Reduction In Neutrophil Count Research Articles

Decreased neutrophils are associated with reduced risk of Type 2 Diabetes Incidence: Results from the CORDIOPREV study.

Numerous studies have reported an association between neutrophils and T2DM, although this relationship remains unclear. This study aims to investigate the interaction of neutrophils and a dietary intervention on T2DM incidence after 60 months of follow-up. A comprehensive analysis was conducted on the framework of the CORDIOPREV study, which included 462 patients without T2DM at the beginning of the study. They were randomly assigned to either a Mediterranean or a low-fat diet, of whom 107 developed T2DM. Absolute neutrophil counts and other related-ratio, were measured. Kaplan-Meier curves showed that the lowest tertile of basal neutrophils was associated with a reduced likelihood of T2DM incidence when compared to the middle [HR=0.499 (95%CI, 0.287-0.866)] and the highest tertiles [HR=0.442 (95%CI, 0.255-0.768)] in overall population, after adjusting for clinical variables. This association only remained significant in patients who follow a Mediterranean diet when compared the lowest to the middle [HR=0.423 (95% CI, 0.213-0.842)] and the highest tertiles [HR=0.371 (95% CI, 0.182-0.762)]. The predictive capacity yielded an AUC of 0.711 (95%CI: 0.652-0.769), being neutrophils the most important variable in the in the model. Decrease in neutrophils over the 60 months were associated with increased insulin sensitivity index (ISI) (R=-0.31; p=0.019), particularly in patients who followed the Mediterranean diet. These findings suggest that monitoring neutrophils can help prevent the development of T2DM, as a reduction in neutrophil counts could be associated with improved insulin sensitivity. Following a Mediterranean diet might be a potential strategy to reduce the incidence of T2DM by lowering neutrophil levels. Further research is necessary to gain a deeper understanding regarding this mechanism.

Delayed neutrophil recovery following BCMA CAR-T therapy in Duffy-null myeloma does not impact severe infections or survival

Duffy-null phenotype is prevalent in self-reported Black individuals and associated with reduced neutrophil counts. In our retrospective multivariable analysis, Duffy-null myeloma patients displayed delayed neutrophil recovery following BCMA-directed CAR-T compared to Duffy non-null patients without impacting severe infections or survival.

Comparison and Analysis of Clinical Characteristics of Common COVID-19 and NSIP Patients

Objective: To investigate the relationship between coronavirus disease 2019 (COVID-19) and non-specific interstitial pneumonia (NSIP), with a focus on the clinical features of COVID-19 and NSIP, and the key points of differential diagnosis. Methods: The clinical data of 20 patients with common-type COVID-19 and NSIP admitted to Linyi People’s Hospital from January 21, 2020, to June 21, 2022, were retrospectively analyzed. Gender, age, history of residence in Hubei province, underlying diseases, clinical manifestations, laboratory test results (including blood routine indexes, inflammatory markers, liver function indexes, and coagulation indexes), and computed tomography (CT) scan images were compared between the two groups. Results: COVID-19 patients were younger than NSIP patients (P < 0.05). Nine COVID-19 patients had a travel history to Hubei province, while none of the NSIP patients did (P < 0.05). Eight COVID-19 patients had underlying chronic conditions, fewer than the NSIP group (12 patients; P < 0.05). Both groups experienced symptoms such as shortness of breath, expectoration, fatigue, and runny nose, but fever and cough were more severe and more frequent in the COVID-19 group. Compared to normal reference ranges, both groups exhibited normal white blood cell counts (WBC) and liver function indexes, but elevated lymphocyte counts (LYMP), inflammatory markers, and coagulation indexes, with reduced neutrophil counts (NE). WBC and LYMP were higher in the COVID-19 group compared to the NSIP group. Male patients in the COVID-19 group had higher erythrocyte sedimentation rates and C-reactive protein values than those in the NSIP group, while procalcitonin levels were lower in the COVID-19 group, although the differences were not statistically significant (all P > 0.05). The NE count in the COVID-19 group was significantly lower than in the NSIP group (P < 0.05). Alanine aminotransferase, total bilirubin, and indirect bilirubin were significantly higher in the COVID-19 group compared to the NSIP group (P < 0.05). Chest CT scans of both groups showed bilateral patchy ground-glass opacities, but the lesions in COVID-19 patients were scattered. NSIP patients’ chest CTs showed diffuse lesions centered around the hilum or multiple lesions in both lungs, with pleural involvement being rare. Conclusion: While there are certain specific clinical, laboratory, and imaging findings in both COVID-19 and NSIP, the specificity of these features is not high. Differentiating the two requires careful consideration of epidemiological history, nucleic acid testing, and antigen-antibody levels.

A retrospective evaluation of therapeutic efficacy and safety of chemoradiotherapy in older patients (aged ≥ 75 years) with limited-disease small cell lung cancer: insights from two institutions and review of the literature.

