Camrelizumab-induced anaphylactic reaction: a case report and literature review.

Camrelizumab is an immune checkpoint inhibitor clinically used to treat various types of tumours. In this study, the authors provided the first report of a case of an anaphylactic reaction induced by camrelizumab in the treatment of a patient with squamous cell carcinoma of the floor of the mouth. The patient, a 58-year-old man, was diagnosed with advanced squamous cell carcinoma of the floor of the mouth, with cancer infiltration and multiple metastases. He underwent treatment for nine cycles, in which cycles 1-5 he received camrelizumab, albumin-bound paclitaxel, and cisplatin (200 mg of camrelizumab each time, every 3 weeks), with no adverse reactions; in cycle 6, he received albumin-bound paclitaxel and cisplatin, with no adverse reactions; and in cycles 7-9, he received camrelizumab and albumin-bound paclitaxel. However, 30 min after 8th administration of camrelizumab (cycle 9), he suddenly developed sweating, a pale complexion, clamminess and cyanosis of the limbs (percutaneous arterial oxygen saturation [SpO2] = 82%, blood pressure [BP] = 79/49 mmHg, heart rate [HR] = 83 beats/min [bpm] and respiratory rate [RR) = 12 bpm). The patient underwent intravenous infusion of methylprednisolone (80 mg) combined with dopamine to boost the BP; he regained consciousness 20 min later, and many parts of his skin appeared smooth, with no desquamation and accompanied by itching erythema, especially on the upper limbs. Approximately 2 h after treatment, the patient's skin erythema subsided (vital sign monitoring results: SpO2 = 100%, BP = 122/84 mmHg, HR = 91 bpm and RR = 17 bpm); the patient did not complain about his obvious discomfort. Despite the rarity of acute anaphylactic reactions among immune-related adverse reactions, great importance should be given to anaphylactic reactions of camrelizumab due to its extensive clinical application.

Apolipoprotein O modulates cholesterol metabolism via NRF2/CYB5R3 independent of LDL receptor.

Apolipoprotein O (APOO) plays a critical intracellular role in regulating lipid metabolism. Here, we investigated the roles of APOO in metabolism and atherogenesis in mice. Hepatic APOO expression was increased in response to hyperlipidemia but was inhibited after simvastatin treatment. Using a novel APOO global knockout (Apoo-/-) model, it was found that APOO depletion aggravated diet-induced obesity and elevated plasma cholesterol levels. Upon crossing with low-density lipoprotein receptor (LDLR) and apolipoprotein E (APOE) knockout hyperlipidemic mouse models, Apoo-/- Apoe-/- and Apoo-/- Ldlr-/- mice exhibited elevated plasma cholesterol levels, with more severe atherosclerotic lesions than littermate controls. This indicated the effects of APOO on cholesterol metabolism independent of LDLR and APOE. Moreover, APOO deficiency reduced cholesterol excretion through bile and feces while decreasing phospholipid unsaturation by inhibiting NRF2 and CYB5R3. Restoration of CYB5R3 expression in vivo by adeno-associated virus (AAV) injection reversed the reduced degree of phospholipid unsaturation while decreasing blood cholesterol levels. This represents the first in vivo experimental validation of the role of APOO in plasma cholesterol metabolism independent of LDLR and elucidates a previously unrecognized cholesterol metabolism pathway involving NRF2/CYB5R3. APOO may be a metabolic regulator of total-body cholesterol homeostasis and a target for atherosclerosis management. Apolipoprotein O (APOO) regulates plasma cholesterol levels and atherosclerosis through a pathway involving CYB5R3 that regulates biliary and fecal cholesterol excretion, independently of the LDL receptor. In addition, down-regulation of APOO may lead to impaired mitochondrial function, which in turn aggravates diet-induced obesity and fat accumulation.

Ephrin B2 (EFNB2) potentially protects against intervertebral disc degeneration through inhibiting nucleus pulposus cell apoptosis.

