tbuckley/cabot-search huggingface dataset:
Abstract P3-08-12: PIK3CA mutations in breast cancer: Mutational landscape and clinical implications in ER+/HER2- subtype
Authors: HK Ahn, S Park, SH Hyun, K Park, E Lee, J-Y Kim, SJ Nam, SW Kim, JE Lee, SK Lee, JH Yu, JS Ahn, Y-H Im, YH Park
Journal: Cancer Research (2019)

Abstract Introduction: PIK3CA mutation is one of the most frequent genomic alterations in breast cancer. We evaluated PIK3CA mutational status including spatial and temporal heterogeneity, clinical characteristics and prognostic impact focused on ER+/HER2- subtype. Methods: We performed targeted ultra-deep sequencing (CancerSCAN™) of breast cancer tissue in a prospective cohort. Burden of disease was assessed by metabolic tumor volume(MTV) in 18F-FDG-PET scan. Association with clinical characteristics or survival were tested in ER+/HER2- subtype, using Chi square test or Kaplan-Meier method. Results: PIK3CA analyses were performed in 1274 breast cancer specimens from 1091 patients. 957 patients had early breast cancer. PIK3CA alterations were found in 397 patients(36.3%), and frequency of PIK3CA mutation was significantly lower in triple negative breast cancer(19.0%), compared with 40.4% in ER+/HER2-, 40.9% in ER+/HER2+, and 45.2% in ER-/HER2+ subtype(p&amp;lt;0.0001). 158 patients had more than two biopsies. Among 92 patients with second biopsy within one month, 11%(10/92) had spatial heterogeneity of PIK3CA mutation. After neoadjuvant chemotherapy, 10%(3/30) of patients had change of PIK3CA mutational status. Serial biopsy at time of recurrence revealed loss or gain of PIK3CA mutation in 10 out of 59 patients (17%). In ER+/HER2- subtype, PIK3CA had a trend toward longer distant disease free survival without statistical significance. In patients with stage IV ER+/HER2- disease, PIK3CA hotspot mutations were associated with significant longer overall survival(OS) (71.0 vs. 37.8 months, p=0.048) and better progression free survival(PFS) at 1st line palliative treatment (37.7 vs. 9.4 months, p = 0.0004). Frequency of symptomatic recurrence, recurrence as oligometastases, and specific metastatic sites were not associated with PIK3CA mutational status, except that bone metastases at first distant metastases was less prevalent in patients with PIK3CA hotspot mutations(35.6% vs. 53.8% in PIK3CA wt, p=0.048). Metabolic tumor volume(MTV) at time of first distant metastases was not associated with presence of PIK3CA mutation. Conclusion: We observed variations in PIK3CA mutational status in more than 10% of patients with &amp;gt;1 repeated biopsy. In stage IV ER+/HER2- disease, PIK3CA hotspot mutation seemed to be associated with longer PFS and OS, however metabolic tumor burden was not associated with PIK3CA alterations. Citation Format: Ahn HK, Park S, Hyun SH, Park K, Lee E, Kim J-Y, Nam SJ, Kim SW, Lee JE, Lee SK, Yu JH, Ahn JS, Im Y-H, Park YH. PIK3CA mutations in breast cancer: Mutational landscape and clinical implications in ER+/HER2- subtype [abstract]. In: Proceedings of the 2018 San Antonio Breast Cancer Symposium; 2018 Dec 4-8; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2019;79(4 Suppl):Abstract nr P3-08-12.
The rise in breast cancer incidence, 1960-2003, is largely confined to ER+ tumors
Authors: Andrew G. Glass, James V. Lacey, Robert N. Hoover
Journal: Cancer Research (2005)

