Markers Of Response Research Articles

The Adverse Effects of Commonly Prescribed Antiseizure Medications in Adults With Newly Diagnosed Focal Epilepsy.

Systematic screening can help identify antiseizure medication (ASM)-associated adverse events (AEs) that may preclude patients from reaching effective doses or completing adequate trial periods. The Adverse Event Profile (AEP) is a self-completed instrument to identify the frequency of common AEs associated with ASM use. This study aimed to compare the AE profile of commonly used ASMs in adults with newly diagnosed focal epilepsy. The Human Epilepsy Project is a prospective, international, observational study investigating markers of treatment response in newly diagnosed focal epilepsy. Participants were enrolled within 4 months of treatment initiation. Adult participants on levetiracetam, lamotrigine, carbamazepine, or oxcarbazepine monotherapy who completed the AEP and Mini International Neuropsychiatric Interview at enrollment were included. Multivariable generalized linear and penalized logistic regression models assessed differences in total and itemized marginal AEP scores and dichotomized responses ("never/rarely" vs "sometimes/always"). A total of 225 adults initiated on levetiracetam (n = 132, 59%), lamotrigine (n = 55, 24%), carbamazepine (n = 19, 8.4%), or oxcarbazepine (n = 19, 8.4%) were included. There were no significant differences in AEP total scores between ASMs. Patients with depression (adjusted marginal score ratio [aMSR] 1.23, 95% CI 1.09-1.39, p = 0.001) and anxiety (aMSR 1.15, 95% CI 1.04-1.26, p = 0.007) had worse AEP total scores than those without. After adjusting for depression and anxiety, levetiracetam users were >3 times more likely to report feelings of aggression (adjusted odds ratio [aOR] 3.38, 95% CI 1.07-10.7, p = 0.038) and almost half as likely to experience unsteadiness (aOR 0.45, 95% CI 0.21-0.99, p = 0.047) than lamotrigine users. Carbamazepine and oxcarbazepine had the highest rates of discontinuation (42.1%, each), followed by levetiracetam (34.8%) and lamotrigine (16.4%). Levetiracetam users had the highest proportion of discontinuations because of AEs alone (18%), and lamotrigine had the lowest (5%). Systematic screening for AEs in adults with newly diagnosed focal epilepsy on ASM monotherapy showed that those with comorbid psychiatric conditions report greater AEs overall, irrespective of ASM. Levetiracetam was associated with >3-fold risk of psychiatric AEs and half the risk of experiencing unsteadiness than lamotrigine. Levetiracetam had the highest proportion of discontinuations because of AEs alone, while lamotrigine had the lowest.

Assessment of Prognostic Factors, Clinical Features Including the Microbiome, and Treatment Outcomes in Patients with Cancer of Unknown Primary Site

Introductions: cancer of unknown primary site (CUP) is a heterogeneous group of cancers in which metastases are found, and the primary tumor is not detected with available diagnostic methods. CUP is a disease that has not been fully researched, and its biology is unclear. The clinical characteristics of CUP are variable, but the prognosis of patients is usually unfavorable, and the possibilities of radical treatment are limited. The microbiome is the genes and gene products of microorganisms residing in a human body. In recent years, thanks to the use of next-generation sequencing, it is possible to assess the impact of the microbiome on human body functions. Head and neck cancers, due to the rich microbiome of this area, are influenced by it, and dysbiosis may be a risk factor for the development of cancer. Objective of this work: the aim of this study was to evaluate prognostic factors, clinical features including the microbiome, and treatment outcomes in patients with cancer of unknown primary site. Results: in the study group, increased numbers of bacteria of the phyla Bacteroides, Fusobacteria, Bacillota, Actinomycetota, Actinobacteria, and Candidatus were detected, while Firmicutes and Proteobacteria were detected in smaller numbers. Independent predictors of CUP occurrence were the following: leukocyte count of at most 6.49 × 103/mm, bacteria from the Proteobacteria phylum in the microbiome below 11.6%, Firmicutes below 22.1%, and Actinobacteria at least 11.0%. Increased numbers of Porphyromonas and Fusobacterium bacteria were associated with the risk of radiotherapy complications and shortened survival rate. Conclusions: clinical diagnosis and treatment of patients with CUP is complicated and difficult due to the lack of consensus on this issue. Treatment and prognosis of patients with CUP is unsatisfactory. The clinical value of the influence of the microbiome on the development, course, and treatment of cancer is becoming increasingly important. The microbiome may become a marker of response to anticancer treatment and the risk of its complications. Immunity modulation with the microbiome provides opportunities for further research on improving the effectiveness of oncological treatment. Fusobacterium and Porphyromonas seem to be the bacteria most important for the development of cancer, also worsening the prognosis of patients by increasing the risk of complications of radiotherapy and shortening the survival rate of patients. Streptococcus and Lactobacillus seem to be bacteria that reduce the risk of cancer, reduce the risk of complications, and improve the prognosis of patients. Total protein deficiency and elevated inflammatory markers are also important predictors of cancer risk.

