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IntroductionImmunoglobulin G (IgG) is important in mediating humoral immunity and in the maintenance of immune homeostasis in the intestinal mucosa. Oregano essential oil (OEO) is a natural herbal extract that possesses antimicrobial, antioxidant, anti-inflammatory, and immunomodulatory properties. As the effects of OEO on intestinal mucosal immunity in Holstein dairy bulls remained unclear, we investigated the effect of dietary supplementation of OEO on IgG levels and IgG+ cells residing in the intestinal tract in Holstein dairy bulls.MethodsTwelve Holstein bulls in good health of approximately 10 months of age were selected for the experiment and randomly equally divided into two groups. The control (CK) group was fed a basal ration, and in the OEO group, the basal ration was supplemented with OEO (20 g/head/day). After 300 days of feeding, tissue samples of the jejunum, ileum, and colon of the bulls in each group were collected for histopathological analysis, immunohistochemistry, and enzyme-linked immunosorbent assays, respectively.ResultsThe jejunum, ileum, and colon of bulls in the CK group had obvious pathological damage, whereas the structure of each intestinal segment was clear and intact. In the OEO group, pathological damage was significantly reduced. IgG+ plasma cells were diffusely distributed in the lamina propria of the jejunum, ileum, and colon in the CK and OEO groups, with no significant difference between the groups. OEO supplementation significantly reduced the number of IgG+ plasma cells in each intestinal segment, with the highest decrease rate being noted for the ileum (22.87%), followed by the colon (19.45%) and jejunum (8.52%). ELISA test results and immunohistochemical results were mutually verified. The change in IgG content was consistent with the trend of change in the number of IgG+ plasma cells.DiscussionOur findings suggest that OEO supplementation does not alter the diffuse spatial distribution of IgG+ plasma cells in the intestines of Holstein dairy bulls, but lowers immunoglobulin levels to normal levels, significantly reduces intestinal damage, and may enhance mucosal immune defence barrier function by inhibiting inflammatory reactions.

Oregano essential oil (OEO) primarily contains phenolic compounds and can serve as a dietary supplement for fattening bulls. However, the precise molecular mechanism underlying this phenomenon remains largely elusive. Therefore, this study investigated the impact of adding OEO to diet on the integrity of the intestinal barrier, composition of the colonic microbiome, and production of microbial metabolites in fattening bulls. Our goal was to provide insights into the utilization of plant essential oil products in promoting gastrointestinal health and welfare in animals. We employed amplicon sequencing and metabolome sequencing techniques to investigate how dietary supplementation with OEO impacted the intestinal barrier function in bulls. The inclusion of OEO in the diet resulted in several notable effects on the colon of fattening bulls. These effects included an increase in the muscle thickness of the colon, goblet cell number, short-chain fatty acid concentrations, digestive enzyme activity, relative mRNA expression of intestinal barrier-related genes, and relative expression of the anti-inflammatory factor IL-10. Additionally, α-amylase activity and the relative mRNA expression of proinflammatory cytokines decreased. Moreover, dietary OEO supplementation increased the abundance of intestinal Bacteroides, Coprobacillus, Lachnospiraceae_UCG_001, and Faecalitalea. Metabolomic analysis indicated that OEO primarily increased the levels of 5-aminovaleric acid, 3-methoxysalicylic acid, and creatinine. In contrast, the levels of maltose, lactulose, lactose, and D-trehalose decreased. Correlation analysis showed that altered colonic microbes and metabolites affected intestinal barrier function. Taken together, these results demonstrate that OEO facilitates internal intestinal environmental homeostasis by promoting the growth of beneficial bacteria while inhibiting harmful ones.

