White Blood Cell Reduction Research Articles

Effect of seven days heat stress on feed and water intake, milk characteristics, blood parameters, physiological indicators, and gene expression in Holstein dairy cows

This study examined the effects of 7 days of heat stress on eight early lactating Holstein cows in climate-controlled chambers. The early lactating Holstein cows (42 ± 2 days in milk, 29.27 ± 0.38 kg/day milk yield, 1.21 ± 0.05 parity) were subjected to two 14-day periods, each consisting of 7 days of adaptation and 7 days of heat stress. Conditions were set to 22 °C and 50% humidity during adaptation, followed by heat stress periods with low-temperature, low-humidity (LTLH, 71 THI) and high-temperature, high-humidity (HTHH, 86 THI) treatments. Data from the last 7 days were analyzed using a mixed procedure in SAS. In the study, the HTHH group displayed marked physiological and biochemical changes on 14 days of heat stress exposure compared to the LTLH group. Firstly, the HTHH group's dry matter intake decreased by approximately 12% while their water intake increased by about 23%. Secondly, both milk yield and milk protein production in the HTHH group decreased by 10% and 20%, respectively. Thirdly, there was a reduction in white blood cells, hemoglobin, mean corpuscular hemoglobin, and platelets in the HTHH group, with concurrent increases in glucose, non-esterified fatty acids, and albumin concentrations. Additionally, the HTHH group exhibited elevated plasma concentrations of cortisol and haptoglobin. Moreover, the gene expression of heat shock protein 70 and heat shock protein 90 was significantly upregulated in the HTHH group's peripheral blood mononuclear cells. Lastly, key physiological indicators such as rectal temperature, heart rate, and skin temperature showed substantial elevations in the HTHH group. Considering the enormous negative effects observed in the analyzed blood metabolites, milk yield and compositions, and heat shock protein gene expression, early lactating Holstein cows were found to be more vulnerable to HTHH than LTLH over a 7 days exposure to heat stress.

Factors influencing delayed high-dose methotrexate excretion and its correlation with adverse reactions after treatment in children with malignant hematological tumors.

High-dose methotrexate (HDMTX) is crucial in treating pediatric malignant hematological tumors. However, its use is often complicated by delayed excretion and associated adverse reactions, which can significantly affect treatment outcomes and patient safety. Identifying risk factors is essential for safer, more effective therapy. This study aimed to investigate the influencing factors for delayed excretion and their correlation with adverse reactions in children with malignant hematological tumors after receiving HDMTX chemotherapy. From April to October 2021, the clinical information of children who had undergone HDMTX chemotherapy and had their blood tested for drug concentration was gathered by the Department of Hematology and Oncology at Shanghai Children's Medical Center. Via univariate and multivariate logistic regression, the factors affecting the delayed excretion of HDMTX were examined, and the relationship between delayed excretion and unfavorable effects in children was determined. This study included 99 patients comprising 199 courses of HDMTX. The occurrence rate of HDMTX delayed excretion was 20.1%. Age ≥9 years and a 24-hour methotrexate (MTX) concentration of 64 µmol/L were independent risk factors for delayed MTX excretion according to multivariate logistic regression analysis (P<0.05). Negative side effects, such as fever, infection, mucositis, gastrointestinal response, and decreased platelet count in children with delayed excretion were statistically significant when compared to those of children with normal excretion. White blood cell reduction, hemoglobin levels below 65 g/L, MTX excretion delay, and concomitant etoposide treatment were all independent risk factors for infection in children. To estimate the risk of delayed MTX excretion during HDMTX therapy, patient laboratory data should be scrutinized, especially for patients ≥9 years or those with a 24-hour MTX concentration of greater than 64 µmol/L.

The therapeutic potential of Melissa officinalis L. hydroalcoholic extract and rosmarinic acid in a rat asthmatic model: A study on anti-inflammatory and antioxidant effects.

The article studies how Melissa officinalis L. extract and rosmarinic acid (RA) affect lung inflammation, pathology, and oxidative stress in rats with ovalbumin-induced asthma. Asthma was induced in rats using ovalbumin injection and inhalation. The study assessed lung inflammation, pathological changes, and oxidative stress in control, untreated asthmatic rats and three treatment groups. These groups received M. officinalis extract (50, 100, 200 mg/kg), RA (0.5, 1, 2 mg/kg), or dexamethasone (Dex) 1 mg/kg. In the sensitized group, white blood cell counts, malondialdehyde, and nitrite levels increased significantly, while thiol levels and the activity of superoxide dismutase and catalase decreased (p<0.001). However, all treatment groups with the extract, RA, and Dex showed a significant reduction in total white blood cells, eosinophils, monocytes, malondialdehyde, and nitrite levels compared to the asthma group (p<0.001 in all groups). Thiol levels and catalase and superoxide dismutase activity were significantly higher in all treated groups with RA and high extract doses (p<0.001). Lung pathological changes were also significantly less severe in the treated groups with dexamethasone, plant extract, and RA compared to the asthma group (p<0.05 to p<0.001). This study showed that M. officinalis and RA have antioxidant and anti-inflammatory effects in an animal asthma model, suggesting their potential for treating asthma symptoms.