The standard treatment for patients in good general condition with limited-disease small cell lung cancer (LD-SCLC) is concurrent platinum/etoposide chemotherapy and thoracic radiotherapy (TRT). However, the efficacy and safety of chemoradiotherapy (CRT) in older patients with LD-SCLC has not been fully explored; moreover, the optimal treatment for this patient group remains unclear. This study aimed to investigate the feasibility and efficacy of CRT in older patients with LD-SCLC. From April 2007 to June 2021, consecutive older patients (aged ≥ 75 years) with stage I to III SCLC who received concurrent or sequential CRT at two institutions were retrospectively evaluated for efficacy and toxicity of CRT. A total of 32 older patients underwent concurrent (n = 19) or sequential (n = 13) CRT for LD-SCLC. The median ages of the patients in the concurrent and sequential CRT groups were 77 (range: 75-81) years and 79 (range: 76-92) years, respectively. The median number of chemotherapeutic treatment cycles was four (range, 1-5), and the response rate was 96.9% in all patients (94.7% in concurrent and 100% in sequential CRT groups). The median progression-free survival (PFS) and median overall survival (OS) for all patients were 11.9 and 21.1 months, respectively. The median PFS was 13.0 and 9.0 months in the concurrent CRT and sequential CRT groups, respectively, with no statistically significant difference (p = 0.67). The median OS from the initiation of CRT was 19.2 and 23.5 months in the concurrent and sequential CRT groups, respectively (p = 0.46). The frequencies of Grade ≥ 3 hematological adverse events were as follows: decreased white blood cell count, 20/32 (62.5%); decreased neutrophil count, 23/32 (71.9%); anemia, 6/32 (18.8%); decreased platelet count, 7/32 (21.9%); and febrile neutropenia, 3/32 (9.4%). Treatment-related deaths occurred in one patient from each group. Although hematological toxicities, particularly reduced neutrophil count, were severe, CRT showed favorable efficacy in both concurrent and sequential CRT groups. However, concurrent CRT may not be feasible for all older patients with LD-SCLC; accordingly, sequential CRT may be considered as a treatment of choice for these patients. Further prospective trials are warranted to identify optimal treatment strategies for this patient group.

Released bacterial ATP shapes local and systemic inflammation during abdominal sepsis

Sepsis causes millions of deaths per year worldwide and is a current global health priority declared by the WHO. Sepsis-related deaths are a result of dysregulated inflammatory immune responses indicating the need to develop strategies to target inflammation. An important mediator of inflammation is extracellular adenosine triphosphate (ATP) that is released by inflamed host cells and tissues, and also by bacteria in a strain-specific and growth-dependent manner. Here, we investigated the mechanisms by which bacteria release ATP. Using genetic mutant strains of Escherichia coli (E. coli), we demonstrate that ATP release is dependent on ATP synthase within the inner bacterial membrane. In addition, impaired integrity of the outer bacterial membrane notably contributes to ATP release and is associated with bacterial death. In a mouse model of abdominal sepsis, local effects of bacterial ATP were analyzed using a transformed E. coli bearing an arabinose-inducible periplasmic apyrase hydrolyzing ATP to be released. Abrogating bacterial ATP release shows that bacterial ATP suppresses local immune responses, resulting in reduced neutrophil counts and impaired survival. In addition, bacterial ATP has systemic effects via its transport in outer membrane vesicles (OMV). ATP-loaded OMV are quickly distributed throughout the body and upregulated expression of genes activating degranulation in neutrophils, potentially contributing to the exacerbation of sepsis severity. This study reveals mechanisms of bacterial ATP release and its local and systemic roles in sepsis pathogenesis.

Released bacterial ATP shapes local and systemic inflammation during abdominal sepsis.

Sepsis causes millions of deaths per year worldwide and is a current global health priority declared by the WHO. Sepsis-related deaths are a result of dysregulated inflammatory immune responses indicating the need to develop strategies to target inflammation. An important mediator of inflammation is extracellular adenosine triphosphate (ATP) that is released by inflamed host cells and tissues, and also by bacteria in a strain-specific and growth-dependent manner. Here, we investigated the mechanisms by which bacteria release ATP. Using genetic mutant strains of Escherichia coli (E. coli), we demonstrate that ATP release is dependent on ATP synthase within the inner bacterial membrane. In addition, impaired integrity of the outer bacterial membrane notably contributes to ATP release and is associated with bacterial death. In a mouse model of abdominal sepsis, local effects of bacterial ATP were analyzed using a transformed E. coli bearing an arabinose-inducible periplasmic apyrase hydrolyzing ATP to be released. Abrogating bacterial ATP release shows that bacterial ATP suppresses local immune responses, resulting in reduced neutrophil counts and impaired survival. In addition, bacterial ATP has systemic effects via its transport in outer membrane vesicles (OMV). ATP-loaded OMV are quickly distributed throughout the body and upregulated expression of genes activating degranulation in neutrophils, potentially contributing to the exacerbation of sepsis severity. This study reveals mechanisms of bacterial ATP release and its local and systemic roles in sepsis pathogenesis.

Population pharmacokinetic and exposure-toxicity analyses of nab-paclitaxel after pegylated recombinant human granulocyte colony-stimulating factor administration in patients with metastatic breast cancer.

