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Siglec-7 (sialic acid–binding immunoglobulin-like lectin 7) is an immune checkpoint-like glycan recognition protein on natural killer (NK) cells. Cancer cells often upregulate Siglec ligands to subvert immunosurveillance, but the molecular basis of Siglec ligands has been elusive. In this study, we investigated Siglec-7 ligands on chronic lymphocytic leukemia (CLL) B cells. CLL B cells express higher levels of Siglec-7 ligands compared with healthy donor B cells, and enzymatic removal of sialic acids or sialomucins makes them more sensitive to NK cell cytotoxicity. Gene knockout experiments have revealed that the sialyltransferase ST6GalNAc-IV is responsible for the biosynthesis of disialyl-T (Neu5Acα2–3Galβ1–3[Neu5Acα2–6]GalNAcα1–), which is the glycotope recognized by Siglec-7, and that CD162 and CD45 are the major carriers of this glycotope on CLL B cells. Analysis of public transcriptomic datasets indicated that the low expression of GCNT1 (encoding core 2 GlcNAc transferase, an enzyme that competes against ST6GalNAc-IV) and high expression of ST6GALNAC4 (encoding ST6GalNAc-IV) in CLL B cells, together enhancing the expression of the disialyl-T glycotope, are associated with poor patient prognosis. Taken together, our results determined the molecular basis of Siglec-7 ligand overexpression that protects CLL B cells from NK cell cytotoxicity and identified disialyl-T as a potential prognostic marker of CLL.

Ovarian cancer is commonly fatal and incidence has persistently risen in Taiwan over the past 20 years. Prevention strategies, however, are limited. Pelvic inflammatory disease (PID) has been suggested to increase the risk of developing ovarian cancer, but the results of studies have been inconsistent. Therefore, we investigated whether PID increases the risk of developing ovarian cancer in a large, nationwide cohort. From the Longitudinal Health Insurance Database 2005 (LHID2005) in Taiwan, we obtained data for women aged 13–65 years for whom a diagnosis of PID, confirmed by multiple episodes, had been recorded between Jan 1, 2004, and Dec 31, 2005. We also obtained data for two controls per patient, matched for age and the year of first entry into the LHID2005. All patients were followed up from the date of entry in the LHID2005 until they developed ovarian cancer or to the end of 2006, whichever was earlier. We used Cox's regression models to assess the risk of developing ovarian cancer, with adjustment for age, comorbid disorders, and socioeconomic characteristics. We identified 67 936 women with PID and 135 872 controls. Among these 90 had developed ovarian cancer during the 3-year follow-up period (42 patients with PID and 48 controls, incidence 2·78 and 1·44 per 10 000 person-years, respectively). The adjusted hazard ratio for ovarian cancer in patients with PID was 1·92 (95% CI 1·27–2·92) compared with controls, which rose to 2·46 (1·48–4·09) in women who had had at least five episodes of PID. The adjusted hazard ratio was slightly higher for women aged 35 years or younger with PID than in older women with PID (2·23, 1·02–4·79 vs 1·82, 1·10–3·04). We found an association between PID and ovarian cancer. PID might, therefore, be a useful marker for ovarian cancer, and early treatment could help to improve prognosis. Whether pelvic inflammation itself accelerates the growth of ovarian cancers or affects cancer-cell differentiation in ways that adversely alter prognosis needs to be investigated. None.

In this study, we used a systems biology approach to investigate changes in the proteome and metabolome of shrimp hemocytes infected by the invertebrate virus WSSV (white spot syndrome virus) at the viral genome replication stage (12 hpi) and the late stage (24 hpi). At 12 hpi, but not at 24 hpi, there was significant up-regulation of the markers of several metabolic pathways associated with the vertebrate Warburg effect (or aerobic glycolysis), including glycolysis, the pentose phosphate pathway, nucleotide biosynthesis, glutaminolysis and amino acid biosynthesis. We show that the PI3K-Akt-mTOR pathway was of central importance in triggering this WSSV-induced Warburg effect. Although dsRNA silencing of the mTORC1 activator Rheb had only a relatively minor impact on WSSV replication, in vivo chemical inhibition of Akt, mTORC1 and mTORC2 suppressed the WSSV-induced Warburg effect and reduced both WSSV gene expression and viral genome replication. When the Warburg effect was suppressed by pretreatment with the mTOR inhibitor Torin 1, even the subsequent up-regulation of the TCA cycle was insufficient to satisfy the virus's requirements for energy and macromolecular precursors. The WSSV-induced Warburg effect therefore appears to be essential for successful viral replication.