4045  Breast cancer incidence has risen for at least 70 years. Hormone use has been v ariously linked to the rise and has recently been implicated particularly in the etiology of lobular, as opposed to ductal, invasive cancer but there has been little consideration of the receptor status of the tumors. Data from the files of the Kaiser Permanente Northwest Tumor Registry allowed us to generate a comprehensive report combining clinical, pathological and receptor data from a single source over 44 years. This Registry collects material from several interlinked clinical and laboratory data systems and enrolls all cases of cancer in a defined population, allowing accurate calculation of rates. All tumor specimens are processed by a single laboratory and diagnoses rendered by a small group of pathologists working exclusively for KPNW. Estrogen receptor determinations became common in 1978 (69% of cases) and were done in 94% of cases by 2003. Determinations have always been done in laboratories surveyed and approved by the cooperative groups for clinical trials in breast cancer. Using these KPNW data, we investigated breast cancer incidence patterns as a function of histologic type, estrogen receptor status, and disease stage over a 44-year period. Of the 8543 breast cancers among women diagnosed and treated at KPNW, 1960-2003, 7275 were invasive, 5323 of ductal histology and 774, lobular. Breast cancer incidence has increased overall by 181% from 1960 to 2003 (80.8 to 145.9); all rates are age-adjusted (2000 standard) annual rates per 100,000 women. Incidence did not change for women less than 45 yrs at diagnosis but rose 150% for women 45-59 yrs and 246% for women over 60 yrs. Ductal cancer increased from 73 to 116.2 between 1960 to1999 and has fallen to 104.5 by 2003. Lobular cancer was essentially undiagnosed in 1960 and rose progressively to 10.2 (1979), then 13.0 (1990) and ultimately to 23.0 by 2003. Most strikingly, the rise in incidence of all cancers, irrespective of histology, has been confined to ER+ tumors. Overall, ER+ cancers rose from 32 to 109.9 (344%) in the period between 1978 and 2003. At the same time ER- cancers fell from 37.3 to 16.4 (44%). Receptor-positive ductal cancers, accounting for about 80% of all breast cancers, rose by 302% but ER+ lobular cancers, relatively uncommon in the earliest years, increased by 799% during this time to constitute nearly 20% of all cancers by 2003. The common thread for the increases in incidence appears to be receptor positivity. Indeed, ER- cancers and those among younger women (more likely to be ER-) are stable or declining in incidence over many years. Because the pattern of age-adjusted incidence rate increases for both lobular and ductal carcinoma resembles the increased use of postmenopausal hormones in the U.S. during the same period, this known breast cancer risk factor may explain these phenomena.
Drp1S600 phosphorylation regulates mitochondrial fission and progression of nephropathy in diabetic mice
Authors: Daniel L. Galvan, Jianyin Long, Nathanael Green, Benny H. Chang, Jamie S. Lin, Paul Schumacker, Luan D. Truong, Paul Overbeek, Farhad R. Danesh
Journal: Journal of Clinical Investigation (2019)

Phosphorylation of dynamin-related protein 1 (Drp1) represents an important regulatory mechanism for mitochondrial fission. Here, we established the role of Drp1 serine 600 (Drp1S600) phosphorylation in mitochondrial fission in vivo and assessed the functional consequences of targeted elimination of the Drp1S600 phosphorylation site in the progression of diabetic nephropathy (DN). We generated a knockin mouse in which S600 was mutated to alanine (Drp1S600A). We found that diabetic Drp1S600A mice exhibited improved biochemical and histological features of DN along with reduced mitochondrial fission and diminished mitochondrial ROS in vivo. Importantly, we observed that the effect of Drp1S600 phosphorylation on mitochondrial fission in the diabetic milieu was stimulus dependent but not cell type dependent. Mechanistically, we show that mitochondrial fission in high-glucose conditions occurs through concomitant binding of phosphorylated Drp1S600 with mitochondrial fission factor (MFF) and actin-related protein 3 (Arp3), ultimately leading to accumulation of F-actin and Drp1 on the mitochondria. Taken together, these findings establish the idea that a single phosphorylation site in Drp1 can regulate mitochondrial fission and progression of DN in vivo and highlight the stimulus-specific consequences of Drp1S600 phosphorylation in mitochondrial dynamics.
News in brief: December 2010
Authors: Toby Reynolds
Journal: BMJ (2010)

Primary care physicians in the United States earn around $60 (£37; €42) an hour, according to a survey of more than 6000 doctors, and of the main specialty groups studied they are the lowest paid for their time.

