tbuckley/cabot-search huggingface dataset:
Transcriptome-wide mutation discovery in patients in a phase II clinical trial of first-line erlotinib for clinically selected patients with advanced non-small cell lung cancer
Authors: J. J. Laskin, T. Pugh, C. Jackson, M. Sutcliffe, D. Ionescu, B. Melosky, C. Ho, S. Sun, N. Murray, M. Marra
Journal: Journal of Clinical Oncology (2009)

8102 Background: The purpose of this study was to clinically select a population of patients (pts) likely to benefit from erlotinib and to perform extensive genetic profiling of fresh tissue tumour to identify predictive biomarkers. Methods: Treatment was erlotinib 150 mg p.o. daily until disease progression. Eligibility criteria included: stage IIIB/IV NSCLC; no prior chemo; ECOG ≤2; at least 2 of the following 4 criteria: women, never-smokers, Southeast Asian origin, adenocarcinoma and/or BAC. All pts had baseline serum samples and a fresh frozen tumour biopsy. EGFR and KRAS were sequenced using traditional methods to identify known mutations of erlotinib. Transcribed coding regions of all other expressed genes were sequenced to uncover novel mutations and other genetic features. Results: From Sept-06 to Oct-08, 65 pts have been enrolled. Of these 60 have completed at least 8 wks of erlotinib (or progressed before 8 wks). 49F and 11M; 45 never smokers. PS 0/1/2: 10/39/11. 18 Caucasian and 42 Asian. Pathology: 44 ACA; 3 BAC;1 squamous carcinoma; 13 NSCLC NOS. Responses: PR - 21 (35%); SD - 24 (DCR 75%); PD - 10; NE - 5. 85% did not progress at 8 weeks. 19 of 51 (37%) pre-treatment samples had an EGFR mutation. 10 of the 28 pts with response data (24pts still on drug) had a PR and 7 of these had either an LREA deletion or L858R point mutation. 1 of 3 post-treatment samples developed a T790M mutation on erlotinib. 3 of 51 pts have KRAS mutations. Analysis of over 21 Giga basepairs of aligned transcriptome sequencing data from 20 tumour samples has uncovered 1089 putative non-conservative gene mutations of which 15 are seen in multiple tumours: TUBA1C, EPS8L1, ARID4B, RPL22, C20orf52, CCT8, HLA-DRB5, TRIP6, and PLP2 in 4 tumours, C20orf52 and CTSL1 in 5 tumours, and SERF2, TMEM173, and an uncharacterized gene in 6 tumours. Conclusions: Clinical selection of pts enriches the EGFR mutation positive and KRAS mutation negative population and leads to high rates of non-progression. Full tumour RNA analysis identified several recurrent mutations that may describe mechanisms of erlotinib response and resistance. The discovery of novel mutations in multiple pts suggests patterns that may shed light on lung cancer specific behaviour. [Table: see text]
Racism: medical student seeks justice for effects of incident at Cardiff University
Authors: Clare Dyer
Journal: BMJ (2020)

A black medical student who says that she was targeted and felt obliged to leave her course after complaining about a racist show at Cardiff University is taking legal advice about how to hold the university accountable.

Natasha Chilambo, 25, was one of eight third year black students who made a formal complaint to the university about the annual medical school revue, Anaphylaxis , in 2016, which involved a student blacking up and wearing an outsize dildo to portray a black lecturer.

She says that after complaining she was subjected to racial harassment, her mental health suffered, and she felt unable to stay at Cardiff. She moved to London and is now in the final year of …
Evaluation of the effectiveness of topical repellent distributed by village health volunteer networks against Plasmodium spp. infection in Myanmar: A stepped-wedge cluster randomised trial
Authors: Paul A. Agius, Julia C. Cutts, Win Han Oo, Aung Thi, Katherine O’Flaherty, Kyaw Zayar Aung, Htin Kyaw Thu, Poe Poe Aung, Myat Mon Thein, Nyi Nyi Zaw, Wai Yan Min Htay, Aung Paing Soe, Zahra Razook, Alyssa E. Barry, Win Htike, Angela Devine, Julie A. Simpson, Brendan S. Crabb, James G. Beeson, Naanki Pasricha, Freya J. I. Fowkes
Journal: PLoS Medicine (2020)

