Isobutyric acid enhances the anti-tumour effect of anti-PD-1 antibody.

The low response rate of immune checkpoint inhibitors (ICIs) is a challenge. The efficacy of ICIs is influenced by the tumour microenvironment, which is controlled by the gut microbiota. In particular, intestinal bacteria and their metabolites, such as short chain fatty acids (SCFAs), are important regulators of cancer immunity; however, our knowledge on the effects of individual SCFAs remains limited. Here, we show that isobutyric acid has the strongest effect among SCFAs on both immune activity and tumour growth. In vitro, cancer cell numbers were suppressed by approximately 75% in humans and mice compared with those in controls. Oral administration of isobutyric acid to carcinoma-bearing mice enhanced the effect of anti-PD-1 immunotherapy, reducing tumour volume by approximately 80% and 60% compared with those in the control group and anti-PD-1 antibody alone group, respectively. Taken together, these findings may support the development of novel cancer therapies that can improve the response rate to ICIs.

Butyricimonas is a key gut microbiome component for predicting postoperative recurrence of esophageal cancer.

BACKGROUND: Recently, intestinal bacteria have attracted attention as factors affecting the prognosis of patients with cancer. However, the intestinal microbiome is composed of several hundred types of bacteria, necessitating the development of an analytical method that can allow the use of this information as a highly accurate biomarker. In this study, we investigated whether the preoperative intestinal bacterial profile in patients with esophageal cancer who underwent surgery after preoperative chemotherapy could be used as a biomarker of postoperative recurrence of esophageal cancer. METHODS: We determined the gut microbiome of the patients using 16S rRNA metagenome sequencing, followed by statistical analysis. Simultaneously, we performed a machine learning analysis using a random forest model with hyperparameter tuning and compared the data obtained. RESULTS: Statistical and machine learning analyses revealed two common bacterial genera, Butyricimonas and Actinomyces, which were abundant in cases with recurrent esophageal cancer. Butyricimonas primarily produces butyrate, whereas Actinomyces are oral bacteria whose function in the gut is unknown. CONCLUSION: Our results indicate that Butyricimonas spp. may be a biomarker of postoperative recurrence of esophageal cancer. Although the extent of the involvement of these bacteria in immune regulation remains unknown, future research should investigate their presence in other pathological conditions. Such research could potentially lead to a better understanding of the immunological impact of these bacteria on patients with cancer and their application as biomarkers.

Nivolumab receptor occupancy on effector regulatory T cells predicts clinical benefit.

Immune checkpoint inhibitor discovery represents a turning point in cancer treatment. However, the response rates of solid tumors remain ~10%-30%; consequently, prognostic and immune-related adverse event (irAE) predictors are being explored. The programmed cell death protein 1 (PD-1) receptor occupancy (RO) of PD-1 inhibitors depends on the number of peripheral blood lymphocytes and their PD-1 expression levels, suggesting that the RO may be related to efficacy and adverse events. As PD-1 inhibition affects each T-cell subset differently, the RO of each cell population must be characterized. However, relevant data have not been reported, and the prognostic relevance of this parameter is not known. In this study, we aimed to clarify the association between the nivolumab RO in each T-cell population and patient prognosis and reveal the development of irAEs in nivolumab-treated patients. Thirty-two patients were included in the study, and the mean follow-up period was 364 days. The nivolumab RO on effector regulatory T cells (eTregs) was significantly lower in the group that presented clinical benefits, and a significant negative association was observed between PD-1 occupancy on eTregs and all-cause mortality. The results suggest that the nivolumab RO on eTregs may be a prognostic factor in PD-1 inhibitor therapy, implying that the inhibition of PD-1/PD-ligand 1 (PD-L1) signaling on eTregs may attenuate antitumor effects.

Non-classical Monocytes Enhance the Efficacy of Immune Checkpoint Inhibitors on Colon Cancer in a Syngeneic Mouse Model.

