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Purpose: African Americans (AA) have the highest incidence of colorectal cancer compared with other U.S. populations and more proximal colorectal cancers. The objective is to elucidate the basis of these cancer disparities.Experimental design: Of note, 566 AA and 328 non-Hispanic White (NHW) colorectal cancers were ascertained in five Chicago hospitals. Clinical and exposure data were collected. Microsatellite instability (MSI) and BRAF (V600E) and KRAS mutations were tested. Statistical significance of categorical variables was tested by the Fisher exact test or logistic regression and age by the Mann–Whitney U test.Results: Over a 10-year period, the median age at diagnosis significantly decreased for both AAs (68–61; P < 0.01) and NHWs (64.5– 62; P = 0.04); more AA patients were diagnosed before age 50 than NHWs (22% vs. 15%; P = 0.01). AAs had more proximal colorectal cancer than NHWs (49.5% vs. 33.7%; P < 0.01), but overall frequencies of MSI, BRAF and KRAS mutations were not different nor were they different by location in the colon. Proximal colorectal cancers often presented with lymphocytic infiltrate (P < 0.01) and were diagnosed at older ages (P = 0.02). Smoking, drinking, and obesity were less common in this group, but results were not statistically significant.Conclusions: Patients with colorectal cancer have gotten progressively younger. The excess of colorectal cancer in AAs predominantly consists of more proximal, microsatellite stable tumors, commonly presenting lymphocytic infiltrate and less often associated with toxic exposures or a higher BMI. Younger AAs had more distal colorectal cancers than older ones. These data suggest two different mechanisms driving younger age and proximal location of colorectal cancers in AAs. Clin Cancer Res; 20(18); 4962–70. ©2014 AACR.

Mixed lineage kinase 3 (MLK3), also known as MAP3K11, was initially identified in a megakaryocytic cell line and is an emerging therapeutic target in cancer, yet its role in immune cells is not known. Here, we report that loss or pharmacological inhibition of MLK3 promotes activation and cytotoxicity of T cells. MLK3 is abundantly expressed in T cells, and its loss alters serum chemokines, cytokines, and CD28 protein expression on T cells and its subsets. MLK3 loss or pharmacological inhibition induces activation of T cells in in vitro, ex vivo, and in vivo conditions, irrespective of T cell activating agents. Conversely, overexpression of MLK3 decreases T cell activation. Mechanistically, loss or inhibition of MLK3 down-regulates expression of a prolyl-isomerase, Ppia, which is directly phosphorylated by MLK3 to increase its isomerase activity. Moreover, MLK3 also phosphorylates nuclear factor of activated T cells 1 (NFATc1) and regulates its nuclear translocation via interaction with Ppia, and this regulates T cell effector function. In an immune-competent mouse model of breast cancer, MLK3 inhibitor increases Granzyme B-positive CD8(+) T cells and decreases MLK3 and Ppia gene expression in tumor-infiltrating T cells. Likewise, the MLK3 inhibitor in pan T cells, isolated from breast cancer patients, also increases cytotoxic CD8(+) T cells. These results collectively demonstrate that MLK3 plays an important role in T cell biology, and targeting MLK3 could serve as a potential therapeutic intervention via increasing T cell cytotoxicity in cancer.

Lynch syndrome is an autosomal dominant disorder, caused by an abnormality in DNA mismatch repair genes and characterized by the development of a variety of cancers. Upper urinary tract urothelial carcinoma is well characterized in Lynch syndrome; however, support for the inclusion of bladder urothelial carcinoma is limited, except for MSH2 mutation carriers. Urologic adenocarcinoma has not been documented in Lynch syndrome. Here we report, to the best of our knowledge, the first case of bladder adenocarcinoma, synchronous with uterine endometrioid dedifferentiated endometrioid adenocarcinoma in a patient with Lynch syndrome. We present a 47-year-old woman with an MLH1 gene mutation (G133X 397G>T) who presented with menorrhagia. Eleven family members have this mutation, 6 with carcinoma: 5 colorectal and 1 with a gynecologic primary of unknown type. Colonoscopy and endoscopy were unremarkable. Positron emission and computed tomography revealed a 3 cm anterior dome bladder mass without additional extrauterine disease or uterine connection. She underwent partial cystectomy, laparoscopic hysterectomy, bilateral salpingo-oophorectomy, and lymphadenectomy. The uterus demonstrated a dedifferentiated endometrioid adenocarcinoma, immunohistochemically positive for vimentin, ER, CK7, MSH2, MSH6, and p53 (focally) and negative for CEA, CDX2, CK20, β-catenin, MLH1, and PMS2. The bladder demonstrated a well-differentiated, enteric-type adenocarcinoma without muscularis propria invasion, positive for CEA, CDX2, CK20, p53, MSH2, and MSH6 and negative for vimentin, ER, CK7, MLH1, and PMS2. Eleven nodes were negative for carcinoma. The morphologic, immunohistochemical, and clinical findings support synchronous bladder adenocarcinoma, enteric type, and uterine dedifferentiated endometrioid adenocarcinoma, in a patient with Lynch syndrome.

The Notch signaling pathway, particularly endothelial Notch signaling, plays a key role in tumor formation and angiogenesis. Inhibiting Notch1 or its ligand, Delta-like ligand 4 (Dll4), can induce hypersprouting of the tumor vasculature and thus can reduce tumor perfusion and progression. However, due to the expression of Notch1 in multiple healthy cell types, pharmacologic blockade poses the challenge of inducing tissue hypoxia, vascular neoplasms, and toxicity in non-target tissues. Unlike Notch1, Notch4 expression is largely restricted to endothelium and is upregulated in models of triple negative breast cancer (TNBC). Loss of Notch4 in mice results in delayed developmental angiogenesis and reduced mammary tumor angiogenesis and perfusion. Therefore, Notch4 is an attractive potential pharmacologic target to interfere with tumorigenesis and minimize nonspecific toxicity. We determined that Notch4 is expressed primarily in tumor endothelium in both human and mouse mammary tumors, including murine syngeneic Py8119 tumors, as well as a selection of other human and syngeneic mouse tumor types such as B16F10 melanoma tumors. We explored the effects of Notch4 inhibition on the progression of murine mammary epithelial carcinoma using newly developed anti-Notch4 antibodies, 6-3-A6 and its humanized derivative E7011. Administration of E7011 or 6-3-A6 to orthotopically implanted Py8119 murine breast carcinoma and B16F10 melanoma significantly reduced tumor size in comparison to IgG-treated controls. We performed single cell RNA sequencing of Py8119 tumors treated with E7011 and found that although Notch4 transcripts were found specifically in the endothelium, the most notable effect of E7011 was a dramatic increase in the number of macrophages and cancer-associated fibroblasts, suggesting a non-cell autonomous effect. To examine the potential role of these immune cell population changes in facilitating E7011’s anti-tumor activity, we investigated treatment of Py8119 murine mammary carcinomas in the absence of macrophages. Administration of clodronate liposomes to eliminate macrophages blocked the anti-tumor effects of E7011 treatment. Taken together, our data suggests that tumor endothelial Notch4 promotes TNBC growth by altering the immune landscape and increasing anti-tumor macrophage recruitment, and that blockade via the novel anti-Notch4 E7011 antibody has potential therapeutic efficacy. Citation Format: Jason W. Eng, L.A. Naiche, Bhairavi Swaminathan, Yu Kato, Krishna Thakkar, Katherine Ann Alexander, Rahul Vadakath, James H. Herts, Rajyasree Emmadi, Junji Matsui, Jan K. Kitajewski. Notch4 inhibition by a novel neutralizing antibody reduces tumor progression and increases macrophage recruitment within the tumor microenvironment [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 2 (Clinical Trials and Late-Breaking Research); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(8_Suppl):Abstract nr LB009.

