Cathepsin K deficiency prevented stress-related thrombosis in a mouse FeCl3 model.

BACKGROUND: Exposure to chronic psychological stress (CPS) is a risk factor for thrombotic cardiocerebrovascular diseases (CCVDs). The expression and activity of the cysteine cathepsin K (CTSK) are upregulated in stressed cardiovascular tissues, and we investigated whether CTSK is involved in chronic stress-related thrombosis, focusing on stress serum-induced endothelial apoptosis. METHODS AND RESULTS: Eight-week-old wild-type male mice (CTSK+/+) randomly divided to non-stress and 3-week restraint stress groups received a left carotid artery iron chloride3 (FeCl3)-induced thrombosis injury for biological and morphological evaluations at specific timepoints. On day 21 post-stress/injury, the stress had enhanced the arterial thrombi weights and lengths, in addition to harmful alterations of plasma ADAMTS13, von Willebrand factor, and plasminogen activation inhibitor-1, plus injured-artery endothelial loss and CTSK protein/mRNA expression. The stressed CTSK+/+ mice had increased levels of injured arterial cleaved Notch1, Hes1, cleaved caspase8, matrix metalloproteinase-9/-2, angiotensin type 1 receptor, galactin3, p16IN4A, p22phox, gp91phox, intracellular adhesion molecule-1, TNF-α, MCP-1, and TLR-4 proteins and/or genes. Pharmacological and genetic inhibitions of CTSK ameliorated the stress-induced thrombus formation and the observed molecular and morphological changes. In cultured HUVECs, CTSK overexpression and silencing respectively increased and mitigated stressed-serum- and H2O2-induced apoptosis associated with apoptosis-related protein changes. Recombinant human CTSK degraded γ-secretase substrate in a dose-dependent manor and activated Notch1 and Hes1 expression upregulation. CONCLUSIONS: CTSK appeared to contribute to stress-related thrombosis in mice subjected to FeCl3 stress, possibly via the modulation of vascular inflammation, oxidative production and apoptosis, suggesting that CTSK could be an effective therapeutic target for CPS-related thrombotic events in patients with CCVDs.

Targeting tumor-infiltrating tregs for improved antitumor responses.

Immunotherapies have revolutionized the landscape of cancer treatment. Regulatory T cells (Tregs), as crucial components of the tumor immune environment, has great therapeutic potential. However, nonspecific inhibition of Tregs in therapies may not lead to enhanced antitumor responses, but could also trigger autoimmune reactions in patients, resulting in intolerable treatment side effects. Hence, the precision targeting and inhibition of tumor-infiltrating Tregs is of paramount importance. In this overview, we summarize the characteristics and subpopulations of Tregs within tumor microenvironment and their inhibitory mechanisms in antitumor responses. Furthermore, we discuss the current major strategies targeting regulatory T cells, weighing their advantages and limitations, and summarize representative clinical trials targeting Tregs in cancer treatment. We believe that developing therapies that specifically target and suppress tumor-infiltrating Tregs holds great promise for advancing immune-based therapies.

Recurrent syncope driven by unique-variant angina pectoris.

The patient's vasospastic variant angina manifested as syncope with asymptomatic ischemic episodes, and repeated 24-h dynamic electrocardiogram and coronary angiography examinations combined with coronary provocation spasm tests were necessary for its diagnosis and management.

MNK: A Novel Promising Target for Cancer Immunotherapy.

Cancer immunotherapy has demonstrated remarkable success in the treatment of multiple advanced malignancies, especially approaches to target the immune checkpoint. Nonetheless, the limited response rate remains a barrier to broader application. Identifying other ways to extend the beneficiaries to a large extent is needed. Emerging evidence has shown that mitogen-activated protein kinase-interacting kinases (MNKs) could be regarded as a novel, attractive target for cancer immunotherapy that is closely correlated with cancer biology and therapies. A comprehensive understanding of the role and mechanism of MNKs in cancer will shed light on the discovery of novel therapeutic strategies for cancer treatment. In this review, we outlined the structure of MNKs, their function and expression, and how MNKs affect tumor progression and elucidated the evidence supporting MNKs as a new promising treatment modality in human cancers.

