Decrease In White Blood Cells Research Articles

Assessing the association between cigarette smoking and blood C-reactive protein levels using restructured cohort data

IntroductionCigarette smoke exposure is known to induce inflammation, leading to elevated levels of inflammatory markers such as white blood cell (WBC) count and C-reactive protein (CRP). Despite extensive research on this relationship, longitudinal studies are limited. We aimed to explore the association between cigarette smoke exposure and WBC count and CRP levels by restructuring community cohort data. MethodsData from a community cohort of the Korean population, followed biennially from 2001 to 2018, were utilized. Smoking status was determined through self-administered questionnaires. WBC and CRP levels were measured in a central laboratory with stringent quality control. Cohort data were restructured into pairs representing before and after measurements. We analyzed smoking effects on WBC and CRP using pairwise before-after tests based on changes in smoking status. Furthermore, parallel group analyses comparing changes in smoking status to no change were conducted. ResultsAnalysis included 4336 pairs for WBC and 3068 pairs for CRP from 10,030 participants. Pairwise analysis showed a significant decrease in WBC transitioning from current smoker to non-smoker and an increase from non-smoker to current smoker. Parallel group analysis demonstrated a significant decrease in WBC transitioning from current smoker to non-smoker compared to remaining current smoker, and an increase from non-smoker to current smoker compared to remaining non-smoker. CRP did not exhibit significant associations in either analysis. ConclusionsIn a community cohort, cigarette smoking was associated with elevated WBC count. However, CRP levels did not consistently reflect inflammation associated with cigarette smoking.

Comprehensive Analysis of Immune Responses to Neoadjuvant Immunotherapy in Resectable Non-small Cell Lung Cancer.

Neoadjuvant immunotherapy using immune checkpoint inhibitors (ICIs) has revolutionized the treatment of early stage non-small cell lung cancer (NSCLC). However, little is known about which patients are likely to benefit most from neoadjuvant immunotherapy. In this study, we performed a multiplatform analysis on samples from resectable NSCLC treated with neoadjuvant immunotherapy to explore molecular characteristics related to immune responses. A total of 17 patients with resectable stage IB-IIIA NSCLC treated with neoadjuvant immunotherapy were included. A multiplex cytokine assay, bulk TCR sequencing in peripheral blood, and multiplexed immunohistochemistry were performed. Low levels of stromal cell-derived factor (SDF)-1alpha at baseline were associated with unfavorable disease-free survival (DFS). Patients with major pathologic response (MPR) showed a decrease in HGF after one cycle of neoadjuvant immunotherapy. An increase in IDO and IP-10 was observed in patients who developed immune-related adverse events (irAEs) after neoadjuvant immunotherapy. There were no correlations between irAEs and MPR or DFS. The MPR group presented a significant decrease in white blood cells and neutrophil count after neoadjuvant immunotherapy. The high peripheral baseline TCR convergence was correlated with MPR and favorable DFS in lung squamous cell carcinoma (LUSC) receiving neoadjuvant immunotherapy. Neoadjuvant immunotherapy led to a significant increase in CD4+, CD8+, and CD8+CD39+ T-cell infiltration in tumor areas. This study suggests the potential roles of cytokines and TCR convergence for predicting ICIs response in resectable NSCLC and LUSC. CD8+CD39+T cells and CD4+ T cells could be involved in the action of neoadjuvant immunotherapy.

Biodistribution and Biotoxicity Assessment of Fluorescent Conjugated Polymer Dots.

Conjugated polymer dots (Pdots) have shown potential in the biomedical fields due to their optical properties and customizable design. However, the limited research on the biotoxicity of Pdots hinders their further application and translation. Lipophilic Pdots are prone to adsorbing specific proteins, leading to targeted tissue accumulation. Therefore, lipophilic fluorescent Pdots (Bare-Pdots) are synthesized using the conjugated polymer poly[2-methoxy-5-(2'-ethylhexyloxy)-1,4-phenylenevinylene] (MEH-PPV) to systematically evaluate their biodistribution and biotoxicity in stem cells, zebrafish embryos, and mice. It is observed that Bare-Pdots are readily internalized by cells and adhered to the embryonic chorion. Additionally, Bare-Pdots exhibit a distinct distribution in brown adipose tissue and heart, closely associated with phagocytosis of capillary endothelial cells involved in lipid metabolism. Notably, injection of Bare-Pdots at 5mgkg-1results in dysfunction of brown adipose tissue and an increased risk of obesity 90days post-injection. Furthermore, hydrophilic COOH-Pdots and NH2-Pdots with reduced lipophilicity are synthesized using amphiphilic ligands. NH2-Pdots show similar distribution but lower biotoxicity compared to Bare-Pdots. Nevertheless, injection of COOH-Pdots at 5mgkg-1 causes a decrease in white blood cells and renal tubular damage. These findings provide valuable insights for optimizing dosage to ensure the safe use of Pdots in preclinical applications.

