A comprehensive evaluation of risk factors for mortality, infection and colonization associated with CRGNB in adult solid organ transplant recipients: a systematic review and meta-analysis.

BACKGROUND: The burden of carbapenem-resistant gram-negative bacteria (CRGNB) among solid organ transplant (SOT) recipients has not been systematically explored. Here, we discern the risk factors associated with CRGNB infection and colonization in SOT recipients. METHODS: This study included observational studies conducted among CRGNB-infected SOT patients, which reported risk factors associated with mortality, infection or colonization. Relevant records will be searched in PubMed, Embase and Web of Science for the period from the time of database construction to 1 March 2023. RESULTS: A total of 23 studies with 13,511 participants were included, enabling the assessment of 27 potential risk factors. The pooled prevalence of 1-year mortality among SOT recipients with CRGNB was 44.5%. Prolonged mechanical ventilation, combined transplantation, reoperation and pre-transplantation CRGNB colonization are salient contributors to the occurrence of CRGNB infections in SOT recipients. Renal replacement therapy, post-LT CRGNB colonization, pre-LT liver disease and model for end-stage liver disease score increased the risk of infection. Re-transplantation, carbapenem use before transplantation and ureteral stent utilization increaesd risk of CRGNB colonization. CONCLUSION: Our study demonstrated that SOT recipients with CRGNB infections had a higher mortality risk. Invasive procedure may be the main factor contribute to CRGNB infection.

Patient Versus Physician Perspective in the Management of Chronic Myeloid Leukemia During Treatment with Tyrosine Kinase Inhibitors.

INTRODUCTION: Chronic myeloid leukemia (CML) is a chronic disease with treatment-free remission (TFR) increasingly regarded as a feasible goal of treatment. However, various factors may influence adherence to international guidelines for CML management. This study aimed to compare the reporting of care between patients with CML and their treating doctors. METHODS: Parallel patient and physician online surveys were conducted between September 22, 2021, and March 15, 2022, which focused on the perceptions of 1882 adult patients with CML and 305 physicians regarding tyrosine kinase inhibitor (TKI) treatment options, monitoring and toxicities, TFR, and challenges faced. RESULTS: Among the enrolled patients, 69.9% received first-line imatinib treatment, 18.6% received nilotinib, and 4.7% received dasatinib. Among the patients treated with imatinib, 36.7% switched to other TKIs due to imatinib resistance/intolerance (71.1%), exploration of more potent TKIs to achieve TFR (8.9%), and treating physicians' recommendation (14.0%), with a median duration of initial treatment of 14 months [interquartile range (IQR) 6-36]. Most (91.8%) physicians agreed that the breakpoint cluster region-Abelson 1 (BCR::ABL1) transcript level should be assessed every 3 months, but only 42.7% of individuals committed to 3-monthly testing and only 17.8% strictly followed their treating physicians' recommendation. Half of the patients aimed for TFR; however, just 45.2% of physicians considered TFR as one of the top three goals for their patients. The major concern in obtaining TFR was patients' adherence. Fatigue was often distressing for patients with TKIs, while physicians were more concerned about platelet and neutrophil counts. A total of 12% and 20.8% of patients reported moderate/severe anxiety and depression, respectively, while only 53.7% of physicians had concerns about their patients' mental health. During the coronavirus disease 2019 (COVID-19) pandemic, 69.2% of patients reported a reduction in their income. Among these patients, 61.8% maintained their current treatment, while 7.3% switched to cheaper alternatives or discontinued treatment, with over 80% of these patients belonging to the low-income group. CONCLUSIONS: Overcoming challenges in patient-physician communication and treatment access is key to improving disease management and quality of life, especially for patients with low income. TRIAL REGISTRATION: ClinicalTrials.gov identifier NCT05092048.

18 months follow-up of deep molecular response 4.5 (MR4.5) with nilotinib in patients with newly diagnosed chronic-phase chronic myeloid leukemia: a prospective, multi-center study in China.

