Double layers of gold nanoparticles immobilized titanium implants improve the osseointegration in rabbit models.

Osseointegration is important in osteopenia and osteoporosis patients due to their low bone densities. Gold nanoparticles (GNPs) are greatly beneficial materials as osteogenic agents. The aim of this study is to investigate osseointegration between bones and double layers of GNP-immobilized titanium (Ti) implants. The physicochemical properties of the Ti surface were evaluated by scanning electron microscopy, by atomic force microscopy, by means of the contact angle using water drops, and by x-ray photoelectron spectroscopy. Osteogenic differentiation of human bone-marrow-derived mesenchymal stem cells was analyzed and showed the higher values in double layers of GNP (GNP2) groups. In addition, we performed an in vivo study using hydroxyapatite (HA) and GNP2 spine pedicle screws in ovariectomized (OVX) and SHAM rabbits. Osseointegration parameters also showed higher values in GNP2 than in HA groups. These findings suggest that implants with double layers of GNPs can be a useful alternative in osteoporotic patients.

Molecular mechanisms of resistance to CDK4/6 inhibitors in breast cancer: A review.

Deregulation of the cyclin D-CDK4/6-INK4-RB pathway leading to uncontrolled cell proliferation, is frequently observed in breast cancer. Currently, three selective CDK4/6 inhibitors have been FDA approved: palbociclib, ribociclib and abemaciclib. Despite promising clinical outcomes, intrinsic or acquired resistance to CDK4/6 inhibitors has limited the success of these treatments; therefore, the development of various strategies to overcome this resistance is of great importance. We highlight the various mechanisms that are directly or indirectly responsible for resistance to CDK4/6 inhibitors, categorizing them into two broad groups; cell cycle-specific mechanisms and cell cycle-nonspecific mechanisms. Elucidation of the diverse mechanisms through which resistance to CDK4/6 inhibitors occurs, may aid in the design of novel therapeutic strategies to improve patient outcomes. This review summarizes the currently available knowledge regarding mechanisms of resistance to CDK4/6 inhibitors, and possible therapeutic strategies that may overcome this resistance as well.

Desmoplastic fibroblastoma mimicking tenosynovial giant cell tumor encasing a tendon of the foot.

Desmoplastic fibroblastoma is an uncommon, benign fibrous soft tissue tumor that usually occurs in the arms, shoulders, neck, hands, and feet in the fifth to seventh decades of life. In general, it is commonly located in the subcutaneous tissue and skeletal muscle. The authors report an unusual case of a desmoplastic fibroblastoma mimicking tenosynovial giant cell tumor encasing a tendon of the foot in a 72-year-old woman. Ultrasonography revealed an inhomogeneously hypoechoic lobulated soft tissue lesion completely wrapped around the extensor digitorum longus tendon. Color Doppler study revealed increased vascularity in the internal and peripheral portions of the lesion. Magnetic resonance imaging revealed a well-defined, lobulated soft tissue mass encasing the extensor digitorum longus tendon with predominantly isointense signal with some areas of hypointense signal on T1-weighted images, predominantly hyperintense signal with some areas of hypointense signal on T2-weighted images, and inhomogeneous enhancement on fat-suppressed contrast-enhanced T1-weighted images. Surgical excision was performed, and the mass was diagnosed on pathological examination as a desmoplastic fibroblastoma. There has been no previously published radiologic case of a desmoplastic fibroblastoma encasing a tendon of the foot in the literature.

New Doppler imaging technique for assessing angiogenesis in breast tumors: correlation with immunohistochemically analyzed microvessels density.