Objectives Insulin-like growth factor-methotrexate (IGF-MTX) is a conjugate of methotrexate and 765IGF, a variant of IGF-1 with high affinity for insulin-like growth factor type 1 receptor. The study aim was to determine the maximum tolerated dose of IGF-MTX in refractory solid organ and hematologic malignancies expressing insulin-like growth factor type 1 receptor. Materials and methods This phase I trial used a modified toxicity probability interval design with 5 cohort dose levels, and expansion cohort at maximum tolerated dose. IGF-MTX was given intravenously over 90 minutes on days 1, 8, and 15 of a 28-day cycle. Results A total of 17 patients were enrolled. The highest tolerated dose tested was 0.80 µEq/kg with dose-limiting toxicity of grade 3 hypoglycemia. Drug-related grade 3 and 4 toxicities included abdominal pain (26%), hypoglycemia (10%), and hypotension (10%). Of the 15 evaluable for response, 3 patients (20%) had stable disease, including the patient with Hodgkin lymphoma with stable disease for 12 cycles of therapy. IGF-MTX concentrations declined rapidly, with half-lives of 5.2 to 14 minutes for the initial distribution phase and 6.5 to 7.5 hours for the terminal elimination phase. Higher IGF-R1 expression did not correlate with better outcome. Conclusions IGF-MTX is well tolerated. IGF-MTX pharmacokinetics suggest rapid cellular uptake. The activity of IGF-MTX in Hodgkin lymphoma should be explored.

We present a case of Langerhans’ cell histiocytosis in a 40-year-old woman presenting with central diabetes insipidus and right ear pain. As this disease process is often clinically challenging, the presence of certain imaging findings should raise the possibility of this diagnosis. We review the pertinent imaging and correlate with histology and immunohistochemistry leading to the diagnosis. Keywords: Langerhans cell histiocytosis, Adult, Histology, CT temporal bone, MRI

Many colorectal cancers (CRCs) that exhibit microsatellite instability (MSI) are not explained by MLH1 promoter methylation or germline mutations in mismatch repair (MMR) genes, which cause Lynch syndrome (LS). Instead, these Lynch-like syndrome (LLS) patients have somatic mutations in MMR genes. However, many of these patients are young and have relatives with cancer, suggesting a hereditary entity. We performed germline sequence analysis in LLS patients and determined their tumor's mutational profiles using FFPE DNA. Six hundred fifty-four consecutive CRC patients were screened for suspected Lynch syndrome using MSI and absence of MLH1 methylation. Suspected LS cases were exome sequenced to identify germline and somatic mutations. Single nucleotide variants were used to characterize mutational signatures. We identified 23 suspected LS cases. Germline sequence analysis of 16 available samples identified 5 cases with LS mutations and 11 cases without LS mutations, LLS. Most LLS tumors had a combination of somatic MMR gene mutation and loss of heterozygosity. LLS patients were relatively young and had excess first-degree relatives with cancer. Four of the 11 LLS patients had rare likely pathogenic variants in genes that maintain genome integrity. Moreover, tumors from this group had a distinct mutational signature compared to tumors from LLS patients lacking germline mutations in these genes. In summary, more than a third of the LLS patients studied had germline mutations in genes that maintain genome integrity and their tumors had a distinct mutational signature. The possibility of hereditary factors in LLS warrants further studies so counseling can be properly informed.

Endothelial Notch signaling is critical for tumor angiogenesis and growth. Inhibition of Notch1 or its ligand, Dll4, can induce tumor vessel hypersprouting, which interferes with perfusion and reduces tumor development. Unfortunately, blocking Notch1 in endothelial cells of normal tissue can lead to tissue hypoxia and vascular neoplasms. Notch4, another member of the Notch family, is upregulated and increased in the endothelium of certain tumor types compared to normal vasculature. Reducing Notch4, unlike Notch1, causes reduction in developmental and tumor angiogenesis. Using a newly developed anti-Notch4 antibody, E7011, we assessed the effects on Notch4 inhibition on developmental retinal angiogenesis. E7011 treatment did not alter capillary density within the vascular plexus or endothelial tip cell number, but did decrease radial outgrowth and vein diameter, supporting the hypothesis that Notch4 functions as a pro-angiogenic signal. These findings suggest that the targeting of Notch4 could interfere with tumor angiogenesis and offer a novel therapeutic avenue. To establish the role of Notch4 within the tumor microenvironment, we analyzed its expression in both human and murine tumor samples. Immunofluorescent staining revealed a range of Notch4 expression in both tumor cells and endothelium in human triple negative breast cancers. Several murine syngeneic tumors examined expressed Notch4 primarily in the endothelium with only rare tumor expression. We treated orthotopically implanted Py8119 murine breast carcinomas and B16F10 melanomas with E7011, which significantly reduced tumor size compared to IgG treated controls, indicating that suppression of Notch4 is anti-tumorigenic. To determine mechanistically how E7011 delays tumor growth, we performed single cell RNA sequencing on E7011 and control treated Py8119 tumors. Surprisingly, we found that while Notch4 transcripts were present only in endothelial cells, E7011 administration dramatically altered macrophage and monocyte populations within the tumor. Taken together, these findings indicate that inhibition of tumor endothelial Notch4 by E7011 can regulate the presence of immune cells within the tumor microenvironment and improve tumor control. Citation Format: Jason Eng, L.A. Naiche, Bhairavi Swaminathan, Yu Kato, Krishna Thakkar, Rahul Vadakath, James Herts, Rajyasree Emmadi, Junji Matsui, Jan Kitajewski. Targeting Notch4 with a novel neutralizing antibody inhibits tumor growth and alters immune cell populations within the tumor microenvironment [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 247.

Objectives: Antiretroviral therapy (ART) has immense survival benefit on human immunodeficiency virus (HIV)-infected people. However, every year, a proportion of patients were failing to the first-line drugs. The aim of this study is to characterize the patients developing first-line failure within 5 years of ART. Materials and Methods: A retrospective observational study was carried out at the Centre of Excellence in HIV care, School of Tropical Medicine, Kolkata. A total of 190 referred patients' data of suspected first-line treatment failure who failed first-line ART within 5 years of initiation were collected and analyzed using R software. Results: Among 190 patients, 100 (52.4%) patients had virologic failure. Male patients 78 (41.05%) outnumbered females 22 (11.57%) and needed to switch to the second-line drugs. The median age was 37 years (range 8–65 years), and the median duration of first-line ART taken was 2.85 years. Among the first-line failed patients, zidovudine, lamivudine, and nevirapine (23.6%) was the most common antiretroviral regimen and 77 (40.5%) referred in the WHO stage I of illness. Seventy-three (38.42%) patients were referred for immunological failure, 26 (13.7%) for both immunological and clinical failure, and only 1 (0.52%) had only clinical failure at the time of referral. We found a significant association of suboptimal adherence (P < 0.05) and high viral load in this study. Conclusion: This study enables that poor adherence was the most important factor responsible for the first-line treatment failure. As adherence is a dynamic process, interventions in every visit following ART initiation should be optimized, and a multidisciplinary approach toward adherence is needed to get the highest treatment outcome benefit.

Background The aim of this study was to evaluate the clinical utility and cost-effectiveness of routine histologic examination of the doughnuts from stapled anastomoses in patients undergoing a low anterior resection for rectal cancer. Methods We performed a retrospective review of 486 patients who underwent a low anterior resection with stapled anastomosis for rectal cancer between 2002 and 2015 at 3 institutions. Pathologic findings in the doughnuts and their impact on patient management were recorded. Tumor characteristics that may influence how often doughnuts were included in the pathology report were analyzed. An approximate cost of histologic examination of doughnuts was also calculated. Results A total of 412 patients (85%) had doughnuts included in their pathology reports. Two patients had cancer cells in their doughnuts, and both patients had a positive distal margin in their primary tumor specimen; 33 patients had benign findings in their doughnuts. Pathologic examination of the doughnut did not change clinical management in any patient. Patients with rectosigmoid tumors were less likely to have their doughnuts included in the pathology report compared to patients with low tumors ( P = .003). Doughnuts were not bundled with the primary tumor specimen in 374 (77%) of our patients; in these patients, pathologic analysis of the doughnut added an additional cost of approximately $643 per specimen. Conclusion This study demonstrates no clinical benefit in sending anastomotic doughnuts for histopathologic evaluation after performing a low anterior resection with a stapled anastomosis for rectal cancer. Overall cost may be decreased if doughnuts are not analyzed or if they are bundled with the primary tumor specimen.

