tbuckley/cabot-search huggingface dataset:
Objective distinction of CIS based on quantitative shape analysis of the basement membrane in oral cancer microscopic images
Authors: Mustafa Sami, Hisakazu Kikuchi, Kamal Al-Eryani, Takashi Saku
Journal: Clinical Cancer Research (2007)

A49    Background:  In oral cancer, the diagnostic decision depends on different interpretations of individual pathologists and it causes a high subjectivity known as inter-observer variability in diagnosis. A computer-aided system that operates on quantitative measures is qualified to compute feature definite values and to understand the levels of changes in borderline malignancies. The successful extraction and shape analysis of the basement membrane are targeted in this study in order to distinct carcinoma in-situ (CIS) from dysplastic and normal epithelia.   Extraction Method:  Several image-processing techniques have been used for accurate extraction of the basement membrane. First, color segmentation in the rHSI (reversible hue-saturation-intensity) color space was applied in order to separate the epithelium layer from the rest of the image based on the assumption that the epithelium layer had lower intensity in the range of I = [0, 150]. Secondly, wide-angle edgel method was used to detect the basement membrane pixels from different neighboring pixels. Inside an appropriate size of window, all pixels were checked in anti-clockwise direction and every set of three pixels defines a view angle. Finally, loops of dilation followed by thinning morphological operations were applied and a precise basement membrane edge segment has been extracted.   Shape Analysis:  The shape analysis based on quantitative analysis for every rete ridge unit of the basement membrane using Fourier descriptor and roundness measurements. Since the rete ridge segment is an open linear segment, a simple geometric central point selection method was applied in order to represent the rete ridge segment in a half circle arc. The Fourier descriptor was used to smooth the rough basement membrane edge segment to a threshold value between [4, 16] before measuring its roundness. The results indicate that oral CIS had irregular round shaped rete ridges.    Conclusions:  Several image-processing techniques have been applied and invented for the extraction and shape analysis of the basement membrane. From the given digital microscopic images of the oral tissue, the basement membrane edge segment was extracted and reached a sufficient level of reality. The shape analysis for every rete ridge unit was qualified to distinct CIS from dysplastic and normal epithelia.
How not to develop a sense of number
Authors: John E Opfer, Koleen McCrink
Journal: Behavioral and Brain Sciences (2017)

Abstract The authors rightly point to the theoretical importance of interactions of space and number through the life span, yet propose a theory with several weaknesses. In addition to proclaiming itself unfalsifiable, its stage-like format and emphasis on the role of selective attention are at odds with what is known about the development of spatial-numerical associations in infancy.
Abstract 5887: The role of FAK in tumor microenvironment
Authors: Hsin-Jung Wu, Syn Kok Yeo, Megan Wilson
Journal: Cancer Research (2017)

Abstract Focal Adhesion Kinase (FAK) is a cytoplasmic non-receptor tyrosine kinase important in mediating signal transduction in cell migration, survival and proliferation. Up-regulation of FAK in the tumor cells has been shown to enhance tumor malignancy and correlate with poor prognosis. FAK signaling has also been implicated in impacting tumor microenvironment, including endothelial cells and fibroblasts. However, much less is known about how FAK in the tumor stroma affects tumor progression, or how stromal FAK cross-talks with cancer cells. Here we use an inducible Col1α2-creERT, FAK f/f genetic engineered mouse model (GEMM) to specifically delete FAK in the fibroblasts. Using the GEMM, we found that FAK in stromal fibroblasts facilitates breast tumor growth and metastasis in vivo. We further showed that conditioned media (CM) from human breast cancer cells induced FAK Y397 autophoslphorylation and expression of smooth muscle actin (SMA, a marker for cancer-associated-fibroblasts [CAFs]) of normal human lung fibroblasts. Interestingly, only the breast cancer CM educated fibroblasts, but not the naive un-treated fibroblasts, were able to promote breast cancer cell migration and invasion. Lastly, knockdown of FAK in these “educated” fibroblasts abolished their ability to promote breast cancer cell migration and invasion. Taken together, these data suggest a potential role of stromal FAK in creating a pro-tumorigenic microenvironment for breast cancer development and progression, and provide further rationale in therapeutic benefits of FAK inhibition against various solid tumors. Citation Format: Hsin-Jung Wu, Syn Kok Yeo, Megan Wilson. The role of FAK in tumor microenvironment [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 5887. doi:10.1158/1538-7445.AM2017-5887
Abstract 5596: Intratumoral administration of a TLR9-adjuvanted nanoparticle cancer vaccine stimulates more effective immunity in both injected and un-injected tumor sites compared to subcutaneous administration
Authors: Edwina Naik, Chi Ying, Robert Milley, Carlo Calacsan, Stewart Chipman, Thomas Tüting, Robert Coffman, Cristiana Guiducci
Journal: Cancer Research (2017)

