Ganglioside GD2 Expression Is Associated With Unfavorable Prognosis in Early Triple-negative Breast Cancer.

BACKGROUND/AIM: Gangliosides (acidic glycosphingolipids) have crucial regulatory roles in normal physiological processes, as well as in pathological conditions, including tumor onset and progression. GD2 is highly expressed in triple-negative breast cancer (TNBC), particularly in cancer stem cells. However, little is known on the clinical impact of GD2 expression on the prognosis of TNBC. Consequently, we aimed to investigate the association between GD2 expression in TNBC and the prognosis of TNBC. PATIENTS AND METHODS: We assessed GD2 expression in 76 patients with primary TNBC who had undergone surgery at our Institute between 2012 and 2015 using immunohistochemical analysis with a tissue microarray technique. We investigated the relationship between GD2 expression and clinicopathological factors in TNBC, recurrence-free survival (RFS), and overall survival (OS). RESULTS: Increased GD2 expression was observed in 45% of TNBC patients. There was no significant association between GD2 expression and clinicopathological factors in TNBC. The 5-year RFS rate among patients with GD2-positive TNBCs was significantly worse than that among patients with GD2-negative TNBCs (75.4% and 94.9%; HR=4.931; 95%CI=1.024-23.752; p=0.027). The OS in patients with GD2-positive TNBCs tended to be inferior to that of patients with GD2-negative TNBCs (HR=5.357; 95%CI=0.599-47.939; p=0.092). Interestingly, in patients with GD2-positive TNBCs, a higher grade of tumor-infiltrating lymphocytes (TILs) displayed a significantly better impact on OS (TILs-high vs. TILs-low; p=0.04). Both univariate and multivariate analyses showed that GD2 expression negatively affected RFS (p=0.027, p=0.021, respectively). CONCLUSION: GD2 expression is an independent unfavorable prognostic factor for TNBC.

Preferences Regarding Breast Surgery Omission Among Patients With Breast Cancer Who Receive Neoadjuvant Chemotherapy.

BACKGROUND/AIM: Currently, several ongoing prospective studies are investigating the safety of breast surgery omission in patients with breast cancer who are exceptional responders to neoadjuvant chemotherapy. However, there is little information about the preferences of these patients regarding omission of breast surgery. PATIENTS AND METHODS: We conducted a questionnaire survey to assess preferences regarding omission of breast surgery among patients with breast cancer who had human epidermal growth factor receptor 2-positive or estrogen receptor-negative tumors and good clinical response after neoadjuvant chemotherapy. Patients' estimation of the risk of ipsilateral breast tumor recurrence (IBTR) after definitive surgery or breast surgery omission was also assessed. RESULTS: Of 93 patients, only 22 (23.7%) said they would omit breast surgery. Under the scenario of omitting breast surgery, the 5-year IBTR rate estimated by patients who said they would omit breast surgery was significantly lower (median, 10%) than the rate estimated by patients who preferred undergoing definitive surgery (median, 30%) (p=0.017). CONCLUSION: The proportion of our surveyed patients who were willing to omit breast surgery was low. Patients who said they preferred to omit breast surgery overestimated the 5-year IBTR risk.

Palladium-Catalyzed para-Selective Allylation of 1-(Cyanomethyl)arenes with Allyl Acetates.

The Pd/PMe3-catalyzed allylation of 1-(cyanomethyl)naphthalenes with allyl acetates proved to be para- rather than α-regioselective. This reaction is thought to proceed through ligand attack of the para-carbon in the arenes, electronically enriched by a cyano-stabilized α-carbanion, to the (π-allyl)palladium and a 1,5-hydrogen shift of the para-hydrogen from the dearomatized intermediate.

Long-term course of the changes in the nipple position after breast-conserving surgery.