Surgeons took home the highest average hourly wage, $92, whereas within subspecialties, neurosurgeons and radiation oncologists earned $132 and $126 an hour respectively, according to the study ( Arch Intern Med 2010;170:1728-34).

The United States has a shortage of family practitioners, and the study’s authors suggest the difference in pay may have contributed to this.

“It’s not just doctors themselves that are looking at this disparity and choosing higher wages,” lead researcher J Paul Leigh, of the University of California Davis School of Medicine, told Reuters Health. “The economic incentives for medical schools and their students have been out of whack. Schools understand that a cardiac unit is going to bring in more money than a …
Helen Salisbury: Metaphors, enemies, and empathy
Authors: Helen Salisbury
Journal: BMJ (2019)

Attitudes are shaped by language, and the metaphors we use to express our ideas inevitably colour the way we think. If, when we open the doors of our surgery on a Monday morning, we talk of “bracing ourselves for the onslaught,” it may say something about our attitude towards our work and patients (or towards Monday mornings in general). Many metaphors are so commonplace as to be largely unremarkable, but sometimes they leap out at you.

Last year I attended an event for GP trainers where the speaker talked of clinical medicine as a “combat zone.” He …
The mTORC2‐Akt1 Cascade Is Crucial for c‐Myc to Promote Hepatocarcinogenesis in Mice and Humans
Authors: Zhong Xu, Meng Xu, Pin Liu, Shu Zhang, Runze Shang, Yu Qiao, Li Che, Silvia Ribback, Antonio Cigliano, Katja Evert, Rosa M. Pascale, Frank Dombrowski, Matthias Evert, Xi Chen, Diego F. Calvisi, Xin Chen
Journal: Hepatology (2019)

Hepatocellular carcinoma (HCC) is a deadly form of liver cancer with limited treatment options. The c‐Myc transcription factor is a pivotal player in hepatocarcinogenesis, but the mechanisms underlying c‐Myc oncogenic activity in the liver remain poorly delineated. Mammalian target of rapamycin complex 2 (mTORC2) has been implicated in cancer by regulating multiple AGC kinases, especially AKT proteins. In the liver, AKT1 and AKT2 are widely expressed. While AKT2 is the major isoform downstream of activated phosphoinositide 3‐kinase and loss of phosphatase and tensin homolog–induced HCC, the precise function of AKT1 in hepatocarcinogenesis is largely unknown. In the present study, we demonstrate that mTORC2 is activated in c‐Myc‐driven mouse HCC, leading to phosphorylation/activation of Akt1 but not Akt2. Ablation of Rictor inhibited c‐Myc‐induced HCC formation in vivo . Mechanistically, we discovered that loss of Akt1 , but not Akt2 , completely prevented c‐Myc HCC formation in mice. Silencing of Rictor or Akt1 in c‐Myc HCC cell lines inhibited phosphorylated forkhead box o1 expression and strongly suppressed cell growth in vitro . In human HCC samples, c‐MYC activation is strongly correlated with phosphorylated AKT1 expression. Higher expression of RICTOR and AKT1, but not AKT2, is associated with poor survival of patients with HCC. In c‐Myc mice, while rapamycin, an mTORC1 inhibitor, had limited efficacy at preventing c‐Myc‐driven HCC progression, the dual mTORC1 and mTORC2 inhibitor MLN0128 effectively promoted tumor regression by inducing apoptosis and necrosis. Conclusion: Our study indicates the functional contribution of mTORC2/Akt1 along c‐Myc‐induced hepatocarcinogenesis, with AKT1 and AKT2 having distinct roles in HCC development and progression; targeting both mTORC1 and mTORC2 may be required for effective treatment of human HCC displaying c‐Myc amplification or overexpression.
Abstract P5-03-15: Mechanism of activation of PPP1R1B drug-resistance gene in trastuzumab-resistant Her2+ breast cancer
Authors: J Momand, R Murad, X Ma, S Geng, A Mortazavi
Journal: Cancer Research (2019)

