Human Milk Exosomes Induce ZO-1 Expression via Inhibition of REDD1 Expression in Human Intestinal Epithelial Cells.

Human milk exosomes (HMEs) enhance intestinal barrier function and contribute to an improvement in inflammation and mucosal injury, such as necrotizing enteritis (NEC), in infants. Here, we aimed to elucidate the intracellular factors involved in HME-induced expression of zonula occludens-1 (ZO-1), a tight junction protein, in Caco-2 human intestinal epithelial cells. HME treatment for 72 h significantly increased transepithelial electrical resistance in these cells. The mean ZO-1 protein levels in cells treated with HME for 72 h were significantly higher than those in the control cells. The mRNA and protein levels of regulated in development and DNA damage response 1 (REDD1) in HME-treated cells were significantly lower than those in the control cells. Although HME treatment did not increase the mechanistic target of rapamycin (mTOR) level in Caco-2 cells, it significantly increased the phosphorylated mTOR (p-mTOR) level and p-mTOR/mTOR ratio. The ZO-1 protein levels in cells treated with an inducer of REDD1, cobalt chloride (CoCl2) alone were significantly lower than those in the control cells. However, ZO-1 protein levels in cells co-treated with HME and CoCl2 were significantly higher than those in cells treated with CoCl2 alone. Additionally, REDD1 protein levels in cells treated with CoCl2 alone were significantly higher than those in the control cells. However, REDD1 protein levels in cells co-treated with HME and CoCl2 were significantly lower than those in cells treated with CoCl2 alone. This HME-mediated effect may contribute to the development of barrier function in the infant intestine and protect infants from diseases.

Effect of toe-out gait modification on patellofemoral joint loading.

BACKGROUND: Toe-out gait has been proposed as a conservative treatment to reduce medial tibiofemoral joint loading. However, patellofemoral joint loading during toe-out gait is not yet understood. RESEARCH QUESTION: Does the toe-out gait modification affect patellofemoral joint loading? METHODS: Sixteen healthy adults were enrolled in this study. The natural gait and toe-out gait were measured using a three-dimensional motion analysis and a force plate. The knee flexion angle and external knee flexion moment during the stance phase were calculated. Thus, dynamic knee joint stiffness, a proxy of patellofemoral joint loading, was defined as a linear regression of the knee flexion moment and knee flexion angle during the early stance. Additionally, the peak patellofemoral compressive force during the early stance was calculated using a musculoskeletal simulation. A paired t-test was used to compare these biomechanical parameters during the natural gait and toe-out gait. RESULTS: The toe-out gait significantly increased the peak patellofemoral compressive force (mean difference = 0.37 BW, P = 0.017) and dynamic knee joint stiffness (mean difference = 0.07%BW*Ht/°, P = 0.001). The 1st peak of the knee flexion moment also significantly increased in the toe-out gait (mean difference = 1.01%BW*Ht, P = 0.003); however, the knee flexion angle did not change significantly (initial contact: mean difference = 1.7°, P = 0.078; peak: mean difference = 1.3°, P = 0.224). SIGNIFICANCE: Toe-out gait increased the patellofemoral compressive force and dynamic knee joint stiffness because of increasing knee flexion moment, but not the knee flexion angle. When the toe-out gait is adapted, clinicians should pay attention to an increase in the patellofemoral joint loading.

Early Changes in Postural Balance Following Inverted V-Shaped High Tibial Osteotomy in Patients With Knee Osteoarthritis.

Patients with knee osteoarthritis and varus knee deformity have impaired postural balance, resulting in decreased walking performance and an increased risk of falls. This study aimed to investigate the early changes in the postural balance following inverted V-shaped high tibial osteotomy (HTO). Fifteen patients with medial knee osteoarthritis were recruited. Postural balance was assessed using the center-of-pressure (COP) data during single-leg standing before and 6 weeks after inverted V-shaped HTO. The maximum range, mean velocity, and area of COP movements in the anteroposterior and mediolateral directions were analyzed. Preoperative and postoperative visual analog scale for knee pain was assessed. The maximum range of COP in the mediolateral direction decreased (P = .017), whereas the mean velocity of COP in the anteroposterior direction increased 6 weeks postoperatively (P = .011). The visual analog scale score for knee pain significantly improved at 6 weeks postoperatively (P = .006). Valgus correction with inverted V-shaped HTO resulted in improved postural balance in the mediolateral direction and good short-term clinical outcomes early following surgery. Early rehabilitation after inverted V-shaped HTO should focus on postural balance in the anteroposterior direction.

