Lipopolysaccharides (LPS) are major outer membrane components of Gram-negative bacteria. Unlike most Gram-negative bacteria, Acinetobacter baumannii can still survive and acquire polymyxin resistance after complete loss of LPS. Previous studies of LPS-deficient Acinetobacter baumannii mostly focused on LPS-deficient strains induced by polymyxin, whose background was complex and unstable. To investigate LPS loss-mediated polymyxin resistant-Acinetobacter baumannii, this study constructed a stable and clear background LPS-deficient strain by knocking out lpxC gene in Acinetobacter baumannii ATCC 19606 with CIRSPR/Cas9, and then studied the phenotypic changes of the lpxC-deficient strain including morphology, growth rate, antibiotic susceptibility, virulence, membrane permeability, and membrane potential. Animal experiments were approved by the Animal Care and Welfare Committee Institute of Medicinal Biotechnology, CAMS and PUMC (approval number: IMB-20240119D₉). The results indicated that the lpxC gene of Acinetobacter baumannii ATCC 19606 was successfully knocked out. After losing the lpxC, the strain underwent the morphological change from rod-shaped to spherical. Furthermore, it leads to reduced growth rate, enhanced membrane permeability, decreased membrane potential, lower virulence, and increased antibiotic susceptibility to β-lactams, quinolones, aminoglycosides, macrolides, glycopeptides. The lpxC deletion results in significant changes in membrane homeostasis and adaptability of Acinetobacter baumannii. Understanding the phenotypic changes of colistin-resistant Acinetobacter baumannii mediated by LPS loss is useful for exploring the resistance mechanism of Acinetobacter baumannii and developing new therapeutic strategies.

Purpose: Re-irradiation for bulky recurrent sarcoma carries significant risks. Pulsed low-dose rate radiotherapy (PLDR) is an attractive option for re-irradiation due to inherent radiobiological advantages. Materials and Methods: We present two patients who underwent reirradiation using PLDR technique, followed by a literature review. Results: The first case is that of a 76-year-old male who developed an in-field recurrence of a bulky pelvic bone high-grade chondrosarcoma after he was treated with definitive radiotherapy using helical TomoTherapy with a total dose of 66 Gy. The patient was re-irradiated using PLDR with a shrinking field technique; 50 Gy in 2 Gy fractions followed by a boost of 20 Gy in 2 Gy fractions. The patient remains disease-free without significant toxicity 60 months post-irradiation. The second case is that of an 82-year-old female who was treated with a definitive irradiation of 66 Gy in 33 fractions for a right shoulder grade II chondrosarcoma. She developed an in-field recurrence 28 months later and presented with bulky disease causing brachial plexopathy and lymphedema. The patient was re-irradiated with a palliative intent to a total dose of 50 Gy in 2 Gy fractions over 5 weeks using PLDR. Brachial plexopathy resolved shortly after re-irradiation, but local progression near the surface was evident 8 months later. She passed away from unrelated causes 11 months later. Conclusion We present two cases highlighting our early experience with PLDR, which was effective in the reirradiation of recurrent bony sarcoma. Our study highlights PLDR as an option for reirradiation in recurrent unresectable tumors.

Taking the Chinese city of Xiamen as an example, simulation and quantitative analysis were performed on the transmissions of the Coronavirus Disease 2019 (COVID-19) and the influence of intervention combinations to assist policymakers in the preparation of targeted response measures. A machine learning model was built to estimate the effectiveness of interventions and simulate transmission in different scenarios. The comparison was conducted between simulated and real cases in Xiamen. A web interface with adjustable parameters, including choice of intervention measures, intervention weights, vaccination, and viral variants, was designed for users to run the simulation. The total case number was set as the outcome. The cumulative number was 4,614,641 without restrictions and 78 under the strictest intervention set. Simulation with the parameters closest to the real situation of the Xiamen outbreak was performed to verify the accuracy and reliability of the model. The simulation model generated a duration of 52 days before the daily cases dropped to zero and the final cumulative case number of 200, which were 25 more days and 36 fewer cases than the real situation, respectively. Targeted interventions could benefit the prevention and control of COVID-19 outbreak while safeguarding public health and mitigating impacts on people's livelihood.
COVID-19/prevention & control* ; China/epidemiology* ; Humans ; Machine Learning ; Pandemics/prevention & control* ; Policy ; Reproducibility of Results ; SARS-CoV-2