Nucleus pulposus (NP) cell apoptosis is a significant indication of accelerated intervertebral disc degeneration; however, the precise mechanism is unelucidated as of yet. Ephrin B2 (EFNB2), the only gene down-regulated in the three degraded intervertebral disc tissue microarray groups (GSE70362, GSE147383 and GSE56081), was screened for examination in this study. Subsequently, EFNB2 was verified to be down-regulated in degraded NP tissue samples. Interleukin-1 (IL-1ß) treatment of NP cells to simulate the IDD environment indicated that IL-1ß treatment decreased EFNB2 expression. In degenerative NP cells stimulated by IL-1ß, EFNB2 knockdown significantly increased the rate of apoptosis as well as the apoptosis-related molecules cleaved-caspase-3 and the Bax to Bcl-2 ratio. EFNB2 was found to promote AKT, PI3K, and mTOR phosphorylation; the PI3K/AKT signaling role was investigated using the PI3K inhibitor LY294002. EFNB2 overexpression significantly increased PI3K/AKT pathway activity in IL-1ß-stimulated NP cells than the normal control. Moreover, EFNB2 partially alleviated NP cell apoptosis induced by IL-1ß, reduced the cleaved-cas3 level, and decreased the Bax/Bcl-2 ratio after the addition of the inhibitor LY294002. Additionally, EFNB2 overexpression inhibited the ERK1/2 phosphorylation; the effects of EFNB2 overexpression on ERK1/2 phosphorylation, degenerative NP cell viability, and cell apoptosis were partially reversed by ERK signaling activator Ceramide C6. EFNB2 comprehensively inhibited the apoptosis of NP cells by activating the PI3K/AKT signaling and inhibiting the ERK signaling, obviating the exacerbation of IDD. EFNB2 could be a potential target to protect against degenerative disc changes.

Advancements in dual-target inhibitors of PI3K for tumor therapy: Clinical progress, development strategies, prospects.

Phosphoinositide 3-kinases (PI3Ks) modify lipids by the phosphorylation of inositol phospholipids at the 3'-OH position, thereby participating in signal transduction and exerting effects on various physiological processes such as cell growth, metabolism, and organism development. PI3K activation also drives cancer cell growth, survival, and metabolism, with genetic dysregulation of this pathway observed in diverse human cancers. Therefore, this target is considered a promising potential therapeutic target for various types of cancer. Currently, several selective PI3K inhibitors and one dual-target PI3K inhibitor have been approved and launched on the market. However, the majority of these inhibitors have faced revocation or voluntary withdrawal of indications due to concerns regarding their adverse effects. This article provides a comprehensive review of the structure and biological functions, and clinical status of PI3K inhibitors, with a specific emphasis on the development strategies and structure-activity relationships of dual-target PI3K inhibitors. The findings offer valuable insights and future directions for the development of highly promising dual-target drugs targeting PI3K.

Diagnostic serum biomarkers associated with ankylosing spondylitis.

Ankylosing spondylitis (AS) is an autoimmune rheumatic disease that mostly affects the axial skeleton. This study aimed to investigate reliable diagnostic serum biomarkers for AS. Serum samples were collected from 20 AS patients and 20 healthy controls (HCs) and analyzed using ultra-performance liquid chromatography-tandem mass spectrometry (UPLC-MS/MS). The differential metabolites between the AS patients and HCs were profiled using univariate and multivariate statistical analyses. Pathway analysis and a heat map were also conducted. Random forest (RF) analysis and the least absolute shrinkage and selection operator (LASSO) were used to establish predictive and diagnostic models. After controlling the variable importance in the projection (VIP) value > 1 and false discovery rate (FDR) < 0.05, a total of 61 differential metabolites were identified from 995 metabolites, which exhibited significant differences in the pathway analysis and heat map between the AS patients and HCs. RF as a predictive model also identified differential metabolites with 95% predictive accuracy and a high area under the curve (AUC) of 1. A diagnostic model comprising nine metabolites (cysteinylglycine disulfide, choline, N6, N6, N6-trimethyllysine, histidine, sphingosine, fibrinopeptide A, glycerol 3-phosphate, 1-linoleoyl-GPA (18:2), and fibrinopeptide A (3-16)) was generated using LASSO regression, capable of distinguishing HCs from AS with a high AUC of 1. Our results indicated that the UPLC-MS/MS analysis method is a powerful tool for identifying AS metabolite profiles. We developed a nine-metabolites-based model serving as a diagnostic tool to separate AS patients from HCs, and the identified diagnostic biomarkers appeared to have a diagnostic value for AS.

