[Clinical Efficacy and Safety of Ixazomib-Containing Regimens in the Treatment of Patients with Multiple Myeloma].

OBJECTIVE: To investigate the clinical efficacy and safety of ixazomib-containing regimens in the treatment of patients with multiple myeloma (MM). METHODS: A retrospective analysis was performed on the clinical efficacy and adverse reactions of 32 MM patients treated with a combined regimen containing ixazomib in the Hematology Department of the First People's Hospital of Lianyungang from January 2020 to February 2022. Among the 32 patients, 15 patients were relapsed and refractory multiple myeloma (R/RMM) (R/RMM group), 17 patients who responded to bortezomib induction therapy but converted to ixazomib-containing regimen due to adverse events (AE) or other reasons (conversion treatment group). The treatment included IPD regimen (ixazomib+pomalidomide+dexamethasone), IRD regimen (ixazomib+lenalidomide+dexamethasone), ICD regimen (ixazomib+cyclophosphamide+dexamethasone), ID regimen (ixazomib+dexamethasone). RESULTS: Of 15 R/RMM patients, overall response rate (ORR) was 53.3%(8/15), among them, 1 achieved complete response (CR), 2 achieved very good partial response (VGPR) and 5 achieved partial response (PR). The ORR of the IPD, IRD, ICD and ID regimen group were 100%（3/3）, 42.9%（3/7）, 33.3%（1/3）, 50%（1/2）， respectively， there was no statistically significant difference in ORR between four groups (χ 2=3.375, P =0.452). The ORR of patients was 50% after first-line therapy, 42.9% after second line therapy, 60% after third line therapy or more, with no statistically significant difference among them (χ2=2.164, P =0.730). In conversion treatment group, ORR was 88.2%(15/17), among them, 6 patients achieved CR, 5 patients achieved VGPR and 4 patients achieved PR. There was no statistically significant difference in ORR between the IPD（100%， 3/3）, IRD（100%， 6/6）, ICD（100%， 3/3） and ID（60%， 3/5） regimen groups (χ2=3.737，P =0.184). The median progression-free survival (PFS) time of R/RMM patients was 9 months (95% CI : 6.6-11.4 months), the median overall survival (OS) time was 18 months (95% CI : 11.8-24.4 months). The median PFS time of conversion treatment group was 15 months (95% CI : 7.3-22.7 months), the median OS time not reached. A total of 10 patients suffered grade 3- 4 adverse event (AE). The common hematological toxicities were leukocytopenia, anemia, thrombocytopenia. The common non-hematological toxicities were gastrointestinal symptoms (diarrhea, nausea and vomit), peripheral neuropathy, fatigue and infections. Grade 1-2 peripheral neurotoxicity occurred in 7 patients. CONCLUSION: The ixazomib-based chemotherapy regimens are safe and effective in R/RMM therapy, particularly for conversion patients who are effective for bortezomib therapy. The AE was manageable and safe.

[Efficacy and Safety of Decitabine Combined with Modified EIAG Regimen in the Treatment of Patients with Relapsed/Refractory Acute Myeloid Leukemia and High-risk Myelodysplastic Syndrome].

OBJECTIVE: To investigate the efficacy, prognosis and safety of decitabine combined with modified EIAG regimen in the treatment of patients with relapsed/refractory acute myeloid leukemia (AML) and high-risk myelodysplastic syndrome (MDS). METHODS: The clinical data of 44 patients with relapsed/refractory AML and high-risk MDS admitted to our hospital from January 2017 to December 2020 were analyzed retrospectively. The patients were equally divided into D-EIAG group (decitabine combined with EIAG regimen) and D-CAG group (decitabine combined with CAG regimen) according to clinical treatment regimen. The complete response (CR), CR with incomplete hematologic recover (CRi), morphologic leukemia-free state (MLFS), partial response (PR), overall response rate (ORR), modified composite complete response (mCRc), overall survival (OS) time, 1-year OS rate, myelosuppression and adverse reactions between the two groups were compared. RESULTS: In D-EIAG group, 16 patients (72.7%) achieved mCRc (CR+CRi+MLFS), 3 patients (13.6%) achieved PR, and ORR (mCRc+PR) was 86.4%. In D-CAG group, 9 patients (40.9%) achieved mCRc, 6 patients (27.3%) achieved PR, and ORR was 68.2%. Difference was observed in mCRc rate between the two groups (P=0.035), but not in ORR (P>0.05). The median OS time of D-EIAG group and D-CAG group was 20 (2-38) months and 16 (3-32) months, and 1-year OS rate was 72.7% and 59.1%, respectively. There was no significant difference in 1-year OS rate between the two groups (P>0.05). After induction chemotherapy, the median time for absolute neutrophil count recovery to 0.5×109/L in D-EIAG group and D-CAG group was 14 (10-27) d and 12 (10-26) d, for platelet count recovery to 20×109/L was 15 (11-28) d and 14 (11-24)d, the median red blood cell suspension transfusion volume was 8 (6-12) U and 6 (6-12) U, and the median apheresis platelet transfusion volume was 4 (2-8) U and 3 (2-6) U, respectively. There were no statistically significant differences in comparison of the above indicators between the two groups (P>0.05). The hematological adverse reactions of patients were mainly myelosuppression. Grade III-IV hematological adverse events occurred in both groups (100%), with no increase in the incidence of non-hematological toxicities such as gastrointestinal reactions or liver function damage. CONCLUSION: Decitabine combined with EIAG regimen in the treatment of relapsed/refractory AML and high-risk MDS can improve remission rate, provide an opportunity for subsequent therapies, and have no increase in adverse reactions compared with D-CAG regimen.

