Anthracycline-induced arrhythmias in breast cancer therapy: A meta-analysis of single-arm trials.

INTRODUCTION: As of 2020, breast cancer has emerged as the predominant cause of cancer incidence globally. Anthracycline-based chemotherapy serves as a crucial element in the treatment regimen for breast cancer. However, these anthracycline-based drugs are associated with cardiac toxicity. This study represents the first clinical quantitative analysis aimed at accurately determining the incidences of arrhythmia and abnormal electrocardiogram (ECG) changes, thereby providing valuable data to bolster clinical drug usage and monitoring. METHODS: A systematic search was conducted across multiple databases including CNKI, VIP, Wanfang, PubMed, Embase, Web of Science, and the Cochrane Library. The incidence of combined arrhythmias in breast cancer patients and the associated heterogeneity were calculated using either a random effect model or a fixed effect model. Statistical analysis was performed using STATA16. RESULTS: The study encompassed a total of 37 articles, which included 5705 breast cancer patients undergoing anthracycline treatment. Among these patients, 2257 developed arrhythmias. The meta-analysis revealed that the incidence of anthracycline-associated arrhythmias and abnormal ECG changes in breast cancer patients was 0.41 (0.37, 0.44). Subgroup analysis indicated that the incidence of ST-T segment change was 0.19 (0.15, 0.23), the incidence of conduction block was 0.04 (0.02, 0.05), the incidence of premature beats was 0.09 (0.07, 0.11), and the incidence of atrial fibrillation was 0.04 (0.00, 0.12). Additional results are presented in Table 3. CONCLUSION: This pioneering study accurately assesses the incidence of arrhythmias in breast cancer patients treated with anthracyclines. The findings provide clinicians with valuable insights into understanding and managing the cardiac toxicity associated with such treatment. Moreover, this study lays the foundation for future research exploring the mechanisms underlying these arrhythmias and potential preventative strategies.

Dendrobium officinale regulate lipid metabolism in diabetic mouse liver via PPAR-RXR signaling pathway: Evidence from an integrated multi-omics analysis.

Dendrobium officinale (DEN) is recognized as a kind of functional food that can effectively ameliorate endocrine and metabolic disruptions. This study delved into the pharmacological mechanism of DEN on hepatic lipotoxicity associated with Type II diabetes mellitus (T2DM). In vivo study experiments on db/db mice indicated that DEN treatment notably enhanced liver function, decreased blood lipid levels, and improved insulin sensitivity. Non-targeted metabolomics analysis revealed that DEN significantly ameliorated metabolism pathways, including lipoic acid, linoleic acid, bile secretion, and the alanine/aspartate/glutamate metabolism, as well as taurine and hypotaurine metabolism. Transcriptomics analysis demonstrated DEN treatment could modulate the expression of genes such as Cpt1b, Scd1, G6pc2, Fos, Adrb2, Atp2a1, Ppp1r1b, and Cyp7a1. Furthermore, Proteomics analysis indicated that the beneficial effect of DEN on lipid metabolism was linked to pathways like AMPK and PPAR signaling. The integrative analysis of multi-omics revealed that the PPAR-RXR signaling was critical to the therapeutic effect of DEN on T2DM-induced fatty liver. Additionally, in vitro study on AML-12 cells confirmed that DEN counteract PA-induced lipid accumulation by activating the PPAR-RXR pathway. Overall, these findings suggested that DEN exhibited the potential to mitigate T2DM-induced hepatic lipo-toxicity and manage lipid imbalances in T2DM.

Sacubitril/valsartan can improve the cardiac function in heart failure patients with a history of cancer: An observational study.

Sacubitril/Valsartan, the combination of angiotensin receptor inhibitor and neprilysin inhibitor, is now becoming the class 1 recommendation for HFrEF. Some studies have shown the positive effect of Sacubitril/Valsartan on HFrEF cancer patients, while there is devoid of evidence about the effect of this drug in aged cancer patients with HFmrEF and HFpEF. By searching the patients with a diagnosis of both cancer and Heart failure (HF) over 65, the patients who had received treatment with Sacubitril/Valsartan were selected as the candidates for Sacubitril/Valsartan group, and the patients who had received conventional HF therapy without Sacubitril/Valsartan were chosen as the control group. Data were collected for up to 9 months. We filtered 38 patients and 50 patients valid for Sacubitril/Valsartan group and control group, respectively. After initiation of heart failure management, our study found a better cardiac condition in Sacubitril/Valsartan group, having better LVEF, LVFS, NT-proBNP in 3rd, 6th, 9th month (P < .05) and better NYHA function classification after the treatment. We also observed fewer cases of deterioration on LAD (P = .029) and LVEDD (P = .023) in Sacubitril/Valsartan group. In subgroup analysis, our study showed that all 3 kinds of HF patients had better LVEF, LVFS, and NT-proBNP in Sacubitril/Valsartan group (P < .05). Our study further indicated that Sacubitril/Valsartan can improve cardiac function and benefit cardiac remolding in aged cancer patients of all 3 kinds of HF. This is the first study to provide new evidence for the use of Sacubitril/Valsartan in aged cancer patients of 3 kinds of HF.