BACKGROUND/AIM: The response rate to immune checkpoint inhibitors (ICIs) is approximately 10%-30% and only in a few cancer types. In the present study, we determined whether non-classical monocytes (NCMs) could enhance ICI efficacy in colon cancer using a syngeneic mouse model. MATERIALS AND METHODS: The MC38 C57BL/6 mouse colon cancer model was used. Cells collected from the bone marrow of C57BL/6 mice were cultured, and NCMs were fractionated by cell sorting and administered via the tail veins to the mice implanted with MC38 cells. The anti-mouse PD-L1 antibody was administered three times, and tumor volume and overall survival were observed. RESULTS: More tumors were eradicated and more complete response occurred, after cotreatment with ICIs and NCMs than after treatment with ICIs alone. Moreover, no efficacy was observed when NCMs were administered alone. CONCLUSION: NCMs enhance ICI efficacy. The underlying mechanisms and clinical applications will be studied in the future.

Novel quantitative immunohistochemical analysis for evaluating PD-L1 expression with phosphor-integrated dots for predicting the efficacy of patients with cancer treated with immune checkpoint inhibitors.

Introduction: Programmed cell death ligand 1 (PD-L1) expression in tumor tissues is measured as a predictor of the therapeutic efficacy of immune checkpoint inhibitors (ICIs) in many cancer types. PD-L1 expression is evaluated by immunohistochemical staining using 3,3´-diaminobenzidine (DAB) chronogenesis (IHC-DAB); however, quantitative and reproducibility issues remain. We focused on a highly sensitive quantitative immunohistochemical method using phosphor-integrated dots (PIDs), which are fluorescent nanoparticles, and evaluated PD-L1 expression between the PID method and conventional DAB method. Methods: In total, 155 patients with metastatic or recurrent cancer treated with ICIs were enrolled from four university hospitals. Tumor tissue specimens collected before treatment were subjected to immunohistochemical staining with both the PID and conventional DAB methods to evaluate PD-L1 protein expression. Results: PD-L1 expression assessed using the PID and DAB methods was positively correlated. We quantified PD-L1 expression using the PID method and calculated PD-L1 PID scores. The PID score was significantly higher in the responder group than in the non-responder group. Survival analysis demonstrated that PD-L1 expression evaluated using the IHC-DAB method was not associated with progression-free survival (PFS) or overall survival (OS). Yet, PFS and OS were strikingly prolonged in the high PD-L1 PID score group. Conclusion: Quantification of PD-L1 expression as a PID score was more effective in predicting the treatment efficacy and prognosis of patients with cancer treated with ICIs. The quantitative evaluation of PD-L1 expression using the PID method is a novel strategy for protein detection. It is highly significant that the PID method was able to identify a group of patients with a favorable prognosis who could not be identified by the conventional DAB method.

Extracellular high molecular weight α-synuclein oligomers induce cell death by disrupting the plasma membrane.

α-Synuclein (αS), the causative protein of Parkinson's disease and other α-synucleinopathies, aggregates from a low molecular weight form (LMW-αS) to a high molecular weight αS oligomer (HMW-αSo). Aggregated αS accumulates intracellularly, induces intrinsic apoptosis, is released extracellularly, and appears to propagate disease through prion-like spreading. Whether extracellular αS aggregates are cytotoxic, damage cell wall, or induce cell death is unclear. We investigated cytotoxicity and cell death caused by HMW-αSo or LMW-αS. Extracellular HMW-αSo was more cytotoxic than LMW-αS and was a crucial factor for inducing plasma membrane damage and cell death. HMW-αSo induced reactive oxygen species production and phospholipid peroxidation in the membrane, thereby impairing calcium homeostasis and disrupting plasma membrane integrity. HMW-αSo also induced extrinsic apoptosis and cell death by activating acidic sphingomyelinase. Thus, as extracellular HMW-αSo causes neuronal injury and death via cellular transmission and direct plasma membrane damage, we propose an additional disease progression pathway for α-synucleinopathies.

Neuroprotective Potential of Raloxifene via G-Protein-Coupled Estrogen Receptors in Aß-Oligomer-Induced Neuronal Injury.

