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Previously, we reported that peripheral vaccination of mice with modified autologous tumor cells secreting granulocyte-macrophage colony-stimulating factor (GM-CSF) combined with ionizing radiation to the whole brain cured 50% of mice using a syngeneic, intracranial model of murine high-grade glioma. Here, we tested the combination of radiotherapy (4 Gy × 2) with an immunotherapeutic approach using an anti-CD137 antibody directed to the co-stimulatory molecule CD137. The CD137 antibody has shown promise in generating effective antitumor responses in several animal models and has demonstrated a favorable toxicity profile in the clinic. The combination of radiation and anti-CD137 therapy resulted in complete tumor eradication and prolonged survival in six of nine (67%) mice with established brain tumors (P  =  0.0009). Five of six (83%) long-term survivors in the combination group demonstrated antitumor immunity by rejecting challenge tumors. Antitumor immunity was associated with an increased number of tumor-infiltrating lymphocytes (TILs) in brain tumors and increased tumor-specific production of γIFN. In view of the finding that radiation enhanced the antitumor effect of anti-CD137 therapy, this approach should be studied further for clinical translation.

Dopamine dysregulation syndrome (DDS) consists of a series of complications such as compulsive use of dopaminergic medications, aggressive or hypomanic behaviors during excessive use, and withdrawal states characterized by dysphoria and anxiety, caused by long-term dopaminergic treatment in patients with Parkinson’s disease (PD). Although several ways to manage DDS have been suggested, there has been no established treatment that can manage DDS without deterioration of motor symptoms. In this article, we present a case of PD in whom the administration of the dopamine D 2 partial agonistic antipsychotic drug aripiprazole improved DDS symptoms such as craving and compulsive behavior without worsening of motor symptoms. Considering the profile of this drug as a partial agonist at D 2 receptors, it is possible that it exerts its therapeutic effect on DDS by modulating the dysfunctional dopamine system.

A promising strategy for cancer immunotherapy is to disrupt key pathways regulating immune tolerance, such as cytotoxic T lymphocyte-associated protein 4 (CTLA-4). However, the determinants of response to anti-CTLA-4 mAb treatment remain incompletely understood. In murine models, anti-CTLA-4 mAbs alone fail to induce effective immune responses to poorly immunogenic tumors but are successful when combined with additional interventions, including local ionizing radiation (IR) therapy. We employed an established model based on control of a mouse carcinoma cell line to study endogenous tumor-infiltrating CD8+ T lymphocytes (TILs) following treatment with the anti-CTLA-4 mAb 9H10. Alone, 9H10 monotherapy reversed the arrest of TILs with carcinoma cells in vivo. In contrast, the combination of 9H10 and IR restored MHC class I-dependent arrest. After implantation, the carcinoma cells had reduced expression of retinoic acid early inducible-1 (RAE-1), a ligand for natural killer cell group 2D (NKG2D) receptor. We found that RAE-1 expression was induced by IR in vivo and that anti-NKG2D mAb blocked the TIL arrest induced by IR/9H10 combination therapy. These results demonstrate that anti-CTLA-4 mAb therapy induces motility of TIL and that NKG2D ligation offsets this effect to enhance TILs arrest and antitumor activity.

Olfactory involvement is well recognized in patients with Parkinson's disease (PD). The purpose of this study was to examine smell function quantitatively, using different types and concentrations of odorants in PD patients. We aimed to elucidate whether a specific odor can affect the severity and duration of PD patients. A total of 89 nondemented PD patients and 20 age-matched controls participated in the study. Quantitative evaluation of smell function was performed using the T and T olfactometer test. This test contains five kinds of odorants at different concentrations. Recognition threshold (RT) scores for all five odorants and for each individual odorant were measured in five groups of PD patients with Hoehn and Yale (HY) stages I (n = 12), II (n = 24), III (n = 43), and IV (n = 10), as well as in control subjects (n = 20). One-way analysis of variance and Ryan's method were used for statistical comparison between the five groups. Compared with controls and HY I patients, total RT scores were significantly higher in HY II, III, and IV patients. There were no statistically significant differences in RT scores between HY I patients and controls. However, total RT scores for three HY I patients (25%) were higher than the mean + two standard deviations of controls. On single odorant testing, significant higher RT scores for methylcyclopentenolone and skatol were found in HY II, III, and IV patients, in comparison with controls and HY I patients. The remaining three odorants did not differ statistically between PD patients and control subjects. The present study indicated that hyposmia in PD patients increased from HY II onwards. A single odorant of methyl cyclopentenolone or skatol had benefits for olfactory evaluation in PD patients. Our data also clarified that olfactory deficits occurred in a subset of HY I patients. Further prospective study is needed to elucidate whether a distinct profile of PD exists between HY I patients with and without hyposmia.