Efficacy and safety of surufatinib, toripalimab, nab-paclitaxel in combination with radiotherapy or surgery in the first-line treatment of esophageal squamous cell cancer: A single-centered prospective clinical trial.

e16047 Background: Chemotherapy(CT) plus immune checkpoint inhibitors (ICIs) has become the current standard of care in the first-line treatment of metastatic esophageal squamous cell cancer(ESCC). In locally advanced setting, radiochemotherapy with or without resection remains the standard of care. Surufatinib, a novel small-molecule kinase inhibitor targeting VEGFR1-3, FGFR and CSF-1R, in combination with PD-1 inhibitors have demonstrated synergistic anti-tumor activities in previous studies. This single-centered prospective clinical trial aims to evaluate the efficacy and safety of surufatinib(SUR), toripalimab(TOR), nab-paclitaxel(NAB) in combination with radiotherapy or surgery in the first-line treatment of locally advanced(LA) or metastatic(R/M) ESCC. Methods: Eligible patients(pts) with confirmed LA or R/M, ECOG PS 0-2 and no prior systematic treatment were enrolled in the trial. Pts would receive 260mg/m2 NAB and TOR 240mg on day 1 and SUR 250mg once daily in each 21-day cycle as induction therapy for two cycles, followed by surgery or another two cycles of concurrent chemoradiotherapy(CCRT) with NAB, SUR and radiotherapy, in which involved-field irradiation were conducted at the dose of 50-63 Gy/25-30F, 1.8-2 Gy per fraction, 5 fractions per week. As maintenance therapy, daily SUR and TOR every three week were administered until disease progression or unacceptable toxicities. Progression-free survival (PFS) was the primary endpoint. Results: As of Jan 7, 2024, 16 pts were enrolled, of whom 15 were evaluable. 14(87.5%) pts were male. The median age was 69.5 (range: 45-79). Tumor located in upper(18.8%), middle(25%) and lower(56.2%) thoracic. 1(6.2%) is Stage II disease, 12(75%) Stage III and 3(18.8%) Stage IV. 8 (50%) pts were with PD-L1 CPS greater than 1, 5 (31.25%) pts greater than 5, and 3 (18.75%) pts greater than 10. PD-L1 CPS of 6(37.50%) pts was unknown. With a median follow-up time of 5 (range: 1-12) months, despite the immatureness of PFS, the 12-month PFS rate was 77.14% (95% CI: 48.89%-100%). The objective response rate was 93.3% (14/15), and disease control rate was 100% (15/15). Five of the included pts met the resection criteria during treatment and underwent subsequent R0 resection. The most common adverse events (≥20%) of all grades were hypoesthesia (62.5%), nausea and vomiting (50%), and white blood cell decrease (43.75%). Conclusions: The combination ofsurufatinib, toripalimab, nab-paclitaxel with radiotherapy or surgery has demonstrated promising efficacy and a well-tolerated safety profile as a potential first-line treatment for LA or R/M ESCC. This ongoing trial merits further investigation and holds significant implications for clinical practice.

HOPE: Harnessing olaparib, palbociclib, and endocrine therapy for BRCA1/2-associated HR+, HER2- metastatic breast cancer.

10616 Background: Thepoly (ADP-ribose) polymerase inhibitor olaparib yields superior progression-free survival, response rates and patient-reported outcomes compared with chemotherapy in patients with BRCA1- or BRCA2- ( BRCA1/2) associated metastatic breast cancer (MBC). Fulvestrant and palbociclib improve outcomes in patients with hormone receptor-positive (HR+) MBC. HOPE (NCT03685331) is a phase I trial to evaluate combination olaparib (O), fulvestrant (F), and palbociclib (P) in patients with BRCA1/2-associated HR+, HER2 negative MBC. Methods: A 3+3 dose escalation was used to assess safety and preliminary efficacy of O, F and P. Eligible participants (pts) had HR+ MBC, a germline (g) or somatic (s) mutation in BRCA1/2, measurable/evaluable disease, any/no prior endocrine therapy, and 0-2 prior lines of chemotherapy for MBC. Prior PARPi and CDK4/6i were permitted but not in combination. Palbociclib was added after a 28-day safety run-in (Cycle 0) of O + F alone. Fulvestrant dose was 500mg IM on day 1 of each 28-day cycle. Dose level 0 (DL0, starting level) was F, O 300mg orally BID continuously, P 75mg orally daily on days 1-21; DL-1 was F, O 250mg orally BID, P 75mg orally daily on days 1-21. The primary endpoint was MTD (adverse events (AEs) based on CTCAE v5.0). Dose limiting toxicity (DLT) period included Cycles 0 and 1. A 30% DLT rate was acceptable; 6 pts had to be treated at a dose for it to be declared MTD. RECIST v1.1 was used to evaluate response. Results: Eight treated pts (s BRCA1:1 ;g BRCA2:6; s BRCA2:1 ) had median (M) age 47; M 0 (0-2) prior lines of endocrine therapy and 0 (0-1) prior chemotherapies for MBC. Three pts each had received O, F, and CDK4/6i as part of their standard of care treatment before study. At DL0, 2/2 pts had DLT with persistent grade(G) 3 neutropenia. Among 6 pts treated at DL-1, none experienced DLT, but 3 pts missed doses of study treatment due to cytopenias (G3 neutropenia, G3 leukopenia, G3 thrombocytopenia) during the DLT period. Following the DLT period, 1 pt reduced O to 200mg orally daily and 1 discontinued P based on provider discretion due to cytopenias (G3 neutropenia, G3 thrombocytopenia). Grade 3 AEs occurring in >1 pt related to study treatment were: neutrophil count decrease (G3/2, n=5/2); white blood cell decrease (G3/2/1, n=3/2/2); platelet count decrease (G3/2/1, n=2/0/1). Overall related AEs in >50% of pts were anemia (n=7), fatigue (n=6) and nausea (n=5). Best responses were CR/PR/SD/PD in 1/1/5/1 pts. Conclusions: MTDof O, F and P (DL-1) was reached and demonstrated antitumor activity. Although no AEs meeting protocol-specified DLT criteria were observed at MTD, hematologic toxicity at this dose complicated drug delivery and required close monitoring during and after the DLT period. Combinations utilizing PARP1 selective inhibitors, lower doses of therapy or sequential rather than combination therapy may improve feasibility. Clinical trial information: NCT03685331 .

