tbuckley/cabot-search huggingface dataset:
Resetting amino acid metabolism of cancer cells by ATB0,+-targeted nanoparticles for enhanced anticancer therapy
Authors: Longfa Kou, Xinyu Jiang, Yingying Tang, Xing Xia, Yingtao Li, Aimin Cai, Hailun Zheng, Hailin Zhang, Vadivel Ganapathy, Qing Yao, Ruijie Chen
Journal: Bioactive Materials (2021)

Reprogramed cellular metabolism is one of the most significant hallmarks of cancer. All cancer cells exhibit increased demand for specific amino acids, and become dependent on either an exogenous supply or upregulated de novo synthesis. The resultant enhanced availability of amino acids supports the reprogramed metabolic pathways and fuels the malignant growth and metastasis of cancers by providing energy and critical metabolic intermediates, facilitating anabolism, and activating signaling networks related to cell proliferation and growth. Therefore, pharmacologic blockade of amino acid entry into cancer cells is likely to have a detrimental effect on cancer cell growth. Here we developed a nanoplatform (LJ@Trp-NPs) to therapeutically target two transporters, SLC6A14 (ATB0,+) and SLC7A5 (LAT1), that are known to be essential for the sustenance of amino acid metabolism in most cancers. The LJ@Trp-NPs uses tryptophan to guide SLC6A14-targeted delivery of JPH203, a high-affinity inhibitor of SLC7A5. In the process, SLC6A14 is also down-regulated. We tested the ability of this strategy to synergize with the anticancer efficacy of lapatinib, an inhibitor of EGFR/HER1/HER2-assocated kinase. These studies show that blockade of amino acid entry amplifies the anticancer effect of lapatinib via interference with mTOR signaling, promotion of apoptosis, and suppression of cell proliferation and metastasis. This represents the first study to evaluate the impact of amino acid starvation on the anticancer efficacy of widely used kinase inhibitor.
Abstract 2403: Pyruvate dehydrogenase mediates chemo-resistance in pancreatic cancer
Authors: Fouzia Zayou, Chintan Chheda, Adrian Lim, Omer H. Elmadbouh, Stephen J. Pandol, Mouad Edderkaoui
Journal: Cancer Research (2021)

Abstract Background: Resistance of pancreatic ductal adenocarcinoma (PDAC) to current treatment regimens contributes to the dismal prognosis for patients diagnosed with the disease. Accumulated evidence indicates that metabolic alterations may play a role in chemo-resistance. In this project, we investigated the role of pyruvate dehydrogenase Alpha1 (PDHA1) in chemo-resistance. Methods: Wild type and Gemcitabine-resistant pancreatic cancer cell lines MIA PaCa-2, HPAF-II, and UN-KPC-961 were used. Mitochondrial respiration, ATP production and glycolytic activities were measured by seahorse. PDHA1 was overexpressed or its activity inhibited by over-expressing PDHA1 kinase in these cells and cancer cell survival was measured by MTT and cancer stemness measured by Western and RT-PCR. PDHA1 level was measured in human and mouse PDAC tissues. Results: Seahorse analysis showed a significantly lower mitochondrial activity, ATP production, and increased glycolytic activity and lactate production in gemcitabine-resistant compared to non- resistant pancreatic cancer cells. PDHA1 mRNA and protein levels were less in gemcitabine-resistant cancer cells compared to non-resistant cells. PDHA1 levels were less in human PDAC tissues from patients and mice who developed resistance to chemotherapy. PDHA1 over-expression in gemcitabine-resistant cancer cells reversed resistance to chemotherapy, decreased cancer cell survival and decreased expression of cancer stemness markers. Whereas, PDHA1 inhibition by over-expressing PDHA1 kinase, in non-resistant cancer cells, induced resistance to chemotherapy, increased cancer cell survival and increased expression of cancer stemness markers. We found that inhibition of histone deacetylase (HDAC) (class 1 and 2) increased transcription level of PDHA1 and reversed chemo-resistance. Conclusion: We show that PDHA1 is a regulator of chemo-resistance in pancreatic cancer cells. PDHA1is a novel target for treating chemo-resistant PDAC. Citation Format: Fouzia Zayou, Chintan Chheda, Adrian Lim, Omer H. Elmadbouh, Stephen J. Pandol, Mouad Edderkaoui. Pyruvate dehydrogenase mediates chemo-resistance in pancreatic cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 2403.
Abstract 1070: SCR6106, an oral and brain penetrant SERD demonstrated anti-tumor activities <i>in vitro</i> and <i>in vivo</i>
Authors: Feng Zhou, Lei Liu, Guimei Yang, Peng Gu, Liting Xue, Wenqing Yang, Ping Chen, Renhong Tang
Journal: Cancer Research (2021)