We describe two female neonates who suffered from four gastrointestinal anomalies, including duodenal stenosis or atresia, malrotation, segmental dilatation of the colon, and anorectal malformation. Each patient was managed by two or three operations, resulting in good bowel movements. Since this is the first report of four gastrointestinal anomalies, these cases may provide clues to elucidate the etiology of gastrointestinal tract developmental abnormalities.

Gastric rupture is extremely rare in childhood beyond the neonatal period. We describe a previously healthy 6-year-old girl with a large laceration along the greater curvature on the posterior wall of the stomach. The patient was admitted to a neighboring hospital because of vertigo with 1-day history of intractable vomiting and epigastric pain. Although abdominal distension was noticed during the physical examination, muscular rigidity was not detected on palpation. Laboratory data showed severe hypotonic dehydration and moderate metabolic acidosis with hyperkalemia. She suddenly developed cardiac arrest within an hour after admission. After resuscitation, surgical consultation was obtained. Abdominal X-ray and ultrasound revealed abdominal free air and massive cloudy ascites. At laparotomy, there was a large laceration on the greater curvature of the stomach. Pathology of the gastric wall showed mucosal necrosis while the musculature remained intact consistent with an acute gastric ulcer. Since clinical condition of gastric rupture deteriorates rapidly, early diagnosis and appropriate treatment is essential for good prognosis. One should consider that ulcer formation might cause gastric rupture in childhood.

Radiation therapy (RT) induces immunogenic cell death and dose-dependent release of ATP in the tumor microenvironment (TME), triggering maturation and activation of tumor-resident dendritic cells (DCs). However, extracellular ATP is rapidly catabolized to adenosine by ectonucleotidases CD39 and CD73, which are expressed by tumor cells and immune cells in the TME. Adenosine has pleiotropic immunosuppressive effects and inhibits activation of DC and effector T cells, while promoting regulatory T cells (Tregs). Here, we tested the hypothesis that conversion of ATP to adenosine hinders generation of effective anti-tumor immunity by high dose RT, reducing its synergy with anti-CTLA-4 antibody.BALB/c mice were inoculated s.c. with 1 x 105 TSA carcinoma cells on day 0 and assigned to treatment with: (1) control mAb; (2) anti-CD73 (TY/23); (3) TY/23+anti-CTLA-4 (9H10); (4) RT; (5) RT+TY/23; (6) RT+9H10; (6) RT+TY/23+9H10. TY/23 (200 µg) was administered i.p. every 4 days starting on day 11. RT was given locally as single 20 Gy dose on day 12. 9H10 (200 µg) was given i.p. on days 11, 14 and 17. On day 18, some tumors were harvested for flow cytometry analysis of DC and T cells. Mice were monitored for tumor growth/regression.In irradiated tumors, CD73-blockade reduced the percentage of Tregs within the tumor-infiltrating CD4+ T cell population (7.9±2.5% in RT+TY/23 vs 20±0.8% in RT, p < 0.01) while increasing CD8+T cells (38.3±0.1% in RT+TY/23 vs 17.3±4% in RT, p < 0.05). Among intratumoral DCs (CD11c+MHCII+), the CD8a+ DC subpopulation was increased after CD73-blockade (37.9±15.7% in TY/23+RT vs 11.3±4.9% in RT, p < 0.01). Importantly, in irradiated mice, TY/23-administration enhanced activation of DCs and effector T cells, shown by increased CD40 expression on CD8a+ DCs (MFI: 218±1 in RT+TY/23 vs 54±41 in RT, p < 0.05) and increased CD69 expression on CD8+ T cells (MFI: 513±126 in RT+TY/23 vs 148±59 in RT, p < 0.01). TY/23 and 9H10 given alone or in combination had no effect on tumor growth. However, each antibody potentiated tumor inhibition obtained with RT (p=0.08 for RT+TY/23 and p < 0.05 for RT+9H10 vs RT). Moreover, blockade of both CD73 and CTLA-4 in combination with RT further improved tumor control resulting in complete tumor regression in 2/5 mice (p < 0.01 for RT+TY/23+9H10 vs RT).Our findings indicate that adenosine regulates the ability of RT to induce anti-tumor immunity, affecting both DC maturation and T cell activation. Data suggest that CD73-blockade is a promising strategy to improve synergy of RT and immunotherapy.

