[Effect of Low-Dose Recombinant Interleukin-2 Therapy on Immunocyte Subsets in Children with Solid Tumor].

OBJECTIVE: To evaluate the effect of low-dose recombinant interleukin-2 (rIL-2) therapy on immunocyte subsets and its side effects in children with solid tumor. METHODS: A total of 22 children (11 males and 11 females) with solid tumor in our department from December 2012 to November 2017 were selected, with a median age of 9 (3-16) years old when starting IL-2 therapy. ALL surgeries and chemotherapy of children had been completed before low-dose rIL-2 therapy, and 17 cases achieved complete remission (CR) and 5 cases achieved partial remission (PR). A low-dose rIL-2 therapy was given 1 month after chemotherapy for 1 year: 4×105 IU/(m2·d), s.c. for every other day, 3 times per week. The immunocyte subsets were detected every 3 months until the end of treatment, meanwhile, disease condition and therapy-related side effects were followed up. RESULTS: After low-dose rIL-2 therapy in 22 children, the absolute values of CD3+ T cells, CD3-CD56+ natural killer cells, CD3+CD4+ helper T cells (Th) and CD3+CD8+ cytotoxic T cells were up-regulated remarkably, as well as Th/suppressor T cells (all P < 0.05). While, there were no significant differences in absolute value and proportion of CD4+CD25+CD127- Treg cells during therapy. Among the 17 children who achieved CR before rIL-2 therapy, 14 cases continued to maintain CR after therapy, while 3 cases relapsed, and with 2 died after treatment abandonment. The 5 children who achieved PR before low-dose rIL-2 therapy were evaluated CR by PET/CT scan after treatment. In the early stage of low-dose rIL-2 therapy, 1 child developed skin rashes at the injection sites, and 2 children ran a slight to mild transient fever. Their symptoms disappeared without any organ damage after symptomatic treatment. CONCLUSION: Low-dose rIL-2 therapy has good drug tolerance, and changes the distribution of anti-tumor immune-cell subgroup in peripheral blood of children with solid tumor remarkably without up-regulation of absolute value and ratio of Treg cells.

[Effect of Recombinant Human Thrombopoietin on Platelet Reconstitution after Autologous Peripheral Blood Stem Cell Transplantation in Patients with Multiple Myeloma].

OBJECTIVE: To analyze the effect of recombinant human thrombopoietin (rhTPO) on platelet (PLT) reconstitution after autologous peripheral blood stem cell transplantation (APBSCT) in patients with multiple myeloma (MM). METHODS: The clinical data of 147 MM patients who were diagnosed in the First Affiliated Hospital of Soochow University and received APBSCT as the first-line therapy were retrospectively analyzed. According to whether rhTPO was used during APBSCT, the patients were divided into rhTPO group (80 cases) and control group (67 cases). The time of PLT engraftment, blood product infusion requirements, the proportion of patients with PLT recovery to≥50×109/L and≥100×109/L at +14 days and +100 days after transplantation, and adverse reactions including the incidence of bleeding were compared between the two groups. RESULTS: There were no significant differences between the two groups in sex, age, M protein type, PLT count at the initial diagnosis, median duration of induction therapy before APBSCT, and number of CD34+ cells reinfused (all P >0.05). The median time of PLT engraftment in the rhTPO group was 10 (6-14) days, which was shorter than 11 (8-23) days in the control group (P < 0.001). The median PLT transfusion requirement in the rhTPO group during APBSCT was 15(0-50)U, which was less than 20 (0-80)U in the control group (P =0.001). At +14 days after transplantation, the proportions of patients with PLT≥50×109/L in the rhTPO group and the control group were 66.3% and 52.2%, while the proportions of patients with PLT≥100×109/L were 23.8% and 11.9%, respectively, with no significant differences (all P >0.05). At +100 days after transplantation, the proportion of patients with PLT≥50×109/L in rhTPO group and control group was 96.3% and 89.6%, respectively (P >0.05), but the proportion of patients with PLT≥100×109/L in rhTPO group was higher than that in control group (75.0% vs 55.2%, P =0.012). There was no difference in the overall incidence of bleeding events in different locations during period of low PLT level of patients between the two groups. In rhTPO group, the rhTPO administration was well tolerated, and the incidences of abnormal liver and kidney function and infection were similar to those in the control group. CONCLUSION: When MM patients undergo first-line APBSCT, subcutaneous injection of rhTPO can shorten the time of platelet engraftment, reduce the transfusion volume of blood products, and be well tolerated, moreover, more patients have achieve a high level of PLT recovery after transplantation, which is very important for ensuring the safety of APBSCT and maintenance therapy.

