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Cryptotanshinone (CTT) is a natural product and a quinoid diterpene isolated from the root of the Asian medicinal plant, Salvia miltiorrhizabunge. Notably, CTT has a variety of anti-cancer actions, including the activation of apoptosis, anti-proliferation, and reduction in angiogenesis. We further investigated the anti-cancer effects of CTT using MTS, LDH, and Annexin V assay, DAPI staining, cell cycle arrest, and Western blot analysis in NSCLC cell lines. NSCLC cells treated with CTT reduced cell growth through PI3K/Akt/GSK3β pathway inhibition, G0/G1 cell cycle arrest, and the activation of apoptosis. CTT induced an increase of caspase-3, caspase-9, poly-ADP-ribose polymerase (PARP), and Bax, as well as inhibition of Bcl-2, survivin, and cellular-inhibitor of apoptosis protein 1 and 2 (cIAP-1 and -2). It also induced G0/G1 phase cell cycle arrest by decreasing the expression of the cyclin A, cyclin D, cyclin E, Cdk 2, and Cdk 4. These results highlight anti-proliferation the latent of CTT as natural therapeutic agent for NSCLC. Therefore, we investigated the possibility of CTT as an anti-cancer agent by comparing with GF, which is a representative anti-cancer drug.

Amphiregulin (AREG) is an epidermal growth factor receptor (EGFR) ligand. The aim of this study was to investigate the effects of baseline plasma AREG levels in KRAS , NRAS , and BRAF wild-type metastatic colorectal cancer (CRC) on treatment outcome with palliative first-line cetuximab + FOLFIRI chemotherapy. Chemotherapy outcomes were analyzed based on baseline plasma AREG levels. The clinical findings were further validated using an in vitro model of CRC. Among 35 patients, the progression-free survival (PFS) was significantly inferior in patients with high AREG than in those with low AREG levels: 10.9 vs . 24.2 months, respectively ( p  = 0.008). However, after failure of first-line chemotherapy, AREG levels were associated with neither PFS (4.8 vs. 11.6 months; p  = 0.215) nor overall survival (8.4 vs. 13.3 months; p  = 0.975). In SNU-C4 and Caco-2 cells which were relatively sensitive to cetuximab among the seven CRC cell lines tested, AREG significantly decreased the anti-proliferative effect of cetuximab ( p  < 0.05) via AKT and ERK activation. However, after acquiring cetuximab resistance with gradual exposure for more than 6 months, AREG neither increased colony formation nor activated AKT and ERK after cetuximab treatment. Our results suggest that plasma AREG is a potential biomarker to predict clinical outcomes after cetuximab-based chemotherapy.

Background Sodium-glucose cotransporter 2 (SGLT-2) inhibitors, widely used for type 2 diabetes and cardiorenal conditions, may induce erythrocytosis, potentially increasing cardiovascular risk. This study investigates its prevalence, risk factors, and thrombotic implications. Methods In a single-center retrospective study, we analyzed 6787 patients prescribed SGLT-2 inhibitors (2014–2024). Erythrocytosis was defined as hemoglobin > 16.5 g/dL or hematocrit > 49% in men, > 16.0 g/dL or > 48% in women. We assessed prevalence, risk factors, and thrombotic events using logistic regression. Results Erythrocytosis occurred in 1145 patients (16.9%) over a median follow-up of 530 days (IQR, 277–981), with a median hemoglobin rise of 1.0 g/dL (IQR, 0.4–1.8). Male sex (OR 3.24, 95% CI 2.47–4.26), BMI ≥ 25 kg/m 2 (OR 1.97, 95% CI 1.63–2.39), and current smoking (OR 2.41, 95% CI 1.96–2.96) significantly increased risk (all p < 0.001), while age ≥ 70 years, hypertension, dyslipidemia, and chronic kidney disease were associated with reduced risk. Thrombosis was rare (0.5%, 33 patients) and associated with antiplatelet use (OR 3.57, 95% CI 1.60–7.97), anticoagulant use (OR 5.93, 95% CI 2.60–13.57), and baseline erythrocytosis (OR 3.75, 95% CI 1.41–9.96). Among 33 patients with thrombosis, five exhibited erythrocytosis at the time of the event and within the prior six months; all had arterial thrombosis associated with underlying conditions (atrial fibrillation, coronary calcification, atherosclerosis), not directly attributable to SGLT-2-induced erythrocytosis. Conclusions SGLT-2 inhibitors are associated with a 16.9% prevalence of erythrocytosis, but thrombotic risk appears primarily driven by pre-existing conditions. Graphical abstract