Introduction: Early stable deep molecular response (DMR) to nilotinib is associated with goal of treatment-free remission (TFR) in patients with chronic-phase chronic myeloid leukemia (CML-CP). It is important to early distinguish between patients who can achieve a DMR and those who are fit for TFR. Methods: We performed a multicenter study to explore the early cumulative MR4.5 rate at 18 months with nilotinib in patients with newly diagnosed CML-CP (ND-CML-CP) in China. Of the 29 institutes, 106 patients with ND-CML-CP received nilotinib (300 mg BID). Results and discussion: The cumulative MR4.5 rate of nilotinib treatment at 18 months was 69.8% (74/106). The cumulative MMR and MR4.0 rates for nilotinib at 18 months were 94.3% (100/106) and 84.9% (90/106), respectively. Patients with an ultra-early molecular response (u-EMR) at 6 weeks were not significantly different in obtaining DMR or MMR by 24 months compared with those without u-EMR (p = 0.7584 and p = 0.9543, respectively). Our study demonstrated that nilotinib treatment in patients with ND-CML-CP contributed to obtain high early MR4.5.

Synthesis, and biological evaluation of pyrazole matrine derivatives as an insecticide against Spodoptera frugiperda.

As one of the major threats to global food security, Spodoptera frugiperda (S. frugiperda) is highly gaining consideration due to its severe damage. Matrine is a widely and effectively used botanical insecticide in controlling S.frugiperda but lacks a rapidly available effect. To further improved the insecticidal activity of matrine based on combination principles, this work synthesized five new pyrazole matrine derivatives (PMDs) using Michael addition and investigated insecticidal activity against 2nd instar larvae of S. frugiperda(in vivo) and its isolated cell(in vitro). Our result demonstrated that PMDs show higher pesticidal activity than that matrine in both in vitro and in vivo assays. The most toxic derivatives in vitro and in vivo are PMD-3 and PMD-1, with IC50 of 2.49 mM and LC50 of 22.76 mg/L respectively. This research also investigates the anti-proliferation mechanism of PMDs based on isolated cells. PMDs decrease mitochondria membrane potential, arrested cell cycle at the G2/M phase, and upregulated Caspase 3, Caspase 9, and Apaf-1 to induce Caspase-dependent apoptosis. For Caspase-independent apoptosis, AIF and Endo G were found to be upregulated. Besides, pro-apoptotic factors like p53, IBM-1, and anti-apoptotic factors like IAP were upregulated. Moreover, we supposed that there was a linkage between lysosomes and PMD-induced apoptosis according to increased apoptosis rate, activated lysosomes, and upregulated Cathepsin B. This research provides new ideas for the synthesis of matrine derivatives and further demonstrated the anti-proliferation mechanism of PMDs.

Fatal Rickettsia Japonica Infection Complicating Disseminated Intravascular Coagulation in Yichang, China.

Background: Severe complications may cause a fatal or disabling outcome in patients with Rickettsia japonica infection but are poorly understood. Methods: We identified 11 patients with only Rickettsia japonica infection with metagenomics next generation sequencing (mNGS) during April to November 2021 at Yichang Central People's Hospital, China. Clinical data were obtained through review of medical records. Results: Most patients realized that they had symptoms about one or two days after being bitten. Fever (91%), pulmonary effusion (91%), rash or erythema (100%), abnormal urine (100%), neutropenia (100%), lymphopenia (100%), and thrombocytopenia (100%) were the most common clinical signs. Six severely ill patients were admitted to the intensive care unit and five had mild symptoms. Systemic manifestations such as vomiting (83%), neurological manifestations (100%), and disseminated intravascular coagulation (100%) were more frequently observed in the severe cases, 33.3% of whom developed purpura fulminans requiring amputation or skin graft, and 16.6% died two days after admission. Some patients experienced sequelae. Conclusion: Our study found that patients with critical Rickettsia japonica infection complicating disseminated intravascular coagulation had high risk of poor outcome.

Synthesis of Halopyrazole Matrine Derivatives and Their Insecticidal and Fungicidal Activities.