Subcutaneous panniculitic-like T-cell lymphoma localized to a site of peginterferon alfa-2a administration.

T cell dyscrasias that demonstrate a proclivity for the subcutaneous fat include atypical lymphocytic lobular panniculitis, lupus profundus, and primary subcutaneous T cell lymphoma, including subcutaneous panniculitis-like T cell lymphoma (SPTCL). We encountered two patients who developed fever and indurated abdominal erythema at their peginterferon alfa-2a injection sites. Biopsies showed an atypical CD8 positive, granzyme positive, CD5 negative, MXA negative lymphocytic lobular panniculitis, diagnostic of SPTCL. Peginterferon alfa-2a was held in both patients. One patient received chemotherapy with an excellent response, while the other continued to have progressive disease. Peginterferon alfa-2a is known to significantly elevate serum MXA, which may induce high levels of MXA expression at the injection site, creating a microenvironment for the development of lupus profundus, which may eventuate into SPTCL. In summation, a potential risk of peginterferon alfa-2a injections is the development of SPTCL potentially arising in a background of an exogenous interferon triggered lymphocytic panniculitis.

Recombinant Deoxyribonuclease I Eye Drops for Ocular Graft Versus Host Disease: Results of a Randomized Clinical Trial.

OBJECTIVE: We have previously shown that neutrophil extracellular traps (NETs) are present on the ocular surface of patients with ocular graft versus host disease (oGVHD), contributing to inflammation and surface disease. Therefore, we performed a clinical trial using deoxyribonuclease I (DNAase) eye drops to test the hypothesis that reducing the abundance of NETs from the ocular surface will reduce signs and symptoms of oGVHD. METHODS: A prospective, phase I or II, randomized, placebo-controlled, double-masked clinical trial was performed to determine the safety and preliminary efficacy of DNAase (0.1%) eye drops four times daily for 8 weeks in patients with oGVHD (n=58). Intent-to-treat analysis was performed to determine the change in safety outcome measures (drug tolerability and proportion of adverse events) and efficacy outcome measures (ocular surface disease index [OSDI] score and corneal staining) between baseline and week 8. RESULTS: Tolerability and adverse events were similar in the vehicle and DNAase groups. Within the DNAase group (but not the vehicle group), corneal staining showed a statistically significant and clinically meaningful reduction at week 8 (3.50 [2.75; 5.00]) compared with baseline (5.00 [3.00; 7.00]). The OSDI score also showed a statistically significant clinically meaningful reduction of 18.4 (9.16; 33.1) ( P <0.001) at week 8 compared with baseline (45.5 [31.8; 50.0]) within the DNAase group. The proportion of eyes that had improvement in subjective global assessment (SGA) and mucous discharge was significantly greater in the DNAase group (55.6% and 57.7% at weeks 4 and 8, respectively; P <0.0001 at both time points) as compared with the vehicle group (35.7% and 34.0% at weeks 4 and 8, respectively). CONCLUSIONS: Treatment of patients with oGVHD using DNAase eye drops is safe and demonstrates preliminary efficacy. Deoxyribonuclease I eye drops can potentially reduce the severity of signs and symptoms of ocular surface disease in patients with oGVHD.

Efficacy of recombinant bovine basic fibroblast growth factor to reduce hemorrhage after cervical loop electrosurgical excision procedure.

