tbuckley/cabot-search huggingface dataset:
EGFR expression in breast cancer: Association with biologic phenotype, prognosis, and resistance to adjuvant therapy
Authors: M. F. Rimawi, H. L. Weiss, P. Bhatia, G. Chamness, R. M. Elledge
Journal: Journal of Clinical Oncology (2006)

513 Background: Expression of the epidermal growth factor receptor (EGFR) in preclinical models of breast cancer is associated with increased proliferation and resistance to apoptosis. In clinical studies, EGFR has been inconsistently linked to poor outcome. We hypothesized that EGFR expression, when objectively and uniformly assessed, is associated with an aggressive biologic phenotype and resistance to systemic adjuvant therapy. Methods: In a database of 54,865 patients with breast cancer, EGFR status was known on 2,567. EGFR levels were measured centrally by ligand binding assay performed on frozen tissue. Tumors with ≥10 fmol/mg of cytosol protein were prospectively deemed positive. Clinical and biological features of EGFR positive and negative tumors were compared. Disease-free survival (DFS) and overall survival (OS) were assessed in systemically untreated patients (untreated patients, n=1068) and those who received hormonal and/or chemotherapy (treated patients, n=1256). Results: 475 out of 2,567 tumors (18.5%) were EGFR positive. Compared to EGFR negative tumors, EGFR positive tumors were more common in younger (&lt;50 years, 40% vs 24% p&lt;0.0001), premenopausal (20% vs 10%, p&lt;0.0001), and black women (10% vs 6% p=0.005). EGFR expression was associated with larger tumors (64% vs 46%, p&lt;0.0001), aneuploidy (68% vs 46%, p&lt;0.0001), high S-phase fraction (53% vs 22%, p&lt;0.0001), and nodal involvement (43% vs 37%, p=0.009). Co-expression of other biomarkers was also studied. EGFR positive tumors were more likely to be HER2 positive (26% vs 16%, p&lt;0.0001), but less likely to be ER positive (60% vs 88%, p&lt;0.0001), and PR positive (26% vs 65%, p&lt;0.0001). In a multivariate analysis, EGFR expression independently correlated with worse DFS (HR=1.6, 95%CI=1.2–2.2, p=0.001) and OS (HR=1.7, 95% CI=1.2–2.4, p=0.001) in treated patients, but not in untreated patients. Conclusions: EGFR expression is more common in breast tumors in young and black women. It is associated with lower hormone receptor levels, higher proliferation, genomic instability, nodal involvement, and HER2 over-expression. It is correlated with significant resistance to adjuvant hormonal and chemotherapy. Blocking EGFR activity may help overcome this resistance in selected patients. No significant financial relationships to disclose.
Book: HIV in Primary Care
Authors: Bryony Kendall, Mike Abbott
Journal: BMJ (2005)

HIV remains a significant and stigmatised disease in the United Kingdom, and estimates suggest that a third of people infected with HIV are unaware of the fact. HIV prevalence is increasing and mortality has dramatically decreased following the introduction of effective treatment. General practitioners are ideally suited to the care of patients with chronic diseases, which now include HIV.​HIV.




Figure 1



Sara Madge, Philippa Matthews, Surinder Singh, Nick Theobald

Medical Foundation for AIDS and Sexual Health (MedFASH), pp 91 Free (to GPs and primary care teams in England) from MedFASH on 020 7383 6345 or available to download at www.medfash.org.uk/publications/ documents/HIV_in_Primary_Care.pdf ISBN 0 9548615 1 5

Rating: ★★★★




All general practitioners should spend an hour reading this excellent little book, which could alter practice and save lives. Written by and for British GPs, it neither assumes knowledge nor patronises, yet addresses most of the primary care questions about HIV.

The book is well laid out and illustrated, with important points clearly highlighted, related internet links throughout and a useful summary chapter. It lends itself to a practice development session, from working through ways of broaching HIV in a consultation with assessment of a patient's risk, to looking at practice protocols for post-exposure prophylaxis and how HIV can be coded and displayed in patient electronic records. The book also includes many useful tips, such as the necessity for planning international travel (some countries restrict entry) and advising the drawing up of wills for gay men whose long term partners can otherwise be excluded from inheritance.

HIV is a diagnosis not to be missed. Confirmation of diagnosis affords the opportunity to ensure access to what is now life saving treatment and to interventions to decrease spread to others. The earlier the diagnosis is made, the better.

