Circadian tumor infiltration and function of CD8+ T cells dictate immunotherapy efficacy.

The quality and quantity of tumor-infiltrating lymphocytes, particularly CD8+ T cells, are important parameters for the control of tumor growth and response to immunotherapy. Here, we show in murine and human cancers that these parameters exhibit circadian oscillations, driven by both the endogenous circadian clock of leukocytes and rhythmic leukocyte infiltration, which depends on the circadian clock of endothelial cells in the tumor microenvironment. To harness these rhythms therapeutically, we demonstrate that efficacy of chimeric antigen receptor T cell therapy and immune checkpoint blockade can be improved by adjusting the time of treatment during the day. Furthermore, time-of-day-dependent T cell signatures in murine tumor models predict overall survival in patients with melanoma and correlate with response to anti-PD-1 therapy. Our data demonstrate the functional significance of circadian dynamics in the tumor microenvironment and suggest the importance of leveraging these features for improving future clinical trial design and patient care.

Androgen-induced upregulation of CFTR in pancreatic ß-cell contributes to hyperinsulinemia in PCOS model.

PURPOSE: Polycystic ovarian syndrome (PCOS) is an endocrine-metabolic condition affecting 5-10% of reproductive-aged women and characterized by hyperandrogenism, insulin resistance (IR), and hyperinsulinemia. CFTR is known to be regulated by steroid hormones, and our previous study has demonstrated an essential role of CFTR in ß-cell function. This study aims to investigate the contribution of androgen and CFTR to hypersecretion of insulin in PCOS and the underlying mechanism. METHODS: We established a rat PCOS model by subcutaneously implanting silicon tubing containing Dihydrotestosterone (DHT). Glucose tolerance test with insulin levels was performed at 9 weeks after implantation. A rat ß-cell line RINm5F, a mouse ß-cell line ß-TC-6, and mouse islets were treated with DHT, and with or without the androgen antagonist flutamide for CFTR and insulin secretion-related functional assays or mRNA/protein expression measurement. The effect of CFTR inhibitors on DHT-promoted membrane depolarization, glucose-stimulated intracellular Ca2+ oscillation and insulin secretion were examined by membrane potential imaging, calcium imaging and ELISA, respectively. RESULTS: The DHT-induced PCOS model showed increased body weight, impaired glucose tolerance, and higher blood glucose and insulin levels after glucose stimulation. CFTR was upregulated in islets of PCOS model and DHT-treated cells, which was reversed by flutamide. The androgen receptor (AR) could bind to the CFTR promoter region, which was enhanced by DHT. Furthermore, DHT-induced membrane depolarization, enhanced glucose-stimulated Ca2+ oscillations and insulin secretion, which could be abolished by CFTR inhibitors. CONCLUSIONS: Excessive androgen enhances glucose-stimulating insulin secretion through upregulation of CFTR, which may contribute to hyperinsulinemia in PCOS.

Dendritic cells direct circadian anti-tumour immune responses.

The process of cancer immunosurveillance is a mechanism of tumour suppression that can protect the host from cancer development throughout its lifetime1,2. However, it is unknown whether the effectiveness of cancer immunosurveillance fluctuates over a single day. Here we demonstrate that the initial time of day of tumour engraftment dictates the ensuing tumour size across mouse cancer models. Using immunodeficient mice as well as mice lacking lineage-specific circadian functions, we show that dendritic cells (DCs) and CD8+ T cells exert circadian anti-tumour functions that control melanoma volume. Specifically, we find that rhythmic trafficking of DCs to the tumour draining lymph node governs a circadian response of tumour-antigen-specific CD8+ T cells that is dependent on the circadian expression of the co-stimulatory molecule CD80. As a consequence, cancer immunotherapy is more effective when synchronized with DC functions, shows circadian outcomes in mice and suggests similar effects in humans. These data demonstrate that the circadian rhythms of anti-tumour immune components are not only critical for controlling tumour size but can also be of therapeutic relevance.

Potassium channel-related genes are a novel prognostic signature for the tumor microenvironment of renal clear cell carcinoma.