Background The World Health Organization has yet to endorse deployment of topical repellents for malaria prevention as part of public health campaigns. We aimed to quantify the effectiveness of repellent distributed by the village health volunteer (VHV) network in the Greater Mekong Subregion (GMS) in reducing malaria in order to advance regional malaria elimination. Methods and findings Between April 2015 and June 2016, a 15-month stepped-wedge cluster randomised trial was conducted in 116 villages in Myanmar (stepped monthly in blocks) to test the effectiveness of 12% N,N-diethylbenzamide w/w cream distributed by VHVs, on Plasmodium spp. infection. The median age of participants was 18 years, approximately half were female, and the majority were either village residents (46%) or forest dwellers (40%). No adverse events were reported during the study. Generalised linear mixed modelling estimated the effect of repellent on infection detected by rapid diagnostic test (RDT) (primary outcome) and polymerase chain reaction (PCR) (secondary outcome). Overall Plasmodium infection detected by RDT was low (0.16%; 50/32,194), but infection detected by PCR was higher (3%; 419/13,157). There was no significant protection against RDT-detectable infection (adjusted odds ratio [AOR] = 0.25, 95% CI 0.004–15.2, p = 0.512). In Plasmodium-species-specific analyses, repellent protected against PCR-detectable P. falciparum (adjusted relative risk ratio [ARRR] = 0.67, 95% CI 0.47–0.95, p = 0.026), but not P. vivax infection (ARRR = 1.41, 95% CI 0.80–2.47, p = 0.233). Repellent effects were similar when delayed effects were modelled, across risk groups, and regardless of village-level and temporal heterogeneity in malaria prevalence. The incremental cost-effectiveness ratio was US$256 per PCR-detectable infection averted. Study limitations were a lower than expected Plasmodium spp. infection rate and potential geographic dilution of the intervention. Conclusions In this study, we observed apparent protection against new infections associated with the large-scale distribution of repellent by VHVs. Incorporation of repellent into national strategies, particularly in areas where bed nets are less effective, may contribute to the interruption of malaria transmission. Further studies are warranted across different transmission settings and populations, from the GMS and beyond, to inform WHO public health policy on the deployment of topical repellents for malaria prevention. Trial registration Australian and New Zealand Clinical Trials Registry (ACTRN12616001434482).
Injectable Gel Scaffolds: All‐Aqueous‐Processed Injectable In Situ Forming Macroporous Silk Gel Scaffolds for Minimally Invasive Intracranial and Osteological Therapies (Adv. Healthcare Mater. 16/2020)
Authors: Keyin Liu, Zhen Fan, Tianji Wang, Zhiheng Gao, Junjie Zhong, Geng Xiang, Wei Lei, Zhifeng Shi, Yafei Feng, Ying Mao, Tiger H. Tao
Journal: Advanced Healthcare Materials (2020)

In article number 2000879 by Yafei Feng, Ying Mao, Tiger H. Tao, and co-workers, a new method is reported for preparing injectable silk gel scaffolds inspired by the liquid crystalline spinning process in natural silk fibers, with controllable porosity and sufficient mechanical strength that can be used for minimally invasive intracranial and osteological therapies. Meanwhile, silk gel scaffolds with 3D spatial patterning of porous materials and bioactive agent gradients are achieved.
A survival comparison between women with uterine serous and/or clear cell carcinoma with and without a history of breast cancer
Authors: A. Mendivil, T. J. Vogel, V. L. Bae-Jump, P. A. Gehrig
Journal: Journal of Clinical Oncology (2009)