Bioinformatics-based Study on the Effects of Umbilical Cord Mesenchymal Stem Cells on the Aging Retina.

BACKGROUND: Retinal aging is one of the common public health problems caused by population aging and has become an important cause of acquired vision loss in adults. The aim of this study was to determine the role of human umbilical cord mesenchymal stem cells (hUCMSCs) in delaying retinal ganglion cell (RGC) aging and part of the network of molecular mechanisms involved. METHODS: A retinal ganglion cell senescence model was established in vitro and treated with UCMSC. Successful establishment of the senescence system was demonstrated using ß- galactosidase staining. The ameliorative effect of MSC on senescence was demonstrated using CCK8 cell viability and Annexin V-PI apoptosis staining. The relevant targets of RGC, MSC, and senescence were mainly obtained by searching the GeneCards database. The protein interaction network among the relevant targets was constructed using the String database and Cytoscape, and 10 key target genes were calculated based on the MCC algorithm, based on which Gene ontologies (GO) enrichment and the Kyoto Encyclopedia of Genes and Genomes (KEGG) enrichment were performed. Changes in relevant target genes were detected using real-time fluorescence quantitative PCR and the mechanism of action of UCMSC was determined by RNA interference. RESULTS: ß-galactosidase staining showed that UCMSC significantly reduced the positive results of RGC. The retinal aging process was alleviated. The bioinformatics screen yielded 201 shared genes. 10 key genes were selected by the MCC algorithm, including vascular endothelial growth factor A (VEGFA), glyceraldehyde-3-phosphate dehydrogenase (GAPDH), albumin (ALB), interleukin- 6 (IL6), tumor necrosis factor (TNF), tumor protein P53 (TP53), insulin (INS), matrix metalloproteinase 9 (MMP9), epidermal growth factor (EGF), interleukin-1ß (IL1B), and enrichment to related transferase activity and kinase activity regulated biological processes involved in oxidative stress and inflammation related pathways. In addition, PCR results showed that all the above molecules were altered in expression after UCMSC involvement. CONCLUSION: This experiment demonstrated the role of UCMSC in delaying retinal ganglion cell senescence and further elucidated that UCMSC may be associated with the activation of VEGFA, TP53, ALB, GAPDH, IL6, IL1B, MMP9 genes and the inhibition of INS, EGF, and TNF in delaying retinal senescence.

Lactobacillus gallinarum-derived metabolites boost anti-PD1 efficacy in colorectal cancer by inhibiting regulatory T cells through modulating IDO1/Kyn/AHR axis.

OBJECTIVE: Gut microbiota is a key player in dictating immunotherapy response. We aimed to explore the immunomodulatory effect of probiotic Lactobacillus gallinarum and its role in improving anti-programmed cell death protein 1 (PD1) efficacy against colorectal cancer (CRC). DESIGN: The effects of L. gallinarum in anti-PD1 response were assessed in syngeneic mouse models and azoxymethane/dextran sulfate sodium-induced CRC model. The change of immune landscape was identified by multicolour flow cytometry and validated by immunohistochemistry staining and in vitro functional assays. Liquid chromatography-mass spectrometry was performed to identify the functional metabolites. RESULTS: L. gallinarum significantly improved anti-PD1 efficacy in two syngeneic mouse models with different microsatellite instability (MSI) statuses (MSI-high for MC38, MSI-low for CT26). Such effect was confirmed in CRC tumourigenesis model. L. gallinarum synergised with anti-PD1 therapy by reducing Foxp3+ CD25+ regulatory T cell (Treg) intratumoural infiltration, and enhancing effector function of CD8+ T cells. L. gallinarum-derived indole-3-carboxylic acid (ICA) was identified as the functional metabolite. Mechanistically, ICA inhibited indoleamine 2,3-dioxygenase (IDO1) expression, therefore suppressing kynurenine (Kyn) production in tumours. ICA also competed with Kyn for binding site on aryl hydrocarbon receptor (AHR) and antagonised Kyn binding on CD4+ T cells, thereby inhibiting Treg differentiation in vitro. ICA phenocopied L. gallinarum effect and significantly improved anti-PD1 efficacy in vivo, which could be reversed by Kyn supplementation. CONCLUSION: L. gallinarum-derived ICA improved anti-PD1 efficacy in CRC through suppressing CD4+Treg differentiation and enhancing CD8+T cell function by modulating the IDO1/Kyn/AHR axis. L. gallinarum is a potential adjuvant to augment anti-PD1 efficacy against CRC.

