Autoimmune diseases are diseases in which the body produces an abnormal immune response to self-antigens and damages its own tissues. Programmed death-1 (PD-1) and its ligands (PD-Ls) have been discovered to be important negative regulators of the immune system, playing crucial roles in autoimmunity.We analyzed the existing scientific literature dealing with this issue. In this review, the PD-1/PD-L pathway in the genetic susceptibility to and pathogenesis of rheumatic diseases is discussed. The PD-1/PD-L pathway might be helpful for diagnosing, evaluating the disease activity of and treating rheumatic diseases.PD-1/PD-L gene polymorphisms are associated with a genetic predisposition to rheumatic disorders, which can provide reference information for diagnosis and disease activity. The conclusion of the crucial role of the PD-1/PD-L pathway in the pathogenesis of rheumatic diseases is consistent, but the details remain controversial. In some animal models, manipulating the PD-1/PD-L pathway could decrease disease severity. PD-1/PD-Ls may enable us to develop new therapeutics for patients with rheumatic diseases in the future.The PD-1/PD-L pathway plays crucial roles in rheumatic disease. More work is needed to provide a better mechanistic understanding of the PD-1/PD-L pathway and to facilitate the precise therapeutic manipulation of this pathway.
Nab-PTX is a special dosage form of antitumor drug that is different from other injections. In order to explore the efficacy and safety of albumin-bound paclitaxel, we developed an analytical method with UPLC-MS/MS to quantify the total and free paclitaxel in plasma, and prospectively evaluate the impact of unbound fraction fu (%) on the prognosis and adverse reactions of patients with gynecological tumors. From 2020.10 to 2021.10, a total of 116 patients with gynecological tumors were included, application of albumin-bound paclitaxel combined with platinum chemotherapy drugs, the blood collection time is 18–30 h after nab-PTX intravenous infusion. The collection time and the start (end) time of intravenous drip are recorded correctly, and a high-precision and sensitive UPLC-MS/MS method for the simultaneous determination of total and free paclitaxel was established. With fu (%) = Cunbound/Ctotal as the evaluation index, the concentration of total paclitaxel and free paclitaxel were determined by UPLC-MS/MS. The value of fu (%) was closely related to clinical adverse reactions, neutropenia, thrombocytopenia, leukopenia and bone marrow suppression. Neurotoxicity was statistically remarkable ( P up0.001), and fu (%) has a significant correlation with clinical efficacy ( P up0.001). We have developed a highly precise, highly sensitive and specific UPLC-MS/MS method for the simultaneous determination of binding and free albumin-bound paclitaxel concentrations in patients’ serum. In addition, we found that fu (%) could be used as the detection index. The higher the fu (%) was, the more taxol could be free, the more adverse reactions related to toxic events occurred in patients.
Abstract Squamous cell carcinomas (SCCs) are common and aggressive malignancies. Immune check point blockade (ICB) therapy using PD-1/PD-L1 antibodies has been approved in several types of advanced SCCs. However, low response rate and treatment resistance are common. Improving the efficacy of ICB therapy requires better understanding of the mechanism of immune evasion. Here, we identify that the SCC-master transcription factor TP63 suppresses interferon-γ (IFNγ) signaling. TP63 inhibition leads to increased CD8 + T cell infiltration and heighten tumor killing in in vivo syngeneic mouse model and ex vivo co-culture system, respectively. Moreover, expression of TP63 is negatively correlated with CD8 + T cell infiltration and activation in patients with SCC. Silencing of TP63 enhances the anti-tumor efficacy of PD-1 blockade by promoting CD8 + T cell infiltration and functionality. Mechanistically, TP63 and STAT1 mutually suppress each other to regulate the IFNγ signaling by co-occupying and co-regulating their own promoters and enhancers. Together, our findings elucidate a tumor-extrinsic function of TP63 in promoting immune evasion of SCC cells. Over-expression of TP63 may serve as a biomarker predicting the outcome of SCC patients treated with ICB therapy, and targeting TP63/STAT/IFNγ axis may enhance the efficacy of ICB therapy for this deadly cancer.