This book is rightly aimed at primary care, but is also ideal reading for students and qualified secondary care clinical staff.
P1107 : Unconsidered misuse of acetaminophen is one of the causal cofactors of acute liver failure in adults with severe dengue fever
Authors: M. Gelu-Simeon, C. Francoz, P. Ichai, A. Cabie, E. Saillard, C. Hermann, P. Bedossa, M. Sebagh, F. Durand, D. Samuel, J. Bernuau
Journal: Journal of Hepatology (2015)
PWE-135 Retrospective audit of management of patients admitted to intensive care unit (ITU) with severe acute pancreatitis (SAP): Abstract PWE-135 Table 1
Authors: O Jalil, C Patel, A Kambal, A Iqbal, A Rasheed
Journal: Gut (2012)

<h3>Introduction</h3> Atlantaclassification stratifies acute pancreatitis (AP) into mild and severe. Severe acute pancreatitis (SAP) is best managed in HDU or ITU setting and associated with high mortality and morbidity despite best efforts at attaining early diagnosis and timely intervention. <h3>Aim</h3> To compare management strategies and mortality of patients admitted to ITU with SAP against national standards and study the group who succumbed to their disease in detail in an attempt to define the circumstances that lead to this event and identify the most accurate prognostic indicators in this group of patients. <h3>Methods</h3> Retrospective audit of management and outcome of consecutive patients admitted to ITU with SAP during the period of 2007–2010. The development of necrosis, infected necrosis (IN) or organ failure (OF) was recorded. Patients were classified into group I (No necrosis or OF), group II (sterile necrosis or transient OF), group III (IN or persistent OF) and group IV (infected necrosis and persistent OF). The four groups were compared regarding the clinical course, radiological/surgical intervention, any post-intervention complications, use of antibiotics/antifungal and nutritional support. <h3>Results</h3> 51 patients were admitted to ITU with SAP (APACHE II &gt;8, modified Glasgow score &gt;3) during the period of 2007–2010. All cases fulfilled the Atlanta criteria of SAP. Median age: 66±17.5. The pancreatitis was alcohol induced in 12% and due to gallstones in 59% of patients; no cause was found in 25% of patients. Median ITU stay was 3.23 days. The overall mortality rate during the study period (3 years) was 38% (n−19) above national standard of 30%. All seven patients in group IV died, five of them underwent necrosectomy and one had CT guided drainage of infected acute fluid collection. The Abstract PWE-135 table 1 shows the total number of patients and respective mortality of SAP in all four groups. Forty-one patients (80%) received antibiotics and 35 patients (69%) had nutritional support but neither of them seems to have a significant impact on survival (p=0.6 and 0.06 respectively). Outcome (death) correlated with organ dysfunction criteria (Atlanta criteria and APACHE II score). <h3>Conclusion</h3> While the presence of infected necrosis or persistent organ failure in SAP (group III) is associated with high mortality, the combination of “infected necrosis and persistent organ failure” (group IV) is uniformly fatal. Further research is necessary to confirm the findings in our study and to explore ways of optimising patients in group III to improve survival. <h3>Competing interests</h3> None declared.
Abstract 161: Single-cell RNA sequencing presents explicit expression signatures in primary breast cancer
Authors: Hye Hyeon Eum, Hae-Ock Lee, Woosung Chung, Kyu-Tae Kim, Kyung-Min Lee, Arum Jo, WonShik Han, Woong-Yang Park
Journal: Cancer Research (2016)