BACKGROUND: Microvessel density (MVD) is associated with grade and prognosis in breast tumors. However, conventional color Doppler flow (CDF) imaging has been limited to represent MVD of breast tumors. PURPOSE: To evaluate whether a new Doppler imaging technique (AngioPLUS) can represent MVD of breast tumors. MATERIAL AND METHODS: The institutional review board approved this retrospective study, and patients' informed consent was waived. CDF and AngioPLUS were available in pathologically confirmed 55 breast tumors of 53 women. For each lesion, vascular flow patterns (distribution and amount) of both Doppler images were retrospectively reviewed, and MVD was measured using immunohistochemical analysis of the biopsied tissue sections. MVD was subcategorized as low or high group with reference to the median. The associations between the Doppler features and MVD were evaluated using Fisher's exact test and Student's t test. RESULTS: Of the 55 masses, 28 (50.9%) were benign and 27 (49.1%) were malignant. Vascular flow distribution and amount of both Doppler imaging were different between the benign and malignant lesions (CDF, P = 0.020 and P = 0.010; AngioPLUS, P = 0.002 and P = 0.005). MVD had no significant relationships with CDF features, but vascular flow distribution on AngioPLUS showed significant differences between the lesions with low and high MVD ( P = 0.020); Combined distribution was more frequent in the high MVD lesions than in the low MVD lesions (17/28, 60.7% vs. 6/27, 22.2%). CONCLUSION: Our data confirmed the correlation between a new Doppler imaging technique, AngioPLUS, and MVD. We suggest that AngioPLUS can be used for assessing MVD in breast tumors.

Glomerular epithelial CD44 expression and segmental sclerosis in IgA nephropathy.

BACKGROUND: CD44 is a marker of activated parietal epithelial cells (PECs), and is expressed in glomerular visceral epithelial cells (VECs) during development of segmental sclerosis. We explored the significance of glomerular epithelial CD44 expression in relation to segmental sclerosis in patients with mild IgA nephropathy (IgAN). METHODS: A total of 126 cases of IgAN were divided into three groups based on glomerular morphology: normal (group A, n = 30), mild mesangial proliferation without segmental sclerosis or synechia (SS) (group B, n = 31), or mild mesangial proliferation with SS (group C, n = 65). The number of CD44-expressing PECs and VECs was counted in each glomerulus and expressed as the mean number per case. RESULTS: CD44 staining was positive in VECs in 59.5 %, in PECs in 79.4 % and in both cell types in 56.3 % of cases. The number of CD44+ PECs or VECs was significantly higher in group C than in groups A or B. Cases with >1 CD44+ cell (PECs and VECs) per glomerulus were associated with increased urine protein/creatinine ratio (UPCr) at last follow-up. The presence of >1 CD44+ VEC/glomerulus was associated with increased UPCr and serum creatinine levels, and decreased estimated glomerular filtration rate (eGFR) even in the absence of SS at the time of biopsy. CONCLUSION: CD44 was expressed in PECs and VECs in association with SS in IgAN. Increased CD44 expression in VECs is a sign of active glomerular injury and dysfunction in these patients.

The expression of redox proteins in phyllodes tumor.

This study aimed to investigate the associations between the expression of redox-related proteins which regulate reactive oxygen species (ROS) production and the histologic factors in phyllodes tumor (PT). We used tissue microarrays to analyze 193 PTs and performed immunohistochemical staining against five redox-related proteins including catalase, thioredoxin reductase (TxNR), glutathione S-transferase π (GST π), thioredoxin interacting protein (TxNIP), and manganese superoxide dismutase (MnSOD). We then compared the immunohistochemical results and histologic parameters. The 193 PTs were classified as benign (n = 145, 75.1 %), borderline (n = 33, 17.1 %), and malignant (n = 15, 7.8 %). With worsening histologic grade, the expression of catalase, TxNR, TxNIP, and MnSOD in the stromal component increased (P < 0.001), and GST π and MnSOD expression in the epithelial component increased (P = 0.014, and 0.038). Significant associations were found between the expression of catalse-TxNR, catalase-TxNIP, catalase-MnSOD, TxNR-TxNIP, TxNR-MnSOD, and TxNIP-MnSOD in both the epithelial and stromal components (P < 0.05). This study confirmed that the stromal expression of catalase, TxNR, TxNIP, and MnSOD increased with worsening histologic grade in PT, reflecting the change in ROS production during the malignant transformation of PT.

Analysis of phyllodes tumor recurrence according to the histologic grade.