Abstract Benefits of endocrine therapy in treating hormone receptor (HR)-positive (HR+) BC are well recorded in clinic. However, ~40% to 50% of HR+ patients eventually developed to endocrine resistance and disease relapsed. Fulvestrant, a selective estrogen receptor degrader (SERD) is approved to treat HR+ metastatic breast cancer in patients with disease progression after endocrine therapy. However, due to its poor bioavailability, it is given by intramuscular injection, which makes inconvenience in administration. Additionally, approximately 14% of hormone positive patients with advanced breast cancer are diagnosed with brain metastases, while, at present, there are no FDA-approved systemic therapies for the treatment of breast cancer brain metastases. Therefore, to develop a new generated oral and brain-penetrant SERD to overcome these challenges is believed to be needed. SCR6106, discovered and currently being developed by Simcere, is a novel, potent, orally delivered and non-steroidal SERD that both antagonizes and degrades ERα. SCR6106 showed high potency on inducing ERα protein degradation (DC50=0.29 nM) and anti-proliferation (IC50=0.43 nM) in MCF7 cells. In addition, SCR6106, showed high activities on ERα degradation and anti-proliferation in a panel of ER+ breast cancer cell lines. Meanwhile, ER target genes transcription were evaluated and SCR6106 exhibit strong suppressive phenotype in T-47D. SCR6106 demonstrated more potent than fulvestrant on anti-tumor growth in vivo. In MCF7 xenograft model, SCR6106 at 3 mpk QD induced 113% tumor growth inhibition (TGI), compared to fulvestrant 56.8% TGI at 250 mpk. Compared to fulvestrant, SCR6106 demonstrated stronger ERα degradation and inhibition of ER target genes transcription in tumors, which was consistent with anti-tumor activities. SCR6106 displayed good oral bioavailability in multiple pre-clinical species, which supports its oral administration in human. Significantly, SCR6106 possess a high BBB permeability, the B/P ratio is more than 4 in pre-clinical species. The exposure of SCR6106 observed in mouse brain is much higher than the IC90 value of anti-proliferation (MCF7), and SCR6106 demonstrated anti-tumor activities in a MCF-7 intracranial tumor xenograft model. In conclusion, SCR6106 is a novel, potent and oral SERD, which demonstrated anti-tumor activities in vitro and in vivo. It showed high potential ability to cross the blood-brain barrier, and could be used to treat HR+ patients with brain metastasis. Citation Format: Feng Zhou, Lei Liu, Guimei Yang, Peng Gu, Liting Xue, Wenqing Yang, Ping Chen, Renhong Tang. SCR6106, an oral and brain penetrant SERD demonstrated anti-tumor activities in vitro and in vivo [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 1070.
Abstract 2938: APOBEC3B and TKI resistance in EGFR mutant lung cancer
Authors: Deborah Caswell, Manasi Mayekar, Emily Law, William Hill, Eva Gronroos, Reuben Harris, Trever Bivona, Charles Swanton
Journal: Cancer Research (2021)