Renal cell neoplasia are heterogeneous with diverse histology, genetic alterations, and clinical behavior that are diagnosed mostly on morphologic features. The Renal Cell Neoplasia Workgroup of the Cancer Genomics Consortium systematically evaluated peer-reviewed literature on genomic studies of renal cell carcinoma (RCC), including clear cell RCC, papillary RCC, chromophobe RCC, and the translocation RCC involving TFE3, TFEB and MITF rearrangements, as well as benign oncocytoma, which together comprise about 95% of all renal cell neoplasia. The Workgroup curated recurrent copy number alterations (CNAs), copy-neutral loss-of-heterozygosity (cnLOH), rearrangements, and mutations, found in each subtype and assigned clinical relevance according to established criteria. In clear cell RCC, loss of 3p has a disease-initiating role and most likely also in progression with mutations detected in VHL and other genes mapped to this arm, and loss of 9p and/or 14q has well-substantiated prognostic utility. Gain of chromosomes 7 and 17 are hallmark CNAs of papillary RCC, but patterns of other CNAs as detected by chromosomal microarray analysis (CMA) afford sub-classification into Type 1 and 2 with prognostic value, and for further sub-stratification of Type 2. Inherent chromosome loss in chromophobe RCC as detected by CMA is useful for distinguishing the eosinophilic variant from benign oncocytoma which in contrast exhibits few CNAs or rearranged CCND1, but share mitochondrial DNA mutations. In morphologically atypical RCCs, rearrangement of TFE3 and TFEB should be considered in the differential diagnosis, portending an aggressive RCC subtype. Overall, this evidence-based review provides a validated role for assessment of CNAs in renal cell neoplasia in the clinical setting to assist in renal cell neoplasm diagnosis and sub-classification within subtypes that is integral to the management of patients, from small incidentally found renal masses to larger surgically resected specimens, and simultaneously identify the presence of key alterations portending outcome in malignant RCC subtypes.

Background Genomic abnormalities in breast cancer have been described according to diverse conceptual frameworks, including histologic subtypes, clinical molecular subtypes, intrinsic DNA, RNA, and epigenetic profiles, and activated molecular pathways. Methods The Cancer Genomics Consortium (CGC) Breast Cancer Workgroup performed an evidence based literature review to summarize current knowledge of clinically significant genomic alterations in breast cancer using CGC levels of evidence. Targetable or disease-defining alterations were prioritized. Results We summarized genomic alterations in breast cancer within a framework of existing clinical tools for diagnosis, risk stratification, and therapeutic management. Using CGC levels of evidence, we catalog copy number profiles, gene expression profiles, and mutations in clinically significant genes. We also describe emerging molecular markers such as methylation profiling and immunotherapy biomarkers. Conclusion A summary of currently available information on breast cancer genomics will enhance precision medicine by serving as an interpretive resource for clinical laboratory geneticists, providing a foundation for future practice guidelines, and identifying knowledge gaps to address in future research.

Invasion of peripheral nerves by epithelial cells has been traditionally regarded as a feature diagnostic of malignancy, its presence therefore being often sought to document a diagnosis of carcinoma, particularly in the breast. Perineural involvement (PNI) by benign breast disease is not often seen and the etiology is uncertain. The first reported case of nerve invasion in a benign breast lesion was by Ackerman in 1957. Subsequent reports have further confirmed this finding in the breast. The most challenging observation is when the glands involving nerves show cytologic and architectural features of the adjacent atypical duct hyperplasia (ADH) or ductal carcinoma in situ (DCIS). Here, we describe a case of ductal carcinoma in situ grade 2 with nerve involvement in a lumpectomy specimen in a 59-year-old woman. To the best of our knowledge, only five cases of atypical duct hyperplasia by Gobbi et al. and four cases of ductal carcinoma in situ, 3 by Gobi et al. and 1 by Tsang and Chan, associated with nerve involvement, have been reported in English medical literature. Two layers of epithelial cells with the immunohistochemical demonstration of the preservation of a continuous myoepithelial layer in the mammary ducts within the nearby small nerves, is the main clue to confirm the in-situ nature of the inclusions. It is necessary to be aware of this phenomenon in breast lesions to avoid over-diagnosis and inappropriate surgery.

Impact of single super phosphate (SSP) on Body weight, Total protein, Amino acids content was studied in Channastriatus by exposing to 400mg/l ofsingle super phosphate dissolved in water for 7 and 15 days. SSP showed differential effect on all parameters analysed. SSP caused signifcant decrease in total body weight and total protein content, but an increase in Amino acid levels in liver, muscle and gill tissue. The study indicates SSP has negative impact on protein metabolism of fish..

Osteogenesis imperfect (OI) type II is a genetic disorder of bone characterized by bone fragility, multiple fractures, severe bowing and shortening of long bones, and perinatal death due to respiratory insufficiency. It is mainly caused by mutations in the COL1A1 or COL1A2 genes, inherited in an autosomal dominant manner.A fetal form of this disorder that included brachydactyly, macrocephaly, frontal bossing, soft calvarium, saddle nose, micrognathia, low set ears, and narrow thoracic cavity is described. A postmortem skeletal survey revealed multiple fractures, unossified skull, and long crumpled bones. The fetal karyotype revealed a balanced translocation t(1;20)(p13;p11.2). DNA sequencing detected a c.3065G T transversion in exon 42 of the COL1A1 gene, a mutation associated with OI type II.Although the balanced translocation t(1:20)(p13;p11.2) appears to be incidental in our case, identification of the specific mutation and translocation is important for estimation of genetic risk for another afflicted child.

Clinical utility describes the benefits of each laboratory test for that patient. Many stakeholders have adopted narrow definitions for the clinical utility of molecular testing as applied to targeted pharmacotherapy in oncology, regardless of the population tested or the purpose of the testing. This definition does not address all of the important applications of molecular diagnostic testing. Definitions consistent with a patient-centered approach emphasize and recognize that a clinical test result's utility depends on the context in which it is used and are particularly relevant to molecular diagnostic testing because of the nature of the information they provide. Debates surrounding levels and types of evidence needed to properly evaluate the clinical value of molecular diagnostics are increasingly important because the growing body of knowledge, stemming from the increase of genomic medicine, provides many new opportunities for molecular testing to improve health care. We address the challenges in defining the clinical utility of molecular diagnostics for inherited diseases or cancer and provide assessment recommendations. Starting with a modified analytic validity, clinical validity, clinical utility, and ethical, legal, and social implications model for addressing clinical utility of molecular diagnostics with a variety of testing purposes, we recommend promotion of patient-centered definitions of clinical utility that appropriately recognize the valuable contribution of molecular diagnostic testing to improve patient care.

We demonstrate for the first time the imaging of unstained breast tissue biopsies using third-harmonic generation (THG) microscopy. As a label-free imaging technique, THG microscopy is compared to phase contrast and polarized light microscopy which are standard imaging methods for breast tissues. A simple feature detection algorithm is applied to detect tumour-associated lymphocyte rich regions in unstained breast biopsy tissue and compared with corresponding regions identified by a pathologist from bright-field images of hematoxylin and eosin stained breast tissue. Our results suggest that THG imaging holds potential as a complementary technique for analysing breast tissue biopsies.

