35 research outputs found
Low HER2 expression is a predictor of poor prognosis in stage I triple-negative breast cancer
IntroductionTriple-negative breast cancer (TNBC) is negative for hormone receptors and human epidermal growth factor receptor 2 (HER2). In stage I TNBC, adjuvant therapy or follow-up are performed according to risk factors, but clinical trial data is scarce. In recent years, it has been reported that HER2-low cases (1+/2+ and in situ hybridization negative) have different prognoses than HER2-0 cases. However, the risk of recurrence and risk factors in this HER2-low population for stage I TNBC have not yet been investigated.MethodsHerein, out of 174 patients with TNBC who underwent surgery from June 2004 to December 2009 at the National Cancer Center Hospital (Tokyo), we retrospectively examined 42 cases diagnosed as T1N0M0 TNBC after excluding those treated with preoperative chemotherapy.ResultsAll patients were female, the median age was 60.5 years, and 11 cases were HER2-low and 31 cases were HER2-0. The median follow-up period was 121 months. Postoperative adjuvant therapy was administered in 30 patients and recurrence occurred in 8 patients. HER2-low cases showed a significantly shorter disease-free survival (HR: 7.0; 95% CI: 1.2– 40.2; P=0.0016) and a trend towards shorter overall survival (hazard ratio [HR]: 4.2, 95% confidence interval [CI]: 0.58–31.4) compared with that of HER2-0 cases. HER2 was also identified as a factor for poor prognosis from the point- estimated values in univariate and multivariate analyses after confirming that there was no correlation between the other factors.ConclusionFor patients with stage I TNBC, the HER2-low population had a significantly worse prognosis than the HER2-0 population
Bromodeoxyuridine (BrdU)-label-retaining cells in mouse terminal bronchioles
Adult male mice were continuously treated
with bromodeoxyuridine (BrdU) for 1, 2, or 4 weeks by
an osmotic pump. To detect BrdU-label-retaining cells
(LRCs), putative progenitor/stem cells, other animals
were continuously treated with BrdU for 2 weeks, and
were then kept without any treatments for 2, 6, or 18
months. The lungs were fixed with 4% paraformaldehyde,
and were paraffin-embedded. We
observed terminal bronchioles with BrdU immunostaining
alone or with BrdU immunostaining
accompanying immunostaining for Clara cell secretory
protein (CCSP), forkhead box protein J1 (FoxJ1), or
calcitonin gene-related peptide (CGRP).
The average incidences of BrdU-incorporated cells
in the terminal bronchioles after 1, 2, and 4 weeks of
continuous BrdU infusion were 6.2%, 11.9%, and
23.1%, respectively. Most BrdU-incorporated cells in
these periods were CCSP-immunoreactive (91.7%,
91.3%, and 88.2%, respectively), which means
progenitor function of Clara cells. FoxJ1-immunoreactive
BrdU-incorporated cells were fewer (5.4%,
3.0%, 2.7%, respectively). The average incidences of
BrdU-LRCs in the terminal bronchioles after 2, 6, and
18 months were 7.2%, 4.3, and 2.7%, respectively. Most
BrdU-LRCs were CCSP-immunoreactive (91.0%,
92.7%, and 89.6%, respectively), and FoxJ1-
immunoreactive BrdU-LRCs were fewer (6.0%, 5.7%,
and 2.1%, respectively). CGRP-positive BrdUincorporated
cells were occasional. CGRP-positive
BrdU-LRCs were detected in 17.6% of neuroepithelial
bodies (NEBs) at 2 months, but disappeared at 6 months.
BrdU-positive stem cell candidates, which locate at the
brochiolo-alveolar duct junction or cover NEB, were few
throughout this study.
In conclusion, in the lungs treated only with BrdU,
CCSP-immunoreactive cells are important to maintain
homeostasis in the terminal bronchiolar epithelium
Zfp238 Regulates the Thermogenic Program in Cooperation with Foxo1
Summary: Obesity has become an explicit public health concern because of its relevance to metabolic syndrome. Evidence points to the significance of beige adipocytes in regulating energy expenditure. Here, using yeast two-hybrid screening, we show that Zfp238 is a Foxo1 co-repressor and that adipose-tissue-specific ablation of Zfp238 (Adipo-Zfp238KO) in mice leads to obesity, decreased energy expenditure, and insulin resistance under normal chow diet. Adipo-Zfp238KO inhibits induction of Ucp1 expression in subcutaneous adipose tissue upon cold exposure or CL316243, but not in brown adipose tissue. Furthermore, knockdown of Zfp238 in 3T3-L1 cells decreases Ucp1 expression in response to cool incubation or forskolin significantly compared with control cells. In contrast, overexpression of Zfp238 in 3T3-L1 cells significantly increases Ucp1 expression in response to forskolin. Finally, double knockdown of both Zfp238 and Foxo1 normalizes Ucp1 induction. These data suggest that Zfp238 in adipose tissue regulates the thermogenic program in cooperation with Foxo1. : Molecular Interaction; Molecular Mechanism of Behavior; Diabetology; Specialized Functions of Cells Subject Areas: Molecular Interaction, Molecular Mechanism of Behavior, Diabetology, Specialized Functions of Cell
Combining Optical Coherence Tomography and Fundus Photography to Improve Glaucoma Screening