12271 Differential Impacts Of Body Composition Indices On Cortisol Response And Hpa Axis Activity

Abstract Disclosure: S.G. Gonsalves: None. A. Ross: None. M.E. Steele: None. L.N. Saligan: None. Aim: The continued interest in the influence of muscle mass and fat distribution on stress stems from its implications on preventative healthcare. Fat mass index (FMI) and fat-free mass index (FFMI) were proposed as valuable indicators of body composition beyond body mass index (BMI). This study investigated correlations of FMI and FFMI with inflammatory stress markers, hypothesizing that these body composition indices identify inflammatory stress markers more distinctly than BMI. Methods: Skeletal muscle mass was assessed by Dual-Energy X-ray Absorptiometry, HPA axis response through an adrenocorticotropic hormone (ACTH) stimulation test, and markers of inflammation and stress response (e.g., dehydroepiandrosterone, DHEA) from peripheral blood of 104 healthy individuals aged 18-71 years, 52% female, with a mean BMI of 26.3 (+4.83). Perceived stress and fatigue were captured using patient-reported outcome questionnaires before the HPA procedure. Results: ACTH correlated with FFMI at baseline (ρ=0.299, p=0.009) and 60 minutes (ρ=0.254, p=0.041). Cortisol correlated with FFMI at 15 (ρ=–0.248, p≤0.025), 30 (ρ=–0.284, p≤0.010), and 60 minutes (ρ=–0.364, p≤0.001), and with BMI at 15 (ρ=–0.228, p=0.041). FMI and BMI did not correlate with ACTH and FMI with cortisol at any timepoint. With repeated measures ANOVA, FFMI at 50th percentile had large effect on cortisol (p=0.005, partial eta=0.094) at each timepoint, higher for the under lean than those with higher FFMI, compared to BMI at the same percentile (p=0.037, partial eta=0.054). None of the indices reached significance with ACTH. FMI correlated with Erythrocyte Sedimentation Rate (ESR) (ρ=0.521), C-reactive protein (CRP, ρ=0.493, both at p≤0.001), DHEA (ρ=0.252, p=0.030), and epinephrine (ρ=–0.246, p=0.045). FFMI was not correlated with ESR and CRP. BMI correlated only with albumin (ρ = –0.412, p ≤ 0.001 and CRP (ρ=0.342, p≤0.003). Discussion: The higher correlations of inflammatory stress markers with FMI and FFMI, as compared to BMI, supports our study hypothesis. These results hint that these body composition indices may detect subtle stress-related inflammatory changes than BMI. Future research should clarify underlying mechanisms driving these associations and explore the impact of targeted interventions on these indices and subsequent changes to inflammation and stress. Presentation: 6/1/2024

A study of pre- and post-treatment hematologic markers of immune response in patients undergoing radiotherapy for soft tissue sarcoma.

