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Purpose: We aimed to identify the risk factors for severe neutropenia in the early phase of trifluridine-tipiracil (FTD/TPI) treatment, and their impact on overall survival (OS)., Methods: This single-center retrospective study included patients with unresectable metastatic colorectal cancer who were treated with FTD/TPI. The primary endpoint was OS, and the secondary endpoint was severe neutropenia during the first and second cycles of FTD/TPI. We assessed the association between outcomes and potential confounders using multivariate analysis., Results: Of the 77 total patients, 33 developed severe neutropenia during the first and second treatment cycles. In Cox hazard analysis, the independent factors associated with OS were neutropenia ≥ grade 1 during cycles 1 and 2 (adjusted hazard ratio 0.43; 95% confidence interval (CI) 0.21-0.87), combined treatment with bevacizumab (0.47; 95% CI 0.27-0.83), number of metastatic organs ≥ 3 (2.15; 95% CI 1.22-3.82), and time since diagnosis of metastasis until commencement of FTD/TPI < 18 months (1.94; 95% CI 1.13-3.33). Severe neutropenia during cycles 1 and 2 was not associated with OS (0.75; 0.44-1.27). The risk of severe neutropenia adjusted for initial dose reduction was defined as renal impairment with creatinine clearance (Ccr) of < 60 ml/min (adjusted odds ratio, 4.67; 95% CI, 1.38-15.80) and absolute neutrophil count (per 1000/μl, 0.47; 0.27-0.81)., Conclusion: The neutropenia ≥ grade 1 during cycles 1 and 2 of FTD/TPI is a predictor of favorable outcomes; however, the effect of severe neutropenia on OS was not clear. Renal impairment was also associated with severe neutropenia., Competing Interests: Declarations. Conflict of interest: The authors declare no competing interests., (© 2025. The Author(s).)

Although several studies have demonstrated a potential correlation of dietary patterns with cognitive function, the relationship between tooth loss and dietary patterns and cognitive function have not been identified. In this cross-sectional study, we used a reduced rank regression (RRR) analysis, a technique used previously to observe dietary patterns based on the intakes of nutrients or levels of biomarkers associated with the condition of interest, to identify tooth loss-related dietary patterns and investigate the associations of such patterns with cognitive impairment in 334 community-dwelling Japanese subjects aged ≥ 60 years. According to Pearson correlation coefficients, the intakes of six nutrients (ash content, sodium, zinc, vitamin B1, α- and β-carotene) correlated significantly with the number of remaining teeth. Using RRR analysis, we extracted four dietary patterns in our subject population that explained 86.67% of the total variation in the intakes of these six nutrients. Particularly, dietary pattern 1 (DP1) accounted for 52.2% of the total variation. Food groups with factor loadings of ≥ 0.2 included pickled green leafy vegetables, lettuce/cabbage, green leaves vegetables, cabbage, carrots/squash; by contrast, rice had a factor loading of <-0.2. In a multivariate regression analysis, the adjusted odds ratios regarding the prevalence of cognitive impairment for the lowest, middle and highest tertiles of the DP1 score were 1.00 (reference), 1.224 (95% confidence interval [CI]: 0.611-2.453) and 0.427 (95% CI: 0.191-0.954), respectively. To our knowledge, this is the first report to show that tooth loss-related dietary patterns are associated with a high prevalence of cognitive impairment. These results may motivate changes in dental treatment and the dietary behaviours and thereby lower the risk of cognitive impairment.

Background: Regulatory T-cells (Tregs) actively engage in the maintenance of immunological self-tolerance and immune homeostasis. The purpose of the present study was to determine how oxaliplatin plus infusional 5-fluorouracil and leucovorin (FOLFOX) and irinotecan plus infusional 5-fluorouracil and leucovorin (FOLFIRI) affect Tregs and other immune effectors., Patients and Methods: A total of 27 patients with metastatic colorectal cancer received the FOLFOX (n=17) or FOLFIRI (n=10) chemotherapeutic regimen. Blood samples were collected from patients before and 7 days after chemotherapy. The prevalence of Tregs co-expressing CD4(+)FoxP3(+) was analyzed with flow cytometry., Results: The percentage and the number of CD4(+)FoxP3(+) Tregs were significantly reduced after FOLFOX and FOLFIRI in the patients who had high levels of Tregs before chemotherapy. On the other hand, the total number of lymphocytes and the population of CD4(+) T lymphocytes were unchanged., Conclusion: FOLFOX and FOLFIRI may enhance antitumor immunity via suppression of Tregs.