This study aimed to establish a population pharmacokinetic (PK) model to evaluate the dynamic relationship between the concentrations of total and unbound paclitaxel, and the exposure-response analysis of albumin-bound paclitaxel (nab-paclitaxel) after pegylated recombinant human granulocyte colony-stimulating factor (PEG-G-CSF) administration in patients with metastatic breast cancer. A total of 653 concentrations corresponding to total paclitaxel and 334 concentrations corresponding to unbound paclitaxel were analyzed in 24 subjects who randomized received a single 260 mg/m2 dose of two nab-paclitaxel formulations with a 21-35-day washout period. PEG-G-CSF was administered to all the patients in each cycle to prevent neutropenia. The exposure-response relationships were evaluated using the exposure to total, albumin-coated, and unbound paclitaxel, as well as the reduction in neutrophil count. The exposure data were analyzed using nonlinear mixed-effect modeling. A linear regression model was used to test the statistical significance of the correlation between percentage of reduction in neutrophil count and exposure. The PK characteristics of total paclitaxel were described using a three-compartment model with first-order elimination, and a mechanism-based model incorporating linear release of nab-paclitaxel and the saturated binding of unbound paclitaxel to plasma components was established. The release ratio of paclitaxel from nab-paclitaxel was estimated to be 4.60% and the maximum unbound fraction (2.76%) was reached at the end of the infusion. The study found that a longer duration of total paclitaxel concentration > 0.19 µmol/L was significantly correlated with a reduction in neutrophil count (r2 = 0.23, P = 0.00062). Specifically, a duration of > 8.6h was a predictor of a decreased neutrophil count. The decrease in neutrophils induced by nab-paclitaxel was significantly correlated with the duration above a total paclitaxel concentration of 0.19 µmol/L despite the use of PEG-G-CSF.

Assessment of Multifunctional Activity of a Postbiotic Preparation Derived from Lacticaseibacillus paracasei Postbiotic-P6.

Postbiotics possess various functional activities, closely linked to their source bacterial strains and preparation methods. Therefore, the functional activities of postbiotics need to be evaluated through in vitro and in vivo methods. This study aims to prepare a postbiotic and explore its antihemolytic, anti-inflammatory, antioxidant, and antibacterial activities. Specifically, a postbiotic preparation named PostbioP-6 was prepared by intercepting 1-5 kDa of Lacticaseibacillus paracasei Postbiotic-P6 fermentation broth. The results demonstrate that PostbioP-6 exhibited notable biological activities across multiple assays. It showed significant antihemolytic activity, with a 4.9-48.1% inhibition rate at 10-50% concentrations. Anti-inflammatory effects were observed both in vitro, where 8-40% PostbioP-6 was comparable to 259.1-645.4 μg/mL diclofenac sodium, and in vivo, where 3.5 and 4.0 μL/mL PostbioP-6 significantly reduced neutrophil counts in inflamed zebrafish (p < 0.05). Antioxidant properties were evident through increased reducing power (OD700 increased from 0.279 to 2.322 at 1.25-12.5% concentrations), DPPH radical scavenging activity (38.9-92.4% scavenging rate at 2.5-50% concentrations), and hydroxyl radical scavenging activity (4.66-10.38% scavenging rate at 0.5-4% concentrations). Additionally, PostbioP-6 demonstrated antimicrobial activity against two Gram-positive bacteria, eight Gram-negative bacteria, and one fungus. Furthermore, PostbioP-6 significantly inhibited the increase in peroxide value and malondialdehyde content in cookies, highlighting its potential application in food preservation. In conclusion, we prepared a novel postbiotic, termed PostbioP-6, which proved to have prominent anti-hemolytic, anti-inflammatory, antioxidant, and broad-spectrum antimicrobial activities. The multifunctional properties of PostbioP-6 position it as a potentially effective functional food supplement or preservative. In the future, further research is necessary to elucidate the precise mechanisms of action, identify the active components, and validate its biological activities in animal models or clinical trials.

Cefuroxime induced agranulocytosis during heart transplant period: A case report

Rationale: Cefuroxime is a commonly prescribed antibiotic known for its overall safety profile. However, in rare instances, it can lead to a life-threatening condition known as idiosyncratic drug-induced agranulocytosis (IDIA). While there have been few documented cases linking cefuroxime to this severe adverse reaction, a recent study sheds light on a critical case involving a patient awaiting a heart transplant. Patient concern: In this study, the patient developed agranulocytosis after 16 days and 72 grams of cefuroxime treatment. Agranulocytosis is characterized by a drastic reduction in neutrophil count, in this case dropping to 0/mm3. Diagnosis: IDIA is characterized by a drastic reduction in neutrophil count, in this case dropping to 0/mm3. Intervention: This IDIA coincided with the availability of a donor heart, prompting the medical team to proceed with an immediate heart transplant despite the patient’s compromised immune status. Ceasing cefuroxime administration and initiating treatment with G-CSF for 3 days played a pivotal role in normalizing neutrophil levels. A meticulously planned immunosuppressant regimen was also initiated. Outcomes: Precise management of immunosuppressants contributed to the patient’s successful recovery, leading to discharge. Lessons: The rationale for studying cases like these lies in the need for heightened awareness among healthcare providers. By documenting and analyzing such cases, medical professionals can better understand the risk factors, clinical presentation, and optimal management strategies for this uncommon yet serious adverse reaction. Furthermore, the study underscores the significance of individualized patient care, especially in complex scenarios such as organ transplantation. Precise adjustments to immunosuppressant therapy are crucial to balance the risks of rejection and infection, particularly in patients with compromised immune systems due to drug-induced agranulocytosis. In conclusion, this case serves as a reminder of the unpredictable nature of drug reactions and the importance of vigilant monitoring and rapid intervention in managing potentially life-threatening complications.