Aloe gel glucomannan induced colon cancer cell death via mitochondrial damage-driven PINK1/Parkin mitophagy pathway.

Mitophagy can selectively remove damaged mitochondria, which is critical in regulating mitochondrial homeostasis in diseases, such as cancer. Herein, we found that Aloe gel glucomannan (AGP) significantly inhibited the proliferation of colon cancer cells. RNA-seq analysis revealed that AGP upregulated autophagy, lysosome and mitochondrial fission signal pathways in colon cancer cell line CT26. Notably, AGP induced the accumulation of impaired and reactive oxygen species (ROS)-generating mitochondria, which triggered excessive mitophagy. Interestingly, the mitophagy activator enhanced AGP-induced mitophagy and cytotoxicity, whereas the mitophagy inhibitor reversed the influence of AGP. Furthermore, activation of PINK1/Parkin mitophagy pathway and transcription factor EB (TFEB) signaling was dependent on ROS overproduction. Taken together, these results indicated that AGP induced cytotoxic mitophagy through ROS-related PINK1/Parkin pathway and TFEB activation in CT26 cells. The research would provide theoretical basis for the development of AGP as a promising anticancer agent.

Glycerophospholipid metabolism is involved in rheumatoid arthritis pathogenesis by regulating the IL-6/JAK signaling pathway.

To explore the metabolic mechanism of differential plasma interleukin (IL)-6 expression in patients with rheumatoid arthritis (RA). A total of 240 RA patients were enrolled in the non-target metabolomics study cohort and 69 healthy volunteers were included as healthy controls (HCs). Plasma IL-6 levels were detected by electrochemiluminescence assay. Plasma metabolites were detected by ultra-high-performance liquid chromatography-quadrupole time-of-flight mass spectrometry. Patients with active RA (n = 20) and remissive RA (n = 20) and 20 HCs were enrolled in the targeted validation cohort. Metabolites identified by non-target metabolomics were quantitatively analyzed by ultra-performance liquid chromatography-triple quadrupole tandem mass spectrometry. Effects of 1-oleoyl-sn-glycero-3-phosphocholine (OGPC) associated with IL-6 on MH7A cells were assessed. After 24-h or 48-h induction by TNF-α, the supernatants were collected for IL-6 quantification by enzyme-linked immunosorbent assay. Furthermore, Western blot was performed to investigate the relative JAK2 and p-JAK2 expressions. With an increasing IL-6 level, OGPC shown to be related to the glycerophospholipid metabolism pathway by Kyoto Encyclopedia of Genes and Genomes analysis displayed a significant decrease. In the validating RA cohort, the OGPC concentrations in remissive RA group and active RA group decreased compared with HC group. OGPC down-regulated IL-6 secretion and p-JAK2 expression in TNF-α-induced MH7A cells in vitro. In conclusion, glycerophospholipid metabolism is the main metabolic pathway associated with the differential IL-6 expression in RA patients. The down-regulated OGPC is a promoting factor for the increased IL-6 plasma level in RA patients, which further affects the downstream JAK signaling pathway.

Estimating the rate of overdiagnosis with prostate cancer screening: evidence from the Finnish component of the European Randomized Study of Screening for Prostate Cancer.