PURPOSE: Even if favorable cosmetic outcomes are obtained shortly after breast-conserving surgery (BCS), cosmetic changes may occur up to several years after BCS. In the present study, we evaluated cosmetic changes while focusing on changes in the nipple position after BCS. METHODS: We examined the long-term course of changes in the nipple position over time after BCS using the proportion of the distance between the sternal notch and nipple (PDSN) in 196 patients. We also evaluated risk factors for long-term nipple position changes. RESULTS: The median follow-up period was 9.9 years. Nipple position changes occurred within eight years after BCS and seemed to plateau beyond that point. The body mass index (BMI), breast size, proportion of excision volume and axillary treatment were significantly associated with the nipple position changes within one to five years after BCS. The BMI, breast size, axillary treatment, chemotherapy and hormonal therapy were significantly associated with the nipple position changes within five to eight years after BCS. CONCLUSIONS: After BCS, the nipple position changes occur within about eight years. Obesity, large breast size, large excision volume, axillary treatment, chemotherapy and hormone therapy were factors that affected the treated breast shrinkage and increase in the left-right difference after BCS.

Probing the Spatiotemporal Dynamics of Oxytocin in the Brain Tissue Using a Simple Peptide Alkyne-Tagging Approach.

The dynamics of oxytocin and its site of action in the brain are poorly understood due to the lack of appropriate tools, despite the interest in the central action of oxytocin signaling. Here, we develop and apply an oxytocin analogue probe by conjugating it with an alkyne via a widely applicable simple coupling reaction. Alkyne-tagged oxytocin behaves similarly to endogenous oxytocin while allowing specific and highly sensitive detection of extracellularly applied oxytocin. Using this probe, we find the existence of high-affinity specific binding sites of oxytocin in the hippocampus. Furthermore, characterization of oxytocin dynamics reveals the cellular basis of its volume transmission in the brain tissue. Finally, we show the wide applicability of this technique for other centrally acting peptides. Thus, the alkyne tagging strategy provides a unique opportunity to characterize the spatiotemporal dynamics of oxytocin and other small-sized peptides in the brain tissue.

Pain in Spinal Muscular Atrophy: A Questionnaire Study.

OBJECTIVE: This study aimed to reveal the chronic pain prevalence in spinal muscular atrophy (SMA) patients and identify the clinical characteristics of these patients with chronic pain. The pain status was also investigated in SMA patients with chronic pain. METHODS: This cross-sectional study was conducted between July 2018 and December 2018. SMA type II and type III patients in Japan were mailed a survey questionnaire. The survey items were chronic pain prevalence, clinical characteristics, and motor function. Patients with chronic pain also answered questions on various pain status parameters: pain intensity, frequency, duration, location using body map, and factors that exacerbated and relieved pain. RESULTS: The questionnaire recovery rate was 61.1%. Sixty-four type II (mean age 17.3 ± 11.7 years) and 22 type III (mean age 44.9 ± 21.6 years) patients were eligible for inclusion. The prevalence of chronic pain in type II and III patients was 40.6% and 40.9%, respectively. Type II patients with chronic pain were more likely to report the inability to sit without manual support than those without pain (p = 0.03). Pain intensity in SMA patients was mild, but pain usually occurred daily, for prolonged durations, most often in the neck, back, and lower extremities. Sitting and high physical activity exacerbated pain the most. CONCLUSION: The percentage of patients with SMA with chronic pain was high, at above 40%. Moreover, the pain experienced by patients with SMA was low in intensity but frequent and most common in the lower extremities.

Eating Dinner Early Improves 24-h Blood Glucose Levels and Boosts Lipid Metabolism after Breakfast the Next Day: A Randomized Cross-Over Trial.

