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Journal of Translational Medicine Mar 2024Tumor regression following immune checkpoint blockade (ICB) is often associated with immune-related adverse events (irAEs), marked by inflammation in non-cancerous...
BACKGROUND
Tumor regression following immune checkpoint blockade (ICB) is often associated with immune-related adverse events (irAEs), marked by inflammation in non-cancerous tissues. This study was undertaken to investigate the functional relationship between anti-tumor and anti-self immunity, to facilitate irAE management while promoting anti-tumor immunity.
METHODS
Multiple biopsies from tumor and inflamed tissues were collected from a patient with melanoma experiencing both tumor regression and irAEs on ICB, who underwent rapid autopsy. Immune cells infiltrating melanoma lesions and inflamed normal tissues were subjected to gene expression profiling with multiplex qRT-PCR for 122 candidate genes. Subsequently, immunohistochemistry was conducted to assess the expression of 14 candidate markers of immune cell subsets and checkpoints. TCR-beta sequencing was used to explore T cell clonal repertoires across specimens.
RESULTS
While genes involved in MHC I/II antigen presentation, IFN signaling, innate immunity and immunosuppression were abundantly expressed across specimens, irAE tissues over-expressed certain genes associated with immunosuppression (CSF1R, IL10RA, IL27/EBI3, FOXP3, KLRG1, SOCS1, TGFB1), including those in the COX-2/PGE2 pathway (IL1B, PTGER1/EP1 and PTGER4/EP4). Immunohistochemistry revealed similar proportions of immunosuppressive cell subsets and checkpoint molecules across samples. TCRseq did not indicate common TCR repertoires across tumor and inflammation sites, arguing against shared antigen recognition between anti-tumor and anti-self immunity in this patient.
CONCLUSIONS
This comprehensive study of a single patient with melanoma experiencing both tumor regression and irAEs on ICB explores the immune landscape across these tissues, revealing similarities between anti-tumor and anti-self immunity. Further, it highlights expression of the COX-2/PGE2 pathway, which is known to be immunosuppressive and potentially mediates ICB resistance. Ongoing clinical trials of COX-2/PGE2 pathway inhibitors targeting the major COX-2 inducer IL-1B, COX-2 itself, or the PGE2 receptors EP2 and EP4 present new opportunities to promote anti-tumor activity, but may also have the potential to enhance the severity of ICB-induced irAEs.
Topics: Humans; Melanoma; Immune Checkpoint Inhibitors; Cyclooxygenase 2; Dinoprostone; Blood Group Antigens; Cyclooxygenase 2 Inhibitors; Inflammation; Receptors, Antigen, T-Cell
PubMed: 38443917
DOI: 10.1186/s12967-024-04973-7 -
Bone Research Mar 2024Bone is a mechanosensitive tissue and undergoes constant remodeling to adapt to the mechanical loading environment. However, it is unclear whether the signals of bone...
Bone is a mechanosensitive tissue and undergoes constant remodeling to adapt to the mechanical loading environment. However, it is unclear whether the signals of bone cells in response to mechanical stress are processed and interpreted in the brain. In this study, we found that the hypothalamus of the brain regulates bone remodeling and structure by perceiving bone prostaglandin E2 (PGE2) concentration in response to mechanical loading. Bone PGE2 levels are in proportion to their weight bearing. When weight bearing changes in the tail-suspension mice, the PGE2 concentrations in bones change in line with their weight bearing changes. Deletion of cyclooxygenase-2 (COX2) in the osteoblast lineage cells or knockout of receptor 4 (EP4) in sensory nerve blunts bone formation in response to mechanical loading. Moreover, knockout of TrkA in sensory nerve also significantly reduces mechanical load-induced bone formation. Moreover, mechanical loading induces cAMP-response element binding protein (CREB) phosphorylation in the hypothalamic arcuate nucleus (ARC) to inhibit sympathetic tyrosine hydroxylase (TH) expression in the paraventricular nucleus (PVN) for osteogenesis. Finally, we show that elevated PGE2 is associated with ankle osteoarthritis (AOA) and pain. Together, our data demonstrate that in response to mechanical loading, skeletal interoception occurs in the form of hypothalamic processing of PGE2-driven peripheral signaling to maintain physiologic bone homeostasis, while chronically elevated PGE2 can be sensed as pain during AOA and implication of potential treatment.