Safety and efficacy of selpercatinib in pediatric patients with RET-altered solid tumors: Updated results from LIBRETTO-121.

10022 Background: Selpercatinib is a highly selective and potent CNS-penetrant oral RET inhibitor, approved for treatment of RET-driven thyroid cancer in adult and adolescent patients (pts), and lung or other solid tumors in adult pts. Here we present updated results from LIBRETTO-121, the first trial to assess the safety and efficacy of a selective RET inhibitor in pediatric and adolescent pts with RET-altered solid tumors. Methods: LIBRETTO-121 (NCT03899792) is a multicenter phase 1/2 trial in pts 0.5-21 yrs of age with advanced, RET-altered solid tumors. Enrollment began in June 2019 and is ongoing. To confirm the recommended phase 2 dose for selpercatinib, dosing started at 92 mg/m2 BID, expecting to result in equivalent exposure to 160 mg BID in adults.The primary objectives were to evaluate safety and dose limiting toxicities (DLTs) in phase 1 and determine the ORR per RECIST 1.1 by independent review in the phase 2 population. Results: At the data cut-off (January 13, 2023), 27 pts aged 2-20 yrs were treated with selpercatinib. Tumor types included RET-mutant medullary thyroid cancer (MTC, n = 14), RET fusion-positive papillary thyroid cancer (PTC, n = 10), or other (n = 3). The most common RET alterations were a M918T mutation (71.4% [10/14] of MTC pts) or NCOA4-RET fusion (50% [5/10] of PTC pts). Pediatric and adolescent patients treated at 92 mg/m2 (up to 160 mg BID) had a similar exposure as adults treated with 160 mg BID at steady state on cycle 1 day 8. Time on selpercatinib ranged from 0.4 to 40.8 mo and 22 pts remain on treatment. There were no treatment discontinuations due to DLTs or TEAEs; 2 pts (7.4%) experienced a dose reduction due to TEAEs (elevated ALT and reduced neutrophil count). The most common TEAEs observed (≥25% of pts) were diarrhea, headache, coronavirus infection, nausea, vomiting, elevated ALT, elevated AST and pyrexia. The most common TEAEs ≥ G3 included constipation, reduced neutrophil count, vomiting and weight gain, each occurring in 2 pts (7.4%). One pt (age 15 yrs) experienced a TEAE ≥ G3 of epiphysiolysis, a risk for selpercatinib in this population based on pre-clinical data. In pts with RECIST measurable disease at baseline, the ORR was 83.3% (10/12), while 1 pt had stable disease (SD) and 1 pt had progressive disease (PD). Among pts with measurable disease at baseline, PTC pts had an ORR of 100% (5/5), and MTC pts had an ORR of 83.3% (5/6), while 1 MTC pt had SD. No PTC or MTC pts had PD. Responses were durable, with a 24 mo DOR rate of 100% (95% CI: NE, NE). With a median follow up of 18 mo, the mPFS among all pts has not yet been reached, and the 24 mo rate of PFS was 92.4% (95% CI: 73.0% - 98.1%). Conclusions: Selpercatinib’s safety profile remains consistent with prior reports from adult trials. These results, including more robust efficacy and PK data, continue to support the use of selpercatinib in pediatric and adolescent pts with RET-altered solid tumors. Clinical trial information: NCT03899792 .

Clopidogrel induced reduction in neutrophil count: An overlooked beneficial effect?

Complement-stimulated neutrophils are able to adhere to the endothelium and damage endothelial cells both in vitro and in vivo. These blood cells participate in the early stages, growth and complications of atherosclerotic plaques. Recent findings, based on mendelian randomization analysis, support the concept that high neutrophil counts are a causal risk factor for ischemic heart disease and myocardial infarction . Clopidogrel decreases leukocyte count and inflammatory markers in patients with acute coronary syndromes; this off-target effect, which is independent of the antiplatelet action, may help explaining secondary prevention data showing a superiority of clopidogrel over aspirin in reducing new cardiovascular events.

Intranasal delivery of PEA-producing Lactobacillus paracasei F19 alleviates SARS-CoV-2 spike protein-induced lung injury in mice

BackgroundSARS-CoV-2 belongs to the coronaviridae family and infects human cells by directly interacting with the angiotensin-converting enzyme-2 (ACE-2) through the viral Spike Protein (SP). While vaccines are crucial, much attention has been directed towards managing the symptoms of acute respiratory distress syndrome. Our present study highlights the potential in counteracting lung inflammation triggered by SARS-CoV-2 SP of the intranasal administration of the engineered probiotic Lactobacillus paracasei F19 expressing the enzyme NAPE-PLD (pNAPE-LP) able to in situ release palmitoylethanolamide (PEA) under a super-low boost of palmitate.MethodsC57BL/6J mice undergo prophylactic treatment with intranasal pNAPE-LP/palmitate for 7 days before a 7 days challenge with intranasal SARS-CoV-2 SP. Then the capability of pNAPE-LP of colonizing the lungs and actively release PEA in situ have been determined by immunofluorescence, western blot and HPLC-MS. Moreover, the innate immune system downregulation and the histological damage rescue exerted by pNAPE-LP have been tested by immunofluorescence, hematoxylin and eosin staining, western blot analysis and ELISA test for the release of the pro-inflammatory mediators.ResultspNAPE-LP effectively colonizes mice lungs and releases the anti-inflammatory compound PEA. Moreover, pNAPE-LP exhibits a protective effect on alveolar morphology, innate immune cells infiltration and in the reduction of neutrophil count, effectively reducing lung injury induced by SARS-CoV-2 SP. This is achieved by mitigating TLR4-mediated NLRP3 activation and the downstream pro-inflammatory products such as ILs, TNFα, C-reactive protein and the myeloperoxidase activity. Interestingly we observed a global reduction ACE2 expression in the lungs.ConclusionpNAPE-LP actively protect from severe inflammatory-related symptoms in SP-challenged mice. Also, it can downregulate the expression of ACE-2 receptors at the lung site potentially preventing the spreading of the infection.