This study investigates the impact of pre- and post-treatment hematologic markers, specifically neutrophil-to-lymphocyte ratio (NLR) and platelet-to-lymphocyte ratio (PLR), on treatment outcomes in soft tissue sarcoma (STS) patients undergoing radiation therapy (RT). Data from 64 patients who underwent RT for curative management of STS were reviewed. Pre-RT and post-RT hematologic measures were evaluated for associations with survival outcomes. A normal tissue complication probability (NTCP) curve for predicting ΔPLR ≥ 75 was modeled using a probit function. Elevated baseline NLR was associated with worse overall survival (OS) and disease-free survival (DFS), while elevated PLR was associated with worse DFS. Post-RT, elevated PLR was linked to worse OS and DFS. Increasing PLR change post-RT was associated with worse OS and DFS. Receiver operating characteristics analysis determined ΔPLR ≥ 75 to be a robust cutoff associated with worse DFS. Bone V10Gy ≥362 cc corresponded to a 50% risk of developing ΔPLR ≥ 75. These results suggest that hematologic markers could serve as prognostic biomarkers in both pre- and post-treatment settings for STS patients undergoing RT. Future studies can consider using bone V10Gy < 362 cc as a potential cutoff to reduce the risk of increased PLR after RT.

The Contribution of the Skin Microbiome to Psoriasis Pathogenesis and Its Implications for Therapeutic Strategies.

Psoriasis is a common chronic inflammatory skin disease, associated with significant morbidity and a considerable negative impact on the patients' quality of life. The complex pathogenesis of psoriasis is still incompletely understood. Genetic predisposition, environmental factors like smoking, alcohol consumption, psychological stress, consumption of certain drugs, and mechanical trauma, as well as specific immune dysfunctions, contribute to the onset of the disease. Mounting evidence indicate that skin dysbiosis plays a significant role in the development and exacerbation of psoriasis through loss of immune tolerance to commensal skin flora, an altered balance between Tregs and effector cells, and an excessive Th1 and Th17 polarization. While the implications of skin dysbiosis in psoriasis pathogenesis are only starting to be revealed, the progress in the characterization of the skin microbiome changes in psoriasis patients has opened a whole new avenue of research focusing on the modulation of the skin microbiome as an adjuvant treatment for psoriasis and as part of a long-term plan to prevent disease flares. The skin microbiome may also represent a valuable predictive marker of treatment response and may aid in the selection of the optimal personalized treatment. We present the current knowledge on the skin microbiome changes in psoriasis and the results of the studies that investigated the efficacy of the different skin microbiome modulation strategies in the management of psoriasis, and discuss the complex interaction between the host and skin commensal flora.

High-grade serous ovarian cancer development and anti-PD-1 resistance is driven by IRE1α activity in neutrophils

ABSTRACT High-grade serious ovarian cancer (HGSOC) is an aggressive malignancy that remains refractory to current immunotherapies. While advanced stage disease has been extensively studied, the cellular and molecular mechanisms that promote early immune escape in HGSOC remain largely unexplored. Here, we report that primary HGSO tumors program neutrophils to inhibit T cell anti-tumor function by activating the endoplasmic reticulum (ER) stress sensor IRE1α. We found that intratumoral neutrophils exhibited overactivation of ER stress response markers compared with their counterparts at non-tumor sites. Selective deletion of IRE1α in neutrophils delayed primary ovarian tumor growth and extended the survival of mice with HGSOC by enabling early T cell-mediated tumor control. Notably, loss of IRE1α in neutrophils sensitized tumor-bearing mice to PD-1 blockade, inducing HGSOC regression and long-term survival in ~ 50% of the treated hosts. Hence, neutrophil-intrinsic IRE1α facilitates early adaptive immune escape in HGSOC and targeting this ER stress sensor might be used to unleash endogenous and immunotherapy-elicited immunity that controls metastatic disease.