OBJECTIVE: It has been reported that recombinant bovine basic fibroblast growth factor (rbFGF) may possess possible biological functions in promoting the process of wound healing. Consequently, our study aimed to investigate the hemostatic effect of topically applied rbFGF in patients who underwent a loop electrosurgical excision procedure (LEEP). METHODS: In this retrospective analysis, we meticulously examined clinicopathologic data from a cohort of 90 patients who underwent LEEP at our institution between 2020 and 2021. Subsequently, we conducted inquiries with the patients to ascertain the degree of vaginal bleeding experienced during the postoperative periods of 3 and 6 weeks, comparing it to their preoperative menstrual flow. The magnitude of the menstrual volume alteration was then quantified using a menstrual volume multiplier(MVM). The primary endpoints of our investigation were to assess the hemostatic effect of rbFGF by means of evaluating the MVM. Additionally, the secondary endpoints encompassed the assessment of treatment-related side effects of such as infection and dysmenorrhea. RESULTS: Our findings demonstrated a significant reduction in hemorrhage following cervical LEEP. Specifically, in the per-protocol analysis, the study group exhibited a statistically significantly decrease in MVM after 3 weeks (0 [0-0] vs. 1 [0-1], respectively; p < 0.001) and after 6 weeks (1 [1] vs. 2 [1-3], respectively; p < 0.001) of the procedure. No notable disparities were observed in the remaining outcomes between the two groups. Moreover, a logistic regression analysis was employed to explore the relationship between significant bleeding and rbFGF treatment (p < 0.001, OR = -2.47, 95% CI -4.07 ~-1.21), while controlling for confounding factors such as age, BMI, and surgical specimen. CONCLUSIONS: In conclusion, our study findings highlight that the application of recombinant bovine basic fibroblast growth factorcan effectively mitigate hemorrhage subsequent to cervical loop electrosurgical excision procedure.

Glibenclamide promotes FGF21 secretion in interscapular BAT and attenuates depression-like behaviors in male mice with HFD-induced obesity.

AIMS: Epidemiological evidence suggests that comorbidity of obesity and depression is extremely common and continues to grow in prevalence. However, the mechanisms connecting these two conditions are unknown. In this study, we explored how treatment with KATP channel blocker glibenclamide (GB) or the well-known metabolic regulator FGF21 impact male mice with high-fat diet (HFD)-induced obesity and depressive-like behaviors. MATERIALS AND METHODS: Mice were fed with HFD for 12 weeks and then treated with recombinant FGF21 protein by infusion for 2 weeks, followed by intraperitoneal injection of 3 mg/kg recombinant FGF21 once per day for 4 days. Measurements were made of catecholamine levels, energy expenditure, biochemical endpoints and behavior tests, including sucrose preference and forced swim tests were. Alternatively, animals were infused with GB into brown adipose tissue (BAT). The WT-1 brown adipocyte cell line was used for molecular studies. KEY FINDINGS: Compared to HFD controls, HFD + FGF21 mice exhibited less severe metabolic disorder symptoms, improved depressive-like behaviors, and more extensive mesolimbic dopamine projections. FGF21 treatment also rescued HFD-induced dysregulation of FGF21 receptors (FGFR1 and co-receptor ß-klotho) in the ventral tegmental area (VTA), and it altered dopaminergic neuron activity and morphology in HFD-fed mice. Importantly, we also found that FGF21 mRNA level and FGF21 release were increased in BAT after administration of GB, and GB treatment to BAT reversed HFD-induced dysregulation of FGF21 receptors in the VTA. SIGNIFICANCE: GB administration to BAT stimulates FGF21 production in BAT, corrects HFD-induced dysregulation of FGF21 receptor dimers in VTA dopaminergic neurons, and attenuates depression-like symptoms.

Phase 1 Trial of Antibody NI006 for Depletion of Cardiac Transthyretin Amyloid.

BACKGROUND: Transthyretin amyloid (ATTR) cardiomyopathy is a progressive and fatal disease caused by misfolded transthyretin. Despite advances in slowing disease progression, there is no available treatment that depletes ATTR from the heart for the amelioration of cardiac dysfunction. NI006 is a recombinant human anti-ATTR antibody that was developed for the removal of ATTR by phagocytic immune cells. METHODS: In this phase 1, double-blind trial, we randomly assigned (in a 2:1 ratio) 40 patients with wild-type or variant ATTR cardiomyopathy and chronic heart failure to receive intravenous infusions of either NI006 or placebo every 4 weeks for 4 months. Patients were sequentially enrolled in six cohorts that received ascending doses (ranging from 0.3 to 60 mg per kilogram of body weight). After four infusions, patients were enrolled in an open-label extension phase in which they received eight infusions of NI006 with stepwise increases in the dose. The safety and pharmacokinetic profiles of NI006 were assessed, and cardiac imaging studies were performed. RESULTS: The use of NI006 was associated with no apparent drug-related serious adverse events. The pharmacokinetic profile of NI006 was consistent with that of an IgG antibody, and no antidrug antibodies were detected. At doses of at least 10 mg per kilogram, cardiac tracer uptake on scintigraphy and extracellular volume on cardiac magnetic resonance imaging, both of which are imaging-based surrogate markers of cardiac amyloid load, appeared to be reduced over a period of 12 months. The median N-terminal pro-B-type natriuretic peptide and troponin T levels also seemed to be reduced. CONCLUSIONS: In this phase 1 trial of the recombinant human antibody NI006 for the treatment of patients with ATTR cardiomyopathy and heart failure, the use of NI006 was associated with no apparent drug-related serious adverse events. (Funded by Neurimmune; NI006-101 ClinicalTrials.gov number, NCT04360434.).