Perspectives for immunotherapy of EBV-associated GLELC: A relatively "hot" tumor microenvironment.

BACKGROUND: Epstein-Barr virus (EBV)-associated gastric lymphoepithelioma-like carcinoma (EBVaGLELC) represents a small number of gastric cancer (GC), and research on tumor microenvironment (TME) and treatment strategy are still lacking. AIMS: Here, we aim to elucidate the immune features of this rare disease and further help to develop more effective treatment options. MATERIALS & METHODS: A retrospective analysis was conducted between 2019 to 2022 in West China Hospital to reveal the immunological characteristics of EBV-positive GLELC. The difference of immune cell subset and tumor vascular structure between gastric denocarcinoma (GAC) and EBVaGLELC will be pointed out. DISCUSSION: 13 patients with GELEC and 8 patients with GAC were retrospectively studied. The heterogeneity of the immune cell profile was then confirmed through multiplexed immunofluorescence staining (mIF), which revealed a higher proportion of CD3+ T cells, CD8+ T cells, and Treg cells in the EBV-associated GLELC group. Such a distinct TME may provide therapeutic advantages, and patients with this rare subtype of GC could be good candidates for immune checkpoint inhibitors (ICIs). Angiogenesis in EBV-positive GLELC may be less intense than that in gastric adenocarcinoma (GAC), a feature that might decrease their susceptibility to antiangiogenic therapy. Furthermore, we reported a 52-year-old male with advanced EBV-positive GLELC who showed a favorable response to the combined therapy with . A repeat evaluation showed sustained partial response (PR), and the progression-free survival (PFS) was more than 34 months until now. CONCLUSION: Compared with GAC, EBVaGLELC revealed higher T cell infiltration and less intense of angiogenesis. It displays relatively "hot" TME that may provide the rationality to treat with immunotherapy in EBV-related GLELC.

Cathepsin S deficiency improves muscle mass loss and dysfunction via the modulation of protein metabolism in mice under pathological stress conditions.

Cathepsin S (CTSS) is a widely expressed cysteinyl protease that has garnered attention because of its enzymatic and non-enzymatic functions under inflammatory and metabolic pathological conditions. Here, we examined whether CTSS participates in stress-related skeletal muscle mass loss and dysfunction, focusing on protein metabolic imbalance. Eight-week-old male wildtype (CTSS+/+ ) and CTSS-knockout (CTSS-/- ) mice were randomly assigned to non-stress and variable-stress groups for 2 weeks, and then processed for morphological and biochemical studies. Compared with non-stressed mice, stressed CTSS+/+ mice showed significant losses of muscle mass, muscle function, and muscle fiber area. In this setting, the stress-induced harmful changes in the levels of oxidative stress-related (gp91phox and p22phox ,), inflammation-related (SDF-1, CXCR4, IL-1ß, TNF-α, MCP-1, ICAM-1, and VCAM-1), mitochondrial biogenesis-related (PPAR-γ and PGC-1α) genes and/or proteins and protein metabolism-related (p-PI3K, p-Akt, p-FoxO3α, MuRF-1, and MAFbx1) proteins; and these alterations were rectified by CTSS deletion. Metabolomic analysis revealed that stressed CTSS-/- mice exhibited a significant improvement in the levels of glutamine metabolism pathway products. Thus, these findings indicated that CTSS can control chronic stress-related skeletal muscle atrophy and dysfunction by modulating protein metabolic imbalance, and thus CTSS was suggested to be a promising new therapeutic target for chronic stress-related muscular diseases.

gC1qR: A New Target for Cancer Immunotherapy.