Abstract Trastuzumab (Herceptin) resistance is a persistent challenge in the treatment of metastatic Her2+ breast cancer, with an average relapse time of 1 year after treatment. Human breast cancer cell-lines (SKBr3 and BT474) selected for trastuzumab resistance have a PPP1R1B gene (chr17:39,626,924-39,636,626) that is transcriptionally activated compared to their drug-sensitive counterparts. PPP1R1B codes for two related protein products, Darpp-32 (long) and t-Darpp (short), that are overexpressed in 50% of clinical breast cancer samples in comparison to normal breast tissue; reintroduction of t-Darpp into drug-sensitive cells confers drug resistance. The mechanism controlling overexpression of these transcripts is unknown. To gain insight into this mechanism we used ATAC-seq to map open chromatin areas in trastuzumab-resistant breast cancer cell lines and compared their open chromatin areas to those in the parental trastuzumab-sensitive counterparts. The PPP1R1B gene consists of 7 canonical exons. In each trastuzumab-resistant line there is two significantly increased open chromatin peaks, one within exon 2 and one within exon 3. We are performing deep sequencing (&amp;gt;200 million reads) to identify transcription factor footprints in these peaks. Furthermore, we performed RNA-seq analysis and identified genes that are similarly regulated in the resistant lines in comparison to their drug-sensitive counterparts. In summary, these results shed light on an area of high clinical importance and point to potential drug targets to be developed to overcome trastuzumab resistance in Her2+ breast cancer. Citation Format: Momand J, Murad R, Ma X, Geng S, Mortazavi A. Mechanism of activation of PPP1R1B drug-resistance gene in trastuzumab-resistant Her2+ breast cancer [abstract]. In: Proceedings of the 2018 San Antonio Breast Cancer Symposium; 2018 Dec 4-8; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2019;79(4 Suppl):Abstract nr P5-03-15.
EVALUATION OF BARRETT'S ESOPHAGUS (BE) USING BLUE LIGHT IMAGING (BLI) AND LINKED COLOR IMAGING (LCI): EXPERIENCE OF 2 UNIVERSITY HOSPITALS
Authors: N Asmar, N Etchepare, G Rahmi, E Coron, G Perrod, M Le Rhun, N Musquer, S Khater, E Samaha, H Benosman, A Vienne, C Cellier
Journal: Endoscopy (2019)

Endoscopic surveillance is mainstream to diagnose BE and its complications. BLI/LCI of ELUXEO system (Fujifilm, Tokyo, Japan) has emerged as powerful image enhancement diagnostic tool for neoplastic lesions. The aim of our study was to evaluate the performance of this system to characterize BE and its complications.
Abstract P4-08-33: The significance of Oncotype DX recurrence score in T1-2N1M0 ER positive HER2 negative breast cancer: An analysis combined with the prognostic stage in the updated AJCC 8th edition
Authors: H Chen, M Wang, P Zhang, M Zhang, K Wu
Journal: Cancer Research (2019)