A Reduction In Hepatic Lipid Markers In Response To Aerobic Exercise In Obese Individuals With Nafld

A Reduction In Hepatic Lipid Markers In Response To Aerobic Exercise In Obese Individuals With Nafld

Stress-induced c-fos expression in the medial prefrontal cortex differentially affects the main residing cell phenotypes

Stress poses a challenge to the body's equilibrium and triggers a series of responses that enable organisms to adapt to stressful stimuli. The medial prefrontal cortex (mPFC), particularly in acute stress conditions, undergoes significant physiological changes to cope with the demands associated with cellular activation. The proto-oncogene c-fos and its protein product c-Fos have long been utilized to investigate the effects of external factors on the central nervous system (CNS). While c-Fos expression has traditionally been attributed to neurons, emerging evidence suggests its potential expression in glial cells. In this study, our main objective was to explore the expression of c-Fos in glial cells and examine how acute stress influences these activity patterns. We conducted our experiments on male Wistar rats, subjecting them to acute stress and sacrificing them 2 h after the stressor initiation. Using double-labelling fluorescent immunohistochemistry targeting c-Fos, along with markers such as GFAP, Iba-1, Olig2, NG2, and NeuN, we analyzed 35 μm brain slices obtained from the mPFC. Our findings compellingly demonstrate that c-Fos expression extends beyond neurons and is present in astrocytes, oligodendrocytes, microglia, and NG2 cells—the diverse population of glial cells. Moreover, we observed distinct regulation of c-Fos expression in response to stress across different subregions of the mPFC. These results emphasize the importance of considering glial cells and their perspective in studies investigating brain activity, highlighting c-Fos as a response marker in glial cells. By shedding light on the differential regulation of c-Fos expression in response to stress, our study contributes to the understanding of glial cell involvement in stress-related processes. This underscores the significance of including glial cells in investigations of brain activity and expands our knowledge of c-Fos as a potential marker for glial cell responses.

Characterization and proteomic analysis of plasma-derived small extracellular vesicles in locally advanced rectal cancer patients.

Neoadjuvant chemoradiotherapy (nCRT) stands as a pivotal therapeutic approach for locally advanced rectal cancer (LARC), yet the absence of a reliable biomarker to forecast its efficacy remains a challenge. Thus, this study aimed to assess whether the proteomic compositions of small extracellular vesicles (sEVs) might offer predictive insights into nCRT response among patients with LARC, while also delving into the proteomic alterations within sEVs post nCRT. Plasma samples were obtained from LARC patients both pre- and post-nCRT. Plasma-derived sEVs were isolated utilizing the TIO2-based method, followed by LC-MS/MS-based proteomic analysis. Subsequently, pathway enrichment analysis was performed to the Differentially Expressed Proteins (DEPs). Additionally, ROC curves were generated to evaluate the predictive potential of sEV proteins in determining nCRT response. Public databases were interrogated to identify sEV protein-associated genes that are correlated with the response to nCRT in LARC. A total of 16 patients were enrolled. Among them, 8 patients achieved a pathological complete response (good responders, GR), while the remaining 8 did not achieve a complete response (poor responders, PR). Our analysis of pretreatment plasma-derived sEVs revealed 67 significantly up-regulated DEPs and 9 significantly down-regulated DEPs. Notably, PROC (AUC: 0.922), F7 (AUC: 0.953) and AZU1 (AUC: 0.906) demonstrated high AUC values and significant differences (P value < 0.05) in discriminating between GR and PR patients. Furthermore, a signature consisting of 5 sEV protein-associated genes (S100A6, ENO1, MIF, PRDX6 and MYL6) was capable of predicting the response to nCRT, yielding an AUC of 0.621(95% CI: 0.454-0.788). Besides, this 5-sEV protein-associated gene signature enabled stratification of patients into low- and high-risk group, with the low-risk group demonstrating a longer overall survival in the testing set (P = 0.048). Moreover, our investigation identified 11 significantly up-regulated DEPs and 31 significantly down-regulated DEPs when comparing pre- and post-nCRT proteomic profiles. GO analysis unveiled enrichment in the regulation of phospholipase A2 activity. Differential expression of sEV proteins distinguishes between GR and PR patients and holds promise as predictive markers for nCRT response and prognosis in patients with LARC. Furthermore, our findings highlight substantial alterations in sEV protein composition following nCRT.