Patients with chemo-refractory metastatic colorectal cancer (mCRC) have poor prognoses. The application of programmed cell death protein 1 (PD-1)/programmed cell death ligand 1 (PD-L1) inhibitors encouragingly improved the survival of mCRC patients with microsatellite instability-high (MSI-H)/mismatch repair-deficient (dMMR). Unfortunately, it was ineffective for mCRC with microsatellite-stable (MSS)/proficient mismatch repair (pMMR), which accounted for 95% of mCRC. Radiotherapy can promote local control by directly killing tumor cells and inducing positive immune activities, which might help synergistically with immunotherapy. We present the report of an advanced MSS/pMMR mCRC patient who had progressive disease (PD) after first-line chemotherapy, palliative surgery and second-line chemotherapy combined with targeted therapy. Then the patient received the therapy of PD-1 inhibitor combined with radiotherapy and granulocyte-macrophage colony-stimulating factor (GM-CSF). According to Response Evaluation Criteria in Solid Tumors version 1.1 (RECIST1.1), the patient showed a complete response (CR) after triple-combined therapy with progression-free survival (PFS) for more than 2 years so far. The patient had no other significant adverse reactions except for fatigue (Grade 1). The triple-combination therapy provided a promising strategy for metastatic chemo-refractory MSS/pMMR mCRC patients.

ObjectiveThis study aims to highlight the use of robots in surgery and that of tube-assisted minimally invasive surgery for spinal metastases, as well as elaborate on the concept of invasion-controlled surgery (ICS).Summary of backgroundMany patients with spinal metastasis cancer cannot afford serious complications when undergoing traditional open surgery because of their poor physical condition. Robots and minimally invasive technology have been introduced into the field of spine surgery and they have shown significant advantages.MethodsSix patients who underwent robot and working tube-assisted ICS for spinal metastases. Relevant demographic, medical, surgical, and postoperative data were collected from medical records and analyzed.ResultsMean operative time was 3.8 h and the mean length of the surgical incision was 4.9 cm. The mean estimated blood loss was 400 ml. The mean bedtime and hospital length of stay were 3.2 days and 6.5 days, respectively. No obvious complications were reported during treatment. The mean accuracy of screw placement was 98%. The mean time for further system treatment after surgery was 5.8 days. All patients experienced significant pain relief. The mean preoperative visual analog scale (VAS) was 7.83 points. The mean VAS at 1 day, 1 week, and 1 month after surgery were 2.83, 1.83, and 1.17 points, respectively. Frankel grade was improved in five of six patients. One patient preoperatively with Frankel grade D was the same postoperatively.ConclusionThe concept of ICS is suitable for patients with spinal metastases. Robot and working tube-assisted ICS for spinal metastases is one of the safest and most effective treatment methods.

ObjectiveOur study aims to estimate intra-fraction six-dimensional (6D) tumor motion with rotational correction and the related correlations between motions of different degrees of freedom (DoF), as well as quantify sufficient anisotropic clinical target volume (CTV) to planning target volume (PTV) margins during stereotactic body radiotherapy (SBRT) of liver cancer with fiducial tracking technique.MethodsA cohort of 12 patients who were implanted with 3 or 4 golden markers were included in this study, and 495 orthogonal kilovoltage (kV) pairs of images acquired during the first fraction were used to extract the spacial position of each golden marker. Translational and rotational motions of tumor were calculated based on the marker coordinates by using an iterative closest point (ICP) algorithm. Moreover, the Pearson product-moment correlation coefficients (r) were applied to quantify the correlations between motions with different degrees of freedom (DoFs). The population mean displacement (MP¯), systematic error (Σ) and random error (σ) were obtained to calculate PTV margins based on published recipes.ResultsThe mean translational variability of tumors were 0.56, 1.24 and 3.38 mm in the left-right (LR, X), anterior-posterior (AP, Y), and superior-inferior (SI, Z) directions, respectively. The average rotational angles θX , θY and θZ around the three coordinate axes were 0.88, 1.24 and 1.12, respectively. (|r|>0.4) was obtainted between Y -Z , Y - θZ , Z -θZ and θX - θY . The PTV margins calculated based on 13 published recipes in X, Y, and Z directions were 1.08, 2.26 and 5.42 mm, and the 95% confidence interval (CI) of them were (0.88,1.28), (1.99,2.53) and (4.78,6.05), respectively.ConclusionsThe maximum translational motion was in SI direction, and the largest correlation coefficient of Y-Z was obtained. We recommend margins of 2, 3 and 7 mm in LR, AP and SI directions, respectively.