Neuroprotective effect of salidroside on hippocampal neurons in diabetic mice via PI3K/Akt/GSK-3ß signaling pathway.

BACKGROUND: Diabetic encephalopathy is manifested by cognitive dysfunction. Salidroside, a nature compound isolated from Rhodiola rosea L, has the effects of anti-inflammatory and antioxidant, hypoglycemic and lipid-lowering, improving insulin resistance, inhibiting cell apoptosis, and protecting neurons. However, the mechanism by which salidroside alleviates neuronal degeneration and improves learning and memory impairment in diabetic mice remains unclear. OBJECTIVE: To investigate the effects and mechanisms of salidroside on hippocampal neurons in streptozotocin-induced diabetic mice. MATERIALS AND METHODS: C57BL/6 mice were randomly divided into 4 groups to receive either sham (control group (CON)), diabetes mellitus (diabetes group (DM)), diabetes mellitus + salidroside (salidroside group (DM + SAL)), and diabetes mellitus + salidroside + phosphatidylinositol 3-kinase (PI3K) inhibitor LY294002 (diabetes mellitus + salidroside + LY294002 group (DM + SAL + LY294002)). After 12 weeks of diabetes onset, the cognitive behaviors were tested using Morris water maze. The number of hippocampal neurons was detected by Nissl staining. The expressions of PI3K, p-PI3K, Akt, p-Akt, GSK-3ß, p-GSK-3ß, cleaved caspase-3, caspase-3, Bax, Bcl-2, MAP2, and SYN in the hippocampus were detected by Western blot. Moreover, the expression of MAP2 and SYN in the hippocampus was further confirmed by immunofluorescence staining. RESULTS: Salidroside increased the time of diabetic mice in the platform quadrant and reduced the escape latency of diabetic mice. Salidroside also increased the expression of p-PI3K, p-Akt, p-GSK-3ß, MAP2, SYN, Bcl-2, while suppressed the expression of cleaved caspase-3, caspase3, and Bax in the DM + SAL group compared with the DM group (P < 0.05). The Nissl staining showed that the number of hippocampus neurons in the DM + SAL group was increased with the intact, compact, and regular arrangement, compared with the DM groups (P < 0.05). Interestingly, the protective effects of salidroside on diabetic cognitive dysfunction, hippocampal morphological alterations, and protein expressions were abolished by inhibition of PI3K with LY294002. CONCLUSIONS: Salidroside exerts neuroprotective properties in diabetic cognitive dysfunction partly via activating the PI3K/Akt/GSK-3ß signaling pathway.

Incidence of adverse cardiovascular events associated with immune checkpoint inhibitors and risk factors for left ventricular dysfunction: A single-center prospective clinical study.

Background: The incidence of immune checkpoint inhibitors (ICI)-related adverse cardiovascular events (ACEs) may be underestimated, and there are few reports on the incidence and risk factors of ICI-induced left ventricular dysfunction (LVD). Objectives: This study aimed to investigate the incidence of ACEs caused by ICI, in particular to analyze the incidence and risk factors of LV systolic and diastolic dysfunction. Materials and methods: A prospective clinical study was performed on patients who received ICI in our hospital from November 2020 to October 2021. They received regular cardiovascular examinations, including echocardiography, ECG, cTnT, and NT-proBNP, etc. The incidence of various ACEs was counted, and the risk factors of LVD were analyzed. Results: A total of 106 cancer patients treated with ICI were recruited. During the follow-up, 41 patients (38.68%) developed various ECG abnormalities, 39 patients (36.79%) developed LVDD, 9 patients (8.49%) developed CTRCD, and 2 patients (1.89%) developed new pericardial effusion. The patients with elevated cTnT, CK-MB, and NT-proBNP were 10 (9.43%), 8 (7.55%), and 8 (7.5%), respectively. Thirteen of the 52 patients with LVD had hypertension, while 4 of the 54 patients without LVD had hypertension (OR = 4.17, 95% CI: 1.26-13.78; P = 0.019). The baseline LVEF and LVFS of patients with LVD were 61.54 ± 4.15% and 33.78 ± 2.73%, while those of the control group were 64.16 ± 3.68% and 34.95 ± 2.84, respectively (P = 0.003 and P = 0.048). Compared with patients without LVD, patients with LVD had lower e' (6.99 ± 1.33 cm/s vs. 7.64 ± 1.39 cm/s, P = 0.029) and higher E to e' ratio (11.89 ± 3.15 cm/s vs. 10.43 ± 2.52, P = 0.024). Multiple regression analysis showed that a history of hypertension (HR = 26.52, 95% CI: 2.479-283.667, P = 0.007) and lower baseline e' (HR = 0.04, 95% CI: 0.003-0.709, P = 0.028) were risk factors for developing LVD. Conclusion: Patients treated with ICI may develop multiple ACEs, including acute myocarditis, pericarditis, ECG abnormalities, and elevated cardiac biomarkers. ICI may lead to a high incidence of LVD, and echocardiography is helpful for early detection of LVD. Patients with hypertension or poor LV systolic or diastolic function at baseline were predictors of LVD after ICI treatment.

