Heart failure in cancer patients

The purpose of the study was to conduct a systematic review of data on the role of heart failure (HF) in the development of cancer, as well as to discuss problems dealing with diagnosis and treatment of heart failure in cancer patients. Material and methods. A literature search was conducted using the Cochrane library, elibrary, medline, and embase databases over the past 7 years. The general mechanisms of heart failure and cancer, cardiotoxicity risk factors, and some aspects of the diagnosis and treatment of HF in cancer patients were analyzed. Results. The literature analysis indicates that cardiovascular disease and cancer have common risk factors. Several common pathophysiological mechanisms that associate HF with cancer have been identified. They include inflammation, oxidative stress, and neurohomonal activation. HF is known to be a common complication of aggressive cardiotoxic cancer therapy that can aggravate or trigger existing HF. Recent epidemiological studies have shown that the development of cancer is more common among patients with pre-existing HF. Although the reason for this relationship has not yet been identified, it is assumed that HF may be a pro-oncogenic condition. There are several strategies to prevent and treat toxicity of various chemotherapeutic drugs. They are all based on accurate patient selection, short- and longterm follow-up, and therapies that can prevent and delay cardiac dysfunction. Conclusion. The main goal of cardio-oncology is to prevent and treat of cardiotoxic effects of chemotherapy drugs. In this context, elucidation of the underlying mechanisms plays an important role in the development of strategies for the prevention of chemotherapy-associated cardiomyopathy. It is necessary to pay attention to the fact that there is more and more evidence that patients with HF have high risks of developing cancer, thereby requiring more attention. In general, understanding the direct and indirect mechanisms of the relationship between HF and cancer can help in the prevention and early diagnosis of these diseases.

cADPR induced calcium influx mediates axonal degeneration caused by paclitaxel

Activation of the NAD hydrolase domain of Sarm1 mediates axonal degeneration caused by chemotherapy drugs, but the downstream events are unknown. In this issue, Li and colleagues (2021. J. Cell Biol.https://doi.org/10.1083/jcb.202106080) demonstrate that cADPR, a breakdown product of NAD, mediates paclitaxel-induced axonal degeneration by promoting influx of calcium into the axons.

A Systematic Review of Nutritional Lab Correlates with Chemotherapy Induced Peripheral Neuropathy

Chemotherapy induced peripheral neuropathy (CIPN) is a dose-limiting side effect of chemotherapy for which no prevention or cure exists. Cancer and cancer treatments can adversely affect nutritional status. Nutrition may play a role in development of CIPN, yet the relationship between nutrition and CIPN is not well understood. Common laboratory values measuring various aspects of nutrition (hemoglobin/hematocrit, vitamin B12, calcium, and magnesium) may be associated with CIPN. The aim of this systematic review is to evaluate the empirical evidence surrounding the relationship between laboratory measures of nutrition and CIPN among persons with cancer who received neurotoxic chemotherapy drugs. We conducted an extensive review of the literature to identify articles that evaluated relationships between laboratory measures of nutrition and CIPN. A total of eleven articles satisfied the inclusion/exclusion criteria. Participants in the studies had breast or colorectal cancer, lymphoma or multiple myeloma and were receiving a variety of neurotoxic drugs. Hemoglobin/hematocrit, vitamin D, albumin, and magnesium were associated with CIPN. The quality of the studies ranges from fair to good. Evidence suggests that low levels of the above-mentioned tests could be associated with CIPN but additional research is needed.