Light chain (AL) amyloidosis following gastrointestinal symptoms that involve multiple organs: a case report

Light chain (AL) amyloidosis is a complex and rare disease characterized by low incidence and diverse clinical manifestations. At the time of diagnosis, most patients exhibit involvement of multiple organs or tissues, leading to severe illness and a poor prognosis. Therefore, early diagnosis, active treatment, and a comprehensive assessment of the disease hold paramount importance. The initial presentation of this rare condition often manifests as gastrointestinal symptoms, posing challenges in clinical identification and differential diagnosis. In this case report, we describe a 70-year-old man with AL amyloidosis, initially misdiagnosed as irritable bowel syndrome and colon polyps. Subsequently, he experienced a series of complications including renal function impairment, pulmonary nodule, pleural effusion, mediastinal lymph node enlargement, spleen enlargement, reduction of white blood cells, red blood cells and platelets, and small intestinal obstruction. Despite multiple pulmonary nodule biopsy and lymph node biopsy, as well as concurrent splenectomy and partial resection of the small intestine, a clear diagnosis remained elusive. Before admission, diarrhea was aggravated, accompanied by emaciation and fatigue. Following the completion of serum immunofixed protein electrophoresis, renal biopsy, bone marrow and rectal biopsy, a conclusive diagnosis of AL amyloidosis involving multiple organs (Mayo 2012 revision stage III) was finally confirmed after a 12-year period. Treatment with proteasome inhibitors, immunomodulators, and glucocorticoids was recommended. The patient underwent methylprednisolone treatment and was discharged after symptom improvement. However, eight months into the follow-up, the patient succumbed to multiple organ failure. The repeated misdiagnoses over the past 12 years were attributed to limited perspectives among some specialists who did not conduct a systematic and detailed medical history analysis or comprehensive physical examinations. Additionally, they did not strictly follow the principle of "monism" in diagnosis. On the contrary, early diagnosis and active treatment of the disease are of great significance to improve the prognosis.

Comparison of the CXCR5-Antibody Drug Conjugate (ADC; VIP924) to a CD19-ADC and a CD79b-ADC in a Humanized Rec-1 Mantle Cell Lymphoma (MCL) Mouse Model

Introduction The chemokine receptor CXCR5 is highly expressed in MCL, which is a rare subtype of non-Hodgkin lymphoma. VIP924 is a first-in-class CXCR5-targeting ADC composed of a legumain-cleavable linker and a kinesin spindle protein inhibitor (KSPi) payload. We compared VIP924 with a CD19- and a CD79b- targeting ADC in a humanized mouse model of MCL. Methods Expression of CXCR5 and the B-cell targets CD19 and CD79b were analyzed on tumor samples from patients with MCL using immunohistochemistry. Slides were examined by a pathologist and scored for expression. NSG-SGM3 mice were transplanted with human hematopoietic stem cells from 4 different donors and after engraftment transplanted subcutaneously with REC-1 MCL cells into their flanks. When subcutaneous tumors reached a size of 100 mm 3, mice were randomized into 5 groups and treated with 10 mg/kg of an isotype control ADC, 3 mg/kg polatuzumab vedotin, 0.66 mg/kg loncastuximab teserine, 3 mg/kg VIP924, or 10 mg/kg VIP924 every 5 days for 4 doses. Immunophenotyping of peripheral blood was performed by flow cytometry before starting treatment (Day 0) and on Day 5 and Day 18 during the treatment. At the end of the experiment, immunophenotyping was also done on tumors, spleen, and bone marrow. Complete blood count was analyzed based on single cell evaluation (Drew Scientific HemaVet 950FS Auto Blood Analyzer). Results By immunohistochemistry CXCR5 and CD19 showed comparable high expression on patient samples, whereas CD79b expression was moderate. Treatment of humanized mice bearing REC-1 tumors with VIP924 at 10 mg/kg reduced tumor growth effectively (p&amp;lt;0.0001 vs. isotype control on Day 10), while treatment with polatuzumab vedotin and loncastuximab teserine showed no effects on tumor growth. This outcome was also reflected in the median survival rates for the different groups with 17 days for isotype control and polatuzumab vedotin, 14 days for loncastuximab teserine and not reached for the 10-mg/kg VIP924 group. However, polatuzumab vedotin treatment significantly reduced hCD45+ cells in peripheral blood and spleen, while loncastuximab teserine treatment showed a clear trend for reduction. VIP924 treatment in both arms had no effect on peripheral or splenic hCD45+ cells. All tested ADCs reduced the CD19+ and more mature CD19+/CXCR5+ B-cells in peripheral blood and spleen, with polatuzumab vedotin and loncastuximab teserine showing significant (p&amp;lt;0.0001 vs. isotype control on Day 18) effects on CD19+ cell reductions, while VIP924 treatment showed a milder reduction in CD19+ cells (p= 0.0051 for 3 mg/kg and p= 0.0407 for 10 mg/kg VIP924). Loncastuximab teserine treatment increased the amount of myeloid derived suppressor cells in the peripheral blood significantly (p= 0.0467). In contrast, VIP924 led to a significant (p&amp;lt; 0.0001) increase in peripheral regulatory T-cells compared with isotype control. Complete blood counts from treated mice showed a reduction of white blood cells (WBC), absolute lymphocyte count, and absolute monocyte count in loncastuximab teserine-treated animals. Loncastuximab teserine treatment also reduced red blood cell count and hemoglobin values. In VIP924-treated animals, no effects on WBC, red blood cell count, or hemoglobin values were observed. All treatments showed no detrimental effects on body weights of the mice. Conclusion CXCR5 is a highly attractive target in B-cell malignancies such as diffuse large B-cell lymphoma and MCL due to high CXCR5 surface expression. VIP924, a CXCR5-targeting ADC, showed high potency and superiority to other B-cell-targeted ADCs in a humanized mouse model of MCL. In this MCL model in humanized mice, VIP924 at 10 mg/kg treatment showed a significant reduction in tumor growth and improvement in survival, while polatuzumab vedotin and loncastuximab teserine had no effect on tumor growth or survival. Interestingly, VIP924 was the only ADC to cause a significant increase in peripheral T regulatory cells, which may enhance tumor growth inhibition. Loncastuximab teserine had a deleterious effect on several hematologic parameters, which was not observed with VIP924 or polatuzumab vedotin. The efficacy and tolerability observed in this study with VIP924 suggests further testing in human clinical trials is warranted.