Abstract Therapeutic success of a cancer vaccine requires substantial expansion of vaccine-primed CTL and efficient differentiation to polyfunctional T cells capable of migrating from the site of vaccination to metastatic sites. We have evaluated the tumor itself as a potential site of vaccination, compared to vaccination at subcutaneous sites distant from the tumor. For vaccination, we have developed a highly efficient nanoparticle platform comprised of multiple copies of a CpG-rich oligonucleotide (a TLR9 agonist) and long peptide tumor antigens, both covalently linked to the sucrose polymer Ficoll. Multiple peptide antigens where studied, including ovalbumin and a long peptide comprising epitopes from three melanocyte differentiation antigens. In all of these models, intratumoral vaccination was superior to subcutaneous vaccination for elimination of both injected tumors and, more importantly, distant site skin and lung metastases. Intratumoral vaccination substantially increased the magnitude of the systemic CTL response measured in the blood and in the spleen and enhanced capacity cell homing to distant site tumors. A greater fraction of tumor-antigen specific CD8+ T cells generated in the tumor were polyfunctional, expressing both IFN-γ and TNF-α. They were also less exhausted as measured by decreased overall PD-1 levels, increased T bet and the increased number of PD-1+ cells that retained cytotoxicity and proliferative capacity. Intratumoral vaccination also induced spread of the CD8+ T cell response to tumor antigens not included in the vaccine. These results demonstrate that direct intratumoral immunization with peptide antigens combined with a strong TLR9-activating adjuvant significantly increases the magnitude and quality of vaccine-primed CTL and enhances control of metastatic disease. Note: This abstract was not presented at the meeting. Citation Format: Edwina Naik, Chi Ying, Robert Milley, Carlo Calacsan, Stewart Chipman, Thomas Tüting, Robert Coffman, Cristiana Guiducci. Intratumoral administration of a TLR9-adjuvanted nanoparticle cancer vaccine stimulates more effective immunity in both injected and un-injected tumor sites compared to subcutaneous administration [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 5596. doi:10.1158/1538-7445.AM2017-5596
Label-free Rapid Viable Enrichment of Circulating Tumor Cell by Photosensitive Polymer-based Microfilter Device
Authors: Yoon-Tae Kang, Il Doh, Jiyoung Byun, Hee Jin Chang, Young-Ho Cho
Journal: Theranostics (2017)

We present a clinical device for simple, rapid, and viable isolation of circulating tumor cells (CTCs) from cancer patient bloods.In spite of the clinical importance of CTCs, the lack of easy and non-biased isolation methods is a big hurdle for implementing CTC into clinical use.The present device made of photosensitive polymer was designed to attach to conventional syringe to isolate the CTCs at minimal resources.Its unique tapered-slits on the filter are capable not only to isolate the cell based on their size and deformability, but also to increase sample flow rate, thus achieving label-free rapid viable CTC isolation.We verified our device performance using 9 different types of cancer cells at the cell concentration from 5 to 100cells/ml, showing that the device capture 77.7% of the CTCs while maintaining their viability of 80.6%.We extended our study using the 18 blood samples from lung, colorectal, pancreatic and renal cancer patients and captured 1-172 CTCs or clustered CTCs by immunofluorescent or immunohistochemical staining.The captured CTCs were also molecularly assayed by RT-PCR with three cancer-associated genes (CK19, EpCAM, and MUC1).Those comprehensive studies proved to use our device for cancer study, thereby inaugurating further in-depth CTC-based clinical researches.
Lessons to be learnt from the study ‘Sham surgery versus labral repair or biceps tenodesis for type II SLAP lesions of the shoulder: a three-armed randomised clinical trial’
Authors: Ann M Cools, Dorien Borms
Journal: British Journal of Sports Medicine (2017)

‘Real surgery is no better than sham surgery in isolated type II SLAP lesions’. That is the first interpretation the reader may make based on the study published by Schroder et al in BJSM. 1 First, let us congratulate the authors for conducting such a well-designed study on a large sample of patients, with a research question that is extremely relevant to patients and to payers.

