Pulse pressure variation guided goal-direct fluid therapy decreases postoperative complications in elderly patients undergoing laparoscopic radical resection of colorectal cancer: a randomized controlled trial.

OBJECTIVE: The use of goal-directed fluid therapy (GDFT) has been shown to reduce complications and improve prognosis in high-risk abdominal surgery patients. However, the utilization of pulse pressure variation (PPV) guided GDFT in laparoscopic surgery remains a subject of debate. We hypothesized that utilizing PPV guidance for GDFT would optimize short-term prognosis in elderly patients undergoing laparoscopic radical resection for colorectal cancer compared to conventional fluid therapy. METHODS: Elderly patients undergoing laparoscopic radical resection of colorectal cancer were randomized to receive either PPV guided GDFT or conventional fluid therapy and explore whether PPV guided GDFT can optimize the short-term prognosis of elderly patients undergoing laparoscopic radical resection of colorectal cancer compared with conventional fluid therapy. RESULTS: The incidence of complications was significantly lower in the PPV group compared to the control group (32.8% vs. 57.1%, P = .009). Additionally, the PPV group had a lower occurrence of gastrointestinal dysfunction (19.0% vs. 39.3%, P = .017) and postoperative pneumonia (8.6% vs. 23.2%, P = .033) than the control group. CONCLUSION: Utilizing PPV as a monitoring index for GDFT can improve short-term prognosis in elderly patients undergoing laparoscopic radical resection of colorectal cancer. REGISTRATION NUMBER: ChiCTR2300067361; date of registration: January 5, 2023.

The Association Between the Use of Zolpidem and the Risk of Alzheimer's Disease Among Older People.

OBJECTIVES: To evaluate the association between zolpidem use and the risk of Alzheimer's disease among older people. DESIGN: A retrospective cohort study using data from 2001 to 2011 from the National Health Insurance Research Database. SETTING: Taiwan. PARTICIPANTS: A total of 6,922 patients aged 65 years or older enrolled from January 2002 to December 2004 (the enrollment period). INTERVENTION (EXPOSURE): Zolpidem users were identified as patients who used zolpidem during the enrollment period. The index date was the date of the first zolpidem prescription. Dosage of zolpidem use was defined using cumulative defined daily dose (cDDD) based on the cumulative dosage that patients took within one year after the index date (grouped as: less than 28, 28-90, 91-180, and more than 180 cDDD). MEASUREMENTS: The occurrence of Alzheimer's disease was defined as the time period from the end of one year after the index date to the date of the Alzheimer's disease diagnosis. The propensity score was used to adjust the measured confounders of Alzheimer's disease. Cox proportional hazards models were used to evaluate the association between zolpidem use and the incidence of Alzheimer's disease. RESULTS: Zolpidem users with a high cumulative dose (>180 cDDD) in the first year after initiation had a significantly greater risk of Alzheimer's disease than non-zolpidem users (HR = 2.97, 95% CI = 1.61-5.49) and low cumulative dose (<28 cDDD) users (HR = 4.18, 95% CI = 1.77-9.86). CONCLUSION: We found the use of a high cumulative dose of zolpidem was associated with an increased risk of Alzheimer's disease among older people living in Taiwan. It is advised to use caution when considering long-term use of zolpidem in older patients.

Exploiting 1,2,3-Triazolium Ionic Liquids for Synthesis of Tryptanthrin and Chemoselective Extraction of Copper(II) Ions and Histidine-Containing Peptides.

Based on a common structural core of 4,5,6,7-tetrahydro[1,2,3]triazolo[1,5-a]pyridine, a number of bicyclic triazolium ionic liquids 1-3 were designed and successfully prepared. In our hands, this optimized synthesis of ionic liquids 1 and 2 requires no chromatographic separation. Also in this work, ionic liquids 1, 2 were shown to be efficient ionic solvents for fast synthesis of tryptanthrin natural product. Furthermore, a new affinity ionic liquid 3 was tailor-synthesized and displayed its effectiveness in chemoselective extraction of both Cu(II) ions and, for the first time, histidine-containing peptides.

Conditioning vaccination site with irradiated MIP-3alpha-transfected tumor cells enhances efficacy of dendritic cell-based cancer vaccine.

Macrophage inflammation protein-3alpha (MIP-3alpha) is a chemokine expressed in inflamed tissue and capable of inducing migration of immature dendritic cells (DCs) or Langerhans cells. We postulated that conditioning vaccination sites with MIP-3alpha might enhance the efficacy of subsequently administered DC-based cancer vaccines. Our results demonstrate that subcutaneously injection of irradiated tumor cells expressing MIP-3alpha induces substantial cell infiltration to the injection site. Vaccination of irradiated tumor cells expressing MIP-3alpha followed by DCs pulsed with irradiated tumor cells can effectively suppress tumor growth in animals, which is significantly better than vaccination with irradiated MIP-3alpha-producing tumor cells or DCs pulsed with tumor cells alone. The protective effect was most evident when the MIP-3alpha-producing tumor cells and DC-based vaccines were injected at the same site. These results support the notion that this combination vaccination strategy might generate a more effective immune response to suppress the growth of tumor cells in animals.

