[A Case of Stage â £ Triple Negative Breast Cancer(TNBC)in Which S-1 Was Successful against Armor-Like Infiltration of the Chest Wall].

A 51-year-old female patient visited our department with a complaint of pain in the left breast. She was found to have Stage Ⅳ breast cancer with liver metastasis. The biopsy-based historical diagnosis was triple negative breast cancer(TNBC). Epirubicin plus cyclophosphamide therapy(EC therapy)plus weekly paclitaxel therapy(weekly PTX)was started for the unresectable advanced breast cancer, but infiltration of an armor-like tumor was observed in the chest wall. It was judged that drug resistance had occurred; hence, the treatment was switched to S-1. Subsequently, almost all the chest wall tumors disappeared after 2 months. However, we did not control the disease, and the patient died. We report about the positioning of S-1 with regard to TNBC, including a literature review.

Antibody Inhibition of Properdin Prevents Complement-Mediated Intravascular and Extravascular Hemolysis.

Paroxysmal nocturnal hemoglobinuria (PNH) is a serious blood disorder characterized by dysregulated complement activation on blood cells. Eculizumab, the current standard therapy and a humanized anti-C5 mAb, relieves anemia and thrombosis symptoms of PNH patients by preventing complement-dependent intravascular hemolysis (IVH). However, up to 20% of PNH patients on long-term eculizumab treatment still suffer from significant anemia and are transfusion dependent because of extravascular hemolysis (EVH) of C3-opsonized PNH erythrocytes. In this study, we show that function-blocking anti-properdin (P) mAbs dose-dependently inhibited autologous, complement-mediated hemolysis induced by factor H dysfunction. Furthermore, anti-human P (hP) mAbs potently and dose-dependently inhibited acidified serum-induced hemolysis of PNH erythrocytes (Ham test). In contrast to erythrocytes rescued by anti-C5 mAb, nonlysed PNH erythrocytes rescued by anti-P mAb incurred no activated C3 fragment deposition on their surface. These results suggested that anti-P mAbs may prevent EVH as well as IVH of PNH erythrocytes. To test the in vivo efficacy of anti-hP mAbs in preventing EVH, we generated a P humanized mouse by transgenic expression of hP in P knockout mice (hP-Tg/P-/-). In a murine EVH model, complement-susceptible erythrocytes were completely eliminated within 3 d in control mAb-treated hP-Tg/P-/- mice, whereas such cells were protected and persisted in hP-Tg/P-/- mice treated with an anti-hP mAb. Collectively, these data suggest that anti-P mAbs can inhibit both IVH and EVH mediated by complement and may offer improved efficacy over eculizumab, the current standard therapy for PNH.

Associations between thyroid-stimulating hormone and hypertension according to thyroid cyst status in the general population: a cross-sectional study.

BACKGROUND: The absence of thyroid cysts may indicate latent thyroid damage, as demonstrated in our previous study. However, the association between the absence of thyroid cysts and latent functional damage of the thyroid is unknown. At low thyroid hormone productivity, which may be associated with latent functional damage of the thyroid, the association between thyroid-stimulating hormone (TSH) and hypertension might be enhanced. Therefore, we evaluated the association between TSH level and hypertension stratified by thyroid cyst status. METHODS: We conducted a cross-sectional study of 1724 euthyroid Japanese individuals aged 40-74 years who participated in an annual health checkup in 2014. RESULTS: In the study population, 564 and 686 participants had thyroid cysts and hypertension, respectively. A significant positive association was observed between TSH and hypertension in subjects without a thyroid cyst but not in subjects with thyroid cysts. There was a significant positive association between hypertension and TSH in subjects without a thyroid cyst (odds ratio [OR] 1.27; 95% confidence intervals [CI] 1.01, 1.61) but not in subjects with thyroid cysts (OR 0.79; CI 0.57, 1.09) in the model fully adjusted for known confounding factors. The correlation between the TSH and free triiodothyronine (fee T3) levels (simple correlation coefficient [r] = - 0.13, p < 0.01) was stronger in the subjects without thyroid cysts than in those with thyroid cysts (r = - 0.03, p = 0.525). CONCLUSIONS: TSH is positively associated with hypertension only in individuals without thyroid cysts. The correlation between the TSH and free T3 levels was stronger in the subjects without thyroid cysts than in those with thyroid cysts. Therefore, the absence of thyroid cysts could be related to the association between TSH level and hypertension, possibly by indicating that the subjects without thyroid cysts had limited thyroid hormone reserves. Therefore, the absence of thyroid cysts could indicate the latent functional damage of the thyroid.