Hen Egg Lysozyme Alleviates Static Mechanical Pain Via NRF1-Parkin-TACAN Signaling Axis in Sensory Neurons.

Mechanical allodynia impinges on the life quality of patients. Hen Egg Lysozyme (HEL) is a substance extracted from eggs that is commonly used to inhibit bacterial activity. The role of HEL in regulating and treating pain is unclear. Here, we find that HEL selectively attenuates static mechanical allodynia of mice induced by complete Freund's adjuvant (CFA), spinal nerve ligation (SNL) and chemotherapeutic agent. RNA-seq screening reveals that CFA significantly reduces the expression of Parkin in dorsal root ganglion (DRG) neurons of mice, while pre-administration of HEL increases the expression of Parkin and remits the static mechanical allodynia induced by Parkin-siRNA. Moreover, HEL increases the interaction between nuclear respiratory factor 1 (NRF1) and histone acetyltransferase P300 and then enhances the NRF1 mediated histone acetylation in prkn promoter region in DRGs of mice. Further, Parkin interacts with mechanotransducing ion channel TACAN (Tmem120a) and knockdown of Parkin significantly increases the membrane trafficking of TACAN in sensory neurons of mice. While pre-administration of HEL inhibits the increased membrane trafficking of TACAN in sensory neurons of mice induced by Parkin-siRNA. In addition, pre-given of HEL also significantly attenuates the static mechanical allodynia induced by overexpression of TACAN in mice, and the effect of HEL can be blocked by Parkin-siRNA. This indicates that HEL increases the expression of Parkin through epigenetic mechanisms and then decreases TACAN membrane trafficking in sensory neurons to relieve static mechanical hypersensitivity. Therefore, we reveal a novel function of HEL, which is a potential substance for the treatment of static mechanical pain.

Open-mouth N-doped carbon nanoboxes embedded with mixed metal phosphide nanoparticles as high-efficiency catalysts for electrolytic water splitting.

The key to develop efficient catalysts is to improve the quantity and activity of catalytic sites of the catalysts through optimal structural and compositional design. Accordingly, open-mouth N-doped carbon nanoboxes embedded with mixed metal phosphide nanoparticles are fabricated from monodisperse Ni3[Fe(CN)6]2·H2O nanocubes through conformal Ni3[Co(CN)6]2·12H2O layer coating, ammonia etching, and thermal phosphorization, sequentially. The product catalyst exhibits highly efficient electrocatalytic performances, achieving low overpotentials of 204 and 129 mV for the oxygen evolution reaction and hydrogen evolution reaction, respectively, and a small working voltage of 1.57 V for the overall water splitting, all at 10 mA cm-2. Its long-term electrocatalytic stability is also outstanding, experiencing only minor chronopotentiometric decay after a 24 h operation at 10 mA cm-2. The enhanced electrocatalytic performance may be attributed to the synergistic effects between the mixed metal phosphides, the protective function offered by the chainmail catalyst design, and the fast mass transport channels for the electrolyte and gaseous products afforded by the large openings on the nanobox shell, as well as the easy access of the inner active sites of the nanobox. The ingenious open-mouth nanobox structure together with embedded mixed metal phosphide nanoparticles is a unique design for improving the quantity and activity of catalytic sites of the catalyst for high efficiency electrolytic water splitting. The present design concept can be readily applied to the fabrication of other heterogeneous catalysts.