Moderate body lipid accumulation in mice attenuated benzene-induced hematotoxicity via acceleration of benzene metabolism and clearance

Recent population and animal studies have revealed a correlation between fat content and the severity of benzene-induced hematologic toxicity. However, the precise impact of lipid deposition on benzene-induced hematotoxicity and the underlying mechanisms remain unclear. In this study, we established a mouse model with moderate lipid accumulation by subjecting the mice to an 8-week high-fat diet (45% kcal from fat, HFD), followed by 28-day inhalation of benzene at doses of 0, 1, 10, and 100 ppm. The results showed that benzene exposure caused a dose-dependent reduction of peripheral white blood cell (WBC) counts in both diet groups. Notably, this reduction was less pronounced in the HFD-fed mice, suggesting that moderate lipid accumulation mitigates benzene-related hematotoxicity. To investigate the molecular basis for this effect, we performed bioinformatics analysis of high-throughput transcriptome sequencing data, which revealed that moderate lipid deposition alters mouse metabolism and stress tolerance towards xenobiotics. Consistently, the expression of key metabolic enzymes, such as Cyp2e1 and Gsta1, were upregulated in the HFD-fed mice upon benzene exposure. Furthermore, we utilized a real-time exhaled breath detection technique to monitor exhaled benzene metabolites, and the results indicated that moderate lipid deposition enhanced metabolic activation and increased the elimination of benzene metabolites. Collectively, these findings demonstrate that moderate lipid deposition confers reduced susceptibility to benzene-induced hematotoxicity in mice, at least in part, by accelerating benzene metabolism and clearance.

Novel plant-derived exosome-like nanovesicles from Catharanthus roseus: preparation, characterization, and immunostimulatory effect via TNF-α/NF-κB/PU.1 axis

BackgroundPlant-derived exosomes-like nanovesicles (PDENs) have been found to be advantageous in disease treatment and drug delivery, but research on their biogenesis, compositional analysis, and key marker proteins is still in its infancy, which limits the standardized production of PDENs. Efficient preparation of PDENs continues to be a major challenge.ResultsNovel PDENs-based chemotherapeutic immune modulators, Catharanthus roseus (L.) Don leaves-derived exosome-like nanovesicles (CLDENs) were isolated from apoplastic fluid. CLDENs were membrane structured vesicles with a particle size of 75.51 ± 10.19 nm and a surface charge of −21.8 mV. CLDENs exhibited excellent stability, tolerating multiple enzymatic digestions, resisting extreme pH environments, and remaining stable in the gastrointestinal simulating fluid. Biodistribution experiments showed that CLDENs could be internalized by immune cells, and targeted at immune organs after intraperitoneal injection. The lipidomic analysis revealed CLDENs’ special lipid composition, which contained 36.5% ether-phospholipids. Differential proteomics supported the origin of CLDENs in multivesicular bodies, and six marker proteins of CLDENs were identified for the first time. 60 ~ 240 μg/ml of CLDENs promoted the polarization and phagocytosis of macrophages as well as lymphocyte proliferation in vitro. Administration of 20 mg/kg and 60 mg/kg of CLDENs alleviated white blood cell reduction and bone marrow cell cycle arrest in immunosuppressive mice induced by cyclophosphamide. CLDENs strongly stimulated the secretion of TNF-α, activated NF-κB signal pathway and increased the expression of the hematopoietic function-related transcription factor PU.1 both in vitro and in vivo. To ensure a steady supply of CLDENs, plant cell culture systems of C. roseus were established to provide CLDENs-like nanovesicles which had similar physical properties and biological activities. Gram-level nanovesicles were successfully obtained from the culture medium, and the yield was three times as high as the original.ConclusionsOur research supports the use of CLDENs as a nano-biomaterial with excellent stability and biocompatibility, and for post-chemotherapy immune adjuvant therapy applications.Graphical

Further Characterization of Multi-Organ DEARE and Protection by 16,16 Dimethyl Prostaglandin E2 in a Mouse Model of the Hematopoietic Acute Radiation Syndrome.

