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An increase in nicotinamide adenine dinucleotide (NAD+) levels alleviates age-related disease progression and promotes healthy life expectancy. Several studies have demonstrated that NAD+ levels can be efficiently replenished via nicotinamide mononucleotide (NMN) intake; additionally, the safety of its oral ingestion has been confirmed in recent clinical trials. However, the efficacy and safety of intravenous NMN administration in humans remain unclear. Therefore, we verified its safety in 10 healthy volunteers. Intravenous administration of NMN did not affect electrocardiograms, pulse, and blood pressure, nor did it affect metabolic markers in the liver, heart, pancreas, and kidneys. These results indicate that intravenous NMN administration is safe and beneficial in humans. Furthermore, NMN administration significantly increased blood NAD+ levels without damaging blood cells and significantly reduced blood triglyceride (TG) levels. These findings imply that intravenous administration of NMN may lead to the prevention and treatment of diseases associated with increased TG levels, such as fatty liver and diabetes.

Photodynamic therapy (PDT) is a minimally invasive treatment that elicits tumor apoptosis using laser light exclusively applied to the tumor site. IR-783, a heptamethine cyanine (HMC) dye, impedes the proliferation of breast cancer cells, even without light. Although studies have investigated the efficacy of IR-783 in cell and animal studies, its efficacy in clinical settings remains unknown. Therefore, we aimed to determine the efficacy of PDT using IR-783 liposomes. An HMC dye, excited by long-wavelength infrared light and with high tissue permeability, was used for PDT after liposomization to enhance tumor tissue accumulation. PDT was performed using IR-783 in two patients with either tongue or breast cancer, one each. IR-783 liposomes inhibited cell proliferation in tongue cancer cells even when not excited by light. Tumor size was markedly reduced in both cases, with no significant adverse events. Furthermore, the patient with tongue cancer exhibited improved respiratory, swallowing, and speech functions, which were attributed not only to the shrinkage of the tumor but also to the improvement in airway narrowing. In conclusion, PDT using IR-783 liposomes effectively reduces tumor size in tongue and breast cancers.

Dry gene powder is a novel non-viral gene-delivery system, which is inhalable with high gene expression. Previously, we showed that the transfection of p16INK4a or TP53 by dry gene powder resulted in growth inhibitions of lung cancer and malignant pleural mesothelioma (MPM) in vitro and in vivo. Here, we report that dry gene powder containing p53- expression-plasmid DNA enhanced the therapeutic effects of cisplatin (CDDP) against MPM even in the presence of endogenous p53. Furthermore, our results indicated that the safe transfection with a higher plasmid DNA (pDNA) concentration suppressed MPM growth independently of chemotherapeutic agents. To develop a new therapeutic alternative for MPM patients without safety concerns over “vector doses”, our in vitro data provide basic understandings for dry gene powder.

This study aimed to evaluate the safety and efficacy of cisplatin (CDDP) liposomes. A patient with multiple recurrent liver metastases from metastatic nasal carcinoma was administered CDDP liposomes with consent. Magnetic resonance imaging showed that the patient remained stable disease; however, no apparent side effects were observed, and blood draw data showed no worsening of renal function. Patients undergoing partial pancreatectomy and jejunoileal biliary anastomosis for biliary tract cancer who consented to receive CDDP liposomes demonstrated a partial response on angiographic computed tomography; however, they showed slight fatigue. To our knowledge, the present study is the first in Japan to suggest that liposomalization of CDDP may have anticancer effects while alleviating renal damage and bone marrow suppression.

A patient with myeloid/natural killer (NK) cell precursor acute leukemia who was also homozygous for protein C deficiency was treated and showed a complete remission while he simultaneously received low molecular weight heparin. He presented with fever spikes, lymphadenopathy, and a bulky tumor of the anterior mediastinum. A bone marrow aspirate showed the infiltration of immature lymphoblastoid cells. The patient's diagnosis was determined to be myeloid/NK cell precursor acute leukemia by morphologic and immunophenotypic analysis (CD7(+)CD33(+)CD34(+)CD56(+)). The patient developed a thrombosis in his jugular vein on cannulation of the internal jugular vein. An examination of the serum levels and the activities of proteins C and S demonstrated a slight decrease in the protein C level but an undetectable protein C activity. The patient received the diagnosis of homozygous protein C deficiency, because both parents were found to have heterozygous protein C activity. Treatment of the patient's leukemia included induction chemotherapy (Ara-C and idarubicin) with concomitant administration of low molecular weight heparin for his homozygous protein C deficiency. He achieved a complete remission without expressing any thrombosis during the course of chemotherapy. To our knowledge, this is the first case ever described in which acute myeloid leukemia was complicated with homozygous protein C deficiency.