Patients with metastatic gastric cancer had limited treatments and often had a somber prognosis, especially when patients were unable to tolerate high-intensity cytotoxic treatment due to poor physical condition or organ dysfunction after the failure of standard therapy. Here, we reported a metastatic and proficient mismatch repair (pMMR) gastric adenocarcinoma patient with the Eastern Cooperative Oncology Group (ECOG) performance status score of 2 associated with hypoproteinemia and fatigue, and poor appetite that was unable to tolerate high-intensity therapy after several chemotherapy regimens and anti-angiogenic therapy. After receiving novel triple-combination therapy, which consists of PD-1 inhibitor, Radiotherapy and Granulocyte-macrophage colony-stimulating factor (GM-CSF) therapy (PRaG for short), the patient achieved a complete response (CR) with a progression-free survival time of 14 months, and ECOG performance status score improved from 2 to 0. A significant systemic effect was observed in this case and the PRaG triple-combination therapy might provide a novel treatment strategy for metastatic pMMR gastric cancer patients.

Patients with metastatic cancer refractory to standard systemic therapies have a poor prognosis and few therapeutic options. Radiotherapy can shape the tumor microenvironment (TME) by inducing immunogenic cell death and promoting tumor recognition by natural killer cells and T lymphocytes. Granulocyte macrophage-colony stimulating factor (GM-CSF) was known to promote dendric cell maturation and function, and might also induce the macrophage polarization with anti-tumor capabilities. A phase II trial (ChiCTR1900026175) was conducted to assess the clinical efficacy and safety of radiotherapy, PD-1 inhibitor and GM-CSF (PRaG regimen). This trial was registered at http://www.chictr.org.cn/index.aspx. A PRaG cycle consisted of 3 fractions of 5 or 8 Gy delivered for one metastatic lesion from day 1, followed by 200 μg subcutaneous injection of GM-CSF once daily for 2 weeks, and intravenous infusion of PD-1 inhibitor once within one week after completion of radiotherapy. The PRaG regimen was repeated every 21 days for at least two cycles. Once the PRaG therapy was completed, the patient continued PD-1 inhibitor monotherapy until confirmed disease progression or unacceptable toxicity. The primary endpoint was objective response rate (ORR). A total of 54 patients were enrolled with a median follow-up time of 16.4 months. The ORR was 16.7%, and the disease control rate was 46.3% in intent-to-treat patients. Median progression-free survival was 4.0 months (95% confidence interval [CI], 3.3 to 4.8), and median overall survival was 10.5 months (95% CI, 8.7 to 12.2). Grade 3 treatment-related adverse events occurred in five patients (10.0%) and grade 4 in one patient (2.0%). Therefore, the PRaG regimen was well tolerated with acceptable toxicity and may represent a promising salvage treatment for patients with chemotherapy-refractory solid tumors. It is likely that PRaG acts via heating upthe TME with radiotherapy and GM-CSF, which was further boosted by PD-1 inhibitors.

Pyropia yezoensis can survive the severe water loss that occurs during low tide, making it an ideal species to investigate the acclimation mechanism of intertidal seaweed to special extreme environments. In this study, we determined the effects of high salinity on photosynthesis using increasing salinity around algal tissues. Both electron transport rates, ETR (I) and ETR (II), showed continuous decreases as the salinity increased. However, the difference between these factors remained relatively stable, similar to the control. Inhibitor experiments illustrated that there were at least three different cyclic electron transport pathways. Under conditions of severe salinity, NAD(P)H could be exploited as an endogenous electron donor to reduce the plastoquinone pool in Py. yezoensis. Based on these findings, we next examined how these different cyclic electron transport (CETs) pathways were coordinated by cloning the gene (HM370553) for ferredoxin-NADP+ oxidoreductase (FNR). A phylogenetic tree was constructed, and the evolutionary relationships among different FNRs were evaluated. The results indicated that the Py. yezoensis FNR showed a closer relationship with cyanobacterial FNR. The results of both real-time polymerase chain reaction and western blotting showed that the enzyme was upregulated under 90–120‰ salinity. Due to the structure-function correlations in organism, Py. yezoensis FNR was proposed to be involved in NAD(P)H-dependent Fd+ reduction under severe salinity conditions. Thus, through the connection between different donors bridged by FNR, electrons were channeled toward distinct routes according to the different metabolic demands. This was expected to make the electron transfer in the chloroplasts become more flexible and to contribute greatly to acclimation of Py. yezoensis to the extreme variable environments in the intertidal zone.