Amyloid-ß (Aß) is one of the causes of Alzheimer's disease (AD), damaging nerve membranes and inducing neurotoxicity. AD is more prevalent in female patients than in male patients, and women are more susceptible to developing AD due to the decline in estrogen levels around menopause. Raloxifene, a selective estrogen receptor modulator, exhibits protective effects by activating the transmembrane G-protein-coupled estrogen receptor (GPER). Additionally, raloxifene prevents mild cognitive impairment and restores cognition. However, the influence of raloxifene via GPER on highly toxic Aß-oligomers (Aßo)-induced neurotoxicity remains uncertain. In this study, we investigated the GPER-mediated neuroprotective effects of raloxifene against the neurotoxicity caused by Aßo-induced cytotoxicity. The impact of raloxifene on Aßo-induced cell damage was evaluated using measures such as cell viability, production of reactive oxygen species (ROS) and mitochondrial ROS, peroxidation of cell-membrane phospholipids, and changes in intracellular calcium ion concentration ([Ca2+]i) levels. Raloxifene hindered Aßo-induced oxidative stress and reduced excessive [Ca2+]i, resulting in improved cell viability. Furthermore, these effects of raloxifene were inhibited with pretreatment with a GPER antagonist. Our findings suggest that raloxifene safeguards against Aßo-induced neurotoxicity by modifying oxidative parameters and maintaining [Ca2+]i homeostasis. Raloxifene may prove effective in preventing and inhibiting the progression of AD.

Monocyte subsets associated with the efficacy of anti­PD­1 antibody monotherapy.

Immune checkpoint inhibitors (ICIs) are among the most notable advances in cancer immunotherapy; however, reliable biomarkers for the efficacy of ICIs are yet to be reported. Programmed death (PD)-ligand 1 (L1)-expressing CD14+ monocytes are associated with shorter overall survival (OS) time in patients with cancer treated with anti-PD-1 antibodies. The present study focused on the classification of monocytes into three subsets: Classical, intermediate and non-classical. A total of 44 patients with different types of cancer treated with anti-PD-1 monotherapy (pembrolizumab or nivolumab) were enrolled in the present study. The percentage of each monocyte subset was investigated, and the percentage of cells expressing PD-L1 or PD-1 within each of the three subsets was further analyzed. Higher pretreatment classical monocyte percentages were correlated with shorter OS (r=-0.32; P=0.032), whereas higher non-classical monocyte percentages were correlated with a favorable OS (r=0.39; P=0.0083). PD-L1-expressing classical monocytes accounted for a higher percentage of the total monocytes than non-classical monocytes with PD-L1 expression. In patients with non-small cell lung cancer (NSCLC), a higher percentage of PD-L1-expressing classical monocytes was correlated with shorter OS (r=-0.60; P=0.012), which is similar to the observation for the whole patient cohort. Comparatively, higher percentages of non-classical monocytes expressing PD-L1 were significantly associated with better OS, especially in patients with NSCLC (r=0.60; P=0.010). Moreover, a higher percentage of non-classical monocytes contributed to prolonged progression-free survival in patients with NSCLC (r=0.50; P=0.042), with similar results for PD-L1-expressing non-classical monocytes. The results suggested that the percentage of monocyte subsets in patients with cancer before anti-PD-1 monotherapy may predict the treatment efficacy and prognosis. Furthermore, more classical monocytes and fewer non-classical monocytes, especially those expressing PD-L1, are involved in shortening OS time, which may indicate the poor efficiency of anti-PD-1 treatment approaches.

Turicibacter and Acidaminococcus predict immune-related adverse events and efficacy of immune checkpoint inhibitor.