Diversity-oriented synthesis is aimed to increase the chemical diversity of target natural products for extensive biological activity evaluation. Indole ring is an important functional group in a large number of drugs and other biologically active agents, and indole-containing natural products have been frequently isolated from marine sources in recent years. In this paper, a series of indole-containing marine natural hyrtioreticulin derivatives, including 19 new ones, were designed, synthesized through a key Pictet-Spengler reaction, and evaluated for their inflammation related activity. Compound 13b displayed the most promising activity by inhibiting TNF-α cytokine release with an inhibitory rate of 92% at a concentration of 20 μmol·L^-1. A preliminary structure-activity relationship analysis was also discussed. This research may throw light on the discovery of marine indole alkaloid derived anti-inflammatory drug leads.
Animals ; Anti-Inflammatory Agents/pharmacology* ; Biological Products/pharmacology* ; Indole Alkaloids/pharmacology* ; Porifera ; Structure-Activity Relationship

OBJECTIVE: To investigate the effects of paclitaxel, quizartinib and their combination on proliferation, apoptosis and FLT3/STAT5 pathway of human leukemia cell line MV4-11 (FLT3-ITD+). METHODS: MV4-11 cells were treated with paclitaxel and quizartinib at different concentrations for 24 h, 48 h and 72 h, respectively, and then the two drugs were combined at 48 h to compare the inhibition of proliferation, the apoptosis rate was detected by flow cytometry, the expression of FLT3 and STAT5 mRNA was determined by fluorescence quantitative PCR, and the protein expression of FLT3, p-FLT3, STAT5 and p-STAT5 was determined by Western blot. RESULTS: Different combination groups of paclitaxel and quizartinib had synergistic inhibitory effect. The cell survival rate in the combination group was significantly lower than that in the single drug group (P<0.05). The cell apoptosis rate in the combination group was significantly higher than that in the single drug group (P<0.001). The expression of FLT3 mRNA in combination group was significantly higher than that in two single drugs (P<0.01). The expression of STAT5 mRNA in combination group was significantly higher than that in quizartinib group (P<0.001); increased compared with paclitaxel group, but there was no statistical significance. The expression level of p-FLT3、p-STAT5 protein in the combination group was significantly lower than that in the single drug group (P<0.05, P<0.05). CONCLUSION Paclitaxel combined with quizartinib can synergistically inhibit the proliferation of MV4-11 cell line and promote the apoptosis of MV4-11 cell line by inhibiting the activity of FLT3/STAT5 pathway.
Apoptosis ; Benzothiazoles ; Cell Line, Tumor ; Humans ; Leukemia, Myeloid, Acute/genetics* ; Paclitaxel/therapeutic use* ; Phenylurea Compounds ; RNA, Messenger ; STAT5 Transcription Factor/pharmacology* ; Signal Transduction ; fms-Like Tyrosine Kinase 3

Dendritic cells (DCs), a type of antigen-presenting cells (APC), are recognized as an important regulator of immune response and immune tolerance, and play a critical role in the host innate immunity and adaptive immunity. Previous studies have shown that the long-term parasization of Echinococcus in the host is strongly associated with the host immune tolerance induced by DCs. This review summarizes the research progress of the role of DCs in host immune tolerance caused Echinococcus infection, aiming to provide the theoretical basis and insights into the management and immunotherapy of Echinococcus infections.

BACKGROUNDBiliverdin (BV) has a protective role against ischemia-reperfusion injury (IRI). However, the protective role and potential mechanisms of BV on lung IRI (LIRI) remain to be elucidated. Thus, we aimed to investigate the protective role and potential mechanisms of BV on LIRI.

METHODSLungs were isolated from Sprague-Dawley rats to establish an ex vivo LIRI model. After an initial 15 min stabilization period, the isolated lungs were subjected to ischemia for 60 min, followed by 90 min of reperfusion with or without BV treatment.