This study introduces a new experimental method for analyzing auditory signals in the presence of background noise and identifying sounds that are consistently easy for humans to notice in daily environments. Attention to a signal was inferred from a physiological orienting response, measured as the change in heart rate (HR) before and after the presentation of a test sound in an experimental environment designed to simulate daily life. The test sounds consisted of eight musical sounds each composed of two piano notes at different pitches, and eight complex sounds, each composed of two pure tones. Each sound interval—C + E or C + G#—was recorded at four different octaves, covering the frequency range of 130.8 Hz to 1661.4 Hz. The change in HR was calculated as the difference in the mean RR interval (RRI) over five beats before and after the test sound. The strength of the orienting response (OR) was quantified as the RRI difference normalized by the standard deviation of RRI. An absolute value greater than 2 was considered to indicate the presence of an orienting response. Twenty-two healthy young male participants participated in the experiment during a three-day, two-night stay, which was repeated after a washout period of at least one week. The results showed that OR values were reproducible for 11 of the 16 test sounds. Based on the corresponding OR values, C3 + E3 (musical sound) was identified as a suitable pre-signal due to its calming response (negative OR), whereas C6 + G#6 (complex sound) was identified as a suitable alarm signal due to its tension-inducing response (positive OR). These findings suggest that the OR metric for assessing physiological responses, provides a novel and effective approach for objectively evaluating human reactions to unexpected auditory stimuli, when combined with an experimental protocol that simulates daily life and background noise.

Mice with the C3H background show greater behavioral propensity for schizophrenia, including lower prepulse inhibition (PPI), than C57BL/6 (B6) mice. To characterize as‐yet‐unknown pathophysiologies of schizophrenia, we undertook proteomics analysis of the brain in these strains, and detected elevated levels of Mpst, a hydrogen sulfide (H 2 S)/polysulfide‐producing enzyme, and greater sulfide deposition in C3H than B6 mice. Mpst ‐deficient mice exhibited improved PPI with reduced storage sulfide levels, while Mpst ‐transgenic (Tg) mice showed deteriorated PPI, suggesting that “sulfide stress” may be linked to PPI impairment. Analysis of human samples demonstrated that the H 2 S/polysulfides production system is upregulated in schizophrenia. Mechanistically, the Mpst‐ Tg brain revealed dampened energy metabolism, while maternal immune activation model mice showed upregulation of genes for H 2 S/polysulfides production along with typical antioxidative genes, partly via epigenetic modifications. These results suggest that inflammatory/oxidative insults in early brain development result in upregulated H 2 S/polysulfides production as an antioxidative response, which in turn cause deficits in bioenergetic processes. Collectively, this study presents a novel aspect of the neurodevelopmental theory for schizophrenia, unraveling a role of excess H 2 S/polysulfides production. Synopsis This study proposes a novel concept that excess hydrogen sulfide production (sulfide stress) underlies a schizophrenia pathophysiology in the realm of neurodevelopmental hypothesis of the disease. Targeting the metabolic pathway of hydrogen sulfide provides a novel therapeutic approach. Mpst‐deficient mice exhibited improved prepulse inhibition (PPI), a typical schizophrenia‐relevant endophenotype, with reduced sulfide levels, while Mpst‐transgenic mice showed deteriorated PPI. Postmortem brains and iPS‐derived cells from a subset of schizophrenia patients displayed evidence for sulfide stress. Sulfide stress condition stemmed from insults in developing brain in mouse models and elicited dampened energy metabolism. MPST expression level in hair follicles has a potential to stratify schizophrenia patients with sulfide stress. Graphical Abstract This study proposes a novel concept that excess hydrogen sulfide production (sulfide stress) underlies a schizophrenia pathophysiology in the realm of neurodevelopmental hypothesis of the disease. Targeting the metabolic pathway of hydrogen sulfide provides a novel therapeutic approach.

PurposeRetinoic acid-induced 2 (RAI2) has been shown to be a putative suppressor of the early hematogenous dissemination of tumor cells to the bone marrow in breast cancer. Here, we investigated the associations of RAI2 mRNA and protein expression with clinicopathological factors and prognosis in breast cancer patients with long-term follow-up.MethodsInvasive breast cancer tissues (n = 604) were analyzed for RAI2 mRNA expression. We examined the associations of clinicopathological factors with the expression levels of RAI2 mRNA in these samples. We also analyzed RAI2 protein expression by immunohistochemistry in invasive breast cancer tissues (n = 422).ResultsWe identified significant positive associations between low expression of RAI2 mRNA and shorter disease-free survival (DFS), breast-cancer-specific survival (BCSS), and overall survival (OS) in breast cancer patients. We also identified significant positive associations between negative for RAI2 protein expression and shorter DFS, BCSS, and OS in breast cancer patients. Low RAI2 mRNA and negative for RAI2 protein expression were positively associated with larger tumor size, higher tumor grade, and ERα-negativity. Multivariate analyses indicated that not only RAI2 mRNA but also RAI2 protein expression were independent risk factors for both DFS and BCSS in breast cancer patients. The median follow-up periods were 10.3 and 9.3 years for the RAI2 mRNA and protein expression analyses, respectively.ConclusionsOur findings suggest that RAI2 has a role in the metastasis of breast cancer, and that RAI2 expression could be a promising candidate biomarker of prognosis in breast cancer patients.