A new cooperative received signal strength-based localization algorithm is proposed which employs relative error estimation and semidefinite programming (SDP). First, the log-normal shadowing RSS ...measurement model is transformed into an equivalent multiplicative model. Then, a relative error estimation criterion is used with this model to develop a nonconvex estimator to approximate the maximum likelihood solution. Finally, semidefinite relaxation is applied to the nonconvex estimator to obtain an SDP estimator. The proposed algorithm is first derived for noncooperative RSS-based localization and then extended to the cooperative case. The Cramer-Rao lower bound is derived for cooperative RSS-based localization. Performance results are presented, which demonstrate that the proposed SDP estimator provides a significant improvement over existing localization methods.
The CD274 (PD-L1)/PDCD1 (PD-1) pathway is crucial for the modulation of immune responses and self-tolerance. Aberrantly expressed CD274 allows tumor cells to evade host immune system and is ...considered to be a mechanism of adaptive immune resistance. Inhibition of the CD274/PDCD1 immune checkpoint offers a promising new therapeutic strategy. Although CD274-expressing tumor cells have been identified in different types of tumors including colorectal cancer, clinicopathologic profile of these CD274-positive tumors has not been extensively studied. In this study, 454 primary colorectal carcinomas were analyzed histologically and immunohistochemically for CD274, mismatch repair (MMR) proteins, intestinal differentiation marker (CDX2), and stem cell markers (ALCAM, ALDH1A1, and SALL4). CD274-positive colorectal carcinomas (54/454 (12%)) usually (83%) involved the right or transverse colon with poorly differentiated and solid/medullary histology. On the basis of multivariate logistic regression analysis, CD274 positivity was significantly associated with poorly differentiated histotype (OR: 3.32; 95% CI: 1.46-7.51; P=0.004), MMR deficiency (OR: 10.0; 95% CI: 4.66-21.5; P<0.001), and 'stem-like' immunophenotype defined by the loss or weak expression of CDX2 and ALCAM-positivity (OR: 5.51; 95% CI: 1.66-18.3; P=0.005). Mutation analysis of 66 arbitrary selected colorectal carcinomas revealed that CD274-positive tumors usually (88%) carried the BRAF V600E mutation. Thus, colorectal carcinomas defined by CD274 positivity displayed features associated with tumors arising via the serrated neoplasia pathway. Moreover, colorectal carcinomas characterized by lack of CDX2 and prominent expression of ALCAM frequently (71%) showed CD274 positivity. This might suggest association of CD274 expression with 'stem-like' phenotype. Further evaluation of a larger cohort or experimental analyses would be needed to confirm this notion.
Gastrointestinal stromal tumors (GIST) harbor driver mutations of signal transduction kinases such as KIT, or, alternatively, manifest loss-of-function defects in the mitochondrial succinate ...dehydrogenase (SDH) complex, a component of the Krebs cycle and electron transport chain. We have uncovered a striking divergence between the DNA methylation profiles of SDH-deficient GIST (n = 24) versus KIT tyrosine kinase pathway-mutated GIST (n = 39). Infinium 450K methylation array analysis of formalin-fixed paraffin-embedded tissues disclosed an order of magnitude greater genomic hypermethylation relative to SDH-deficient GIST versus the KIT-mutant group (84.9 K vs. 8.4 K targets). Epigenomic divergence was further found among SDH-mutant paraganglioma/pheochromocytoma (n = 29), a developmentally distinct SDH-deficient tumor system. Comparison of SDH-mutant GIST with isocitrate dehydrogenase-mutant glioma, another Krebs cycle-defective tumor type, revealed comparable measures of global hypo- and hypermethylation. These data expose a vital connection between succinate metabolism and genomic DNA methylation during tumorigenesis, and generally implicate the mitochondrial Krebs cycle in nuclear epigenomic maintenance.