Clear cell renal cell carcinoma (ccRCC) accounts for 80% of renal cell carcinomas (RCCs), and its morbidity and prognosis are unfavorable. Surgical resection is the first-line treatment for ccRCC, but the oncogenesis of ccRCC is very complex. With the development of high-throughput sequencing technology, it is necessary to analyze the transcriptome to determine more effective treatment methods. The tumor microenvironment (TME) is composed of tumor cells, various immune-infiltrating cells, fibroblasts, many cytokines, and catalysts. It is a complex system with a dynamic balance that plays an essential role in tumor growth, invasion, and metastasis. Previous studies have confirmed that potassium channels can affect the immune system, especially T lymphocytes that require potassium channel activation. However, the effect of potassium channels on the TME of ccRCC remains to be studied. Therefore, this study aims to construct a prognostic signature for ccRCC patients based on potassium ion channel-related genes (PCRGs), assess patient risk scores, and divide patients into high- and low-risk groups based on the cutoff value. In addition, we investigated whether there were differences in immune cell infiltration, immune activator expression, somatic mutations, and chemotherapeutic responses between the high- and low-risk groups. Our results demonstrate that the PCRG signature can accurately assess patient prognosis and the tumor microenvironment and predict chemotherapeutic responses. In summary, the PCRG signature could serve as an auxiliary tool for the precision treatment of ccRCC.

IFN-γ-dependent tumor-antigen cross-presentation by lymphatic endothelial cells promotes their killing by T cells and inhibits metastasis.

Tumor-associated lymphatic vessels promote metastasis and regulate antitumor immune responses. Here, we assessed the impact of cytotoxic T cells on the local lymphatic vasculature and concomitant tumor dissemination during an antitumor response. Interferon-γ (IFN-γ) released by effector T cells enhanced the expression of immunosuppressive markers by tumor-associated lymphatic endothelial cells (LECs). However, at higher effector T cell densities within the tumor, T cell-based immunotherapies induced LEC apoptosis and decreased tumor lymphatic vessel density. As a consequence, lymphatic flow was impaired, and lymph node metastasis was reduced. Mechanistically, T cell-mediated tumor cell death induced the release of tumor antigens and cross-presentation by tumor LECs, resulting in antigen-specific LEC killing by T cells. When LECs lacked the IFN-γ receptor expression, LEC killing was abrogated, indicating that IFN-γ is indispensable for reducing tumor-associated lymphatic vessel density and drainage. This study provides insight into how cytotoxic T cells modulate tumor lymphatic vessels and may help to improve immunotherapeutic protocols.

[Application of Tiaoshen Jianpi acupuncture and moxibustion in hospice care for terminal cancer patients].

To analyze the application feasibility of Tiaoshen Jianpi acupuncture and moxibustion in hospice care for terminal cancer patients. Tiaoshen Jianpi acupuncture and moxibustion adjusts the spirit to regulate emotions and fortifies the spleen to supplement and boost foundation of acquired (postnatal) constitution. And it could relieve adverse reactions after radiotherapy and chemotherapy, alleviate pain and regulate emotions in hospice care for terminal cancer patients, so as to promote the progress of hospice care for terminal cancer patients.

A Bibliometric Analysis of Research Trends of Acupuncture Therapy in the Treatment of Migraine from 2000 to 2020.

BACKGROUND: Migraine is the second-leading cause of disability worldwide. It is often characterized by attacks of severe, mostly unilateral, pulsating headache associated with symptoms such as photophobia, phonophobia, nausea, vomiting, and cutaneous allodynia. Acupuncture therapy has been used worldwide for the treatment of migraine. However, no visual bibliometric analysis has been conducted on the effects of acupuncture on migraine over the past 20 years. Therefore, this study aimed to explore the current status and trends on the use of acupuncture in the treatment of migraine from 2000 to 2020. PURPOSE: The objective of this study is to identify the current status and emerging trends of the global use of acupuncture on migraine from 2000 to 2020 using CiteSpace and VOSviewer. METHODS: Web of Science databases were searched for publications related to acupuncture therapy for treating migraine between 2000 and 2020. CiteSpace and VOSviewer were used to analyze the number of publications per year, countries, institutions, authors, journals, references, and keywords. RESULTS: A total of 572 publications were included in the final analysis. The total number of publications has continued to increase with some fluctuations over the past 20 years. The most productive country and institution in this field were the USA, and Chengdu University of Traditional Chinese Medicine, respectively. The most active and cited authors were Liang FR and Linde K, respectively. Cephalalgia was the most productive, cited, and co-cited journal. The Linde K (2005) had the highest co-citation, citation number and centrality. The keywords "migraine" ranked first in frequency. The common type of migraine (tension-type headache), research method (randomized controlled trial, multicenter, double-blind), acupuncture's role (prophylactic, quality of life, pain), and evaluation (meta-analysis, systematic review) were the hotspots and frontier trends of acupuncture therapy on migraine between 2000 and 2020. CONCLUSION: The present study examined the research-related trend in acupuncture therapy on migraine using bibliometric methods and identified the statement and research frontiers over the past two decades. This may help researchers to identify potential hotspots and new directions for future research in this field.