[Andexanet alfa (ONDEXXYA® for Intravenous Injection 200†mg), a reversal agent for direct factor Xa inhibitors: pharmacological characteristics and clinical evidence].

Andexanet alfa is a modified recombinant human factor Xa (FXa) that was designed to serve as a binding target for FXa inhibitors as decoy protein. It sequesters FXa inhibitors from binding to endogenous FXa, thereby reversing anticoagulant effect of FXa inhibitors. Andexanet alfa has been approved in March 2022 in Japan for patients with life-threatening or uncontrolled bleeding while on treatment with a FXa inhibitor, apixaban, rivaroxaban, or edoxaban tosilate hydrate. It is administered via two dosing regimens, based on the type of FXa inhibitor, dose, and time since the last dose. In nonclinical studies, andexanet alfa significantly inhibited bleeding induced by FXa inhibitors in animal bleeding models. In the development for Japanese patients, the following two clinical studies have been conducted to confirm the efficacy and safety. First, safety and the reversal effect of andexanet alfa on the FXa inhibitor-mediated anticoagulant activity in healthy adults were confirmed in the overseas phase 2 study including Japanese subjects. Next, the reversal effect of andexanet alfa on the anticoagulation activity and the hemostasis were demonstrated in patients with acute major bleeding while on FXa inhibitor treatment in the global phase 3b/4 study (ANNEXA-4 study). The subgroup analysis of Japanese population showed that the efficacy and safety results were consistent with those of overall population. Andexanet alfa is the first approved reversal agent for FXa inhibitors in Japan and is expected to contribute to the improvement of prognosis in patients with fatal and/or uncontrolled bleeding by timely reversing anticoagulant effect of FXa inhibitors.

Ciprofloxacin and pegylated G-CSF combined therapy mitigates brain hemorrhage and mortality induced by ionizing irradiation.

Introduction: Brain hemorrhage was found between 13 and 16 days after acute whole-body 9.5 Gy 60Co-γ irradiation (IR). This study tested countermeasures mitigating brain hemorrhage and increasing survival from IR. Previously, we found that pegylated G-CSF therapy (PEG) (i.e., Neulasta®, an FDA-approved drug) improved survival post-IR by 20-40%. This study investigated whether Ciprofloxacin (CIP) could enhance PEG-induced survival and whether IR-induced brain hemorrhage could be mitigated by PEG alone or combined with CIP. Methods: B6D2F1 female mice were exposed to 60Co-γ-radiation. CIP was fed to mice for 21 days. PEG was injected on days 1, 8, and 15. 30-day survival and weight loss were studied in mice treated with vehicles, CIP, PEG, or PEG + CIP. For the early time point study, blood and sternums on days 2, 4, 9, and 15 and brains on day 15 post-IR were collected. Platelet numbers, brain hemorrhage, and histopathology were analyzed. The cerebellum/pons/medulla oblongata were detected with glial fibrillary acidic protein (GFAP), p53, p16, interleukin-18 (IL-18), ICAM1, Claudin 2, ZO-1, and complement protein 3 (C3). Results: CIP + PEG enhanced survival after IR by 85% vs. the 30% improvement by PEG alone. IR depleted platelets, which was mitigated by PEG or CIP + PEG. Brain hemorrhage, both surface and intracranial, was observed, whereas the sham mice displayed no hemorrhage. CIP or CIP + PEG significantly mitigated brain hemorrhage. IR reduced GFAP levels that were recovered by CIP or CIP + PEG, but not by PEG alone. IR increased IL-18 levels on day 4 only, which was inhibited by CIP alone, PEG alone, or PEG + CIP. IR increased C3 on day 4 and day 15 and that coincided with the occurrence of brain hemorrhage on day 15. IR increased phosphorylated p53 and p53 levels, which was mitigated by CIP, PEG or PEG + CIP. P16, Claudin 2, and ZO-1 were not altered; ICAM1 was increased. Discussion: CIP + PEG enhanced survival post-IR more than PEG alone. The Concurrence of brain hemorrhage, C3 increases and p53 activation post-IR suggests their involvement in the IR-induced brain impairment. CIP + PEG effectively mitigated the brain lesions, suggesting effectiveness of CIP + PEG therapy for treating the IR-induced brain hemorrhage by recovering GFAP and platelets and reducing C3 and p53.