Mixed Metal Phosphide Chainmail Catalysts Confined in N-Doped Porous Carbon Nanoboxes as Highly Efficient Water-Oxidation Electrocatalysts with Ultralow Overpotentials and Tafel Slopes.

Electrocatalytic hydrogen production driven by surplus electric energies is considered a promising sustainable process for hydrogen supply. The high overpotential and low energy-conversion efficiency caused by the slow kinetics of the four-electron transfer oxygen-evolution reaction (OER), however, hamper its competitiveness. Herein, a highly stable, efficient OER catalyst was developed, taking the effects of both composition and nanostructure into account for the catalyst design. N-doped carbon-armored mixed metal phosphide nanoparticles confined in N-doped porous carbon nanoboxes, a particle-in-box nanostructure, were synthesized from monodisperse Ni3[Fe(CN)6]2·H2O nanocubes through sequential conformal polydopamine coating, ammonia etching, and thermal phosphorization. The product exhibited outstanding catalytic abilities for the OER in 1.0 M KOH, delivering 10, 100, and 250 mA/cm2 at ultrasmall overpotentials of 203, 242, and 254 mV, respectively, with an ultrasmall Tafel slope of 38 mV/dec, outperforming most recently reported top-notch iron-group-based OER catalysts. The long-term stability was also excellent, showing a small chronopotentiometric decay of 2.5% over a 24 h operation at 50 mA/cm2. The enhanced catalytic efficiency and stability may be attributable to the unique particle-in-box structure as a nanoreactor offering a local, fast reaction environment, the conductive N-doped porous carbon shell for fast charge and mass transport, the synergistic effect between multicomponent metal phosphides for enhanced intrinsic activities, and the carbon protection layer to prevent/delay the catalyst core from being deactivated. This combined particle-in-box and chainmail design concept for electrocatalysts is unique and advantageous and may be readily applied to the general field of heterogeneous reactions.

N-doped carbon armored metal phosphides grown in-situ on nickel foam as chainmail catalysts toward high efficiency electrolytic water splitting.

N-doped carbon armored metal phosphides were anchored in-situ on backbones of nickel foam (NF), by using polydopamine as both carbon source and targeted precursor delivery vehicle. The product served as a highly efficient chainmail bi-functional catalyst toward electrolytic water splitting, requiring small operating cell voltages of only 1.65, 1.73, and 1.79 V at 50, 100, and 250 mA/cm2, respectively for overall water splitting. More importantly, the product catalyst also possessed excellent long-term stability, even tested at 250 mA/cm2. The excellent activity and durability may be ascribed to the positive synergistic effects between well-mixed metal phosphides, advantageous nanostructure of interwoven thin vertical nanosheets, protective and conductive N-doped carbon matrix, hydrophilic and aerophobic characteristics, and well dispersed and utilized active materials on skeleton surfaces of the highly conductive NF. This synergistic effect boosting and protective layer armored design for highly efficient and stable electrocatalysts is unique and scalable, suitable for large-scale applications not only in the field of electrocatalysis, but also in other heterogeneous catalysis.

Pharmacokinetics of ceftiofur sodium in cats following a single intravenous and subcutaneous injection.

Ceftiofur, a third-generation cephalosporin antibiotic, is being extensively used by pet doctors in China. In the current study, the detection method was developed for ceftiofur and its metabolites, desfuroylceftiofur (DCE) and desfuroylceftiofur conjugates (DCEC), in feline plasma. Then, the pharmacokinetics studies were performed following one single intravenous and subcutaneous injection of ceftiofur sodium in cats both at 5 mg/kg body weight (BW) (calculated as pure ceftiofur). Ceftiofur, DCE, and DCEC were extracted from plasma samples, then derivatized and further quantified by high-performance liquid chromatography. The concentrations versus time data were subjected to noncompartmental analysis to obtain the pharmacokinetics parameters. The terminal half-life (t1/2λz ) was calculated as 11.29 ± 1.09 and 10.69 ± 1.31 hr following intravenous and subcutaneous injections, respectively. After intravenous treatment, the total body clearance (Cl) and volume of distribution at steady-state (VSS ) were determined as 14.14 ± 1.09 ml hr-1  kg-1 and 241.71 ± 22.40 ml/kg, respectively. After subcutaneous injection, the peak concentration (Cmax ; 14.99 ± 2.29 µg/ml) was observed at 4.17 ± 0.41 hr, and the absorption half-life (t1/2ka ) and absolute bioavailability (F) were calculated as 2.83 ± 0.46 hr and 82.95%±9.59%, respectively. The pharmacokinetic profiles of ceftiofur sodium and its related metabolites demonstrated their relatively slow, however, good absorption after subcutaneous administration, poor distribution, and slow elimination in cats. Based on the time of drug concentration above the minimum inhibitory concentration (MIC) (T>MIC) calculated in the current study, an intravenous or subcutaneous dose at 5 mg/kg BW of ceftiofur sodium once daily is predicted to be effective for treating feline bacteria with a MIC value of ≤4.0 µg/ml.