Anti-inflammatory effect of melatonin therapy in sepsis

Background The biggest cause of illness and death in children across the globe is sepsis. Melatonin, which is an endogenous lipophilic indoleamine that is primarily made from serotonin inside the pineal gland, has been shown in clinical research to be useful as an adjuvant treatment in septic newborns, improving outcomes and reducing complications, because of its strong antioxidant and immunological activities. Aim The goal of the present study is to evaluate the anti-inflammatory effects of melatonin as an additional treatment to antibiotics in children with sepsis, on laboratory markers and inflammatory cytokines: interleukin 6 (IL-6) and IL-8 as well as to study its impact on the outcome of these children. Patients and methods Our research is a prospective randomized controlled double-blinded trial from February 2017 to February 2018 at Mansoura University Children’s Hospital. This was accomplished by examining 30 children who were diagnosed with sepsis according to the Third International Consensus Definitions for Sepsis and Septic Shock. The study’s subjects were divided into two groups: group A (cases group) 15 children with sepsis in which antibiotics as well as a total oral dosage of 20 mg melatonin were given. Group B (control group) 15 matched septic children who received antibiotics as well as a cumulative oral dosage of 20 mg of a placebo. Results The research showed that melatonin administration as an adjuvant treatment was associated with a significant decrease in the C-reactive protein after treatment in group A than in group B (P=0.031). While there was a statistically insignificant decrease in white blood cells and an increase in hemoglobin as well as in platelets. Furthermore, serum IL-6 and IL-8 levels were significantly lower in the melatonin receiving group when matched with the control group 72 h after treatment (P=<0.001, 0.021, respectively). Melatonin administration improved the outcome in melatonin-treated group better than the control group (P=0.01). Conclusion Melatonin can be used as an adjuvant treatment for children with sepsis as it significantly reduced the C-reactive protein, serum IL-6, and IL-8 levels as well as it improves the outcome of sepsis in these children.

Mentha piperita and Thymus vulgaris ameliorate hematological changes induced by chronic consumption of oxidized palm oil in rats

Objective: The aim of this study was to investigate the effect of Mentha piperita L and/or Thymus vulgaris in ameliorating the hematological changes induced by chronic consumption of oxidized palm oil (OPO) in rats. Methodology: Fifty rats were divided into five groups as follows: rats received a basal diet (control), rats received a basal diet sustained with OPO, rats fed OPO and received Mentha piperita extract, rats fed OPO and received Thymus vulgaris extract, and finally rats fed OPO and received both extracts. After 6 weeks, blood samples were withdrawn and a complete blood count test was done. Results: Rats fed a diet containing OPO showed a significant decrease in red blood cells (RBCs), hematocrit (Hct), mean corpuscular volume (MCV), hemoglobin (Hb), mean corpuscular hemoglobin (MCH), mean corpuscular hemoglobin concentration (MCHC), lymphocytes (LYM), and platelets (PLTs) accompanied by a significant increase in white blood cells (WBCs), red cell distribution width (RDW), and mean platelet volume (MPV) compared to rats fed a normal diet. In contrast, rats fed on diet containing OPO and the aqueous extract of either Mentha piperita or Thymus vulgaris showed a significant increase in RBCs, Hct, MCV, Hb, MCH, MCHC, LYM, and PLTs accompanied by a significant decrease in RDW, WBCs, and MPV relative to rats fed on diet containing OPO only. Treatment with a combination of both plants showed better improvements. Conclusion: Both Mentha piperita and Thymus vulgaris ameliorate the hematological changes induced by OPO.

Evaluation of the Therapeutic Impact of Probiotic-Enriched Orange and Pomegranate Juices on Some Health Parameters in Diarrhea-Induced Laboratory Rats

This research endeavor was undertaken to craft a functional beverage by blending orange and pomegranate juices, enriched with the inclusion of therapeutic probiotic strains, specifically Lactobacillus acidophilus, Lactobacillus plantarum, and Lactobacillus rhamanous. A comprehensive assessment was conducted to investigate the physicochemical, microbial, and sensory characteristics of the resulting beverage. Furthermore, we explored the potential health benefits of this fortified beverage within a rat model afflicted with E. coli infection, focusing on its influence on blood parameters and lipid profiles in male rats. The research findings revealed the presence of four distinct bacterial strains, namely Staphylococcus hominis, Staphylococcus aureus, E. coli, and Enterococcus gallinarum, in natural juices obtained from local markets in Tikrit. Regarding the physicochemical properties and bacterial counts in the manufactured juices, the results indicated a decline in pH levels and total sugar content over time, coupled with an increase in total acidity during refrigerated storage of functional juices. Additionally, the enumeration and viability of fortifying bacteria surpassed the prescribed probiotic threshold in the tested juice varieties. Sensory evaluation outcomes demonstrated the overall acceptability of the manufactured juices. The research findings demonstrated that E. coli-induced diarrhea led to a significant elevation (P<0.05) in key blood parameters, including white blood cell and platelet counts (12.63 and 747 mm^3/liter), along with a notable reduction in red blood cell counts and hemoglobin concentration (6.0 and 13.1 mm^3/liter, respectively). However, oral administration of functional juices resulted in a decrease in white blood cell and platelet counts and an increase in red blood cell counts and hemoglobin concentration across all measured parameters. Regarding lipid profiles, the diarrheal group exhibited elevated levels of detrimental lipid markers, including cholesterol, triglycerides, and low-density lipids (73.59, 71.61, and 14.8, respectively), accompanied by reduced high-density lipoproteins concentration (31.5). Conversely, treatment with oral doses of functional juices led to a reduction in these adverse lipid indicators for all treatment groups.