In the title compound, {[Cu(C(9)H(15)N(13))(2)](ClO(4))(2)}(n), the Cu(2+) cation lies on an inversion center and is coordinated by the tetra-zole N(4) atoms of six symmetry-equivalent tris-[2-(1H-tetra-zol-1-yl)eth-yl]amine ligands (t(3)z) in the form of a Jahn-Teller-distorted octa-hedron with Cu-N bond distances of 2.0210 (8), 2.0259 (8) and 2.4098 (8) Å. The tertiary amine N atom is stereochemically inactive. The cationic part of the structure, viz. [Cu(t(3)z)(2)](2+), forms an infinite two-dimensional network parallel to (100), in pockets of which the perchlorate anions reside. The individual networks are partially inter-locked and held together by C-H⋯O inter-actions to the perchlorate anions and C-H⋯N inter-actions to tetra-zole N atoms.

The title compound, C(16)H(14)N(8), is a new chiral ligand designed for applications in supra-molecular chemistry and Fe(2+) spin-crossover complexes. The crystal structure shows a herring-bone arrangement of the mol-ecules, which are mutually linked via inter-molecular C-H⋯N inter-actions mainly donated by the alkyl and tetra-zole H atoms.

Background: Although recent studies have shown that FoxP3 represent the most specific Treg marker only a few studies have reported on the presence of FoxP3(+)Treg in peripheral blood., Patients and Methods: Peripheral blood mononuclear cells (PBMC) were harvested from 37 healthy volunteers and 94 patients with gastrointestinal cancer. The prevalence of Treg co-expressing CD4(+)FoxP3(+) was analyzed using flow cytometry., Results: The prevalence of Treg in the peripheral blood of gastrointestinal cancer patients was significantly higher than that in healthy volunteers (p=0.012). In early stage I cancer, Treg levels tended to be higher than those in healthy volunteers (p=0.069); these levels were significantly reduced after tumor resection (p=0.0027)., Conclusion: The prevalence of Treg was increased in patients with gastrointestinal cancer, even in the early stages of the disease. Since Treg levels decreased after curative resection, it is possible that tumor cells may have induced and expanded the Treg pool.

Background: Human leukocyte antigen (HLA) class I expression is reportedly frequently reduced in cancer. We examined heat-shock protein (HSP) expression in hepatocellular carcinoma (HCC)., Patients and Methods: HCV-related HCC was examined in 73 patients who had undergone hepatectomy, and the relationship between HSP70 and HLA class I expressions, clinicopathological factors and survival was evaluated., Results: Immunohistochemically positive results for HSP70 and HLA class I were seen in 67 (92%) and 43 cases (59%), respectively, while 38 patients (52%) were positive for both. Increased HSP70 immunoreactivity was significantly associated with high histological grade of tumor differentiation (p = 0.0179), whereas reduced HLA class I immunoreactivity was significantly associated with large tumor size (p = 0.0082). No differences were apparent between disease-free and overall survival in regard to expression levels., Conclusion: These results suggest that HSP70 expression may be related to tumor differentiation and HLA class I loss may occur with tumor growth in HCV-related HCC.

A sampling method to isolate headspace volatiles of freshly brewed drip coffee using a solid-phase microextraction fiber (fiber type: divinylbenzene/carboxen/polydimethylsiloxane) in a short time (2 min) immediately after extraction has been developed. Volatile compounds and potent odorants obtained from each headspace aroma of various arabica coffee extracts (3 production countries: Ethiopia, Tanzania, and Guatemala; 3 roasting degrees for each country: L26, L23, and L18) using the sampling method were examined by gas chromatography/mass spectrometry (GC/MS) and GC/olfactometry (GC/O, CharmAnalysis). The results of principal component analysis (PCA) using the data of GC/O analysis showed that the aroma profile of Ethiopian coffee was discriminately different from those of Tanzanian coffee and Guatemalan coffee. In addition, it was suggested from the factor loading of the PCA that 4-(4'-hydroxyphenyl)-2-butanone (raspberry ketone; sweet-fruity odor) characterized the aroma profile of freshly brewed Ethiopian coffee. Therefore, the 4-(4'-hydroxyphenyl)-2-butanone was quantified in the 9 kinds of coffee extracts. Ethiopian coffee extract of the lightly roasted degree (roasting degree: L26) contained the highest amount of this component, while it was only a little over the reported threshold. In the sensory test, the headspace aromas of Tanzanian and Guatemalan coffees in which 4-(4'-hydroxyphenyl)-2-butanone was added were, respectively, discriminated from not added samples, and "sweet" odor was selected as an odor description that assessors found similarity between the added Tanzanian or Guatemalan coffee aroma and the Ethiopian coffee aroma. It was suggested that 4-(4'-hydroxyphenyl)-2-butanone made some detectable change on total aroma profile even though the added amount was only near threshold level.

