Previous studies have suggested that statins can be repurposed for cancer treatment. However, the therapeutic efficacy of statins in chronic myeloid leukemia (CML) has not yet been demonstrated. In ...this study, we retrospectively evaluated the outcomes of 408 CML patients who underwent imatinib therapy. The deep molecular response rates in patients treated with the statin/TKI combination were significantly higher than those in patients treated with TKI alone (p = 0.0016). The statin/TKI combination exerted potent cytotoxic effects against wild-type and ABL1 mutant CML, BaF3, and K562/T315I mutant cells. Furthermore, the statin/TKI combination additively inhibited the colony-forming capacity of murine CML-KLS+ cells in vitro. In addition, we examined the additive growth-inhibitory effects of the statin/tyrosine kinase inhibitor (TKI) combination against CML patient-derived CD34+ cells. The growth-inhibitory effects of the statin/imatinib combination against CD34+/CML primary cells were higher than those against CD34+/Norm cells (p = 0.005), suggesting that the combination of rosuvastatin and imatinib exerted growth-inhibitory effects against CML CD34+ cells, but not against normal CD34+ cells. Furthermore, results from RNA sequencing of control and statin-treated cells suggested that statins inhibited c-Myc-mediated and hematopoietic cell differentiation pathways. Thus, statins can be potentially repurposed to improve treatment outcomes in CML patients when combined with TKI therapy.
Programmed death ligand 1 (PD-L1) plays a pivotal role in cancer immune evasion and is a critical target for cancer immunotherapy. This review focuses on the regulation of PD-L1 through the dynamic ...processes of ubiquitination and deubiquitination, which are crucial for its stability and function. Here, we explored the intricate mechanisms involving various E3 ubiquitin ligases and deubiquitinating enzymes (DUBs) that modulate PD-L1 expression in cancer cells. Specific ligases are discussed in detail, highlighting their roles in tagging PD-L1 for degradation. Furthermore, we discuss the actions of DUBs that stabilize PD-L1 by removing ubiquitin chains. The interplay of these enzymes not only dictates PD-L1 levels but also influences cancer progression and patient response to immunotherapies. Furthermore, we discuss the therapeutic implications of targeting these regulatory pathways and propose novel strategies to enhance the efficacy of PD-L1/PD-1-based therapies. Our review underscores the complexity of PD-L1 regulation and its significant impact on the tumor microenvironment and immunotherapy outcomes.
Shrimp is one of the most valuable aquaculture species globally, and the most internationally traded seafood product. Consequently, shrimp aquaculture practices have received increasing attention due ...to their high value and levels of demand, and this has contributed to economic growth in many developing countries. The global production of shrimp reached approximately 6.5 million t in 2019 and the shrimp aquaculture industry has consequently become a large-scale operation. However, the expansion of shrimp aquaculture has also been accompanied by various disease outbreaks, leading to large losses in shrimp production. Among the diseases, there are various viral diseases which can cause serious damage when compared to bacterial and fungi-based illness. In addition, new viral diseases occur rapidly, and existing diseases can evolve into new types. To address this, the review presented here will provide information on the DNA and RNA of shrimp viral diseases that have been designated by the World Organization for Animal Health and identify the latest shrimp disease trends.
Background
In this post hoc analysis of the PRODIGY study, we aimed to investigate factors associated with survival outcomes and provide evidence for designing optimal perioperative treatment ...strategies for gastric cancer patients receiving neoadjuvant chemotherapy.
Patients and methods
A total of 212 patients in the neoadjuvant chemotherapy group of the PRODIGY study were included as the study population. The prognostic impact of clinicopathologic factors, including the initial radiological clinical stage (cStage) and post-neoadjuvant chemotherapy pathological stage (ypStage), was analyzed.
Results
The median age was 58 years. The majority of patients (77.4%) had cStage III disease, and about 10% and 25% had ypStage 0 and I disease, respectively. According to the initial cStage, progression-free survival (PFS) and overall survival (OS) were significantly different (
P
< 0.01). PFS and OS were also different according to the ypStage (
P
< 0.01). In multivariate analyses, cStage IIIC disease (vs. cStage II) and ypStage II and III disease (vs. ypStage 0/I) were independent factors for poor survival outcomes. Based on the patterns of PFS and OS according to both cStage and ypStage, three patient groups were defined. These groups showed distinct PFS and OS (
P
< 0.01) with 5-year PFS rates of 95.7%, 77.9%, and 31.3% and 5-year OS rates of 95.7%, 82.4%, and 42.5%, respectively.