Introduction: Immune checkpoint inhibitors have had a major impact on cancer treatment. Gut microbiota plays a major role in the cancer microenvironment, affecting treatment response. The gut microbiota is highly individual, and varies with factors, such as age and race. Gut microbiota composition in Japanese cancer patients and the efficacy of immunotherapy remain unknown. Methods: We investigated the gut microbiota of 26 patients with solid tumors prior to immune checkpoint inhibitor monotherapy to identify bacteria involved in the efficacy of these drugs and immune-related adverse events (irAEs). Results: The genera Prevotella and Parabacteroides were relatively common in the group showing efficacy towards the anti-PD-1 antibody treatment (effective group). The proportions of Catenibacterium (P = 0.022) and Turicibacter (P = 0.049) were significantly higher in the effective group than in the ineffective group. In addition, the proportion of Desulfovibrion (P = 0.033) was significantly higher in the ineffective group. Next, they were divided into irAE and non-irAE groups. The proportions of Turicibacter (P = 0.001) and Acidaminococcus (P = 0.001) were significantly higher in the group with irAEs than in those without, while the proportions of Blautia (P = 0.013) and the unclassified Clostridiales (P = 0.027) were significantly higher in the group without irAEs than those with. Furthermore, within the Effective group, Acidaminococcus and Turicibacter (both P = 0.001) were more abundant in the subgroup with irAEs than in those without them. In contrast, Blautia (P = 0.021) and Bilophila (P= 0.033) were statistically significantly more common in those without irAEs. Discussion: Our Study suggests that the analysis of the gut microbiota may provide future predictive markers for the efficacy of cancer immunotherapy or the selection of candidates for fecal transplantation for cancer immunotherapy.

Structural Dynamics of Amyloid-ß Protofibrils and Actions of Anti-Amyloid-ß Antibodies as Observed by High-Speed Atomic Force Microscopy.

Amyloid-ß (Aß) aggregation intermediates, including oligomers and protofibrils (PFs), have attracted attention as neurotoxic aggregates in Alzheimer's disease. However, due to the complexity of the aggregation pathway, the structural dynamics of aggregation intermediates and how drugs act on them have not been clarified. Here we used high-speed atomic force microscopy to observe the structural dynamics of Aß42 PF at the single-molecule level and the effect of lecanemab, an anti-Aß PF antibody with the positive results from Phase 3 Clarity AD. PF was found to be a curved nodal structure with stable binding angle between individual nodes. PF was also a dynamic structure that associates with other PF molecules and undergoes intramolecular cleavage. Lecanemab remained stable in binding to PFs and to globular oligomers, inhibiting the formation of large aggregates. These results provide direct evidence for a mechanism by which antibody drugs interfere with the Aß aggregation process.

The effect of hand therapy on alleviating chemotherapy-induced peripheral neuropathy in a model mouse.

The use of neurotoxic chemotherapeutic agents induces numbness in the limbs through chemotherapy-induced peripheral neuropathy (CIPN). Recently, we found that hand therapy involving finger massage improved mild to moderate numbness in CIPN patients. In this study, we behaviorally, physiologically, pathologically, and histologically investigated the mechanisms underlying hand therapy-induced numbness improvement in a CIPN model mouse. Hand therapy was performed for 21 days after the disease induction. Its effects were evaluated using mechanical and thermal thresholds and blood flow in the bilateral hind paw. Moreover, 14 days after the hand therapy was administered, we assessed the blood flow and conduction velocity in the sciatic nerve, the level of serum galectin-3, and the histological myelin and epidermis-related changes in the hindfoot tissue. Hand therapy significantly improved allodynia, hyperalgesia, blood flow, conduction velocity, serum galectin-3, and epidermal thickness in the CIPN model mouse. Furthermore, we observed the images of repairs of the myelin degeneration. Thus, we found that hand therapy could improve numbness in the CIPN model mouse and that it could help to repair peripheral nerves by promoting blood circulation in the limbs.

The Curcumin Derivative GT863 Protects Cell Membranes in Cytotoxicity by Aß Oligomers.