Brusatol suppresses the tumor growth and metastasis of colorectal cancer via upregulating ARRDC4 expression through modulating PI3K/YAP1/TAZ Pathway.

BACKGROUND: Colorectal cancer (CRC) is one of the most commonly diagnosed cancers with high metastasis and lethality. Arrestin domain-containing 4 (ARRDC4) is involved in inhibiting cancer glycolytic phenotypes. Brusatol (BR), extracted from Bruceae Fructus, exerts good anti-cancer effects against a number of cancers. PURPOSE: In the present study, we aimed to explore the efficacy of BR on inhibiting CRC metastasis and elucidate the underlying mechanisms involving the upregulation of the ARRDC4 expression. METHODS: Cell viability, colony formation, wound healing and transwell assay were used to detect the anti-proliferative and anti-metastatic effects of BR against CRC in vitro. Microarray analysis was performed to find out differential genes in CRC cells after treatment with BR. Analysis of the CRC patients tumor samples and GEPIA database were first conducted to identify the expression of ARRDC4 on CRC. Stable overexpression and knockdown of ARRDC4 CRC cells were established by lentiviral transfection. The role of ARRDC4 in mediating the anti-metastatic effects of BR on CRC was measured using qRT-PCR, western blotting, immunohistochemical and immunofluorescence analysis. Orthotopic xenograft and pulmonary metastasis mouse models of CRC were established to determine the anti-cancer and anti-metastatic effects of ARRDC4 and BR. RESULTS: BR markedly suppressed the cell proliferation, migration, invasion and inhibited tumor growth and tumor metastasis. Microarray analysis demonstrated that BR treatment markedly increased the gene expression of ARRDC4 in CRC cells. ARRDC4 was significantly repressed in CRC in the clinical samples and GEPIA analysis. ARRDC4 overexpression plus BR produced better inhibitory effects on CRC metastasis than BR treatment alone, while ARRDC4 knockdown could partially eliminate the inhibitory effects of BR against CRC metastasis. BR exerted anti-metastatic effects against CRC via upregulating ARRDC4 and inhibiting epithelial-mesenchymal transition (EMT) processing through modulating PI3K/Hippo pathway. CONCLUSION: This study reported for the first time that BR is a potent ARRDC4 agonist, and is worthy of further development into a new therapeutic strategy for CRC.

Galectin-3 and Myeloperoxidase May Monitor Cancer-Therapy-Related Cardiotoxicity? A Systematic Review and Meta-Analysis.

Galectin-3 and myeloperoxidase (MPO) are novel biomarkers in the field of cardio-oncology, but conflicting results have been reported. Hence, a meta-analysis was performed to assess the monitoring value of galectin-3 and MPO in cancer-therapy-related cardiotoxicity. PubMed, Cochrane, Web of Science, Embase, CNKI databases and ClinicalTrials.gov were queried. According to the predefined inclusion and exclusion criteria, eight studies with 1979 patients were included in this meta-analysis. The examination of the study's heterogeneity (I2), quality assessment and statistical analysis were performed by two reviewers. No significant differences in galectin-3 levels were noted before and after treatment (WMD = -0.10, 90% CI -6.06-5.85, I2: 99%), and a weaker relationship was observed between galectin-3 evaluations and cancer-therapy-related cardiotoxicity (HR = 1.39, 90% CI 0.97-1.98, I2: 0%). However, MPO levels were increased in patients post-treatment (SMD = 0.58, 90% CI 0.35-0.80, I2: 56%), and an increased risk of cardiotoxicity was associated with early pre-post MPO assessments (HR = 1.16, 90% CI 1.02-1.32, I2: 21%). Surprisingly, the MPO levels were a more effective indicator of the response to tumor treatment compared with the TnI (SMD = 2.46, 90% CI -0.26-5.19, I2: 96%) and NT-proBNP levels (SMD = 1.08, 90% CI -0.82-2.98, I2: 96%). In conclusion, our meta-analysis suggests that MPO may rep-resent a potential biomarker for the early detection of cardiotoxicity in current cardio-oncology practice, but the monitoring value of galectin-3 requires further study.

The Relationship Between Klotho and SIRT1 Expression in Renal Aging Related Disease.