A genome-wide association study of neutrophil count in individuals associated to an African continental ancestry group facilitates studies of malaria pathogenesis

Background'Benign ethnic neutropenia' (BEN) is a heritable condition characterized by lower neutrophil counts, predominantly observed in individuals of African ancestry, and the genetic basis of BEN remains a subject of extensive research. In this study, we aimed to dissect the genetic architecture underlying neutrophil count variation through a linear-mixed model genome-wide association study (GWAS) in a population of African ancestry (N = 5976). Malaria caused by P. falciparum imposes a tremendous public health burden on people living in sub-Saharan Africa. Individuals living in malaria endemic regions often have a reduced circulating neutrophil count due to BEN, raising the possibility that reduced neutrophil counts modulate severity of malaria in susceptible populations. As a follow-up, we tested this hypothesis by conducting a Mendelian randomization (MR) analysis of neutrophil counts on severe malaria (MalariaGEN, N = 17,056).ResultsWe carried out a GWAS of neutrophil count in individuals associated to an African continental ancestry group within UK Biobank, identifying 73 loci (r2 = 0.1) and 10 index SNPs (GCTA-COJO loci) associated with neutrophil count, including previously unknown rare loci regulating neutrophil count in a non-European population. BOLT-LMM was reliable when conducted in a non-European population, and additional covariates added to the model did not largely alter the results of the top loci or index SNPs. The two-sample bi-directional MR analysis between neutrophil count and severe malaria showed the greatest evidence for an effect between neutrophil count and severe anaemia, although the confidence intervals crossed the null.ConclusionOur GWAS of neutrophil count revealed unique loci present in individuals of African ancestry. We note that a small sample-size reduced our power to identify variants with low allele frequencies and/or low effect sizes in our GWAS. Our work highlights the need for conducting large-scale biobank studies in Africa and for further exploring the link between neutrophils and severe malaria.

Assessment of patients’ characteristics associated with the efficacy and safety of oral valganciclovir treatment for infants with symptomatic congenital cytomegalovirus disease

IntroductionInsurance coverage for oral valganciclovir (VGCV) began in Japan in April 2023 on the basis of results, including our clinical trials for symptomatic congenital cytomegalovirus (CMV) disease. The VGCV treatment is available throughout Japan, so clinicians must consider the likelihood of hearing improvement and the possibility of neutropenia before dosing. Materials and methodsWe performed a substudy of an investigator-initiated, single-arm, prospective, multicenter, clinical trial in which 24 infants with symptomatic congenital CMV disease were orally administered 16 mg/kg VGCV twice daily for 6 months as an intervention. We examined the infants’ baseline characteristics associated with improved hearing impairment or a severely reduced neutrophil count. ResultsOf the 24 patients, 4 had normal hearing on assessment of their ear with the best hearing. Hearing impairment improved in 14 patients and did not respond to VGCV treatment in 6 patients at the 6-month hearing assessment. CMV DNA levels in plasma at baseline were higher in patients in whom hearing did not respond to treatment. A neutrophil count <500/mm3 occurred in 5 (21%) patients for the first 6 weeks and in 8 (33%) patients for the first 6 months. A neutrophil count at screening and the lowest neutrophil count over the 6 months showed the highest correlation (r = 0.477, p = 0.019). ConclusionsInfants with a low plasma viral load at screening tend to have an improvement in hearing impairment. Clinicians should be aware of neutropenia during VGCV treatment particularly in patients with a low neutrophil count during screening.

Albumin-to-D-dimer ratios: A novel prognostic factor for evaluating first-line chemotherapy efficacy in advanced lung adenocarcinoma patients.