In Alzheimer's disease (AD), accumulation of amyloid ß-protein (Aß) is one of the major mechanisms causing neuronal cell damage. Disruption of cell membranes by Aß has been hypothesized to be the important event associated with neurotoxicity in AD. Curcumin has been shown to reduce Aß-induced toxicity; however, due to its low bioavailability, clinical trials showed no remarkable effect on cognitive function. As a result, GT863, a derivative of curcumin with higher bioavailability, was synthesized. The purpose of this study is to clarify the mechanism of the protective action of GT863 against the neurotoxicity of highly toxic Aß oligomers (Aßo), which include high-molecular-weight (HMW) Aßo, mainly composed of protofibrils in human neuroblastoma SH-SY5Y cells, focusing on the cell membrane. The effect of GT863 (1 µM) on Aßo-induced membrane damage was assessed by phospholipid peroxidation of the membrane, membrane fluidity, membrane phase state, membrane potential, membrane resistance, and changes in intracellular Ca2+ ([Ca2+]i). GT863 inhibited the Aßo-induced increase in plasma-membrane phospholipid peroxidation, decreased membrane fluidity and resistance, and decreased excessive [Ca2+]i influx, showing cytoprotective effects. The effects of GT863 on cell membranes may contribute in part to its neuroprotective effects against Aßo-induced toxicity. GT863 may be developed as a prophylactic agent for AD by targeting inhibition of membrane disruption caused by Aßo exposure.

Short-term administration of Polypodium leucotomos extract does not inhibit CYP3A4-mediated metabolism of midazolam in healthy subjects: an open-label, two-period, fixed-sequence study.

The extract of Polypodium leucotomos is used as a dietary supplement for its ultraviolet radiation-protective properties. Polypodium leucotomos extract reportedly inhibits CYP3A, which is important for drug metabolism in vitro in human microsomes and in vivo in rats. In this study, we explored the inhibitory effect of the P. leucotomos extract on CYP3A4-mediated midazolam metabolism in humans. This open-label, two-period, fixed-sequence study was performed on six healthy, Japanese, male volunteers. During period 1 (control), midazolam (1 mg) was orally administered. After a wash-out period of at least 5 days, period 2 was initiated. Subjects ingested P. leucotomos extract (240 mg) once in the morning and once at noon on the day before midazolam administration, and once the next morning (thrice overall). Midazolam was administered as in period 1. Blood samples were regularly collected for 8 hours after drug administration, and serum midazolam concentration was determined by ultra-fast liquid chromatography-tandem mass spectrometry. The pharmacokinetic parameters of midazolam were calculated and compared between the two periods. The area under the concentration-time curve was 19.18 ± 3.65 ng h/ml, maximum serum concentration was 7.81 ± 1.25 ng/ml, and half-life was 2.32 ± 0.35 hours during period 2. These parameters did not differ from those recorded in period 1 (area under the concentration-time curve: 18.74 ± 2.97 ng h/ml, maximum serum concentration: 8.78 ± 1.67 ng/ml, half-life: 2.52 ± 0.52 h). Therefore, short-term oral administration of P. leucotomos extract did not cause food-drug interactions mediated by CYP3A4 inhibition in humans.

Increased expression of human herpes virus 6 receptor CD134/OX40 in skin lesions of patients with drug-induced hypersensitivity syndrome/drug reaction with eosinophilia and systemic symptoms.

CD134/OX40, a member of the tumor necrosis factor receptor superfamily, is a cell-specific receptor for human herpesvirus 6 (HHV-6) variant B. Patients with drug-induced hypersensitivity syndrome (DIHS)/drug reaction with eosinophilia and systemic symptoms (DRESS) present a significant increase in CD134 expression in peripheral blood CD4+ T cells. We aimed to investigate the frequency of CD134+ CD4 T cells infiltrating skin lesions in patients with DIHS/DRESS and its association with disease severity. We retrospectively included 21 patients with DIHS/DRESS and 11 patients with erythema multiforme (EM). By immunohistochemistry, the frequency of CD134+ CD4 T cells in DIHS was significantly higher than that in EM (p = 0.0083). The DIHS/DRESS severity score was significantly correlated with the frequency of CD134+ CD4 T cells (p = 0.0272); moreover, there was a significant difference between severe and mild/moderate cases. Double immunofluorescence staining revealed that numerous cells presented CD134/CD4 and CD134/Foxp3 overlap in patients with DIHS/DRESS. These data suggest increased susceptibility to HHV-6 infection at localized skin sites. HHV-6 may be involved in the mechanism underlying the progression and pathophysiology of DIHS/DRESS.

Combined Treatment with Curcumin and Ferulic Acid Suppressed the Aß-Induced Neurotoxicity More than Curcumin and Ferulic Acid Alone.