Superior labral tear from anterior to posterior(SLAP) lesions have been much written about and likely been overdiagnosed and overtreated.2 Numerous papers presented new diagnostic tests3 and postoperative outcome after SLAP repairs,4 and a few studies explored the benefit of conservative, non-operative treatment.5–7 

Schroder and colleagues show that surgery consisting of labral repair or biceps tenodesis provides no benefit over sham surgery for isolated type II SLAP lesions. Although the study was …
Abstract 4384: Targeted sequencing reveals distinct and rare pathogenic variants in Caucasians with colorectal cancer
Authors: Pooneh Mokarram, Sudhir Varma, Hamed Azimi, Hasti Olumi, Ali reza Safarpour, Michael Nickerson, Hassan Brim, Hassan Ashktorab
Journal: Cancer Research (2017)

Abstract PURPOSE: Next-generation sequencing (NGS) is currently used to establish mutational profiles in many multigene diseases such as colorectal cancer (CRC) which is on the rise in many parts of the developing World including in the Middle East. Little is known about its genetic hallmarks in these populations. AIM: To identify variants in 15 CRC-associated genes in patients of Iranian descent. METHODS: CRC specimens from 63 patients were used to establish the variants’ profile on an Ion Torrent platform by targeted exome sequencing. To rule out technical artifacts, the variants were validated in 13 of these samples using an Illumina NGS platform. Validated variants were annotated and compared to variants from publically available databases. An in-silico functional analysis was performed. MSI status of the analyzed samples was established. RESULTS: There were 51 validated variants distributed on 12 genes: 22% MSH3 (n=11/51), 10% MSH6 (n=5/51), 8% AMER1 (n=4/51), 20% APC (n=10/51), 2% BRAF (n=1/51), 2% KRAS (n=1/51), 12% PIK3CA (n=6/51), 8% TGFβR2A (n=4/51), 2% SMAD4 (n=1/51), 4% SOX9 (n=2/51), 6% TCF7L2 (n=3/51), and 6% TP53 (n=3/51). Most known and distinct variants were in mismatch repair genes (MMR, 32%) and APC (20%). Among oncogenes, PIK3CA was the top target (12%). MSH3 variants were more frequent and predominantly homozygous in the analyzed population. CONCLUSION: These results illustrate for the first time CRC mutational profile in Iranian patients. MSH3, MSH6, APC and PIK3CA genes seem to play a bigger role in the path to cancer in this population. This is especially true for MSH3 variants that were very frequent and predominantly homozygous as these will associate with the EMAST phenotype that has prognostic implications. These findings will potentially lead to informed genetic diagnosis protocol and targeted therapeutic strategies. Citation Format: Pooneh Mokarram, Sudhir Varma, Hamed Azimi, Hasti Olumi, Ali reza Safarpour, Michael Nickerson, Hassan Brim, Hassan Ashktorab. Targeted sequencing reveals distinct and rare pathogenic variants in Caucasians with colorectal cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 4384. doi:10.1158/1538-7445.AM2017-4384
Thousands more mental health posts will be created in England
Authors: Ingrid Torjesen
Journal: BMJ (2017)

The government has announced a major expansion of the mental health workforce as part of its £1.3bn (€1.45bn: $1.71bn) commitment to transform mental health services and treat an extra million patients by 2020-21.1

The announcement of an extra 21 000 posts in mental health is made in the Mental Health Workforce plan, published on 30 July.2 The plan, developed by Health Education England (HEE) together with NHS Improvement, NHS England, the Royal College of Psychiatrists, and other key mental health experts, also outlines how new and existing staff will be incentivised to work in mental health.

