[Clinical analysis of combined immunotherapy in patients with malignant pleural mesothelioma].

Objective: To observe the present situation, efficacy and safety of immunotherapy in patients with malignant pleural mesothelioma (MPM). Methods: The data of 39 patients with MPM in two centers from 2016 to 2021 were collected and the efficacy and safety were evaluated. According to the application of immune checkpoint inhibitors (ICIs), these patients, whose median clinical follow-up amounting to 18.97 months, were divided into immunotherapy group (19 cases) and control group (20 cases). Kaplan-Meier method and Log-rank test were used for the survival analysis. Results: The objective response rate (ORR) and the disease control rate (DCR) in the immunotherapy group is 21.05% and 79.0% respectively, compared with 10.0% and 55.0% in the control group; and the difference was not statistically significant (P>0.05). The median overall survival (OS) in the immunotherapy group was significantly longer than that in the control group (14.53 months vs 7.07 months, P=0.015), but there was no significant difference in the median progression free survival (PFS) between two groups (4.80 months vs 2.03 months, P=0.062). Single factor survival analysis showed that the nature of pleural effusion, pathological subtype and the efficacy of immunotherapy were related to both PFS and OS of the patients with MPM (P<0.05). The incidence of adverse reactions in immunotherapy group was 89.5% (17 out of 19 cases), and the most common adverse event was hematological toxicity (9 cases), followed by nausea and vomiting (7 cases), fatigue (6 cases) and skin damage (6 cases). Five patients had immune checkpoint inhibitors (ICIs) related adverse reactions with grade 1-2. Conclusions: Patients with MPM have begun to receive immunotherapy in more than 2-line mainly combined chemotherapy in the real world, and the median treatment line is 2-line. Either combined with chemotherapy or anti-angiogenesis therapy, ICI inhibitors have significant efficacy, controllable adverse events and good clinical value.

Predictors of catheter-related bladder discomfort after gynaecological surgery.

BACKGROUND: Urinary catheterization is universally used during surgery, and the incidence of postoperative catheter-related bladder discomfort (CRBD) is very high during recovery. We conducted this study to identify the incidence and predictors of postoperative CRBD after gynaecological surgery in the post-anesthesia care unit (PACU). METHODS: This was a prospective observational study. Patients undergoing gynaecological surgery under general anesthesia with intra-operative urinary catheterization were enrolled. We collected the clinical data, incidence and severity of CRBD, and postoperative pain for the patients. Predictive factors of CRBD were analysed by univariate and multivariate analysis. RESULTS: A total of 407 patients were included in this study. The incidence of CRBD after gynaecological surgery was 64.6% (mild CRBD: 22.8%; moderate CRBD: 34.2%; and severe CRBD: 7.6%). Univariate analysis showed that age, type of surgery, type of laparoscopic surgery, additional analgesics, and postoperative pain were influencing factors for CRBD. Based on multivariate logistic regression analysis, age ≥ 50 years, uterus-related laparoscopic surgery, and lack of additional analgesics were independent predictors of moderate or severe CRBD. CONCLUSIONS: This observational study revealed that the incidence of CRBD after gynaecological surgery in PACU was very high. Age ≥ 50 years, uterus-related laparoscopic surgery, and lack of additional analgesics were independent predictors of CRBD. TRIAL REGISTRATION: ChiCTR1800016390. Registered on 30 May 2018.

Effects of alkylated-chitosan-DNA nanoparticles on the function of macrophages.

Chitosan could form nanoparticles with DNA through electrostatic interaction, and hence protect the DNA from enzymatic degradation. Numerous studies have been working on modifying chitosan aiming at improving its transgenic efficacy. While the modification of chitosan with alkyl group has been shown to significantly improve the cell transfection efficiency, little is known about its impact on its biocompatibility. The current study was performed to investigate the impact of alkylated-chitosan/DNA nanoparticles on the function of the murine macrophage through observing its phagocytic activity and production of pro-inflammatory cytokines (IL-1beta, IL-6, IL-10, IL-12 and TNF-alpha). Our results demonstrated that the alkylated-chitosan/DNA nanoparticles at the concentration of 20 microg/ml DNA content had no significant impact on the production of cytokines and phagocytic activity of the macrophages as compared with the unmodified chitosan/DNA nanoparticles and negative control even after 24 h co-incubation. It suggested that the modification of chitosan with alkyl group should not have negative impact on the function of the macrophages.