Matrine is a traditional botanical pesticide with a broad-spectrum biological activity that is widely applied in agriculture. Halopyrazole groups are successfully introduced to the C13 of matrine to synthesize eight new derivatives with a yield of 78-87%. The insecticidal activity results show that the introduction of halopyrazole groups can significantly improve the insecticidal activity of matrine on Plutella xylostella, Mythimna separata and Spodoptera frugiperda with a corrected mortality rate of 100%, which is 25-65% higher than matrine. The fungicidal activity results indicate that derivatives have a high inhibitory effect on Ceratobasidium cornigerum, Cibberella sanbinetti, Gibberrlla zeae and Collectot tichum gloeosporioides. Thereinto, 4-Cl-Pyr-Mat has the best result, with an inhibition rate of 23-33% higher than that of matrine. Therefore, the introduction of halogenated pyrazole groups can improve the agricultural activity of matrine.

Primary Cutaneous Nocardiosis Due to Nocardia Farcinica: A Case Report of an Often Overlooked Infection.

Primary cutaneous nocardiosis by Nocardia farcinica is exceedingly rare. Only six cases have been reported from PubMed in the past 15 years. We encounter such a case in a 55-year-old man receiving long-term steroid and cyclophosphamide. Owing to no characteristic symptoms, the disease can be so easily overlooked and causes fatal consequences. Therefore, we herein discuss common features of primary cutaneous nocardiosis by Nocardia farcinica that remind clinicians considering it.

High-resolution mass spectrometry-based approach for the identification and profiling of the metabolites of taletrectinib formed in liver microsomes.

Taletrectinib is a potent, orally active, and selective ROS1/NTRK kinase inhibitor. The aim of this study was to study the metabolism of taletrectinib in rat, dog, and human liver microsomes. The biotransformation of taletrectinib was carried out using rat, dog, and human liver microsomes supplemented with nicotinamide adenine dinucleotide phosphate tetrasodium salt (NADPH) and uridine diphosphate glucuronic acid (UDPGA). The microsomal incubations were conducted at 37°C for 60 min. The formed metabolites were identified by ultrahigh performance liquid chromatography coupled to high-resolution tandem mass spectrometry (UHPLC-HRMS) using electrospray ionization in the positive ion mode. They were identified by accurate masses and MS/MS spectra and based on their fragmentation pathways. With UHPLC-HRMS, a total of 10 metabolites including one glucuronide conjugate (M7) were structurally identified. M9 and M10 were unambiguously identified as taletrectinib alcohol and taletrectinib ketone, respectively, using reference standards. The phase I metabolic pathways of taletrectinib involved N-dealkylation, O-dealkylation, oxidative deamination, and oxygenation; the phase II metabolic pathways referred to glucuronidation. The current study investigated the in vitro metabolic fate of taletrectinib in animals and human species, which would bring us considerable benefits for the subsequent studies focusing on the pharmacological effect and toxicity of this drug.

A rare jejunum retroperitoneal hernia case report and literature review.

This report describes a rare case of retroperitoneal hernia and its preoperative diagnosis. Contrast-enhanced CT and multiplanar reconstruction were used to observe the hernia ring, hernia tract, contents and blood flow of a retroperitoneal hernia. The diagnosis of and conditions related to the retroperitoneal hernia were confirmed by CT soon after hospitalisation. There are no reports on the diagnosis of primary retroperitoneal hernia on CT in the literature to date, and we share this case to facilitate the accurate and timely identification of small intestine retroperitoneal hernias in the future.

Synthesis, characterization of two matrine derivatives and their cytotoxic effect on Sf9 cell of Spodoptera frugiperda.

The invasion of Spodoptera frugiperda has imposed a serious impact on global food security. Matrine is a botanical pesticide with a broad spectrum of insecticidal activity which was recommended for controlling Spodoptera frugiperda. In order to discover effective insecticide for Spodoptera frugiperda, two matrine derivatives modified with carbon disulfide and nitrogen-containing groups were systhesized. And their inhibition activities on Sf9 cell were evaluated. The structural configuration of compounds were characterized by IR, HPLC, MS, NMR and XRD, with yields of 52% and 65%, respectively. The IC50 of the two newly synthesized compounds on Sf9 cell reduced to 0.648 mmol/L and 1.13 mmol/L, respectively, compared with that of matrine (5.330 mmol/L). In addition, microscopic observation of Sf9 cell treated with the compounds showed that the number of adherent cells decreased, the cells shrunk, vacuolated and apoptotic bodies appeared. The two newly synthesized compounds exhibited better inhibitory effect on Sf9 cell than that of the parent matrine, suggesting that the positive effect of the introduction of 1-pyrrolidinecarbodithioate and diethylcarbamodithioate groups to matrine. The morphological observation of Sf9 cell induced by derivatives indicated that apoptosis induction may be a mechanism that inhibits insect cell proliferation and exerts insecticidal effect.