Topics: Animals; Mice; Dinoprostone; Ankle; Interoception; Brain; Pain; Osteoarthritis
PubMed: 38443372
DOI: 10.1038/s41413-024-00316-w -
The British Journal of Nutrition Jun 2024The primary goal of the investigation was to analyse the anti-inflammatory and antioxidant properties of Gamma-linolenic acid (GLA) on rats with indomethacin...
The primary goal of the investigation was to analyse the anti-inflammatory and antioxidant properties of Gamma-linolenic acid (GLA) on rats with indomethacin (IND)-induced gastric ulcers. Thirty rats were divided into five groups: Control, IND (50 mg/kg, p.o.), IND pretreated with GLA 100 mg/kg (p.o. for 14 d), IND pretreated with GLA 150 mg/kg (p.o. for 14 d) and IND pretreated with omeprazole (20 mg/kg, p.o. for 14 d). The stomach tissues were examined to calculate the ulcer index and pH and analyse biochemical markers (prostaglandin E2 (PGE2), cyclooxygenase 1 (COX1), TNF-1, IL-6 and intercellular adhesion molecule-1 (ICAM1)) and oxidative stress parameters (malondialdehyde: (MDA), superoxide dismutase (SOD), glutathione (GSH) and CAT (catalase)) as well as undergo histopathological assessment. GLA 100 and 150 mg/kg showed a protective effect against IND-induced gastric damage. It reduced levels of COX1, TNF-1, IL-6 and ICAM and increased PGE2 levels. GLA also normalised antioxidant function by modulating MDA, SOD, GSH and CAT. GLA intervention protects against IND-induced gastric ulcers by restoring oxidant/antioxidant balance and reducing inflammation.
Topics: Animals; Stomach Ulcer; Indomethacin; Antioxidants; Rats; Oxidative Stress; gamma-Linolenic Acid; Male; Rats, Wistar; Dinoprostone; Gastric Mucosa; Interleukin-6; Intercellular Adhesion Molecule-1; Superoxide Dismutase; Anti-Ulcer Agents; Glutathione; Tumor Necrosis Factor-alpha; Anti-Inflammatory Agents; Cyclooxygenase 1; Malondialdehyde; Omeprazole
PubMed: 38443203
DOI: 10.1017/S0007114524000382 -
International Journal of Radiation... 2024Radiotherapy with bladder preservation is highly acceptable among patients bearing bladder cancer (BCa), but the occurrence of secondary tolerance (ARR) during treatment...
PURPOSE
Radiotherapy with bladder preservation is highly acceptable among patients bearing bladder cancer (BCa), but the occurrence of secondary tolerance (ARR) during treatment is one of the important reasons for the failure of clinical radiotherapy. COX-2 has been frequently reported to be highly expressed and associated with radio-resistance in various cancers. In this study, the feasibility of Taraxasterol (Tara) as a radiosensitizer was investigated, and the target effect of Tara on COX-2 and its underlying mechanism were explored.
METHODS AND MATERIALS
The toxicity of Tara toward BCa cells was detected with the MTT method and cells in response to IR or Tara + IR were compared by clone formation assay. Next, a small RNA interference system (siRNA) was employed to decrease endogenous COX-2 expression in BCa cells, and the stem cell-like features and motion abilities of BCa cells under different treatments were investigated using microsphere formation and transwell chamber assay, respectively. Meanwhile, the expression of a series of inflammation-related molecules and stem cell characteristic molecules was determined by qRT-PCR, western blot and ELISA method. In vivo studies, BCa cells were subcutaneously injected into the right flank of each male mouse. Those mice were then grouped and exposed to different treatment: Tara, IR, IR + Tara and untreated control. The volumes of each tumor were measured every two days and target proteins were detected with immunohistochemical (IHC) staining.
