vesicles (EVs), lipid bilayer enclosed particles released by cells, can be efficiently engineered via inverse electron demand Diels-Alder (iEDDA)-mediated conjugation to display multiple immunomodulatory ligands on their surface. Display of immunomodulatory ligands on the EV surface conferred substantial enhancements in signaling efficacy, particularly for tumor necrosis factor receptor superfamily (TNFRSF) agonists, where the EV surface display served as an alternative FcγR-independent approach to induce ligand multimerization and efficient receptor crosslinking. EVs displaying a complementary combination of immunotherapeutic ligands were able to shift the tumor immune milieu toward an anti-tumorigenic phenotype and significantly suppress tumor burden and increase survival in multiple models of metastatic cancer to a greater extent than an equivalent dose of free ligands. In summary, we present an EV-based delivery platform for cancer immunotherapeutic ligands that facilitates superior anti-tumor responses at significantly lower doses with fewer side effects than is possible with conventional delivery approaches.

CXCL5 expression is associated with active signals of macrophages in the microenvironment of papillary thyroid carcinoma.

BACKGROUND: C-X-C motif chemokine ligand 5 (CXCL5) is a chemokine molecule that is secreted by immune cells in attracting granulocytes. Studies showed that CXCL5 was related to the progression of papillary thyroid carcinoma (PTC) tumor cells. However, the in vivo effects of CXCL5 on PTC tumor cells and their microenvironment have not been elucidated. The present study aimed to investigate the biological effects of CXCL5 on tumor cells, microenvironment, and clinical progression of PTC. MATERIALS AND METHODS: The PTC patients from The Human Cancer Genome Atlas (TCGA) - thyroid carcinoma (THCA) were retrieved. There were a total of 500 patients who met the criteria of our study. Differential expression (DEA) and pathway analyses were used to explore the biological effects of CXCL5 gene expression. RESULTS: In DEA, we found that CXCL5 was mostly associated with PBPP, SLC11A1, and MRC1 (adjusted p<0.001). Samples with CXCL5 FPKM≥1 were related to a different immune profile (p<0.001). In pathway analyses, samples with higher CXCL5 expression possessed higher activities of RAS-RAF, NF-kB, PRC2, IL2, IL5, and Wnt pathways (adjusted p<0.001). In microenvironment analysis, CXCL5 was highly correlated with the activity of macrophage (Rho=0.76; adjusted p<0.001). Clinically, high level of CXCL5 expression was an indicator of tumor stages (p<0.001), nodal metastasis (AUC=0.68), and prognosis (p=0.001). CONCLUSION: CXCL5 was a significant biomarker of PTC. CXCL5 was highly associated with tumor immunology and microenvironment. Samples with higher CXCL5 expression had more advanced disease status and worse prognosis. CXCL5 target therapy is potentially helpful in advanced PTC.