Long-term combined blockade of CXCR4 and PD-L1 with in vivo reassembly for intensive tumor interference.

Negative immunoregulatory signal (PD-L1, CXCR4, et al.) and weak immunogenicity elicited immune system failing to detect and destroy cancerous cells. CXCR4 blockade promoted T cell tumor infiltration and increased tumor sensitivity to anti-PD-L1 therapy. Here, pH-responsive reassembled nanomaterials were constructed with anti-PD-L1 peptide and CXCR4 antagonists grafting (APAB), synergized with photothermal therapy for melanoma and breast tumor interference. The self-assembled APAB nanoparticles accumulated in the tumor and rapidly transformed into nanofibers in response to the acidic tumor microenvironment, leading to the exposure of grafted therapeutic agents. APAB enabling to reassemble around tumor cells and remained stable for over 96 h due to the aggregation induced retention (AIR) effect, led to long-term efficiently combined PD-L1 and CXCR4 blockade. Photothermal efficiency (ICG) induced immunogenic cell death (ICD) of tumor cells so as to effectively improve the immunogenicity. The combined therapy (ICG@APAB) could effectively inhibit the growth of primary tumor (∼83.52%) and distant tumor (∼76.24%) in melanoma-bearing mice, and significantly (p < 0.05) prolong the survival time over 42 days. The inhibition assay on tumor metastasis in 4 T1 model mice exhibited ICG@APAB almostly suppressed the occurrence of lung metastases and the expression levels of CD31, MMP-9 and VEGF in tumor decreased by 82.26%, 90.45% and 41.54%, respectively. The in vivo reassembly strategy will offer novel perspectives benefical future immunotherapies and push development of combined therapeutics into clinical settings.

Apoptosis gene reprograming of human peripheral blood mononuclear cells induced by radioiodine-131 (131I) irradiation.

Background & objectives: The nature of adaptable change of B-cell lymphoma-2 (BCL-2) and/or Bcl2-associated X protein (BAX) gene expression in the human peripheral blood mononuclear cells (PBMCs) irradiated by radioiodine in thyroid diseases therapy is not fully understood. In this study, the alternation of apoptotic gene expression was evaluated while the PBMCs collected from healthy volunteers were irradiated by the radioiodine-131 (131I). Methods: Fasting blood samples were obtained from healthy volunteers. PBMCs from group 0 to 6 were incubated and exposed to different doses of 131I in cell suspension for 6, 12, 24 and 48 h. The apoptosis rates and expression of BCL-2 and BAX genes of PBMCs were examined. Results: The apoptosis rate in the human PBMCs was gradually enhanced after six hour irradiation. The values of BCL-2 and BAX gene expression in groups 1-6 were higher than in group 0 within 6 h of irradiation, and then, these were decreased gradually from 6 to 12 h. BCL: -2 gene expression increased in groups 1-3 after 12 h irradiation, but there was no difference in groups 4-6. The ratio of BCL-2/BAX gene expression among groups 4-6 gradually decreased during the period from 6 to 12 h, and it was significantly lower than in the group 0 at 12, 24 and 48 h. Interpretation & conclusions: The expression of BCL-2 and BAX genes was initially upregulated following irradiation. Later, the balance of BCL-2/BAX genes expression was adjusted, and then, PBMCs underwent apoptosis at higher doses of radiation.

Proportion of neuropathic pain in the back region in chronic low back pain patients -a multicenter investigation.

Neuropathy can contribute to low back pain (LBP) in the region of the back. Our study investigated the proportion of neuropathic pain (NP) in low back region in chronic LBP patients from multicenter and clinics in China and identified associated factors. Assessment was made using a questionnaire and the Leeds Assessment of Neuropathic Symptoms and Signs (LANSS, only tested in low back region), as well as Quantitative Sensory Testing (QST, merely applied to the low back region), the Hospital Anxiety and Depression Scale (HADS) and the Oswestry Disability Index (ODI). Our questionnaire collected demographic information, behavioral habits and medical records. 2116 outpatients over 18 years old complaining of LBP lasting more than 3 months were enrolled in this study. The NP proportion in low back region in chronic LBP patients was 2.8%. Multivariable logistic regression analysis showed that histories of lumbar surgery, abdominal or pelvic surgery, and drinking alcohol were independent positive predictors for LBP of predominantly neuropathic origin (LBNPO), while history of low back sprain and frequently carrying weight as independent negative predictor. Using these parameters may help the identification of patients with chronic LBP likely to develop NP leading to improved treatment outcomes.

Immunoglobulin G4-Related Lung Disease Presenting as Lung Cavitating Mass and Mimicking Lung Cancer.

Immunoglobulin G4-related lung disease (IgG4-RLD) is a disease in which abundant activated IgG4-positive plasma cells and lymphocytes infiltrate lung tissues with high 18F-fluorodeoxyglucose uptake. Although various forms of radiologic features of IgG4-RLD have been reported, cavitating mass is a rare imaging feature and should be differentiated from cancer. Therefore, in this article, we report two cases both with unprovoked cough, bloody sputum and presenting quite similar cavitating lesions with high 18F-fluorodeoxyglucose uptake on positron emission tomography/ computed tomography, one of which diagnosed as IgG4-RLD and the other as lung cancer based on biopsy eventually. The awareness of the imaging features of IgG4-RLD and lung cancer described in the present study may help physicians to distinguish one from the other. IgG4-RLD should be considered in the differential diagnosis of cavitary lung lesions.