Semi-synthesis and characterization of some new matrine derivatives as insecticidal agents.

BACKGROUND: Matrine is an important traditional plant-derived insecticide with broad-spectrum activity. However, due to its moderate activity, matrine is mainly applied in combination with other pesticides. In order to discover new potential natural-product-based crop protection agents, a series of matrine derivatives characterized by cyclohexylamine group were synthesized to screen their insecticidal activity against seven typically agricultural pests. RESULTS: The structural configurations of compounds were characterized by IR, 1 H NMR, 13 C NMR, MS and XRD, with the pure yields of 42%, 65% and 71%, respectively. Although all compounds showed poor insecticidal activity against five lepidoptera pests, the compounds 2 and 4 displayed remarkable insecticidal activities against Lipaphis erysimi and Mulberry Root-Knot Nematode with a concentration-dependent manner within 0.5~1.5 mg/ mL. Compared with matrine (60%), compounds 2 and 4 exhibited potent insecticidal activities against L. erysimi, with a corrected mortality of 83.3% and 89.7%, respectively. They also showed excellent control effects on Mulberry Root-Knot Nematode, with corrected mortality as high as 88% and 80%, respectively. CONCLUSION: All four synthesized matrine derivatives showed poor insecticidal activity against five lepidoptera pests, but the compounds 2 and 4 exhibited much stronger insecticidal activities against L. erysimi and Mulberry Root-Knot Nematode than matrine. Combined with the structural characteristics of compounds 1~4, we conclude that 4-methylcyclohexylamine, not the carbon disulfide group or cyclohexylamine group alone, mainly contributed to the improvement of insecticidal activities of matrine derivatives against these two agricultural pests. This work provides a direction and foundation for structural optimization of the matrine pesticides in the future. © 2020 Society of Chemical Industry.

Synthesis, characterization and in vitro biological evaluation of two matrine derivatives.

Matrine is a traditional Chinese medicine and botanical pesticide with broad biological activities, including pharmacological and agricultural activities. In present work, two matrine derivatives have been successfully synthesized via introducing indole and cyclohexylamino to 13 position of matrine, respectively, with sophocarpine as starting material, and structurally characterized via infrared spectroscopy(IR), MS, 1 H NMR, 13 C NMR and X-ray crystal diffraction. The results of the in vitro biological activity tests showed that these two matrine derivatives exhibited even better activities against human cancer cells Hela229 and insect cell line Sf9 from Spodoptera frugiperda (J. E. Smith) than that of parent matrine, suggesting that the heterocyclic or cyclic group can dramatically increase the biological activity of matrine. It is worth to mention that 13-indole-matrine could possibly inhibit the growth of insect cells or human cancer cells by inducing cell apoptosis. The results of the present study provide useful information for further structural modifications of these compounds and for exploring new, potent anti-cancer agents and environment friendly pesticides.

[Establishment of a Xenografted Acute Myeloid Leukemia Model by using Zebrafish].