Abstract Intratumoral heterogeneity has emerged as a problem to be resolved for precise diagnosis and effective treatment of cancer. Breast cancer is one of the most heterogeneous cancer in its molecular subtypes and its intratumoral genomic diversity has been demonstrated as well. Single-cell sequencing approach would reveal heterogeneity in gene expression signatures and the common gene expression characteristics across tumor cells within a tumor. In this study, we isolated live individual cells and amplified cDNAs using C1™Single-cell Auto Prep System (Fluidigm) then performed RNA sequencing using HiSeq2500 System (Illumina). Single-cell transcriptomes were acquired from four primary tumor (ER+/HER2-, ER-/HER2+, ER+/HER2+ and triple negative breast cancer) and two matched lymph node metastases (ER+/HER2+ and triple negative breast cancer). Because the tumor tissue isolates may include stromal and immune cells in the tumor microenvironment, we defined ‘epithelial cell adhesion molecule signature’ to filter out non-tumor populations (Poster# presented by Woosung Chung et. al) After the removal of non-tumor cells, collected tumor single-cell transcriptomes largely recapitulated bulk tumor-expression profiles. The ER+/HER2- tumor cells showed highly activated estrogen receptor-associated pathways. Although both ER-/HER2+ and ER+/HER2+ tumors had the HER2 gene amplification and overexpression, HER2/HER3 pathway is activated only in ER-/HER2+ tumor cells. The association of gene expression for cancer stem cells and chemoresistance, such as IL8 and CXCL1, with HER2/HER3 signaling pathway activation was prominent. By contrast, the ER+/HER2+ tumor cells had highly activated estrogen receptor signaling, presenting them as the luminal type. The triple negative breast cancer cells highly expressed adhesion molecules and proteases suggesting their invasive nature, yet demonstrated extensive gene expression heterogeneity. Collectively these data revealed the power of single cell gene expression profiling in the precise characterization of tumor cell properties. The explicit gene expression signatures for patient specific tumors may be defined as subtype-specific signatures and helpful to unmask targets for molecular directed therapies. Citation Format: Hye Hyeon Eum, Hae-Ock Lee, Woosung Chung, Kyu-Tae Kim, Kyung-Min Lee, Arum Jo, WonShik Han, Woong-Yang Park. Single-cell RNA sequencing presents explicit expression signatures in primary breast cancer. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 161.
Long-term remissions in relapsed/refractory primary central nervous system lymphoma (PCNSL) after topotecan chemotherapy
Authors: L. Fischer, E. Thiel, H. A. Klasen, K. Hans, K. Jahnke, H. Pees, J. Birkmann, K. Agnieszka
Journal: Journal of Clinical Oncology (2005)

1528 Background: Up to 30% of PCNSL patients (pts.) are refractory to primary therapy and about 60% relapse. Salvage therapy prolongs survival in PCNSL, however, no standard regimen has been defined. Topotecan reaches therapeutic levels in CNS and showed activity in aggressive lymphomas. Methods: Immunocompetent pts. with relapsed or refractory PCNSL were treated with topotecan 1.5mg/m2 d1–5 iv. every 3 to 4 weeks (depending on hematological recovery). Response was evaluated by MRI or CT scan after the first and then at least after every second therapy course. Progression free survival (PFS) was measured from start of topotecan therapy to first documentation of progression, last follow up or death. Results: Twenty four pts. were included in this study. All PCNSL were of B type with 22 of high grade and two of low grade histology. Median age was 52.5 years (26–76). All pts. had been pretreated with up to three different therapies; 10 with chemotherapy (CHT) and whole brain irradiation (WBI), 13 with CHT alone and one with WBI alone. CHT included high-dose methotrexate in all pts. A median of two (1–6) courses topotecan were applied. Four pts. achieved a complete remission and five a partial remission for on overall response rate of 37.5%. Three pts. were stable, 11 progressed and one patient dropped out before response evaluation. In three pts. a long term remission was observed without further therapy: One relapsed after 10 months, one developed an intraocular relapse after 28 months, and one patient is alive with minimum residual disease after 13 months. The median PFS was 2,0 months, in responders 4,0 months. Eleven pts. received up to five further therapy regimen including WBI (nine pts.) and high dose chemotherapy with stem cell support (one pt.). Median OAS from first diagnosis was 30 months. Conclusions: Salvage therapy with topotecan can induce long term remissions in PCNSL. The short median PFS reflects the overall poor prognosis in this collective. Further improvement may be achieved with topotecan as a potent partner in a combination therapy. An update of results and late neurotoxicity analysis will be presented. No significant financial relationships to disclose.
Abstract 197: Phospholipids regulate the localization and oncogenic potential of protein tyrosine kinase 6 in prostate cancer
Authors: Darren J. Wozniak, Ben Hitchinson, Wenjun Bie, Vadim Gaponenko, Angela L. Tyner
Journal: Cancer Research (2016)