RESULTSLungs in the I/R group exhibited significant decrease in tidal volume (1.44 ± 0.23 ml/min in I/R group vs. 2.41 ± 0.31 ml/min in sham group; P< 0.001), lung compliance (0.27 ± 0.06 ml/cmH2O in I/R group vs. 0.44 ± 0.09 ml/cmH2O in sham group; P< 0.001; 1 cmH2O=0.098 kPa), and oxygen partial pressure (PaO2) levels (64.12 ± 12 mmHg in I/R group vs. 114 ± 8.0 mmHg in sham group; P< 0.001; 1 mmHg = 0.133 kPa). In contrast, these parameters in the BV group (2.27 ± 0.37 ml/min of tidal volume, 0.41 ± 0.10 ml/cmH2O of compliance, and 98.7 ± 9.7 mmHg of PaO2) were significantly higher compared with the I/R group (P = 0.004, P< 0.001, and P< 0.001, respectively). Compared to the I/R group, the contents of superoxide dismutase were significantly higher (47.07 ± 7.91 U/mg protein vs. 33.84 ± 10.15 U/mg protein; P = 0.005) while the wet/dry weight ratio (P < 0.01), methane dicarboxylic aldehyde (1.92 ± 0.25 nmol/mg protein vs. 2.67 ± 0.46 nmol/mg protein; P< 0.001), and adenosine triphosphate contents (297.05 ± 47.45 nmol/mg protein vs. 208.09 ± 29.11 nmol/mg protein; P = 0.005) were markedly lower in BV-treated lungs. Histological analysis revealed that BV alleviated LIRI. Furthermore, the expression of inflammatory cytokines (interleukin-1β, interleukin-6, and tumor necrosis factor-β) was downregulated and the expression of cyclooxygenase-2, inducible nitric oxide synthase, and Jun N-terminal kinase was significantly reduced in BV group (all P< 0.01 compared to I/R group). Finally, the apoptosis index in the BV group was significantly decreased (P < 0.01 compared to I/R group).

CONCLUSIONBV protects lung IRI through its antioxidative, anti-inflammatory, and anti-apoptotic effects.

OBJECTIVETo evaluate the impacts on the short-term efficacy and the long-term prevention of recurrence of allergic rhinitis treated with the triple-strong stimulation at Dazhui (GV 14) so as to provide the convenient and long-term effective therapy of acupuncture and moxibustion for allergic rhinitis.

METHODSOne hundred and twenty cases of allergic rhinitis were randomized into an acupuncture group, an acupuncture + medication group and a triple-strong stimulation group, 40 cases in each one. In the acupuncture group, acupuncture was applied at Dazhui (GV 14), Fengchi (GB 20), Baihui (GV 20), Yintang (GV 29) and the others, stimulating with reinforcing manipulation for the deficiency and reducing manipulation for the excess, once every day. In the acupuncture + medication group, on the basis of acupuncture therapy, claritin (loratadine tablets) was supplemented for oral administration, 10 mg, once every two days, continuously for 30 days. In the triple-strong stimulation group, on the basis of acupuncture therapy, the strong needling, strong cupping and strong moxibustion were applied at Dazhui (GV 14). This combined therapy was given once every day in the first 3 days and once every two days afterwards. The 10 day treatment made one session, at the interval of 3 days between the sessions and totally 3 sessions were required in the three groups. Separately, before treatment, after treatment and in 6 months after treatment, the changes of symptom and physical sign score and value of single item symptom including nasal itching, nasal blockage, sneezing and rhinorrhea were observed in the patients of the three groups. And the long-term clinical efficacy was compared among the three groups.

RESULTSThe symptom and physical sign score and the value of single item symptom were all reduced in the three groups after treatment and in 6 months after treatment (P < 0.001, P < 0.01, P < 0.05). The results in the triple-strong stimulation group were superior to the other two groups (all P < 0.05). In the triple-strong stimulation group, the total effective rate was 92.5% (36/40) in the follow-up of 6 months after treatment, which was better than 60.5% (23/38) in the acupuncture group and 69.2% (27/39) in the acupuncture + medication group (both P < 0.01).