This will include a retention programme to be run by NHS Employers; a range of initiatives to improve career pathways and bolster access to learning and development opportunities; encouragement of more flexible and supportive …
Abstract 875: Improved resection and prolonged overall survival with PD-1-IRDye800CW fluorescent probe-guided surgery and PD-1 adjuvant immunotherapy
Authors: Yang Du, Jie Tian
Journal: Cancer Research (2017)

Abstract Purpose: An intraoperative technique to accurately identify microscopic tumor residuals could be applied to decrease the risk of positive surgical margins. Several lines of evidence support the expression and immunotherapeutic effect of PD-1 in breast cancer. Here, we sought to develop a fluorescence labeled PD-1 probe for in vivo breast tumor imaging and image-guided surgery. The efficacy of PD-1 monoclonal antibody (mAb) as adjuvant immunotherapy after surgery was also assessed. Experimental Design: A near-infrared dye labeled PD-1-IRDye800CW probe was developed and examined for its application in tumor imaging and image-guided tumor resection in an immunocompetent 4T1 mammary mouse tumor model that recapitulates clinical metastatic cancer. Fluorescence molecular imaging (FMI) was performed to monitor probe biodistribution and intraoperative imaging. Bioluminescence imaging (BLI) was carried out concurrently to monitor tumor growth and evaluate post-surgical tumor residuals, recurrences, and metastases. Results: The PD-1-IRDye800CW probe exhibited a specific and stable signal at the tumor region compared to the IgG control, and exhibited the highest tumor-to-background ratio (TBR) 8 h post-injection (11.62 ± 0.79), approximately 5 fold higher than the IgG control (2.13 ± 0.30). Furthermore, PD-1-IRDye800CW guided surgery combined with PD-1 adjuvant immunotherapy inhibited tumor regrowth and microtumor metastases, as determined by BLI imaging, and thus improved survival rate with no obvious side effects. Conclusions: Our study demonstrated the feasibility of using PD-1-IRDye800CW for breast tumor imaging and image-guided tumor resection. Moreover, we found that PD-1 mAb adjuvant immunotherapy reduces cancer recurrences and metastases emanating from minimal tumor residuals. Citation Format: Yang Du, Jie Tian. Improved resection and prolonged overall survival with PD-1-IRDye800CW fluorescent probe-guided surgery and PD-1 adjuvant immunotherapy [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 875. doi:10.1158/1538-7445.AM2017-875
Abstract 2876: Loss of the stem cell and basal lineage regulator LBH delays onset of basal-like triple negative breast cancer
Authors: Kilan C. Ashad-Bishop, Karoline Briegel
Journal: Cancer Research (2017)

Abstract There is increasing evidence that basal-like triple negative breast cancer (TNBC) originates from luminal mammary epithelial cells. Specific gene signatures have already been experimentally proven to serve as genetic lineage switches that, when overexpressed, transform pre-malignant luminal cells to oncogenic cells with basal, stem-like characteristics. Conversely, depletion of these genes in oncogenic cells with basal, stem-like characteristics leads to luminal differentiation. These studies suggest that during the earliest steps of neoplastic transformation, specific gene sets can alter cell fate decisions and differentiation status in mammary epithelial cells, which ultimately contributes to the heterogeneity of breast tumors. Our lab has identified a novel Wnt/β-Catenin target gene, Limb bud and heart (LBH) that is majorly overexpressed in TNBC. LBH is a regulator of the basal mammary stem cell lineage and repressor of luminal differentiation via induction of ΔNp63 and repression of estrogen receptor alpha. LBH is required for the self-renewal and maintenance of adult basal mammary stem cells, which tend to be enriched in TNBC. Knockout studies in mice have shown that genetic ablation of LBH does not impair embryogenesis or normal adult organ function, making it a possible therapeutic target. Using crosses between MMTV-Wnt-1 transgenic mice and K14Cre LBHloxP knockout mice, we are studying the effect of LBH ablation in the basal cells of the mammary epithelium downstream of ectopic Wnt expression in the mammary gland. We postulated that LBH may be an effector of Wnt-driven TNBC, therefore its inhibition would lead to decreased Wnt-induced mammary gland hyperplasia and tumor formation. In our model, LBH ablation in the basal mammary epithelium of female Wnt transgenic mice reduces mammary gland hyperplasia and delays tumor onset. MMTV-Wnt-1 driven, LBH-null tumors also exhibit histopathological differences indicative of a luminal to basal conversion. There is an urgent need to elucidate mechanisms underlying TNBC development and progression and find reliable avenues for treatment. Our data indicates a role for Lbh as a novel effector for Wnt-driven TNBC and further studies may prove antagonism of Lbh to be a novel method to control TNBC progression. Citation Format: Kilan C. Ashad-Bishop, Karoline Briegel. Loss of the stem cell and basal lineage regulator LBH delays onset of basal-like triple negative breast cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 2876. doi:10.1158/1538-7445.AM2017-2876
Abstract 302: A novel epigenetic pathway in medulloblastoma
Authors: Nagi Ayad, Clara Penas
Journal: Cancer Research (2017)