RESULTS
The results show that COX-2 decline, due to COX-2 knocking-down or Tara treatment, could greatly enhance BCa cells' radiosensitivity and significantly decrease their migration, invasion and microsphere formation abilities, companied with the reduce of JAK2, phos-STAT3, MMP2 and MMP9 expression. However, Tara could not further reduce the expression of an above molecule of cells in COX-2-deficient BCa cells. Correspondingly, Tara treatment could not further enhance those siCOX-2 BCa cells response to IR.
CONCLUSIONS
Our data support that Tara can improve the radiosensitivity of BCa cells by targeting COX-2/PGE. The mechanism may involve regulating STAT3 phosphorylation, DNA damage response protein activation, and expression of MMP2/MMP9.
Topics: Janus Kinase 2; Humans; Cyclooxygenase 2; Urinary Bladder Neoplasms; Animals; Cell Line, Tumor; STAT3 Transcription Factor; Mice; Radiation Tolerance; Dinoprostone; Signal Transduction; Sterols; Triterpenes; Radiation-Sensitizing Agents; Male
PubMed: 38442139
DOI: 10.1080/09553002.2024.2324475 -
The Journal of Biological Chemistry Apr 2024Regulators of G protein signaling (RGS) proteins constrain G protein-coupled receptor (GPCR)-mediated and other responses throughout the body primarily, but not...
Regulators of G protein signaling (RGS) proteins constrain G protein-coupled receptor (GPCR)-mediated and other responses throughout the body primarily, but not exclusively, through their GTPase-activating protein activity. Asthma is a highly prevalent condition characterized by airway hyper-responsiveness (AHR) to environmental stimuli resulting in part from amplified GPCR-mediated airway smooth muscle contraction. Rgs2 or Rgs5 gene deletion in mice enhances AHR and airway smooth muscle contraction, whereas RGS4 KO mice unexpectedly have decreased AHR because of increased production of the bronchodilator prostaglandin E2 (PGE2) by lung epithelial cells. Here, we found that knockin mice harboring Rgs4 alleles encoding a point mutation (N128A) that sharply curtails RGS4 GTPase-activating protein activity had increased AHR, reduced airway PGE2 levels, and augmented GPCR-induced bronchoconstriction compared with either RGS4 KO mice or WT controls. RGS4 interacted with the p85α subunit of PI3K and inhibited PI3K-dependent PGE2 secretion elicited by transforming growth factor beta in airway epithelial cells. Together, these findings suggest that RGS4 affects asthma severity in part by regulating the airway inflammatory milieu in a G protein-independent manner.
Topics: Animals; Humans; Mice; Asthma; Bronchoconstriction; Dinoprostone; Epithelial Cells; GTPase-Activating Proteins; Mice, Knockout; Phosphatidylinositol 3-Kinases; Respiratory Hypersensitivity; RGS Proteins; Cell Line
PubMed: 38432633
DOI: 10.1016/j.jbc.2024.107127 -
Kidney International Jul 2024Despite the recent advances in our understanding of the role of lipids, metabolites, and related enzymes in mediating kidney injury, there is limited integrated...
Despite the recent advances in our understanding of the role of lipids, metabolites, and related enzymes in mediating kidney injury, there is limited integrated multi-omics data identifying potential metabolic pathways driving impaired kidney function. The limited availability of kidney biopsies from living donors with acute kidney injury has remained a major constraint. Here, we validated the use of deceased transplant donor kidneys as a good model to study acute kidney injury in humans and characterized these kidneys using imaging and multi-omics approaches. We noted consistent changes in kidney injury and inflammatory markers in donors with reduced kidney function. Neighborhood and correlation analyses of imaging mass cytometry data showed that subsets of kidney cells (proximal tubular cells and fibroblasts) are associated with the expression profile of kidney immune cells, potentially linking these cells to kidney inflammation. Integrated transcriptomic and metabolomic analysis of human kidneys showed that kidney arachidonic acid metabolism and seven other metabolic pathways were upregulated following diminished kidney function. To validate the arachidonic acid pathway in impaired kidney function we demonstrated increased levels of cytosolic phospholipase A2 protein and related lipid mediators (prostaglandin E2) in the injured kidneys. Further, inhibition of cytosolic phospholipase A2 reduced injury and inflammation in human kidney proximal tubular epithelial cells in vitro. Thus, our study identified cell types and metabolic pathways that may be critical for controlling inflammation associated with impaired kidney function in humans.