Impediment of Cerebrospinal Fluid Drainage Through Glymphatic System in Glioma

BackgroundCerebrospinal fluid (CSF) plays an important role in maintaining tissue homeostasis in the central nervous system. In 2012, the new CSF outflow pathway, “the glymphatic system,” was discovered. The glymphatic system mediates CSF and interstitial fluid exchange through the perivascular pathway, which eliminates harmful solutes in the brain parenchyma. In recent studies, the importance of the glymphatic system has been demonstrated in healthy and neurodegenerative disease brains. However, there is limited research on the function of the CSF in brain tumors. Intracranial hypertension caused by glioma can affect CSF drainage, which impacts the delivery of chemotherapy drugs via intrathecal injection. This study focused on changes in the glymphatic system and the role of aquaporin 4 (AQP4) in glymphatic transport in glioma.MethodsIn glioma-bearing rats, the effect of tracer infusion on the intracranial pressure (ICP) was evaluated using an ICP microsensor. In vivo magnetic resonance imaging and ex vivo bright field were used to monitor CSF tracer distribution after cisterna magna injection. AQP4 expression was quantitatively detected, and AQP4 in the astrocytes around the vessels was observed using immunofluorescence.ResultsThe ICP of the tumor group was higher than that of the control group and the infusion rate of 2 µl/min did not affect ICP. In vivo and ex vivo imaging showed that the circulation of CSF tracers was significantly impaired in the tumor. High-power confocal microscopy revealed that, in the tumor, the surrounding of AQP4 by Evans Blue was decreased. In both tumor and contralateral areas, data indicated that the number of cluster designation 34 (CD34+) alpha-smooth muscle actin (α-SMA−) veins were more than that of CD34+α-SMA+ arteries. Moreover, in the tumor area, AQP4 in the astrocytes around the vessels was decreased.ConclusionsThese findings indicate that the para-arterial influx of subarachnoid CSF is limited in glioma, especially in those with reduced levels of the fundamental protein AQP4. Our results provide evidence toward a potential new treatment method for glioma in the future.

Immune-Related lncRNA Pairs as Prognostic Signature and Immune-Landscape Predictor in Lung Adenocarcinoma

BackgroundSuppressive tumor microenvironment is closely related to the progression and poor prognosis of lung adenocarcinoma (LUAD). Novel individual and universal immune-related biomarkers to predict the prognosis and immune landscape of LUAD patients are urgently needed. Two-gene pairing patterns could integrate and utilize various gene expression data.MethodsThe RNA-seq and relevant clinicopathological data of the LUAD project from the TCGA and well-known immune-related genes list from the ImmPort database were obtained. Co-expression analysis followed by an analysis of variance was performed to identify differentially expressed immune-related lncRNA (irlncRNA) (DEirlncRNA) between tumor and normal tissues. Two arbitrary DEirlncRNAs (DEirlncRNAs pair) in a tumor sample underwent pairwise comparison to generate a score (0 or 1). Next, Univariate analysis, Lasso regression and Multivariate analysis were used to screen survival-related DEirlncRNAs pairs and construct a prognostic model. The Acak information standard (AIC) values of the receiver operating characteristic (ROC) curve for 3 years are calculated to determine the cut-off point for high- or low-risk score. Finally, we evaluated the relationship between the risk score and overall survival, clinicopathological features, immune landscape, and chemotherapy efficacy.ResultsData of 54 normal and 497 tumor samples of LUAD were enrolled. After a strict screening process, 15 survival-independent-related DEirlncRNA pairs were integrated to construct a prognostic model. The AUC value of the 3-year ROC curve was 0.828. Kaplan–Meier analysis showed that patients with low risk lived longer than patients with high risk (p <0.001). Univariate and Multivariate Cox analysis suggested that the risk score was an independent factor of survival. The risk score was negatively associated with most tumor-infiltrating immune cells, immune score, and microenvironment scores. The low-risk group was correlated with increased expression of ICOS. The high-risk group had a connection with lower half inhibitory centration (IC50) of most chemotherapy drugs (e.g., etoposide, paclitaxel, vinorelbine, gemcitabine, and docetaxel) and targeted medicine—erlotinib, but with higher IC50 of methotrexate.ConclusionThe established irlncRNA pairs-based model is a promising prognostic signature for LUAD patients. Furthermore, the prognostic signature has great potential in the evaluation of tumor immune landscape and guiding individualized treatment regimens.