Secretory Leucoprotease Inhibitor (SLPI) Promotes Survival during Acute Pseudomonas aeruginosa Infection by Suppression of Inflammation Rather Than Microbial Killing.

Secretory leucoprotease inhibitor (SLPI) has multifaceted functions, including inhibition of protease activity, antimicrobial functions, and anti-inflammatory properties. In this study, we show that SLPI plays a role in controlling pulmonary Pseudomonas aeruginosa infection. Mice lacking SLPI were highly susceptible to P. aeruginosa infection, however there was no difference in bacterial burden. Utilising a model of P. aeruginosa LPS-induced lung inflammation, human recombinant SLPI (hrSLPI) administered intraperitoneally suppressed the recruitment of inflammatory cells in the bronchoalveolar lavage fluid (BALF) and resulted in reduced BALF and serum levels of inflammatory cytokines and chemokines. This anti-inflammatory effect of hrSLPI was similarly demonstrated in a systemic inflammation model induced by intraperitoneal injection of LPS from various bacteria or lipoteichoic acid, highlighting the broad anti-inflammatory properties of hrSLPI. Moreover, in bone-marrow-derived macrophages, hrSLPI reduced LPS-induced phosphorylation of p-IkB-α, p-IKK-α/ß, p-P38, demonstrating that the anti-inflammatory effect of hrSLPI was due to the inhibition of the NFκB and MAPK pathways. In conclusion, administration of hrSLPI attenuates excessive inflammatory responses and is therefore, a promising strategy to target inflammatory diseases such as acute respiratory distress syndrome or sepsis and could potentially be used to augment antibiotic treatment.

Survey of Anaphylaxis during Rasburicase Re-Administration in Patients with Hematological Malignancies Using a Japanese Claims Database.

Management of tumor lysis syndrome (TLS) associated with cancer chemotherapy for malignant tumors is important because of its potentially fatal course. The use of rasburicase, a recombinant urate oxidase, is recommended for TLS; however, because rasburicase is an enzymatic drug, one should be cautious of anaphylaxis during administration. Using claims data in Japan, we investigated the rate of rasburicase re-administration and the occurrence of anaphylaxis during re-administration in patients with hematopoietic malignancies in a multicenter setting. Re-administration of rasburicase was defined as administration after an interval of 21 days from the first dose. Of 373 patients, 18 were re-administered rasburicase (re-administration rate: 4.8%). No patient developed anaphylaxis. The median number of days from the first to the last dose of rasburicase was 256.5 days (interquartile range: 138.8-455.8 days). The median daily dose was 7.5 mg (4.5-11.3 mg), and the median total dose was 33.8 mg (19.1-64.1 mg). This claims database analysis revealed that the re-administration rate of rasburicase was low in Japanese patients with hematopoietic malignancies, suggesting that rasburicase was being used appropriately, and that associated anaphylaxis was not observed.

Safety and efficacy of a new modified intravenous recombinant tissue plasminogen activator (rt-PA) regimen in Chinese patients with acute ischemic stroke: A descriptive retrospective cohort study with subgroup-analysis of different rt-PA dose.