Survivors of acute radiation exposure suffer from the delayed effects of acute radiation exposure (DEARE), a chronic condition affecting multiple organs, including lung, kidney, heart, gastrointestinal tract, eyes, and brain, and often causing cancer. While effective medical countermeasures (MCM) for the hematopoietic-acute radiation syndrome (H-ARS) have been identified and approved by the FDA, development of MCM for DEARE has not yet been successful. We previously documented residual bone marrow damage (RBMD) and progressive renal and cardiovascular DEARE in murine survivors of H-ARS, and significant survival efficacy of 16,16-dimethyl prostaglandin E2 (dmPGE2) given as a radioprotectant or radiomitigator for H-ARS. We now describe additional DEARE (physiological and neural function, progressive fur graying, ocular inflammation, and malignancy) developing after sub-threshold doses in our H-ARS model, and detailed analysis of the effects of dmPGE2 administered before (PGE-pre) or after (PGE-post) lethal total-body irradiation (TBI) on these DEARE. Administration of PGE-pre normalized the twofold reduction of white blood cells (WBC) and lymphocytes seen in vehicle-treated survivors (Veh), and increased the number of bone marrow (BM) cells, splenocytes, thymocytes, and phenotypically defined hematopoietic progenitor cells (HPC) and hematopoietic stem cells (HSC) to levels equivalent to those in non-irradiated age-matched controls. PGE-pre significantly protected HPC colony formation ex vivo by >twofold, long term-HSC in vivo engraftment potential up to ninefold, and significantly blunted TBI-induced myeloid skewing. Secondary transplantation documented continued production of LT-HSC with normal lineage differentiation. PGE-pre reduced development of DEARE cardiovascular pathologies and renal damage; prevented coronary artery rarefication, blunted progressive loss of coronary artery endothelia, reduced inflammation and coronary early senescence, and blunted radiation-induced increase in blood urea nitrogen (BUN). Ocular monocytes were significantly lower in PGE-pre mice, as was TBI-induced fur graying. Increased body weight and decreased frailty in male mice, and reduced incidence of thymic lymphoma were documented in PGE-pre mice. In assays measuring behavioral and cognitive functions, PGE-pre reduced anxiety in females, significantly blunted shock flinch response, and increased exploratory behavior in males. No effect of TBI was observed on memory in any group. PGE-post, despite significantly increasing 30-day survival in H-ARS and WBC and hematopoietic recovery, was not effective in reducing TBI-induced RBMD or any other DEARE. In summary, dmPGE2 administered as an H-ARS MCM before lethal TBI significantly increased 30-day survival and ameliorated RBMD and multi-organ and cognitive/behavioral DEARE to at least 12 months after TBI, whereas given after TBI, dmPGE2 enhances survival from H-ARS but has little impact on RBMD or other DEARE.

Characterization of a Highly Virulent Noncytopathic Bovine Viral Diarrhea Virus 2b Isolate Detected in Cattle in Inner Mongolia, China

Bovine viral diarrhea virus (BVDV) infection causes subclinical to severe acute disease in cattle all over the world. Two genotypes of BVDV are recognized, BVDV1 and BVDV2. Currently, the subtypes of BVDV1b and BVDV2a are mainly circulating in China. Here, a newly noncytopathic (ncp) BVDV strain named BVDVNM21 was isolated and identified from cattle. We determined the complete genome sequence of BVDVNM21, phylogenetic analysis of 5′ untranslated region (5′UTR), Npro, and E2 gene, and complete genome showed the virus belongs to BVDV2b subtype and formed an independent clade within BVDV2b. Genome-wide sequence analysis showed that BVDVNM21 had high homology with SD1301 (98.10%) isolated from China. In the experimental infection study of guinea pigs and calves, they all developed similar clinical signs, including a pronounced and prolonged febrile response lasting more than 3 days and pronounced reduction in white blood cells (WBC) and platelets of more than 40%. Moreover, guinea pigs showed more acute infection characteristics after infection, and WBC decreased by more than 50% at 1 day postinfection (dpi), and they recovered in less than 3 days. The results indicated that the BVDVNM21 strain showed high virulence in calves. It was the first confirmed isolation of a highly pathogenic ncpBVDV2b in cattle, as well as the establishment of the BVDV-guinea pig model. This study may provide a basis for further research and control of the prevalence of BVDV2b in China.