Abstract Medulloblastoma is the most common malignant pediatric brain tumor with variable prognosis due to its clinical and genomic heterogeneity. Despite recent treatment advances, approximately 40% of children experience tumour recurrence, and 30% will die from this disease. Therefore there is a need to develop novel therapies for patients. We recently reported that Casein kinase 1δ (CK1δ) may be an attractive therapeutic target for medulloblastoma. CK1δ is a serine/threonine kinase that controls cell cycle progression, signal transduction and neurogenesis. We found high levels of CK1δ protein in mouse models of medulloblastoma and human medulloblastoma samples. Furthermore, CK1δ inhibition dramatically reduced medulloblastoma tumor progression. We demonstrate here that CK1δ phosphorylates the epigenetic reader bromodomain-containing protein 4 (BRD4). BRD4 has been identified as a therapeutic target in several cancers, including medulloblastoma. We demonstrate that CK1δ phosphorylates BRD4 and that CK1δ is required for BRD4 binding to the Gli1 promoter in vitro and in vivo. Furthermore, combined CK1δ/BRD4 inhibition is a novel means of reducing medulloblastoma growth downstream of SUFU and SMO. These studies define a novel therapeutic means of inhibiting SMO inhibitor resistant medulloblastoma. Citation Format: Nagi Ayad, Clara Penas. A novel epigenetic pathway in medulloblastoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 302. doi:10.1158/1538-7445.AM2017-302
Abstract 1120: Chronopharmacology of cisplatin: role of the circadian rhythm in modulating cisplatin-induced toxicity in melanoma mouse model
Authors: Panshak Dakup, Kenneth Porter, Rajendra Gajula, Shobhan Gaddameedhi
Journal: Cancer Research (2017)

Abstract Purpose: The goal of this research is to highlight novel and divergent molecular mechanisms of the circadian system in modulating the response of cisplatin therapy against melanoma tumors. Cisplatin is one of the most commonly used chemotherapeutic drugs in treating a variety of tumors including cancers of ovaries, testis, lungs, blood and solid tumors of the head and neck, and is more recently under clinical trials for potential application in melanoma tumors. However, the major limitation of cisplatin as a chemotherapeutic drug is its tumor resistance and nephrotoxicity. Hence, improving the effectiveness and reducing the toxicities associated with cisplatin therapy are desirable outcomes. Studies on human models have shown decreased renal and blood toxicity by time-of-the-day. Consequently, our project seeks to study the chronopharmacological effects and understand the mechanisms that have been successfully demonstrated in human models. We hypothesize a mechanistic, circadian rhythm-based cause for these outcomes. Experimental Design: Studies were done on B16F10 melanoma mouse models of wild-type and circadian disrupted Per1/2 -/- animals treated with 3 doses of 5 mg/kg cisplatin in the morning (7 AM) and evening (5 PM). Animal weights and tumor sizes were measured regularly post-treatment. Upon sacrifice, tissues (skin, kidney, and tumor) were harvested and analyzed for cisplatin-induced toxicities and DNA damage responses using H &amp; E staining, western blot, and KIM-1 and immuno-slot blot assays. Results: Weight measurements show a clock-regulated response to cisplatin toxicity. AM-treated wild-type animals showed significant weight loss compared to PM-treated wild-type animals. This treatment time differential is lost in the Per1/2 -/-. On a molecular level, kidney tissue DNA samples showed clock-controlled cisplatin-DNA repair activity in wild-type animals compared to Per1/2 -/-. These initial findings strongly suggest that nephrotoxicity and DNA damage response function might be regulated by the circadian rhythm. Conclusions: These findings indicate a possible mechanism for the chronopharmacology of cisplatin in minimizing the toxicity associated with it and reveal a target for future study of additional mechanistic causes of circadian dosing changes in cisplatin and other genotoxic stress-mediated anti-cancer agents. Citation Format: Panshak Dakup, Kenneth Porter, Rajendra Gajula, Shobhan Gaddameedhi. Chronopharmacology of cisplatin: role of the circadian rhythm in modulating cisplatin-induced toxicity in melanoma mouse model [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 1120. doi:10.1158/1538-7445.AM2017-1120