Suppression of milk-derived miR-148a caused by stress plays a role in the decrease in intestinal ZO-1 expression in infants.

BACKGROUND & AIMS: Milk-derived miR-148a-3p (miR-148a), which is abundant in breast milk, has been shown to be associated with the development of infants' intestines. Although it is well known that stress during lactation changes milk constituents in terms of lipid and protein, no studies have examined the influence of stress on miR-148a expression in breast milk. The objective of this study is to investigate the relationship between stress and miR-148a expression in milk, and to evaluate whether the changes in milk-derived miR-148a expression-caused by the mother's exposure to stress-influence intestinal ZO-1 expression in infants. METHODS: The participants of this study were healthy Japanese women who were nursing. Psychological stress evaluation of the subjects was conducted using a short form of the Profile of Mood State Second Edition-Adult (POMS-2). Additionally, miR-148a expressions in restraint stressed nursing mice were investigated using quantitative real-time PCR. The levels of a tight junction protein zonula occludens-1 (ZO-1) and DNA methyltransferase 1 (DNMT1), which is a direct target of miR-148a, in ileum in neonatal mice breastfed by stressed nursing mice were investigated using Western blot. Furthermore, to investigate the influence of miR-148a on ZO-1 expression within the intestine, the levels of ZO-1 and DNMT1 in human intestinal epithelial Caco-2 cells with lentivirus-mediated miR-148a overexpression were evaluated. RESULTS: A significantly negative correlation was observed between relative miR-148a expression in breast milk and the total mood disturbance T-score. Each T-score on negative mood subscales of anger-hostility, confusion-bewilderment, depression-dejection, fatigue-inertia, and tension-anxiety was significantly negatively correlated with relative miR-148a expression in breast milk: a positive mood subscale vigor-activity T-score was significantly positively correlated with relative miR-148a expression in breast milk. A positive mood friendliness T-score, estimated separately from other scores, was significantly positively correlated with relative miR-148a expression in breast milk. Additionally, the relative expression of miR-148a in the milk obtained from stressed mice was significantly lower than that of control mice. The relative level of ZO-1 in ileum of neonatal mice nursed by stressed mice was significantly lower than that of neonatal mice nursed by control mice. Additionally, the relative level of DNMT1 in ileum of neonatal mice nursed by stressed mice was significantly higher than that of neonatal mice nursed by control mice. Furthermore, the relative level of ZO-1 in miR-148a-overexpressed Caco-2 cells was significantly higher than that in control cells. The relative level of DNMT1 in miR-148a-overexpressed Caco-2 cells was significantly lower than that in control cells. CONCLUSIONS: Mothers' exposure to stress during lactation may cause miR-148a expression in breast milk. Additionally, stressed-induced suppression of miR-148a expression in breast milk may cause a decrease in intestinal ZO-1 level via the increase in DNMT1 in infants' intestines. These observations are beneficial information for breastfeeding mothers and their families and perinatal medical professionals. Our findings encourage monitoring maternal psychological stress during lactation to promote breastfeeding and adequate infant nutrition.

Renin-angiotensin system inhibitors may have an advantage over calcium channel blockers in reducing proteinuria in gastric cancer patients receiving ramucirumab.

This study aimed to investigate whether renin-angiotensin system inhibitors (RAS-I) have an advantage over calcium channel blockers (CCB) for suppression of proteinuria in hypertensive patients with gastric cancer receiving ramucirumab (RAM) treatment. Adult Japanese patients with gastric cancer who were outpatients at Asahikawa Medical University Hospital, National Hospital Organization Hokkaido Cancer Center, and Iwate Medical University Hospital between July 1, 2015, and March 31, 2021, were included in this study. Of these patients, those who had received first-time RAM treatment, and those treated with antihypertensive agents including RAS-I or a CCB at initial RAM administration were included. A total of 36 patients were analyzed in this study. Of these patients, 17 patients were classified into the RAS-I group and the remaining 19 into the CCB group. After 12 weeks of RAM administration, the prevalence of proteinuria in the RAS-I group was significantly lower than that in the CCB group. Additionally, Kaplan-Meier analysis showed that the cumulative occurrence of proteinuria in the RAS-I group over 12 weeks following RAM administration was significantly lower than that in the CCB group. Furthermore, simulation of the time course of RAM blood concentrations based on the O'Brien model showed that there may not be differences in the RAM blood concentration profiles over 12 weeks between the two groups. RAS-I may have an advantage over CCB for suppressing proteinuria in hypertensive patients with gastric cancer treated with blood pressure antihypertensive agents. Our results provide useful information to healthcare professionals involved in the administration of RAM treatment.