Aim: To examine whether mild early time-restricted eating (eating dinner at 18:00 vs. at 21:00) improves 24-h blood glucose levels and postprandial lipid metabolism in healthy adults. Methods: Twelve participants (2 males and 10 females) were included in the study. In this 3-day (until the morning of day 3) randomized crossover study, two different conditions were tested: eating a late dinner (at 21:00) or an early dinner (at 18:00). During the experimental period, blood glucose levels were evaluated by each participant wearing a continuous blood glucose measuring device. Metabolic measurements were performed using the indirect calorimetry method on the morning of day 3. The study was conducted over three days; day 1 was excluded from the analysis to adjust for the effects of the previous day's meal, and only data from the mornings of days 2 and 3 were used for the analysis. Results: Significant differences were observed in mean 24-h blood glucose levels on day 2 between the two groups (p = 0.034). There was a significant decrease in the postprandial respiratory quotient 30 min and 60 min after breakfast on day 3 in the early dinner group compared with the late dinner group (p < 0.05). Conclusion: Despite a difference of only 3 h, eating dinner early (at 18:00) has a positive effect on blood glucose level fluctuation and substrate oxidation compared with eating dinner late (at 21:00).

Alkyne-Tagged Dopamines as Versatile Analogue Probes for Dopaminergic System Analysis.

The dopaminergic system is essential for the function of the brain in health and disease. Therefore, detailed studies focused on unraveling the mechanisms involved in dopaminergic signaling are required. However, the lack of probes that mimic dopamine in living tissues, owing to the neurotransmitter's small size, has hampered analysis of the dopaminergic system. The current study aimed to overcome this limitation by developing alkyne-tagged dopamine compounds (ATDAs) that have a minimally invasive and uniquely identifiable alkyne group as a tag. ATDAs were established as chemically and functionally similar to dopamine and readily detectable by methods such as specific click chemistry and Raman scattering. The ATDAs developed here were verified as analogue probes that mimic dopamine in neurons and brain tissues, allowing the detailed characterization of dopamine dynamics. Therefore, ATDAs can act as safe and versatile tools with wide applicability in detailed studies of the dopaminergic system. Furthermore, our results suggest that the alkyne-tagging approach can also be applied to other small-sized neurotransmitters to facilitate characterization of their dynamics in the brain.

Walking Attainment in Very Low Birth Weight Infants in Japan.

OBJECTIVE: To clarify the corrected age of walking attainment in very low birth weight infants by birth weight and gestational age, and determine perinatal factors affecting the delay in walking attainment. METHOD: This was a longitudinal study. We investigated walking attainment and perinatal factors in 145 very low birth weight infants without neurological abnormalities (mean birth weight 1019.3 ± 299.7 g, gestational age 29.0 ± 2.9 weeks). The study infants were stratified by birth weight (group A: <1,000 g, group B: 1,000 g≤, <1,500 g) and gestational age (group I: <28 weeks, group II: 28 weeks≤, <37 weeks) and were compared using unpaired t-tests. Furthermore, we examined the perinatal factors that affect the delay in walking attainment using multiple regression analysis. RESULTS: Of the walking attainment, infants in Group A were older than those in Group B (50th percentile, 15.8 vs. 14.7 months). Infants in Group I were older than those in Group II (50th percentile, 16.0 vs. 14.8 months). Using multiple regression analysis with walking attainment age as the dependent variable, the duration of mechanical ventilation was found to be significantly related. CONCLUSION: Very low birth weight infants with light weight and short gestational age have delayed walking attainment, and longer duration of mechanical ventilation increases the risk of delay.

Effects of continued positioning pillow use until a corrected age of six months on cranial deformation and neurodevelopment in preterm infants: A prospective case-control study.

