Systemic lupus erythematosus genome scan: Support for linkage at 1q23, 2q33, 16q12–13, and 17q21–23 and novel evidence at 3p24, 10q23–24, 13q32, and 18q22–23

Objective

To identify chromosome regions likely to harbor genes that predispose to the development of systemic lupus erythematosus (SLE) by analyzing a full genome scan in nuclear families ascertained for siblings with SLE.

Methods

Approximately 400 multiallelic markers spaced an average of 10 cM apart were genotyped in a multiethnic panel of 238 individuals from 62 multiplex SLE families having 88 affected sibling pairs and 456 total sibling pairs. Findings were analyzed by 2 model‐free statistical linkage procedures.

Results

Evidence supporting linkage to 4 previously reported (1q23, 2q33, 16q12–13, and 17q21–23) and 4 novel (3p24, 10q23–24, 13q32, and 18q22–23) chromosome regions was revealed. Stratification by family ethnicity indicated that linkage to 3 regions, 2q33, 10q23–24, and 18q22–23, was derived primarily from the Caucasian families, while linkage to 17q21–23 was seen primarily in the non‐Caucasian families.

Conclusion

Linkage to the same chromosome regions in independent cohorts is a critical step in finding the genes that predispose to a complex disorder such as SLE. Four linked regions also seen in independent SLE cohorts lend credibility to the 4 novel regions identified by these analyses. Substantial linkage information was gleaned by genotyping and analyzing the unaffected siblings. These results provide additional evidence that the SLE clinical phenotype is genetically complex, multigenic, and heterogeneous.

     

MK‐6, a novel not‐α IL‐2, elicits a potent antitumor activity by improving the effector to regulatory T cell balance

IL‐2 is a pleiotropic cytokine that regulates immune cell homeostasis. Its immunomodulatory function has been used clinically as an active immunotherapy agent for metastatic cancers. However, severe adverse effects, including the vascular leak syndrome and the preferential stimulation of anti‐immunogenic Treg rather than effector T cells, have been obstacles. We newly designed a mutein IL‐2, Mutakine‐6 (MK‐6), with reduced IL‐2Rα–binding capability. MK‐6 induced comparable cell growth potential toward IL‐2Rβγ–positive T cells but was far less efficient in in vitro Treg proliferation and STAT5 activation. Unlike IL‐2, in vivo administration of MK‐6 produced minimal adverse effects. Using CT26 and B16F10‐syngeneic tumor models, we found MK‐6 was highly efficacious on tumor regression. Serum albumin conjugation to MK‐6 prolonged in vivo half‐life and accumulated in CT26 tumors, showing enhanced antitumor effect. Tumor‐infiltrating leukocytes analysis revealed that albumin‐fused MK‐6 increased the ratio of effector CD8⁺ T cells to CD4⁺ Treg cells. These results demonstrated that MK‐6 is an efficient immunomodulator potentially used for improved immunotherapy with decreased adverse effects and attenuated Treg stimulation.     

The Effect of Aerobic Exercise Training Frequency on Arterial Stiffness in a Hyperglycemic State in Middle-Aged and Elderly Females

The frequency of aerobic exercise training in reducing the increase in arterial stiffness during acute hyperglycemia, a risk factor for cardiovascular disease, is unknown. The aim of the study was to determine the aerobic exercise training frequency on arterial stiffness in a hyperglycemic state in middle-aged and elderly females. Twenty healthy elderly people were randomly assigned to a two-times-a-week (T2, n = 10) and four-times-a-week (T4, n = 10) exercise group. All participants exercised for 35 min per session, which consisted of jogging exercises with a heart rate intensity of 65%. Brachial-ankle (ba), and heart-brachial (hb) pulse wave velocity (PWV) were measured before, 4 and 8 weeks after intervention; before the oral ingestion of 75-g of glucose; and 30, 60, and 90 min after ingestion. The baPWV before and 4 weeks after the intervention increased in both groups (p < 0.05), but only increased 8 weeks after intervention in the T2 group. hbPWV was unchanged before, 4 and 8 weeks after intervention in both groups. These findings show that frequent aerobic exercise suppresses the increase in arterial stiffness following glucose intake. The results of this study can be used to support the implementation of exercise programs for middle-aged and elderly patients.     

Late-onset Pleural and Pericardial Effusion as Immune-related Adverse Events after 94 Cycles of Nivolumab

A 67-year-old man with primary lung adenocarcinoma was hospitalized due to massive bilateral pleural effusion and pericardial effusion after 94 cycles of nivolumab therapy. We were unable to identify the cause of these effusions using blood tests, cytology tests, or bacterial culture of pleural effusion and thoracoscopy. Finally, we administrated corticosteroids, which immediately improved the fluid accumulation. This case may support the introduction of corticosteroids for late-onset pleural and pericardial effusion during immune checkpoint inhibitor (ICI) treatment. However, the safety of rechallenge of ICIs after the improvement of fluid accumulation is controversial.     