PURPOSE: Screening for prostate cancer may have limited impact on decreasing prostate cancer-related mortality. A major disadvantage is overdiagnosis, whereby lesions are identified that would not have become evident during the man's lifetime if screening had not taken place. The present study aims to estimate the rate of overdiagnosis using Finnish data from the European randomized trial of prostate cancer screening. METHODS: We used data from 80,149 men randomized to a screening or a control group, distinguishing four birth cohorts. We used the "catch-up method" to identify when the difference in the cumulative incidence of prostate cancer between the screening and control groups had stabilized, implying that the screening has no further effect. We define the overdiagnosis rate to be the relative excess cumulative incidence in the screened group at that point. As an independent method, we also examined the diagnosis rates of T1c tumors as an indicator of early tumors detected by PSA. RESULTS: The estimates of overdiagnosis rates from the catch-up method using the full period of available follow-up ranged between cohorts from 2.3% to 15.4%, and the T1c analysis gave very similar results. CONCLUSION: Some overdiagnosis has occurred, but there is uncertainty about its extent. A long follow-up is required to demonstrate the full impact of screening. We evaluated the overdiagnosis rates at a population level, associated with being offered screening, taking account of contamination (screening among the controls). The overall evaluation of screening should incorporate mortality benefit, cost-effectiveness, and quality of life.

The Relationship Between Tumor-Stroma Ratio, the Immune Microenvironment, and Survival in Patients With Spinal Chordoma.

BACKGROUND: Currently, little is known about the clinical relevance of tumor-stroma ratio (TSR) in chordoma and data discussing the relationship between TSR and immune status of chordoma are lacking. OBJECTIVE: To characterize TSR distribution in spinal chordoma, and investigated its correlation with clinicopathologic or immunological features of patients and outcome. METHODS: TSR was assessed visually on hematoxylin and eosin-stained sections from 54 tumor specimens by 2 independent pathologists. Multiplex immunofluorescence was used to quantify the expression levels of microvessel density, Ki-67, Brachyury, and tumor as well as stromal PD-L1. Tumor immunity status including the Immunoscore and densities of tumor-infiltrating lymphocytes (TILs) subtypes were obtained from our published data and reanalyzed. RESULTS: Bland-Altman plot showed no difference between mean TSR derived from the two observers. TSR was positively associated with stromal PD-L1 expression, the Immunoscore and CD3+ as well as CD4+ TILs density, but negatively correlated with tumor microvessel density, Ki-67 index, surrounding muscle invasion by tumor and number of Foxp3+ and PD-1+ TILs. Low TSR independently predicted poor local recurrence-free survival and overall survival. Moreover, patients with low TSR and low Immunoscore chordoma phenotype were associated with the worst survival. More importantly, combined TSR and Immunoscore accurately reflected prognosis and enhanced the ability of TSR or Immunoscore alone for outcome prediction. CONCLUSION: These data reveal the significant impact of TSR on tumor progression and immunological response of patients. Subsequent use of agents targeting the stroma compartment may be an effective strategy to treat chordoma especially in combination with immune-based drugs.

Apolipoprotein O expression in mouse liver enhances hepatic lipid accumulation by impairing mitochondrial function.

Apolipoprotein O (ApoO) was recently observed in the cellular mitochondrial inner membrane, which plays a role in mitochondrial function and is associated with myocardiopathy. Empirical information on the physiological functions of apoO is therefore limited. In this study, we aimed to elucidate the effect of apoO on hepatic fatty acid metabolism. An adenoviral vector expressing hApoO was constructed and introduced into chow diet and high-fat diet induced mice and the L02 human hepatoma cell line. High levels of hApoO mRNA and protein were detected in the liver, and the expression of lipid metabolism genes was significantly altered compared with negative controls. The liver function indices (serum ALT and AST) were clearly elevated, and the ultrastructure of cellular mitochondria was distinctly altered in the liver after apoO overexpression. Further, mitochondrial membrane potential decreased with hApoO treatment in L02 cells. These results establish a link between apoO and lipid accumulation and could suggest a new pathway for regulating non-alcoholic fatty liver disease progression.

Bronchogenic cyst of the conus medullaris with spinal cord tethering: a case report and review of the literature.