Evidence for effects of the dose of recombinant tissue plasminogen activator(rt-PA) in Asian populations is inconclusive. The standard dose may cause drug waste and increase economic burden in developing country. Therefore, we preliminarily describe the safety and efficacy of a new modified dose of rt-PA regimen(0.6 or 0.9 mg/kg, with a maximum dose of 50 mg) in real world settings. 265 consecutive patients with ischemic stroke were treated with intravenous(IV) rt-PA alone from all the 323 consecutive patients treated with reperfusion therapy between January 1, 2017 and March 31, 2020. Safety and Efficacy was assessed by early neurological improvement(ENI), early neurological deterioration(END), symptomatic intracranial hemorrhage(sICH) and 90-day outcome defined by modified Rankin scale(mRS). Subgroup analysis was conducted to draw comparisons between different dose groups ([0.5,0.6)mg/kg, [0.6,0.7)mg/kg, [0.7,0.8)mg/kg, [0.8,0.9]mg/kg). Among the 265 patients, 150(56.60%) had a favorable outcome at 3 months(3 M); Mortality occurred in 17(6.40%) in 3 M; sICH in 12(4.50%); ENI in 70(26.40%); END2 in 29(10.90%) and END4 in 18(6.80%). In subgroup analysis, there was a significant difference in sICH that more patients developed sICH in [0.8-0.9]mg/kg group(P = 0.044) in univariate analysis of different dose. After adjusting, there was no significant difference between 4 dosage groups. Significant differences were seen in gender, atrial fibrillation and baseline NIHSS in the multivariable model of favorable outcome at 3 M. Our study preliminarily shows a good safety and efficacy of our modified rt-PA regimen, indicating that this regimen should be worthy of further study especially in developing country to reduce the financial burden of patients and avoid drug waste.

Plasma-derived FVIII/VWF complex shows higher protection against inhibitors than isolated FVIII after infusion in haemophilic patients: A translational study.

INTRODUCTION: Presence of von Willebrand factor (VWF) in FVIII concentrates offers protection against neutralizing inhibitors in haemophilia A (HA). Whether this protection is more evident in plasma-derived (pd) FVIII/VWF or recombinant (r) FVIII concentrates remains controversial. AIM: We investigated the protection exerted by VWF against FVIII inhibitors in an in vivo mouse model of HA exposed to pdFVIII/VWF or to various rFVIII concentrates. METHODS: Haemophilia A mice received the different FVIII concentrates after administration of vehicle or an inhibitory IgG purified from a commercial pool of HA plasma with inhibitors and FVIII:C recoveries were measured. Furthermore, using a novel clinically oriented ex vivo approach, Bethesda inhibitory activities (BU) of a commercial pool of HA plasma with inhibitors were assessed using normal plasma, or plasma from severe HA patients, without inhibitors, after treatment with the same concentrates. RESULTS: in vivo studies showed that pdFVIII/VWF offers markedly higher protection against inhibitors when compared with any of the FVIII products without VWF. More importantly, in the ex vivo studies, plasma from patients treated with pdFVIII/VWF showed higher protection against inhibitors (P values ranging .05-.001) in comparison with that observed in plasma from patients who received FVIII products without VWF, regardless of the type of product evaluated. CONCLUSION: Data indicate that FVIII+VWF complexes assembled in the circulation after rFVIII infusion are not equivalent to the naturally formed complex in pdFVIII/VWF. Therefore, rFVIII infused into HA patients with inhibitors would be less protected by VWF than the FVIII in pdFVIII/VWF concentrates.

Metabolic Impacts of Discontinuation and Resumption of Recombinant Human Growth Hormone Treatment during the Transition Period in Patients with Childhood-Onset Growth Hormone Deficiency.

BACKGROUND: Discontinuing growth hormone (GH) treatment during the transition to adulthood has been associated with adverse health outcomes in patients with childhood-onset growth hormone deficiency (CO-GHD). This study investigated the metabolic changes associated with interrupting GH treatment in adolescents with CO-GHD during the transition period. METHODS: This study included 187 patients with CO-GHD who were confirmed to have adult GHD and were treated at six academic centers in Korea. Data on clinical parameters, including anthropometric measurements, metabolic profiles, and bone mineral density (BMD) at the end of childhood GH treatment, were collected at the time of re-evaluation for GHD and 1 year after treatment resumption. RESULTS: Most patients (n=182, 97.3%) had organic GHD. The median age at treatment discontinuation and re-evaluation was 15.6 and 18.7 years, respectively. The median duration of treatment interruption was 2.8 years. During treatment discontinuation, body mass index Z-scores and total cholesterol, low-density lipoprotein, and non-high-density lipoprotein (HDL) cholesterol levels increased, whereas fasting glucose levels decreased. One year after GH treatment resumption, fasting glucose levels, HDL cholesterol levels, and femoral neck BMD increased significantly. Longer GH interruption (>2 years, 60.4%) resulted in worse lipid profiles at re-evaluation. The duration of interruption was positively correlated with fasting glucose and non-HDL cholesterol levels after adjusting for covariates. CONCLUSION: GH treatment interruption during the transition period resulted in worse metabolic parameters, and a longer interruption period was correlated with poorer outcomes. GH treatment should be resumed early in patients with CO-GHD during the transition period.