Anti-thyroid peroxidase antibody and thyroid cysts among the general Japanese population: a cross-sectional study.

BACKGROUND: Anti-thyroid peroxidase antibody (TPO-Ab) has been shown to cause autoimmune thyroiditis by inducing a deleterious influence on thyroid hormone synthesis. Further, thyroglobulin, which has an important role in thyroid hormone synthesis, is reported to be high in the fluid from thyroid cysts. Therefore, TPO-Ab could be associated with the presence of thyroid cyst, partly by affecting the activity of thyroid hormone synthesis. METHODS: To investigate the association between TPO-Ab and thyroid cysts, we conducted a cross-sectional study of 1432 Japanese with normal thyroid function [i.e., normal range of free triiodothyronine (free T3) and free thyroxine (free T4)] between the ages of 40 and 74 years, who participated in an annual health check-up. RESULTS: In men, the statistical power did not reach a statistical significance value. Additionally, subjects with TPO-Ab showed lower odds ratios (ORs) of thyroid cysts than those without TPO-Ab. In women, subjects with TPO-Ab showed significantly lower ORs of thyroid cysts than those without TPO-Ab. The fully adjusted ORs were 0.68 (0.40, 1.18) for men and 0.40 (0.27, 0.60) for women. When evaluating the association between logarithmic values of TPO-Ab titer and thyroid cysts in both men and women, a notable inverse correlation was observed. The fully adjusted ORs were 0.68 (0.50, 0.92) for men and 0.68 (0.57, 0.81) for women. CONCLUSION: TPO-Ab titer revealed to be inversely associated with thyroid cysts among Japanese with normal thyroid function. The presence of a thyroid cyst could indicate a lower risk of having TPO-Ab among the general population with normal thyroid function.

Add-on iguratimod as a therapeutic strategy to achieve remission in patients with rheumatoid arthritis inadequately responding to biological DMARDs: A retrospective study.

OBJECTIVES: In this study, iguratimod (IGU) was added to rheumatoid arthritis (RA) patients inadequately responding to 24-week or longer treatment with biological disease-modifying antirheumatic drug (bDMARDs), its effectiveness was assessed, and factors contributing to remission were evaluated. METHODS: RA patients who fulfilled the following criteria were included: (i) ≥ 24-week of bDMARDs; (ii) 2.6 < disease activity score (DAS) 28-erythrocyte sedimentation rate (ESR) < 5.1 or the presence of synovitis with a power Doppler (PD) score ≥2 in at least 1 of the 28 joints on joint ultrasonography. Disease activity and joint ultrasound findings were evaluated at baseline and at 12 and 24 weeks. RESULTS: DAS assessing 28 joints with ESR (DAS28-ESR) decreased significantly from 3.45 ± 0.92 at baseline to 2.85 ± 1.13 at 24 weeks (p < .001). Overall, 38.3% achieved clinical remission (c-remission). The total PD score decreased significantly from 8.7 ± 6.1 at baseline to 5.5 ± 5.0 at 24 weeks (p < .001). A lower baseline DAS28-ESR was related to c-remission after 24 weeks (p =.002). Shorter duration of disease (p =.020) was related to ultrasound remission, in addition to a lower baseline DAS28-ESR (p < .001). CONCLUSIONS: IGU add-on therapy can be a therapeutic strategy to achieve remission in RA patients inadequately responding to ≥24-week treatment with bDMARDs.

[The consciousness survey and the effect of educational intervention of Advance Care Planning (ACP) including post-mortem to elderly residents living in old New Town of big city].