CONCLUSIONThe combined therapy of acupuncture and the triple-strong stimulation at Dazhui (GV 14) achieves the reliable and effective result in the clinical treatment of allergic rhinitis and displays the good role on the prevention from long-term recurrence.

Acupuncture Points ; Acupuncture Therapy ; Adolescent ; Adult ; Child ; Combined Modality Therapy ; Female ; Humans ; Male ; Middle Aged ; Moxibustion ; Rhinitis, Allergic ; Rhinitis, Allergic, Perennial ; therapy ; Young Adult

OBJECTIVETo evaluate the clinical efficacy and safety of the three therapies of strong stimulation for children peripheral facial palsy so as to deal with the problem on the inactive acceptance of acupuncture in children.

METHODSEighty cases of children peripheral facial palsy were randomized into a moxa stick group (group A) and a group with three therapies of strong stimulation (group B). Baihui (GV 20), Sibai (ST 2), Dicang (ST 4), Jiache (ST 6) and the other acupoints were selected in the two groups and stimulated with half-needling technique. In the group A, 3 moxa sticks were bunched together for surrounding moxibustion over one of Dazhui (GV 14), Yangbai (GB 14), Xiaguan (ST 7) and Jiache (ST 6) in each treatment. In the group B, the strong pricking therapy, strong cupping therapy and strong moxibustion were adopted at the same acupoints as the group A. The treatment was given twice every day in the first 5 days. Afterwards, the clinical efficacy was analyzed statistically. The treatment was kept on for the effective case. Those with failed effect were transferred to the other group. Since the 6th day, the treatment was given once every day. In 15 days, the clinical efficacy was compared between the two groups and House-Brackmann (H-B) facial nerve function grade was compared before and after treatment.

RESULTSIn 5 days of treatment, the total effective rate was 94.7% (36/38) in the group B, which was better than 52.4% (22/42) in the group A, (P < 0.001). In 15 days of treatment, the cured rate and the total effective rate in the group B were 67.3% (35/52) and 96.2% (50/52), which were better than 9.5% (2/21) and 85.7% (18/21) in the group A, respectively (P < 0. 001, P < 0.05). Additionally, the result of H-B facial nerve function grade in the group B was superior to the group A (P < 0.001).

CONCLUSIONThe half-needling technique and the three therapies of strong stimulation in combination achieve the superior efficacy on children peripheral facial palsy as compared with the half-needling technique combined with moxa stick therapy. And the obvious adverse reaction has not been found.

Acupuncture Points ; Acupuncture Therapy ; Adolescent ; Child ; Child, Preschool ; Combined Modality Therapy ; Facial Paralysis ; therapy ; Female ; Humans ; Infant ; Male ; Moxibustion ; Treatment Outcome

The aim of this study was to investigate the effect of intracellular acidification on the P-gp in K562/A02 cells. Confocal laser microscope was used to determine the intracellular acidification. MTT assay was used to detect the cytotoxicity of intracellular acidification on K562 and K562/A02 cells. Flow cytometry was applied to measure the influence of intracellular acidification on the activity of P-gp. The P-gp expression at protein and mRNA levels were determined by Western blot and real-time RT-PCR respectively. The results indicated that intracellular acidification had no obvious cytotoxicity on K562 and K562/A02 cells. The function of P-gp in K562/A02 cells weakened along with decrease of intracellular acidification, the intracellular acidification significantly increased the accumulation of Rhodamine 123 (Rh 123) and suppressed the efflux of Rh 123 mediated by P-gp. The intracellular acidification also inhibited the expression of P-gp in K562/A02 cells at protein and mRNA levels which showed intracellular acidification with time-dependence. It is concluded that the intracellular acidification can inhibit the expression and function of P-gp in K562/A02 cells.
ATP Binding Cassette Transporter, Sub-Family B ; ATP-Binding Cassette, Sub-Family B, Member 1 ; metabolism ; Drug Resistance, Multiple ; Drug Resistance, Neoplasm ; Humans ; Hydrogen-Ion Concentration ; K562 Cells