Hypoxia-inducible factor-1alpha-induced differentiation of myeloid leukemic cells is its transcriptional activity independent.

Hypoxia or hypoxia mimetic has been shown to induce differentiation together with the accumulation of hypoxia-inducible factor-1alpha (HIF-1alpha) protein of myeloid leukemic cells and normal hematopoietic progenitors. To provide direct evidence for the role of HIF-1alpha in acute myeloid leukemia (AML) cell differentiation and its mechanisms, we generated myeloid leukemic U937T transformants, in which HIF-1alpha was tightly induced by tetracycline withdrawal. The results showed that the conditional HIF-1alpha induction triggered granulocytic differentiation of these transformants, while the suppression of HIF-1alpha expression by specific short hairpin RNAs (shRNAs) effectively inhibited hypoxia-induced differentiation of U937 cells, as evidenced by morphology, maturation-related antigens as well as expressions of myeloid differentiation signatures and hematopoietic cells-specific cytokine receptors. The specific shRNAs-inhibited expression of HIF-1beta, an essential partner for transcription activity of HIF-1, failed, while the inhibition of hematopoietic differentiation-critical CCAAT/enhancer-binding protein-alpha (C/EBPalpha) significantly eliminated HIF-1alpha-mediated myeloid leukemic cell differentiation. Collectively, this work provided several lines of direct evidence for the role of HIF-1alpha protein through its nontranscriptional activity in myeloid cell differentiation, in which C/EBPalpha elicits a role as an effector downstream to HIF-1alpha. These discoveries would shed new insights for understanding mechanisms underlying leukemogenesis and designing the new therapeutic strategy for differentiation induction of AML.

Dynamic distribution of Thr3-phosphorylated histone H3 in CHO cells in mitosis.

The phosphorylation of histone H3 at Ser10, Ser28, Thr11 and Thr3 of the amino terminal has been proved related to mitosis of the mammalian cells. However, the function of the Thr3 phosphorylation of H3 remains unclear. In this study, indirect immunofluorescence labelling and laser confocal microscopy were used to examine the cellular dynamic distribution of Thr3-phosphorylated H3 at mitosis in CHO cells. The results showed that the Thr3 phosphorylation began at early prophase and spread throughout the chromosomes at late prophase. At metaphase, most of the Thr3-phosphorylated H3 was distributed along the entire chromosomal arms and maintained until early anaphase. During late anaphase and telophase, the fluorescent signal of Thr3-phosphorylated H3 disappeared from chromosomes. There was a precise spatial and temporal correlation between H3 phosphorylation of Thr3 and stages of chromatin condensation. The timing of Thr3 phosphorylation and dephosphorylation in mitosis were similar to that reported for Thr11 phosphorylation of H3. The Thr3-phosphorylated H3 localized along the arms of chromosomes during metaphase and early anaphase. It was different from the Ser10-phosphorylated H3, which localized at telomere regions, and Thr11-phosphorylated H3, which localized at centromeres. The results suggest that the Thr3 phosphorylation of histone H3 may play a specific role, which is different from Ser10 phosphorylation and Thr11 phosphorylation in mitosis.

Hypoxia-mimetic agents desferrioxamine and cobalt chloride induce leukemic cell apoptosis through different hypoxia-inducible factor-1alpha independent mechanisms.