Analysis of the Safety of Pegfilgrastim Addition in Bleomycin, Etoposide, and Cisplatin Treatment Patients With Germ Cell Tumors

It has been reported that chemotherapy drugs and granulocyte colony-stimulating factor (G-CSF) administered on the same day can aggravate neutropenia. In the present study, we investigated the safety of pegfilgrastim during bleomycin, etoposide, and cisplatin (BEP) therapy. This single-center retrospective study, including 137 cycles of BEP therapy for germ cell tumors between January 2008 and April 2021, investigated safety. Short-acting G-CSF was used for 84 cycles and pegfilgrastim was used for 53 cycles. In the pegfilgrastim group, neutrophil count at nadir was significantly higher than in the G-CSF group (median 1,650/μl and 680/μl, respectively). The incidence of grade 3–4 neutropenia was significantly higher and the duration longer in the G-CSF group. Also, there was no significant difference in the incidence of febrile neutropenia. In conclusion, concomitant use of pegfilgrastim during BEP therapy did not increase neutropenia and was effective in terms of safety.

Immunostimulatory Properties of Chemotherapy in Breast Cancer: From Immunogenic Modulation Mechanisms to Clinical Practice

Breast cancer (BC) is the most common malignancy among females. Chemotherapy drugs remain the cornerstone of treatment of BC and undergo significant shifts over the past 100 years. The advent of immunotherapy presents promising opportunities and constitutes a significant complementary to existing therapeutic strategies for BC. Chemotherapy as a cytotoxic treatment that targets proliferation malignant cells has recently been shown as an effective immune-stimulus in multiple ways. Chemotherapeutic drugs can cause the release of damage-associated molecular patterns (DAMPs) from dying tumor cells, which result in long-lasting antitumor immunity by the key process of immunogenic cell death (ICD). Furthermore, Off-target effects of chemotherapy on immune cell subsets mainly involve activation of immune effector cells including natural killer (NK) cells, dendritic cells (DCs), and cytotoxic T cells, and depletion of immunosuppressive cells including Treg cells, M2 macrophages and myeloid-derived suppressor cells (MDSCs). Current mini-review summarized recent large clinical trials regarding the combination of chemotherapy and immunotherapy in BC and addressed the molecular mechanisms of immunostimulatory properties of chemotherapy in BC. The purpose of our work was to explore the immune-stimulating effects of chemotherapy at the molecular level based on the evidence from clinical trials, which might be a rationale for combinations of chemotherapy and immunotherapy in BC.

Multi-Omics Analysis Based on Genomic Instability for Prognostic Prediction in Lower-Grade Glioma

Background: Lower-grade gliomas (LGGs) are a heterogeneous set of gliomas. One of the primary sources of glioma heterogeneity is genomic instability, a novel characteristic of cancer. It has been reported that long noncoding RNAs (lncRNAs) play an essential role in regulating genomic stability. However, the potential relationship between genomic instability and lncRNA in LGGs and its prognostic value is unclear.Methods: In this study, the LGG samples from The Cancer Genome Atlas (TCGA) were divided into two clusters by integrating the lncRNA expression profile and somatic mutation data using hierarchical clustering. Then, with the differentially expressed lncRNAs between these two clusters, we identified genomic instability-related lncRNAs (GInLncRNAs) in the LGG samples and analyzed their potential function and pathway by co-expression network. Cox and least absolute shrinkage and selection operator (LASSO) regression analyses were conducted to establish a GInLncRNA prognostic signature (GInLncSig), which was assessed by internal and external verification, correlation analysis with somatic mutation, independent prognostic analysis, clinical stratification analysis, and model comparisons. We also established a nomogram to predict the prognosis more accurately. Finally, we performed multi-omics-based analyses to explore the relationship between risk scores and multi-omics data, including immune characteristics, N6-methyladenosine (m6A), stemness index, drug sensitivity, and gene set enrichment analysis (GSEA).Results: We identified 52 GInLncRNAs and screened five from them to construct the GInLncSig model (CRNDE, AC025171.5, AL390755.1, AL049749.1, and TGFB2-AS1), which could independently and accurately predict the outcome of patients with LGG. The GInLncSig model was significantly associated with somatic mutation and outperformed other published signatures. GSEA revealed that metabolic pathways, immune pathways, and cancer pathways were enriched in the high-risk group. Multi-omics-based analyses revealed that T-cell functions, m6A statuses, and stemness characteristics were significantly disparate between two risk subgroups, and immune checkpoints such as PD-L1, PDCD1LG2, and HAVCR2 were significantly highly expressed in the high-risk group. The expression of GInLncSig prognostic genes dramatically correlated with the sensitivity of tumor cells to chemotherapy drugs.Conclusion: A novel signature composed of five GInLncRNAs can be utilized to predict prognosis and impact the immune status, m6A status, and stemness characteristics in LGG. Furthermore, these lncRNAs may be potential and alternative therapeutic targets.