Expression profiles of hsa-miR-148a-3p and hsa-miR-125b-5p in human breast milk and infant formulae.

BACKGROUND: Milk-derived microRNAs (miRNAs), including hsa-miR-148a-3p (miR-148a) and hsa-miR-125b-5p (miR-125b), have been shown to be beneficial to the gastrointestinal function in infants. Here, we investigated their expression during lactation in humans and determined whether the infant formulae available in Japan contain these miRNAs. METHODS: Healthy Japanese women (n = 16) who gave birth vaginally or by cesarean section at the Teine Keijinkai Hospital between 1 September 2020, and 31 April 2021 were included in this study. Breast milk was collected by nurses on days 4 or 5 after delivery (hereinafter, transition milk) and on day 30 of postpartum (hereinafter, mature milk). The levels of miR-148a and miR-125b in breastmilk and six commercially available infant formulae were compared and evaluated using quantitative reverse transcription-polymerase chain reaction. RESULTS: In all participants, the miR-148a level in mature breastmilk was significantly lower than that in the transition milk. The changes in miR-125b expression during lactation showed similar trends to the changes in miR-148a expression. The miR-148a and miR-125b levels in all analyzed infant formulae were lower than 1/500th and 1/100th of those in mature breastmilk, respectively. CONCLUSIONS: The levels of both miR-148a and miR-125b in human breast milk decreased on day 30 postpartum compared with those in the transition milk. Additionally, the expression of these miRNAs in infant formulae available in Japan was very low. Further studies with larger populations are required to understand precisely the lactational changes in the expression of miR148a and miR-125b in breast milk.

Changes in postural control strategy during quiet standing in individuals with knee osteoarthritis.

BACKGROUND: Knee osteoarthritis (OA) impairs postural control and may affect how the lower limb joints are used for postural control. OBJECTIVE: To investigate how individuals with knee OA use lower limb joints for static postural control. METHODS: Ten patients with knee OA and thirteen healthy controls performed quiet standing for 30 s. The standard deviation of the center of mass (COM) and lower limb joint motions in the anterior-posterior (AP) and medial-lateral (ML) planes were calculated from three-dimensional marker trajectories. Pearson's correlation analysis and independent t-tests were conducted to investigate the relationship between COM and lower limb joint motion and to compare group difference, respectively. RESULTS: The AP hip angular velocity alone in the knee OA group and the AP hip and knee angular velocity in the control group were significantly correlated with the AP COM velocity. The ML hip angular velocity was significantly correlated with the ML COM velocity in both groups. The knee OA group exhibited a significantly larger standard deviation of AP COM velocity than the control group. CONCLUSIONS: Individuals with knee OA depended solely on the contribution of the hip to the AP COM velocity, which could not be successfully controlled by the knee.

Effects of Posterior Spinal Correction and Fusion on Postural Stability in Patients with Adolescent Idiopathic Scoliosis.

The present study aimed to assess the effects of posterior spinal correction and fusion on postural stability in patients with adolescent idiopathic scoliosis (AIS). The study included 41 female patients with AIS at our institution. All patients performed three 10 s single-leg standing trials on a force plate. The center of pressure (COP) was measured preoperatively, and at 1 week and 6 months postoperatively. The postural stability parameters were absolute minimum time-to-boundary (TTB), mean of the minimum TTB, mean COP velocity, standard deviation, range, and 95% confidence ellipse area. One-way repeated analysis of variance or Friedman test was applied to the postural stability parameters. Multiple comparisons were performed using the Bonferroni correction. The absolute minimum TTB and the mean minimum TTB showed a significant increase 6 months post-operation as compared to preoperatively and 1 week postoperatively. The COP velocity significantly decreased at 6 months post-operation compared to preoperatively and 1 week postoperatively. These changes in postural stability indicate that spinal correction and fusion can be considered to improve postural stability during single-leg standing tests in the postoperative period.