Abstract Lung cancer is the leading cause of cancer-related deaths worldwide. EGFR mutations, which account for about 25% of lung cancer cases, are more commonly associated with lung cancer in never smokers. Although response rates to EGFR tyrosine kinase inhibitors (TKI) used as a first line therapy are high, acquired resistance inevitably occurs. Elevated tumor mutation burden in EGFR mutant lung cancer is associated with a shorter progression free survival, and worse overall survival with both first and second generation TKIs. Increasing our understanding of drivers of mutagenesis in lung cancer is critical in our efforts to prevent tumor reoccurrence and resistance. APOBEC-driven mutagenesis has been shown to occur in multiple cancer types including lung adenocarcinoma. Using the TCGA and TRACERx datasets we have demonstrated that APOBEC3B is significantly upregulated when compared with other APOBEC family members in EGFR mutant lung adenocarcinoma, and that the APOBEC mutation signature is enriched in a subset of patients with EGFR mutant lung adenocarcinoma. To model APOBEC mutagenesis in lung cancer, we have developed a novel lung cancer mouse model, by crossing the ROSA26LSL-APOBEC3B (A3B) mouse model with several different EGFR mutant mouse models. Using these models, we find that APOBEC3B expression is selected for post-TKI and contributes to resistance to TKI therapy. Citation Format: Deborah Caswell, Manasi Mayekar, Emily Law, William Hill, Eva Gronroos, Reuben Harris, Trever Bivona, Charles Swanton. APOBEC3B and TKI resistance in EGFR mutant lung cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 2938.
Abstract 3188: β-catenin in metastatic ovarian cancer cells mediates polyploidy induced by tumor-associated macrophages
Authors: Sally Kit Yan To, Jue Shi, Alice Sze Tsai Wong
Journal: Cancer Research (2021)

Abstract Tumor-associated macrophages (TAMs) closely associate with tumor progression and could promote metastatic spread. However, how TAMs interact with individual cancer cell in the heterogeneous cancer cell population is unknown. Here, using an isogenic cell line pair with different metastatic potentials, we showed that highly metastatic (HM) cells, but not non-metastatic (NM) cells, could skew the co-cultured macrophages to TAM-like phenotypes. Single-cell tracking by time lapse imaging revealed that during co-culture, macrophages could induce failed cytokinesis in a subset of HM cells. Subsequent analyses suggested that this induction could be facilitated by direct cell-cell contact. We further identified that the cell-surface metadherin expression induced by β-catenin in HM cells is involved in this induction, while surface CEACAM1 expressed on macrophages could be responsible for the interaction with metadherin. HM-macrophage interaction promotes macrophage secretion of the cytokine CCL3, a strong chemoattractant for monocytes, which may further amplify the interaction. In an orthotopic humanized mice model, knockdown of β-catenin in HM cells reduced tumor burden as well as the number of tumor-infiltrating CD163+ TAMs. These findings demonstrate a positive feedback loop between macrophages and a subpopulation of cancer cells mediated by β-catenin to enhance the metastatic cascade (This work is supported by RGC GRF grant 17141216). Citation Format: Sally Kit Yan To, Jue Shi, Alice Sze Tsai Wong. β-catenin in metastatic ovarian cancer cells mediates polyploidy induced by tumor-associated macrophages [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 3188.
Clinical Images: Diffuse systemic sclerosis, skin bleaching, and telangiectasia
Authors: Cindy Flower
Journal: Arthritis & Rheumatology (2021)

This Afro-Caribbean female was diagnosed with diffuse systemic sclerosis in 2004 at age 15 when she presented with Raynaud’s, sclerodactyly and diffuse sclerodermatous skin with pigmentary changes. Images A and B at time of diagnosis revealed focal areas of depigmentation at the inner corner of both eyes, patchy hyperpigmentation of the upper eyelids and hyperpigmentation with loss of wrinkling of the skin of the neck.
Abstract 1803: Newly emerged immunogenic neoantigens enable to break the resistance of immune checkpoint inhibitors
Authors: Daisuke Sugiyama, Tomoaki Muramatsu, Takuro Noguchi, Yoshiki Akatsuka, Hiroyoshi Nishikawa
Journal: Cancer Research (2021)