Objective: We aim to characterize the incidence and relative risk of rheumatic and systemic immune-related adverse effects (irAEs) among immune checkpoint inhibitor (ICI) therapy compared with those after placebo treatment. Methods: Randomized clinical trial studies with placebo control with the following keywords were searched from Embase, PubMed, Cochrane databases: immune checkpoint inhibitors, neoplasms, randomized controlled trials, and adverse effects. Results: Among the 5444 published and 316 registration records, nine placebo-controlled randomized clinical trials met our selection criteria, and included data from 5560 patients. Compared with placebo use, using ICIs increases the risk of overall-rheumatic irAEs. The incidence and relative risk of all-grade rheumatic irAEs were 18.40% [95% confidence interval (CI) 12.16–25.59%, p < 0.01] and 2.30 (95% CI 1.32–4.02), respectively, while musculoskeletal irAEs were 11.30% (95% CI 9.76–12.85%) and 1.01 (95% CI 0.84–1.22). The incidence and relative risk of severe rheumatic irAEs were 5.72% (95% CI 3.92–7.82%), and 8.29 (95% CI 3.75–18.35), respectively. Arthralgia was the most common rheumatic irAE (incidence 11.00%, 95% CI 9.55–12.64%; relative risk 0.99, 95% CI 0.82–1.19), although usually not severe. Colitis (incidence 3.23%, 95% CI 1.27–7.98%; relative risk 6.53, 95% CI 2.66–16.04) and pneumonitis (incidence 3.11%, 95% CI 1.56–6.21; relative risk 4.04, 95% CI 1.65–9.89) were commonly observed and tended to be severe. Hepatitis, hypophysitis, thyroiditis, and myositis were rare and less recorded, yet can be severe and life threatening. Other extremely rare severe rheumatic irAEs included sarcoidosis ( n = 11), autoimmune arthritis ( n = 8), autoimmune uveitis ( n = 3), autoimmune pericarditis, bursitis, osteochondrosis, psoriasis, polymyalgia rheumatica, systemic inflammatory response syndrome, and Sjögren syndrome ( n = 1, each). Conclusion: ICI therapy increased the incidence and relative risk of all-grade and severe rheumatic irAEs. Arthralgia was the most commonly observed non-severe irAE, while colitis and pneumonitis were commonly observed severe irAEs. Rare rheumatic irAEs like hepatitis, hypophysitis, thyroiditis, and myositis warrant special attention.
Cancer is a disease with high morbidity and mortality in the world. In the past, the main treatment methods for cancer patients were surgery, radiotherapy and chemotherapy. However, with early treatment, the recurrence rate of cancer is higher, and the drug resistance of cancer cells is faster. In recent years, with the discovery of immune escape mechanism of cancer cells, Immunotherapy, especially Immune Checkpoint Inhibitors (ICIs), has made a breakthrough in the treatment of solid tumors, significantly prolonging the overall survival time and disease-free progression in some solid tumors, and its clinical benefits are more prominent than those of traditional anti-tumor drugs, which has become the hope of cancer patients after the failure of multi-line therapy. More and more studies have shown that there is a correlation between cancer driving genes and the clinical benefits of ICIs treatment, and the therapeutic effects and adverse reactions of ICIs can be predicted by the status of driving genes. Therefore, screening potential biomarkers of people who may benefit from immunotherapy in order to maximize the therapeutic benefits is a top priority. This review systematically summarizes the cancer driving genes that may affect the clinical benefits of immune checkpoint inhibitors, and provides accurate scientific basis for clinical practice.
This study aimed to evaluate the clinical significance of metabolomics in stratifying the risk of decompensation in cirrhosis and identifying differential serum metabolites implicated in this process.
Methods
This prospective study examined the alterations in serum metabolites among cirrhotic patients with and without ascites at baseline, as well as those with and without decompensation at the 1-year mark, through the employment of liquid chromatography/mass spectrometry. Univariate and multivariate analyses were utilized to unveil differential metabolites. The identified differential metabolites, along with clinical parameters, underwent Cox regression analyses to construct predictive models for 1-year decompensation. These models were subsequently validated using C-index, Kaplan-Meier analysis, receiver operating characteristic (ROC) curves, and calibration curves to assess their effectiveness.
Results
This study included a cohort of 58 cirrhotic patients and followed up for 1 year. In contrast to their respective control groups, 134 differential metabolites were identified at baseline, while 22 were at the 1-year mark. The chenodeoxycholic acid glycine conjugate (GCDCA) and bilirubin diglucuronide (BDG) were consistently detected at two-time points, exhibiting enrichment in the primary bile acid biosynthesis and porphyrin metabolism pathways, respectively (IDDF2024-ABS-0027 Figure 1). The prognostic prediction models, which utilized differential metabolites and clinical parameters, demonstrated high discriminatory capability and notable consistency (IDDF2024-ABS-0027 Figure 2). Moreover, the area under the ROC for these models exceeded that of other noninvasive parameters.
Conclusions
During the progression of cirrhosis, fluctuations in the levels of GCDCA and BDG might be detected, while relevant models could be employed to predict the probability of decompensation within one year.