The prognosis of advanced lung adenocarcinoma (LUAD) remains unfavorable, with chemotherapy constituting a primary treatment modality. Discerning the efficacy of chemotherapy for advanced LUAD is imperative. Prior investigations have demonstrated the prognostic value of albumin and D-dimer individually for malignancies; however, the predictive capacity of albumin-to-D-dimer ratios (ADR) for advanced LUAD subjected to first-line platinum-based chemotherapy remains unexplored. A cohort of 313 patients with advanced LUAD was retrospectively examined in this study, spanning from January 2017 to January 2021. ADR threshold values were ascertained via receiver operating characteristic analysis, followed by the evaluation of the association between pretreatment ADR and clinicopathological characteristics, disease control rate (DCR), and overall response rate (ORR) pertinent to first-line chemotherapy. Prognostic factors for progression-free survival (PFS) were determined employing Cox univariate and multivariate analyses. Subsequently, survival data were illustrated utilizing the Kaplan-Meier method and scrutinized through the log-rank test across the entire and subgroup populations. ADR demonstrated a superior area under the curve (AUC) value relative to albumin and D-dimer individually and exhibited enhanced prognostic predictive capability compared to albumin-to-fibrinogen ratios (AFR) for advanced LUAD (AUC: 0.805 vs. 0.640, DeLong test: p<0.001). ADR yielded a cut-off value of 16.608. A greater proportion of non-smokers was observed within the high-ADR group (ADR>16.608) compared to the low-ADR group (ADR≤16.608). Patients in the high-ADR group displayed elevated BMI and Na+ levels and reduced neutrophil count, monocyte count, globulin, and alkaline phosphatase (all p<0.05). Notably, the high-ADR group exhibited heightened DCR (96.7% vs. 89.2%, p=0.008) and ORR rates (70.1% vs. 51.0%, p=0.001) relative to the low-ADR group. Multivariate analysis outcomes indicated that high ADR constituted an independent risk factor for PFS (hazard ratio: 0.24, p<0.001). Furthermore, patients in the high-ADR cohort displayed a significantly prolonged median PFS (254 vs. 142 days, p<0.0001) compared to their low-ADR counterparts. In subpopulations exhibiting favorable implications for PFS, as determined by multivariate analysis, high-ADR patients consistently demonstrated extended PFS durations relative to the low-ADR group (all p<0.0001). Collectively, our findings suggest that ADR constitutes a novel and promising prognostic indicator for advanced LUAD patients, surpassing the accuracy of albumin and D-dimer individually and AFR. ADR thus serves as a potent instrument for assessing treatment effects and PFS in advanced LUAD patients undergoing first-line chemotherapy.

Deciphering the Differential Impact of Thrombopoietin/MPL Signaling on Hematopoietic Stem Cell Function in Bone Marrow and Spleen

Introduction Thrombopoietin (TPO) and its receptor MPL are key regulators of hematopoietic stem cell (HSC) function. In humans, ablation of either TPO or MPL leads to bone marrow failure in the early years of life. In contrast, mice lacking TPO or MPL display marked thrombocytopenia and severely reduced HSC numbers but manage to maintain normal survival up to one year of age. In this study, we investigated whether these mice eventually develop marrow failure with longer follow up, with a specific focus on understanding the effects of TPO/MPL signaling on HSC regulation in different hematopoietic niches. Methods Marrow and spleen hematopoiesis in the TPO -/- mice and MPL -/- mice were examined during a 2-yr follow-up. Results At 2 yrs of age, TPO -/- and MPL -/- mice exhibited not only a severely decreased platelet count (TPO -/- vs. MPL -/- vs. control: 38 vs. 107 vs. 1255 x 10 9/L) but also a moderate reduction in neutrophil count compared to age-matched wild-type controls (TPO -/- vs. MPL -/- vs. control: 1.1 vs. 1.7vs.3.3 x 10 3/ul). Femur marrow cell count or spleen cell count was not significantly different between TPO -/- or MPL -/- mice and control mice. There was no significant difference in overall survival between the TPO -/- or MPL -/- mice and wild-type controls. Marrow Lin -cKit +Sca1 +CD150 +CD48 - HSC cell numbers were significantly decreased in young (4-6mo) TPO -/- and MPL -/- mice (~4-fold) compared to age-matched control mice. This HSC loss was further worsened in old (~24mo) TPO -/- (25-fold) and MPL -/- (12-fold) mice compared to control mice. In contrast, there was no significant difference in splenic HSC cell numbers between young TPO -/- or MPL -/- mice and control mice, with only a moderate decrease of HSCs in old TPO -/- and MPL -/- (~4-fold) mice compared to control mice. I n vivo using BrdU labeling revealed an increased proliferation of marrow HSCs in TPO -/- and MPL -/- mice compared to age-matched control mice. In contrast, there was no significant increase in splenic HSC proliferation in TPO -/- or MPL -/- mice. These findings suggest that TPO/MPL signaling has distinct effects on both the number and the function of HSCs in the marrow and spleen. Competitive repopulation assays revealed that HSCs from 2yr old TPO -/- or MPL -/- marrow failed to engraft the recipient mice at 12 weeks post-transplantation. We also conducted competitive repopulation assays in which spleen cells from old TPO -/- mice (CD45.2) were injected together with spleen cells from 2yr old wild-type competitor mice (CD45.1) into lethally irradiated wild-type recipients (CD45.1). At 12 days after transplantation, the TPO -/- spleen donor showed comparable engraftment in the Lin -cKit +Sca1 + stem/progenitor cell compartment, similar to the wild-type competitor spleen donor, suggesting that at least the short-term engraftment capacity of the TPO -/- spleen donor was not impaired. We are currently conducting further investigation to assess the long-term repopulation capacity of TPO -/- spleen HSCs. To investigate how TPO/MPL ablation impacts the hematopoietic niche in the marrow and spleen, we used quantitative flow cytometry and/or fluorescence imaging to examine these niche cells and their expression of niche factors. First, while there was no significant difference in the marrow vascular area (measured by in vivo VE-cadherin labeling) between TPO -/- or MPL -/- mice and control mice, we observed a significant increase in the splenic vascular area in TPO -/- and MPL -/- mice. Second, CXCL12 levels were significantly decreased in marrow endothelial cells (ECs; CD45 -CD31 +) from TPO -/- and MPL -/- mice compared to control mice; in contrast, CXCL12 levels were significantly increased in splenic ECs from TPO -/- and MPL -/- mice. Similar results were also observed with marrow and splenic perivascular stromal cells (CD45 -CD31 -Ter119 -Sca1 -). Therefore, TPO/MPL ablation enhanced both the quantity and quality of the splenic hematopoietic niche, which could contribute to the maintenance of splenic hematopoiesis in TPO -/- and MPL -/- mice. Last, consistent with findings from the TPO/MPL ablated mice, exogenous TPO treatment increased marrow HSC proliferation but did not alter splenic HSC proliferation. In addition, TPO treatment increased CXCL12 expression in marrow ECs, but decreased CXCL12 levels in splenic ECs. Taken together, our study revealed the complexity of TPO/MPL signaling in HSC regulation which differs between the marrow and spleen