We aimed to evaluate the accuracy of glaucoma screening using fundus photography combined with optical coherence tomography and determine the agreement between ophthalmologists and ophthalmology residents. We used a comprehensive ophthalmologic examination dataset obtained from 503 cases (1006 eyes). Of the 1006 eyes, 132 had a confirmed glaucoma diagnosis. Overall, 24 doctors, comprising two groups (ophthalmologists and ophthalmology residents, 12 individuals/group), analyzed the data presented in three screening strategies as follows: (1) fundus photography alone, (2) fundus photography + optical coherence tomography, and (3) fundus photography + optical coherence tomography + comprehensive examination. We investigated the diagnostic accuracy (sensitivity and specificity). The respective sensitivity and specificity values for the diagnostic accuracy obtained by 24 doctors, 12 ophthalmologists, and 12 ophthalmology residents were as follows: (1) fundus photography: sensitivity, 55.4%, 55.4%, and 55.4%; specificity, 91.8%, 94.0%, and 89.6%; (2) fundus photography + OCT: sensitivity, 80.0%, 82.3%, and 77.8%; specificity, 91.7%, 92.9%, and 90.6%; and (3) fundus photography + OCT + comprehensive examination: sensitivity 78.4%, 79.8%, and 77.1%; specificity, 92.7%, 94.0%, and 91.3%. The diagnostic accuracy of glaucoma screening significantly increased with optical coherence tomography. Following its addition, ophthalmologists could more effectively improve the diagnostic accuracy than ophthalmology residents. Screening accuracy is improved when optical coherence tomography is added to fundus photography
Essential role of Gas6 for glomerular injury in nephrotoxic nephritis
Growth-arrest specific gene 6 (Gas6) is a vitamin K–dependent growth factor for mesangial and epithelial cells. To investigate whether Gas6 is essential for progressive glomerular injury, we constructed Gas6(–/–) mice and examined the role of Gas6 in accelerated nephrotoxic nephritis (NTN), a model of progressive glomerulonephritis. We found less mortality and proteinuria in Gas6(–/–) mice than in wild-type mice following injection of nephrotoxic serum. Glomerular cell proliferation, glomerular sclerosis, crescent formation, and deposition of fibrin/fibrinogen in glomeruli were also reduced in Gas6(–/–) mice. Furthermore, administering Gas6(–/–) mice recombinant wild-type Gas6, but not Gas6 lacking a previously characterized N-terminal γ-carboxyl group, induced massive proteinuria, glomerular cell proliferation, and glomerulosclerosis, comparable to responses seen in wild-type mice. These data indicate that Gas6 induces glomerular cell proliferation in NTN and suggest that this factor contributes to glomerular injury and the progression of chronic nephritis
Uterine sensitization-associated gene–1 (USAG-1), a novel BMP antagonist expressed in the kidney, accelerates tubular injury
Dialysis dependency is one of the leading causes of morbidity and mortality in the world, and once end-stage renal disease develops, it cannot be reversed by currently available therapy. Although administration of large doses of bone morphogenetic protein–7 (BMP-7) has been shown to repair established renal injury and improve renal function, the pathophysiological role of endogenous BMP-7 and regulatory mechanism of its activities remain elusive. Here we show that the product of uterine sensitization-associated gene–1 (USAG1), a novel BMP antagonist abundantly expressed in the kidney, is the central negative regulator of BMP function in the kidney and that mice lacking USAG-1 (USAG1(–/–) mice) are resistant to renal injury. USAG1(–/–) mice exhibited prolonged survival and preserved renal function in acute and chronic renal injury models. Renal BMP signaling, assessed by phosphorylation of Smad proteins, was significantly enhanced in USAG1(–/–) mice with renal injury, indicating that the preservation of renal function is attributable to enhancement of endogenous BMP signaling. Furthermore, the administration of neutralizing antibody against BMP-7 abolished renoprotection in USAG1(–/–) mice, indicating that USAG-1 plays a critical role in the modulation of renoprotective action of BMP and that inhibition of USAG-1 is a promising means of development of novel treatment for renal diseases
Lymphocyte-to-monocyte ratio as a prognostic and potential tumor microenvironment indicator in advanced soft tissue sarcoma treated with first-line doxorubicin therapy
Abstract Prognostic value of hematologic indices and their association with the tumor microenvironment (TME) remain unclear in advanced soft tissue sarcoma (STS). We aimed to evaluate their prognostic value and correlation with the TME status in advanced STS treated with first-line doxorubicin (DXR) therapy. Clinical data and three hematological indices, including lymphocyte-to-monocyte ratio (LMR), platelet-to-lymphocyte ratio, and neutrophil-to-lymphocyte ratio, were collected from 149 patients with advanced STS. The TME status was pathologically examined by CD3, CD68, and CD20 staining of resected tumor slides. In a multivariate Cox analysis, low LMR and absence of primary tumor resection were independently associated with worse overall survival (OS) (HR 3.93, p = 0.001; HR 1.71, p = 0.03). A prognostic model using these variables predicted OS with greater area under curves than those obtained using Systemic Inflammatory Score and Glasgow Prognostic Score. The LMR significantly correlated with the tumoral CD3/CD68-positive cell ratio in surgical specimens (R = 0.959, p = 0.04). In conclusion, LMR was a prognostic factor in advanced STS treated with first-line DXR therapy. LMR could partially reflect anti-tumor immunity in the TME and have the prognostic value. The potential role of LMR as an indicator of TME status warrants further investigation