Local recurrence of phyllodes tumor (PT) of the breast is an adverse outcome that can result in sarcomatous degeneration. The aim of this study was to investigate the histologic and surgical factors associated with local recurrence. A total of 193 PT cases were studied: 145 (75.1 %) benign cases, 33 (17.1 %) borderline cases, and 15 (7.8 %) malignant cases. Stratifying our analysis according to histologic grade, we investigated the relationship between disease-free survival (DFS) and both histologic and surgical factors, including histologic grade, stromal cellularity, stromal atypia, stromal mitosis, stromal overgrowth, tumor margin, type of surgical procedure (local excision, wide excision, and mastectomy), surgical margin status, and radiation therapy. In the case of benign PT, all patients with local recurrences (3.4 %) had been treated with local excision, and all recurrent tumors were also benign. The local recurrence rate for locally excised benign PTs was not associated with surgical margin status or radiation therapy. In the case of borderline PT, local excision was associated with an increased local recurrence rate (P = 0.046). In malignant PT, small tumor size (≤4.0 cm) was associated with an increased local recurrence rate (P = 0.041). Univariate analyses indicated that surgical procedure (mastectomy < local excision < wide excision; P < 0.001) was significantly associated with shorter DFS in borderline PT. A positive surgical resection margin (P < 0.001) was associated with DFS in malignant PT. The factors associated with local recurrence differed with the histologic grade of PT, as did the features of local recurrence itself. In particular, benign PT had very low rate of local recurrence regardless of surgical margin status or radiation therapy, even when treated with local excision. In the case of benign PT, no recurrent tumors had worse histologic grades than the initial tumors.

The expression of glutamine-metabolism-related proteins in breast phyllodes tumors.

The aim of this study was to investigate the expression of glutamine-metabolism-related proteins according to the histologic grade of phyllodes tumors (PTs) and to assess its clinical implication. We generated tissue microarrays of 224 PTs and performed immunohistochemical staining and western blot analysis of glutamine-metabolism-related molecules, including GLS1, GDH, and ASCT2. The associations between immunohistochemical results and clinicopathologic parameters were evaluated. The expression of GLS1 (p < 0.001), GDH (p < 0.001), and ASCT2 (p = 0.005) in stromal components significantly increased with worsening PT histological grade. GDH expression in epithelial components significantly increased in high-grade PT (p = 0.026). In western blot, stromal expression of GLS1, GDH, and ASCT2 increased as histologic grade increased. By univariate analysis, stromal GLS1 expression (p = 0.022) and stromal GDH expression (p = 0.009) were independent predictors of shorter DFS. Stromal GLS1 expression (p < 0.001) and stromal GDH expression (p < 0.001) were independent predictors of shorter OS. This study demonstrated that the stromal expression of the glutamine-metabolism-related proteins GLS1, GDH, ASCT2 increases with worsening histological PT grade.

Metabolic phenotypes in triple-negative breast cancer.

The aim of study was to investigate the metabolism of tumor and stromal cells necessary to determine differential tumor-stroma metabolic interactions according to the molecular subtypes of triple-negative breast cancer (TNBC). Tissues from 132 patients of TNBC were prepared for use as tissue microarrays (TMA). Expression of CK5/6, EGFR, claudin 3, claudin 4, claudin7, E-cadherin, AR, GGT1, STAT1, and interleukin-8 was evaluated by immunohistochemical staining using TMA to classify molecular subtypes of TNBC. In addition, immunohistochemical staining for Glut1, CAIX, BNIP3, MCT4, Beclin-1, LC3A, LC3B, and p62 was performed. According to glycolytic status determined by the immunohistochemical expression of Glut-1 and CAIX in tumor and stroma, the metabolic phenotypes of the TNBCs were defined as follows: Warburg type (tumor: glycolysis, stroma: non-glycolysis), reverse Warburg type (tumor: non-glycolysis, stroma: glycolysis), mixed metabolic type (tumor: glycolysis, stroma: glycolysis), and metabolic null type (tumor: non-glycolysis, stroma: non-glycolysis). TNBCs were classified as follows: 79 Warburg type (59.8 %), 7 reverse Warburg type (5.3 %), 24 mixed metabolic type (18.2 %), and 22 metabolic null type (16.7 %). There was no statistical significance between the metabolic phenotypes and molecular subtypes (P=0.706). Reverse Warburg type showed the most dysfunctional mitochondrial status for stromal cells, while Warburg type showed the most functional mitochondrial status (P=0.036). Regarding stromal autophagy status, reverse Warburg type showed the most activated status, while all of the Warburg and metabolic null types showed a non-activated status (P<0.001). In conclusion, Warburg type was the most common metabolic phenotype in TNBC, while reverse Warburg type was the most unusual. Metabolic phenotypes did not differ among the molecular subtypes of TNBCs.