The Association between Serum Level of Vitamin D and Inflammatory Biomarkers in Hospitalized Adult Patients: A Cross-Sectional Study Based on Real-World Data.

The association between vitamin D status and inflammation remains unclear in hospitalized patients. We performed the current study based on real-world data from two teaching hospitals. Serum level of vitamin D (assessed by 25-hydroxyvitamin D) was evaluated within 2 days after admission. All the patients were further classified into three groups: deficiency (<12 ng/mL), insufficiency (12-20 ng/mL), and adequate (≥20 ng/mL). White blood cell (WBC) count, serum level of C-reactive protein (CRP), and procalcitonin were also measured and used to evaluate inflammation. Other potential covariates were abstracted from medical records. Charlson comorbidity index (CCI) was calculated to assess the severity of disease. A total number of 35,528 hospitalized adult patients (21,171 men and 14,357 women) were included. The average age and BMI were 57.5 ± 16.2 years and 23.4 ± 3.7 kg/m2, respectively, while medium vitamin D level was 16.1 ng/mL (interquartile range: 11.4 ng/mL, 21.6 ng/mL) and median CCI was one point (interquartile range: 0 point, two points). The prevalence of deficiency and insufficiency was 28.0% and 40.5%. Multivariate linear regression model showed that serum level of vitamin D was significantly associated with WBC and CRP but not associated with procalcitonin. Each standard deviation (≈7.4 ng/mL) increase in vitamin D was associated with a decrease in WBC by 0.13 × 109/mL (95% CI: 0.2 × 109/mL, 0.06 × 109/mL) and 0.62 mg/L (95% CI: 0.88 mg/L, 0.37 mg/L) for CRP. Subgroup analysis and sensitivity analysis (excluding those whose eGFR <60 ml/min/1.73 m2, those whose daily calorie intake <1,000 kcal, and those who were recruited from Xin Hua hospital) generated similar results. The deficiency and insufficiency of vitamin D in the hospitalized adult patients was very common. However, the results should be interpreted with caution for limited representation of the whole inpatients. Low level of vitamin D was associated with inflammatory biomarkers, which provide the evidences to early intervention for lower the risk of infection.

Prophylactic effects of Combretum molle boughs on changes in the hematological, biochemical, and histological parameters in dexamethasone-induced insulin-resistant rats

BackgroundCombretum molle (Combretaceae) is a plant used in Cameroon traditional medicine to treat diabetes mellitus. To our knowledge, no studies have been performed on the preventive effects of C. molle on change in hematological, biochemical, and histological parameters of insulin-resistant rats. The aim of the study was to evaluate the preventive effect of C. molle on changes in the hematological biochemical, and histological parameters of insulin-resistant rats. MethodsInsulin resistance was induced for 10 days by subcutaneous injection of dexamethasone (1 mg/kg), one hour after oral pretreatment of animals with distilled water, metformin (40 mg/kg), and C. molle extract (250 and 500 mg/kg). Hematological profile (red blood cells, white blood cells, platelets and their indices), biomarkers of renal and hepatic function, hepatic glycogen level, activity of hepatic enzymes of carbohydrate metabolism, and histological sections of kidney, liver and pancreas were assessed. ResultsC. molle extract (250 and 500 mg/kg) caused a significant decrease (p < 0.05 to p < 0.001) in white blood cells, platelets count, and the activities of fructose 6-diphosphatase, glucose-6-phosphate dehydrogenase, and transaminases. It also caused significant increase (p < 0.05 to p < 0.001) in red blood cells, hemoglobin, albumin, glycogen, urea, uric acid, and creatinine values, and fructose-1,6-diphospatase and glucokinase activity. Histological examination revealed regeneration of beta-cells of the pancreatic islets and preventive renal and hepatic tissues against damages caused by impact of dexamethasone. ConclusionC. molle extract protected insulin-resistant patients from hematological, biochemical, and histopathological changes, there by validating the merits of the use of this plant in traditional medicine to treat diabetes mellitus and its complications.