Alzheimer's disease (AD) is a neurodegenerative disease that leads to progressive cognitive decline. Several effective natural components have been identified for the treatment of AD. However, it is difficult to obtain conclusive evidence on the safety and effectiveness of natural components, because a variety of factors are associated with the progression of AD pathology. We hypothesized that a therapeutic effect could be achieved by combining multiple ingredients with different efficacies. The purpose of this study was thus to evaluate a combination treatment of curcumin (Cur) and ferulic acid (FA) for amyloid-ß (Aß)-induced neuronal cytotoxicity. The effect of Cur or FA on Aß aggregation using thioflavin T assay was confirmed to be inhibited in a concentration-dependent manner by Cur single or Cur + FA combination treatment. The effects of Cur + FA on the cytotoxicity of human neuroblastoma (SH-SY5Y) cells induced by Aß exposure were an increase in cell viability, a decrease in ROS and mitochondrial ROS, and repair of membrane damage. Combination treatment showed an overall higher protective effect than treatment with Cur or FA alone. These results suggest that the combined action mechanisms of Cur and FA may be effective in preventing and suppressing the progression of AD.

The Sympathetic Nervous System Contributes to the Establishment of Pre-Metastatic Pulmonary Microenvironments.

Emerging evidence suggests that neural activity contributes to tumor initiation and its acquisition of metastatic properties. More specifically, it has been reported that the sympathetic nervous system regulates tumor angiogenesis, tumor growth, and metastasis. The function of the sympathetic nervous system in primary tumors has been gradually elucidated. However, its functions in pre-metastatic environments and/or the preparation of metastatic environments far from the primary sites are still unknown. To investigate the role of the sympathetic nervous system in pre-metastatic environments, we performed chemical sympathectomy using 6-OHDA in mice and observed a decrease in lung metastasis by attenuating the recruitment of myeloid-derived suppressor cells. Furthermore, we note that neuro-immune cell interactions could be observed in tumor-bearing mouse lungs in conjunction with the decreased expression of Sema3A. These data indicate that the sympathetic nervous system contributes to the preparation of pre-metastatic microenvironments in the lungs, which are mediated by neuro-immune cell interactions.

Serum cystatin C and CRP are early predictive biomarkers for emergence of hypoxia in COVID-19.

BACKGROUND: In Japan, during the coronavirus disease 2019 (COVID-19) pandemic, patients with non-hypoxia are recommended to recuperate at home or in pre-hospital facilities. However, it was observed that unexpected hypoxia may occur and become severe subsequently in patients whose symptoms were initially expected to improve naturally. The aim of this study is to validate biomarkers that can predict at an early stage the emergence of hypoxia in COVID-19 patients without hypoxia. METHODS: We retrospectively enrolled 193 patients with COVID-19, excluding patients with hypoxia and severe disease from the onset. Participants were classified into two groups according to the emergence of hypoxia during the clinical course, and the laboratory data were compared to identify biomarkers that could predict early the emergence of hypoxia. RESULTS: The areas under the curve for serum cystatin C (CysC) and C-reactive protein (CRP) levels for the emergence of hypoxia during the clinical course were higher than those for other biomarkers (CysC, 0.84 and CRP, 0.83). Multivariate analysis showed that high serum CysC and CRP levels were associated with the emergence of hypoxia during the clinical course. CONCLUSIONS: Elevated serum CysC and CRP levels were associated with the emergence of hypoxia during the clinical course in COVID-19 patients without hypoxia. These findings may help determine the need for hospitalization in initially non-hypoxic COVID-19 patients.

Inhibition of CYP3A-mediated Midazolam Metabolism by Kaempferia Parviflora.