Development and Verification of a Hypoxic Gene Signature for Predicting Prognosis, Immune Microenvironment, and Chemosensitivity for Osteosarcoma

Objective: Hypoxic tumors contribute to local failure and distant metastases. Nevertheless, the molecular hallmarks of hypoxia remain ill-defined in osteosarcoma. Here, we developed a hypoxic gene signature in osteosarcoma prognoses.Methods: With the random survival forest algorithm, a prognostic hypoxia-related gene signature was constructed for osteosarcoma in the TARGET cohort. Overall survival (OS) analysis, receiver operating characteristic (ROC) curve, multivariate cox regression analysis, and subgroup analysis were utilized for assessing the predictive efficacy of this signature. Also, external validation was presented in the GSE21257 cohort. GSEA was applied for signaling pathways involved in the high- and low-risk samples. Correlation analyses between risk score and immune cells, stromal/immune score, immune checkpoints, and sensitivity of chemotherapy drugs were performed in osteosarcoma. Then, a nomogram was built by integrating risk score, age, and gender.Results: A five-hypoxic gene signature was developed for predicting survival outcomes of osteosarcoma patients. ROC curves confirmed that this signature possessed the well predictive performance on osteosarcoma prognosis. Furthermore, it could be independently predictive of prognosis. Metabolism of xenobiotics by cytochrome P450 and nitrogen metabolism were activated in the high-risk samples while cell adhesion molecules cams and intestinal immune network for IgA production were enriched in the low-risk samples. The low-risk samples were characterized by elevated immune cell infiltrations, stromal/immune scores, TNFRSF4 expression, and sensitivity to cisplatin. The nomogram accurately predicted 1-, 3-, and 5-years survival duration.Conclusion: These findings might offer an insight into the optimization of prognosis risk stratification and individualized therapy for osteosarcoma patients.

Tanshinone IIA: New Perspective on the Anti-Tumor Mechanism of A Traditional Natural Medicine

The search for natural and efficacious antineoplastic drugs, with minimal toxicity and side effects, is an important part of antitumor drug research and development. Tanshinone IIA is the most evaluated lipophilic active component of Salvia miltiorrhiza. Tanshinone IIA is a path-breaking traditional drug applied in cardiovascular treatment. It has also been found that tanshinone IIA plays an important role in the digestive, respiratory and circulatory systems, as well as in other tumor diseases. Tanshinone IIA significantly inhibits the proliferation of several types of tumors, blocks the cell cycle, induces apoptosis and autophagic death, in addition to inhibiting cell migration and invasion. Among these, the regulation of tumor-cell apoptosis signaling pathways is the key breakthrough point in several modes of antitumor therapy. The PI3K/AKT/MTOR signaling pathway and the JNK pathway are the key pathways for tanshinone IIA to induce tumor cell apoptosis. In addition to glycolysis, reactive oxygen species and signal transduction all play an active role with the participation of tanshinone IIA. Endogenous apoptosis is considered the main mechanism of tumor apoptosis induced by tanshinone IIA. Multiple pathways and targets play a role in the process of endogenous apoptosis. Tanshinone IIA can protect chemotherapy drugs, which is mainly reflected in the protection of the side effects of chemotherapy drugs, such as neurotoxicity and inhibition of the hematopoietic system. Tanshinone IIA also has a certain regulatory effect on tumor angiogenesis, which is mainly manifested in the control of hypoxia. Our findings indicated that tanshinone IIA is an effective treatment agent in the cardiovascular field and plays a significant role in antitumor therapeutics. This paper reviews the pharmacological potential and inhibitory effect of tanshinone IIA on cancer. It is greatly anticipated that tanshinone IIA will be employed as an adjuvant in the treatment of various cancers.