AIM: Awareness reform aims to enable survival in an aging society, and ultimately, improve healthcare. An ideal way to achieve this is by implementing Advance directive (Ad) and Advance Care Planning (ACP), which do not usually include postmortem events. This study aims to create opportunities for Ad and ACP to include the postmortem period as a trigger for this awareness reform. METHODS: We conducted an Ad/ACP enlightenment lecture, and a questionnaire survey pre- and post-lecture for the elderly in old New Town, which is known for its aging society. The questionnaire comprised 38 multiple-choice questions covering 6 themes assuming an advanced state of dementia. RESULTS: There were 35 participants (7 men and 22 women) aged 40-89 years. Several people left during the lecture, making it difficult to capture the precise transformation effect with regard to changing of mind. However, the effect of enlightenment was identified as a result of the consciousness survey. A statistically significant change in consciousness occurred in response to social contribution after death. Furthermore, notably more people wanted emergency transportation compared to those wanting resuscitation and extension of life. CONCLUSIONS: The medical treatment desired might vary over time. Even the desire for life extension may differ significantly among individuals. This survey indicated a divergent view between the general public and medical staff, regarding a series of medical actions. We must persistently promote opportunities for enlightenment in cooperation with the general public (i.e., the communities and families we serve).

Nutritional status and management of risks due to physical therapy in patients hospitalized for long periods.

[Purpose] This study aimed to understand the nutritional status of patients hospitalized for long periods and the risk of physical therapy (PT) for such patients. [Subjects and Methods] Participants were selected from patients who were hospitalized at a designated medical long-term care sanatorium. The participants were divided into 5 groups (A-E) depending on their mode of energy intake and ambulatory ability during PT. The serum albumin level, energy intake, total daily energy expenditure, and total daily energy expenditure per session of PT (EEPT) were evaluated for each group. [Results] Protein-energy malnutrition was observed in 69.6% of the participants. No significant association was identified between the serum albumin level and body mass index. Energy intake was significantly higher in Groups D and E, whose energy intake was via ingestion, than in Groups A and B, whose intake was via tube feeding. EEPT was highest in patients of Group E who had gait independence different from the ability of those in groups A-D. [Conclusion] The actual energy intake is lower with tube feeding than with ingestion. Risk management and energy intake should be revisited in elderly patients who have been hospitalized for long periods and subsequently obtain gait independence.

Long-term effects of radiation exposure on health.

Late-onset effects of exposure to ionising radiation on the human body have been identified by long-term, large-scale epidemiological studies. The cohort study of Japanese survivors of the atomic bombings of Hiroshima and Nagasaki (the Life Span Study) is thought to be the most reliable source of information about these health effects because of the size of the cohort, the exposure of a general population of both sexes and all ages, and the wide range of individually assessed doses. For this reason, the Life Span Study has become fundamental to risk assessment in the radiation protection system of the International Commission on Radiological Protection and other authorities. Radiation exposure increases the risk of cancer throughout life, so continued follow-up of survivors is essential. Overall, survivors have a clear radiation-related excess risk of cancer, and people exposed as children have a higher risk of radiation-induced cancer than those exposed at older ages. At high doses, and possibly at low doses, radiation might increase the risk of cardiovascular disease and some other non-cancer diseases. Hereditary effects in the children of atomic bomb survivors have not been detected. The dose-response relation for cancer at low doses is assumed, for purposes of radiological protection, to be linear without a threshold, but has not been shown definitively. This outstanding issue is not only a problem when dealing appropriately with potential health effects of nuclear accidents, such as at Fukushima and Chernobyl, but is of growing concern in occupational and medical exposure. Therefore, the appropriate dose-response relation for effects of low doses of radiation needs to be established.

Regulation of gene expression via retrotransposon insertions and the noncoding RNA 4.5S RNAH.