Topics: Humans; Phenotype; Acute Kidney Injury; Male; Middle Aged; Metabolomics; Female; Kidney Transplantation; Adult; Image Cytometry; Kidney; Phospholipases A2; Arachidonic Acid; Kidney Tubules, Proximal; Transcriptome; Dinoprostone; Fibroblasts; Gene Expression Profiling; Epithelial Cells; Biopsy; Multiomics
PubMed: 38431215
DOI: 10.1016/j.kint.2024.01.041 -
BJOG : An International Journal of... Feb 2024Induction of labour (IOL) is common practice and different methods carry different effectiveness and safety profiles. (Review)
Review
Vaginal misoprostol versus vaginal dinoprostone for cervical ripening and induction of labour: An individual participant data meta-analysis of randomised controlled trials.
BACKGROUND
Induction of labour (IOL) is common practice and different methods carry different effectiveness and safety profiles.
OBJECTIVES
To compare the effectiveness, and maternal and perinatal safety outcomes of IOL with vaginal misoprostol versus vaginal dinoprostone using individual participant data from randomised clinical trials.
SEARCH STRATEGY
The following databases were searched from inception to March 2023: CINAHL Plus, ClinicalTrials.gov, Cochrane Pregnancy and Childbirth Group Trial Register, Ovid Embase, Ovid Emcare, Ovid MEDLINE, Scopus and the World Health Organization (WHO) International Clinical Trials Registry Platform (ICTRP).
SELECTION CRITERIA
Randomised controlled trials (RCTs), with viable singleton gestation, no language restrictions, and all published and unpublished data.
DATA COLLECTION AND ANALYSIS
An individual participant data meta-analysis was carried out.
MAIN RESULTS
Ten of 52 eligible trials provided individual participant data, of which two were excluded after checking data integrity. The remaining eight trials compared low-dose vaginal misoprostol versus dinoprostone, including 4180 women undergoing IOL, which represents 32.8% of all participants in the published RCTs. Of these, 2077 were assigned to low-dose vaginal misoprostol and 2103 were assigned to vaginal dinoprostone. Compared with vaginal dinoprostone, low-dose vaginal misoprostol had a comparable rate of vaginal birth. Composite adverse perinatal outcomes did not differ between the groups. Compared with vaginal dinoprostone, composite adverse maternal outcomes were significantly lower with low-dose vaginal misoprostol (aOR 0.80, 95% CI 0.65-0.98, P = 0.03, I = 0%).
CONCLUSIONS
Low-dose vaginal misoprostol and vaginal dinoprostone for IOL are comparable in terms of effectiveness and perinatal safety. However, low-dose vaginal misoprostol is likely to lead to a lower rate of composite adverse maternal outcomes than vaginal dinoprostone.
PubMed: 38425020
DOI: 10.1111/1471-0528.17794 -
Cureus Jan 2024Cervical ripening is commonly performed before oxytocin administration during labor induction in pregnant women with an unfavorable cervix. In Japan, a...
AIM
Cervical ripening is commonly performed before oxytocin administration during labor induction in pregnant women with an unfavorable cervix. In Japan, a controlled-release Dinoprostone vaginal insert (CR-DVI) was approved in 2020. Although many studies have compared the mechanical methods of ripening and prostaglandins, few have examined the impact of additional options for labor induction. This study aimed to assess the impact of CR-DVI as an additional option for labor induction in women with an unfavorable cervix.