Gal-3 blocks the binding between PD-1 and pembrolizumab

IntroductionImmune checkpoint inhibitors (ICI) have revolutionized the treatment of metastatic malignant melanoma (MM) and improved long-term survival. Despite the impressive results, some patients still have progressive disease, and the search...

Sex-differential markers of psychiatric risk and treatment response based on premature aging of functional brain network dynamics and peripheral physiology

BackgroundAging is a multilevel process of gradual decline that predicts morbidity and mortality. Independent investigations have implicated senescence of brain and peripheral physiology in psychiatric risk, but it is unclear whether these effects stem from unique or shared mechanisms. MethodsTo address this question, we analyzed clinical, blood chemistry and resting state functional neuroimaging data in a healthy aging cohort (N= 427; age 36-100 years) and two disorder-specific samples encompassing patients with early psychosis (100 patients, 16-35 years) and major depressive disorder (MDD) (104 patients, 20-76 years). ResultsWe identified sex-dependent coupling between blood chemistry markers of metabolic senescence (i.e., homeostatic dysregulation), functional brain network aging, and psychiatric risk. In females, premature aging of frontoparietal and somatomotor networks was linked to greater homeostatic dysregulation. It also predicted the severity and treatment resistance of mood symptoms (depression/anxiety [all three samples], anhedonia [MDD]) and social withdrawal/behavioral inhibition (avoidant personality disorder [healthy aging]; negative symptoms [early psychosis]). In males, premature aging of the default mode, cingulo-opercular, and visual networks was linked to reduced homeostatic dysregulation and predicted severity and treatment resistance of symptoms relevant to hostility/aggression (antisocial personality disorder [healthy aging]; mania/positive symptoms [early psychosis]), impaired thought processes (early psychosis, MDD) and somatic problems (healthy aging, MDD). ConclusionsOur findings identify sexually dimorphic relationships between brain dynamics, peripheral physiology, and risk for psychiatric illness, suggesting that the specificity of putative risk biomarkers and precision therapeutics may be improved by considering sex and other relevant personal characteristics.

In vitro testing of drug response in primary multiple myeloma cells using a microwell-based technology

Multiple myeloma is an aggressive neoplasm of plasma cells. While numerous drugs have gained approval, the absence of established predictive markers for individual drug responses poses a challenge. In this study, we explored the microwell- and fluorescence-based Cellply CC-Array® technology for high-throughput analysis of in vitro drug responses as a potential predictive marker for patient treatment outcomes. Furthermore, we investigated its application for evaluating effector cell effectiveness. Mononuclear cells were isolated from the bone marrow of 22 patients, and in vitro drug response of primary myeloma cells was analyzed. In vitro responses towards melphalan, bortezomib, and dexamethasone in primary patient samples correlated with clinical response of the patients. The approach exhibited limitations in identifying sensitivity towards lenalidomide, daratumumab, and elotuzumab due to limited culturing time caused by poor myeloma viability in vitro. Through the analysis of cell proximity, the platform enabled the assessment of individual anti-tumor activity from NK and T cells. In summary, the CC-Array microwell technology allowed assessment of myeloma cell responses to selected drugs used in multiple myeloma therapy in vitro. To further validate these in vitro results against in vivo outcomes, screening a larger cohort is necessary.