Neutropenic ulcers in oncology: terminology, diagnosis, and management.

Neutropenic ulcerations are characterized by mucosal ulcerations which occur in the presence of neutropenia, suggesting a direct link between neutropenia and mucosal ulceration. An oral ulcer can be labeled as "neutropenic" only if the patients have primary (typically congenital) or secondary neutropenia, and neutropenia is the sole causative factor. Oral mucosal ulcers observed in patients undergoing oncologic therapy may also be termed as "neutropenic ulcers", but the pathogenesis of these oral ulcers more likely involves mucosal events related to trauma, microbial factors, and direct cytotoxicity. In cancer patients, the early appearance of oral ulcers is often attributed to oral mucositis which is a condition primarily caused by the direct mucosal cytotoxicity of chemotherapeutic agents and radiation therapy. Oral ulcers that develop later during or after active cancer therapy may result from intraoral trauma and typically manifest on non-keratinized areas of the oral mucosa which are more susceptible to mucosal damage. In patients undergoing chemotherapy, factors such as disturbances in mucosal barrier function as well as bone marrow suppression lead to reduced neutrophil count and function, and can contribute to the development of oral ulcers. While the etiology of oral ulcers in cancer therapy receiving patients can vary, it is important to emphasize that the host's response plays a crucial role in the progression and repair process of these lesions.This narrative review presents the etiopathogenesis, clinical presentation, and potential management approaches for oral ulcerations in neutropenic patients, with a particular focus on clarifying the usage of the term "neutropenic ulcer" since this term lacks diagnostic specificity and can be misleading in clinical practice regarding the underlying causes and treatment strategies.

CSL112 (apolipoprotein A-I [human]) reduces the elevation in neutrophil-lymphocyte ratio (NLR) induced by acute myocardial infarction

Abstract Background CSL112 (apolipoprotein A-I [human]) is a novel therapy designed to reduce the risk of recurrent cardiovascular events following acute myocardial infarction (AMI). Preclinical data suggest that apolipoprotein A-I has anti-inflammatory properties which might contribute to atherosclerotic plaque stabilization (1). The neutrophil-lymphocyte ratio (NLR) is a clinically accessible measure of inflammatory status and predicts incident cardiovascular events in large outcome trials (2). It is unknown whether CSL112 can reduce inflammation as measured by the NLR. Purpose To evaluate whether infusion of CSL112 inhibits post-AMI inflammation as measured by NLR. Methods In a Phase 2 multicenter, double-blind study, 83 AMI patients with stage 3 chronic kidney disease were randomized 2:1 to receive 4 infusions of either 6 g CSL112 (n=55) or saline placebo (n=28) each separated by one week. The first infusion delivered on protocol Day 1 occurred 12h to 7d after presentation (mean 83 h). Blood samples were drawn prior to each infusion on Days 1, 8, 15 and 22 as well as at both Day 29 and 60 post the first infusion. Leukocyte data were available for up to 75 participants across the 6 sampling timepoints and neutrophil and lymphocyte counts were measured at the central laboratory. NLR was calculated and found to be non-normal in distribution and so analyses were performed on Loge transformed data. A mixed model repeated measures (MMRM) analysis was used to compare change from baseline (Day 1) in LogeNLR, neutrophil count and lymphocyte count between treatment groups (CSL112 6g versus Placebo) at the other 5 timepoints. An analysis of covariance (ANCOVA) was used to assess the effect of time from index MI to first infusion on change from baseline (Day 1) in LogeNLR at Day 8. Results The LogeNLR increased after AMI (between Day 1 and Day 8) with placebo treatment, whereas CSL112 infusion given after the Day 1 blood sample resulted in a decline (p=0.012; Fig 1, left panel, mean±SD). This effect of CSL112 was driven by reduction in neutrophil count (p=0.002; Fig 1, right panel) with lymphocyte levels remaining stable (p=0.537). Importantly, the magnitude of the effect of CSL112 to reduce NLR was greater if the timing of administration was closer to the index MI (treatment X time interaction and treatment effect both p=0.008). Conclusion CSL112 inhibits post-AMI elevation in NLR and this effect is maximized when infusion occurs early after presentation. It remains to be determined whether these anti-inflammatory effects of CSL112, in conjunction with previously demonstrated enhancement in cholesterol efflux capacity, will improve cardiovascular outcomes (3).Fig 1: Change in LogeNLR from baseline