Trends in Piezo Channel Research Over the Past Decade: A Bibliometric Analysis.

Purpose: We used bibliometric methods to evaluate the global scientific output of research on Piezo channels and explore the current status and trends in this field over the past decade. Methods: Piezo channel-related studies published in 2010-2020 were retrieved from Web of Science. The R bibliometrix package was used for quantitative and qualitative analyses of publication outputs and author contributions. VOSviewer was used to construct networks based on co-authorship of countries/institutions/authors, co-citation analysis of journals/references, citation analysis of documents, and co-occurrence of keywords. Results: In total, 556 related articles and reviews were included in the final analysis. The number of publications has increased substantially with time. The country and institution contributing the most to this field was the United States and Scripps Research Institute, respectively. Ardem Patapoutian was the most productive author and ranked first among the cited authors, h-index, and m-index. The top cited reference was the article published by Coste B et al. in Science (2010) that identified Piezo1/2 in mammalian cells. The top journals in terms of the number of selected articles and citations were Nature Communications and Nature, respectively. The co-occurrence analysis revealed that Piezo channels are involved a variety of cell types (Merkel cells, neurons, endothelial cells, red blood cells), physiological processes (touch sensation, blood pressure, proprioception, vascular development), related ion channels (transient receptor potential, Gardos), and diseases (pain, distal arthrogryposis, dehydrated hereditary stomatocytosis, cancer), and pharmacology (Yoda1, GsMTx-4). Conclusion: Our bibliometric analysis shows that Piezo channel research continues to be a hotspot. The focus has evolved from Piezo identification to architecture, activation mechanism, roles in diseases, and pharmacology.

Effect of electroacupuncture on chemotherapy-induced diarrhea: study protocol for a randomized controlled trial.

BACKGROUND: Chemotherapy-induced diarrhea (CID) is one of the side effects of chemotherapy. Diarrhea not only affects the overall treatment effectiveness but also reduces patients' quality of life. Severe diarrhea can lead to electrolyte imbalance and even be life-threatening. Although acupuncture has been widely used in clinical practice and its effectiveness for managing functional diarrhea has been recognized, there is no sound evidence of its efficacy in managing CID. Therefore, the aim of the proposed randomized controlled trial is to examine the effectiveness and potential risks of using acupuncture for the management of CID and to describe its protocol herein. METHODS: This trial will be conducted in a double-blinded manner and comprise two arms that will be investigated across multiple centers in parallel. The study cohort will comprise 168 outpatients who have CID from six Chinese hospitals. The patients will be randomly and equally divided between an intervention group (electroacupuncture) and a control group (micro-electroacupuncture). In the former, acupuncture will be performed with the conventional method to induce the de qi sensation, and in the latter group, acupuncture will be performed with a sham procedure that does not involve the insertion of needles. The acupoints ST25, SP14, SP6, and ST37 will be applied in the two methods. These procedures will be performed three times a week for four consecutive weeks. The number of days on which CID occurred, the incidence of CID, and fecal characteristics are considered as the primary outcomes, and the Functional Assessment of Chronic Illness Therapy for Patients with Diarrhea subscale score and the World Health Organization Quality of Life assessment are considered as secondary outcomes. The patients will be closely observed for complications and fluctuations in vital signs. DISCUSSION: If the findings from the trial demonstrate the effectiveness and safety of using acupuncture to treat CID, they could serve as evidence for the clinical application of acupuncture as a complementary treatment for cancer patients during chemotherapy. TRIAL REGISTRATION: Chinese Clinical Trial Registry, ChiCTR2000035715, registered on August 16, 2020.