5580 Background: The association between breast and uterine is well known. However, the effect that a prior breast cancer diagnosis may have on women with a new endometrial cancer diagnosis is less well described. The goal of our study was to determine the effect that a prior history of breast cancer would have on the outcome for women with type II uterine cancer. Methods: After obtaining IRB exemption, a retrospective chart review was performed. All women treated for uterine carcinoma between 1994 and 2007 were identified and we identified women with either uterine serous (UPSC) or clear cell carcinoma (UCCC) as the study group. The patients were then divided between those with and those without a prior breast cancer diagnosis. Patient demographics, cancer histologies, and stage of disease data were collected. Fisher's exact test and unpaired t test were used as appropriate. Progression-free (PFS) and overall survival (OS) were calculated using the Kaplan Meier method. Results: Approximately 1,083 patients were treated for uterine carcinoma during the study period of which 74 had pre-existing breast carcinoma (6.9%). One hundred and fifty women had USC and/or UCCC (13.8%) of whom 23 also had pre-existing breast carcinoma (13.3%). The women with breast cancer where older at the time of their uterine cancer diagnosis (77 y.o.) compared to those without breast cancer (68 y.o.) (p = 0.0089); were more likely to develop USC/UCCC (OR 2.56; 95% CI 1.47–4.44); and were more likely to be white compared to black (OR 4.6; 95% CI 1.74–11.99). At five years, there was no significant difference in PFS or OS between those women with and without a prior history of breast cancer. Conclusions: Women with a history of breast cancer have more the twice the likelihood of developing USC and/or UCCC. While having two primary malignancies can be devastating, our study indicated that women who developed a type II uterine cancer and also had a history of a prior breast cancer had the same outcomes as those women without a prior cancer diagnosis. This finding may help to allay patients’ fears about developing another malignancy and its impact on their prognosis. No significant financial relationships to disclose.
Zena Werb, Ph.D, “Queen of the Matrix”: In Memoriam (1945–2020)
Authors: Shahin Rafii, David Lyden
Journal: Cancer Research (2020)

![][1] 

To understand Zena's beginnings is to understand the essence of who Zena was as a person, mentor, matriarch, and as a world-class scientist. We are fortunate to have crossed paths with her.

Zena's achievements are remarkable, considering the hardships she faced as she
Evaluation of recombinant bacillus Calmette-Guerin expressing pertussis toxin in bladder cancer
Authors: D. C. Chade, R. Borra, K. R. Leite, F. E. Villanova, I. Nascimento, L. C. Liete, M. Srougi, P. M. Andrade
Journal: Journal of Clinical Oncology (2009)

3064 Background: Pertussis toxin (S1PT) was combined to BCG, creating a recombinant variant (rBCG-S1PT) with the capacity to promote an immune response targeted to the T helper type 1 (Th1), which may increase the effectiveness of its antitumor effect. Objective: Compare the antitumor effects of rBCG-S1PT and BCG in an experimental model of bladder cancer. Methods: The development of the animal model of bladder cancer was conducted by transurethral instillation of bladder tumor cell line MB49 of the mouse strain C57BL/6. The animal models were divided into three groups, which received 4 weekly intravesical applications of rBCG-S1PT, BCG, or saline. After 7 days of the last instillation, bladders were extracted and weighed in order to infer the tumor weight. Then, the bladders were divided for molecular analysis to assess the pattern of immune response and histopathological analysis. In another experiment, animals were monitored for 60 days for analysis of survival. Also, a test was carried out as previously described, but with no tumor cells instillation. Results: The rate of tumor implantation was 90% of the animals submitted to tumor inoculation. We obtained reduction of the average weights of bladder in groups BCG and rBCG-S1PT ((p&lt;0.001). In both groups treated with immunotherapy, there was an increase of expression of interleukins related to Th1, which was more intense in the group treated with rBCG-S1PT (p&lt;0.05). The analysis of survival showed a significant increase in the group of animals treated with rBCG-S1PT. The instillation of immunotherapeutic agents in animals without tumor did not demonstrate histological differences when compared to the control group. Conclusions: The establishment of the syngeneic orthotopic animal model was successful. The immunotherapy with rBCG-S1PT demonstrated more benefits than BCG in the treatment of bladder cancer in mice, reducing the bladder weight and increasing survival. The immune response obtained with the rBCG-S1PT expressed higher cytokines related to Th1. This new recombinant agent may promote better bladder tumor control than BCG imunotherapy in a clinical setting. No significant financial relationships to disclose.
Reducing Intraoperative Hypotension Using a Machine Learning–Derived Early Warning System
Authors: Christian de Tymowski, Dan Longrois, Philippe Montravers
Journal: JAMA (2020)