Objectve: To investigate the feasibility of establishing xenografted leukemia model by zebrafish, so as to provide the more direct model in vitro and experimental evidence for study of acute myeloid leukemia and screening of the drugs for targeting therapy. METHODS: Acute myeloid leukemia cell line KG-1a was labeled with red fluorescent dye-MitoRed, then the labeled cells were injected into the yolk sac of zebrafish embryos. Morphological observation, cell count and histopathological detection were used to analyse the infiltration and metastasis of KG-1a cells in zebrafish. RESULTS: KG1a cells could proliferate and gradually spread to the entire abdominal cavity of the zebrafish after KG-1a cells were injected into the yolk sac during 1-7, the results of cell counting in vitro also proved a significant proliferation of KG-1a cells in zebrafish, suggesting that the implanted leukemia stem cells could survive, proliferate and spread in zebrafish. Further study showed that the implanted cells could be transfered to the liver of zebrafish, these cells displayed the signature of KG-1a cells by hematoxylin-eosin(HE) staining. CONCLUSIONS: Human acute myeloid leukemia cells KG1a can survive, proliferate and migrate in zebrafish, suggesting xenografted leukemia model of zebrafish has been successfully established. This model may be benefitcial for the study of acute myeloid leukemia and the screening of the drugs for targeting therapy of acute myeloid leukemia.

Expression of cartilage glycoprotein 39 in peripheral blood monocytes of septic rat and its role in TLR 4-NF-κB signaling pathways.

OBJECTIVE: To investigate Cartilage glycoprotein 39 (Cgp-39) expression in peripheral blood monocytes of septic rats, and analyze the relationship between Toll-like receptor 4 (TLR4)-NF-κB signalling pathway and Cgp-39 expression. METHODS: The ligation puncture was performed to establish rat sepsis model, and ELISA was used to measure serum Cgp-39 concentration. Peripheral blood mononuclear cells was isolated and cultured for 72 h. RNA interference technology was used to inhibit TLR4 and NF-κB gene expression, and real-time PCR and Western blot were performed to detect mRNA and protein expression of TLR4 and NF-κB. RESULTS: At 1 h, there was no significant differences in serum Cgp-39 concentration between sepsis group and the control group (P > 0.05), however, at 6 h, 12 h, 24 h and 48 h, serum Cgp-39 concentrations in sepsis group were significantly higher than those in the control group at the corresponding time points (P < 0.05). Compared with the control group, TLR4 mRNA and protein expression were increased significantly in sepsis group and sepsis NF-κB interference group; NF-κB mRNA and protein expression were increased significantly in sepsis group and sepsis TLR4 interference group. However, compared with sepsis group, Cgp-39 concentrations decreased significantly in either sepsis TLR4 interference group or NF-κB interference group (P < 0.05 for both). CONCLUSION: Cgp-39 is highly expressed in peripheral blood monocytes of septic rat and TLR4-NF-κB signalling pathways may be involved in the regulation of Cgp-39 expression.

[Impact of human cytomegalovirus viremia on relapse after allogeneic hematopoietic stem cell transplantation in acute myeloid leukemia patients].

OBJECTIVE: To explore the relationship between cytomegalovirus (CMV) infection and risk factors for relapsing patients with acute myeloid leukemia (AML) (non- acute promyelocytic leukemia) after hematopoietic stem cell transplantation (HSCT). METHODS: A total of 62 allo-HSCT patients from January 2005 to January 2014 were enrolled and analyzed retrospectively. And the clinical characteristics of donors and recipients and post-transplantation relapse were recorded. RESULTS: Single factor analysis indicated that there were 5 risk factors correlated with disease relapse (P < 0.05). Leucocytosis (>100×10(9)/L), high-risk AML and cyclosporine A concentration under 200 µg/L were correlated with high relapsing rates while CMV reaction and chronic graft versus host disease had a low relapsing rate. Cox regression analysis revealed that high-risk AML (RR = 3.296, 95%CI:1.274-8.530, P = 0.014), CMV negativity (RR = 0.285, 95%CI:0.084-0.973, P = 0.045) and non-chronic GVHD (RR = 0.167, 95%CI:0.042-0.668, P = 0.011) were major risk factors of relapse. CONCLUSION: Human CMV viremia after allo-HSCT has a decreased relapsing risk in patients with AML.

Low-dose arsenic trioxide combined with aclacinomycin A synergistically enhances the cytotoxic effect on human acute myelogenous leukemia cell lines by induction of apoptosis.