Nanoemulsion of D-limonene in water system prepared by ultrasonic emulsification.

D-Limonene is a component of essential oil extracted from citrus fruits. This component has shown chemopreventive and therapeutic activity against a wide variety of experimental tumors, but D-limonene is unstable and lose its lemon-like flavor under normal storage condition, and it is almost insoluble in water. Therefore, studying the formation of nanoemulsion in D-limonene in water system is probably a good method to prevent the oxidation degradation of D-limonene. For the purpose of our study, we used mixed surfactant to form D- limonene-in-water emulsion, and found the best formula for forming nanoemulsion droplets with specified hydrophilic-lipophilic balance (HLB) value and droplet size. The results demonstrated that nanoemulsion droplets formed at So ratio of 0.4 and applied power of 18 W for 120 s under mixed surfactant at HLB values 12 and had droplet size of 20-50 nm.

Effect of neurolytic celiac plexus block guided by computerized tomography on pancreatic cancer pain.

The efficacy of neurolytic coeliac plexus block (NCPB) guided by computerized tomography (CT) was compared with pharmacological therapy in the treatment of pain due to pancreatic cancer. The study involved 56 patients who were placed randomly in either a NCPB group and pharmacological therapy group. At day 1, 7, and 14, the visual analogue scale (VAS) pain scores of the NCPB group were significantly lower than those of the pharmacological therapy group (P < 0.01), with values of 1.3 +/- 0.8 versus 4.1 +/- 0.9, 1.7 +/- 1.1 versus 3.1 +/- 1.1, and 2.0 +/- 1.1 versus 2.9 +/- 0.6, respectively. However, the differences in the improvement of quality of life (QOL) between two groups were not statistically significant. Moreover, the dose of opioid was significantly lower in the patients of group 1 than those of group 2, while the complications related to NCPB were transient. We therefore concludes that CT-guided NCPB with alcohol is an effective and safe modality in the management of intractable pancreatic cancer pain.

Hippocampus bcl-2 and bax expression and neuronal apoptosis after moderate hypothermic cardiopulmonary bypass in rats.

Using a rat model of moderate hypothermic (26 degrees C-28 degrees C) cardiopulmonary bypass (CPB) with hemodilution, we investigated hippocampal apoptotic gene expression and neuronal apoptosis up to 6 h after CPB. The CPB was performed on male rats (380-400 g) under general anesthesia with isoflurane and fentanyl. The right atrium and tail artery were cannulated, and a peristaltic pump and membrane oxygenator were used for CPB. Two groups were studied: Group 1 consisted of fasted rats (n = 15) subjected to 60 min of moderate hypothermic nonpulsatile CPB; Group 2 consisted of sham-operated rats (n = 15). At 1 h after CPB, in 6 rats per group, hippocampus was processed for the apoptotic gene (bcl-2 and bax) messenger RNAs detection by reverse transcriptase polymerase chain reaction, and messenger RNA expression was determined by the ratio of the polymerase chain reaction product of bcl-2 or bax to the beta-actin gene. At 6 h after CPB, in 6 rats per group, hippocampus expression of Bcl-2 and bax protein was determined by immunohistochemistry, and neuronal apoptosis was detected by TUNEL. At 6 h after CPB, in three rats per group, changes in hippocampal CA1 neuronal ultra structure were determined with electron microscopy. Group 1 had increased ratios of bcl-2/beta-actin, bax/beta-actin, and bax/bcl-2 mRNA at 1 h after CPB (bcl-2/beta-actin, 0.82 +/- 0.14 versus 0.63 +/- 0.07; P = 0.03; bax/beta-actin, 1.04 +/- 0.14 versus 0.56 +/- 0.03; P = 0.00; bax/bcl-2, 1.31 +/- 0.12 versus 0.84 +/- 0.09; P = 0.02; Group 1 versus Group 2, respectively). Group 1 had increased bcl-2 and bax protein expression in hippocampal CA1 region at 6 h after CPB (bcl-2, 0.18 +/- 0.05 versus 0.09 +/- 0.01; P = 0.02; bax, 0.20 +/- 0.06 versus 0.04 +/- 0.02; P = 0.01; Group 1 versus Group 2, respectively). Group 1 had increased TUNEL staining in hippocampus CA1 at 6 h after CPB (0.14 +/- 0.02 versus 0.03 +/- 0.01; P = 0.00; Group 1 versus Group 2, respectively). In Group 1 CA1 hippocampus neurons, ultra-structural changes consistent with apoptosis occurred. In rats, moderate hypothermic CPB with hemodilution is associated with CA1 hippocampus bax and bcl-2 gene expression and neuronal apoptosis during the early post-CPB recovery period.