Analysis of risk factors for skin disorders caused by anti-epidermal growth factor receptor antibody drugs and examination of methods for their avoidance.

WHAT IS KNOWN AND OBJECTIVE: Cancer drug treatment is often discontinued because of skin disorder aggravation. However, information on risk factors for skin disorders caused by anti-epidermal growth factor receptor (EGFR) antibody drugs is limited. The aim of this study was to analyse the factors associated with skin disorders caused by anti-EGFR antibody drugs and establish a method to minimize such aggravations. METHODS: We retrospectively examined 67 colorectal cancer patients treated with anti-EGFR antibody drugs for the first time. RESULTS AND DISCUSSION: A higher proportion of males than females experienced drug withdrawal, dose reduction or treatment discontinuation. The multiple logistic regression analysis revealed body weight as a risk factor affecting drug withdrawal, dose reduction or treatment discontinuation because of an acneiform rash. An examination of methods to avoid the aggravation of skin disorders revealed the acneiform rash grade in patients who received prophylactic minocycline was significantly lower than that in patients who did not receive prophylactic minocycline. Furthermore, among patients with grade 1 acneiform rash at the initiation of minocycline, the proportion of those who withdrew, required dose reduction or discontinued treatment was lower than that among patients with grade 2 acneiform rash. WHAT IS NEW AND CONCLUSION: High body weight was identified as a novel factor for skin disorder aggravation caused by anti-EGFR antibody drugs. The aggravation of skin disorders during cancer treatment with anti-EGFR antibody drugs can potentially be avoided by carefully observing the onset of acneiform rash in affected patients with high body weight and using minocycline prophylactically or as an early-stage intervention.

Switching from Intravenous to Oral Tacrolimus Reduces its Blood Concentration in Paediatric Cancer Patients.

BACKGROUND/AIM: Tacrolimus is an essential immunosuppressant for successful allogeneic haematopoietic stem cell transplantation (Allo-HSCT). This study aimed to examine the change in the blood concentration of tacrolimus during switching from intravenous to oral administration in allo-HSCT for paediatric cancer to predict the optimal dosage. PATIENTS AND METHODS: We retrospectively examined the medical records of 63 patients who received allo-HSCT and were administered tacrolimus. To compare bioavailability among different dose ranges, the blood concentration was divided by the dose (C/D). RESULTS: Thirty-nine patients (age range=children 1-15 years, adults 17-67 years) were switched to oral administration of tacrolimus. The C/D after switching was significantly lower in children than in adults (p=0.039). There was a strong positive correlation between age and C/D in children, whereas no correlation was observed in adults. CONCLUSION: In paediatric cancer patients, switching tacrolimus administration route may result in reduced blood concentrations. This tendency is more prominent in younger children.

Dynamic postural control correlates with activities of daily living and quality of life in patients with knee osteoarthritis.

BACKGROUND: Knee osteoarthritis (OA) negatively affects dynamic postural control, which is a basic function that individuals use to perform activities of daily living (ADL). The purpose of this study was to investigate the associations of center of pressure (COP) control during the transition from double-leg to single-leg standing with subjective assessments of ADL and quality of life (QOL) in patients with knee OA. METHODS: Thirty-six patients (29 females) with moderate-to-severe knee OA participated. Dynamic postural control was evaluated during the transition from double-leg to single-leg standing. Each patient stood on a force plate, lifted the less affected limb as fast as possible, and maintained single-leg standing with the more affected limb. The COP movements corresponding to anticipatory postural adjustment (APA) and transitional phases were assessed. The maximum displacement and peak velocity of the COP movements in the medial-lateral direction were calculated. The Knee Injury and Osteoarthritis Outcome Score (KOOS) was used for the subjective assessment of ADL and QOL. Pearson's product correlation analysis was performed to investigate the associations of COP movements in the APA and transitional phases with KOOS-ADL and KOOS-QOL. RESULTS: In the APA phase, the maximum COP displacement was significantly correlated with KOOS-ADL (r = -0.353, P = 0.035) and KOOS-QOL (r = -0.379, P = 0.023). In the transitional phase, the maximum COP displacement and peak COP velocity were significantly correlated with KOOS-ADL (maximum displacement: r = 0.352, P = 0.035; peak velocity: r = 0.438, P = 0.008) and with KOOS-QOL (maximum displacement: r = 0.357, P = 0.032; peak velocity: r = 0.343, P = 0.040). CONCLUSIONS: The present study showed that smaller COP movements in the APA phase and smaller and slower COP movements in the transitional phase correlated with poorer ADL and QOL conditions in patients with knee OA. These findings suggest that poor dynamic postural control is associated with poor ADL and QOL conditions in patients with moderate-to-severe medial knee OA. Conservative treatment for patients with knee OA may need to focus on dynamic postural control during the transition from double-leg to single-leg standing.