Evaluation of differential white blood cell count and cheek pouch epithelium in 7,12-dimethylbenza[a]anthracene hamster carcinogenesis model, managed with three phytochemicals

Objectives: Nigella sativa (NS), thymoquinone (TQ), and epigallocatechin-3-gallate (EGCG) are phytochemicals that might have antioxidant protective potentials on the hamster cheek pouch epithelium (HCPE). We aimed at evaluating and comparing the potential therapeutic outcomes of these 3 phytochemicals by analysis of peripheral white blood cells (WBCs) counts. Materials and Methods: NS whole oil, TQ and EGCG were administered before, with or after 7,12-dimethylbenza[a]anthracene (DMBA) painting the hamster left cheek pouch. Before sacrificing each animal, 2 ml of blood was withdrawn into a fine heparin-containing tube to estimate the total WBCs, lymphocytes, MID cells, and granulocytes counts by an automatic count system. All cheek pouches were surgically excised and examined with light microscope. Results: Severe epithelial dysplasia was evident after 6 weeks of DMBA administration, and when NS was given for 2 weeks followed by DMBA for 6 weeks. When NS or EGCG were given for 2 weeks then continued with DMBA for 6 weeks, mild dysplasia was seen. When DMBA was given for 6 weeks followed by NS or TQ for 6 weeks, mild dysplasia was noted. Administration of DMBA for 6 weeks resulted in significant reduction in total WBCs and lymphocytes counts compared to healthy controls. Administration of NS or TQ for 2 weeks resulted in significant elevation in lymphocytes count compared to healthy controls. Significant elevation in total WBCS and lymphocytes counts was noted when EGCG was given for 2 weeks and continued with DMBA for other 6 weeks. Similar results were noted when DMBA was given for 6 weeks followed by TQ for 6 weeks when compared to NS, DMBA or healthy controls. Discussion: The three phytochemicals showed different levels of protection against DMBA carcinogenic activity, more specifically, TQ and NS had higher therapeutic potential and might be used for treatment and/or preventive management of oral cancer in the future. Conclusion: However, further investigations are required to address the mechanism of action and feasibility of clinical application of each phytochemical.

CD19-Targeted CAR-T Cells in Refractory Systemic Lupus Erythematosus: Safety, Efficacy, and Mechanistic Insights from the First Five Patients

Background: Systemic lupus erythematosus (SLE) is an auto-immune disease that is based on dysregulation of the adaptive immune system, autoantibody production and immune complex-mediated tissue damage. While treatment of SLE has substantially improved, a subset of patients experiences severe progressive disease despite T- and B-cell targeted therapy. Aim: For patients with refractory SLE, we aimed to achieve deep depletion of B cells using autologous CD19-CAR T cells with the goal of achieving an immunological reset and drug free remission. Methods: Five patients (4 women, 1 men) with SLE refractory to several immune-suppressive drugs including pulsed steroids, hydroxychloroquine, mycophenolate, cyclophosphamide, intravenous immunoglobulins, rituximab, and belimumab were treated with CD19 CAR T cells in a compassionate use program. Mean patient age was 21.8 ± 2.3 years, mean disease duration was 4.6 ± 3.0 years and mean SLE disease activity index (SLEDAI) was 11.8±3.8. Autologous T cells were transduced with a lentiviral anti-CD19 CAR vector composed of the FMC63 scFv, a CD8-derived hinge region, TNFRSF19-derived transmembrane domain, CD3ζ intracellular domain, and 4-1BB co-stimulatory domain and expanded within the local GMP facility utilizing the closed automated CliniMACS Prodigy® system (Miltenyi Biotec, Bergisch Gladbach, Germany). CAR T cells were re-infused at a dose of 1x106 CAR T cells/kg body weight after lymphodepletion with fludarabine/ cyclophosphamide. All SLE treatments with the exception of low dose prednisolone was stopped before CAR-T cell administration. After CAR-T cell treatment, no other immune-modulatory or immune-suppressive treatment was given. Tolerability was assessed following international guidelines. Results: Despite long-lasting high dose steroid treatment, sufficient numbers of CD19 CAR-T cells could be generated from 5/5 SLE patients. Lymphodepletion led to expected reduction of white blood cells. Following lymphodepletion, CAR T cells expanded in vivo with a peak on day 9 and a deep depletion of B cells was achieved in all patients. Bone marrow toxicity towards non-B cells was short and all patients recovered neutrophils (>500/nL) before day 14 post CAR T cells. Only mild CRS of °I occurred in all five patients. One patient received a single dose of tocilizumab due to persisting fever >24 hours. There were no ICANS, no CRS of any organ, and no infections. Remission of SLE according to DORIS criteria was achieved in all 5 patients after 3 months and the mean (±SD) SLEDAI score after 3 months was 0.4±0.9. Laboratory parameters normalized in all SLE patients after CAR-T transfer including seroconversion of anti-dsDNA antibodies and all patients were free of immune-suppressive drugs by month 3. One patient presented with proteinuria at month 4. Kidney biopsy as well as serum diagnostics showed no signs of SLE. After a steroid pulse, proteinuria went back to normal. Despite reconstitution of B cells no relapse of SLE was observed in the follow up of any of the patients which are now 17, 12, 8, 7, and 5 months after CAR T cell therapy. Reappearing B cells were naïve and showed non-class switched B cell receptors. While pre-existing vaccine-specific antibodies towards measles or VZV persisted, several auto-reactive antibodies were abrogated. Quality of life was poor at decision to treatment and improved substantially at month three. Improvement was mostly driven by abrogation of joint pain and of fatigue. Conclusions: Taken together, the preliminary data from this pilot study show that CD19 CAR T-cell therapy is very well tolerated in patients with a non-malignant B cell derived autoimmune disease and induce rapid remission of severe refractory SLE. Longer follow-up and higher patient numbers from controlled clinical trials are needed to confirm these promising results.

