Protection from UV-induced skin carcinogenesis by genetic inhibition of the ataxia telangiectasia and Rad3-related (ATR) kinase

Multiple human epidemiologic studies link caffeinated (but not decaffeinated) beverage intake with significant decreases in several types of cancer, including highly prevalent UV-associated skin carcinomas. The mechanism by which caffeine protects against skin cancer is unknown. Ataxia telangiectasia and Rad3-related (ATR) is a replication checkpoint kinase activated by DNA stresses and is one of several targets of caffeine. Suppression of ATR, or its downstream target checkpoint kinase 1 (Chk1), selectively sensitizes DNA-damaged and malignant cells to apoptosis. Agents that target this pathway are currently in clinical trials. Conversely, inhibition of other DNA damage response pathways, such as ataxia telangiectasia mutated (ATM) and BRCA1, promotes cancer. To determine the effect of replication checkpoint inhibition on carcinogenesis, we generated transgenic mice with diminished ATR function in skin and crossed them into a UV-sensitive background, Xpc(-/-). Unlike caffeine, this genetic approach was selective and had no effect on ATM activation. These transgenic mice were viable and showed no histological abnormalities in skin. Primary keratinocytes from these mice had diminished UV-induced Chk1 phosphorylation and twofold augmentation of apoptosis after UV exposure (P = 0.006). With chronic UV treatment, transgenic mice remained tumor-free for significantly longer (P = 0.003) and had 69% fewer tumors at the end of observation of the full cohort (P = 0.019), compared with littermate controls with the same genetic background. This study suggests that inhibition of replication checkpoint function can suppress skin carcinogenesis and supports ATR inhibition as the relevant mechanism for the protective effect of caffeinated beverage intake in human epidemiologic studies.     

Differences in masticatory function of subjects with different closing path

PurposeThe purpose of this study was to clarify whether there was a difference in the masticatory function between two masticatory path patterns: a convex closing path and a concave closing path.MethodsFor 80 healthy subjects, the masticatory function (masticatory muscular activity, mandibular movement, and masticatory performance) when chewing a gummy jelly was recorded. Out of the 160 chewing cases (80 subjects chewing on either side), 65 cases (Group I) in which the incisal point opened in a linear or concave manner toward the working side and closed in a convex manner, and 15 cases (Group II) in which the opening path was the same as that in Group I, but the closing followed a concave path, were selected. For the masticatory function, the integral values per unit time of masseter and temporal muscular activities, the gape and masticatory width, the indicators representing the stability of movement path, and the glucose extraction from chewing gummy jelly were measured and compared between the two groups.ResultsThe integral values of muscular activities and the amount of glucose extraction were significantly greater in Group I. The gape and masticatory width were not significantly different between the groups. The values of the indicators representing the stability of path were smaller in Group I than in Group II.ConclusionFrom these results, it was suggested that there was a functional difference between Group I (with a convex closing path) and Group II (with a concave closing path), and that Group I had a superior masticatory function to Group II.     

Olfactory dysfunction in idiopathic REM sleep behavior disorder

BackgroundOlfactory dysfunction is frequently observed in patients with idiopathic REM sleep behavior disorder (iRBD) such as Parkinson’s disease or dementia with Lewy bodies.MethodsOlfactory function tests using Sniffin’ Sticks and Odor Stick Identification Test for Japanese (OSIT-J) were performed in 73 consecutive middle-aged (range, 50–69 years) patients with iRBD, 33 consecutive older-aged (71–82 years) patients with iRBD, and 28 control subjects (55–70 years).ResultsOdor identification was more frequently impaired than odor threshold or discrimination among the iRBD group and allowed better discrimination between the middle-aged iRBD group and age-adjusted control subjects. The area under the curve for threshold, discrimination, identification, TDI score and OSIT-J score determined from receiver operating characteristic curves were 0.831 (0.753–0.909), 0.761 (0.666–0.855), 0.938 (0.894–0.982), 0.939 (0.897–0.981), and 0.965 (0.931–0.999), respectively. Discrimination and identification scores were significantly lower in the older-aged iRBD group than in the middle-aged iRBD group. A significant correlation was observed between the identification score on Sniffin’ Sticks and OSIT-J score (r = 0.5910, P < 0.0001, n = 106, Spearman’s rank).ConclusionAnosmia/hyposmia may be a feature of iRBD. Olfactory dysfunction in iRBD is a consistent, widespread central nervous abnormality of different olfactory modalities with different cognitive complexity.     

Relevance of substantia nigra hyperechogenicity and reduced odor identification in idiopathic REM sleep behavior disorder

BackgroundSubstantia nigra (SN) hyperechogenicity determined by transcranial sonography (TCS) and olfactory dysfunction are common findings in Parkinson disease (PD), which may reveal a prodromal synucleinopathy in idiopathic REM sleep behavior disorder (iRBD).MethodsTCS and the Odor Stick Identification Test for Japanese (OSIT-J) were performed in 34 consecutive patients with iRBD (67.9 ± 6.1 years), 17 consecutive patients with PD (66.4 ± 6.7 years), and 21 control group subjects (64.4 ± 5.8 years).ResultsThere was a significantly increased area of echogenicity in the SN in the iRBD group (0.20 ± 0.13 cm²) and PD group (0.22 ± 0.11 cm²) compared with the control group (0.06 ± 0.06 cm²). We found pathological SN hyperechogenicity (?0.20 cm²) in 41.2% of the iRBD group, 52.6% of the PD group, and 9.5% of the control group. Further, there were abnormal findings of both pathological SN hyperechogenicity (?0.20 cm²) and functional anosmia or hyposmia in 4 (11.8%) or 9 (26.5%) of the iRBD group subjects, respectively, and 7 (57.9%) or 2 (11.8%) of the PD group subjects, respectively.ConclusionPathological SN hyperechogenic abnormality and functional anosmia in iRBD may be a disease state in the transition to a neurodegenerative disease.     