Short interspersed elements (SINEs) comprise a significant portion of mammalian genomes and regulate gene expression through a variety of mechanisms. Here, we show that Myodonta clade-specific 4.5S RNAH (4.5SH), an abundant nuclear noncoding RNA that is highly homologous to the retrotransposon SINE B1, controls the expression of reporter gene that contains the antisense insertion of SINE B1 via nuclear retention. The depletion of endogenous 4.5SH with antisense oligonucleotides neutralizes the nuclear retention and changes the subcellular distribution of the reporter transcripts containing the antisense SINE B1 insertion. Importantly, endogenous transcripts with antisense SINE B1 were increased in the cytoplasm after knockdown of 4.5SH, leading to a decrease in cellular growth. We propose a tentative hypothesis that the amplification of the 4.5SH cluster in specific rodent species might delineate their evolutionary direction via the regulation of genes containing the antisense insertion of SINE B1.

Periodontal pathogens participate in synovitis in patients with rheumatoid arthritis in clinical remission: a retrospective case-control study.

OBJECTIVE: The objective of this study was to investigate the role of periodontal pathogens in RA in remission. METHODS: Twenty-one patients with active RA and 70 patients in clinical remission, including 48 patients with synovitis [US power Doppler (USPD)(+) group] and 22 patients without synovitis [USPD(-) group] were clinically assessed by US. CRP, ESR, haemoglobin, MMP-3, RF and ACPA were measured. Antibody titres against four types of periodontal pathogen [Aggregatibacter actinomycetemcomitans, Eikenella corrodens (Ec), Porphyromonas gingivalis and Prevotella intermedia (Pi)] were analysed using ELISA. RESULTS: Musculoskeletal US examination showed that 68.6% of patients with RA in clinical remission exhibited synovitis. CRP, ESR, haemoglobin, MMP-3 and RF levels in both the USPD(+) and USPD(-) groups were clearly lower compared with the RA group in non-remission. The IgG serum antibody titre against Ec in the non-remission RA(+) group was significantly greater than that in the USPD(+) group, and the IgG antibody titre against Pi in the non-remission RA and USPD(+) groups was greater than in the USPD(-) group. CONCLUSION: More than half of RA patients in remission showed persistent synovitis. This synovitis may be associated with periodontal disease-causing Pi. Thus, treating periodontal disease should also be considered in order to achieve more profound remission of RA.

Combination of factor H mutation and properdin deficiency causes severe C3 glomerulonephritis.

Factor H (fH) and properdin both modulate complement; however, fH inhibits activation, and properdin promotes activation of the alternative pathway of complement. Mutations in fH associate with several human kidney diseases, but whether inhibiting properdin would be beneficial in these diseases is unknown. Here, we found that either genetic or pharmacological blockade of properdin, which we expected to be therapeutic, converted the mild C3 GN of an fH-mutant mouse to a lethal C3 GN with features of human dense deposit disease. We attributed this phenotypic change to a differential effect of properdin on the dynamics of alternative pathway complement activation in the fluid phase and the cell surface in the fH-mutant mice. Thus, in fH mutation-related C3 glomerulopathy, additional factors that impact the activation of the alternative pathway of complement critically determine the nature and severity of kidney pathology. These results show that therapeutic manipulation of the complement system requires rigorous disease-specific target validation.

Hepatocellular carcinoma with gastric adenocarcinoma treated with atezolizumab and bevacizumab.

Atezolizumab and bevacizumab combination therapy might be one of the treatment options for hepatocellular carcinoma concurrent with gastric adenocarcinoma.

Contribution of complement activation pathways to neuropathology differs among mouse models of Alzheimer's disease.