Abstract Purpose: Oncotype DX recurrence score (Oncotype DX RS) is applied in the prognostic stage in T1-2N0M0 ER+/HER2- breast cancer. But its significance is unclear in cases with T1-2N1M0 ER+/HER2- disease. Our study was to evaluate the prognostic significance of Oncotype DX RS in combination with the prognostic stage in the updated AJCC 8th edition. Methods: The Surveillance, Epidemiology, and End Results (SEER) database was searched to identify invasive ductal breast cancer cases in T1-2N1M0 stage with ER positive HER2 negative status and Oncotype DX RS diagnosed between 2004 and 2012. Patients with unknown histologic grade or PR status, no or unknown surgery performed, or less than 6 months of follow up were excluded. Patients with RS 0-10, 11-25, &amp;gt;25 were categorized into low risk, midrange risk and high risk groups respectively. Comparisons of the distribution of RS groups among prognostic stages were performed using Pearson's chi-square. Breast cancer-specific survival (BCSS) and overall survival (OS) were estimated using the Kaplan-Meier method and compared across RS groups using the log-rank statistic. Cox models were fitted to compare the association between RS groups, prognostic stages and BCSS or OS after adjusting for other characteristics. Results: Altogether 4059 cases were enrolled, which were categorized into prognostic stage IA-IIIA (only 357 cases in stage IIB and 35 cases in stage IIIA). More than 60% cases in prognostic stage IA-IIA had their RS in midrange risk group. There were decreasing proportion of low risk RS group and increasing proportion of high risk RS group with the ascending of prognostic stages (P&amp;lt;0.001). The median follow up was 59 months. There were significant differences in BCSS and OS among RS groups (log-rank P&amp;lt;0.001). In the subgroup analysis, there were also significant differences in BCSS and OS among RS groups in prognostic stages IA-IIA. In the multivariate Cox analysis, the RS group was an independent prognostic factor for BCSS (midrange risk vs. low risk, HR=3.647, 95% CI: 1.124-11.837, P=0.031; high risk vs. low risk, HR=15.372, 95% CI: 4.600-51.374, P&amp;lt;0.001) and OS (midrange risk vs. low risk, HR=1.718, 95% CI: 1.039-2.840, P=0.035; high risk vs. low risk, HR=4.225, 95% CI: 2.462-7.251, P&amp;lt;0.001) along with the prognostic stage. Conclusions: Oncotype DX RS has prognostic significance in T1-2N1M0 ER+/HER2- disease. Further prospective research is warranted. Citation Format: Chen H, Wang M, Zhang P, Zhang M, Wu K. The significance of Oncotype DX recurrence score in T1-2N1M0 ER positive HER2 negative breast cancer: An analysis combined with the prognostic stage in the updated AJCC 8th edition [abstract]. In: Proceedings of the 2018 San Antonio Breast Cancer Symposium; 2018 Dec 4-8; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2019;79(4 Suppl):Abstract nr P4-08-33.
Conversion disorder for lay public consumption
Authors: Maham Khan
Journal: BMJ (2011)

Kristallnacht , the Night of the Broken Glass, was the infamous night when Nazi soldiers launched savage attacks on the German Jews; ransacking houses, smashing shop fronts, destroying synagogues, and beating those in their way. The hearts of the world were set ablaze as people across the globe read of those whose livelihoods were burnt to the ground. Broken Glass follows one woman’s dramatic response to these events as it shatters the world of her husband and smashes the doctor-patient relationship beyond recognition.

The play, set in 1930s Brooklyn, follows the lives of respectable Jewish couple Sylvia and Phillip Gellburg. On …
Abstract B24: Role of Dermcidin in growth and survival of melanoma tumor cells
Authors: Jennifer N. Montoya, Marcela N. Perez-Sosa, Beatriz A. Sangiuliano, Jose E. Belizario
Journal: Clinical Cancer Research (2018)