Background: This study focused on renal arteriosclerosis and aimed to explore the relationship between Klotho and SIRT1 by morphological staining, which will help to provide new ideas for the treatment of renal-aging-related diseases and a theoretical basis for the development of new drugs. Methods: Kidney tissue samples were collected from patients who underwent nephrectomy. HK-2 cells were cultured. The Hematoxylin-eosin (HE) staining, Periodic Acid-Schiff (PAS) staining, Masson's Trichrome staining, Immunohistochemistry (IHC) staining, Immunofluorescence (ICC) and bioinformatics means were used for this study. Results: HE staining showed that glomerulosclerosis was atrophic and cast was significantly increased luminal narrowing of renal arterioles in aging group. PAS staining showed that the number of podocytes was reduced, the mesangial matrix expansion and the intimal fibrosis of renal arterioles. Masson's trichrome staining showed that there was massive collagen proliferation in the tubulointerstitial in aging group, as well as intimal thickening and fibrin deposition in the tubular walls of arterioles. IHC staining showed that the expression of Klotho and SIRT1 protein was downregulated in aging group and the trend of the two was positively correlated (P < 0.01). Klotho and SIRT1 co-localized in HK-2 cells and kidney tissue. The GEPIA database analysis showed a significant positive correlation between Klotho and SIRT1 in multiple human tissues and tumors. Conclusion: Glomerulosclerosis in aging group is accompanied by low expression of Klotho and SIRT1 in renal tissue, and Klotho is positively correlated with SIRT1. Klotho-SIRT1 pathway may be involved in the occurrence and development of renal-aging-related diseases.

Extrauterine adenomyoma of the lesser omentum: A case report and review of the literature.

RATIONALE: The extrauterine adenomyoma is rare and it is extremely rare outside the pelvic cavity. Herein, we reported the first case of a single extrauterine adenomyoma occurring in the lesser omentum. PATIENTS CONCERNS: This case involved a 55-year-old woman who had undergone subtotal gastrectomy and omentectomy for gastric carcinoma. During postoperational pathological examination, 1 lymph node-like mass was coincidentally found in the lesser omentum. The patient had a history of hysterectomy for uterine leiomyoma 8 years ago. DIAGNOSES: The resected 17 "lymph nodes" from the lesser omentum were routinely checked for possible metastasis of gastric carcinoma. One of lymph node-like mass was microscopically showed that it was composed of benign smooth muscle components, endometrial glands and stroma by HE staining. Therefore, adenomyoma was initially considered. INTERVENTIONS: The lymph node-like mass was removed together with the lesser omentum during the subtotal gastrectomy and omentectomy for gastric carcinoma. No special intervention was performed for the adenomyoma. OUTCOMES: Immunohistochemical staining confirmed that smooth muscle tissue was diffusely and strongly positive for Desmin, smooth muscle actin, estrogen receptor, and progesterone receptor, and negative for CD117, Dog-1, S100, and CD34. Endometrial glands and stroma were positive for estrogen receptor and progesterone receptor, and the endometrium interstitium was also positive for CD10. The final diagnosis of extrauterine adenomyoma occurring in the lesser omentum was established. LESSONS: So far, to the best of our knowledge, total 53 cases of extrauterine adenomyoma have been reported in 45 English reports. The most common location for a single mass was pelvic cavity (37 cases), but rarely outside the pelvic cavity. This is the first case of a single extrauterine adenomyoma occurring in the lesser omentum.

Examining patterns of traditional Chinese medicine use in pediatric oncology: A systematic review, meta-analysis and data-mining study.

BACKGROUND: Traditional Chinese medicine (TCM) is becoming a popular complementary approach in pediatric oncology. However, few or no meta-analyses have focused on clinical studies of the use of TCM in pediatric oncology. OBJECTIVE: We explored the patterns of TCM use and its efficacy in children with cancer, using a systematic review, meta-analysis and data mining study. SEARCH STRATEGY: We conducted a search of five English (Allied and Complementary Medicine Database, Embase, PubMed, Cochrane Central Register of Controlled Trials, and ClinicalTrials.gov) and four Chinese databases (Wanfang Data, China National Knowledge Infrastructure, Chinese Biomedical Literature Database, and VIP Chinese Science and Technology Periodicals Database) for clinical studies published before October 2021, using keywords related to "pediatric," "cancer," and "TCM." INCLUSION CRITERIA: We included studies which were randomized controlled trials (RCTs) or observational clinical studies, focused on patients aged < 19 years old who had been diagnosed with cancer, and included at least one group of subjects receiving TCM treatment. DATA EXTRACTION AND ANALYSIS: The methodological quality of RCTs and observational studies was assessed using the six-item Jadad scale and the Effective Public Healthcare Panacea Project Quality Assessment Tool, respectively. Meta-analysis was used to evaluate the efficacy of combining TCM with chemotherapy. Study outcomes included the treatment response rate and occurrence of cancer-related symptoms. Association rule mining (ARM) was used to investigate the associations among medicinal herbs and patient symptoms. RESULTS: The 54 studies included in this analysis were comprised of RCTs (63.0%) and observational studies (37.0%). Most RCTs focused on hematological malignancies (41.2%). The study outcomes included chemotherapy-induced toxicities (76.5%), infection rate (35.3%), and response, survival or relapse rate (23.5%). The methodological quality of most of the RCTs (82.4%) and observational studies (80.0%) was rated as "moderate." In studies of leukemia patients, adding TCM to conventional treatment significantly improved the clinical response rate (odds ratio [OR] = 2.55; 95% confidence interval [CI] = 1.49-4.36), lowered infection rate (OR = 0.23; 95% CI = 0.13-0.40), and reduced nausea and vomiting (OR = 0.13; 95% CI = 0.08-0.23). ARM showed that Radix Astragali, the most commonly used medicinal herb (58.0%), was associated with treating myelosuppression, gastrointestinal complications, and infection. CONCLUSION: There is growing evidence that TCM is an effective adjuvant therapy for children with cancer. We proposed a checklist to improve the quality of TCM trials in pediatric oncology. Future work will examine the use of ARM techniques on real-world data to evaluate the efficacy of medicinal herbs and drug-herb interactions in children receiving TCM as a part of integrated cancer therapy.