Leukoreductive response to the combination of sorafenib and chemotherapy in hyperleukocytosis of FLT3-ITD mutated pediatric AML.

Twelve to 22% of pediatric acute myeloid leukemia (AML) patients present with hyperleukocytosis, which is one of the main risk factors of early death due to its clinical complications: leukostasis, causing pulmonary or central nervous system injuries, tumor lysis syndrome, and disseminated intravascular coagulation. Sorafenib is a multi-kinase inhibitor that blocks the Fms-Related Tyrosine Kinase 3 receptor (FLT3) in AML patients with a FLT3-internal tandem duplication (FLT3-ITD), leading to a reduction of proliferation. Here we report four de novo diagnosed or relapsed pediatric FLT3-ITD-positive AML patients with hyperleukocytosis, which were treated with sorafenib in combination with cytoreductive chemotherapy prior to the start of the induction phase. We observed a fast reduction of white blood cells in peripheral blood and bone marrow. This resulted in a rapid clinical stabilization of the patients. Adverse side effects-such as dermatologic toxicity, elevation of transaminases and hypertension-occurred but were mild and inductive chemotherapy could be started in parallel or subsequently. This implies sorafenib as a safe and effective treatment option in combination with chemotherapy during cytoreductive prephase for children with this life-threatening condition.

Optimizing antidotal treatment with the oral HSP90 inhibitor TAS-116 against hydrochloric acid-induced pulmonary fibrosis in mice.

Exposure to high concentrations of hydrochloric acid (HCl) can lead to severe acute and chronic lung injury. In the aftermath of accidental spills, victims may be treated for the acute symptoms, but the chronic injury is often overlooked. We have developed a mouse model of acute and chronic lung injury, in which the peak of acute lung injury occurs on the day 4 after HCl exposure. We have also demonstrated that HSP90 inhibitors are effective antidotes when administered starting 24h after HCl. In this study we examined the hypothesis that the novel oral HSP90 inhibitor TAS-116 can effectively ameliorate HCl-induced lung injury even when treatment starts at the peak of the acute injury, as late as 96h after HCl. C57BI/6J mice were intratracheally instilled with 0.1N HCl. After 24 or 96h, TAS-116 treatment began (3.5, 7 or 14mg/kg, 5 times per week, p. o.) for either 2,3 or 4 orweeks. TAS-116 moderated the HCl-induced alveolar inflammation, as reflected in the reduction of white blood cells and total protein content in bronchoalveolar lavage fluid (BALF), overexpression of NLRP3 inflammasome, and inhibited the activation of pro-fibrotic pathways. Furthermore, TAS-116 normalized lung mechanics and decreased the deposition of extracellular matrix proteins in the lungs of mice exposed to HCl. Delayed and shortened treatment with TAS-116, successfully blocked the adverse chronic effects associated with acute exposure to HCl.

Evaluation of beneficial effects of Epilobium hirsutum on hematological parameter in iron intoxicated Sprague–Dawley rats

Objectives: This study was carried out to investigate the protective role of different fractions of Epilobium hirsutum on the toxic effects of iron on hematological value in Sprague–Dawley rats. Material and Methods: Iron overload was induced by injecting six IP injections of iron dextran (12.5 mg/100 g) uniformly for 30 days. Different fractions of E. hirsutum were given orally and deferoxamine subcutaneously for 30 days. The hematological parameters were evaluated on 15–30 days of treatment. Results: The animal exposed to iron presented a significant (P &lt; 0.01) reduction in red blood corpuscles, total and differential white blood cells, and platelet levels. This shows that the overabundance of iron in iron overloaded conditions can lead to bone marrow suppression. These influences of iron overload were prevented by concurrent daily administration of a methanolic fraction of methanolic extract and a methanolic fraction of aqueous extract of E. hirsutum. Conclusion: The results indicate that 300 mg/kg for 30 days shows better beneficial effects as compared to 150 mg/kg for 15 days of treatment. Our results endorsed that E. hirsutum has beneficial effects on hematological parameters in iron intoxicated Sprague–Dawley rats.