Safety and efficacy of non-reduced use of caspofungin in patients with Child–Pugh B or C cirrhosis: a real-world study

Background and purposeThe need for dose adjustment of caspofungin in patients with hepatic impairment is controversial, especially for those with Child–Pugh B or C cirrhosis. The purpose of this study was to investigate the safety and efficacy of standard-dose caspofungin administration in Child–Pugh B and C cirrhotic patients in a real-world clinical setting.Patients and methodsThe electronic medical records of 258 cirrhotic patients, including 67 Child–Pugh B patients and 191 Child–Pugh C patients, who were treated with standard-dose of caspofungin at the Second Affiliated Hospital of Chongqing Medical University, China, from March 2018 to June 2023 were reviewed retrospectively. The white blood cells (WBC), hepatic, renal and coagulation function results before administration and post administration on days 7, 14 and 21 were collected, and the efficacy was assessed in all patients at the end of caspofungin therapy.ResultsFavorable responses were achieved in 137 (53.1%) patients while 34 (13.2%) patients died. We observed that some patients experienced an increase of prothrombin time (PT) or international normalized ratio (INR), or a decrease of WBC, but no exacerbation of hepatic or renal dysfunction were identified and no patient required dose interruption or adjustment because of an adverse drug reaction during treatment with caspofungin.ConclusionsStandard-dose of caspofungin can be safely and effectively used in patients with Child–Pugh B or C cirrhosis, and we appealed to re-assess the most suitable dosing regimen in this population to avoid a potential subtherapeutic exposure.

Efficacy and safety of fruquintinib with nab-paclitaxel in advanced G/GEJ cancer after exposure to immune checkpoint inhibitors: A single-center prospective clinical trial.

327 Background: Immune checkpoint inhibitors (ICIs) expanded choices of early-line therapies in advanced gastric (G)/gastro-esophageal junction (GEJ) cancer. In addition, it’s observed that early-line ICI therapy, compared to chemotherapy, could enhance the efficacy of VEGFR inhibitors with chemotherapy in late lines. This single-center prospective clinical trial was aimed to explore the efficacy and safety of fruquintinib with nab-paclitaxel as second-line in patients (pts) with G/GEJ cancer exposed to ICIs in early lines. Methods: This is a single-center, prospective, open-label clinical trial. Pts with advanced G/GEJ cancer who had been exposed to ICIs before the second line were eligible. 42 pts would receive 100g/m2 nab-paclitaxel on day 1 and day 8 every 3 weeks, and 4mg fruquintinib from day 1 to day 14 every 3 weeks. Progression-free survival (PFS) was set as the primary endpoint. The Kaplan–Meier method would be used to evaluate time-to-event outcomes. Results: Up to Aug 10, 2023, 25 pts had been enrolled, 23 of whom were evaluable. 14 (60.9%) pts in evaluable set were male. All these pts was with stage Ⅳ of TNM staging. The median age was 58 (range: 33-74), and 6 (26.1%) pts were elder than 65 yr. 12 (63.2%) pts were with PD-L1 CPS greater than 1, 9 (47.4%) pts greater than 5, and 4 (17.4%) pts greater than 10. PD-L1 CPS of 4 pts was unknown. The pts had received a median of 5 (range: 1-20) cycles in early-line ICI therapy. 17 (73.9%) pts suffered metastasis in retroperitoneal lymph node and 7 (30.4%) pts in liver. With a median follow up time of 5.6 (range: 2.1-16.6) mo, the PFS achieved 4.8 (95% CI: 4.6-NA) mo. Despite the immatureness of overall survival (OS), the 1-year OS rate was 56.25% (95% CI: 17.27%-95.23%). The ORR was 47.8% (n=11), and DCR was 100% (n=23). As to safety, the most common (≥20%) AEs of all grades were white blood cell decrease, peripheral sensory neuropathy, and neutrophil count decrease, while that of grade≥3 was white blood cell decrease. Conclusions: Fruquintinib with nab-paclitaxel as second-line therapy demonstrated good efficacy and safety in advanced G/GEJ cancer after exposure to ICIs. ICIs might increase benefit from this therapy, which warrants further investigations in a large cohort. Clinical trial information: ChiCTR2200059976 .

Evaluation of the Immunosafety of Cucurbit[n]uril In Vivo.

Cucurbiturils are a family of macrocyclic oligomers capable of forming host-guest complexes with various molecules. Due to noncovalent binding to drug molecules and low toxicity, cucurbiturils has been extensively investigated as potential carriers for drug delivery. However, the immune system's interactions with different drug carriers, including cucurbiturils, are still under investigation. In this study, we focused on cucurbiturils' immunosafety and immunomodulation properties in vivo. We measured blood counts and lymphocyte subpopulations in blood, spleen, and bone marrow, and assessed the in vivo toxicity to spleen and bone marrow cells after intraperitoneal administration to BALB/c mice. When assessing the effect of cucurbit[6]uril on blood parameters after three intraperitoneal injections within a week in laboratory animals, a decrease in white blood cells was found in mice after injections of cucurbit[6]util, but the observed decrease in the number of white blood cells was within the normal range. At the same time, cucurbit[7]uril and cucurbit[8]uril did not affect the leukocyte counts of mice after three injections. Changes in the number of platelets, erythrocytes, and monocytes, as well as in several other indicators, such as hematocrit or erythrocyte volumetric dispersion, were not detected. We show that cucurbiturils do not have immunotoxicity in vivo, with the exception of a cytotoxic effect on spleen cells after сucurbit[7]uril administration at a high dosage. We also evaluated the effect of cucurbiturils on cellular and humoral immune responses. We founded that cucurbiturils in high concentrations affect the immune system in vivo, and the action of various cucurbiturils differs in different homologues, which is apparently associated with different interactions in the internal environment of the body.