Although breakthroughs in cancer treatment have been achieved, immunotherapy yields only modest benefits in most patients. There is still a gap in clarifying the immune evasiveness and immune-resistance mechanisms. Identifying other candidate targets for cancer immunotherapy is therefore a clear unmet clinical need. The complement system, a pillar of innate immunity, has recently entered the limelight due to its immunoregulatory functions in the tumor microenvironment (TME). In particular, gC1qR, a receptor for globular heads of C1q, serves as a promising new target and has attracted more attention. gC1qR, also named P32/C1qBP/HABP1, is a multifunctional protein that is overexpressed in various cancers and holds prognostic value. It regulates the tumorigenic, progression and metastatic properties of tumor cells through several downstream signaling pathways, including the Wnt/ß-catenin, PKC-NF-κB and Akt/PKB pathways. A few preclinical experiments conducted through gC1qR interventions, such as monoclonal antibody, chimeric antigen receptor T-cell (CAR-T) therapy, and tumor vaccination, have shown encouraging results in anticancer activity. The efficacy may rely on the regulatory role on the TME, induction of tumor cells apoptosis and antiangiogenic activity. Nevertheless, the current understanding of the relationship between cancer immunotherapy and gC1qR remains elusive and often contradictory, posing both opportunities and challenges for therapeutic translation in the clinic. In this review, we focus on the current understanding of gC1qR function in cancer immunology and highlight the vital roles in regulating the TME. We also examines the rationale behind targeting gC1qR and discusses the potential for translating into clinical practice.

Cathepsins in the extracellular space: Focusing on non-lysosomal proteolytic functions with clinical implications.

Cathepsins can be found in the extracellular space, cytoplasm, and nucleus. It was initially suspected that the primary physiological function of the cathepsins was to break down intracellular protein, and that they also had a role in pathological processes including inflammation and apoptosis. However, the many actions of cathepsins outside the cell and their complicated biological impacts have garnered much interest. Cathepsins play significant roles in a number of illnesses by regulating parenchymal cell proliferation, cell migration, viral invasion, inflammation, and immunological responses through extracellular matrix remodeling, signaling disruption, leukocyte recruitment, and cell adhesion. In this review, we outline the physiological roles of cathepsins in the extracellular space, the crucial pathological functions performed by cathepsins in illnesses, and the recent breakthroughs in the detection and therapy of specific inhibitors and fluorescent probes in associated dysfunction.

Intrinsic Differences in Immune Checkpoint Inhibitor-Induced Myocarditis: A Retrospective Analysis of Real World Data.

Immune-related myocarditis is a severe and even life-threatening immune-related adverse event (irAE) which may also be underestimated due to the challenge in diagnosis. The inherent difference between individuals with immune-associated myocarditis has received little attention. Our study aimed to identify which baseline characteristics could contribute to distinguishing mild from severe ICI myocarditis. A retrospective analysis was conducted between March 2019 and June 2020 in West China Hospital, and 18 patients with immune-related myocarditis were studied. Patients were classified as having mild (n = 12) or severe myocarditis (n = 6), according to the clinical manifestations and hemodynamic complications. Factors associated with severe myocarditis were identified by comparing covariates derived from medical records in various groups. In this retrospective analysis, the median age of the 18 patients was 60 years old. Most myocarditis cases occur early and approximately after the first or second ICI infusion. The severity of myocarditis may be correlated with lactate dehydrogenase (LDH) (p = 0.04) and troponin levels (p = 0.0057). The relationship between troponin and myocarditis was further confirmed in another cohort, which included 30 patients. In addition, patients are more likely to develop multi-irAEs, and myositis was the most common second irAE. Those who experience multi-irAEs usually had significantly higher LDH (p = 0.02) and myoglobin levels (p = 0.02) than those who did not experience them. All patients were treated with steroids timely, and the mortality rate was 5.6% in our study. In this study, we explored risk factors for severe myocarditis and emphasized the importance of a multidisciplinary team in assisting diagnosis and treatment options. It is critical to initiate corticosteroid therapy, regardless of the severity of the myocarditis.

Glypican-3: A Novel and Promising Target for the Treatment of Hepatocellular Carcinoma.

Glypican-3 (GPC3) is a membrane-associated proteoglycan that is specifically up-regulated in hepatocellular carcinoma (HCC) although rarely or not expressed in normal liver tissues, making it a perfect diagnostic and treatment target for HCC. Several GPC3-based clinical trials are ongoing and recently several innovative GPC3-targeted therapeutic methods have emerged with exciting results, including GPC3 vaccine, anti-GPC3 immunotoxin, combined therapy with immune checkpoint blockades (ICBs), and chimeric antigen receptor (CAR) T or NK cells. Here, we review the value of GPC3 in the diagnosis and prognosis of HCC, together with its signaling pathways, with a specific focus on GPC3-targeted treatments of HCC and some prospects for the future GPC3-based therapeutic strategies in HCC.