The relationship between diet and glycemic response and inflammatory markers in children with cystic fibrosis

The relationship between diet and glycemic response and inflammatory markers in children with cystic fibrosis

Vascular Endothelial Growth Factor as a Marker of Response to Sorafenib Treatment in Patients with Hepatocellular Carcinoma

Abstract Background Liver cancer remains a global health challenge and its incidence is growing worldwide. It is estimated that by year 2025, more than one million individuals will be affected by liver cancer annually. Hepatocellular carcinoma (HCC) is the most common form of liver cancer and accounts for 90% of cases. Hepatitis B virus (HBV) infection is the most prominent risk factor for HCC development, accounting for 40% of cases and Hepatitis C virus (HCV) infection is the leading cause of HCC in Egypt by 84%. Aim of the Work The present study aimed to evaluate the level of VEGF before and after 3 months of treatment with Sorafenib, and evaluate the efficacy of VEGF as a prognostic marker by Correlating it’s level with the radiological response after 3 months of Sorafenib. Patients and Methods This was a prospective cohort study that was carried out in The Hepatocellular carcinoma outpatient clinic and Tropical Medicine department, at Ain Shams University Hospitals. A total of 30 patients were enrolled, including 23 males and 7 females, with a mean age 62 years (51-76 years). all the included patients were CHILD A or B score 7 with performance status zero or 1 during the interval between June 2022 and June 2023. Results Thirty patients were included in the current study, twenty-sex of them were with BCLC-C and 4 patients were with BCLC-B with multiple untreatable sessions of TACE. The etiology of HCC in 28 patients was due to HCV infection while the etiology of 2 patients was due to HBV infection. Before treatment there were 17 patients of the included patients with CHILD A score 5, six patients were with CHILD A score 6 and 7 patients were with CHILD B score 7. After 3 months of Sorafenib, there was deterioration of liver function as 9 patients of the included patients were with CHILD A score 5, ten patients were with CHILD A score 6, seven patients were with CHILD B score 7 and 4 patients were with CHILD B score 8. Nine of the included patients achieved disease control (DC) in the form of either partial response (PR) {4 patients} or stationary disease (SD) {5 patients}. The level of VEGF before Sorafenib couldn’t predict the clinical and the radiological outcomes of the included patients. While, the post-treatment VEGF level showed a significant relation with the radiological assessment (mRECIST) 3 months after treatment as the highest level of VEGF was in patients with progressive disease (PD) and the lowest value in partial response (PR). Conclusion This study characterizes the pattern of VEGF levels before and 3 months after treatment of Sorafenib in post-hepatitis HCC cirrhotic patients. The pre-therapeutic serum VEGF levels in HCC patients couldn’t predict the clinical and the radiological outcomes of the included patients but the post-treatment level showed a significant correlation with a HCC progression according to mRECIST criteria.

Bronchial asthma with normal forced expiratory volume in 1 second (FEV1) compared with low FEV1.

Cough variant asthma (CVA) is characterized by cough as a sole symptom and normal pulmonary function. However, it is unclear whether CVA really common among asthmatic patients with normal forced expiratory volume in 1 second (FEV1). The aim of this study was to evaluate the incidence of cough alone symptom among the subjects with normal FEV1 and to evaluate their differences from ordinary asthmatic subjects. We defined normal FEV1 as ≥90% predicted based on the article of Kotti GH. Of the patients with normal FEV1, we chose subjects without wheeze, and the duration of cough was not to ask, since the symptoms often occurred with acute exacerbation and timing of visiting a doctor depended on each patient's perception. Test for airway hyperresponsiveness was not performed in this study. Visual analogue scale (VAS) scores for cough and dyspnea, FEV1, and fractional exhaled nitric oxide (FeNO) responsiveness to inhaled corticosteroid (ICS)/long-acting beta2 agonist (LABA) treatment were compared in patients with normal FEV1 and with low FEV1 <90%. Correlations of changes in symptoms with changes of FEV1, FeNO, peripheral eosinophil count, and serum immunoglobulin E (IgE) at single time point were also examined in each group and in overall patients. The participants were 329 physician-diagnosed treatment-naive patients with asthma who were divided into 187 in normal FEV1 and 142 in low FEV1 groups. Cough without dyspnea was present in 16 patients (8.6%) in the normal FEV1 group, suggesting candidates for CVA in this analysis were quite few. Improvement in symptoms after treatment was similar between both groups. But VAS scores of dyspnea were still higher in the low FEV1 group. The degree of improvement in FEV1 after ICS/LABA treatment was less in the normal FEV1 group than in the low FEV1 group, but was still evident. Peripheral eosinophil count, serum IgE, and FeNO values before treatment were lower in the normal FEV1 group. In overall patients, improvements of symptoms after treatment were significantly correlated with FEV1 changes. Improvement of dyspnea was also significantly related to peripheral eosinophil count and change of FeNO, whereas improvement of cough was not related to these T helper 2 (Th2) response markers. Candidates for CVA among the patients with asthma with predicted FEV1 ≥90% were few. Participants with normal FEV1 respond well to ICS/LABA treatment for improvement of symptom. The change of FEV1 after treatment, and the pre-treatment blood eosinophil count, serum IgE, and FeNO were lower in normal FEV1 cases than in low FEV1 cases. These observations suggest asthmatic patients with normal FEV1, including candidates for CVA having just common mild asthma. In overall participants, symptoms of cough and dyspnea were similar, but were not identical in relation to the Th2 background.