Real-world data on herb-drug interactions in oncology: A scoping review of pharmacoepidemiological studies.

BACKGROUND: The concurrent use of conventional drugs and herbal medicines is becoming popular among patients with cancer. However, the potential risk of herb-drug interactions (HDI) remains under-addressed in the literature. Previous reviews have mainly focused on the prevalence of interactions, with less attention paid to the methods used by pharmacoepidemiological studies on evaluating HDI. This scoping review aims to summarize the existing pharmacoepidemiological studies that evaluate HDI using real-world data and to identify gaps to be addressed in future research. METHODS: A comprehensive search was performed in nine English- and Chinese-language databases from their inception to May 2021. Gray literature and manual searches were conducted to identify additional studies. The recommended components of the pharmacoepidemiological studies and key findings related to HDI were summarized. The proportion (%) of patients with cancer at risk of HDI was estimated by combining data from eligible studies. RESULTS: Twenty-eight studies were included in the review. More than half of these studies were cross-sectional studies (n = 18, 64.3%), followed by retrospective cohort studies (n = 5, 17.9%) and prospective cohort studies (n = 2, 7.1%). The three cancer drugs most commonly studied for their interaction potential with herbs were tamoxifen (n = 11, 39.3%), cyclophosphamide (n = 6, 21.4%), and paclitaxel (n = 6, 21.4%). Most cross-sectional studies identified potential HDI using tertiary databases and primary literature searches. Conversely, prospective and retrospective studies mainly investigated actual clinical outcomes, such as adverse events and secondary cancer occurrences. Most interaction outcomes identified using real-world data did not lead to negative clinical consequences. Collectively, 45.4% of herbal medicine users of the included studies were found to be at risk of HDI. We infer from this review that the common limitations of these studies were limited sample size, lack of data on herbal medicine use and details of HDI, and lack of evidence of HDI. Based on the study limitations, several recommendations to enrich the data sources and optimize the study designs were proposed. CONCLUSIONS: There is a high demand for pharmacoepidemiological research on HDI, considering the increasing popularity of herbal medicine among patients with cancer. It is anticipated that emerging real-world data in this field can guide the development of safe and effective approaches to integrative oncology.

Efficacy and safety of a bridging strategy that uses intravenous platelet glycoprotein receptor inhibitors for patients undergoing surgery after coronary stent implantation: a meta-analysis.

BACKGROUND: Current guidelines indicate we can consider a bridging strategy that uses intravenous, reversible glycoprotein inhibitors for patients that required surgery following recent stent implantation. However, no strong clinical evidence exists that demonstrates the efficacy and safety of this treatment. Therefore, in this study, the efficacy and safety of a bridging strategy that uses intravenous platelet glycoprotein receptor inhibitors will be evaluated. METHODS: A meta-analysis was performed on preoperative bridging studies in patients undergoing coronary stent surgery. The primary outcome was the success rate of no major adverse cardiovascular events (MACE). The secondary outcomes were the success rate of no reoperations to stop bleeding. RESULTS: A total of 10 studies that included 382 patients were used in this meta-analysis. For the primary endpoint, the success rate was 97.7% (95% CI 94.4-98.0%) for glycoprotein IIb/IIIa inhibitors, 98.8% (95% CI 96.0-100%) for tirofiban (6 studies) and 95.8% (95% CI 90.4-99.4%) for eptifibatide (4 studies). For secondary endpoints, the success rate was 98.0% (95% CI 94.8-99.9%) for glycoprotein IIb/IIIa inhibitors, 99.7% (95% CI 97.1-100%) for tirofiban (5 studies), and 95.3% (95% CI 88.5-99.4%) for eptifibatide (4 studies). CONCLUSION: The results of this study showed that the use of intravenous platelet glycoprotein IIb/IIIa inhibitors as a bridging strategy might be safe and effective for patients undergoing coronary stent implantation that require surgery soon after.