Background: Pancreatic cancer has a poor prognosis. The clinical efficacy of immunotherapy using both dendritic cells pulsed with MUC1 peptide (MUC1-DC) and, cytotoxic T lymphocyte (CTL) sensitized with a pancreatic cancer, YPK-1, expressing MUC1 (MUC1-CTL) was evaluated., Patients and Methods: Twenty patients with unresectable or recurrent pancreatic cancer were enrolled. Peripheral blood mononuclear cells (PBMCs) were separated into adherent cells for induction of MUC1-DCs and floating cells for MUC1-CTLs. MUC1-DCs were generated by culture with granulocyte monocyte colony stimulating factor (GM-CSF) and interleukin-4 (IL-4) and then exposed to MUC1 peptide and TNF-alpha. MUC1-CTLs were induced by co-culture with YPK-1 and then with interleukin-2 (IL-2). MUC1-DCs were injected intradermally and MUC1-CTLs were given intravenously., Results: Patients were treated from 2 to 15 times. One patient with multiple lung metastases experienced a complete response. Five patients had stable disease. The mean survival time was 9.8 months. No grade II-IV toxicity was observed., Conclusion: Adoptive immunotherapy with MUC1-DC and MUC1-CTL may be feasible and effective for pancreatic cancer.

Headspace volatiles of freshly brewed drip coffee were investigated by gas chromatography/mass spectrometry (GC/MS) and gas chromatography/olfactometry (GC/O, CharmAnalysis) analyses. For this purpose, a solid-phase microextraction (SPME) sampling method for the headspace volatiles of freshly brewed drip coffee was developed. SPME fiber coated with divinylbenzene (DVB)/carboxen/polydimethylsiloxane (PDMS) was selected from 6 types, and sampling time was determined at 2 min. The headspace coffee volatiles stayed constant in proportion for the first 2 min to keep the freshness of the brewed coffee aroma. Using this sampling method, the headspace volatiles of freshly brewed drip coffee (Ethiopian arabica coffee, roast degree: L value; 23) were examined by GC/MS and GC/O analyses. From the GC/O results, 1-(3,4-dihydro-2H-pyrrol-2-yl)-ethanone (nutty-roast odor) and 4-(4'-hydroxyphenyl)-2-butanone (raspberry ketone, sweet-fruity odor) were newly detected as components in the aroma of coffee.

[reaction: see text] A novel and efficient synthesis of cyanidin 3-O-beta-D-glucoside (1) was accomplished the first time by a biomimetic oxidation route. From (+)-catechin, 3-OH was glucosylated, and the 4-position of the nucleus was then oxidized and dehydrated to give the 5,7,3',4'-tetra-O-(tert-butyldimethylsilyl)flav-3-en-3-ol 3-O-glucoside (8) as a key intermediate. 8 was deprotected and oxidized under air in hydrogen chloride-MeOH to give 1.