Case Report: Pathological fracture in a Li-Fraumeni osteosarcoma patient: "Capasquelet'' femoral reconstruction and tumor vascular analysis with endomucin immunofluorescence multiplexing

We describe the case report of an Osteosarcoma patient, with a Li-Fraumeni Syndrome, presenting with a pathological femoral fracture. The patient was treated with a multidisciplinary approach associating neoadjuvant and adjuvant chemotherapy with excisional surgery. The femoral reconstruction consisted of a ``Capasquelet'' reconstruction combining an induced membrane and a vascularized fibula allograft allowing a good functional result with an early weight-bearing. We managed to complete our histological analysis in this patient, in order to evaluate the tumor vascularization. Indeed, using the syngeneic osteosarcoma MOS-J mouse model, we highlighted previously that CD31+/\ensuremath{\alpha}-SMA+ vessels may be indicators of vasculature normalization and therefore may be used as specific markers of a good therapeutic response. Thus, we search for its interest in this specific case as preliminary work. The aim was to assess the feasibility and technical validity of the vascularization analysis of a human osteosarcoma tumor specimen. Therefore, we propose an immunohistochemistry methodology with multiplexed immunofluorescence to assess the vascularization as a promising marker in human osteosarcoma tissue.

Effect of basic periodontal treatment on CRP in elderly pregnant women with periodontal disease

Periodontal disease is a chronic infectious disease, which is common and frequent disease in pregnant women. It is an infectious disease caused by a variety of microorganisms, and the physiological changes in pregnant women after pregnancy can promote the occurrence and development of periodontal disease. Women no less than 35 years old are at an increased risk of maternal and fetal complications in pregnancy, older pregnant women with periodontal disease are prone to preterm birth, fetal growth retardation, premature rupture of membranes, and the incidence of neonatal low birth weight is significantly higher than that in older women with healthy oral health, i.e., these risks are increased with age. CRP is an acute-phase protein produced by liver organs, which is produced by hepatocytes under the promotion of inflammatory factors, and serves as the most direct and sensitive marker of inflammatory response. Studies have shown that basic periodontal treatment relieve periodontal tissue inflammation in pregnant women with periodontitis, while significantly reducing their serum CRP concentration, thereby decreasing the occurrence of adverse pregnancy outcomes. The objective of this study is to investigate the effect of basic periodontal treatment on CRP in elderly pregnant women with periodontal disease.