Abstract Dermcidin (DCD) is a candidate oncogene localized at 12q13.1 which is normally expressed in the skin sweat gland and brain and overexpressed in various tumor cells. We have established the role of DCD in melanoma growth and survival by silencing DCD via shRNA expression in human melanoma G361 cell line. Biologic and biochemical assays showed that DCD gene knockdown decreased significantly melanoma cell growth in culture and tumor formation in NUDE mice. A DNA microarray-based study identified a total of 162 upregulated and 212 downregulated genes, in a G-361 control clone (pLKO) and clones expressing shRNA to DCD mRNA (IBC-I). We found, notably, genes involved in the nucleosome organization and signaling pathway to APRIL/BAFF receptor. Additionally, we examined DCD expression by immunohistochemistry in TMA (tissue microarray) of 101 patients and found that DCD-negative tumor had a 65.54% survival rate and DCD-positive tumor 43.33% survival rate in 5 years. We found an association with BRAF V600E and ERBB4 mutation in DCD-positive tumor with most frequent E43K mutation. Finally, we have screened clones resistant to Vemurafenib after long-term treatment in vitro and in xenografts in nude mice. Overall, these studies provide further support for DCD as oncogene to melanomas. Financial support: FAPESP, CNPq and CAPES. Citation Format: Jennifer N. Montoya, Marcela N. Perez-Sosa, Beatriz A. Sangiuliano, Jose E. Belizario. Role of Dermcidin in growth and survival of melanoma tumor cells [abstract]. In: Proceedings of the AACR International Conference held in cooperation with the Latin American Cooperative Oncology Group (LACOG) on Translational Cancer Medicine; May 4-6, 2017; São Paulo, Brazil. Philadelphia (PA): AACR; Clin Cancer Res 2018;24(1_Suppl):Abstract nr B24.
Growing up with your airway microbiota: a risky business
Authors: Bushra Ahmed, Michael J Cox, Leah Cuthbertson
Journal: Thorax (2019)

Childhood is a critical time for respiratory health, with environmental and infectious exposures being linked to future respiratory disease and susceptibility.1 2 Respiratory microbiome research has introduced a new context for these exposures due to the presence of a pre-existing microbial community in both the upper and lower respiratory tract in healthy children.3–5 Variation in community composition has been observed in chronic lung diseases,6 7 and particular micro-organisms or combinations of organisms in infants have been associated with future disease development. Thus deviation from a healthy microbiota in early life appears to play an important role in disease development, with changes evident by 1 week of age.8 The dynamics of the infant airway microbiota and its relationship to disease development has therefore been the focus of increasing attention.

Acute respiratory infections (ARIs) are common in children under 5 years of age,9 and indications suggest that susceptibility might be, at least partly, determined by the microbiota.5 8 Toivonen and colleagues10 have conducted the largest study of the respiratory microbiome in infants to date, obtaining a nasal swab at 2 months of age from 839 infants and parent-recorded data on respiratory infections until 24 months of age to look at the incidence of ARI.

The study was conducted, described and controlled, taking into account many of the methodological issues that can arise when using the 16S …
Sudden onset chest pain and respiratory distress
Authors: Nicholas A Faure Walker, Rebecca Duerden, Simon Croxson
Journal: BMJ (2011)

An 80 year old gentleman presented to the emergency department with sudden onset shortness of breath with right sided chest and back pain. He was housebound and using short burst oxygen therapy for severe lung fibrosis and was noted to have oxygen saturations of 91% on room air at his last clinic appointment. He stopped smoking 20 years before, but previously he had smoked 70 packs a year. He had been heavily exposed to asbestos for 22 years while working as an electrician in a factory that put carbon black into tyres. He was taking omeprazole, alendronate, aspirin, and long term prednisolone. There was no other medical or family history of note, and there had been no recent trauma.

On examination, he was very unwell and cyanosed, with SaO2 of 66% on 10 L oxygen. He had a respiratory rate of 44 breaths a minute, blood pressure of 140/89 mm Hg, and his pulse was 122 beats a minute. His Glasgow Coma Scale score was 15/15, and he was agitated.

Respiratory examination revealed intercostal recession and tachypnoea signifying respiratory distress. Palpation revealed no tracheal deviation and decreased expansion on the right. Percussion …