Complex treatment of lower limb ulcers in patients with diabetes mellitus type 2

To estimate the efficiency of stimulation of reparative processes in patients with diabetes mellitus type 2 and trophic ulcers of the lower limbs. There were 94 patients with diabetes mellitus type 2 complicated by trophic ulcers of the lower limbs. Mean age of patients was 67.8±8.6 years. The main group consisted of 50 (53.2%) patients who underwent stimulation of reparative processes, control group - 44 (46.8%) patients with standard treatment and hydrocolloid dressings. Efficiency of treatment was analyzed every 5 days considering wound healing and cytological data. We found significant reduction of neurotrophic ulcer volume by 29.9% after 10 days. Positive macroscopic data were accompanied by reduction of white blood cells count up to 40-50% and increase in the number of histiocytes and endothelial cells. Among patients with ischemic ulcers, we obtained significant reduction of ulcerative defect only after 15-20 days in 3 (60%) cases. Overall efficiency of original management way 96%, mean duration of treatment - 37.1±5.9 days. In the control group, overall efficiency of treatment was 70.5%, duration of treatment - 45.9±6.1 days. The original method was valuable to improve the outcomes in patients with diabetes mellitus type 2 and trophic ulcers of the lower limbs. The best results were obtained for neurotrophic ulcers. In case of ischemic ulcers, these technologies should be combined with measures on improvement of pulsatile blood flow and microcirculation. This method does not require hospitalization and reduces treatment cost.

Cellular Therapy: The Hope for Covid-19.

Coronaviruses (CoVs) are a group of very diverse viruses that cause a broad spectrum of diseases from mild to severe enteric, respiratory, systemic diseases, and common cold or pneumonia among humans and animals. This virus is associated with Middle East Respiratory Syndrome (MERS), Severe Acute Respiratory Syndrome (SARS), and lung disease that lead to Acute Respiratory Distress Syndrome (ARDS). In December 2019, researchers identified a novel coronavirus type, called Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV2), which was associated with symptoms of high fever, dry cough, headache, diarrhea, and reduction of White Blood Cells (WBC). Coronavirus-associated acute respiratory disease was named Coronavirus Disease 19 (COVID-19). No proven treatment has been discovered for COVID-19 so far, but researchers are trying to find the best effective way to treat this disease. Therefore, therapeutic strategies that facilitate the recovery of COVID-19 patients and reduce life-threatening complications are urgently needed now. Today, Mesenchymal Stem Cells (MSCs) and their secretion are utilized as one of the most applied tools to treat various diseases such as inflammation and cancer. MSC-derived vesicles are rich in various growth factors, cytokines, and interleukins that are produced and secreted under different physiological or pathological conditions. These vesicles were considered a suitable and effective tool in regeneration medicine because of their high power in repairing damaged tissues and modulating immune responses. Recently, evidence has shown MSC-derived vesicles through reduced expression of pro-inflammatory cytokines could improve damaged tissues in COVID-19 patients. In addition to MSCs and MSC-derived exosomes, Natural Killer (NK) cells, T cells, and platelet lysates were used against viral infection. In this review, we tried to provide an overview of MSC secretion and immune cells for COVID-19 therapy.

Bradykinin-Potentiating Peptide-Paclitaxel Conjugate Directed at Ectopically Expressed Angiotensin-Converting Enzyme in Triple-Negative Breast Cancer.

Triple-negative breast cancer (TNBC) is a heterogeneous subtype of breast cancer with poor prognosis. Here, we present a peptide-drug conjugate (PDC)─bradykinin-potentiating peptide-paclitaxel (BPP-PTX) conjugate─synthesized by conjugating BPP9a with PTX via a succinyl linker. BPP-PTX targets the angiotensin-converting enzyme (ACE) on TNBC cells. ACE was found to be ectopically expressed in two TNBC cell lines but was absent in both the receptor-positive breast cancer cell line and healthy kidney cell line. Overexpression, knockdown, and competitive inhibition experiments demonstrated ACE-mediated cytotoxicity of BPP-PTX. In vivo, ACE-positive tumors were enriched with BPP-PTX, with the PDC being better tolerated than plain PTX. Compared with plain PTX, BPP-PTX exhibited improved tumor-suppressive effects in MDA-MB-468 xenografted female nude mice. Meanwhile, BPP-PTX resulted in less body weight loss and white blood cell reduction toxicity. These results collectively imply the novelty, efficacy, and low-toxicity profile of BPP-PTX as a potential therapeutic for ACE-positive TNBC.

Effect of Colchicine in Reducing Inflammatory Biomarkers and Cardiovascular Risk in Coronary Artery Disease: A Meta-analysis of Clinical Trials.