METHODS
In this single-center retrospective study conducted in Japan, 265 participants were divided into two groups: before (January 2018 to May 2020) and after (June 2020 to November 2022) CR-DVI introduction. Before CR-DVI was introduced, hygroscopic dilators were used for all cases instead. On the other hand, after the introduction of CR-DVI, the first choice for cervical ripening was CR-DVI. The CR-DVI was retained vaginally for up to 12 hours after insertion. However, if hyper-stimulation or non-reassuring fetal status was suspected, or if a new membrane rupture occurred, it was removed immediately according to the removal criteria. Oxytocin infusions were used during both periods if needed. We compared delivery and neonatal outcomes between the groups.
RESULTS
The 265 participants were divided into two groups: before (n=116) and after (n=149) CR-DVI introduction. There were no significant differences in maternal characteristics except for the primiparous proportion. CR-DVI was used in 93% of cases after introduction. Hygroscopic dilators also continued to be used; however, their use decreased to about 34%. The vaginal delivery rate was significantly higher after the introduction of CR-DVI than before its introduction (50.9% vs. 66.4%; p=0.01). Multivariable analysis revealed a significantly higher rate of vaginal delivery after CR-DVI introduction. Of the 149 cases in which a CR-DVI was used, 111 (79.9%) were removed before 12 hours. There were no significant differences in neonatal outcomes.
CONCLUSION
The rate of vaginal delivery was higher after CR-DVI introduction than before its introduction, and adverse pregnancy outcomes did not increase. Therefore, introducing CR-DVI as an option for labor induction may increase the probability of vaginal delivery. Safety can also be ensured by adhering to the removal criteria.
PubMed: 38420080
DOI: 10.7759/cureus.53180 -
Zhen Ci Yan Jiu = Acupuncture Research Feb 2024To observe the curative efficacy of auricular comprehensive therapy on menstrual migraine(MM) and its effect on serum prostaglandin F2α(PGF), prostaglandin E2(PGE)... (Randomized Controlled Trial)
Randomized Controlled Trial
OBJECTIVES
To observe the curative efficacy of auricular comprehensive therapy on menstrual migraine(MM) and its effect on serum prostaglandin F2α(PGF), prostaglandin E2(PGE) contents and ratio, so as to explore its possible mechanism.
METHODS
A total of 66 patients with MM of liver-fire syndrome were randomly divided into observation group (33 cases, 2 cases dropped off) and control group (33 cases, 2 cases dropped off), and 20 healthy women were included in the normal group. Patients in the control group were given flunarizine hydrochloride capsules orally, twice a day, for 3 consecutive weeks. Patients in the observation group were treated with auricular comprehensive therapy, starting 2-5 days before menstrual cramps, once a week, for a total of 3 weeks. The visual analogue scale (VAS) and migraine score were evaluated before and after treatment, and follow-up for 1 and 2 menstrual cycles. Serum PGF and PGE contents were measured before and after treatment, and the PGF/PGE ratio was calculated. The clinical effective rates in the two groups were calculated.
RESULTS
After treatment and follow-up for 1 and 2 menstrual cycles, the VAS scores, headache degree, the frequency and duration of headache attacks, as well as accompanying symptoms of the observation and control groups were lower than those before treatment(<0.05), and those of the observation group was lower than those of the control group(<0.05). Before treatment, the PGF contents in the observation and control group were significantly higher(<0.05), while the PGE contents lower(<0.05) and PGF/PGE ratio higher(<0.05) than those in the normal group. After treatment, the serum PGF contents in the observation and control group were significantly reduced compared with which before treatment(<0.05), and were lower in the observation group than that in the control group (<0.05). The serum PGE contents in the observation and control groups were significantly increased after treatment compared with which before treatment(<0.05), with the contents in the observation group higher than that in the control group(<0.05). The serum PGF/PGE ratio in the observation and control group was significantly reduced after treatment compared with which before treatment(<0.05), with the control group higher than the normal group(<0.05), and the observation group lower than the control group(<0.05). The clinical effective rate of the observation group was 93.5% (29/31), and that of the control group was 77.4% (24/31). The effective rate of the observation group was significantly higher than that of the control group(<0.05).