Prognostic impact of the primary tumor location based on the hilar structures in non-small cell lung cancer with mediastinal lymph node metastasis

The status of mediastinal lymph node metastasis is one of the main factors determining the treatment strategy for non-small cell lung cancer (NSCLC), but the primary tumor location is not considered crucial in the tumor-node-metastasis (TMN) classification at present. The aim of this study was to estimate the prognostic value of the primary tumor location on the basis of the hilar structures in NSCLC with mediastinal lymph node metastasis. We retrospectively reviewed the cases of 337 consecutive patients who underwent surgical resection for NSCLC between 1995 and 2004, divided the pN2 NSCLC cases (n=40) into central- and peripheral-type tumors according to the distance of the primary tumor from the first branch of the extrapulmonary bronchus, and compared the surgical outcomes between these tumor groups. Eighteen and twenty-two cases were classified as central- and peripheral-type tumors, respectively. The 5-year survival rate was significantly better for patients with central-type tumors than peripheral-type tumors (51.5% vs. 21.2%, P=0.034). The location-specific prognostic tendency was noted irrespective of the presence (n=13) or absence of skip metastasis. In a multivariate Cox analysis of the N2 NSCLC cases, the primary tumor location was a significant (P=0.026) prognostic factor for overall survival. In conclusion, evaluation of the primary tumor location based on the hilar structures is useful to predict the prognosis in N2 NSCLC.     

Classifications of N2 Non–Small-Cell Lung Cancer Based on the Number and Rate of Metastatic Mediastinal Lymph Nodes

BackgroundSubdivisions of N2 non–small-cell lung cancer (NSCLC) cases based on metastatic status of mediastinal and non-mediastinal lymph nodes have been proposed. This study aimed to evaluate N2 disease classification by mediastinal lymph nodes alone.Patients and MethodsWe reviewed 187 patients with NSCLC pN1-N2 who were surgically treated to evaluate the proposed classifications: number, rate, nodal zone of metastatic lymph nodes. We evaluated N2 disease classification based on mediastinal lymph nodes alone in 136 pN2 cases.ResultsThe number (1-2, 3-5, and 6≤) or rate (15%≥, 15%< to 40%>, and 40%≤) classification based on all metastatic lymph nodes was validated by the log-rank test and Cox proportional hazards model. After reclassification by number or rate of metastatic mediastinal lymph nodes alone, a significant difference was maintained among all groups except between the 3-5 and 6≤ groups. The 5-year survival rates of the 1-2, 3-5, and 6≤ groups were 63.4%, 32.4%, and 18.2%, respectively (1-2 vs. 3-5, P = .015; 3-5 vs. 6≤, P = .134). With rate classification, the 5-year survival rates of the 15%≥, 15%-40% (15%< to 40%>), and 40%≤ groups were 56.0%, 27.3%, and 5.04%, respectively (15%≥ vs. 15%-40%, P = .011; 15–40% vs. 40%≤, P = .011). The Spearman's rank correlation coefficient showed a highly significant correlation of metastatic status between mediastinal lymph nodes and all lymph nodes (both P < .001).ConclusionClassification by number and rate of mediastinal lymph nodes alone enabled subdivision of N2 NSCLC cases. Metastatic status of mediastinal lymph nodes reflects that of all lymph nodes and is prognostic indicators.     

Comparison of cisplatin and 5-fluorouracil chemotherapy protocols combined with concurrent radiotherapy for esophageal cancer

Purpose  The optimal chemotherapeutic protocol for the treatment of esophageal cancer has not yet been established. This study was performed to identify the differences in toxicity and completion rates of various chemotherapy protocols with that goal in mind. Materials and methods  A total of 61 patients with esophageal cancer were enrolled in this study between June 2002 and January 2004. The total radiotherapy dose was 64 Gy. Three chemotherapy protocols were used. Arm A comprised daily low-dose cisplatin (CDDP) and 5-fluorouracil (5FU) (CF protocol) (3 mg/m² and 180 mg/m², respectively). Arm B was intermediate between arm A and C (CDDP 7 mg/m² and 5FU 250 mg/m² on days 1–5, 8–12, 29–33, and 36–40). Arm C comprised two courses of standard CF (CDDP 70 mg/m² on day 1 and 5FU 600 mg/m²/24 h on days 1–4). Results  Although there were no significant differences in hematological toxicity between the protocols, leukocytopenia was slightly milder in arm A. Nausea was significantly more severe in arm C. The completion rate was higher in arm A. The 3-year survival rates were 40%, 31%, and 62%, respectively. Conclusion  The daily low-dose CF protocol showed a trend of mild toxicity regarding leukocytopenia. However, we could not find statistical difference between arms. It also showed a better completion rate than the other two arms.