Background: Traditional Chinese medicine is effective in the treatment of psoriasis and can significantly reduce skin inflammation and psoriatic lesions with minimal side effects. Shikonin (SHI) and β,β-dimethylacryloyl alkannin (DMA), the main active components of Lithospermum erythrorhizon, have strong anti-inflammatory effects. This systematic review aimed to evaluate the efficacy and safety of Lithospermum erythrorhizon and its main active components and to elucidate the potential mechanisms of their action in psoriasis treatment. Methods: PubMed, Embase, Cochrane Central Register of Controlled Trials, China National Knowledge Infrastructure, Chinese Scientific Journals, Wan Fang, and Chinese Biomedicine databases were systematically searched for articles published between 1 January 1970, and 31 February 2021. We included clinical and preclinical studies that examined the effects of Lithospermum erythrorhizon and its active components on psoriasis. All data were analyzed using RevMan 5.3 software. The Cochrane and SYRCLE's risk-of-bias tools were used to assess the quality of all studies. Results: Eleven clinical trials including 1024 participants and 23 preclinical studies were assessed. Meta-analysis showed that when treating patients with psoriasis, the Chinese herbal medicine (CHM) formulas with Lithospermum erythrorhizon as the sovereign herb can significantly improve psoriatic dermatitis, which can significantly reduce the psoriasis area and severity index (PASI) score (mean difference [MD] = -2.00, 95% confidence interval [CI] [-3.19, -0.80], p = 0.001; I2 = 85%). The incidence rates of diarrhea (risk ratio = 0.21, 95% CI [0.06, 0.81], p = 0.02) were higher in the CHM formulas group than in the control group, whereas other adverse events were not significantly different between the two groups (p > 0.05). We evaluated the PASI score of mice on day 7 and found that SHI and DMA also alleviated psoriatic lesions (MD = -3.36, 95% CI [-4.67, -2.05], p < 0.00001, I2 = 94%). Furthermore, the epidermal thickness decreased more after SHI or DMA treatment than in the control group (MD = -34.42, 95%CI [-41.25, -27.59], p < 0.00001, I2 = 93%). Based on preclinical studies, we also summarized and mapped the mechanisms of SHI and DMA in the treatment of psoriasis. Conclusion: Available findings demonstrated that Lithospermum erythrorhizon combined with other conventional treatments is useful in treating psoriasis. Preclinical evidence has shown that the active components of Lithospermum erythrorhizon exhibit a potential anti-inflammatory effect, promote keratinocyte apoptosis, inhibit keratinocyte proliferation and angiogenesis, and block the cell cycle. In summary, our findings suggest that Lithospermum erythrorhizon and its active components can be used to treat psoriasis.
Histology slide, tissue microbes, and the host gene expression can be independent prognostic factors of colorectal cancer (CRC), but the underlying associations and biological significance of these multimodal omics remain unknown. Here, we comprehensively profiled the matched pathological images, intratumoral microbes, and host gene expression characteristics in 527 patients with CRC. By clustering these patients based on histology slide features, we classified the patients into two histology slide subtypes (HSS). Onco-microbial community and tumor immune microenvironment (TIME) were also significantly different between the two subtypes (HSS1 and HSS2) of patients. Furthermore, variation in intratumoral microbes-host interaction was associated with the prognostic heterogeneity between HSS1 and HSS2. This study proposes a new CRC classification based on pathological image features and elucidates the process by which tumor microbes-host interactions are reflected in pathological images through the TIME.
Background: Immune checkpoint inhibitors (ICIs) such as PD-1/PD-L1/CTLA-4 inhibitors have brought new opportunities for the cure of cancer patients and have been widely used and which are the most successful cancer immunotherapy drug in recent years. Gut microbiome and metabolites exert a critical regulatory function in cancer immunotherapy of ICIs, which can be affected by antibiotics intervention. However, inflammatory infections caused by impaired immune function in tumor patients often require antibiotic treatment.Objective: In this review, we briefly discussed the correlation between antibiotics and ICIs treatment to evaluate the impact of antibiotics on cancer progression.Methods: By searches of PubMed, we collected the data such as progression-free survival time (PFS) and overall survival time (OS) in patients with non-small cell lung cancer (NSCLC), kidney cancer, Melanoma, colorectal cancer, and other tumors.Results: Antibiotics have a negative effect on the prolongation of survival in cancer patients treated with ICIs. This may depend on the patient's cancer type and the type of ICIs and antibiotics they have used.Conclusions: Antibiotics may reduce the effectiveness of immunotherapy by depleting the body's microbiome. Therefore, paying attention to the changes in the level of microorganisms in cancer patients, while making more individualized and precise improvements in treatment regimens, may bring new opportunities to improve the efficacy of immunotherapy.
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