Endothelial Notch signaling is critical for tumor angiogenesis and growth. Inhibitors of Notch1 or its ligand Dll4 cause tumor vessel hypersprouting but interfere with vessel perfusion causing reduced tumor growth. Unfortunately, normal tissue vessels respond to these inhibitors causing tissue hypoxia or vascular neoplasms. Mice null for Notch4, unlike Notch1 mutants, exhibit reduced developmental and tumor angiogenesis. Notch4 expression is increased in the endothelium of some tumor types. These results suggest that specifically targeting Notch4 could reduce tumor angiogenesis with fewer effects on normal tissue and represents an unexplored therapeutic opportunity. We use a newly developed anti-Notch4 antibody, E7011, and show that in endothelial cells, inhibition of Notch4 signaling suppresses expression of a subset of canonical Notch target genes. Treatment with E7011 also suppresses expression of a unique set of genes not regulated by canonical Dll4-Notch1 signaling, which appear to be distinct Notch4 targets. We administered E7011 to neonatal mice to examine the effects on developmental retinal angiogenesis. A single dose of E7011 significantly reduced retinal vascular outgrowth, demonstrating that E7011 has anti-angiogenic activity in vivo. E7011 treatment did not alter capillary density within the vascular plexus or endothelial tip cell number, both of which are typically increased by loss of Notch1 signaling. Because the E7011 phenotype was markedly distinct from the Notch1 loss of function, we combined E7011 treatment with endothelial-specific loss of Notch1 (Notch1ECKO) to compare Notch1 to Notch4 function. E7011-treated Notch1ECKO retina showed a compound phenotype, exhibiting both the loss of vascular outgrowth characteristic of E7011/Notch4 and the hypersprouting characteristic of Notch1 loss of function. These results suggest that Notch1 and Notch4 have distinct roles in developmental angiogenesis, with Notch4 being a pro-angiogenic signaling pathway. We evaluated Notch4 expression in the breast cancer tumor microenvironment to determine if Notch4 functions in tumor vessels. Human triple negative breast cancer (TNBC) shows a range of expression of Notch4 in both tumor cells and tumor endothelium. The anti-angiogenic effects that we observe in the retina lead us to hypothesize that E7011 will show anti-tumor activity against tumors that induce Notch4 expression in neighboring endothelium, and that targeting endothelial Notch4 is a novel anti-angiogenic approach. Citation Format: L. A. Naiche, Bhairavi Swaminathan, Yu Kato, Sarita Das, Jason W. Eng, Qanber Raza, Krishna Thakkar, James H. Herts, Rajyasree Emmadi, Junji Matsui, Jan K. Kitajewski. A novel Notch4 neutralizing antibody inhibits angiogenesis and tumor growth via a distinct mechanism from endothelial Notch1 inhibition [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 1488.

African Americans (AAs) have higher incidence and mortality rates of colorectal cancer (CRC) compared to other US populations. AAs present with more right-sided, microsatellite stable disease, and they are diagnosed at earlier ages compared to non-Hispanic whites (NHWs). Data from the Chicago Colorectal Cancer Consortium (CCCC) suggest that the right-sided and early-onset CRCs are distinct diseases, because early-onset CRC arises more often in the distal colon (1). In addition, analysis of stage at presentation data from the SEER database suggests that early-onset CRC is on average a more rapidly developing disease that is less likely to be prevented by colonoscopy (2). To better understand these trends, we conducted exome sequencing (n=45), copy number (n=33), and methylation analysis (n=11) of microsatellite stable AA CRCs. Results were compared to data from The Cancer Genome Atlas (TCGA). In the 43 non-hypermutable tumors, only 27 (63%) contained loss-of-function mutations in APC as compared to 80% of TCGA NHW CRCs. Importantly, APC mutation-negative CRCs were associated with an earlier age of onset of CRC (p=0.01). In the TCGA, APC mutation-negative CRCs were also associated with an earlier age of onset of CRC (p=10−5). In CCCC CRCs, APC mutation-negative CRCs were also associated with previous cancer, lower overall mutation burden, and fewer copy number variants. We conducted an analysis of DNA methylation patterns and found an epigenetic signature that was distinct from the CpG island methylator phenotype characterized in microsatellite unstable disease, referred to as CIMP. Included in the list of genes that were differentially hypermethylated in APC mutation-negative CRCs were genes that regulate the WNT signaling pathway, such as SOX9, GATA6, TET1, GLIS1, and FAT1. Using the most variable differentially methylated regions from the CCCC data, we found that these regions similarly clustered in APC mutation-negative CRCs from the TCGA. These data strongly suggest that a novel epigenetic mechanism accounts for cancer development in early-onset CRCs. Contrary to the mechanism that predominates in later-onset CRC, the early-onset mechanism does not depend on mutation in the APC gene but is associated with differential methylation of WNT pathway regulating genes instead. Our data support the claim that early-onset CRC is driven by a distinct subtype of CRC that is associated with lack of APC mutation, microsatellite and chromosome stability, lower mutation burden, and distinctive DNA methylation changes. CRC driven by epigenetic changes is consistent with the epidemiologic data suggesting that early-onset CRC develops as a more rapidly advancing disease. A deeper understanding is needed of the pathways affected by the epigenetic changes and the exposures that drive those changes in order to develop therapeutic approaches to early-onset CRC. References 1. Xicola et al. Clin Cancer Res 2014;20:4962-70. 2. Augustus et al. PLOS One 2018 13:e0200462. Citation Format: Rosa Xicola, Zarko Manojlovic, Gaius Augustus, Sonia Kupfer, Rajyasree Emmadi, Victoria Alagiozian-Angelova, Tim Triche, Salhia Bodour, John Carpten, Xavier Llor, Nathan Ellis. Mechanistic differences in early-onset colorectal cancer [abstract]. In: Proceedings of the Eleventh AACR Conference on the Science of Cancer Health Disparities in Racial/Ethnic Minorities and the Medically Underserved; 2018 Nov 2-5; New Orleans, LA. Philadelphia (PA): AACR; Cancer Epidemiol Biomarkers Prev 2020;29(6 Suppl):Abstract nr IA26.

We present the results of polarimetric analysis of collagen on varying pathologies of breast tissues using second-harmonic patterned polarization-analyzed reflection confocal (SPPARC) microscopy. Experiments are conducted on a breast tissue microarray having benign tissues (BT), malignant invasive lobular carcinoma (ILC), and benign stroma adjacent to the malignant tissues (called the benign adjacent tissue, or BAT). Stroma in BAT and ILC exhibit the largest parameter differences. We observe that stromal collagen readings in ILC show lower depolarization, lower diattenuation and higher linear degree-of-polarization values than stromal collagen in BAT. This suggests that the optical properties of collagen change most in the vicinity of tumors. A similar trend is also exhibited in the non-collagenous extrafibrillar matrix plus cells (EFMC) region. The three highlighted parameters show greatest sensitivity to changes in the polarization response of collagen between pathologies.

African Americans (AAs) have higher incidence and mortality rates of colorectal cancer (CRC) compared with other US populations. They present with more right-sided, microsatellite stable disease and are diagnosed at earlier ages compared with non-Hispanic Whites (NHWs). To gain insight into these trends, we conducted exome sequencing (n = 45), copy number (n = 33) and methylation analysis (n = 11) of microsatellite stable AA CRCs. Results were compared with data from The Cancer Genome Atlas (TCGA). Two of the 45 tumors contained POLE mutations. In the remaining 43 tumors, only 27 (63%) contained loss-of-function mutations in APC compared with 80% of TCGA NHW CRCs. APC-mutation-negative CRCs were associated with an earlier onset of CRC (P = 0.01). They were also associated with lower overall mutation burden, fewer copy number variants and a DNA methylation signature that was distinct from the CpG island methylator phenotype characterized in microsatellite unstable disease. Three of the APC-mutation-negative CRCs had loss-of-function mutations in BCL9L. Mutations in driver genes identified by TCGA exome analysis were less frequent in AA CRC cases than TCGA NHWs. Genes that regulate the WNT signaling pathway, including SOX9, GATA6, TET1, GLIS1 and FAT1, were differentially hypermethylated in APC-mutation-negative CRCs, suggesting a novel mechanism for cancer development in these tumors. In summary, we have identified a subtype of CRC that is associated with younger age of diagnosis, lack of APC mutation, microsatellite and chromosome stability, lower mutation burden and distinctive methylation changes.