Abstract Immune checkpoint inhibitors (ICIs) and other cancer immunotherapies resurge T cell responses that target tumor antigens expressed by cancer cells, particularly tumor neoantigens derived from genetic alterations. However, tumors establish immune escape mechanisms during tumor development and progression, including the loss of pre-existing tumor antigens and impaired T cell responses. In the last decade, various strategies to overcome the immune escape mechanisms have been investigated in the clinic to achieve a cure for cancer. Here, we show that a newly emerged immunogenic neoantigen changes the tumor environment and inhibits tumor growth. To develop animal models, we employed a Tet-on gene expression system, in which immunogenic neoantigens including chicken ovalbumin (OVA) and human cancer-testis antigen NY-ESO-1 were newly emerged upon doxycycline (Dox) treatment. MC-38 (colorectal cancer) inducing OVA, CT26 (colorectal cancer) inducing NY-ESO-1 and B16 (melanoma) inducing NY-ESO-1 were developed, and these cell lines were administered into mice. Induction of these model neoantigens by Dox treatment after tumor establishment (approximately 8~10 mm) significantly inhibited tumor growth. The antitumor effects were not observed in nude mice lacking T cells or CD8+ T-cell depleted mice, indicating an important role of CD8+ T cells. Furthermore, PD-1/PD-L1 blockade further enhanced CD8+ T cell responses against the newly emerged immunogenic neoantigens, resulting in a far stronger tumor growth inhibition. We then propose that newly-emerged immunogenic neoantigens are sufficient to induce antitumor effects that can overcome immune escape mechanisms in the tumor microenvironment, thereby inhibiting tumor growth and that induction of immunogenic tumor neoantigens is a novel strategy to overcome the resistance to ICI therapy. Citation Format: Daisuke Sugiyama, Tomoaki Muramatsu, Takuro Noguchi, Yoshiki Akatsuka, Hiroyoshi Nishikawa. Newly emerged immunogenic neoantigens enable to break the resistance of immune checkpoint inhibitors [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 1803.
Abstract 9885: Progressive Worsening of Left Ventricular Size and Function is Associated with Increased Ventricular Arrhythmia Burden Among Patients Undergoing Cardiac Resynchronization Therapy
Authors: Daniel J Friedman, Robert K Altman, Mi Young Park, Mary Orencole, Carmella M Britt, Michael H Picard, Jeremy N Ruskin, Jagmeet P Singh, Edwin K Heist
Journal: Circulation (2011)

Background Ventricular tachycardia and fibrillation (VT/VF) may increase as systolic heart failure worsens. The effect of progressive decline in LV function despite cardiac resynchronization therapy (CRT) on the incidence of VT/VF has not been described. Methods The relationships between changes in LV size and function and incident VT/VF were analyzed in 115 patients who underwent CRT implant. Baseline and 6 month post-CRT echocardiograms were used to determine LV remodeling. Progressors were defined by both increase in LV end-systolic dimension (LVESD) and decrease in left ventricular ejection fraction (LVEF) after CRT. Responders were defined as &gt;5% absolute increase in LVEF or 10% decrease in LVESD, and all other patients were defined as Non-Progressors. The primary endpoint was time to VT/VF requiring device therapy for 5 years after CRT implant. Results At 6 months, 67% of patients were Responders, 22% were Non-Progressors and 11% were Progressors. There were no baseline differences between the 3 groups in medications, comorbidities, LVEF, LVESD, cardiomyopathy type, NYHA class, prior VT/VF, or renal function. Progressors were at significantly increased risk of VT/VF compared to either Non- Progressors (p=0.0431) or Responders (p = 0.0018)(figure). There was no significant difference in VT/VF comparing Non-Progressors to Responders (p=0.4151). Conclusions CRT patients with worsening in both LV size and function 6 months after CRT placement have a significantly increased incidence of VT/VF compared to patients with no change or improvements in these parameters. “Progressors” despite CRT thus represent a high-risk population for VT/VF who warrant close follow-up.
Abstract 283: Target cell-derived, G401-CLENs for selective delivery of model therapeutics to rhabdoid tumors
Authors: Lindsay Bourdeau, Carlos Cruz, Taylor Williams
Journal: Cancer Research (2021)