The optimal period for oocyte retrieval after the administration of recombinant human chorionic gonadotropin in in vitro fertilization.

BACKGROUND: Our objective was to investigate the existence of an optimal period for oocyte retrieval in regards to the clinical pregnancy occurrence after the administration of recombinant human chorionic gonadotropin (rhCG) (Ovitrelle®). METHODS: We studied the digital records of 3362 middle eastern couples who underwent in vitro fertilization (IVF) treatment between 2019 and 2021. RESULTS: Through statistical testing, we found that there is a significant positive correlation between the oocyte retrieval period and the clinical pregnancy occurrence up to the 37th hour, where retrieval at the 37th hour was found to provide the most optimal outcome, especially in the case of gonadotropin-releasing hormone agonist (GnRHa) long protocol. CONCLUSIONS: This cohort study recommends retrieval at hour 37 after ovulation triggering under the described conditions.

A journey through anticoagulant therapies in the treatment of left ventricular thrombus in post-COVID-19 heparin-induced thrombocytopenia: a case report.

BACKGROUND: Heparin-induced thrombocytopenia (HIT) is an immune-mediated adverse drug reaction associated with thrombosis. Clinical scoring systems and the presence of anti-platelet factor 4 (anti-PF4)/heparin antibodies determine the diagnosis. CASE PRESENTATION: A 57-year-old man who was treated with acenocoumarol due to a chronic left ventricular thrombus was admitted to the hospital for severe SARS-CoV-2 pneumonia and pulmonary embolism. The patient was started on bemiparin and discharged. Left lower limb acute arterial ischemia and thrombocytopenia were diagnosed 18 days later. Computed tomography angiography revealed a large left ventricular thrombus and multiple arterial thrombi. Left femoral-popliteal thromboembolectomy was performed. Anti-PF4/heparin antibodies confirmed an HIT diagnosis. Fondaparinux (7.5 mg/24 h) was initiated, but cardiac surgery was necessary. Bivalirudin was used during surgery, with an initial load (1.25 mg/kg) and maintenance infusion (2.5 mg/kg/h). The cardiac thrombus was extracted, but the patient experienced a postsurgical myocardial infarction. Percutaneous cardiovascular intervention (PCI) required a bivalirudin load (0.75 mg/kg) and maintenance infusion (1.75 mg/kg/h). No coronary lesions were detected, and argatroban was started afterwards (0.5 µg/kg/min). When the platelet count exceeded 100 × 109/L, acenocoumarol was initiated. Thereupon, acetylsalicylic acid (100 mg/24 h) was added. No other complications have been reported to date. CONCLUSION: The clinical presentation of intraventricular and multiple arterial thrombi is remarkable. SARS-CoV-2 infection likely contributed to a hypercoagulable state. The management of patients with HIT undergoing cardiac surgery is challenging. If surgery cannot be delayed, then treatment with bivalirudin is recommended. Additionally, this drug is recommended for PCI. Bivalirudin is safe and well-tolerated in both procedures.

Osteopontin on the Dental Implant Surface Promotes Direct Osteogenesis in Osseointegration.

After dental implantation, osteopontin (OPN) is deposited on the hydroxyapatite (HA) blasted implant surface followed by direct osteogenesis, which is significantly disturbed in Opn-knockout (KO) mice. However, whether applying OPN on the implant surface promotes direct osteogenesis remains unclarified. This study analyzed the effects of various OPN modified protein/peptides coatings on the healing patterns of the bone-implant interface after immediately placed implantation in the maxilla of four-week-old Opn-KO and wild-type (WT) mice (n = 96). The decalcified samples were processed for immunohistochemistry for OPN and Ki67 and tartrate-resistant acid phosphatase histochemistry. In the WT mice, the proliferative activity in the HA binding peptide-OPN mimic peptide fusion coated group was significantly higher than that in the control group from day 3 to week 1, and the rates of OPN deposition and direct osteogenesis around the implant surface significantly increased in the recombinant-mouse-OPN (rOPN) group compared to the Gly-Arg-Gly-Asp-Ser peptide group in week 2. The rOPN group achieved the same rates of direct osteogenesis and osseointegration as those in the control group in a half period (week 2). None of the implant surfaces could rescue the direct osteogenesis in the healing process in the Opn-KO mice. These results suggest that the rOPN coated implant enhances direct osteogenesis during osseointegration following implantation.