CONCLUSIONS
The curative efficacy of auricular comprehensive therapy on MM with liver-fire syndrome is significantly better than that of oral flunarizine hydrochloride capsules, especially in relieving hea-daches, reducing the frequency and duration of headache attacks, as well as accompanying symptoms. Its mechanism may be related to regulating the abnormal PGF and PGE contents of patients and reducing the ratio of PGF/PGE.
Topics: Humans; Female; Prostaglandins; Flunarizine; Dinoprostone; Migraine Disorders; Headache; Syndrome
PubMed: 38413039
DOI: 10.13702/j.1000-0607.20221424 -
Zhen Ci Yan Jiu = Acupuncture Research Feb 2024To observe the effects of the local stimulation with 3 acupuncture techniques, i.e. (needle insertion method like dark tortoise detecting point) technique,... (Randomized Controlled Trial)
Randomized Controlled Trial
OBJECTIVES
To observe the effects of the local stimulation with 3 acupuncture techniques, i.e. (needle insertion method like dark tortoise detecting point) technique, electroacupuncture (EA) and warm needling (WN) with filiform needles on shoulder pain, shoulder joint function, quality of life, inflammatory indicators and recurrence rate in the patients with chronic scapulohumeral periarthritis (CSP), so as to explore the optimal needling method of acupuncture for the predominant symptoms of CSP during the attack stage in the patients.
METHODS
A total of 108 patients with CSP were randomly divided into a manual acupuncture (MA) group (36 cases, one case dropped off), a WN group (36 cases, 3 cases dropped off) and an EA group (36 cases, 1 case dropped off). In the three groups, Jianqian (EX-UE12), Jianyu (LI15), Jianzhen (SI9), Ashi (Extra) and Yanglingquan (GB34) on the affected side were selected. needling technique, WN technique and EA were delivered in the MA group, the WN group and the EA group, respectively, 30 min each time, 3 times weekly for 4 weeks. The Neer test scores were compared;the visual analogue scale (VAS) was used to assess the degree of shoulder joint pain;the daily life activity abilities was evaluated using the activities of daily living (ADL) scale;the serum prostaglandin E2 (PGE2) content was measured using ELISA before and after treatment. The effectiveness rate and recurrence rate were calculated, and the occurrences of adverse reactions were recorded.
RESULTS
Compared with the scores before treatment, the scores of pain, joint function, and range of motion as well as the total score of Neer test were all increased after treatment in the three groups (<0.05);the VAS score, ADL score and the content of serum PGE2 were decreased (<0.05). After treatment, the pain score of Neer test in the EA group and the WN group were higher than those of the MA group (0.05), the joint function score of Neer test in the MA group and the WN group were higher than that of the EA group (<0.05), and the range of motion score of Neer test in the MA group was higher when compared with the EA and WN groups (<0.05). There was no statistical difference in the total score of Neer score among the three groups. VAS score in the EA group was lower than that of either the WN group or the MA group (<0.05). ADL score in the MA group was lower compared with that of the WN group (0.05). PGE2 levels in both the WN group and the MA group were lower than that of the EA group (<0.05). The total effective rate was 85.71% (30/35) in the MA group, 91.43% (32/35) in the EA group and 90.91% (30/33) in the WN group, there was no statistical differences among the three groups. At the end of the 6-month follow-up visit after treatment, there was no significant difference in the recurrence rate among three groups. No serious adverse reaction was found.
CONCLUSIONS
In the treatment of CSP, the short-term effect is equivalent among EA, WN and MA. But, the analgesic effect is the best in the EA group, the treatment for anti-inflammation is the most effective in the MA and WN groups, and the needling technique of in the MA group obtains the most favorable effect of releasing adhesion and recovering the range of motion in the shoulder joint.
Topics: Humans; Periarthritis; Activities of Daily Living; Dinoprostone; Quality of Life; Acupuncture Points; Acupuncture Therapy; Shoulder Pain; Treatment Outcome
PubMed: 38413037
DOI: 10.13702/j.1000-0607.20221004