Background Clinical evidence for the rapidity and effectiveness of fentanyl buccal soluble film (FBSF) in reducing pain intensity of breakthrough cancer pain (BTcP) remains inadequate. This study aimed to evaluate the efficacy of FBSF proportional to the around-the‐clock (ATC) opioid regimens in rapidly relieving the intensity of BTcP episodes by determining the percentage of patients requiring further dose titration. Methods The study procedure included a dose-finding period followed by a 14-day observation period. Pain intensity was recorded with a Numeric Rating Scale (NRS) at onset and 5, 10, 15, and 30 min after FBSF self-administration. Meaningful pain relief was defined as the final NRS score ≤ 3. Satisfaction survey was conducted for each patient after treatment using the Global Satisfaction Scale. Results A total of 63 BTcP episodes occurred in 30 cancer patients. Only one patient required rescue medication at first BTcP episode and then achieved meaningful pain relief after titrating FBSF by 200 µg. Most BTcP episodes relieved within 10 min. Of 63 BTcP episodes, 30 (47.6%), 46 (73.0%), and 53 (84.1%) relieved within 5, 10, and 15 min after FBSF administration. Only grade 1/2 adverse events were reported, including somnolence, malaise, and dizziness. Of the 63 BTcP episodes, 82.6% were rated as excellent/good satisfaction with FBSF. Conclusion FBSF can be administrated “on demand” by cancer patients at the onset of BTcP, providing rapid analgesia by achieving meaningful pain relief within 10 min. Trial registration This study was retrospectively registered 24 December, 2021 at Clinicaltrial.gov (NCT05209906): https://clinicaltrials.gov/study/NCT05209906 .

Fatigue is a common and debilitating symptom in patients with advanced cancer, resulting in poor quality of life and reduced treatment efficacy. Phytotherapeutic agents have shown potential effects to relieve cancer-related fatigue in these patients. The aim of this study was to evaluate the efficacy and safety of Astragalus Polysaccharides injection and identify predictive factors associated with this treatment. Patients with advanced cancer receiving palliative care with moderate to severe cancer-related fatigue were enrolled in this study for two treatment cycles. Fatigue improvement response rates were analyzed as the primary endpoint at the end of the first cycle to determine treatment efficacy. The drug safety profile was evaluated by the reporting of adverse events. Three hundred and ten patients were enrolled in this study and 214 patients were included ITT population. Improvement in fatigue scores by at least 10% was observed in greater than 65% of subjects after one treatment cycle compared to scores at baseline. Patients with higher Karnofsky Performance Status (KPS) responded better to the Astragalus Polysaccharides injection. Drug-related adverse event rates were less than 9%. This study identified KPS as a promising predictive factor for the therapeutic efficacy of Astragalus Polysaccharides injection.

Background Siglecs-11 and -16 are members of the sialic acid recognizing Ig-like lectin family, and expressed in same cells. Siglec-11 functions as an inhibitory receptor, whereas Siglec-16 exhibits activating properties. In humans, SIGLEC11 and SIGLEC16 gene sequences are extremely similar in the region encoding the extracellular domain due to gene conversions. Human SIGLEC11 was converted by the nonfunctional SIGLEC16P allele, and the converted SIGLEC11 allele became fixed in humans, possibly because it provides novel neuroprotective functions in brain microglia. However, the detailed evolutionary history of SIGLEC11 and SIGLEC16 in other primates remains unclear. Results We analyzed SIGLEC11 and SIGLEC16 gene sequences of multiple primate species, and examined glycan binding profiles of these Siglecs. The phylogenetic tree demonstrated that gene conversions between SIGLEC11 and SIGLEC16 occurred in the region including the exon encoding the sialic acid binding domain in every primate examined. Functional assays showed that glycan binding preference is similar between Siglec-11 and Siglec-16 in all analyzed hominid species. Taken together with the fact that Siglec-11 and Siglec-16 are expressed in the same cells, Siglec-11 and Siglec-16 are regarded as paired receptors that have maintained similar ligand binding preferences via gene conversions. Relaxed functional constraints were detected on the SIGLEC11 and SIGLEC16 exons that underwent gene conversions, possibly contributing to the evolutionary acceptance of repeated gene conversions. The frequency of nonfunctional SIGLEC16P alleles is much higher than that of SIGLEC16 alleles in every human population. Conclusions Our findings indicate that Siglec-11 and Siglec-16 have been maintained as paired receptors by repeated gene conversions under relaxed functional constraints in the primate lineage. The high prevalence of the nonfunctional SIGLEC16P allele and the fixation of the converted SIGLEC11 imply that the loss of Siglec-16 and the gain of Siglec-11 in microglia might have been favored during the evolution of human lineage.