Our website uses cookies to enhance your experience. By continuing to use our site, or clicking "Continue," you are agreeing to our Cookie Policy | Continue JAMA HomeNew OnlineCurrent IssueFor Authors Publications JAMA JAMA Network Open JAMA Cardiology JAMA Dermatology JAMA Health Forum JAMA Internal Medicine JAMA Neurology JAMA Oncology JAMA Ophthalmology JAMA Otolaryngology–Head & Neck Surgery JAMA Pediatrics JAMA Psychiatry JAMA Surgery Archives of Neurology & Psychiatry (1919-1959) Podcasts Clinical Reviews Editors' Summary Medical News Author Interviews More JN Learning / CMESubscribeJobsInstitutions / LibrariansReprints & Permissions Terms of Use | Privacy Policy | Accessibility Statement 2023 American Medical Association. All Rights Reserved Search All JAMA JAMA Network Open JAMA Cardiology JAMA Dermatology JAMA Forum Archive JAMA Health Forum JAMA Internal Medicine JAMA Neurology JAMA Oncology JAMA Ophthalmology JAMA Otolaryngology–Head & Neck Surgery JAMA Pediatrics JAMA Psychiatry JAMA Surgery Archives of Neurology & Psychiatry Input Search Term Sign In Individual Sign In Sign inCreate an Account Access through your institution Sign In Purchase Options: Buy this article Rent this article Subscribe to the JAMA journal
Phase I and pharmacokinetic (PK) study of dasatinib (D) and cetuximab (C) in patients (pts) with advanced solid malignancies
Authors: T. M. Feinstein, S. Agrawal, R. G. Stoller, M. J. Egorin, A. Argiris
Journal: Journal of Clinical Oncology (2009)

3540 Background: D is a small molecule inhibitor of several kinases, including SRC. SRC can potentiate Epidermal Growth Factor Receptor (EGFR) signaling and is implicated in resistance to EGFR inhibitors. Combined inhibition of EGFR and SRC may lead to improved therapeutic effect. We evaluated the combination of D and C, a chimeric IgG1 monoclonal anti-EGFR antibody. Methods: Eligible pts had advanced solid malignancies treated with any number of prior regimens but without EGFR or SRC inhibitors, ECOG performance status 0–2, QTc interval on baseline EKG &lt;450 msec, and adequate laboratory parameters. C was administered i.v as a loading dose of 400 mg/m 2 on cycle 1, day 1 and then weekly at 250 mg/m 2 on days 1, 8 and 15. D was administered orally, once daily, on a continuous schedule, on days 1–21. We used a standard up-and-down dose escalation scheme to assign pts on 3 dose levels (DL): 1- 100 mg QD, 2- 150 mg, 3- 200 mg. PK studies of D were performed on days 0 (prior to starting C) and 15 of cycle 1. Results: 25 pts (DL 1, 3 pts; DL 2; 19 pts; DL 3; 3 pts) were enrolled; 15 male; median age 62; median prior regimens: 2 (range: 0–5). Pts received a median of 2 cycles of D plus C (range: 1–15). 3 pts developed dose-limiting toxicities (DLT): 1 at DL 2 (headache; HA) and 2 at DL 3 (HA and nausea). Thus, MTD was reached at DL 2. DL 2 was expanded by an additional 12 pts to obtain further clinical and PK data. PK parameters (AUC and T-1/2) of D were comparable when given alone or in combination with C. Grade 3–4 toxicities in &gt; 2 pts included: dyspnea (4), vomiting (4), nausea (3), allergic reactions (3), HA (3) and anemia (3). 21 pts developed HA (grade 1, 8 pts; grade 2, 10 pts). HA occurred after the loading of C, and took a median of 2 days to resolve. Pleural effusion developed in 4 pts (grade 2, 3 pts; grade 3, 1 pt) after 2–5 months of treatment. In 17 evaluable pts, there were no objective responses; 9 pts had stable disease: salivary gland cancer (3), thyroid (2), sarcoma (1), unknown primary (1), esophagus (1), and NSCLC (1). Conclusions: D 150 mg plus C was well tolerated, but early-onset HA was frequent. C administration did not affect D PK. We plan to treat 6 additional pts starting D 3 days after the C loading dose in an attempt to ameliorate early-onset HA. A phase II trial of C plus D in head and neck cancer is planned. [Table: see text]
High spatial endothelial shear stress gradient independently predicts site of acute coronary plaque rupture and erosion
Authors: Vikas Thondapu, Chris Mamon, Eric K W Poon, Osamu Kurihara, Hyung Oh Kim, Michele Russo, Makoto Araki, Hiroki Shinohara, Erika Yamamoto, Jouke Dijkstra, Mark Tacey, Hang Lee, Andrew Ooi, Peter Barlis, Ik-Kyung Jang
Journal: Cardiovascular Research (2020)