Norepinephrine transporter expressed on mammary epithelial cells incorporates norepinephrine in milk into the cells.

Mammary epithelial cells synthesize and secrete norepinephrine (NE) into breast milk to regulate ß-casein expression through the adrenergic ß2 receptor. We investigated the expression, localization, and roles of NE transporter (NET) in the mammary epithelium during lactation. mRNA and protein levels of NET were determined in primary normal human mammary epithelial cells (pHMECs) and non-malignant human mammary epithelial MCF-12A cells. In nursing CD1 mice, NET localized to the apical membranes of the mammary epithelium. The intracellular NE content of pHMECs incubated with NE increased. Although the ß-casein concentration in milk was slightly higher at day 10 than at day 2 of lactation, the NE concentration and lactation-related proteins were only slightly changed on days 2-10. Restraint stress increased the NE concentration in milk from nursing mice and NET protein levels were significantly higher than in non-stressed nursing mice. NET is expressed on the apical membrane of mammary epithelial cells and incorporates NE in milk into cells, potentially regulating the NE concentration in milk.

Physiologic changes in serotonin concentrations in breast milk during lactation.

OBJECTIVES: Serotonin (5-hydroxytryptamine; 5-HT) plays an important role in milk volume homeostasis in the mammary glands during lactation, and 5-HT in milk also may affect infant development. The aim of this study was to investigate changes in 5-HT concentration in breast milk according to the duration of lactation and evaluate whether the 5-HT concentration varied before and after nursing. METHODS: Healthy nursing Japanese women who had a natural delivery or underwent a cesarean delivery at Iwate Medical University Hospital were included in this study. RESULTS: The mean 5-HT concentration in milk was obtained from multiparous mothers 6 to 7 d after delivery (colostrum) and was significantly higher compared with primiparous mothers (24.3 ± 2.63 versus 18.5 ± 2.60 ng/mL). Additionally, mean 5-HT concentration increased with increasing lactation duration in primiparous women (colostrum: 18.5 ± 2.60; 1 mo postdelivery: 19.8 ± 2.46; 3 mo postdelivery: 22.7 ± 2.55 ng/mL); in particular, the mean 5-HT concentration in breast milk 3 mo after delivery was significantly higher than in colostrum. The mean 5-HT concentrations in breast milk in primiparous mothers immediately before nursing, 1 to 2 h after nursing, and immediately before the next nursing event were 23.6 ± 1.48, 22.82 ± 1.65, and 21.84 ± 1.31 ng/mL, respectively; mean 5-HT concentrations in multiparous women were 25.4 ± 1.65, 23.6 ± 2.20, or 22.4 ± 2.09 ng/mL, respectively. There was no significant difference in 5-HT concentrations at each time point between the groups. CONCLUSION: This information may be useful in determining the role of 5-HT in breast milk on infant development and growth.

Cancer Cachexia May Hinder Pain Control When Using Fentanyl Patch.