Effect of growth hormone therapy on liver enzyme and other cardiometabolic risk factors in boys with obesity and nonalcoholic fatty liver disease.

BACKGROUND: Non-alcoholic fatty liver disease (NAFLD) has become the most common causes of liver disease in children and adolescents. Although several reports have confirmed the significant correlation between NAFLD and growth hormone (GH)-insulin-like growth factor 1(IGF-1) axis, no study further investigates whether or not recombinant human GH (rhGH) treatment can improve NAFLD in obese children. METHODS: This study was a randomized, open-label study comprising 44 boys with obesity and NAFLD (11.76 ± 1.67 year) to evaluate the effects of 6 months of rhGH administration for boys with obesity and NAFLD. The subjects were randomized divided into treatment group (subjects with recombinant human GH (rhGH)) and control group for 6 months. RESULTS: After 6 months, IGF-1 increased significantly during rhGH treatment, in comparison with the control group (582.45 ± 133.00 vs. 359.64 ± 129.00 ng/ml; p < 0.001). A significant reduction in serum alanine aminotransferase(ALT) (15.00 vs. 28.00 U/L; p = 0.001), aspartate aminotransferase(AST) (20.00 vs. 24.50U/L; p = 0.004), gamma glutamyl transferase(GGT) (14.50 vs. 28.50 U/L; p < 0.001) was observed in the GH-treated boys. In addition, the rhGH group showed a significant decrease in C reactive protein (CRP) (1.17 ± 0.76 vs. 2.26 ± 1.43 mg/L) and body mass index standard deviation scores (BMI SDS) (2.28 ± 0.80 vs. 2.71 ± 0.61) than the control group (p = 0.003, p = 0.049 respectively). GH treatment also reduced low density lipoprotein cholesterol (LDL-C) (2.19 ± 0.42 vs. 2.61 ± 0.66 mmol/L; p = 0.016) and increased high density lipoprotein cholesterol (HDL-C) (1.30 vs. 1.15 mmol/L; p = 0.005), and there were no changes in total cholesterol (TC), triglycerides (TG) and uric acid(UA) between the treatment group and the control group. CONCLUSION: Our findings suggest that 6 months treatment with rhGH may be beneficial for liver enzyme and can improve obesity-related other cardiovascular and metabolic complications in boys with obesity and NAFLD.

Intraperitoneal infusion of recombinant human endostatin improves prognosis in gastric cancer ascites.

Objective: To investigate the efficacy and safety of intraperitoneal administration of recombinant human endostatin in gastric cancer with malignant ascites. Methods: Clinical data of 90 patients (37 in an Endostar® combined with cisplatin group and 53 in a cisplatin group) were retrospectively analyzed. The primary end point was overall survival, and the secondary end points were objective response rate (ORR), disease control rate (DCR) and so on. Results: Median overall survival was longer in the combination group (9.7 vs 8.1 months; p = 0.01). ORR and DCR were higher in the combination group (ORR: 75.7% vs 54.7%; p = 0.04; DCR: 94.6% vs 75.5%; p = 0.02). There were no significant differences in adverse effects between the two groups. Conclusion: Intraperitoneal administration of recombinant human endostatin improved efficacy and survival for gastric cancer with ascites.

Ascites (a buildup of fluid in the abdomen) resulting from the spread of gastric cancer (GC) results in extremely poor clinical outcomes, and current treatments have shown little effectiveness. Previous results showed that abdominal injection with chemotherapeutic agents enabled an increase in the dose of chemotherapeutic agents and reduced side effects or undesirable effects in the abdominal cavity. This study aimed to investigate the effectiveness and safety of abdominal injection with the anticancer drug recombinant human endostatin in GC with ascites. Clinical data of 90 patients were inspected and analyzed in this study. Thirty-seven patients who received abdominal infusion with both cisplatin (CDDP) and recombinant human endostatin were included in an Endostar^® combined with CDDP group, and 53 patients who received abdominal infusion with CDDP alone were included in a CDDP group. The results showed that median survival time was longer in the combination group than in the CDDP group (9.7 months vs 8.1 months). Besides, therapeutic outcomes, including objective response rate and disease control rate, were better in the combination group. Side effects or undesirable effects were similar in the two groups. To conclude, abdominal injection with recombinant human endostatin improved survival time and therapeutic outcomes for GC patients with ascites.