Impact of soluble BCMA and non–T-cell factors on refractoriness to BCMA targeting T-cell engagers in multiple myeloma

AbstractAdoptive T-cell therapy is a promising therapy for multiple myeloma (MM), but its efficacy hinges on understanding the relevant biologic and predictive markers of response. B-cell maturation antigen (BCMA) is a key target antigen in MM with active development of multiple anti-BCMA T-cell engagers (TCEs) and chimeric antigen receptor T-cell therapies. The regulation of surface BCMA expression by MM cells, which leads to shedding of soluble BCMA (sBCMA), has triggered debate about the significance of sBCMA as a predictive marker and its potential impact on treatment outcomes. To address this, we leveraged whole-genome sequencing and in vitro assays to demonstrate that sBCMA may independently predict primary refractoriness to anti-BCMA therapies. In addition to sBCMA, tumor burden and surface BCMA antigen density collectively influenced the anti-BCMA TCE cytotoxic efficacy. Correlative analyses of 163 patients treated with the anti-BCMA TCE teclistamab validated and further underscored the association between elevated baseline sBCMA (>400 ng/mL) and refractoriness. Importantly, increasing the TCE dose, using TCE against alternative targets (eg, GPRC5D), and gamma secretase inhibitors were able to overcome the high sBCMA levels. These findings highlight the importance of taking into account the baseline sBCMA levels, disease burden, and TCE dose intensity when administering anti-BCMA TCEs, thereby offering critical insights for optimizing therapeutic strategies to overcome specific high-risk features and primary anti-BCMA TCE refractoriness.

Lymphoma cell-driven IL-16 is expressed in activated B-cell-like diffuse large Bcell lymphomas and regulates the pro-tumor microenvironment.

The activated B-cell-like subtype of diffuse large B-cell lymphoma (ABC-DLBCL) displays a worse outcome than the germinal center B-cell-like subtype (GCB-DLBCL). Currently, targeting tumor microenvironment (TME) is the promising approach to cure DLBCL with profound molecular heterogeneity, however, the factors affecting the tumor-promoting TME of ABCDLBCL are elusive. Here, cytokine interleukin-16 (IL-16) is expressed in tumor cells of ABCDLBCL and secreted by the cleavage of active caspase-3. The serum IL-16 levels are not only a sensitive marker of treatment response but also positively correlated with unfavorable prognosis in DLBCL patients. While IL-16 shows few direct promotional effects on tumor cell growth in vitro, its bioactive form significantly promotes tumor progression in vivo. Mechanically, IL-16 increases the infiltration of macrophages by the chemotaxis of CD4+ monocytes in the TME enhancing angiogenesis, and the expression of cytokine IL-6 and IL-10, as well as decreasing T cell infiltration to accelerate tumor progression. This study demonstrates that IL-16 exerts a novel role in coordinating the bidirectional interactions between tumor progression and the TME. IMM0306, a fusion protein of CD20 mAb with the CD47 binding domain of SIRPα, reverses the tumorpromoting effects of IL-16,which provides new insight into treatment strategy in ABC-DLBCL.

Histone demethylase enzymes KDM5A and KDM5B modulate immune response by suppressing transcription of endogenous retroviral elements.

The histone demethylases KDM5A and KDM5B are transcriptional repressors that play an important role in cancer and immune response, making them attractive drug targets. Unfortunately, small molecule inhibitors, including CPI-455, that block KDM5A and KDM5B enzymatic activity, have shown only limited effectiveness at suppressing cancer cell viability as single agents in vitro. In this study we undertook a multi-omics approach to map transcriptional and chromatin changes in KDM5A and KDM5B deficient cells compared to those treated with CPI-455. The datasets revealed that KDM5A and KDM5B modulate the expression of KRAB-ZNF genes and that loss of either gene was associated with increased expression of ERV genes and upregulation of immune response markers. Surprisingly, pharmacological inhibition of these enzymes did not phenocopy genetic ablation. In contrast, acute degradation of KDM5A using a dTAG system caused an increase in ERV expression, providing evidence that this immune modulation is independent of demethylase activity. Together with the limited success of small molecule inhibitors, our data provide strong rationale for the development of KDM5A and KDM5B degraders to modulate tumor immune responses.