Characteristics and survival outcomes of primary splenic cancers: A SEER population-based study.

ABSTRACT: Primary splenic cancers represent a small number of cancer cases and studies on its clinicopathological features and outcomes are limited. Splenic lymphomas and primary splenic angiosarcoma (PSA) are the 2 most common histological types of splenic cancers. This population-based study aimed to investigate the clinical characteristics and survival outcomes of patients with splenic lymphomas or PSA.Patients diagnosed with splenic lymphomas or PSA between 2000 and 2015 were identified from the Surveillance Epidemiology and End Results database of the National Cancer Institutes. Overall survival (OS) and cancer-specific survival (CSS) rates were calculated using the Kaplan-Meier method. A Cox proportional hazard models were used to identify independent predictors of cancer-specific mortality.A total of 700 patients with splenic lymphoma and 48 patients with PSA were included in this study. The median age of patients with splenic lymphoma was 65 years and 57 years for patients with PSA. For patients with splenic lymphoma, the most prevalent histological subtypes were splenic marginal zone lymphoma and diffuse large B-cell lymphoma. A total of 52.6% of the cases had stage IV disease based on the Ann Arbor staging system. Five-year OS and CSS were 76.9% and 83.4%, respectively. Multivariate analysis revealed that independent predictors of splenic lymphoma CSS included race, stage, chemotherapy, and histological subtype. However, a much shorter OS time was seen in the PSA cohort which had a 5-year OS of 11.8%, a median OS of 10.0 months and the 5-year CSS of 12.4%. Chemotherapy was correlated with better outcomes in patients with PSA. However, the survival benefits of surgery for splenic cancer were not statistically significant in our study.The current study is the largest cohort of primary splenic cancer presented in literature based on the Surveillance Epidemiology and End Results database and our large series describe the characteristics and survival outcomes of such rare diseases which may provide reliable information for further studies and clinicians.

Unexpected Favorable Outcome to PD-1 Antibody Plus Lenvatinib in a Patient With Recurrent Intestinal Follicular Dendritic Cell Sarcoma: A Case Report and Literature Review.

Background: Follicular dendritic cell sarcoma (FDCS) is an uncommon malignant cancer, and there is no standard treatment to date. Resection followed by adjuvant chemotherapy or radiation is considered the most commonly used strategy for treatment. However, the treatment for patients who have progressed after systemic treatment is more controversial. Case summary: In this case report, we describe a 57-year-old man with primary small intestine FDCS where surgery and second-line systemic chemotherapy failed. After disease progression (PD), the patient received sintilimab plus lenvatinib as third-line treatment and achieved a progression-free survival (PFS) with 7 months. Conclusion: This is the first report of a FDCS patient treated with immune checkpoint inhibitors (ICIs) and antiangiogenic agents, sintilimab and lenvatinib, as third-line therapy. Our case provides a potential therapeutic option for patients with FDCS who progressed after multiline therapy.

A Distinct Clinicopathological Feature and Prognosis of Young Gastric Cancer Patients Aged ≤ 45 Years Old.

PURPOSE: The aim of this retrospective study was to probe into clinicopathological features and prognosis of early-onset gastric cancer (EOGC) patients aged ≤ 45 years old. METHODS: This study selected 154 young gastric cancer patients aged ≤ 45 years old and 158 elderly gastric cancer patients aged > 50 years old admitted to West China Hospital of Sichuan University in 2009-2019 as the research object. These patients were further divided into two groups according to whether tumor can be resected radically. The following parameters were analyzed: age, gender, helicobacter pylori (HP) infection status, Her-2 status, pathological type and stage, chemotherapy, tumor differentiation degree, overall survival (OS). RESULTS: More than 3,000 patients with gastric carcinoma were screened, and 154 young gastric cancer patients aged ≤ 45 years old were identified as EOGC. Among them, the number of female patients in EOGC group was significantly higher than that of males, accounting for 63.6%. In addition, EOGC were associated with diffuse Laur´en type and poorly differentiated tumors. Interestingly, the Kaplan-Meier method showed that the OS of unresectable EOGC group was significantly lower than that of unresectable LOGC group (P = 0.0005) and chemotherapy containing paclitaxel tended to be more effective in the young people (P = 0.0511). Nevertheless, there was no significant difference in OS between young and elderly patients with gastric cancer in the radical resection group (P = 0.3881). CONCLUSION: EOGC patients have a worse prognosis than late-onset gastric cancer (LOGC) patients with advanced unresectable gastric cancer. Palliative surgery or chemotherapy containing paclitaxel may improve the OS of unresectable young individuals with gastric cancer. Additional randomized controlled trials are required for guiding clinical practice.