Diffuse malignant mesothelioma of the pleura is a highly aggressive tumor typically associated with short survival. ALCAM (CD166), a type I transmembrane protein, is a member of the immunoglobulin ...superfamily. In normal cells, ALCAM regulates physiological processes such as angiogenesis and immune response. In cancer, it is associated with neoplastic progression, including invasion, migration, and metastasis. Furthermore, ALCAM is considered one of the cancer stem cell markers such as ALDH1 (ALDH1A1) and SALL4. The PD-L1 (CD274)/PD-1 (PDCD1, CD279) pathway is crucial for the modulation of immune responses in normal cells. Nevertheless, pathologic activation of the PD-L1/PD-1 pathway participates in immune evasion by tumor cells. Many PD-L1–expressing tumor cells have been identified in different types of cancer, including malignant mesothelioma. In this study, 175 well-characterized primary diffuse pleural mesotheliomas, including the epithelioid (n = 148), biphasic (n = 15), and sarcomatoid (n = 12) histotypes, were evaluated immunohistochemically for cancer stem cell markers (ALCAM, ALDH1, and SALL4) and PD-L1 expression. Twenty-five percent of the mesotheliomas (43/175) expressed ALCAM, whereas ALDH1 and SALL4 positivity was seen in 1% to 2% of cases. Thirty-three percent of the analyzed tumors (57/175) contained PD-L1–positive cells. Overall survival was significantly decreased in the cohort of patients with ALCAM- or PD-L1–positive tumors (both P < .01). Furthermore, the multivariate Cox hazards regression analysis identified ALCAM and PD-L1 (both P < 0.01) as potential independent risk factors. Thus, a combination of these 2 markers might be useful for prognostication and planning the treatment of patients with malignant pleural mesothelioma.
•PD-L1 and stem cell marker expressions were analyzed in malignant mesotheliomas.•PD-L1 and ALCAM were expressed in 33% and 25% of mesothelioma cases, respectively.•The Cox proportional hazards model identified these proteins as independent risk factors for death.
Summary Mesenchymal chondrosarcoma, a rare malignant round cell and hyaline cartilage tumor, is most commonly intraosseous but can occur in extraskeletal sites. We intensively observed the morphology ...and applied Sox9 (master regulator of chondrogenesis), β-catenin (involved in bone formation, thought to inhibit chondrogenesis in a Sox9-dependent manner), and osteocalcin (a marker for osteoblastic phenotype) to 22 central nervous system and musculoskeletal mesenchymal chondrosarcoma. Cases of mesenchymal chondrosarcoma were retrieved and reviewed from our files. Immunohistochemistry and follow-up were obtained on mesenchymal chondrosarcoma and tumor controls. Twenty-two mesenchymal chondrosarcomas included 5 central nervous system (all female; mean age, 30.2; mean size, 7.8 cm; in frontal lobe n = 4 and spinal cord n = 1) and 17 musculoskeletal (female-male ratio, 11:6; mean age, 31.1; mean size, 6.2 cm; 3 each of humerus and vertebrae; 2 each of pelvis, rib, tibia, neck soft tissue; one each of femur, unspecified bone, and elbow soft tissue). The hyaline cartilage in most tumors revealed a consistent linear progression of chondrocyte morphology, from resting to proliferating to hypertrophic chondrocytes. Sixty-seven percent of cases demonstrated cell death and acquired osteoblastic phenotype, cells positive for osteocalcin at the site of endochondral ossification. Small round cells of mesenchymal chondrosarcoma were negative for osteocalcin. SOX9 was positive in both components of 21 of 22 cases of mesenchymal chondrosarcoma. β-Catenin highlighted rare nuclei at the interface between round cells and hyaline cartilage in 35% cases. Control skull and central nervous system cases were compared, including chondrosarcomas and small cell osteosarcoma, the latter positive for osteocalcin in small cells. Mesenchymal chondrosarcoma demonstrates centrally located hyaline cartilage with a linear progression of chondrocytes from resting to proliferative to hypertrophic, which undergoes endochondral ossification, recapitulating growth plate cartilage and suggesting that this component of mesenchymal chondrosarcoma may be a differentiated (benign or metaplastic) component of a malignant metastasizing tumor. This hyaline cartilage component is morphologically different from cartilage of control chondrosarcoma. Mesenchymal chondrosarcoma can be separated from small cell osteosarcoma, using Sox 9 for cartilage and osteocalcin for osteoblastic phenotype. Rare nuclear β-catenin expression at the interface between hyaline cartilage and small round cells potentially implicates the APC/Wnt pathway during endochondral ossification in morphologically benign hyaline cartilage component of mesenchymal chondrosarcoma.