Orally administered bismuth drug together with N-acetyl cysteine as a broad-spectrum anti-coronavirus cocktail therapy.

The emergence of SARS-CoV-2 variants of concern compromises vaccine efficacy and emphasizes the need for further development of anti-SARS-CoV-2 therapeutics, in particular orally administered take-home therapies. Cocktail therapy has shown great promise in the treatment of viral infection. Herein, we reported the potent preclinical anti-SARS-CoV-2 efficacy of a cocktail therapy consisting of clinically used drugs, e.g. colloidal bismuth subcitrate (CBS) or bismuth subsalicylate (BSS), and N-acetyl-l-cysteine (NAC). Oral administration of the cocktail reduced viral loads in the lung and ameliorated virus-induced pneumonia in a hamster infection model. The mechanistic studies showed that NAC prevented the hydrolysis of bismuth drugs at gastric pH via the formation of the stable component [Bi(NAC)3], and optimized the pharmacokinetics profile of CBS in vivo. Combination of bismuth drugs with NAC suppressed the replication of a panel of medically important coronaviruses including Middle East respiratory syndrome-related coronavirus (MERS-CoV), Human coronavirus 229E (HCoV-229E) and SARS-CoV-2 Alpha variant (B.1.1.7) with broad-spectrum inhibitory activities towards key viral cysteine enzymes/proteases including papain-like protease (PLpro), main protease (Mpro), helicase (Hel) and angiotensin-converting enzyme 2 (ACE2). Importantly, our study offered a potential at-home treatment for combating SARS-CoV-2 and future coronavirus infections.

Immune-related myocarditis in two patients receiving camrelizumab therapy and document analysis.

INTRODUCTION: Camrelizumab is an antibody against programmed death protein 1 (PD-1) and is one of immune checkpoint inhibitors (ICI). ICI may lead to autoimmune myocarditis, which has a variety of clinical manifestations and usually has a poor prognosis. This article will discuss these clinical manifestations through 2 cases of ICI-related myocarditis caused by carrelizumab. CASE REPORT: We reviewed the patients who received tumor treatment in our hospital from September 2019 to June 2020. A total of 155 patients received camrelizumab treatment. there were 2 cases of acute myocarditis, accounting for 1.29%, and 8 cases of new-onset arrhythmia. Here we present 2 cases of active myocarditis in a 69-year-old man with primary liver cancer and a 75-year-old man with non-small-cell lung cancer after treatment with camrelizumab.Management and outcome: The first patient presented with severe heart failure and died of malignant arrhythmia after being treated with glucocorticoid. The second patient presented with numbness of the extremities, weakness, and mild dyspnea. The symptoms gradually improved after treatment with glucocorticoid. The Naranjo scores of these two cases were 6 and 7, which suggested that myocarditis was probably caused by carrelizumab. DISCUSSION: ICI has been successfully used to treat a variety of malignant tumors with good results. However, blocking immune checkpoints by ICI may lead to autoimmune myocarditis with a poor prognosis. Early detection of cardiotoxicity may be possible through the patient's clinical manifestations and some commonly used cardiac examination methods.

Effect of autoinduction and food on the pharmacokinetics of furmonertinib and its active metabolite characterized by a population pharmacokinetic model.

Furmonertinib (AST2818) is a novel third-generation irreversible EGFR TKI and recently has been approved in China for the treatment of non-small cell lung cancer (NSCLC) with EGFR-sensitizing and T790M resistance mutations. In the current study, we developed a semi-mechanistic population pharmacokinetic model to characterize the nonstationary pharmacokinetics (PK) of the furmonertinib and its active metabolite AST5902 simultaneously. The PK data of furmonertinib and AST5902 were obtained from 38 NSCLC patients and 16 healthy volunteers receiving 20-240 mg furmonertinib in three clinical trials. A nonlinear mixed-effects modeling approach was used to describe the PK data. The absorption process of furmonertinib was described by a transit compartment model. The disposition of both furmonertinib and AST5902 was described by a two-compartment model. An indirect response model accounted for the autoinduction of furmonertinib metabolism mediated by CYP3A4. The model-based simulation suggested that furmonertinib clearance was increased in one cycle of treatment (orally once daily for 21 days) compared to baseline, ranging from 1.1 to 1.8 fold corresponding to the dose range of 20-240 mg. The concentration of furmonertinib was decreased over time whereas that of AST5902 was increased. Interestingly, the concentration of the total active compounds (furmonertinib and AST5902) appeared to be stable. The food intake, serum alkaline phosphatase and body weight were identified as statistically significant covariates. The mechanism of food effect on PK was investigated, where the food intake might increase the bioavailability of furmonertinib via increasing the splanchnic blood flow. Overall, a population PK model was successfully developed to characterize the nonstationary PK of furmonertinib and AST5902 simultaneously. The concentrations of total active compounds were less affected by the autoinduction of furmonertinib metabolism.