Introduction Disseminated histoplasmosis is a treatable common opportunistic infection in HIV infected people and not uncommon in others in a tropical country like India. The objective of our study was to evaluate clinical-pathological correlation and treatment outcome of disseminated histoplasmosis treated with conventional Amphotericin B in an endemic area.Material and methodsThis was a retrospective observational study of twenty-two cases of disseminated histoplasmosis admitted to a tertiary care hospital from January 2009 to December 2012 and treated with Amphotericin B followed by oral Itraconazole therapy for one year. Results of treatment outcome including relapse and mortality were analyzed in January 2014.ResultsHistoplasmosis was diagnosed in patients with advanced HIV (72%) illness with a mean CD4 count of 63.43/l. Tuberculosis and diabetes were other co-morbid illnesses and it was less common among immunocompetent patients (9%). Fifty percent of the patients presented with cutaneous lesions along with systemic manifestations while 27% had only mucocutaneous lesions. Adrenal histoplasmosis (18%) was common in HIV negative subjects. HIV positive patients showed excellent response to Amphotericin B followed by Itraconazole therapy. In 27% HIV positive patients, the disease manifested as IRIS (immune reconstitution inflammatory syndrome). Relapse was seen in 2(9%) patients. After one year of completion of therapy 16 patients were cured, 3 patients (13.6%) died in the early part of treatment and one was lost to follow up. Treatment response in HIV infected patients showed excellent results but long term maintenance itraconazole therapy was inevitable (12-32 months).ConclusionsIt is concluded that early diagnosis and treatment can prevent a fatal disease like disseminated histoplasmosis with conventional Amphotericin B followed by Itraconazole. Adrenal histoplasmosis was common among the HIV negative population. Extensive follow up is required to identify early relapse which may need further prolongation of therapy for cure.

The transparent glasses with composition 30PbO–10GeO 2 –(60−x)SiO 2 −xNb 2 O 5 (mol%) (0 ≤ x ≤ 2.5) are prepared by conventional melt quenching technique. The amorphous nature of the prepared glasses is characterized by XRD. The spectroscopic studies such as optical absorption, FTIR, Raman spectra were carried out at room temperature on these glasses. Besides this electrical properties, like dielectric constant e ' , loss tan δ , ac conductivity σ a c etc., were also investigated over a moderately wide range of frequency (10 3 –10 6 Hz) and temperature (30–300 °C). The optical absorption spectrum of the prepared glasses has exhibited absorption bands around 325 nm and 340 nm and these are due to the triplet – singlet electronic transition of Ge 2+ state presents in the glass matrix as conversion of GeO 2 into GeO is much easier rather than SiO 2 . From FTIR spectra of as prepared glasses, it is noticed that the intensity of octahedral NbO 6 structural units is found to increase up to 2 mol% of Nb 2 O 5 there after it is observed to decrease. It is also supported by Raman shift of NbO 6 structural units observed around 650 and 930 cm −1 . The analysis of electrical studies is also revealed that the conductivity of prepared glasses is found to increase gradually up to 2 mol% of Nb 2 O 5 beyond this concentration it is observed to decrease. When the spectroscopic investigations are coupled with electrical studies it is concluded that the glass samples doped with 2 mol% of Nb 2 O 5 are found to exhibit good semiconducting nature among the prepared glasses. Such glasses are suitable for fabrication of solid state devices.

Transparent glass ceramics, synthesized from melt quenching followed by heat treatment, of the composition 10Na 2 O–30PbO–10Bi 2 O 3 –(50 − x )SiO 2 : x Cr 2 O 3 (mol%), where 0 ⩽ x ⩽ 0.5, were characterized with XRD, DTA, SEM and EDS. Physical and spectroscopic studies, viz., optical absorption, electron paramagnetic resonance (EPR), FTIR and Raman were investigated. The characterization of the host glass ceramic has revealed that the formation of a major phase of sodium silicate along with two minor phases such as lead silicate and bismuth oxide. By integrating Cr 2 O 3 to the host glass additional crystal phases viz., NaCrO 2 , Na 2 Cr 2 O 7 and Pb(CrO 4 ) which are the complexes of Cr 3+ and Cr 6+ ions were also developed. As the concentration of nucleating agent is increased, a part of the Cr 6+ ions is found to reduce in to Cr 3+ ions. Spectroscopic studies have revealed that with an increase in the concentration of Cr 2 O 3 from 0.1 to 0.5 mol%, there is a gradual increase in the intensity of vibrational modes of various asymmetric structural units of silicate, bismuthate and chromate in the glass ceramic network at the expense of symmetrical structural units. The analysis of the results of these studies has indicated that in the samples containing higher concentration of Cr 2 O 3 , chromium ions exists predominantly in Cr 3+ state and occupy the octahedral positions in glass ceramic matrix and such glass ceramic samples are suitable for lasing action.

Background Activating mutations in the PIK3CA gene represent the most common molecular aberration in luminal breast cancers. Three hot-spot mutations (E542K, E545K, H1047R) account for approximately 70% of the PIK3CA mutations identified. The presence of a mutation is likely to become an important predictive biomarker to select patients for treatment with PIK3CA inhibitors. Tumor-derived DNA can be detected in the systemic circulation in the form of cell-free plasma DNA (cfpDNA), and the ability to interrogate tumor-derived DNA from an easily acquired biospecimen like cfpDNA has practical advantages over analysis of tissue specimens. Furthermore, cfpDNA can be monitored serially and could provide a dynamic measure of tumor progression and response to therapy. Droplet digital PCR (ddPCR) is a high-throughput technique that provides highly precise and sensitive detection of rare alleles in samples with ultra-low abundance of target DNA. Methods A nested case-control study was conducted with plasma samples collected as part of a study to identify blood-based biomarkers. Blood was collected from women scheduled for a breast biopsy at one of seven participating mammography units. All blood samples were collected prior to the biopsy procedure and were processed using a standard protocol. Cases are women diagnosed with invasive ductal carcinoma, stage I-III, that is positive for the estrogen receptor (ER+) and negative for HER2/neu (0 or 1+ by IHC). Controls are women with a benign, non-proliferative lesion, matched by collection site, year of collection and age. cfpDNA was isolated using a commercial kit (Macherey-Nagel, Bethlehem, PA). DNA was extracted from FFPE biopsy specimens by standard techniques. Central pathologic review confirmed at least 10% tumor cellularity in biopsy specimens from cases. A ddPCR assay was developed on a BioRad QX100 Droplet Digital PCR instrument using standard TaqManR assays with probe pairs designed to detect the 3 PIK3CA hotspot mutations and corresponding wild type (wt) alleles. The assay was validated using DNA from four cell lines, each positive for one of the hotspot mutations or wt at all 3 loci (Horizon Diagnostics, Cambridge, UK). ddPCR was performed on cfpDNA and DNA extracted from FFPE biopsy specimens in cases and controls. Next generation DNA sequencing (NGS) of exons 9 and 20 of PIK3CA was performed on biopsy specimens from cases using an Ion Torrent Personal Genome Sequencer. Results Validation of the ddPCR assay with serial dilutions of cell line DNA demonstrated the assay is highly sensitive with mutant alleles detected at an allele frequency down to 25% when input DNA template is as low as 2 ng. With DNA template input of 20 ng (typical recovery of cfpDNA), mutations can be detected down to an allele frequency of 0.78%. We will present data on the rate of hotspot mutation detection with the ddPCR assay performed on cfpDNA and FFPE samples in cases (n=80) and controls (n=80), and we will report performance characteristics of the assay. Mutation status of tumors determined by NGS will serve as the gold standard. Conclusion We have developed a ddPCR assay to detect PIK3CA hotspot mutations in cfpDNA, and will report the performance characteristics of the assay in 80 cases of untreated, ER+ early breast cancer. Citation Format: Kent F Hoskins, Amer Sidani, Tiffany Jones, Stefan Green, Rajyasree Emmadi, Anjen Chenn. Detection of PIK3CA mutations in cell-free plasma DNA from women with early breast cancer [abstract]. In: Proceedings of the Thirty-Seventh Annual CTRC-AACR San Antonio Breast Cancer Symposium: 2014 Dec 9-13; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2015;75(9 Suppl):Abstract nr P3-06-42.