Episodic angioedema with eosinophilia (Gleich syndrome) is a rare disorder characterized by episodes of angioedema and eosinophilia that occur at monthly intervals and resolve spontaneously without ...therapy. Despite the striking periodicity of this disorder, its similarity to other cyclic hematopoietic disorders with multilineage involvement has not been assessed. To characterize the involvement of cell lineages in the etiology and pathogenesis of episodic angioedema with eosinophilia, four subjects were evaluated by blood counts and other analyses over the course of 1-2 months. Surface marker expression was assessed on T cells by flow cytometry and clonality by polymerase chain reaction. Intracellular cytokine evaluation, bone marrow and skin biopsies were performed during different parts of the cycle. Cycling of multiple cell lineages, including neutrophils, lymphocytes and eosinophils, was observed in the four subjects with the disorder with a periodicity of 25-35 days. An aberrant CD3(-)CD4(+) T-cell population was detected in all four subjects, and T-cell receptor rearrangement studies showed a clonal pattern in three subjects. A peak of type II cytokines was detected in the serum of subjects prior to the onset of symptoms and eosinophil cycling and corresponded to ex-vivo type II cytokines detected intracellularly in CD3(+)CD4(+)CD154(+) T cells. Although the etiology of episodic angioedema with eosinophilia is not yet known, multiple lineages, including lymphocytes, neutrophils and mast cells, are involved and may be related to disease pathogenesis. Whether these cells act directly or promote eosinophilia and eosinophil activation remains to be elucidated. All subjects gave informed consent and were evaluated under an Institutional Review Board-approved protocol (NCT00001406).
Tumors of the central nervous system are the second most common malignancy in children. In particular, diffuse intrinsic pontine gliomas (DIPGs) are aggressive tumors with poor prognosis and account ...for 10% to 25% of pediatric brain tumors. The majority of DIPGs are astrocytic, infiltrative, and localized to the pons. Studies have shown median survival times of less than a year, with 90% of children dying within 2 years. We built multitissue arrays with 24 postmortem DIPG samples and analyzed the morphology and expression of several proteins (p53, EGFR, GFAP, MIB1, BMI1, β-catenin, p16, Nanog, Nestin, OCT4, OLIG2, SOX2) with the goal of identifying potential treatment targets and improving our understanding of the biology of these tumors. The majority of DIPGs were high-grade gliomas (22), with 18 cases having features of glioblastoma (World Health Organization WHO grade IV) and 4 cases with high-grade features consistent with anaplastic astrocytoma (WHO grade III). One case was low grade (WHO grade II), and 1 case showed intermediate features between a grade II and grade III glioma (low mitotic rate but increased cellularity and cell atypia), being difficult to grade precisely. The majority of the tumors were positive for GFAP (24/24), MIB1 (23/24), OLIG2 (22/24), p16 (20/24), p53 (20/24), SOX2 (19/24), EGFR (16/24), and BMI1 (9/24). Our results suggest that dysregulation of EGFR and p53 may play an important role in the development of DIPGs. The majority of DIPGs express stem cell markers such as SOX2 and OLIG2, consistent with a role for tumor stem cells in the origin and maintenance of these tumors. Targeted therapies against these proteins could be beneficial in treatment.
To improve localization accuracy and reduce system costs, a new range-free localization algorithm for wireless sensor networks using connectivity and received signal strength (RSS) rank is proposed. ...An unknown node is first localized in an initial residence area according to the connectivity constraints. Then, the residence area is refined using the RSS rank vector. The RSS rank vector of an unknown node is formed from the ranks of the RSS values obtained from neighboring anchors. The estimated location of the unknown node is the centroid of the refined residence area. The proposed localization algorithm uses a grid scan approach to avoid the complex geometric computations. This algorithm is improved by using an adaptive strategy to determine the grid size. The performance of these methods is examined via analysis and simulation. The results obtained verify that the proposed approaches provide better localization accuracy than competing algorithms in the literature.