Galactomannan (GM) is a polysaccharide cell wall component released by Aspergillus spp., and an immunoenzymatic GM assay is used for the diagnosis of invasive pulmonary aspergillosis. We evaluated the cause of strong positivity for GM in patients with no typical signs of aspergillosis. Repeat assays were performed using different instruments and reagent lots, but there were no differences in results among the assays. Patients with strongly positive GM results were investigated. Medication histories revealed that 14 of 23 patients had been administered total parenteral nutrition solution from one manufacturer and 4 patients had been administered dextrose solution from a different manufacturer before being tested. The results of GM assays conducted on samples of dextrose solution and the glucose fraction of the total parenteral nutrition solution were strongly positive, confirming the causes of the false-positive reactions. We hypothesize that a trace amount of GM was introduced into the glucose-containing solutions because glucoamylase, which is necessary for the saccharification step of glucose synthesis, was derived from Aspergillus niger . To enhance patient care and prevent unnecessary antifungal prescriptions, healthcare providers and manufacturers of healthcare products need to be aware of the possibility of false-positive reactions for GM.

Background Preclinical data have shown the immunomodulatory effects of metformin and dipeptidyl peptidase 4 (DPP4) inhibitors in patients with diabetes. However, its clinical impact remains unclear in lung cancer. Methods Between 2017 and 2021, 466 patients received ICI monotherapy. Patients were categorized into concurrent (MET; metformin or combination of metformin and DPP4 inhibitor) and without concomitant (NMET; nonmetformin/DPP4 inhibitors) administration of metformin and DPP4 inhibitors groups at least 8 weeks before and during ICI therapy. The primary objectives were the objective response rate (ORR) and progression‐free survival (PFS). The second objective was to evaluate the overall survival (OS) and the occurrence of immune‐related adverse events (irAEs). Results Among 466 patients, 89 (19.0%) and 377 (81%) were categorized into the MET and NMET groups, respectively. MET group had a significantly higher ORR (MET group: 24.7% vs. NMET group: 14.8%, p = 0.025) and longer PFS than those in the NMET group (MET group 5.1 month vs. NMET group 2.8 months, p = 0.018). After patients were stratified based on the prior line of therapy and PD L1 expression status, the PFS of the second‐line therapy and PD L1 ≥50 was significantly higher in the MET than in the NMET group. The proportion of patients experiencing all‐grade irAEs was numerically higher in the MET group (19.1%) than in the NMET group (14.3%), without statistical significance (p = 0.382). Conclusions Concurrent use of metformin and DPP4 inhibitors with ICIs significantly improved the clinical outcomes without increasing the incidence of irAEs in NSCLC.

PurposeSome metastatic colorectal cancer (mCRC) patients receive conversion surgery (CS), including metastasectomy after palliative chemotherapy. Although targeted agents significantly improved the outcomes, the clinical outcome of CS in the targeted agent era has not yet been thoroughly investigated.MethodsWe analyzed the clinical data of 96 mCRC patients who initially had unresectable liver- and/or lung-limited metastases and underwent first-line cetuximab or bevacizumab plus FOLFIRI between January 2013 and June 2017.ResultsLiver-limited metastasis was seen in 44 patients (45.8%), lung-limited metastases in 21 patients (21.9%), and both liver and lung metastases in 31 patients (32.3%). Among them, 37 patients (38.5%) received cetuximab, and 59 patients (61.5%) received bevacizumab plus FOLFIRI. Overall response rate was 63.9% and 40.7%, respectively (p = 0.035). After median 8.7 (range 2.5–27.3) months, CS was performed in 11 patients (29.7%) in cetuximab group and 15 patients (25.4%) in bevacizumab group (p = 0.646). Median overall survival has not been reached in R0-resected patients (n = 23), during the median follow-up period of 22.5 (range 9.8–54.5) months. Median disease-free survival was 7.1 (95% CI 2.5–11.7) months: 11.0 (95% CI 3.1–19.0) months in cetuximab group and 3.2 (95% CI 0.0–7.8) months in bevacizumab group (p = 0.422). There was no progression after 18.5 months and disease-free survival reached a plateau at 19.9%.ConclusionsA substantial proportion of patients could receive CS after cetuximab or bevacizumab plus FOLFIRI chemotherapy. R0-resected patients had excellent overall survival, although 80.1% of them eventually experienced recurrence. Some patients could achieve durable disease-free state.