BACKGROUND: Complement proteins and activation products have been found associated with neuropathology in Alzheimer's disease (AD). Recently, a C5a receptor antagonist was shown to suppress neuropathology in two murine models of AD, Tg2576 and 3xTg. Previously, a genetic deficiency of C1q in the Tg2576 mouse model showed an accumulation of fibrillar plaques similar to the complement sufficient Tg2576, but reactive glia were significantly decreased and neuronal integrity was improved suggesting detrimental consequences for complement activation in AD. The goal of this study was to define the role of the classical complement activation pathway in the progression of pathology in the 3xTg mouse that develops tangles in addition to fibrillar plaques (more closely reflecting human AD pathology) and to assess the influence of complement in a model of AD with a higher level of complement hemolytic activity. METHODS: 3xTg mice deficient in C1q (3xTgQ-/-) were generated, and both 3xTg and 3xTgQ-/- were backcrossed to the BUB mouse strain which has higher in vitro hemolytic complement activity. Mice were aged and perfused, and brain sections stained for pathological markers or analyzed for proinflammatory marker expression. RESULTS: 3xTgQ-/- mice showed similar amounts of fibrillar amyloid, reactive glia and hyperphosphorylated tau as the C1q-sufficient 3xTg at the ages analyzed. However, 3xTg and 3xTgQ-/- on the BUB background developed pathology earlier than on the original 3xTg background, although the presence of C1q had no effect on neuropathological and pro-inflammatory markers. In contrast to that seen in other transgenic models of AD, C1q, C4 and C3 immunoreactivity was undetectable on the plaques of 3xTg in any background, although C3 was associated with reactive astrocytes surrounding the plaques. Importantly, properdin a component of the alternative complement pathway was associated with plaques in all models. CONCLUSIONS: In contrast to previously investigated transgenic models of AD, development of neuropathology in 3xTg mice, which progresses much slower than other murine models, may not be influenced by fibrillar amyloid mediated activation of the classical complement pathway, suggesting that the alternative complement pathway activation or a C3-independent cleavage of C5 could account for the detrimental effects in these mice that are prevented by the C5a receptor antagonist. Furthermore, the paucity of complement activation may be a factor in the slower kinetics of progression of pathology in the 3xTg model of this disease.

Complement-dependent T-cell lymphopenia caused by thymocyte deletion of the membrane complement regulator Crry.

Although complement lysis is frequently used for the purification of lymphocyte subpopulations in vitro, how lymphocytes escape complement attack in vivo has not been clearly delineated. Here, we show that conditional gene targeting of a murine membrane complement regulator Crry on thymocytes led to complement-dependent peripheral T-cell lymphopenia. Notably, despite evidence of hypersensitivity to complement attack, Crry-deficient T cells escaped complement injury and developed normally in the thymus, because of low intrathymic complement activity. Crry-deficient T cells were eliminated in the periphery by a C3- and macrophage-mediated but C5-independent mechanism. Thus, Crry is essential for mature T-cell survival in the periphery but not for lymphogenesis in the thymus. The observation that the thymus is a complement-privileged site may have implications for complement-based antitumor therapies.

[Use of the critical path with the electronic chart system using meropenem, vancomycin, liposome amphotericin B for the febrile neutropenia].

Febrile neutropenia (FN) is a serious complication associated with morbidity and mortality. To manage infections in neutropenic patients, it is necessary to administer empirical antibiotic therapy in a timely and efficient manner. We developed an electronic critical pathway system for a computer-stored medical record system (EGMAIN-GX, Fujitsu), which matches FN patients to either: i) the first-line therapy with meropenem (3 g/day) alone, or ii) the second-line therapy with meropenem plus vancomycin (2 g/day). If patients do not respond to the first-line therapy within 72 hours, then they are provided with the second-line therapy. A total of 28 FN events were treated in 14 patients presenting with hematological malignancies. The mean and median neutrophil counts were 42 (0-300)/microl and 0/microl, respectively. The response rates with the first-line and second-line therapies were 57% and 93%, respectively. There were no serious adverse events. Meropenem is a highly effective treatment for FN. Use of an electronic critical pathway system could ensure that neutropenic patients receive this necessary empiric therapy in a timely manner so as to prevent the serious complications associated with FN.

Ion polarisation-assisted hydrogen-bonded ferroelectrics in liquid crystalline domains.