Kaempferia parviflora (KP) extract has recently attracted attention in Japan as a dietary supplement; however, there is little information regarding food-drug interactions (FDIs). The current study was conducted to clarify the FDI of KP extract via inhibition of cytochrome P450 3A (CYP3A), a typical drug-metabolizing enzyme. The inhibitory effects of KP extract and its main ingredients, 5,7-dimethoxyflavone (5,7-DMF) and 3,5,7,3',4'-pentamethoxyflavone (3,5,7,3',4'-PMF), on CYP3A-mediated midazolam 1'-hydroxylation (MDZ 1'-OH) activity were investigated in human liver microsomes. In addition, the effect of a single oral treatment with KP extract (135 mg/kg) on oral MDZ (15 mg/kg) metabolism was investigated in rats. Serum MDZ concentration was analyzed and pharmacokinetic parameters were compared with the control group. KP extract competitively inhibited MDZ 1'-OH activity with an inhibition constant value of 78.14 µg/ml, which was lower than the estimated concentration in the small intestine after ingestion. Furthermore, KP extract, 5,7-DMF, and 3,5,7,3',4'-PMF inhibited the activity in a time-, NADPH-, and concentration-dependent manner. In vivo study showed that administration of KP extract to rats 2 h before MDZ significantly increased the area under the serum concentration-time curve and the maximum concentration of MDZ significantly by 2.3- and 1.9- fold, respectively (p < 0.05). Conversely, administration of MDZ 18 h after KP extract treatment displayed a weaker effect. These results suggest that KP extract competitively inhibits CYP3A-mediated MDZ metabolism, and that this inhibition may be time-dependent but not irreversible. This work suggests an FDI through CYP3A inhibition by KP extract.

Effects of Quinolinate-Induced Lesion of the Medial Prefrontal Cortex on Prefrontal and Striatal Concentrations of D-Serine in the Rat.

D-Serine has been shown to play an important role in the expression and control of a variety of brain functions by acting as the endogenous coagonist for the N-methyl-D-aspartate type glutamate receptor (NMDAR), at least, in the forebrain. To obtain further insight into the still debatable cellular localization of the D-amino acid, we have examined the effects of the selective destruction of the neuronal cell bodies by quinolinate on the tissue or extracellular D-serine concentrations in the medial prefrontal cortex of the rat. A local quinolinate infusion into the bilateral medial prefrontal cortex produced a cortical lesion with a marked (- 65%) and non-significant alteration (- 5%) in the cortical and striatal tissue D-serine concentrations, respectively, 7 days post-infusion. In vivo microdialysis experiments in the right prefrontal lesion site 9 days after the quinolinate application revealed that the basal extracellular D-serine levels were also dramatically reduced (- 64%). A prominent reduction in the tissue levels of GABA in the interneurons of the prefrontal cortex (- 78%) without significant changes in those in the striatum (+ 12%) verified that a major lesion part was confined to the cortical portion. The lack of a significant influence of the prefrontal quinolinate lesion on its dopamine concentrations in the mesocortical dopamine projections suggests that the nerve terminals and axons in the lesion site may be spared. These findings are consistent with the perikarya-selective nature of the present quinolinate-induced lesion and further support the view that neuronal cell bodies of intrinsic neurons in the prefrontal cortical region contain substantial amounts of D-serine, which may sustain the basal extracellular concentrations of D-serine.

Predictors of Opioid Resistance: An Investigation in Cancer Pain.

Appropriate use of opioid analgesics according to the World Health Organization pain relief ladder has provided pain relief to many patients with cancer pain. However, a proportion of patients fail to achieve sufficient pain relief and develop opioid resistance. Individual risk factors may relate to opioid resistance. Therefore, we conducted a historical cohort study to identify risk factors for opioid resistance and to construct an index to predict it. We investigated salient factors at the time of opioid initiation in the medical records of 233 patients. The outcome was the achievement of stable pain at 14 days after opioid introduction. We identified factors contributing to opioid resistance by multivariate analysis (p < 0.05). We created a resistance score from the regression equation of the identified factors to predict opioid resistance. Forty-nine (21.0%) patients were opioid resistant without achieving the outcome. Age, neuropathic pain, and alkaline phosphatase were extracted as significant factors for opioid resistance (p < 0.05). A resistance score was created from these factors and classified into binary values, the sensitivity was 80.6% and the negative predictive value was 91.6%. The findings suggest that the resistance score could be a sensitive predictor of opioid resistance before opioid initiation.