GATA3 is a transcription factor important in the differentiation of breast epithelia, urothelia, and subsets of T lymphocytes. It has been suggested to be useful in the evaluation of carcinomas of ...mammary or urothelial origin or metastatic carcinomas, but its distribution in normal and neoplastic tissues is incompletely mapped. In this study, we examined normal developing and adult tissues and 2040 epithelial and 460 mesenchymal or neuroectodermal neoplasms for GATA3 expression to explore its diagnostic value in surgical pathology, using monoclonal antibody (clone L50-823) and Leica Bond automated immunohistochemistry. GATA3 was expressed in trophoblast, fetal and adult epidermis, adult mammary and some salivary gland and sweat gland ductal epithelia, urothelia, distal nephron in developing and adult tissues, some prostatic basal cells, and subsets of T lymphocytes. It was expressed stronger in fetal than in adult mesothelia and was absent in respiratory and gastrointestinal epithelia. In epithelial neoplasms, GATA3 was expressed in >90% of primary and metastatic ductal and lobular carcinomas of the breast, urothelial, and cutaneous basal cell carcinomas and trophoblastic and endodermal sinus tumors. In metastatic breast carcinomas, it was more sensitive than GCDFP. Among squamous cell carcinomas, the expression was highest in the skin (81%) and lower in cervical (33%), laryngeal (16%), and pulmonary tumors (12%). Common positivity was found in skin adnexal tumors (100%), mesothelioma (58%), salivary gland (43%), and pancreatic (37%) ductal carcinomas, whereas frequency of expression in adenocarcinomas of lung, stomach, colon, endometrium, ovary, and prostate was <10%. Chromophobe renal cell carcinoma was a unique renal tumor with frequent positivity (51%), whereas oncocytomas were positive in 17% of cases but other types only rarely. Among mesenchymal and neuroectodermal tumors, paragangliomas were usually positive, which sets these tumors apart from epithelial neuroendocrine tumors. Mesenchymal tumors were only sporadically positive, except epithelia of biphasic synovial sarcomas. GATA3 is a useful marker in the characterization of not only mammary and urothelial but also renal and germ cell tumors, mesotheliomas, and paragangliomas. The multiple specificities of GATA3 should be taken into account when using this marker to detect metastatic mammary or urothelial carcinomas.
Brachyury is a transcription factor of the T-box family typically expressed in notochord and chordoma. Some studies report brachyury as highly specific for chordoma, whereas others have concluded ...that brachyury is expressed in many types of common carcinomas by reverse transcription polymerase chain reaction and immunohistochemistry and could be involved in the epithelial-mesenchymal transition and metastatic process. In this study, we immunohistochemically evaluated 5229 different tumors for nuclear brachyury expression using a new rabbit monoclonal antibody and automated immunostaining (Leica Bond Max). Only nuclear labeling was scored, and antibody dilution of 1:2000 was used. In normal tissues, only rare cells in seminiferous tubules were labeled; all other organs were negative. All chordomas (75/76), except a sarcomatous one, were positive, whereas chondrosarcomas were negative. Among epithelial tumors, positivity was often detected in embryonal carcinoma (74%) and seminoma (45%). Pulmonary small cell carcinoma was often positive (41%), whereas pulmonary and pancreatic adenocarcinomas only rarely showed nuclear brachyury positivity (3% to 4%). Common carcinomas such as ductal carcinomas of the breast or adenocarcinomas of the prostate only exceptionally showed nuclear positivity (<1%). No colorectal, hepatocellular, renal cell, squamous cell, thyroid or urothelial carcinoma, or mesothelioma showed nuclear brachyury positivity. Among mesenchymal and neuroectodermal tumors, only isolated cases of melanoma, malignant peripheral nerve sheath tumor, rhabdomyosarcoma, synovial sarcoma, and follicular lymphoma showed nuclear expression. However, as shown previously with lung carcinoma, experiments with lower antibody dilutions (1:200 to 1:500) showed weak cytoplasmic and nuclear labeling in breast cancers. In addition to chordoma, we show here for the first time that nuclear brachyury expression is prevalent in embryonal carcinoma, seminoma, and small cell carcinoma of the lung but very rare in common carcinomas, sarcomas, and melanoma. With these reservations, we have demonstrated the presence of nuclear brachyury immunoreactivity to be a sensitive and fairly specific marker for chordoma.
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