This study investigates the role of Early Growth Response 1 (EGR1) in extranodal natural killer/T-cell lymphoma (ENKTL) and its correlation with PD-L1 expression. Analysis of 62 ENKTL patient samples revealed that high EGR1 expression was linked to PD-L1 positivity, the immune evasion-A subtype, and early-stage disease. Although EGR1 expression was not an independent prognostic factor for overall survival, patients with higher EGR1 levels showed a trend toward better outcomes. In ENKTL cell lines (YT, SNK6), EGR1 positively regulated LMP1 and PD-L1 expression. Knockdown of EGR1 reduced PD-L1 levels, decreased PTEN, increased AKT phosphorylation, and abrogated STAT3 phosphorylation. Conversely, EGR1 overexpression enhanced PD-L1. Treatment with the histone deacetylase inhibitor entinostat upregulated both EGR1 and PD-L1, but this effect was lost in EGR1-depleted cells, indicating EGR1’s necessity for HDAC inhibitor–induced PD-L1 expression. These findings reveal EGR1’s pivotal role in tumor immune modulation and highlight potential combination therapies targeting EGR1, epigenetic regulators, and PD-1/PD-L1 checkpoints.

We analyzed treatment outcomes and prognostic factors in adult patients with therapy-related myeloid neoplasms (t-MNs) to select patients who would be benefited by active anticancer treatment. After excluding 18 patients who received palliative care only and 13 patients with acute promyelocytic leukemia, 72 t-MN patients (45 with acute myeloid leukemia and 27 with myelodysplastic syndrome) were retrospectively evaluated. Among them, 10 (13.9%), 32 (44.4%), and 30 patients (41.7%) had favorable, intermediate- and adverse-risk cytogenetics, respectively. Among patients with intermediate-risk cytogenetics, patients with a normal karyotype (NK; N = 20) showed superior allogeneic stem cell transplantation-censored overall survival (AC-OS) and OS compared to those with non-NK-intermediate-risk cytogenetics (P < 0.001). In the multivariate analysis, male sex, age ≥ 70 years, and unfavorable cytogenetics (non-NK-intermediate plus adverse risk cytogenetics) were associated with inferior AC-OS. Those results suggest that a more-refined subdivision of risk stratification would be necessary in patients with intermediate-risk cytogenetics.

Myeloproliferative neoplasms are rare at a young age, and few reports have described the disease characteristics and outcomes in this group. This study aimed to elucidate the clinical course of essential thrombocythemia (ET) and polycythemia vera (PV) in children and young adults aged <39 years focusing on thromboembolic events (TE) and second primary malignancies (SPMs). A total of 990 patients who were diagnosed from 2008 to 2017 were included by analyzing the Health Insurance Review and Assessment Service database in Korea. The incidence was 2.53 per 1,000,000 for ET (643 patients; 276 male patients; median 31 years) and 1.37 per 1,000,000 for PV (347 patients; 309 male patients; median 32 years). Three ET patients developed secondary acute myelogenous leukemia and three developed secondary myelofibrosis. The 5-year cumulative incidence of TE was 14.2% in ET and 21.3% in PV. Thus, the incidence was higher in PV; in particular, arterial TE (ATE) was evidently higher in PV than in ET. The 5-year cumulative incidence of SPMs was 2.5% in ET and 2.6% in PV. While the use of both aspirin and hydroxyurea reduced the incidence of ATE, hydroxyurea significantly increased the incidence of SPMs. The incidence of ET and PV was very low, and ET was more common than PV in children and young adults. The high incidence of TE in young patients suggests the importance of thrombosis prevention. However, hydroxyurea appears to increase the incidence of SPMs; therefore, the risks and benefits should be considered.

Recent studies have reported that changes in gut microbiota composition could induce neuropsychiatric problems. In this study, we investigated alterations in gut microbiota induced by early-life stress (ELS) in rats subjected to maternal separation (MS; 6 h a day, postnatal days (PNDs) 1–21), along with changes in inflammatory cytokines and tryptophan-kynurenine (TRP-KYN) metabolism, and assessed the differences between sexes. High-throughput sequencing of the bacterial 16S rRNA gene showed that the relative abundance of the Bacteroides genus was increased and that of the Lachnospiraceae family was decreased in the feces of MS rats of both sexes (PND 56). By comparison, MS increased the relative abundance of the Streptococcus genus and decreased that of the Staphylococcus genus only in males, whereas the abundance of the Sporobacter genus was enhanced and that of the Mucispirillum genus was reduced by MS only in females. In addition, the levels of proinflammatory cytokines were increased in the colons (IFN-γ and IL-6) and sera (IL-1β) of the male MS rats, together with the elevation of the KYN/TRP ratio in the sera, but not in females. In the hippocampus, MS elevated the level of IL-1β and the KYN/TRP ratio in both male and female rats. These results indicate that MS induces peripheral and central inflammation and TRP-KYN metabolism in a sex-dependent manner, together with sex-specific changes in gut microbes.