Abstract Aims To investigate local haemodynamics in the setting of acute coronary plaque rupture and erosion. Methods and results Intracoronary optical coherence tomography performed in 37 patients with acute coronary syndromes caused by plaque rupture (n = 19) or plaque erosion (n = 18) was used for three-dimensional reconstruction and computational fluid dynamics simulation. Endothelial shear stress (ESS), spatial ESS gradient (ESSG), and oscillatory shear index (OSI) were compared between plaque rupture and erosion through mixed-effects logistic regression. Lipid, calcium, macrophages, layered plaque, and cholesterol crystals were also analysed. By multivariable analysis, only high ESSG [odds ratio (OR) 5.29, 95% confidence interval (CI) 2.57–10.89, P &amp;lt; 0.001], lipid (OR 12.98, 95% CI 6.57–25.67, P &amp;lt; 0.001), and layered plaque (OR 3.17, 95% CI 1.82–5.50, P &amp;lt; 0.001) were independently associated with plaque rupture. High ESSG (OR 13.28, 95% CI 6.88–25.64, P &amp;lt; 0.001), ESS (OR 2.70, 95% CI 1.34–5.42, P = 0.005), and OSI (OR 2.18, 95% CI 1.33–3.54, P = 0.002) independently associated with plaque erosion. ESSG was higher at rupture sites than erosion sites [median (interquartile range): 5.78 (2.47–21.15) vs. 2.62 (1.44–6.18) Pa/mm, P = 0.009], OSI was higher at erosion sites than rupture sites [1.04 × 10−2 (2.3 × 10−3–4.74 × 10−2) vs. 1.29 × 10−3 (9.39 × 10−5–3.0 × 10−2), P &amp;lt; 0.001], but ESS was similar (P = 0.29). Conclusions High ESSG is independently associated with plaque rupture while high ESSG, ESS, and OSI associate with plaque erosion. While ESSG is higher at rupture sites than erosion sites, OSI is higher at erosion sites and ESS was similar. These results suggest that ESSG and OSI may play critical roles in acute plaque rupture and erosion, respectively.
A randomized trial of personalized peptide vaccine (PPV) plus low-dose estramustine (EMP) versus full-dose EMP in patients with hormone-refractory prostate cancer
Authors: M. Noguchi, H. Uemura, H. Kumon, Y. Nasu, Y. Hirao, K. Matsuoka, T. Kakuma, A. Yamada, K. Itoh
Journal: Journal of Clinical Oncology (2009)