Hepatocellular carcinoma (HCC) is a leading cause of worldwide cancer-related mortality, and even with established treatment paradigms, its global burden demands greater research into therapeutic options. In the following case report, a patient suffering from HCC with lung metastasis demonstrated regression of metastatic disease while consuming guyabano fruit extract in the absence of conventional chemotherapy. While the antineoplastic effects of the guyabano fruit is well documented, there is sparse clinical documentation of HCC regression associated with it, and a better understanding of guyabano and its antineoplastic activity may trigger discovery of novel therapeutic options for this deadly disease.

Protein Tyrosine kinase 6 (PTK6/BRK) is overexpressed in the majority of human breast tumors and breast tumor cell lines. It is also expressed in normal epithelial linings of the gastrointestinal tract, skin, and prostate. To date, expression of PTK6 has not been extensively examined in the normal human mammary gland. We detected PTK6 mRNA and protein expression in the immortalized normal MCF-10A human mammary gland epithelial cell line, and examined PTK6 expression and activation in a normal human breast tissue microarray, as well as in human breast tumors. Phosphorylation of tyrosine residue 342 in the PTK6 activation loop corresponds with its activation. Similar to findings in the prostate, we detect nuclear and cytoplasmic PTK6 in normal mammary gland epithelial cells, but no phosphorylation of tyrosine residue 342. However, in human breast tumors, striking PTK6 expression and phosphorylation of tyrosine 342 is observed at the plasma membrane. PTK6 is expressed in the normal human mammary gland, but does not appear to be active and may have kinase-independent functions that are distinct from its cancer promoting activities at the membrane. Understanding consequences of PTK6 activation at the plasma membrane may have implications for developing novel targeted therapies against this kinase.

Since 2006, the US Food and Drug Administration, Congress, and other policymakers have explored the appropriate way to guarantee the clinical and analytical validity of laboratory-developed tests. In the past, the Association for Molecular Pathology has publicly urged the Food and Drug Administration to exercise caution in implementing regulatory changes that could potentially hinder innovation or interfere with the practice of medicine. In 2012, the Association for Molecular Pathology Professional Relations Committee chose to develop this paper with the goal of outlining the best methods for ensuring appropriate oversight and validation of molecular diagnostic procedures. At the conclusion of this process, the workgroup reaffirmed the Association's previous position that the Centers for Medicare and Medicaid Services Clinical Laboratory Improvement Amendments program can provide the appropriate level of oversight for the vast majority of diagnostic tests.

Aim Hypersensitivity to the anti-retroviral agents is a common problem encountered in the treatment of HIV/AIDS patients. However, in resource-limited settings, where only fixed-dose combinations of the drugs are the only available option and expensive facilities of pharmacological analysis are not available, isolating the offending agent can be a challenging task. Background We, at our centre, follow a protocol to isolate such offending drug – a protocol of gradual de-challenge and re-challenge – by a method of exclusion. Materials and Methods Here, we have described a series of four cases, providing examples of usage of our own protocol to isolate the offending drug by a method of exclusion. Results and Conclusion In a resource-limited setting, where we have to use fixed-dose combination of anti-retroviral agents, management of a patient with drug hypersensitivity is a problem. Our protocol of systematic de-challenge and re-challenge, as exemplified in these cases, can be of help where expensive facilities are not available.

Transparent glasses with the composition 20RO–10Na 2 O–69B 2 O 3 –1Fe 2 O 3 (where R = Ca, Sr and Ba) were prepared by melt quenching technique. The amorphous nature of the glass was confirmed by X-ray diffraction pattern of the sample. Physical parameters and spectroscopic studies such as EPR, optical absorption and FTIR were carried out for the glass samples. Besides dielectric properties i.e. dielectric constant (e′), and loss (tan δ), a.c. conductivity (σ ac ) in the frequency range 10 3 –10 6 Hz and the temperature range 30–300 °C in air of the present glasses were also investigated. The dielectric and spectroscopic properties have been analyzed in the light of different oxidation states of iron ions in order to understand the influence of alkaline earth oxides as modifier oxide on the structure and insulating strength/conductivity of glass matrix.

Transparent BaBiBO 4 :CoO glasses of composition 10BaO·20Bi 2 O 3 ·(70 − x )B 2 O 3 · x CoO (wt%) where 0 ⩽ x ⩽ 2.0, were synthesized and characterized by XRD. Physical properties coupled with Spectroscopic (optical absorption, photoluminescence and FTIR spectra) and dielectric studies were carried out. The area under the absorption band corresponds to 4 A 2 ( 4 F) → 4 T 1 ( 4 F) transition of Co 2+ (IV) is gradually increased up to 1.5 wt% of CoO and then it is decreased at 2.0 wt% of CoO. It is also supported by decrease in Co 2+ ion concentration N i , at 2.0 wt% of CoO calculated from density values. The concentration of luminescence centers of bismuth ions [Bi 2+ ions in the visible region] decreased up to 1.5 wt% of CoO and increased beyond this concentration. Further, it is also noted that at higher concentrations of dopant Co 2+ ions acts as redox partner of Bi 3+ and reduce it to Bi 2+ state. The optical band gap energy ( E g ) is found to increase than the pure with 0.5 wt% of CoO and beyond this concentration the E g value is gradually decreased. It is due to the formation of covalent Co–O–B bonds in the glass network with tetrahedral CoO 4 units. From FTIR studies, at higher concentrations due to gradual increase in CoO 6 units leads to formation of BO 3 and BiO 6 units along with NBOs. The above results are also supported by observed decrease in dielectric constant e ′, loss tan δ and σ ac with the initial introduction 0.5 wt% of CoO in the glass matrix at any frequency and temperature except in the relaxation temperature region.

Purpose To test the hypothesis that a modified approach to portal vein embolization (PVE)—termed ablative liver partition (ALP) and PVE (ALP-PVE)—is feasible and results in greater future liver remnant (FLR) growth compared with PVE alone in a rabbit model. Materials and Methods Eighteen rabbits (median weight, 2.7 kg) underwent PVE (n = 9) or ALP-PVE (n = 9). PVE to cranial liver lobes was performed with 100–300-μm microspheres and metallic coils; the caudal lobe was spared as the FLR. In the ALP-PVE cohort, a liver partition between cranial and caudal lobes was created by using microwave ablation (40 W, 1 min). Animals were euthanized and livers were harvested on postprocedure day 7. Caudal and cranial liver lobes were weighed after 4 weeks of oven drying. Ki-67 immunohistochemistry was used to quantify liver mitotic index. ALP-PVE feasibility was determined based on procedure technical success. Standardized FLR (sFLR; ie, FLR divided by whole liver weight) and mitotic index were compared between PVE and ALP-PVE groups by two-tailed independent-samples Mann–Whitney U test. Results One PVE-group rabbit died during anesthesia induction and was excluded from technical success calculation. Eight of 8 (100%) and 8 of 9 rabbits (89%) underwent technically successful PVE and ALP-PVE, respectively. There was no difference in sex or weight distribution between groups. sFLR (0.32 vs 0.29; P = .022) and mitotic index (17.5% vs 6.2%; P = .051) were higher in ALP-PVE vs PVE caudal lobes when the first "learning-curve" case from each group was excluded. Conclusions ALP-PVE is feasible and may stimulate greater FLR growth compared with PVE in a rabbit model.