A promising strategy for cancer immunotherapy is to disrupt key pathways regulating immune tolerance, such as cytotoxic T lymphocyte-associated protein 4 (CTLA-4). However, the determinants of response to anti CTLA-4 mAb treatment remain incompletely understood. In murine models, anti-CTLA-4 mAbs alone fail to induce effective immune responses to poorly immunogenic tumors but are successful when combined with additional interventions, including local ionizing radiation (IR) therapy. We employed an established model based on control of a mouse carcinoma cell line to study endogenous tumor-infiltrating CD8+ T lymphocytes (TILs) following treatment with the anti-CTLA-4 mAb 9H10. Alone, 9H10 monotherapy reversed the arrest of TILs with carcinoma cells in vivo. In contrast, the combination of 9H10 and IR restored MHC class I-dependent arrest. After implantation, the carcinoma cells had reduced expression of retinoic acid early inducible-1 (RAE-1), a ligand for natural killer cell group 2D (NKG2D) receptor. We found that RAE-1 expression was induced by IR in vivo and that anti-NKG2D mAb blocked the TIL arrest induced by IR/9H10 combination therapy. These results demonstrate that anti-CTLA-4 mAb therapy induces motility of TIL and that NKG2D ligation offsets this effect to enhance TILs arrest and antitumor activity.

Yuji Kawase1, Kazuko Hasegawa2, Noriko Kawashima3, Emiko Horiuchi2, Ken Ikeda11Department of Neurology, Toho University Omori Medical Center, Tokyo; 2Department of Neurology, Sagamihara National Hospital, Kanagawa; 3Kawashima Neurology Clinic, Kanagawa, JapanAbstract: Olfactory involvement is well recognized in patients with Parkinson’s disease (PD). The purpose of this study was to examine smell function quantitatively, using different types and concentrations of odorants in PD patients. We aimed to elucidate whether a specific odor can affect the severity and duration of PD patients. A total of 89 nondemented PD patients and 20 age-matched controls participated in the study. Quantitative evaluation of smell function was performed using the T and T olfactometer test. This test contains five kinds of odorants at different concentrations. Recognition threshold (RT) scores for all five odorants and for each individual odorant were measured in five groups of PD patients with Hoehn and Yale (HY) stages I (n = 12), II (n = 24), III (n = 43), and IV (n = 10), as well as in control subjects (n = 20). One-way analysis of variance and Ryan’s method were used for statistical comparison between the five groups. Compared with controls and HY I patients, total RT scores were significantly higher in HY II, III, and IV patients. There were no statistically significant differences in RT scores between HY I patients and controls. However, total RT scores for three HY I patients (25%) were higher than the mean + two standard deviations of controls. On single odorant testing, significant higher RT scores for methylcyclopentenolone and skatol were found in HY II, III, and IV patients, in comparison with controls and HY I patients. The remaining three odorants did not differ statistically between PD patients and control subjects. The present study indicated that hyposmia in PD patients increased from HY II onwards. A single odorant of methyl cyclopentenolone or skatol had benefits for olfactory evaluation in PD patients. Our data also clarified that olfactory deficits occurred in a subset of HY I patients. Further prospective study is needed to elucidate whether a distinct profile of PD exists between HY I patients with and without hyposmia.Keywords: Parkinson’s disease, Hoehn and Yale stage, olfactory dysfunction, odorants