CAG RNAs induce DNA damage and apoptosis by silencing NUDT16 expression in polyglutamine degeneration.

DNA damage plays a central role in the cellular pathogenesis of polyglutamine (polyQ) diseases, including Huntington's disease (HD). In this study, we showed that the expression of untranslatable expanded CAG RNA per se induced the cellular DNA damage response pathway. By means of RNA sequencing (RNA-seq), we found that expression of the Nudix hydrolase 16 (NUDT16) gene was down-regulated in mutant CAG RNA-expressing cells. The loss of NUDT16 function results in a misincorporation of damaging nucleotides into DNAs and leads to DNA damage. We showed that small CAG (sCAG) RNAs, species generated from expanded CAG transcripts, hybridize with CUG-containing NUDT16 mRNA and form a CAG-CUG RNA heteroduplex, resulting in gene silencing of NUDT16 and leading to the DNA damage and cellular apoptosis. These results were further validated using expanded CAG RNA-expressing mouse primary neurons and in vivo R6/2 HD transgenic mice. Moreover, we identified a bisamidinium compound, DB213, that interacts specifically with the major groove of the CAG RNA homoduplex and disfavors the CAG-CUG heteroduplex formation. This action subsequently mitigated RNA-induced silencing complex (RISC)-dependent NUDT16 silencing in both in vitro cell and in vivo mouse disease models. After DB213 treatment, DNA damage, apoptosis, and locomotor defects were rescued in HD mice. This work establishes NUDT16 deficiency by CAG repeat RNAs as a pathogenic mechanism of polyQ diseases and as a potential therapeutic direction for HD and other polyQ diseases.

Multifunctional ginsenoside Rg3-based liposomes for glioma targeting therapy.

Liposomes have been widely used for targeted drug delivery. However, nonselective distribution, low blood-brain barrier penetration, and the disadvantages of cholesterol greatly limit the application of conventional liposomes in the treatment of brain tumors. In the present study, we aimed to develop a multifunctional ginsenoside Rg3-based liposomal system (Rg3-LPs). Compared to cholesterol liposomes (C-LPs), Rg3-LPs not only significantly improved cellular uptake and penetration across glioma spheroids in vitro, but also remarkably enhanced active glioma targeting and intratumoral diffusion capability in vivo. Paclitaxel-loaded Rg3-LPs (Rg3-PTX-LPs) exhibited a substantially stronger anti-proliferation effect on C6 glioma cells than paclitaxel-loaded C-LPs and re-educated tumor-associated macrophages from the protumor M2 phenotype to the antitumor M1 phenotype in vivo. Rg3-PTX-LPs significantly prolonged median survival time of intracranial C6-bearing mice/rats by activating the immune microenvironment in glioma, facilitating T-cell immune responses with expansion of the CD8+ T-cell population, increasing the M1/M2 ratio, and decreasing regulatory T and myeloid-derived suppressor cells. Together, the results demonstrated that ginsenoside Rg3 is a good alternative for cholesterol in drug delivery liposomes and has a synergistic effect with loaded anticancer drugs. Rg3-PTX-LPs can serve as a multifunctional potential drug for the treatment of glioma.

Real-world cardiovascular toxicity of immune checkpoint inhibitors in cancer patients: a retrospective controlled cohort study.

Over the past decade, immune checkpoint inhibitors (ICI) have dramatically improved the prognosis of many cancer patients, but many immune-related adverse cardiovascular events (ACEs) have been observed. We aimed to investigate the occurrence of ACEs in the real world after receiving ICI and provide clinical reference for how to evaluate it. The study retrospectively included 204 patients who received ICI from October 2019 to November 2020 and 205 patients who only received traditional chemotherapy. The mean duration of follow-up for ICI group was 4.88 months, and the control group was 4.79 months. Patients in the control group did not develop myocarditis, only 2 cases of new-onset pericardial effusion occurred. In contrast, among ICI group, there were 3 cases of ICI-associated myocarditis, accounting for 1.47% (3/204), 6 cases of pericardial effusion. The incidence of new-onset ECG abnormalities in the ICI group was significantly higher than that of the control group (38/180 VS 16/178, HR 2.71, 95% CI: 1.449-5.067, P=0.001). In the ICI group, after receiving ICI treatment, cardiac biomarkers including average cardiac troponin T and N terminal pro B type natriuretic peptide increased significantly, peak in about 1 month, and then gradually decreasing. After the third or fourth month, the cardiac biomarkers gradually increased again. In conclusion, ICI may lead to various ACEs, and its incidence is higher than that of patients who only receive traditional chemotherapy. The changing trend of cardiac biomarkers reflects that ICI may cause acute and chronic myocardial damage. Regularly performing ECG, echocardiogram and cardiac biomarker examinations are helpful for early detection of ACEs caused by ICI and providing timely treatment.