Disseminated Talaromyces marneffei infection associated with haemophagocytic syndrome in an HIV-negative patient in northern China: a case report

BackgroundTalaromyces marneffei is endemic to eastern India, Southeast Asia, and Guangdong and Guangxi provinces in China. It is common in immunocompromised individuals, especially in HIV-infected patients.Case presentationA 66-year-old male who had a history of hypertension and resided in Shandong Province (Northern China) was admitted for recurrent fever for one month. The patient had recurrent fever, multiple lymphadenopathies, hepatosplenomegaly, a back rash, and a progressive decrease in white blood cells and platelets. Talaromyces marneffei was isolated from peripheral blood and bone marrow after admission, and suspected fungal cells were found via lymph node pathology. The patient’s infection secondary to haemophagocytic syndrome continued to worsen despite antifungal, anti-inflammatory, and symptomatic treatment, leading to death due to multiple-organ failure.ConclusionAlthough rare, infection due to Talaromyces marneffei in HIV-negative patients has been increasing in recent years, and we should be vigilant about “new” infections in nonendemic areas.

Immunological studies on the effects of toltrazuril and neem extract in broiler chickens suffering from coccidiosis.

The prevalence of avian coccidiosis in the poultry industry has grown, resulting in substantial financial losses from high mortality, stunted growth, reduced productivity, and expensive medical expenses. The purpose of the current study was to assess the immunological effects of neem leaf extract and toltrazuril on broilers that had contracted coccidiosis. In this investigation, 100 one-day-old Cobb broiler chicks without sexes were employed. The chicks were divided into five equal groups, with 20 birds in each. On the 14th day of life, the birds in groups 2, 3, 4, and 5 received an oral inoculation with 1 × 105 sporulated oocysts of Eimeria tenella (E. tenella) (field isolate). The first group (Gp), which consists of 20 healthy broilers, served as a negative control. Gp (2) contains experimentally infected broilers and nontreated (served as a positive control). Gp (3) contains experimentally infected broilers treated with toltrazuril (1 ml/l drinking water) for two consecutive days. Gp (4) contains experimentally infected broilers treated with neem leaf extract 4% (50 ml/l drinking water) for 5 successive days, and Gp (5) contains experimentally infected broilers treated with toltrazuril (1 ml/l drinking water) and a half dose of neem leaves extract 4% (25 ml/l drinking water) for 5 successive days. For the purpose of estimating body weight growth and feed conversion ratio, each broiler was weighed separately at the start of the trial and again on the 1st and 10th day after treatment. In addition to obtaining intestinal samples for immunohistochemistry, blood samples were also obtained for immunological examination. As compared to the negative control group, the experimentally infested broilers with E. tenella showed significant decreases in serum nitric oxide, lysosome, phagocytic percent, and phagocytic index, along with significant increases in white blood cells (WBCs), lymphocyte, heterophilis, eosinophilis, basophilis, monocyte, serum total protein, γ globulin, fibrinogen, and haptoglobin. When compared to the control positive group, experimentally infested broilers treated with either neem or toltrazuril alone or in combination demonstrated significant increases in serum total protein, nitric oxide, lysozyme, phagocytic percent, and phagocytic index, but significant decreases in WBCs, lymphocytes, heterophile, eosinophile, basophile, and monocyte. The intestinal peroxidase stain of broilers infected with E. tenella exhibited a significant positive expression for CD4, but the infected broilers treated with toltrazuril and half a dosage of neem displayed a negative expression for CD4, identical to the negative control. The broiler chickens infested with E. tenella may have a variety of negative impacts on their immune systems and immunohistopathological findings. Nonetheless, toltrazuril and neem extract, either separately or in combination, function as anticoccidial medications that may enhance the broiler chicks' immune state.

Update Results of a Phase II Trial of Venetoclax in Combination with Azacitidine and Chidamide in Relapsed/Refractory Acute Myeloid Leukemia