124 Investigating the Role of Soybean Meal and its Innate Bioactive Compounds on Nursery Pig Systemic Health, Inflammatory Markers, and Gastrointestinal Physiology

Abstract Soybean meal (SBM) inclusion is reduced in young pig diets due to antinutritional factors that may negatively impact performance and gut function. However, when SBM is fed to grower pigs under disease or environmental stress, health may improve through modulation of immunity. Presently it is unknown if a parallel effect will be realized in nursery pigs. Therefore, the experimental objective was to examine the role of SBM and its bioactive compounds on nursery pig gastrointestinal physiology, systemic health, and inflammatory markers. Two replications of 18 barrows (8.12 ± 0.80 kg BW; PIC800×Camborough), were randomly assigned to 1 of 6 dietary treatments: a high SBM positive control (SBMC; 28.6%), a negative control void of SBM (SP), but included soy protein isolate and concentrate to provide amino acids equivalent to SBM in SBMC; SP formulated to similar contribution and composition of isoflavones as SBMC (SP+ISO; 528 mg/kg of soy-isoflavones); SP diet fortified with soybean lecithin and phytosterols at similar concentrations to SBMC (SP+LIP; 2.85 g/kg of functional lipids); SP formulated to an equivalent ratio of insoluble to soluble fiber as SBM in SBMC (SP+FIB; 30 g/kg of soy fiber); or SP diet fortified with lunasin-peptide at 3.81 g/kg (SP+LUN). Pigs were individually housed, and limit-fed 2.5 times maintenance for a metabolism study consisting of a 6-d adaptation period, followed by 72-h of urine and fecal collections, and a 12-h lactulose:mannitol test. On d 11, whole blood and serum were collected before feeding, and at 2, 5, and 24 h post-feeding via jugular-venipuncture. Serum was analyzed for total antioxidant capacity (TAC) and malondialdehyde (MDA). Hematology was measured on whole blood. On d 12, pigs were necropsied for intestinal tissues collection. Data were analyzed as a linear mixed model with treatment as a fixed effect, replicate as a random effect, and initial BW as a covariate where appropriate. A dependent covariance structure was used for repeated measurements (Table 1). Pigs fed either SBMC or SP+LIP had greater mean corpuscular volume and hematocrit % (P = 0.027). Relative to the SP diet, pigs fed SP+LIP tended to have 11.4% greater hemoglobin concentrations (P=0.086). Circulating total white blood cells (WBC) were 21.2% and 22.6% less in pigs fed SBMC and SP+ISO diet, respectively, relative to SP (P = 0.002). Similarly, SBMC and SP+ISO had reduced neutrophil counts (P = 0.043). Relative to SP, SBMC, SP+ISO, and SP+FIB tended to have increased systemic TAC (P=0.086). Pigs fed either SBMC or SPC+ISO had over a 2-fold increase in the TAC of the jejunum, relative to SP (P = 0.039), but those fed SPC+FIB had increased TAC in the ileum and reduced MDA (P &amp;lt; 0.05). In conclusion, SBM and its isoflavones altered WBC concentrations. Whereas, SBM functional lipids may alter red blood cells, and SBM fiber modulated oxidative status.

Unveiling the role of neutrophils in chronic spontaneous urticaria: Beyond mast cells.

Mast cells and eosinophils are considered pivotal contributors to the pathogenesis of chronic spontaneous urticaria (CSU). However, emerging evidence suggests that neutrophils also play a central role. Cutaneous mast cells and macrophages orchestrate the recruitment of neutrophils through the regulation and activation of diverse processes, including heightened local vascular permeability and chemokine release. Studies have demonstrated increased activation and elevated levels of neutrophil-related cytokines in CSU patients. Moreover, neutrophils have been proposed as antigen-presenting cells during the late-phase reaction of immunoglobulin E-mediated allergy and have been associated with the expression of calcitonin gene-related protein and vascular endothelial growth factor in CSU. Histopathological analysis of lesional skin in CSU patients revealed significantly higher eosinophil and neutrophil counts than unaffected skin. However, the extent of neutrophil infiltration in the skin does not appear to correlate with the number of neutrophils in peripheral blood. The utility of the neutrophil-lymphocyte ratio as a marker for disease activity or remission in CSU remains inconclusive. Neutrophil-targeted therapy may confer benefits for CSU patients who exhibit resistance to antihistamines. Omalizumab has demonstrated its ability to reduce neutrophil counts, the neutrophil-lymphocyte ratio, and the neutrophil-monocyte ratio in peripheral blood. While dapsone and colchicine are recommended as alternative treatment options for CSU, their evidential support from published studies remains limited. Inhibitors targeting interleukin-1 and neutrophil-related cytokines have been proposed as potential therapeutic interventions for patients exhibiting neutrophil predominance. Further research is warranted to gain deeper insights into the involvement of neutrophils in CSU and to explore potential therapeutic interventions.