Background Although beta blockers, such as metoprolol, have been widely used in the management of vasovagal syncope (VVS), their efficacy remains debated, with larger studies showing limited benefit. Identifying patient-specific characteristics that predict a positive response to metoprolol could optimize its use. This study aims to investigate the key factors that may determine which VVS patients are suitable candidates for metoprolol treatment. Methods This retrospective study was conducted at a single center. Patients diagnosed with VVS and treated with metoprolol for a minimum of three months were included. A 50% reduction in syncope symptom score (SS) after three months of metoprolol treatment was used to define metoprolol responders, while those who did not achieve this reduction were classified as non-responders. After a three-month follow-up, patients were divided into two groups: responders and non-responders. Baseline data—including age, gender, comorbidities, laboratory tests, and the type of VVS—were analyzed for each patient. Changes in heart rate (HR) and blood pressure during the head-up tilt test (HUTT) were also evaluated between the two groups. Logistic regression analysis was performed to identify potential predictors of metoprolol response, and receiver operating characteristic (ROC) curve analysis was used to assess the value of these predictors in selecting potential responders. Results A total of 168 VVS patients were enrolled between January 2016 and December 2020. Of these, 100 patients responded positively to metoprolol, while 68 did not. No significant differences in baseline characteristics or HUTT results were observed between the two groups ( p  > 0.05). However, responders exhibited a significantly higher peak HR compared to non-responders during the HUTT (120.13 ± 19.33 vs. 106.60 ± 22.32, p  < 0.001). The increase in HR was also more pronounced in responders (0.60 ± 0.23 vs. 0.41 ± 0.25, p  < 0.001). Additionally, HR variability was significantly greater in responders than in non-responders (16.18 ± 5.51 vs. 12.61 ± 5.50, p  < 0.001). Conclusion Higher peak HR, larger increases in HR, and greater HR variability during the HUTT may serve as reliable predictors of a positive response to metoprolol in patients with VVS.

In the medieval and early modern periods, Spain shaped a global empire from scattered territories spanning Europe, Africa, and the Americas. Historians either have studied this empire piecemeal-one territory at a time-or have focused on monarchs endeavoring to mandate the allegiance of far-flung territories to the crown. For Yuen-Gen Liang, these approaches do not adequately explain the forces that connected the territories that the Spanish empire comprised. InFamily and Empire, Liang investigates the horizontal ties created by noble family networks whose members fanned out to conquer and subsequently administer key territories in Spain's Mediterranean realm. Liang focuses on the Fernández de Córdoba family, a clan based in Andalusia that set out on mobile careers in the Spanish empire at the end of the fifteenth century. Members of the family served as military officers, viceroys, royal councilors, and clerics in Algeria, Navarre, Toledo, Granada, and at the royal court. Liang shows how, over the course of four generations, their service vitally transformed the empire as well as the family. The Fernández de Córdoba established networks of kin and clients that horizontally connected disparate imperial territories, binding together religious communities-Christians, Muslims, and Jews-and political factions-Comunero rebels and French and Ottoman sympathizers-into an incorporated imperial polity. Liang explores how at the same time dedication to service shaped the personal lives of family members as they uprooted households, realigned patronage ties, and altered identities that for centuries had been deeply rooted in local communities in order to embark on imperial careers.

Protein phosphorylation can induce signal transduction to change sperm motility patterns during sperm capacitation. However, changes in the phosphorylation of sperm proteins in mice are still incompletely understood. Here, capacitation-related phosphorylation in mouse sperms were firstly investigated by label-free quantitative (LFQ) phosphoproteomics coupled with bioinformatics analysis using ingenuity pathway analysis (IPA) methods such as canonical pathway, upstream regulator, and network analysis. Among 1632 phosphopeptides identified at serine, threonine, and tyrosine residues, 1050 novel phosphosites, corresponding to 402 proteins, were reported. Gene heatmaps for IPA canonical pathways showed a novel role for GSK-3 in GP6 signaling pathways associated with capacitation for 60 min. At the same time, the reduction of the abundant isoform-specific GSK-3α expression was shown by western blot (WB) while the LFQ pY of this isoform slightly decreased and then increased. The combined results from WB and LFQ methods explain the less inhibitory phosphorylation of GSK-3α during capacitation and also support the predicted increases in its activity. In addition, pAKAP4 increased at the Y156 site but decreased at the Y811 site in a capacitated state, even though IPA network analysis and WB analysis for overall pAKAP revealed upregulated trends. The potential roles of GSK-3 and AKAP4 in fertility are discussed.

Heterozygosity for missense mutations in 1 of 3 seemingly redundant calmodulin-encoding (CALM-encoding) genes can cause life-threatening arrhythmias, suggesting that small fractions of mutant CALM protein suffice to cause a severe phenotype. However, the exact molar ratios of wild-type to mutant CALM protein in calmodulinopathy hearts remain unknown. The aim of the present study was to quantitate mutant versus wild-type CALM transcript and protein levels in hearts of knockin mice harboring the p.N98S mutation in the Calm1 gene. We found that the transcripts from the mutant Calm1 allele were the least abundantly expressed Calm transcripts in both hetero- and homozygous mutant hearts, while mutant hearts accumulated high levels of N98S-CALM protein in a Calm1N98S allele dosage-dependent manner, exceeding those of wild-type CALM protein. We further show that the severity of the electrophysiological phenotype incrementally increased with the graded increase in the mutant/wild-type CALM protein expression ratio seen in homozygous versus heterozygous mutant mice. We finally show a decrease in N98S-CALM protein degradation, suggesting that mutant CALM stabilization contributed to its enrichment in the heart. Our results support what we believe to be a novel mechanism by which a mutation in a single Calm gene can give rise to a severe phenotype.