Bronchogenic cysts (BCs) are congenital malformations that originate from remnants of the primitive foregut. Intraspinal BCs, especially those of the conus medullaris are rare with only one case reported until now. To date, a bronchogenic cyst with spinal cord tethering has not been previously reported. We reviewed the clinical course of a 44-year-old woman, who presented with low back pain and leg weakness as well as sphincter disturbance. Magnetic resonance imaging showed an intradural oval mass located at the conus medullaris. A tethered cord was also observed, as well as a dermal sinus tract. The mass was totally removed after an L3-L4 laminectomy without detethering during operation. Pathologic examination confirmed the diagnosis of bronchogenic cyst. By six months after treatment, the patient had experienced nearly complete recovery. The review of literature indicated that detethering was performed in most reported cases of neurenteric cysts with spinal cord tethering, and one of six patients was diagnosed with a postoperative recurrence. The co-existence of bronchogenic cyst and a tethered spinal cord would imply associated developmental errors in embryogenesis. It is worth noting that whether detethering is necessary after the cyst removal.

[Contrast study of full-endoscopic interlaminar approach for the surgical treatment of lumbar disc herniation].

OBJECTIVE: To evaluate the minimally invasive efficacy and surgical outcome of full-endoscopic discectomy via interlaminar approach for lumbar disc herniation (LDH). METHODS: From August 2008 to February 2009, 56 patients with lumbar disc herniation were retrospectively studied. The patients were divided into two groups according to the surgical methods. Full endoscopic discectomy (FED) group included 16 males and 12 females, the age was 20 - 51 years with a mean (36 ± 8) years, and the course of disease was 18 - 120 d with a mean (68 ± 26) days. There was L(5)-S(1) LDH in 22 and L(4-5) LDH in 6. Headlamp-assisted mini-open discectomy (HAMOD) group, there were 17 males and 11 females. The age was 17-53 years with an average age of (35 ± 9) years, the course of disease was 19 - 110 d with an average (66 ± 24) days, and the herniated disc located at L(5)-S(1) in 15 cases, and L(4-5) in 13 cases. Perioperative parameters (operation time, bleeding volume and length of hospital stay), complications and VAS of leg and back pain (preoperatively, 3 months postoperatively and final follow-up) were statistically analyzed. RESULTS: All patients were followed up in both groups, and the average follow-up time of full endoscopic was 1.8 years, and headlamp assisted mini-open was 1.7 years. The average operation time in full endoscopic group was (71 ± 30) min and the headlamp group was (60 ± 12) min, which there was no statistical difference (P > 0.05). There was no measurable bleeding in full endoscopic group, and the headlamp group was (59 ± 10) ml. The average hospital days in full endoscopic group was (5.7 ± 1.4) days, and the headlamp group was (12.3 ± 3.0) days, there was statistically significant difference in both groups (P < 0.01). The complication rate in full endoscopic group was 7.1%, and in headlamp group was 10.7%, without statistical difference (P > 0.05). There was no recurrent case in either group. With regard to VAS of back pain and leg pain, statistically significant difference was found in each group between preoperatively and 3 months postoperatively, but not between 3 months postoperatively and at final follow-up. With regard to the final follow-up VAS, there was no statistical difference in leg pain between full endoscopic and headlamp group (P > 0.05). However, there was statistical significance in VAS back pain between the two groups (P < 0.01). CONCLUSIONS: Compared to the headlamp assisted mini-open technique, the full-endoscopic interlaminar approach for the surgical treatment of lumbar disc herniation can achieve similar clinical outcomes with advantage of less iatrogenic trauma and sooner rehabilitation.

Gα13 is closely related to hematopoiesis in zebrafish.

Heterotrimeric guanine nucleotide-binding regulatory proteins (G proteins) function as signal transducers and control many different physiologic processes. G proteins can be grouped into four families: Gs, Gi, Gq and G12. Gα13 belongs to the G12 family. In zebrafish, there are two isoforms of Gα13: Gα13a and Gα13b. We show here that knockdown of Gα13b in zebrafish results in hematopoietic and angiogenic defects. The Gα13b morphants don't show complete loss of expression of gata1, pu.1 or flk until 35 hpf suggests that Gα13b is closely related to the development of hematopoietic cells. Further studies reveal that blood cells and vascular endothelial cells have undergone apoptosis through a p53-dependent pathway in Gα13b-depleted embryos. Injection of p53 morpholino could partially rescue the phenotype of Gα13b morphants. These data possibly demonstrate a new role for Gα13 in cell survival.