3007 Background: Personalized selection of the right peptides for each patient could be a novel peptide-based immunotherapy for boosting anti-cancer immunity in many patients (pts). This randomized study evaluated the anti-tumor effect and safety of PPV plus a low-dose EMP compared with full dose EMP for patients with hormone-refractory prostate cancer (HRPC). Methods: This was a randomized (1:1), open labeled, cross-over study in pts with HRPC. Pts were randomized to arm A; PPV plus low-dose EMP (280 mg/day) or arm B; full dose EMP (560 mg/day) according to age and PSA levels. In arm A, prevaccination plasma were measured for their IgG levels for each of the 14 or 12 candidate peptides which can induce HLA-A2 or A24-restricted CTL activity against cancer cells followed by biweekly subcutaneous administration of the top four peptides (3mg each) showing the strongest IgG responses. Disease progression (PD) was defined as three consecutive and 125% increase from baseline PSA levels at least two weeks apart or objective PD by RECIST criteria. After PD, pts were treated with the opposite regime. The primary endpoint was progression-free survival (PFS), and the secondary endpoints were overall survival and toxicity. The planned sample size was 80. Results: A total of 54 pts from 4 institutions were enrolled between June 2006 and December 2008. The accural into arms A and B was 27 and 27 pts, respectively. The main pts characteristics are (arm A/B): median age 71/69 years, EOCG performance status 0/1 96%/4% and 100%/0%, HLA A2/A24/A2A24 40%/32%/28% and 54%/27%/19%, median PSA 27/25 ng/ml, and metastatic HRPC 96%/85%. All pts were evaluable for their response at the time of interim analysis. The personalized peptide vaccination was well tolerated with no major adverse effects. Increased levels of IgG responses to the vaccinated peptides were observed in 20 of 23 (87%) patients tested. The median PFS time was 246 days in the arm A group and 85 days in the arm B, respectively. The PFS time in the arm A was statistically longer than that in the arm B (log-rank test: p = 0.0007, hazard ratio: 0.27, 95%CI: 0.12 to 0.615). Conclusions: PPV plus low-dose EMP was associated with improvement in PSA-based PFS compared to full-dose EMP alone. No significant financial relationships to disclose.
Targeting lactate dehydrogenase A (<i>LDHA</i>) exerts antileukemic effects on T‐cell acute lymphoblastic leukemia
Authors: Haizhi Yu, Yafei Yin, Yifang Yi, Zhao Cheng, Wenyong Kuang, Ruijuan Li, Haiying Zhong, Yajuan Cui, Lingli Yuan, Fanjie Gong, Zhihua Wang, Heng Li, Hongling Peng, Guangsen Zhang
Journal: Cancer Communications (2020)

Abstract Background T‐cell acute lymphoblastic leukemia (T‐ALL) is an uncommon and aggressive subtype of acute lymphoblastic leukemia (ALL). In the serum of T‐ALL patients, the activity of lactate dehydrogenase A ( LDHA ) is increased. We proposed that targeting LDHA may be a potential strategy to improve T‐ALL outcomes. The current study was conducted to investigate the antileukemic effect of LDHA gene‐targeting treatment on T‐ALL and the underlying molecular mechanism. Methods Primary T‐ALL cell lines Jurkat and DU528 were treated with the LDH inhibitor oxamate. MTT, colony formation, apoptosis, and cell cycle assays were performed to investigate the effects of oxamate on T‐ALL cells. Quantitative real‐time PCR (qPCR) and Western blotting analyses were applied to determine the related signaling pathways. A mitochondrial reactive oxygen species ( ROS ) assay was performed to evaluate ROS production after T‐ALL cells were treated with oxamate. A T‐ALL transgenic zebrafish model with LDHA gene knockdown was established using CRISPR/Cas9 gene‐editing technology, and then TUNEL, Western blotting, and T‐ALL tumor progression analyses were conducted to investigate the effects of LDHA gene knockdown on T‐ALL transgenic zebrafish. Results Oxamate significantly inhibited proliferation and induced apoptosis of Jurkat and DU528 cells. It also arrested Jurkat and DU528 cells in G0/G1 phase and stimulated ROS production (all P &lt; 0.001). Blocking LDHA significantly decreased the gene and protein expression of c‐Myc , as well as the levels of phosphorylated serine/threonine kinase (AKT) and glycogen synthase kinase 3 beta (GSK‐3β) in the phosphatidylinositol 3′‐kinase (PI3K) signaling pathway. LDHA gene knockdown delayed disease progression and down‐regulated c‐Myc mRNA and protein expression in T‐ALL transgenic zebrafish. Conclusion Targeting LDHA exerted an antileukemic effect on T‐ALL, representing a potential strategy for T‐ALL treatment.