BACKGROUND: Preterm infants have a high risk of cranial deformity resulting from external pressures. Such deformity is associated with delayed neurodevelopment. AIMS: We aimed to clarify the effects of continuous use of positioning pillows on cranial deformity and neurodevelopment in preterm infants. METHODS: This prospective case-control study was conducted between November 2018 and August 2019. The continuous use of a pillow was initiated after discharge from the neonatal intensive care unit, up to a corrected age of six months. Preterm infants weighing less than 1800 g without neurological abnormalities were included in the study. Patients were divided into two groups: non-pillow group (NP-group) and pillow group (P-group). The primary outcome was the Bayley Scales of Infant Development III (BSID-III) score. We compared asymmetrical cranial deformity and the BSID-III scores in the two groups at a corrected age of six months using the Fisher's exact test and unpaired t-test, respectively. RESULTS: There were 19 preterm infants (mean gestational age 32.5 ± 1.9 weeks, birth weight 1461.3 ± 244.7) eligible during the study period. The P-group (n = 11) showed asymmetrical cranial deformity at six months less frequently than the NP-group (n = 8) (p = 0.001, Fisher's exact test). Infants in the P-group had significantly higher scores on the BSID-III cognitive scales (95.0 ± 8.4 vs. 86.9 ± 2.6; p = 0.02, unpaired t-test) and fine motor scores on the motor scales (8.6 ± 2.2 vs. 6.6 ± 0.7, p = 0.02, unpaired t-test). CONCLUSIONS: Continuous pillow use in preterm infants is effective in reducing cranial deformity and improved cognitive and fine motor skills. TRIAL REGISTRATION: UMIN Clinical Trials Registry, trial no. UMIN000034400 (http://www.umin.ac.jp/ctr/index.htm).

Antimicrobial cathelicidin peptide LL­37 induces NET formation and suppresses the inflammatory response in a mouse septic model.

LL­37 is the only known member of the cathelicidin family of antimicrobial peptides in humans. In addition to its broad spectrum of antimicrobial activities, LL­37 may modulate various inflammatory reactions. The authors previously revealed that LL­37 improves the survival of a murine cecal ligation and puncture (CLP) sepsis model. In the present study, the mechanism for the protective action of LL­37 was elucidated using the CLP model, focusing on the effect of LL­37 on the release of neutrophil extracellular traps (NETs). The results indicated that the intravenous administration of LL­37 suppressed the increase of damage-associated molecular patterns (DAMPs), including histone­DNA complex and high­mobility group protein 1, in addition to interleukin­1ß, tumor necrosis­α and soluble triggering receptor expressed on myeloid cells (TREM)­1 in plasma and peritoneal fluids. Notably, LL­37 significantly suppressed the decrease of mononuclear cell number in blood, and the increase of polymorphonuclear cell (neutrophil) number in the peritoneal cavity during sepsis. Furthermore, LL­37 reduced the bacterial burden in blood and peritoneal fluids. Notably, LL­37 increased the level of NETs (myeloperoxidase­DNA complex) in plasma and peritoneal fluids. In addition, it was verified that LL­37 induces the release of NETs from neutrophils, and NETs possess the bactericidal activity. Overall, these observations suggest that LL­37 improves the survival of CLP septic mice by possibly suppressing the inflammatory responses as evidenced by the inhibition of the increase of cytokines, soluble TREM­1 and DAMPs (host cell death) and the alteration of inflammatory cell numbers, and bacterial growth via the release of NETs with bactericidal activity.

The gross motor function measure is valid for Fukuyama congenital muscular dystrophy.

Fukuyama congenital muscular dystrophy (FCMD) is the second most common muscular dystrophy in Japan. FCMD is an autosomal recessive disorder caused by mutations in the fukutin gene. The main features of FCMD are a combination of infantile-onset hypotonia, generalized muscle weakness, eye abnormalities, and mental retardation associated with cortical migration defects, and most patients are never able to walk. To date, the development of a quantitative motor scale for FMCD has been difficult due to the moderate-to-severe intellectual impairment that accompanies FCMD. Gross motor function measure (GMFM), originally developed as a quantitative motor scale for cerebral palsy, can precisely and quantitatively assess motor function without complicated instructions, and was recently reported to be useful in the assessment of Down syndrome and spinal muscular atrophy. To confirm the validity of GMFM for the assessment of FCMD, 41 FCMD patients (age range: 0.6-24.4 years) were recruited for this study. The GMFM scores correlated significantly with those of two previously used motor scales, and the time-dependent change in GMFM scores was consistent with the natural course of FCMD. The inter-rater reliability, based on determinations made by four physiotherapists blinded to each other's assessment results, was excellent. We concluded GMFM to be a useful and valid measure of motor function in FCMD patients.