To determine the nature of intracellular Mg2+ stores and Mg2+ release mechanisms in differentiated PC12 cells, Mg2+ and Ca2+ mobilizations were measured simultaneously in living cells with KMG-104, a fluorescent Mg2+ indicator, and fura-2, respectively. Treatment with the mitochondrial uncoupler, carbonyl cyanide p-(trifluoromethoxy) phenylhydrazone (FCCP), increased both the intracellular Mg2+ concentration ([Mg2+]i) and the [Ca2+]i in these cells. Possible candidates as intracellular Mg2+ stores under these conditions include intracellular divalent cation binding sites, endoplasmic reticulum (ER), Mg-ATP and mitochondria. Given that no change in [Mg2+]i was induced by caffeine application, intracellular IP3 or Ca2+ liberated by photolysis, it appears that no Mg2+ release mechanism thus exists that is mediated via the action of Ca2+ on membrane-bound receptors in the ER or via the offloading of Mg2+ from binding sites as a result of the increased [Ca2+]i. FCCP treatment for 2 min did not alter the intracellular ATP content, indicating that Mg2+ was not released from Mg-ATP, at least in the first 2 min following exposure to FCCP. FCCP-induced [Mg2+]i increase was observed at mitochondria localized area, and vice versa. These results suggest that the mitochondria serve as the intracellular Mg2+ store in PC12 cell. Simultaneous measurements of [Ca2+]i and mitochondrial membrane potential, and also of [Ca2+]i and [Mg2+]i, revealed that the initial rise in [Mg2+]i followed that of mitochondrial depolarization for several seconds. These findings show that the source of Mg2+ in the FCCP-induced [Mg2+]i increase in PC12 cells is mitochondria, and that mitochondrial depolarization triggers the Mg2+ release.

The role of intracellular magnesium ions is of high interest in the fields of pharmacology and cellular biology. To accomplish the dynamic and three-dimensional imaging of intracellular Mg2+, there is a strong desire for the development of optimized Mg2+ fluorescent probes. In this paper we describe the design, synthesis, and cellular application of the three novel Mg2+ fluorescent probes KMG-101, -103, and -104. The compounds of this series feature a charged beta-diketone as a binding site specific for Mg2+ and a fluorescein residue as the fluorophore that can be excited with an Ar+ laser such as is widely used in confocal scanning microscopy. This molecular design leads to an intensive off-on-type fluorescent response toward Mg2+ ions. The two fluorescent probes KMG-103 and -104 showed suitable dissociation constants (Kd,Mg2+ = 2 mM) and nearly a 10-fold fluorescence enhancement over the intracellular magnesium ion concentration range (0.1-6 mM), allowing high-contrast, sensitive, and selective Mg2+ measurements. For intracellular applications, the membrane-permeable probe KMG-104AM was synthesized and successfully incorporated into PC12 cells. Upon application of the mitochondria uncoupler FCCP to the probe-incorporated cells, the resulting increase in the free magnesium ion concentration could be followed over time. By using a confocal microscope, the intracellular 3D magnesium ion concentration distributions were satisfactorily observed.

Objective and Methods: PC12 cells were loaded with a novel Mg indicator KMG-104 and Ca indicator fura-2, and intracellular Mg was studied in the endoplasmic reticulums (ERs), mitochondria, and Mg-ATP. Under coexistence of the two indicators, fluorescent signals of Mg and Ca can be measured separately. Mg release from the ER was investigated by photolysis of caged compounds., Results: Transient [Ca]i increase by uncaging of caged Ca or caged IP3 or bath-application of caffeine (10 mM) induced no [Mg]i increase. These results suggest that there is no mechanism for Mg release from the ER through ryanodine receptors or IP3 receptors. In order to investigate the possibility of Mg release from Mg-ATP by energy consumption, we depleted ATP by oligomycin, an inhibitor of mitochondrial ATP synthase. Treating with oligomycin (4 microM) for several minutes showed no change of [Mg]i and [Ca]i., Conclusions: This result shows that Mg-ATP is not a Mg store. Since, when cells were treated by an uncoupler FCCP (3 microM), [Mg]i and [Ca]i increased, we concluded that mitochondria participate in maintenance of intracellular Mg stores.

Mg(2+) buffering mechanisms in PC12 cells were demonstrated with particular focus on the role of the Na(+)/Mg(2+) transporter by using a newly developed Mg(2+) indicator, KMG-20, and also a Na(+) indicator, Sodium Green. Carbonyl cyanide p-(trifluoromethoxy) phenylhydrazone (FCCP), a protonophore, induced a transient increase in the intracellular Mg(2+) concentration ([Mg(2+)](i)). The rate of decrease of [Mg(2+)](i) was slower in a Na(+)-free extracellular medium, suggesting the coupling of Na(+) influx and Mg(2+) efflux. Na(+) influxes were different for normal and imipramine- (a putative inhibitor of the Na(+)/Mg(2+) transporter) containing solutions. FCCP induced a rapid increase in [Na(+)](i) in the normal solution, while the increase was gradual in the imipramine-containing solution. The rate of decrease of [Mg(2+)](i) in the imipramine-containing solution was also slower than that in the normal solution. From these results, we show that the main buffering mechanism for excess Mg(2+) depends on the Na(+)/Mg(2+) transporter in PC12 cells.