Circ-IGF1R has pro-proliferative and anti-apoptotic effects in HCC by activating the PI3K/AKT pathway.

Circular RNAs (circRNAs), a novel class of widespread and diverse endogenous RNAs, have been identified as critical regulators of various cancers, including hepatocellular carcinoma (HCC). However, the specific roles of circRNAs in HCC are largely unknown. In this study, we identified a novel circRNA, circ-IGF1R, in HCC tumour tissues and cell lines. Circ-IGF1R levels were found to be significantly upregulated in HCC tissues compared with levels in paired peritumoural tissues. The high expression levels of circ-IGF1R in HCC were associated with tumour size. Moreover, knocking down circ-IGF1R with siRNA significantly attenuated cell proliferation and induced cell apoptosis and cell cycle arrest in vitro. Further investigation revealed that PI3K/AKT signalling pathway activation was involved in the oncogenic functions of circ-IGF1R in HCC. Our study suggests that circ-IGF1R may be a potential target for the prevention and treatment of HCC.

[IDH1 Gene Mutation and Its Clinical Significance in patients with Acute Myeloid Leukemia].

OBJECTIVE: To evaluate the incidence rate of IDH1 in acute myeloid leukemia and analyze its effect on clinical characteristics and prognosis. METHODS: Mononuclear cells in bone marrow samples were collected from 192 adult patients with newly diagnosed AML. Polymerase chain reaction (PCR) and direct sequencing were used to amplify exon 4 of IDH1 gene, the gene sequencing was used to analyze the gene mutations, at same time, the detection of NPM1, FLT3-TKD, FLT3-ITD, C-KIT, CEPBA, TET2 and JAK2V617F and MLL mutations were carried out, the follow-up was used to determine its therapeutic efficacy and outcomes of patients. The clinical and laboratory data of these cases were collected, and their clinical characteristics and prognosis were then analyzed. RESULTS: Among the 192 AML patients, 13 cases were detected with IDH1 gene mutation, the mutation rate was 6.77% [95% CI (5.70%-13.38%)]. The sequencing chart of IDH1 gene showed double peaks, the mutations were heterozygous, out of them c.G395A (p.R132H) was found in 8 cases, c.C394T was found in 4 cases (p.R132C), c.C394A (p.R132S) was found in 1 cases, R132H and R132C are common, 13 cases showed missense mutation. The median age in mutation group was 52 years old, the median age in unnutration group was 40 years, there was significant difference between them (P = 0.010). Mutation rate of IDH1 gene in M1 and M2 was significantly higher than that in other FAB subtypes. There were no significant difference in sex, newly diagnosed peripheral white blood cell count, hemoglobin, platelet count, peripheral blood and bone marrow original cell proportion of primitive cells between them. Mutation of IDH1 gene had certain correlation with NPM1 gene mutation, but no correlation with FLT3-TKD, FLT3-ITD, C-KIT, TET2 and JAK2V617F and MLL natations was found. In addition, the IDH1 mutation easily occurred in patients with normal karyotype or in patients with middle prognostic risk karyotype, IDH1 mutation occurred in 11 cases with normal karyotype, the mutation rate was 10.28%, IDH1 mutation were observed in 2 cases with abnormal karyotype, the mutation rate was 3.50%, there was significant difference. In AML patients with middle prognostic risk karyotype. The complete remission (CR) and the 3 year survival (OS) rate of IDH1 mut patients were less than that in IDH1 wt, there was significant difference (P < 0.05). CONCLUSIONS: The IDH1 mutation more easily occurr in older AML patients and mutations effect of IDH1 on clinical characteristics may represent a molecular marker for poor prognosis in AML.