Reproducibility of nighttime home blood pressure measured by a wrist‐type nocturnal home blood pressure monitoring device

The authors investigated the reproducibility of nighttime home blood pressure (BP) measured by a wrist‐type BP monitoring device. Forty‐six hypertensive patients (mean 69.0±11.6 years, 56.5% male) self‐measured their nighttime BP hourly using simultaneously worn wrist‐type and upper arm‐type nocturnal home BP monitoring devices at home on two consecutive nights. Using the average 7.4±1.3 measurements on the first night and the average 7.0 ± 1.8 measurements on the second night, the authors assessed the reliability and the reproducibility of nighttime BP measured on the two nights. The difference between nights in systolic BP (SBP) measured by the wrist‐device was not significant (1.6±7.0 mmHg, p = .124), while the difference in diastolic BP (DBP) was marginally significant (1.4±4.9 mmHg, p = .050). The intraclass correlation coefficients (ICCs) for agreement between nights were high both in SBP and DBP average (SBP: 0.835, DBP: 0.804). Averaging only three points of SBP resulted in lower ICC values, but still indicated good correlations (ICC > 0.6). On the other hand, the correlations of the standard deviation and average real variability of SBP between nights were low, with ICCs of 0.220 and 0.436, respectively. In conclusion, the average SBP values measured on the first night were reliable even when averaging only three readings. The reproducibility of nighttime BP variability seemed inferior to that of BP average; it might be better to measure nighttime BP over multiple nights to assess BP variability. However, this hypothesis needs verification in other study population. In addition, our study population had well‐controlled BP, which limits the generalizability of this findings to all hypertensive patients.     

HLA class-I-restricted and tumor-specific CTL in tumor-infiltrating lymphocytes of patients with gastric cancer

Immune recognition of human cancers except melanoma is not well understood at either the cellular or the molecular level. We demonstrate in this study the existence of HLA class-I-restricted and tumor-specific CTL in IL-2-activated TIL (tumor-infiltrating lymphocytes) of all 4 gastric cancer patients tested. We established HLA A2-restricted and adenocarcinoma-specific CTL in 2 HLA A0201⁺ patients, and HLA A2402-restricted CTL recognizing both adenocarcinoma and squamous-cell carcinomas (SCC) in the 2 remaining HLA A2402⁺ patients. Further, HLA A3101-restricted and adenocarcinoma-specific CTL were established in 1 of the 2 HLA A2402⁺ patients who had HLA A3101 allele. HLA A2-, A2402- and A3101-restricted CD8⁺ CTL clones were established from these parental CTL lines. The 2 HLA A2-restricted CTL lines lysed 8 of 13 HLA A2⁺ adenocarcinoma cell lines established from different organs (stomach, colon, lung and breast) with different subtypes (HLA A0201, A0206 and A0207). The HLA A2-restricted CTL line recognized 9 and 6 different HPLC fractions of peptides eluted from the HLA A0201⁺ breast and HLA A0201⁺ colon adenocarcinoma cell lines, respectively. Allele-specific deletion of HLA A2 or A24 molecules was observed in some tumor lines that were not susceptible to lysis by the CTL lines. These results suggest that TIL of gastric cancer possess CTL recognizing different peptide antigens binding to different HLA-A alleles that are widely expressed on adenocarcinomas and also, to some extent, on SCC from different organs. Int. J. Cancer 70:631–638, 1997. © 1997 Wiley-Liss, Inc.     

Metastasis of breast cancer to liver through direct lymphatic drainage: a case report

Breast cancer liver metastasis (BCLM) is considered to occur by hematogenous spread of primary breast cancer cells. We herein present a case of lymphatic BCLM that was confirmed by preoperative imaging for sentinel lymph node biopsy (SLNB). A woman in her early 70s was diagnosed with clinical stage T2N0M0 invasive lobular cancer of the left breast. She underwent mastectomy with SLNB. Preoperative lymphoscintigraphy showed intense accumulation of isotope in the upper abdomen, corresponding to segment IV of the liver on single-photon emission computed tomography/computed tomography (SPECT/CT). However, no abnormalities were detected on magnetic resonance imaging. At 2.5 years postoperatively, the patient’s serum CA15-3 concentration was elevated, and positron emission tomography/computed tomography (PET/CT) showed a solitary liver metastasis. The PET/CT findings were similar to the SPECT/CT findings obtained 2.5 years earlier, indicating that the BCLM had developed lymphatically. To the best of our knowledge, this is the first case report of lymphatic BCLM proven by imaging examination.     

Fabricated CAD/CAM Post-Core Using Glass Fiber-Reinforced Resin Shows Innovative Potential in Restoring Pulpless Teeth

The prevention of root fractures of pulpless teeth is an important clinical issue to maintain healthy teeth through lifetime. The aim of this study was to examine a clinically effective treatment method for strengthening vulnerable pulpless teeth using CAD/CAM (computer-aided design/computer-aided manufacturing) fiber-reinforced post-core by conducting a fracture resistance test. A post-core made with a fiber-reinforced resin disk TRINIA (TR, SHOFU, Kyoto, Japan) was fabricated using a CAD/CAM system. The fiber-layer orientation of the CAD/CAM post-core was parallel to the axis of the restored tooth. A post-core using a conventional composite and a fiber post (CF) was also prepared. A fracture resistance test of teeth restored with the post-cores and zirconia crowns was conducted using a universal testing machine, and fracture patterns were identified by micro-CT observation. The fracture load of the roots restored with TR was 1555.9 ± 231.8 N, whereas that of CF was 1082.1 ± 226.7 N. The fracture load of TR was 43.8% that was significantly higher than that of CF (Student’s t-test, p < 0.05). The restored teeth with CAD/CAM resin post-core were found to be repairable even after fracture. These results suggest that the CAD/CAM indirect fiber post-core has the potential to strengthen the vulnerable pulpless teeth.