The objective of this study was to evaluate the influence of cancer cachexia on pain control in cancer patients receiving a transdermal fentanyl patch (FP) and to investigate whether dry skin was a factor related to cancer cachexia and uncontrolled pain. We retrospectively reviewed the medical records of 77 patients receiving FP treatment for the first time, who were classified into cancer cachexia and non-cancer-cachexia groups, according to European Palliative Care Research Collaborative criteria. On day 7 after FP administration, the mean FP dose and morphine equivalent dose (MED) in the cancer cachexia group were significantly higher than in the non-cancer-cachexia group. Additionally, in the cancer cachexia group, there was a significantly larger degree of variation in pain intensity over 7 d than in the non-cachexia group. In patients who were switched from FP to morphine injection, the mean pain intensity and MED on day 3 after morphine injection were significantly lower than those immediately before morphine injection. Subsequently, to investigate whether dry skin was involved in poor pain control in the cancer cachexia group, transepidermal water loss (TEWL) was compared between 15 additional patients classified into cancer cachexia and non-cancer cachexia groups; the mean TEWL in the cancer cachexia group was found to be significantly lower. Our data suggest that cancer cachexia may be a risk factor for poor pain control in patients receiving FP treatment, and that uncontrolled pain in FP treatment may be caused by the inhibition of fentanyl transdermal absorption due to dry skin.

Abdominal draw-in maneuver changes neuromuscular responses to sudden release from trunk loading in patients with non-specific chronic low back pain.

BACKGROUND: Abdominal draw-in maneuver (ADIM) has been recommended to achieve appropriate trunk muscle response for patients with non-specific chronic low back pain (CLBP). However, it has remained unclear whether the intervention with ADIM could change the trunk muscle response to sudden release from loading, which is considered to contribute mechanical circumstances to low back pain. The purpose of the present study was to investigate the effects of the intervention with ADIM on electromyography (EMG) activities of trunk muscles following sudden release from loading. METHODS: Seventeen subjects with non-specific CLBP participated. Subjects resisted trunk flexion or extension loading in semi-seated position, and then the loading was suddenly released. EMG recordings of 6 trunk muscles were acquired using a wireless surface EMG system. Onset and offset times were calculated from the EMG data. The intervention with ADIM was provided for 4 weeks. The onset and offset times were compared between pre- and post-intervention with ADIM. RESULTS: At the post-intervention, the onset of trunk flexors following release from trunk flexion loading became significantly earlier than pre-intervention (P = 0.028). The offset of flexors following release from trunk extension loading of post-intervention was significantly earlier than that of pre-intervention (P = 0.001). CONCLUSIONS: We showed that the intervention with ADIM changed the EMG activity of trunk flexors in response to sudden release from loading. These results suggest a possibility that ADIM might be effective to improve the neuromuscular control of trunk flexors for the treatment of young patients with non-specific CLBP.

Stress-Induced Suppression of Milk Protein Is Involved in a Noradrenergic Mechanism in the Mammary Gland.

Stress decreases milk components such as milk protein and milk yield. The objective of this study was to investigate whether noradrenaline (NA) in milk constituted a factor associated with stress-induced changes in milk proteins such as ß-casein. Breast milk obtained from eight healthy, nursing women contained NA at concentrations ranging from 12.7 to 115.5 nM. The expression of tyrosine hydroxylase (TH), a rate-limiting enzyme of NA synthesis, was observed in primary normal human mammary epithelial cells (HMECs), and in MCF-12A and MCF-10A cell lines. The mean NA concentration in culture medium used by MCF-12A transfected with TH small interfering RNA (siRNA) was significantly lower than that of cells transfected with control siRNA. NA concentration in milk in restraint-stressed nursing mice was significantly higher than that in nonstressed nursing mice, owing to elevated TH expression in the mammary epithelium. The mean ß-casein concentration in milk in restraint-stressed mice was significantly lower than that in nonstressed mice. NA treatment resulted in a concentration-dependent decrease in ß-casein expression in HMECs. ß2 adrenergic receptor (ADRB2) expression was observed in HMECs, MCF-12A, and MCF-10A, and immunohistochemical analysis of ADRB2 using mammary epithelium sections obtained from mice at day 10 of lactation showed that ADRB2 was expressed at the apical membrane of mammary epithelium. Treatment with salbutamol, an ADRB2 stimulant, decreased ß-casein expression in a concentration-dependent manner in MCF-12A. Our results showed that endogenous NA derived from mammary epithelial cells likely comprises one of the factors involved in stress-induced changes in milk proteins such as ß-casein.

Deterioration of Glycemic Control Contributes to the Prevalence of Proteinuria among Bevacizumab-Treated Cancer Patients with Type 2 Diabetes Mellitus.