Conclusions
Both initial cStage and ypStage were independent factors for survival outcomes of gastric cancer patients treated with neoadjuvant chemotherapy. Efforts should be made to develop optimal peri-operative treatment strategies for patients at different risks according to cStage and ypStage.
Olfactory receptors (ORs) account for 49% of all G protein-coupled receptors (GPCRs), which are important targets for drug discovery, and hence ORs may also be potential drug targets. Various ORs are ...expressed in breast cancer cells; however, most of them are orphan receptors, and thus, their functions are unknown. Herein, we present an experimental strategy using a surface plasmon resonance (SPR) system and a cell-based assay that allowed the identification of orphan OR6M1 as a new anticancer target in the MCF-7 breast cancer cell line. After the construction of stable OR6M1-expressing cells, the SPR-based screening of 108 chemicals for ligand activity was performed against OR6M1-expressing whole cells (primary screening) or membrane fragments (secondary screening). As a result, anthraquinone (AQ) and rutin were discovered to be new OR6M1 ligands. Based on calcium imaging in OR6M1-expressing Hana3A cells, AQ and rutin were classified as an OR6M1 agonist and antagonist, respectively. Cell viability and live/dead assays showed that AQ induced the death of MCF-7 cells, which was inhibited by rutin. Therefore, OR6M1 may be considered an anticancer target, and AQ may be considered a chemotherapeutic agent. This combined method can be widely used to discover the ligands and functions of other orphan GPCRs.
Background
There is increasing interest in the influence of body composition on oncological outcomes. We evaluated the role of skeletal muscle and fat among patients with gastric cancer (GC) who ...underwent gastrectomy with or without adjuvant chemotherapy, as well as those changes’ associations with survival outcomes.
Methods
The present study evaluated 136 patients with GC who were enrolled in the CLASSIC Trial at Yonsei Cancer Center. Baseline body compositions including skeletal muscle area, Hounsfield units (HU), visceral fat area, and subcutaneous fat area were measured by preoperative computed tomography (CT). CT before and after the gastrectomy were used to determine the 6-month relative changes in body composition parameters. Continuous variables were dichotomized according to the best cutoff values by Contal and O’Quigley method.
Results
Seventy-three patients (53.7%) underwent surgery alone, and 63 patients (46.3%) underwent surgery followed by adjuvant chemotherapy. The baseline body composition parameters were not associated with disease-free survival (DFS) or overall survival (OS). Except for the HU, the marked loss of muscle, visceral fat, or subcutaneous fat significantly predicted shorter DFS and OS. Patients with a marked loss in at least one significant body composition parameter had significantly shorter DFS (hazard ratio 2.9, 95% confidence interval 1.7–4.8,
P
< 0.001) and OS (hazard ratio 2.9, 95% confidence interval 1.7–5.0,
P
< 0.001).
Conclusions
Marked loss in body composition parameters significantly predicted shorter DFS and OS among patients with GC who underwent gastrectomy. Postoperative nutrition and active healthcare interventions could improve the prognosis of these GC patients.
Background
Mucinous gastric adenocarcinoma (MGC) is a rare but distinctive histologic subtype of gastric cancer (GC). The clinico-pathologic and genomic characteristics of MGC have not been well ...evaluated.
Methods
We collected individual data from five cohorts targeting the microsatellite instability (MSI) of GC (
n
= 5089) to evaluate the clinico-pathologic characteristics of MGC. In addition, public genomic databases were used for genomic analysis. The characteristics of MGC were compared with those of non-mucinous GC (NMGC).
Results
MGC (
n
= 158, 3.1%) showed distinctive characteristics in terms of age, sex, and TNM stage compared to NMGC (
n
= 4931). MGC was frequently associated with MSI-high (OR: 2.24, 95% confidence interval CI 1.44–3.40,
p
< 0.001), while mutually exclusive to the Epstein–Barr virus type. The prognosis of MGC was better than that of NMGC (adj.HR: 0.731, 95% CI 0.556–0.962,
p
= 0.025). There was no clear benefit from postoperative chemotherapy in MGC.