An alkylamide-substituted (-NHCOC10H21) hydrogen-bonded dibenzo[18]crown-6 derivative (1) was prepared to stabilise the ionic channel structure in a discotic hexagonal columnar (Colh) liquid crystal. The introduction of simple M+X- salts such as Na+PF6 - and K+I- into the ionic channel of 1 enhanced the ionic conductivity of the Colh phase of the M+·(1)·X- salts, with the highest ionic conductivity reaching ∼10-6 S cm-1 for K+·(1)·I- and Na+·(1)·PF6 - at 460 K, which was approximately 5 orders of magnitude higher than that of 1. The introduction of non-ferroelectric 1 into the ferroelectric N,N',N''-tri(tetradecyl)-1,3,5-benzenetricarboxamide (3BC) elicited a ferroelectric response from the mixed Colh phase of (3BC) x (1)1-x with x = 0.9 and 0.8. The further doping of M+X- into the ferroelectric Colh phase of (3BC)0.9(1)0.1 enhanced the ferroelectric polarisation assisted by ion displacement in the half-filled ionic channel for the vacant dibenzo[18]crown-6 of (3BC)0.9[(M+)0.5·(1)·(X-)0.5]0.1.

Association between thyroid-stimulating hormone (TSH) and proteinuria in relation to thyroid cyst in a euthyroid general population.

BACKGROUND: High normal levels of thyroid-stimulating hormone (TSH) have been reported to be associated with chronic kidney disease (CKD) among euthyroid individuals. However, there has been only limited research on the association between TSH and proteinuria, a major risk factor for the progression of renal disease. METHODS: A cross-sectional study of 1595 euthyroid individuals was conducted. All participants were within the normal range for free triiodothyronine (T3), free thyroxine (T4), and TSH. Analyses were stratified by thyroid cyst status to test the hypothesis that the absence of thyroid cysts, an indicator of latent thyroid damage, is associated with declining ability to synthesis thyroid hormone. RESULTS: For participants with thyroid cysts, a significant inverse association between TSH and proteinuria was observed (adjusted odds ratio (95% confidence intervals) of log-transformed TSH for proteinuria 0.40 (0.18, 0.89)). In participants without thyroid cysts, a significant positive association between those two factors was observed (2.06 (1.09, 3.90)). CONCLUSIONS: Among euthyroid individuals in the general population, being in the normal range of TSH was found to have an ambivalent association with proteinuria. Thyroid cyst status could be an effect modifier for those associations.

Deficiency of decay-accelerating factor and complement receptor 1-related gene/protein y on murine platelets leads to complement-dependent clearance by the macrophage phagocytic receptor CRIg.

Complement activation on human platelets is known to cause platelet degranulation and activation. To evaluate how normal platelets escape complement attack in vivo, we studied the fate of murine platelets deficient in 2 membrane complement regulatory proteins using an adoptive transfer model. We show here that deficiency of either decay-accelerating factor (DAF) or complement receptor 1-related gene/protein y (Crry) on murine platelets was inconsequential, whereas DAF and Crry double deficiency led to rapid clearance of platelets from circulation in a complement- and macrophage-dependent manner. This finding contrasted with the observation on erythrocytes, where Crry deficiency alone resulted in complement susceptibility. Quantitative flow cytometry showed DAF and Crry were expressed at similar levels on platelets, whereas Crry expression was 3 times higher than DAF on erythrocytes. Antibody blocking or gene ablation of the newly identified complement receptor CRIg, but not complement receptor 3 (CR3), rescued DAF/Crry-deficient platelets from complement-dependent elimination. Surprisingly, deficiency of CRIg, CR3, and other known complement receptors failed to prevent Crry-deficient erythrocytes from complement-mediated clearance. These results show a critical but redundant role of DAF and Crry in platelet survival and suggest that complement-opsonized platelets and erythrocytes engage different complement receptors on tissue macrophages in vivo.

Successful abatacept treatment for Felty's syndrome in a patient with rheumatoid arthritis.

We report the case of a 69-year-old man with a 38-year history of rheumatoid arthritis (RA), who developed Felty's syndrome, successful treatment with abatacept (ABT). He was treated with etanercept 50 mg/w and methotrexate 8 mg/w for the past 5 years. He was suffered from febrile neutropenia 6 months ago. Etanercept and methotrexate was discontinued 3 months ago, however, neutrophil count was not changed. Abdominal ultrasound showed splenomegaly, the diagnosis of Felty's syndrome was made. Granulocyte colony-stimulating factor therapy showed no effect on neutropenia, he was treated with ABT. After ABT therapy, absolute neutrophil count was elevated 234/µL to 1840/µL.