Statins Mitigate Stress-Related Vascular Aging and Atherosclerosis in apoE-Deficient Mice Fed High Fat-Diet: The Role of Glucagon-Like Peptide-1/Adiponectin Axis.

OBJECTIVES: Exposure to chronic psychosocial stress is a risk factor for atherosclerotic cardiovascular diseases. Given that the 3-hydroxy-3-methylglutaryl-coenzyme reductase inhibitor statins prevent atherogenesis, we evaluated whether pitavastatin prevents chronic stress- and high fat diet-induced vascular senescence and atherogenesis in apolipoprotein E-deficient (ApoE -/-) mice, with a special focus on glucagon-like peptide-1 (GLP-1)/adiponectin (APN) axis. METHODS AND RESULTS: 6-week-old ApoE -/- mice loaded a high-fat diet were randomly assigned into non-stress (n = 12) and stress (n = 13) groups for 12 weeks. Non-stress control mice were left undisturbed. Chronic stress accelerated high fat diet-induce arterial senescence and atherosclerotic plaque growth. The chronic stress lowered the levels of circulating GLP-1 as well as adipose and plasma APN. As compared with the stress alone mice, the pitavastatin-treated mice had reduced macrophage infiltration, elastin fragments, and increased plaque collagen volume, and lowered levels of osteopontin, toll-like receptor-2/-4, macrophage chemoattractant protein-1, C-X-C chemokine receptor-4, p47 phox , p47 phox , gp91 phox , cathepsins S, p16, and p21, mRNAs and/or proteins. Pitavastatin increased plasma GLP-1 and APN levels and suppressed matrix metalloproteinase-2/-9 gene expressions and activities in the aortas. Finally, the protective effect of pitavastatin was abrogated by APN blocking. CONCLUSION: These findings suggested that the pitavastatin-mediated pleiotropic vasculoprotective effects are likely attributable, at least in part, to the elevation of GLP-1 and APN levels and the inhibition of diet-induced plaque inflammation, oxidative stress, and proteolysis in ApoE -/- mice received chronic stress conditions.

Locally advanced gastroesophageal junction cancer with pathological complete response to neoadjuvant therapy: a case report and literature review.

Most gastric cancer and gastroesophageal junction carcinoma (GEJ) patients are already in the advanced stage at the time of diagnosis. Thus, the probability of radical gastrectomy is low, and surgical treatment alone has a poor prognosis due to the high recurrence rate. In order to reduce the recurrence and distant metastasis after surgery, there have been many attempts made to improve the perioperative treatment of advanced localized gastric cancer, but no uniform criteria exist. Over recent years, immunotherapy has revolutionized cancer treatment, and immune checkpoint inhibitors (ICIs) have shown excellent efficacy across various types of tumors, becoming a potential treatment after surgery, chemotherapy, radiotherapy, and targeted therapy. However, the efficacy of single-agent ICIs for gastric cancer is still unsatisfactory. As comprehensive, chemotherapy-based treatment has become the standard care for locally advanced gastric cancer, exploring combination treatment with immune checkpoint inhibitors (ICIs) may be valuable to improving survival outcomes. Here, we report a 66-year-old male with dysphagia diagnosed with GEJ and was defined as clinical stage (cT4N2M0) and Siewert type II, characterized as mismatch repair proficient (pMMR) and programmed cell death ligand-1 (PD-L1) negative; surprisingly, with anti-PD-1 antibody plus SOX (S-1: a combination of tegafur, gimeracil, and oteracil+ oxaliplatin) as perioperative therapy, the patient achieved pathological complete remission (pCR), which indicates that the addition of ICIs to chemotherapy as a perioperative comprehensive treatment might provide a promising strategy option for GEJ. In addition, we review the current status of perioperative comprehensive treatment, in hope that this may provide some reference value for clinical decision-making.