A dynamic solid-phase microextraction (SPME) method to sample fresh headspace volatile compounds released during the grinding of roasted coffee beans was described and the analytical results using gas chromatography/mass spectrometry (GC/MS) and GC/olfactometry (GC/O) were compared to those of the conventional static SPME sampling methods using ground coffee. Volatile compounds released during the grinding of roasted coffee beans (150 g) were obtained by exposing the SPME fiber (poly(dimethylsiloxane)/divinylbenzene, PDMS/ DVB) for 8 min to nitrogen gas (600 mL/min) discharged from a glass vessel in which the electronic coffee grinder was enclosed. Identification and characterization of volatile compounds thus obtained were achieved by GC/MS and GC/O. Peak areas of 47 typical coffee volatile compounds, separated on total ion chromatogram (TIC), obtained by the dynamic SPME method, showed coefficients of variation less than 5% (n = 3) and the gas chromatographic profile of volatile compounds thus obtained was similar to that of the solvent extract of ground coffee, except for highly volatile compounds such as 4-hydroxy-2,5-dimethyl-3(2H)-furanone and 4-ethenyl-2-methoxyphenol. Also, SPME dilution analysis of volatile compounds released during the grinding of roasted coffee beans showed linear plots of peak area versus exposed fiber length (R (2) > 0.89). Compared with those of the headspace volatile compounds of ground coffee using GC/MS and GC/O, the volatile compounds generated during the grinding of roasted coffee beans were rich in nutty- and smoke-roast aromas.

To investigate if spontaneous ischemic events in mice with severe multi-organ atherosclerosis could adapt to ischemia, apolipoprotein E/LDL receptor knockout mice were fed an atherogenic diet for 7 to 9 months. Signs of spontaneous ischemia occurred. One to two days later, hearts were excised, Langendorff-perfused with induced global ischemia, and compared with mice without signs of disease. In vivo heart or brain infarctions were verified by heart histology and/or increased serum levels of cardiac troponin T and S100B. Hearts of mice with spontaneous ischemic events had improved function and reduced Langendorff-induced infarctions. To investigate the remote preconditioning effect of brain ischemia, bilateral ligation of the internal carotid arteries was performed in C57BL6 mice. Twenty-four hours later, their isolated hearts were protected against induced global ischemia. A possible role of inducible NO synthase (iNOS) was studied in iNOS knock out mice, who were not preconditioned by induced brain ischemia. Cardiac iNOS was unchanged 24 hours after preconditioning, suggesting that NO is a trigger rather than a mediator of protection. These findings suggest that spontaneous ischemic events in the brain and heart adapt the heart to ischemia. This can be mimicked by induced brain ischemia, with iNOS as a key factor of protection.

In the presence of tripropylsulfonium bromide (TPS) (1 X 10(-4) g/ml), a new compound, the phasic contraction of the isolated guinea pig ileum to 5-hydroxytryptamine (5-HT) (5 X 10(-7) g/ml) was consistently enhanced ("TPS effect"). TPS alone increased moderatley the spontaneous movement of the ileum. When the contraction height was calculated as the percentage of that to 5-HT alone, such was observed in the "TPS effect" to be 167.1 +/- 3.6% (mean +/- S.E., n = 80). TPS did not enhance the contraction due to acetylcholine or histamine. The "TPS effect" remained unaffected in the presence of dibenzyline (1 X 10(-7) g/ml), was abolished by morphine(1 X 10(-6) g/ml), tetrodotoxin (2 X 10(-8) g/ml) adenosine (3 X 10(-6) g/ml) and atropine (1 X 10(-7) g/ml) and was not observed under anoxic conditions. Eserine (1 X 10(-8) g/ml) strengthened the "TPS effect" markedly. It is concluded that this effect may be the result of the potentiating effect of TPS on the action of 5-HT through the M receptors, possibly by the facilitation of the acetylcholine-liberation from the nervous tissue.