Abstract Background: Protein tyrosine kinase 6 (PTK6, also called BRK) is an intracellular SRC-related tyrosine kinase that does not possess canonical localization signals. Lack of targeting yields flexibility in its intracellular localization and access to substrates. PTK6 is observed in the nuclei of prostate epithelial cells where it promotes differentiation and inhibits growth. PTK6 is activated at the plasma membrane in PTEN-deficient mouse prostate tumors where the concentration of PIP3 is high due to PTEN loss of function. Membrane-associated PTK6 induces cell transformation, the epithelial-mesenchymal transition, and tumor cell metastasis. In human prostate cancer, active PTK6 associates with the plasma membrane and its increased expression correlates with metastasis and poor survival. Our studies aimed to characterize how the mislocalization and activation of PTK6 in prostate cancer is regulated. Results: Based on our observation that loss of PTEN induces accumulation of PTK6 at the membrane, we hypothesized that PTK6 binds to the plasma membrane secondary messenger phosphatidylinositol (3,4,5)-trisphosphate (PIP3). Amino acid sequence alignment predicts H52, Y53, and K54 of PTK6 as a potential PIP3 binding site, which resembles the lipid-binding HYK domain of tyrosine kinases BTK and Abl. Using NMR saturation transfer difference (STD) experiment, we observed that the SH2 domain of PTK6 contains a binding site for inositol trisphosphate (IP3) a soluble PIP3 mimic. As predicted, statistical analysis identified Y53 of the PTK6 HYK motif within the SH2 domain as a residue with substantial chemical shift perturbations (CSPs) induced by independent titrations with PIP3 analogs IP3, IP4, and 1,2-dihexanoyl PIP3 in 15N HSQC, as compared to controls. Using autophosphorylated and unphosphorylated PTK6, NMR STD experiments show that only active (pY342) PTK6 binds to IP3. Treatment of prostate cancer cells with the PI3K inhibitor wortmannin reduces active PTK6 at the plasma membrane. Conclusions: Our data demonstrate that active PTK6 is recruited to the plasma membrane through direct interactions with PIP3. Membrane association places PTK6 in close proximity to its oncogenic substrates AKT, FAK and BCAR1, thereby promoting tumor progression. These findings may facilitate identification of novel PTK6 inhibitors that block its association with the membrane, while not affecting its tumor suppressive role in the nucleus. This work is funded by NIH grant 1R01CA188427 to ALT and VG. Citation Format: Darren J. Wozniak, Ben Hitchinson, Wenjun Bie, Vadim Gaponenko, Angela L. Tyner. Phospholipids regulate the localization and oncogenic potential of protein tyrosine kinase 6 in prostate cancer. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 197.
ALK Immunohistochemistry in NSCLC: Discordant Staining Can Impact Patient Treatment Regimen
Authors: Merdol Ibrahim, Suzanne Parry, Dawn Wilkinson, Neil Bilbe, David Allen, Steven Forrest, Perry Maxwell, Anthony O’Grady, Jane Starczynski, Philippe Tanier, John Gosney, Keith Kerr, Keith Miller, Erik Thunnissen
Journal: Journal of Thoracic Oncology (2016)
Abstract 2488: Stat3 inhibitor (BBI-608) with radiation therapy is promising in malignant pleural mesothelioma
Authors: Seiji Matsumoto, Hiroshi Doi, Tohoru Nakamichi, Ayumi Kuroda, Masaki Hashimoto, Teruhisa Takuwa, Nobuyuki Kondo, Seiki Hasegawa
Journal: Cancer Research (2016)