Acute myeloid leukemia (AML) is a common disorder in the elderly. Although remarkable progress has been made over recent decades, the outcome remains poor. Thus, the development of a more effective method to overcome this problem is necessary. In this study, we aimed to investigate the synergistic cytotoxic effect of low-dose arsenic trioxide (As2O3) combined with aclacinomycin A (ACM) on the human AML cell lines KG-1a and HL-60, and to clarify the underlying mechanism. Results showed that As2O3 combined with ACM exerted a synergistic cytotoxic effect by activation of the apoptosis pathway. Additionally, we found that the combination treatment decreased Bcl-2, c-IAP and XIAP expression but increased SMAC and caspase-3 expression more significantly than the single drug treatments. Furthermore, combination index (CI) values were < 1 in all matched combination groups. Additional evaluation of As2O3 combined with ACM as a potential therapeutic benefit for AML seems warranted.

[Effect of glycolytic inhibitor 3-BrPA on the proliferation and apoptosis of mouse splenic lymphocytes in mixed lymphocytes culture].

OBJECTIVE: To study the effect of glycolytic inhibitor 3-Bromopyruvate (3-BrPA) on the proliferation and apoptosis of mouse spleen lymphocytes and explore its mechanism. METHODS: An one-way mixed lymphocyte culture (MLC) system was established, including BALB/c mouse spleen cells (H-2d) as stimulator and C57BL/6 mouse spleen cells (H-2b) as responder. With treatment of 3-BrPA at different concentrations (0-200 µmol/L), lymphocyte proliferation capacity was detected by the CCK-8 method, the expression of CD3, CD4, and CD8 by flow cytometry, and the concentrations of cytokine interleukin (IL)-4 and interferon (IFN)-γ in the supernatant by ELISA. RESULTS: At a middle or high dose (over 20 µmol/L), 3-BrPA displayed a dose-dependent inhibitory effect on lymphocyte proliferation in the MLC system. The 50% inhibitory concentration (IC50) were 48.6, 41.2, and 41.9 µmol/L after 24, 36, and 48 h culture, respectively. With treatment of 50 µmol/L 3-BrPA, the IFN-γ level [(164.25 ± 20.14) ng/L] was significantly lower, compared with control [(277.61 ± 18.46) ng/L]. The IL-4 level [(31.06 ± 6.06) ng/L] was significantly higher, compared with control [(28.64 ± 3.97) ng/L]. Consequently, the IFN-γ/IL-4 ratio decreased significantly. CONCLUSION: These results indicate that 3-BrPA had a significant inhibitory effect on the proliferation of mouse spleen lymphocytes cultured in MLC system, accompanied with the Th2-biased secretion of cytokines.

[Effects of recombinant human interleukin 11 on hematological malignancy after allogeneic hematopoietic cell transplantation].

OBJECTIVE: To investigate the effects of recombinant human interleukin 11 (rhIL-11) on hematological malignancy after allogeneic hematopoietic stem cell transplantation (allo-HSCT). METHODS: A total of 48 patients with hematological malignancy from January 2006 to June 2010 were alternately enrolled into a prospective randomized study. And they were assigned into the control and rhIL-11 injection groups. Later the investigators compared two groups with regards to hematopoietic reconstitution, graft versus host disease (GVHD) classification, clinical recurrence rate and disease-free survival. RESULTS: With the therapy of rhIL-11, the absolute neutrophil counts recovering to 0.5 × 10(9)/L and platelet recovering to 20 × 10(9)/L were (15.1 ± 1.6) and (18.2 ± 3.3) days respectively. And they were significantly lower than those in control group [(16.1 ± 1.6) vs (22.4 ± 5.5) days, P = 0.032, 0.003]. The incidence of acute GVHD was surprisingly low in the study group (26.1% vs 50.0%, P = 0.048). There was no significant difference in chronic GVHD (36.8% vs 38.9%, P = 0.899) or relapse rate (5.1% vs 7.7%, P = 0.662) between two groups during a median follow-up period of 11.7 months. A trend of improved 3-year-disease-free survival was observed in the study group (65.4% vs 50.9%, P = 0.637). CONCLUSION: The application of rhIL-11 after allo-HSCT may accelerate both neutrophil and platelet engraftment and lower the occurrence of acute GVHD.