Background: Therapies for relapsed or refractory (R/R) AML remain limited, with low response rates and short duration of response, especially in patients ineligible for intensive cytotoxic chemotherapy. Combinations of venetoclax (VEN), chidamide (CHI) plus azacytidine (AZA) have shown to be synergistic with low intensity and intensive chemotherapy in preclinical data and in relapsed or refractory (R/R) setting (Phase II, 2022 ASH). Here we present updated results of this Phase II trial. Methods: Eligible patients were &amp;gt;18 yrs old with R/R AML, defined as lack of response rate after at least one cycle of induction or relapsed disease with any prior number of treatments. Patients received AZA 100mg on D1-7, VEN 200mg on D1-14, and CHI 30mg biweekly in 28-day cycles. The primary objective was evaluation of CR/CRi. Secondary objectives included event-free survival (EFS), overall survival (OS) and adverse events (AEs). Clinical responses were determined using the 2017 ELN criteria. Results: Between January 2022 and April 2023, 53 patients with R/R AML were enrolled in the study. The median age was 51 years (range 18-73). This regimen was salvage 1 in 79% (42) of patients, salvage 2 in 11% (6) and salvage 3 in 9% (5). 17%, 36%, and 47% of patients were classified as favorable, intermediate, and adverse ELN risk, respectively ( Table 1). 11% of patients had TP53 mutation, 22% had DNMT3A mutation, 21% had FLT3-ITD mutation, 9% had ASXL1 mutation, 19% had NPM1 mutation, 9% had IDH1 mutation, 11% had IDH2 mutation ( Fig. A). Among the 53 patients, the ORR of these patients was 68% with CRc rate of 53% after one cycle, and 81% with CRc rate of 72% after two cycles ( Fig. B). By ELN risk, ORR and CRc rates were 70% and 50% for favorable risk, 40% and 40% for intermediate risk, and 43% and 30% for adverse risk. Pretreatment IDH1 and IDH2 mutations were associated with higher CRc rates (75% and 50%, respectively). The CRc rate in patients with TP53 mutations was 67%, with response noted among patients with concurrent IDH1/ IDH2 mutations. With a median follow-up of 6.7 months, the median EFS and OS were 6 (95%CI 3.3-8.6) months and not reached (NR), respectively. Among patients with CRc, the 6-month EFS and OS were 64% and 88%, respectively, among those receiving this regimen as first salvage had encouraging outcomes (median EFS, NR) ( Fig. C-D). Of the 8 patients that proceeding with allogeneic hematopoietic stem cell transplant (allo-HSCT), the median EFS and OS were not reached after transplant ( Fig. E-F) No non-hematologic AEs of grade ≥3 were observed. The most common grade 1-2 non-hematologic AEs included nausea (28%), fatigue (28%), hypokalemia (17%), hypoproteinemia (17%), elevated transaminase levels (33%) and hyperbilirubinemia (11%). The occurrence rates of grade 3/4 hematologic adverse events (AEs) were as follows: white blood cell decrease (87%), median time to white blood cell recovery 23 (range 4-29) days; neutropenia (96%), neutropenia with fever (17%), median time to neutrophil recovery 25 (range 10-29) days; platelet decrease (68%), median time to platelet recovery 28.5 (range 7-44) days; anemia (64%), median time to hemoglobin recovery 29 (range 13-56) days. 30-day and 60-day mortality were 0% and 5.7%, respectively. 3 deaths occurred within 60 days in patients with persistent leukemia. Conclusions: Thecombination of VEN and CHI plus AZA (VCA) demonstrated manageable safety and encouraging efficacy in patients with R/R AML. IDH1/ IDH2 mutations were associated with the sensitivity of VCA, even in some patients with concurrent TP53 mutations.

Neutrophil Gelatinase-Associated Lipocalin in Peritoneal Dialysis-Related Peritonitis: Correlation with White Blood Cells over Time and a Possible Role as the Outcome Predictor

Introduction: The present study aimed to monitor peritoneal neutrophil gelatinase-associated lipocalin (pNGAL) during peritonitis episodes and to enhance its diagnostic value by evaluating pNGAL at scheduled times in parallel with white blood cell (WBC) count. In addition, we investigated possible correlations between pNGAL and the etiology of peritonitis, evaluating it as a possible marker of the clinical outcome. Methods: Twenty-two patients with peritoneal dialysis (PD)-related peritonitis were enrolled. Peritonitis was divided into Gram-positive, Gram-negative, polymicrobial, and sterile. WBC count and neutrophil gelatinase-associated lipocalin (NGAL) in PD effluent were measured at different times (days 0, 1, 5, 10, 15, and/or 20 and 10 days after antibiotic therapy discontinuation). NGAL was measured by standard quantitative laboratory-based immunoassay and by colorimetric NGAL dipstick (NGALds) (dipstick test). Results: We found strong correlations between peritoneal WBC, laboratory-based NGAL, and NGALds values, both overall and separated at each time point. On day 1, we observed no significant difference in WBC, both NGALds (p = 0.3, 0.9, and 0.2) between Gram-positive, Gram-negative, polymicrobial, and sterile peritonitis. No significant difference has been found between de novo versus relapsing peritonitis for all markers (p > 0.05). We observed a parallel decrease of WBC and both NGAL in patients with favorable outcomes. WBC count and both pNGAL resulted higher in patients with negative outcomes (defined as relapsing peritonitis, peritonitis-associated catheter removal, peritonitis-associated hemodialysis transfer, peritonitis-associated death) at day 10 (p = 0.04, p = 0.03, and p = 0.05, respectively) and day 15 (p = 0.01, p = 0.04, and tendency for p = 0.005). There was a tendency toward higher levels of WBC and NGAL in patients with a negative outcome at day 5. No significant difference in all parameters was proven at day 1 (p = 0.3, p = 0.9, p = 0.2) between groups. Conclusion: This study confirms pNGAL as a valid and reliable biomarker for the diagnosis of PD-peritonitis and its monitoring. Its trend is parallel to WBC count during peritonitis episodes, in particular, patients with unfavorable outcomes.