Progress and Challenges of Predictive Biomarkers for Immune Checkpoint Blockade.

Over the past decade, immune checkpoint blockade (ICB) therapy has revolutionized the outlook for oncology with significant and sustained improvement in the overall patient survival. Unlike traditional cancer therapies, which target the cancer cells directly, ICB acts on the immune system to enhance anti-tumoral immunity. However, the response rate is still far from satisfactory and most patients are refractory to such treatment. Unfortunately, the mechanisms underlying such heterogeneous responses between patients to ICB therapy remain unclear. In addition, escalating costs of cancer care and unnecessary immune-related adverse events also are pertinent considerations with applications of ICB. Given these issues, identifying explicit predictive biomarkers for patient selection is an urgent unmet need to increase the efficacy of ICB therapy. The markers can be classified as tumor related and non-tumor-related biomarkers. Although substantial efforts have been put into investigating various biomarkers, none of them has been found to be sufficient for effectively stratifying patients who may benefit from immunotherapy. The present write up is an attempt to review the various emerging clinically relevant biomarkers affecting the efficacy of immune checkpoint inhibitors, as well as the limitations associated with their clinical application.

A Highlight of the Mechanisms of Immune Checkpoint Blocker Resistance.

In recent years, as our understanding of tumor immunology is continuously improved, immunotherapy has come to the center stage of cancer therapy and is deemed as the most promising approach for cancer control. Although immunotherapy, particularly immune checkpoint blockade (ICB), has achieved a milestone in several types of tumors, the majority of cancer patients do not benefit from immunotherapy. The dismal outcome of cancer immunotherapy is mainly due to primary or acquired resistance arising from tumor immune evasion. Exploring the mechanisms of tumor immune evasion in the course of immunotherapy may identify biological targets to conquer tumor resistance to immunotherapy. In this review, we highlight tumor cell-intrinsic and -extrinsic factors that may underlie tumor resistance to immune checkpoint blockers. Targeting these factors in combination with immune checkpoint blockers points to the future direction of cancer immunotherapy.

PLF-1 (Proliferin-1) Modulates Smooth Muscle Cell Proliferation and Development of Experimental Intimal Hyperplasia.

Background Although apoptosis and cell proliferation have been extensively investigated in atherosclerosis and restenosis postinjury, the communication between these 2 cellular events has not been evaluated. Here, we report an inextricable communicative link between apoptosis and smooth muscle cell proliferation in the promotion of vascular remodeling postinjury. Methods and Results Cathepsin K-mediated caspase-8 maturation is a key initial step for oxidative stress-induced smooth muscle cell apoptosis. Apoptotic cells generate a potential growth-stimulating signal to facilitate cellular mass changes in response to injury. One downstream mediator that cathepsin K regulates is PLF-1 (proliferin-1), which can potently stimulate growth of surviving neighboring smooth muscle cells through activation of PI3K/Akt/p38MAPK (phosphatidylinositol 3-kinase/protein kinase B/p38 mitogen-activated protein kinase)-dependent and -independent mTOR (mammalian target of rapamycin) signaling cascades. We observed that cathepsin K deficiency substantially mitigated neointimal hyperplasia by reduction of Toll-like receptor-2/caspase-8-mediated PLF-1 expression. Interestingly, PLF-1 blocking, with its neutralizing antibody, suppressed neointima formation and remodeling in response to injury in wild-type mice. Contrarily, administration of recombinant mouse PLF-1 accelerated injury-induced vascular actions. Conclusions This is the first study detailing PLF-1 as a communicator between apoptosis and proliferation during injury-related vascular remodeling and neointimal hyperplasia. These data suggested that apoptosis-driven expression of PLF-1 is thus a novel target for treatment of apoptosis-based hyperproliferative disorders.