TP53
was the main driver mutation in the MGC without recurrent variants. MGC was related to high expression of
GPR120
and
B3GNT6
and moderate regulation of epithelial–mesenchymal transition (EMT)-up signature with a high EMT-down signature, and those characteristics was related to favorable prognosis of GC (log-rank
p
= 0.044,
p
< 0.001,
p
< 0.001, respectively). MSI-H of MGC was associated with low cancer-associate fibroblasts but high
CD274
(PD-L1) expression compared to microsatellite stable MGC, suggesting that immune checkpoint inhibitors may be useful for the MSI-H of MGC.
Conclusion
MGC could be a surrogate for performing MSI but not the EBV test in GC. Further, its genetic characteristics lead to a favorable prognosis for MGC.
Nonalcoholic fatty liver disease (NAFLD) is an important health concern worldwide and progresses into nonalcoholic steatohepatitis (NASH). Although prevalence and severity of NAFLD/NASH are higher in ...men than premenopausal women, it remains unclear how sex affects NAFLD/NASH pathophysiology. Formyl peptide receptor 2 (FPR2) modulates inflammatory responses in several organs; however, its role in the liver is unknown. Here we show that FPR2 mediates sex-specific responses to diet-induced NAFLD/NASH. NASH-like liver injury was induced in both sexes during choline-deficient, L-amino acid-defined, high-fat diet (CDAHFD) feeding, but compared with females, male mice had more severe hepatic damage. Fpr2 was more highly expressed in hepatocytes and healthy livers from females than males, and FPR2 deletion exacerbated liver damage in CDAHFD-fed female mice. Estradiol induced Fpr2 expression, which protected hepatocytes and the liver from damage. In conclusion, our results demonstrate that FPR2 mediates sex-specific responses to diet-induced NAFLD/NASH, suggesting a novel therapeutic target for NAFLD/NASH.
This study aims to assess various perceived adverse effects of noise on construction sites according to the different stages and machinery used in the stages, and to examine whether or not ...personal-situational factors affect the judgment of managers regarding the adverse impact of noise at work through a self-reported survey method. Four primary construction stages and twenty-four types of construction machines were evaluated. The effects of personal (noise sensitivity) and situational (types of jobs, and years of working) factors on the adverse impacts of noise on annoyance, work performance, work safety, and speech interference at work were examined. The results show significant differences in perceived noise annoyance in the various construction stages. The demolition stage is the most annoying, followed by the foundation, earthwork, and concrete framing stages. In addition, the annoying equipment differs for each construction stage. A breaker, pile driver, and hammer compactor are rated as the most annoying construction machines in the demolition, foundation, and earthwork stages, respectively. Individual noise sensitivity appears to have the most significant influence on the adverse impacts of noise on annoyance, work performance, work safety, and speech interference. A high noise sensitivity group tends to judge construction noise to be more adverse than the rest. In addition, different interrelationships between the adverse items of noise are found across their types of jobs: building construction, civil construction, and safety management. The findings of this study will provide further knowledge to facilitate better noise management planning on construction sites.
•Demolition stage is the most annoying stage on construction sites.•Machines that emits high noise level with high temporal variation are more annoying.•Noise sensitivity appears to have the most significant influence on the adverse impacts.•Significantly different correlations between the adverse impacts of noise are found across job types.
Background
The clinical relevance and general applicability of the 8th American Joint Committee on Cancer TNM gastric cancer staging system vs the 7th version have not been examined using datasets ...from both the East and West.
Methods
Patients (n = 29 984) treated for gastric adenocarcinoma at two high‐volume centers (Severance Hospital SH and Gangnam Severance Hospital GSH) in Korea and data from the Surveillance, Epidemiology, and End Results (SEER) database were retrospectively analyzed. Survival curves, the performance of tumor staging, and the homogeneity of modified subgroups were compared.
Results
Minute changes were noted in the stage IIB subgroup; most changes were noted in stage III. Applying the 8th staging system facilitated better prediction of survival than applying the 7th version for SH data according to the log‐rank test, C‐index, and AIC (8444.5 vs 9263.8, 0.796 vs 0.798, and 104152 vs 103909, respectively). Its performance was also superior for GSH and SEER data. In a subgroup analysis of stages IIB to IIIC in SH, GSH, and SEER data, the 8th staging system showed similar or more homogeneous survival for each sub‐classification than the 7th version.
Conclusion
Compared with the 7th gastric cancer staging system, the newer version more accurately predicted prognosis and stratified subgroups more homogeneously.
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