Purpose To quantify the correlation between doxorubicin (DOX) delivery and tumor necrosis after drug-eluting bead (DEB) transarterial chemoembolization (TACE). Materials and Methods In this animal care committee-approved study, New Zealand white rabbit VX2 liver tumors were treated transarterially with DOX-loaded 70-150-μm DEBs in five treatment groups with varying drug doses: sham (saline), 0 mg, 12.5 mg, 25 mg, and 37.5 mg. DEB TACE was followed by 3- and 7-day sacrifice, tumor harvest, and sectioning. Drug delivery was assessed by using fluorescence imaging, and tumor necrosis was quantified by means of histologic analysis. Statistical correlation of DOX delivery and tumor necrosis was performed by using the Spearman rank correlation coefficient (ρ). Results Thirty-six VX2 tumors (median diameter, 1.3 cm) in 20 rabbits (median weight, 2.8 kg) underwent successful DEB TACE. Treatment groups included eight, seven, eight, five, and eight tumors of similar size (P > .05). Tumors showed progressively greater DOX extent (sham, 0%; 0 mg, 0%; 12.5 mg, 3%; 25 mg, 20%; and 37.5 mg, 27%) and intensity (sham, 0.4; 0 mg, 1.9; 12.5 mg, 8.5; 25 mg, 9.6; and 37.5 mg, 18.3) and higher median percentage necrosis (sham, 68%; 0 mg, 64%; 12.5 mg, 76%; 25 mg, 78%; and 37.5 mg, 83%) across DOX treatment groups. Correlation of DOX extent (ρ = 0.975, P = .005) and intensity (ρ = 0.900, P = .037) with percentage tumor necrosis was statistically significant. Conclusion Incremental increases in DOX correlate with greater necrosis in rabbit VX2 liver tumors after DEB TACE. This result indicates an essential role for chemotherapy-induced cytotoxicity in TACE effectiveness and supports the use of chemotherapeutic drugs in transarterial therapy. (©) RSNA, 2016 Online supplemental material is available for this article.

Glasses doped with different concentrations of MoO3 (ranging from 0 to 10 mol %) in the system ZnF2–Bi2O3–P2O5 were crystallized and characterized by X-ray diffraction(XRD), scanning electron microscopy (SEM) and differential thermal analysis (DTA) techniques. The presence of BiPO4, α-Zn3(PO4)2, Bi2MoO6, γ‐Bi2MoO6, Bi2Mo2O9, MoOPO4, α-ZnMoO4 microcrystalline phases were exposed by XRD and SEM studies. The DTA indicated that the surface crystallization prevails over the bulk crystallization as the concentration of the crystallizing agent is increased. Spectroscopic properties (FTIR, Raman, optical absorption and ESR) at room temperature and dielectric properties (dielectric constant, loss tanδ, ac conductivity) over a range of frequency and temperature are studied. The IR and Raman spectra exhibit bands due to MoO4 and MoO6 units in structural groups in addition to various conventional phosphate groups. The existence of Mo5 + state in addition to Mo6 + state in these glass ceramic samples has been identified by the optical absorption, ESR and magnetic susceptibility studies. The variations observed in all these properties with the concentration of the crystallizing agent have been analyzed in the light of different oxidation states and environment of molybdenum ions in the glass ceramic network.

Transparent glasses of composition 10BaO.20Bi 2 O 3 .(70 − x )B 2 O 3 . x Fe 2 O 3 (wt.%) where 0 ≤ x ≤ 2.0, were characterized by XRD and SEM. Physical, spectroscopic and dielectric properties were investigated. At higher dopant of Fe 2 O 3 , EPR results revealed that, the number of Fe 3+ ions participate in the resonance is decreased by forming a new signal at g ≈ 3.015 due to increase of antiferromagnetic interaction of Fe 3+ ions and/or formation of low spin Fe 3+ ions in the glass matrix. With initial 0.5 wt.% doping of Fe 2 O 3 , less dense glass is formed with colloids of metallic Bi 0 atoms. The absorption bands at 604 and 712 nm in F5 glass are ascribed to Bi 0 and Bi + radicals respectively. No characteristic Fe 3+ absorption bands (spin-forbidden) are found. Fe 2+ ions are increased at higher concentration of Fe 2 O 3 . Higher concentration of Fe 2 O 3 is favorable for BO 2 O − , BO 3 , BiO 6 and FeO 6 symmetry unit leads to low band gap and high Urbach energy. By doping of Fe 2 O 3 the dielectric parameters like dielectric constant (e′), loss (tanδ and ac electrical conductivity (σ ac ) are found to increase.

Transparent glasses 20ZnF2–40Bi2O3–(40 − x)GeO2:xCoO; 0 ⩽ x ⩽ 1 wt% are prepared by melt quenching technique. The amorphous nature of the samples is characterized by X-ray diffraction (XRD) and differential thermal analysis (DTA). Spectroscopic studies like optical absorption, FTIR, Raman and dielectric parameters (e′, loss tan δ, conductivity σac over a wide range of frequency and temperature as well as dielectric breakdown strength at room temperature) of these samples have been carried out. Optical absorption data has revealed that the bismuth radicals, observed in pure sample C0, are combined with cobalt ions with increase in concentration of CoO. Further, Co2+ and Co3+ ions occupy octahedral positions at larger dopant concentrations of CoO. From FTIR and Raman studies the coordination of germanium is changed from GeO4 to GeO6 with increase in the concentration of CoO. Dielectric parameters such as dielectric constant e′, loss tan δ, a.c. conductivity σac are increased and activation energy for a.c. conduction is decreased and hence opens the glass network with the increase of divalent cobalt ion concentration; which is also confirmed by decrease in glass transition temperature (Tg) and band gap energy (Eg). Density of defect energy states (EF) is explained with quantum mechanical tunneling (QMT) model.

Transparent glasses 40Sb2O3–20ZnF2–(40 − x)GeO2:xCuO, and 40Bi2O3–20ZnF2–(40 − y)GeO2:yCuO with x = 0, 0.6 and 0 ≤ y ≤ 1 wt% were prepared by melt quenching technique and were characterized by XRD and differential thermal analysis. Spectroscopic studies like optical absorption, FTIR, Raman, EPR and dielectric parameters (such as ɛ′, loss(tan δ), and σac) were carried out to examine the modifier and dopant effect on zinc germanate glass network. Optical absorption and EPR data have revealed that the environment of Cu2+ ions is more ionic in bismuth series rather than antimony glasses. Reduced bismuth ions have been found in pure and at lower concentration of dopant in Bi2O3 mixed glasses, which are useful for IR amplifications. FTIR and Raman spectra have indicated the conversion of GeO4 to GeO6 structural units by forming cross linking bonds like Bi–O–Ge, Ge–O–Cu, etc., and open the glass network with integration of Bi2O3 and CuO doping. It is also confirmed by decreasing Tg and Eg values. The temperature dependence of dielectric parameters at different frequencies was interpreted in terms of structural changes in the glass network.

Transparent glasses, melt quenching derived, containing 10RO·20Bi2O3·(70 − x)B2O3·xTiO2 [R = Ca, Sr] with x = 0, 0.5, 1.0 wt% were characterized by X-ray powder diffraction. Physical and spectroscopic properties viz., density, absorption, emission, electron paramagnetic resonance (EPR) and FTIR were investigated. The absorption band around 823 nm in pure glass samples is attributed to the electronic transition of 3P0 to 3P2 of Bi+ radicals. A small absorption hump centered around 609 nm is found in all doped glasses due to 2T2g to 2Eg transition of octahedral Ti3+ ions. The emission results revealed that all the samples exhibit a broad emission band covering entire visible-light range, with λex = 360 nm, centered 470–520 nm corresponds to electronic transition of 3P1 to 1S0 of Bi3+ ions, therefore the present materials can be potentially used as tunable or full-color display systems. And a strong emission around 706 nm with λex = 514 nm due to transition of 2P3/2 to 2P1/2 of Bi2+ ions. In SrO mixed glasses Ti4+ ions effect the environment of Bi3+ ion symmetry units from C2 to C3i. A small EPR signal (at room temperature) is observed in titanium doped glasses due to Ti3+ ions. In both the series with increase of TiO2 concentration BO4 units are gradually converted into BO3 units and new cross linkages are formed, like B–O–Ti, Bi–O–Ti at the expense of B–O–B bonds.