Abstract Background: The prognosis of Malignant pleural mesothelioma (MPM) is very poor, the new drug for MPM is need. IL-6 in serum with MPM patients is high, IL-6/Stat3 pathway is activated. We investigated that Stat3 is the potential target for the treatment of MPM. Methods: Cell viability was assayed with Cell Counting Kit-8 (CCK-8: WST-8 Dojindo). MPM cells (NCI-H28, NCI-H226, NCI-H2052, NCI-H2452, MSTO-211H) were seeded into 96-wellplates. After the treatment with Stat3 inhibitor (BBI-608). Cell Counting Kit-8 solution was added to each well of the plate and measured the absorbance using a microplate reader. The levels of phosphorylated Stat3 (p-Stat3) were measured in cell lysates using an InstantOne ELISA assays (eBioscience). The translocated p-Stat3, c-Myc were analyzed by Confocal immunofluorescent. In vivo study, H226 cells were injected into the subcutaneous over the flank region of nude mice. Mice were randomly assigned into four groups (5 mice each group) 1) vehicle control 2) treated with BBI-608 3) Radiation 4) BBI608/RT. Tumor is measured twice per week. Results: BBI-608 inhibited MPM cell lines (NCI-H28, NCI-H226, NCI-H2052, NCI-H2452, MSTO-211H) viability in a dose-dependent manner. The level of p-Stat3 was decreased 90% by BBI-608 10μM treatment in H226. Untreated H226, p-stat3 was observed in cytoplasma and localized in the nucleus. As compared with untreated cells, p-stat3, c-Myc were decrease in cytoplasma and was not localized in the nucleus with BBI-608 treated cells. BBI-608 suppressed tumor growth (p&amp;lt;0.05) and completely suppressed tumor growth with radiation in mouse model. Conclusion: In this study, we have shown that BBI-608 inhibited the proliferation of all MPM cell (epithelial, biphasic, sarcomatoid) lines and inhibited Stat3 phosphorylation and blocked the translocation to the nucleus. We also demonstrated that BBBI-608 completely suppressed tumor growth with radiation in mouse model. Furthermore, Stat3 inhibitor with Radiation Therapy (START) is promising in MPM therapy. Citation Format: Seiji Matsumoto, Hiroshi Doi, Tohoru Nakamichi, Ayumi Kuroda, Masaki Hashimoto, Teruhisa Takuwa, Nobuyuki Kondo, Seiki Hasegawa. Stat3 inhibitor (BBI-608) with radiation therapy is promising in malignant pleural mesothelioma. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 2488.
Efficacy and Toxicity of Conditioning Regimens BEAM and BEM in Autologous Hematopoietic Cell Transplantation for Lymphomas: Preliminary Results of a Comparative (Matched Pair) Analysis
Authors: Ioanna Sakellari, Despina Mallouri, Batsis Ioannis, Constantinou Varnavas, Iskas Michalis, Baliakas Panayotis, Karypidis Kyriakos, Georgiadou Elissavet, Douka Vassiliki, Ampela Elma, Anastasia Marvaki, Apostolou Chrysoula, Damianos Sotiropoulos, Evangelia Yannaki, Panayotis Kaloyannidis, Achilles Anagnostopoulos
Journal: Blood (2012)
Abstract 5159: Smad7 knockdown in colon cancer cells activates protein kinase RNA-associated eIF2α pathway thereby leading to cell death
Authors: Veronica De Simone, Gerolamo Bevivino, Silvia Sedda, Roberta Izzo, Massimo Claudio Fantini, Giovanni Monteleone
Journal: Cancer Research (2016)

Abstract Background. Up-regulation of Smad7, an inhibitor of TGF-β1, occurs in sporadic colorectal cancer (CRC). Knockdown of Smad7 with a specific antisense oligonucleotide (AS) leads to activation of eIF2α, an attenuator of protein synthesis, and arrest of CRC cells in the S phase of the cell cycle with the downstream effect of inducing cell death. Aim. To investigate the mechanisms by which Smad7 knockdown activates eIF2α. Methods. Phosphorylation of eIF2α was evaluated in CRC cell lines (i.e. HCT116 and DLD-1) either untreated or treated with Smad7 sense (S) or AS by Western blotting (WB) and immunofluorescence (IF). Expression of ATF4 and CHOP, two downstream targets of EIF2α, were evaluated by IF and activation of PKR, GCN2 and PERK, up-stream kinases that induce eIF2α phosphorylation, was assessed by WB. Wild type or PKR-deficient CRC cells treated with Smad7 AS were monitored for eIF2α activation and induction of death. Finally, we assessed whether enhanced phosphorylation of eIF2α seen in cells treated with Smad7 AS was also associated with reduced interaction between eIF2α and PP1, a phosphatase that normally dephosphorylates eIF2α. Results. Smad7 knockdown increased ATF4 and CHOP expression thus confirming previous data showing activation of eIF2α phosphorylation in CRC cells treated with Smad7 AS. Among kinases that induce eIF2α phosphorylation, only PKR was activated by Smad7 knockdown. Consistently, silencing of PKR reduced but did not abolish Smad7 AS-induced eIF2α phosphorylation and cell death, thus suggesting the existence of further mechanisms that control eIF2α phosphorylation in Smad7-deficient cells. Indeed, in CRC cells, Smad7 interacted with PP1 and Smad7 knockdown reduced association of PP1 with eIF2α. Conclusions Data show that Smad7 is involved in CRC cell survival and suggest that Smad7 is a valid target for therapeutic intervention in CRC. Citation Format: Veronica De Simone, Gerolamo Bevivino, Silvia Sedda, Roberta Izzo, Massimo Claudio Fantini, Giovanni Monteleone. Smad7 knockdown in colon cancer cells activates protein kinase RNA-associated eIF2α pathway thereby leading to cell death. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 5159.