Hypoxia presents pro-apoptotic and anti-apoptotic biphasic effects that appear to be dependent upon cell types and conditions around cells. The substantial reports demonstrated that commonly used hypoxia-mimetic agents cobalt chloride (CoCl(2)) and desferrioxamine (DFO) could also induce apoptosis in many different kinds of cells, but the mechanism was poorly understood. In this work, we compare the apoptosis-inducing effects of these two hypoxia-mimetic agents with acute myeloid leukemic cell lines NB4 and U937 as in vitro models. The results show that both of them induce these leukemic cells to undergo apoptosis with a loss of mitochondrial transmembrane potentials (DeltaPsi m), the activation of caspase-3/8 and the cleavage of anti-apoptotic protein Mcl-1, together with the accumulation of hypoxia-inducible factor-1 alpha (HIF-1alpha) protein, a critical regulator for the cellular response to hypoxia. Metavanadate and sodium nitroprusside significantly abrogate DFO rather than CoCl(2)-induced mitochondrial Delta Psi m collapse, caspase-3/8 activation, Mcl-1 cleavage and apoptosis, but they fail to influence DFO and CoCl(2)-induced HIF-1alpha protein accumulation. Moreover, inducible expression of HIF-1alpha gene dose not alter DFO and CoCl(2)-induced apoptosis in U937 cells. In conclusion, these results propose that although both DFO and CoCl(2)-induced leukemic cell apoptosis by mitochondrial pathway-dependent and HIF-1alpha-independent mechanisms, DFO and CoCl(2)-induced apoptosis involves different initiating signal pathways that remain to be investigated.

Tomography of joint P-wave traveltime and polarization data: a simple approach for media with low to moderate velocity gradients.

An elastic wave tomography method utilizing joint traveltime and polarization data is proposed that is computationally simpler than the existing methods [Hu and Menke, Geophys. J. Int. 110, 63 (1992); Farra and Begat, Geophys. J. Int. 121, 371 (1995)]. In the linearization problem for the use of polarization data, we start with ray perturbation theory and assume that the medium is weakly inhomogeneous. Then the problem formulation for polarization data is approximately expressed as a linear integral of the gradient of the medium slowness perturbation along a reference ray. We call this a quasi-linear approximation which ignores the effect of the perturbation of the ray position on the first-order perturbation of the ray slowness vector. To efficiently obtain the solution for multi-data sets, a quadratic objective functional is constructed by including the data misfit terms and a model constraint term. Then a new conjugate gradient type of iterative reconstruction algorithm is developed to solve this minimization problem. This algorithm is also an extension of the conjugate gradient approach for standard least-squares problems. The feasibility and capability of the proposed tomography method is illustrated by conducting both noise-free and noisy synthetic experiments in a cross-hole geometry. The numerical results demonstrate that the additional use of polarization data not only improves the image quality, but also has a stabilizing effect on the iterative tomography solution. However, the limitation of the method is that it becomes inaccurate if the velocity variations in the medium change rapidly with position.

Singular value decomposition-based reconstruction algorithm for seismic traveltime tomography.

A reconstruction method is given for seismic transmission traveltime tomography. The method is implemented via the combinations of singular value decomposition, appropriate weighting matrices, and variable regularization parameter. The problem is scaled through the weighting matrices so that the singular spectrum is normalized. Matching the normalized singular values, a regularization parameter varies within the interval [0, 1], and linearly increases with singular value index from a small, initial value rather than a fixed one to eliminate the impacts of smaller singular values' components. The experimental results show that the proposed method is superior to the ordinary singular value decomposition (SVD) methods such as truncated SVD and Tikhonov regularization.

Stabilizing the iterative solution to ultrasonic transmission tomography.

A stable iterative reconstruction algorithm is presented for ultrasonic tomography through the uses of weighting matrices, damping factor, and the features of conjugate gradient method. The weighting matrices are chosen according to Berryman's analysis of nonlinear tomography. An implicit conjugate gradient-type iterative formula is used to solve a weighted least-squares problem. In the iterative process, a damping factor of linear increase rather than a constant is used to filter out the influences of smaller singular values' components. The results of simulated data show that our method can efficiently stabilize the iteration, and provide a robust solution.