Tumor surgical resection margin status is important for any malignant lesion. When this occurs in conjunction with efforts to preserve or conserve the afflicted organ, these margins become extremely important. With the demonstration of no difference in overall survival between mastectomy versus lumpectomy and radiation for breast carcinoma, there is a definite trend toward smaller resections combined with radiation, constituting “breast-conserving therapy.” Tumor-free margins are therefore key to the success of this treatment protocol. We discuss the various aspects of margin status in this setting, from a pathology perspective, incorporating the past and current practices with a brief glimpse of emerging future techniques.

10MO·20Bi 2 O 3 ·(70− x )B 2 O 3 · x CuO [M=Pb, Zn] with x =0, 0.4 and 0.8 (wt%) glasses were synthesized by the melt-quenching technique and were characterized using X-ray diffraction (XRD) and scanning electron microscopy (SEM) techniques. Physical parameters, like density, and spectroscopic studies (optical absorption, EPR, FTIR and photoluminescence) were used to understand the role of modifier oxide and CuO in the glass matrix. A red shift of the absorption band corresponds to 2 B 1g → 2 B 2g transition of Cu 2+ ions from P2 to Z4 samples and the increase of hyperfine splitting factor ( A ‖ ) from P2 to Z2 shows that with the integration of PbO by ZnO the electron density around copper ion is increased. It is also supported by the gradual increase in theoretical optical basicity values of ZnO mixed glasses, as compared to that of PbO mixed glass matrix. Reduced bismuth radicals are found in undoped and 0.4% CuO doped glasses of both the series. Analysis of the absorption and emission studies indicates that the concentration of luminescence centers of bismuth ions (Bi 3+ ions in UV region) is decreased by the integration of ZnO as well as by increasing the dopant concentration. In lead series PbO 4 and BiO 3 units are increased from P2 to P4 and in zinc series BiO 3 units are decreased from Z0 to Z4. The conductivity of the glass matrices is increased in both the series with the dopant of CuO.

Melt quenching derived (in air) transparent glasses containing 30LiF 10SrO (60 − x )B 2 O 3 x V 2 O 5 , with 0 ⩽ x ⩽ 1.0 (mol%) were investigated for physical, spectroscopic measurements, viz., optical absorption, electron spin resonance (ESR) and FTIR along with dielectric properties (dielectric constant e ′, loss tan δ , conductivity σ ac, etc.). The results were analyzed to correlate with each other in the light of local environment and oxidation states of vanadyl ion in the glass network. The observed blue shift in 3 T 1g (F) → 3 T 2g (F) and red shift in 2 B 2g → 2 E g transitions and decrease in Δ g ∥ /Δ g ⊥ values up to V 8 indicates that the decrease in tetragonality of the vanadium site. The increase in area of optical absorption peak, ESR signal intensity and in the relative value of ac conductivity up to 0.8 mol% of V 2 O 5 doped glasses is due to the predominant presence of V 4+ and V 3+ ions. Beyond this concentration, the redox ratio V 4+ /V 5+ is found to decrease. By the gradual replacement of B 2 O 3 by V 2 O 5 up to 0.8 mol% the semi conducting nature of the glass network is found to increase due to increase of BO 3 structural units beyond this concentration insulating strength of glass matrix is increased.

The superior sensitivity and specificity associated with the use of molecular assays has greatly improved the field of infectious disease diagnostics by providing clinicians with results that are both accurate and rapidly obtained. Herein, we review molecularly based infectious disease diagnostic tests that are Food and Drug Administration approved or cleared and commercially available in the United States as of December 31, 2010. We describe specific assays and their performance, as stated in the Food and Drug Administration's Summary of Safety and Effectiveness Data or the Office of In Vitro Diagnostic Device Evaluation and Safety's decision summaries, product inserts, or peer-reviewed literature. We summarize indications for testing, limitations, and challenges related to implementation in a clinical laboratory setting for a wide variety of common pathogens. The information presented in this review will be particularly useful for laboratories that plan to implement or expand their molecular offerings in the near term.

Transparent glasses of the composition 10RO.20Bi 2 O 3 .(70 − x) B 2 O 3 .xCuO [R = Ca, Ba] with x = 0, 0.4, 0.8 (wt.%) were prepared via melt-quenching technique and characterized using X-ray powder diffraction. Spectroscopic measurements, viz., optical absorption, EPR, FTIR and photoluminescence (PL) were studied at room temperature. Analysis of the present investigations indicates that the concentration of luminescence centers of bismuth ions (Bi 2+ ions in visible region) decreased by the integration of BaO and also by increasing dopent concentration. It is also observed that addition of CuO decreases stability of the glass network in calcium series and strengthens in barium series.

Cardiac amyloidosis is an important cause of restrictive cardiomyopathy and congestive heart failure. There are two major types of cardiac amyloidosis: cardiac amyloid light-chain (AL) and transthyretin-related cardiac amyloidosis (ATTR) [1, 2]. The treatment options and prognosis for these two subtypes are different. The AL subtype cardiac amyloidosis is associated with greater than 50 % mortality within 6 months after the diagnosis, while the ATTR subtype has a more favorable prognosis of 98–100 % 2-year survival [3, 4]. Therefore, differentiating the type of cardiac amyloidosis (AL vs. ATTR) is crucial in guiding patient care. Due to its variable clinical symptoms, as well as the nonspecific ECG and echocardiographic presentations, cardiac amyloidosis is a diagnostic challenge and usually underdiagnosed [5, 6]. Endomyocardial biopsy remains the gold standard for diagnosis (Fig. 1). Fig. 1 A 68-year-old male with prostate cancer underwent a bone scan for disease staging. Diffuse cardiac uptake of the bone-seeking radiotracer, Tc-99m MDP (methylene diphosphonate), was incidentally found (arrow, a: bone scan). Given the patient’s ... Perugini et al. [7] demonstrated Tc-99m 3,3-diphosphono-1,2-propanodicarboxylic acid (Tc-99m DPD) bone scan findings among patients with cardiac amyloidosis of ATTR (n = 15) and AL (n = 10) subtypes in which cardiac Tc-99m DPD uptake was present in all ATTR patients and absent in all AL patients at visual assessment. Rapezzi et al. [8] evaluated myocardial uptake of Tc-99m DPD in patients with ATTR-related (n = 45, 28 mutant and 17 wild-type) and AL-related (n = 34) cardiac amyloidosis as well as 15 nonaffected controls. On semiquatitative analysis, patients with ATTR had higher visual scoring of cardiac retention (range: score 0, absent cardiac uptake and normal bone uptake; score 1, mild cardiac uptake, inferior to bone uptake; score 2, moderate cardiac uptake accompanied by attenuated bone uptake; score 3, strong cardiac uptake with attenuated bone uptake), with positive and negative predictive values of 88 and 100 % (visual score ≥2). On quantitative analyses, compared to AL and unaffected controls, ATTR patients also had significantly higher (p

Altered expression of miRNAs has been observed in many types of cancer, including breast cancer, and shown to contribute to cancer growth, aggressiveness, and response to therapies. In this pilot study, we investigated the possible correlation of miRNAs with risk of recurrence of estrogen receptor positive, lymph node-negative mammary carcinomas as determined by the Oncotype DX® Breast Cancer assay. To accomplish this, we extracted RNA from a collection of breast carcinomas that had previously been analyzed by Oncotype DX®. Multiple Let-7 family members were negatively correlated with the recurrence score (RS), which is consistent with their tumor suppressor properties. Additional miRNAs were found to positively correlate with RS, including miR-377-5p, miR-633b, miR-548t and miR-3648. Pathway analysis of putative and validated targets suggests that these miRNAs may have a diverse range of functions that may contribute to tumor recurrence. Taken together, these findings provide evidence that a miRNA expression signature can be developed to aid existing methods to determine the risk of recurrence for women with estrogen receptor positive breast cancers treated with endocrine therapy.