The objective of this study was to investigate whether improving glycemic control reduces the prevalence and progression of proteinuria among bevacizumab (BEV)-treated cancer patients with type 2 diabetes mellitus (DM). We retrospectively reviewed the medical records of 55 patients with type 2 DM who were treated with BEV between July 1 2011 and May 31 2018 at Iwate Medical University Hospital. The patients were classified based on changes in glycated hemoglobin (HbA1c) level during the 3 months following BEV administration into the "HbA1c elevated" group (+0.5% or above, n=24) and the "HbA1c non-elevated" group (indicating no change or decrease; n=31). At 3 months following BEV administration, the means of HbA1c and its change rate in the 'HbA1c elevated' group was significantly higher than that in the 'HbA1c non-elevated' group, and the prevalence of proteinuria in the 'HbA1c elevated' group was significantly higher than that in the 'HbA1c non-elevated' group. Additionally, our subjects were classified into the proteinuria group and non-proteinuria group. The mean HbA1c level in the proteinuria group was significantly higher than that in the non-proteinuria group at 3 months following BEV administration. Furthermore, the mean rates of change of HbA1c level in patients experiencing grades 1 and 2 proteinuria were +9.97±2.26 and +14.0±3.82%, respectively. These values were significantly higher than those of patients with no proteinuria (-2.15±1.96%). Our results suggest that deterioration of glycemic control contributes to the prevalence of proteinuria among BEV-treated cancer patients with type 2 DM.

[Endogenous Serotonin and Milk Production Regulation in the Mammary Gland].

　Intrinsic serotonin (5-hydroxytryptamine; 5-HT) synthesized within the mammary epithelium has an important physiological role in milk volume homeostasis in many species including mice, cows, and humans. During lactation, mammary epithelial cells activate 5-HT synthesis by tryptophan hydroxylase 1 (TPH1). TPH1 catalyzes the rate-limiting step in 5-HT biosynthesis within mammary glands. 5-HT synthesized in mammary glands is released into both the apical (milk) and basolateral spaces by a vesicular monoamine transporter. 5-HT released into milk is incorporated by the apical membrane-expressed serotonin reuptake transporter and degraded by the monoamine oxidase A enzyme. Suckling maintains 5-HT at low levels in milk. When the mammary gland becomes filled with milk, 5-HT provides a negative feedback signal that suppresses further milk synthesis in the mammary epithelium. Our research, using human mammary epithelial MCF-12A cells, shows that the expression of ß-casein, a differentiation marker, is suppressed via 5-HT-mediated inhibition of signal transducer and activator of transcription 5. Additionally, our results show that reduced ß-casein expression in MCF-12A cells is associated with 5-HT7 receptor expression. Furthermore, we show that 5-HT7 receptor-mediated suppression of ß-casein expression is involved in the activation of protein kinase A and protein-tyrosine phosphatase 1B. Thus, this mechanism might be associated with the feedback signals by 5-HT within the mammary epithelium. Hence, further research that builds on our findings should include the elucidation of the physiological roles of 5-HT present in milk synthesized by mammary epithelial cells in vivo and its effects on nursing infants.

Antiproteinuric effects of renin-angiotensin inhibitors in lung cancer patients receiving bevacizumab.

PURPOSE: The objective of this study was to investigate the effect of renin-angiotensin system inhibitors (RASIs) on bevacizumab (BV)-induced proteinuria in non-small cell lung cancer (NSCLC) patients. MATERIALS AND METHODS: We retrospectively reviewed the medical records of NSCLC patients receiving BV between 2008 and 2014 at 11 hospitals. The patients were categorized into three groups according to their antihypertensive drug use: RASI user, non-RASI user, and non-user groups. The primary outcome was a proteinuria event of any grade during the first 6 cycles of BV treatment. RESULTS: A total of 211 patients were included, 89 of whom received antihypertensive drugs. Of these 89 patients, 49 were in the RASI user group, and 40 were in the non-RASI user group. The non-user group comprised 122 patients. The occurrence of proteinuria in the RASI user group was significantly lower than that in the non-RASI user group (P = 0.037) but was not significantly lower than that in the non-user group (P = 0.287). Patients using RASIs had a lower rate of proteinuria than those who did not use RASIs according to multivariate analysis (odds ratio 0.32; 95% confidence interval 0.12-0.86; P = 0.024). CONCLUSION: Our study suggests that RASI administration reduces the risk of proteinuria in patients receiving BV.