Unnatural amino acid-substituted (hydroxyethyl)urea peptidomimetics inhibit gamma-secretase and promote the neuronal differentiation of neuroblastoma cells.

Gamma-secretase, exhibiting characteristics of aspartyl protease, mediates the intramembranous proteolysis of beta-amyloid precursor protein (APP) and Notch, and it is considered to be a prime pharmacological target in the development of therapeutics for Alzheimer's disease (AD). To identify compounds that block gamma-secretase-mediated proteolysis, we used a highly sensitive cell-based reporter gene assay for gamma-secretase in which Gal4/VP16-tagged C99-APP was expressed as the immediate substrate of gamma-secretase, and Gal4/VP16-tagged APP intracellular domain released by the gamma-secretase cleavage then activated the expression of the Gal4-driven luciferase reporter gene. Using this reporter assay, we demonstrated that the newly synthesized (hydroxyethyl)urea peptidomimetics, which contain unnatural amino acid moieties at positions P1' and/or P3', can effectively inhibit gamma-secretase activity and significantly reduce Abeta production. The gamma-secretase-dependent S3 cleavage of Notch was also consistently blocked by these (hydroxyethyl)ureas as evidenced by the decreased generation of the Notch intracellular domain, a prerequisite for the activation of Notch signaling. The inhibition of Notch signaling by active Jia compounds efficiently promotes the neuronal differentiation of neuroblastoma cells, intervening in tumorigenesis and the malignancy of neuroblastomas. Our results suggest that (hydroxyethyl)urea peptidomimetics containing unnatural amino acid substitutions could represent a novel class of gamma-secretase inhibitors with enhanced stability, providing the basis for the further development of effective therapeutics for AD and neuroblastomas.

Tumor necrosis factor-alpha, interleukin-1beta, and interferon-gamma stimulate gamma-secretase-mediated cleavage of amyloid precursor protein through a JNK-dependent MAPK pathway.

The deposition of the amyloid beta (Abeta) peptide in neuritic plaques plays a critical role in the pathogenesis of Alzheimer's disease (AD). Abeta is generated through the proteolysis of amyloid precursor protein (APP) by the sequential actions of beta- and gamma-secretases. Although recent evidence has unveiled much about the biochemical identity and characteristics of gamma-secretase, the mechanism regulating endogenous gamma-secretase activity remains elusive. To identify possible extracellular signals and associated signaling cascades that could regulate APP proteolysis by gamma-secretase activity, we have developed a cell-based reporter gene assay by stably cotransfecting HEK293 cells with the Gal4-driven luciferase reporter gene and the Gal4/VP16-tagged C-terminal fragment of APP (C99-GV), the immediate substrate of gamma-secretase. The cleavage of C99-GV by gamma-secretase releases the transcription factor that activates luciferase expression, providing a quantitative measurement of gamma-secretase activity. Using this reporter assay, we have demonstrated that interferon-gamma, interleukin-1beta, and tumor necrosis factor-alpha can specifically stimulate gamma-secretase activity, concomitant with increased production of Abeta and the intracellular domain of APP (AICD). The gamma-secretase-dependent cleavage of Notch is also enhanced upon the stimulation of these cytokines. The cytokine-enhanced gamma-secretase activity can be suppressed by a potent inhibitor of c-Jun N-terminal kinase (JNK). Furthermore, cells transfected with dominant-positive MEKK1, one of the most potent activators of the JNK cascade, exhibit increased gamma-secretase activity, suggesting that the JNK-dependent mitogen-activated protein kinase pathway could mediate the cytokine-elicited regulation of gamma-secretase. Our studies provide direct evidence that cytokine-elicited signaling cascades control Abeta production by modulating gamma-secretase activity.

Concurrent delivery of tumor antigens and activation signals to dendritic cells by irradiated CD40 ligand-transfected tumor cells resulted in efficient activation of specific CD8+ T cells.

To improve the efficacy of tumor cell-based and dendritic cell (DC)-based cancer vaccines, this study explored the potential of a new cancer vaccine strategy, that is, the use of CD40 ligand-transfected tumor (CD40L-tumor) cells to simultaneously deliver both tumor-derived antigens (Ag) and maturation stimuli to DCs. Materials from frozen/thawed or irradiated human tumor cells, with or without surface CD40L, were internalized efficiently by immature DCs after coincubation. However, during the internalization process, only coculturing with irradiated CD40L-tumor cells resulted in concurrent, optimal DC maturation and production of proinflammatory chemokines and pro-Th1 cytokines, such as IL-6, IL-8, IL-12, IFN-gamma, and TNF-alpha. These activated DCs were the most potent cells to support the growth of CD8+, IFN-gamma-producing T cells, and to process tumor Ag for the generation of specific cytotoxic T cells in vitro. Animals vaccinated with irradiated CD40L-tumor cell-pulsed DCs were better protected against subsequent challenge of a weakly immunogenic tumor cell line than animals vaccinated with irradiated CD40L-tumor cells alone. Thus, our results strongly support the future clinical application of using DCs pulsed with irradiated CD40L-tumor cells as a cancer vaccine.