Colchicine's role in reducing inflammation and cardiovascular adverse events despite standard care in coronary artery disease (CAD) is controversial. Can colchicine reduce inflammation [high-sensitivity C-reactive protein (hs-CRP)] in CAD? PubMed, Cochrane Library, and Trial registries. The meta-analysis included 15 studies using add-on colchicine in patients with CAD. The outcomes evaluated were hs-CRP, white blood cell and neutrophil count, a composite end point of major cardiovascular events, myocardial infarction (MI), cardiovascular and all-cause mortality, and gastrointestinal adverse events. The analysis was performed using a random-effects model to calculate pooled mean difference and odds ratio (OR). The meta-analysis revealed a mean reduction of 0.36 mg/L in hs-CRP levels [95% confidence interval (CI): -0.51 to -0.20] with add-on colchicine. The mean white blood cell reduction of 371.75 per µL (95% CI: -544.27 to -199.24) and the mean neutrophil reduction also favored the add-on colchicine group. There was a reduction in composite end point of major cardiovascular events [OR, 0.65 (95% CI: 0.51-0.83)] and MI [OR, 0.77 (95% CI: 0.63-0.95)] with add-on colchicine therapy. There was no reduction in cardiovascular/overall mortality. Gastrointestinal adverse events were less with low-dose colchicine than those with high dose. Add-on colchicine has reduced the inflammation in CAD as implicated by a decrease in inflammatory markers. It has also lowered the incidence of MI but not mortality. With this present trend, the authors recommend further trials to validate the effectiveness of add-on colchicine in the secondary prevention of CAD.

Effects of Anti-Inflammatory Treatment and Surgical Intervention on Endothelial Glycocalyx, Peripheral and Coronary Microcirculatory Function and Myocardial Deformation in Inflammatory Bowel Disease Patients: A Two-Arms Two-Stage Clinical Trial.

Sixty inflammatory bowel disease (IBD) patients (45 Crohn disease and 15 ulcerative colitis, 40 ± 13 years, 53% male) were examined at baseline and 4 months after intervention (surgical (35 patients) or anti-TNFa treatment (25 patients)). IBD severity, using Mayo score, Harvey–Bradshaw Index (HBI) and biomarkers, was correlated with cardiovascular markers. At baseline, the disease severity, the white blood cells (WBC) values and the reducing power (RP) were significantly correlated with the aortic pulse wave velocity (PWV) (r = 0.4, r = 0.44 and r = 0.48, p < 0.05) and the lateral mitral E’ velocity (r = 0.35, p < 0.05 and r = 0.3, p < 0.05). Four months after intervention, there was a reduction of WBC (1962.8/mm3 ± 0.425/mm3, p < 0.001), C-reactive protein (CRP) (8.1 mg/L ± 1.7 mg/L, p < 0.001), malondialdehyde (MDA) (0.81 nmol/mg ± 0.37, p < 0.05) and glycocalyx perfused boundary region (PBR 5-25) (0.24 μm ± 0.05 μm, p < 0.01). Moreover, the brachial flow mediated dilatation (FMD), the coronary flow reserve (CFR) and the left ventricle global longitudinal strain (LV GLS) were significantly improved for both groups (4.5% ± 0.9%, 0.55 ± 0.08, 1.4% ± 0.35%, p < 0.01), while a more significant improvement of PWV/GLS was noticed in the anti-TNFa group. IBD severity is associated with vascular endothelial, cardiac diastolic, and coronary microcirculatory dysfunction. The systemic inflammatory inhibition and the local surgical intervention lead to significant improvement in endothelial function, coronary microcirculation and myocardial deformation.

Astragaloside IV and Saponins of Rhizoma Polygonati Cure Cyclophosphamide-Induced Myelosuppression in Lung Adenocarcinoma via Down-Regulating miR-142-3p

Our previous study revealed that Shuanghuang Shengbai granule could cure the myelosuppression induced by cyclophosphamide (CTX) in lung cancer. However, its hematopoietic effects and molecular mechanisms remain not fully understood. Therefore, this study was intended to investigate the effects and the underlying mechanisms of Astragaloside IV (AS) and saponins of rhizoma polygonati (SRP), the two main bioactive ingredients of Shuanghuang Shengbai granule, on CTX-induced myelosuppression. CTX inhibited the proliferation and promoted apoptosis in bone marrow hematopoietic stem cells (BMHSCs), accompanied by the increased expression of miR-142-3p. AS and/or SRP treatment could alleviate CTX-induced cell injury and suppress the expression of miR-142-3p. Over-expression of miR-142-3p partially reversed the therapeutic effect of AS and/or SRP on CTX-induced cell injury in BMHSCs. Further mechanism exploration discovered that HMGB1 was the target gene of miR-142-3p, and miR-142-3p negatively regulated the expression of HMGB1. To further explore the function of AS and/or SRP in vivo, we constructed a lung cancer xenograft combined with CTX-induced myelosuppression mouse model, and we found that AS and SRP remarkably reversed the CTX-induced reduction of white blood cells, bone marrow nucleated cells, and thymus index in vivo and did not affect the chemotherapy effect of lung cancer. Collectively, our results strongly suggested that AS and SRP could improve the hematopoietic function of myelosuppressed lung cancer mice, and their effects may be related to the inhibition of miR-142-3p expression in BMHSCs.