RADT-27. BONE MARROW SUPPRESSION AFTER REIRRADIATION THERAPY WITH PROTON VERSUS PHOTON THERAPY FOR RECURRENT GLIOMA

Abstract INTRODUCTION High grade radiation-induced lymphopenia has been implicated to worse prognostic outcomes and overall survival in numerous malignancies. Understanding factors which influence lymphopenia can help optimize radiation delivery and overall patient care. Proton therapy (PRT), due to its distinct dose fall-off, spares tissues and organ-contained blood pools from excess radiation compared to conventional photon radiation (XRT) and may thereby reduce hematologic toxicity. METHODS Patients with confirmed glioma diagnosis who underwent reirradiation with either PRT or XRT were retrospectively analyzed. Complete blood counts (CBCs) within one month of reirradiation start, and CBCs within one month of reirradiation completion were reviewed. Values of interest included total white blood cell (WBC), absolute neutrophil count (ANC), and absolute lymphocyte count (ALC). Dosimetric data was collected to assess whole brain mean dose (WBMD), and volume of brain tissue receiving 5-50 Gy (V5-V50). RESULTS 16 patients receiving either PRT (n = 8) or XRT (n = 8) were included. Treatment doses ranged from 35-59.4 Gy. Across all patients there was a decrease in WBC, ANC, and ALC after reirradiation in both PRT and XRT (p &amp;lt; 0.05). Compared to reirradiation with XRT, patients who underwent PRT had significantly lesser reductions in WBC (PRT: 8.60% decrease, XRT: 22.58% decrease; p &amp;lt; 0.05). PRT reirradiation also resulted in lesser ANC and ALC reductions, though did not reach statistical significance. On dosimetric comparison of XRT and PRT plans, PRT demonstrated significant reductions in V5, V10, V20, and V30 (p &amp;lt; 0.05). V5 through V40 and WBMD were significantly correlated with decreased WBC, ANC, and ALC (p &amp;lt; 0.01). CONCLUSION Preliminary results show PRT reirradiation leads to decreased WBMD and volumes of brain tissues receiving 5 to 30 Gy. Given that these parameters are associated with greater reductions in lymphocytic counts, PRT reirradiation may confer reduced hematologic toxicity in patients seeking adjuvant radiation therapy.

CTIM-22. PHASE I STUDY RESULTS OF THE ANTIBODY-CYTOKINE FUSION PROTEIN L19TNF IN COMBINATION WITH LOMUSTINE FOR PATIENTS WITH RECURRENT GLIOBLASTOMA REVEAL PROMISING SAFETY AND DURABLE TUMOR RESPONSES

Abstract Treatment options for recurrent glioblastoma are limited and there is a need for novel effective therapies. Recently, we showed synergistic preclinical anti-tumor activity of the immunocytokine L19TNF in combination with lomustine in orthotopic immunocompetent glioma mouse models. L19TNF is an antibody-cytokine fusion protein, comprising the pro-inflammatory cytokine tumor necrosis factor (TNF) fused to the antibody L19 that binds to a tumor-specific epitope of the extracellular matrix protein fibronectin. This allows a targeted delivery of therapeutically relevant doses of TNF to the tumor site through intravenous administration while sparing healthy tissues. Here, we present results of the completed phase I part of a phase I/II open label, multicenter, randomized study to investigate L19TNF in combination with lomustine for patients with recurrent glioblastoma (NCT04573192). Fifteen patients were enrolled from February 2021 – January 2023 and treated at three different dose levels of L19TNF in combination with lomustine. Overall, the treatment was well tolerated. The most common adverse events were asymptomatic increase of liver function tests and a decrease of white blood cells and platelets. Serial MRI assessments revealed near-complete responses in 3 patients (20%) and stable disease in 8 (53%) patients. The median progression-free survival was 4.2 months, progression-free survival rate at 6 months was 46% (7/15 patients), and median overall survival has not been reached after a median follow-up of 11 months. Serial blood assessments demonstrated a treatment-associated increase in C-reactive protein, a peripheral marker for inflammation, which correlated with progression-free survival. A patient, who showed a near-complete response that lasted 12 months relapsed at a different location. Subsequent re-challenge with L19TNF and lomustine again led to a partial response. These encouraging results justify further investigations within the phase II part of the clinical trial that is recruiting patients in four countries.

Efficacy of Khaya grandifoliola Stem Bark Ethanol Extract in the Treatment of Cerebral Malaria in Swiss albino Mice Using Plasmodium berghei NK65 Strain.

Cerebral malaria is one of the most severe and dangerous forms of malaria and is potentially fatal. This study was aimed at evaluating the anticerebral malaria efficacy of Khaya grandifoliola used by traditional healers. Fifty grams of Khaya grandifoliola stem bark was macerated in 1 L ethanol (95%) for 72 h. The filtrate was dried at 40°C until the obtention of a dry extract. The antimalarial test was evaluated using the Peter 4-day suppressive test and the Rane curative test. Mice were group into 6 groups of 6 mice each. For the antioxidant test, parameters such as malondialdehyde (MDA), superoxide dismutase (SOD), glutathione (GSH), catalase (CAT), and nitric oxide (NO) were assessed. The livers of mice were crushed and centrifuged in order to be measured. Aspartate aminotransferase (ASAT) and alanine aminotransferase (ALAT) using the Dutch Diagnostics Kit and blood were collected for haematological parameters. The ethanol extract showed a suppressive activity of 78.12%, 75.30%, and 68.69% at 500 mg/kg, 250 mg/kg, and 125 mg/kg, respectively. Similarly, the curative activity showed a statistically significant reduction in parasitemia (p < 0.05). Antioxidant parameter assays showed a low value of MDA and a high value of SOD, CAT, NO, and GSH in the negative control group. A statistically significant higher values of ASAT and ALAT were observed in the negative control compared to the other test groups (p < 0.05). Haematological parameters showed a statistically significant decrease in white blood cells, red blood cells, haemoglobin, and platelets in the negative control group (p < 0.05). The results of this study justify the traditional usage of Khaya grandifoliola in the treatment of cerebral malaria. However, in vivo toxicity assessment is still necessary to verify its safeness.