Abstract One of the rarest and most aggressive pediatric cancers to date is the malignant rhabdoid tumor (MRT), maintaining a survival rate of 16%. Considered a renal cancer, approximately 20-25 new cases are diagnosed in the USA each year, with the average age of diagnosis being about 11 months old. Conventional strategies for treating MRT are limited due to several factors including off-target associated toxicities, patient population, age, metastasis to brain tissue, and diminished survival rates. CLENs (cell membrane lipid-extracted nanoliposomes), a novel drug delivery system, was previously developed and evaluated for selective delivery of cytotoxic drug agents to breast cancer cells and compared to more conventional liposomes. The purpose of this investigation was to optimize and characterize G401-CLENs for selective targeting and delivery of model payloads to a cellular model of rhabdoid tumors. The MRT cell line (G-401 [G401] (ATCC® CRL-1441™) was cultured in McCoy's 5A Medium (ATCC® 30-2007™), supplemented by 10% FBS. The G401 cellular lipid materials (otherwise known as lipid extracts (LE)) were derived from G401 cells. Follow up studies include the incorporation of G401-LE in liposomes to form G401-CLENs. For development, special consideration was given to distinct determinants of targeting (i.e., particle size and zeta potential) and cellular uptake by G401-CLENs. Other analyses include a comparison of delivery of model and functional siRNA (BRD9 Silencer Select Pre-designed, siRNA ID s35295, Ambion) to G401 target cells using G401-CLENs, and conventional nano-preparations in vitro. G401-LE cell membrane components were extracted from rhabdoid G401 cells. On-going physiochemical characterization studies of G401-CLENs and functional in vitro and fluorescence microscopic analyses are currently underway. Citation Format: Lindsay Bourdeau, Carlos Cruz, Taylor Williams. Target cell-derived, G401-CLENs for selective delivery of model therapeutics to rhabdoid tumors [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 283.
Infantile Hepatic Hemangiomas
Authors: Coen T. Butters, Margot Nash
Journal: New England Journal of Medicine (2021)

A 16-day-old girl who had not returned to her birth weight was brought to the emergency department with lethargy. She was found to have marked hepatomegaly, and ultrasonography showed numerous rounded hypoechoic lesions in the liver. A diagnosis of infantile hepatic hemangiomas was made.
Promoting Inclusion of Members of Racial and Ethnic Minority Groups in Cancer Drug Development
Authors: Lola Fashoyin-Aje, Julia A. Beaver, Richard Pazdur
Journal: JAMA Oncology (2021)

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 Oncology HomeNew OnlineCurrent IssueFor Authors Podcast 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) 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 Oncology journal
Robot-assisted partial nephrectomy for ruptured angiomyolipomas: A multi institutional series
Authors: A. Uleri, P. Diana, G. Lughezzani, M. Lazzeri, P. Casale, F. Porpiglia, D. Amparore, P. Verri, G. Rosiello, A. Mottrie, G. De Naeyerd, R. De Grooted, J. Porter, N. Buffi
Journal: European Urology (2021)
Functional and sexual symptoms improvement after Rezum water vapor therapy for the treatment of LUTS/BPE: 3-year results from the first European observational study
Authors: G. Siena, A. Cocci, J.I.M. Salamanca, G. Ferrari, D. Maruzzi, F. Varvello, G.I. Russo, P. Spatafora, B. Somani, M.E. Noureldin, A. Emara, D. Whiting, R.G. Hindley, L. Cindolo
Journal: European Urology (2021)
BMA will support legal fight of whistleblowing junior doctor Chris Day
Authors: Abi Rimmer
Journal: BMJ (2021)

The BMA will back the legal case of a junior doctor, Chris Day, as part of plans to improve its support for whistleblowers.

Day has previously claimed that the BMA initially offered support for his case but then withdrew it.1

He fought a four year legal battle to have his claims of unfair dismissal heard after raising concerns in 2014 about understaffing and safety at the intensive care unit of the Queen Elizabeth Hospital in Woolwich, London, where he was a specialist registrar in emergency medicine.2 He claimed that after he repeated the concerns to Health Education England (HEE) it deleted his training …
HTLV-1関連成人T細胞白血病/リンパ腫患者の管理における放射線治療
Authors: Simone Charles B., C Morris John, M Stewart Donn, E Urquhart Nicole, E Janik John, J Kreitman Robert, Lita Elena, Conlon Kevin, Wharfe Gilian, Waldmann Thomas A. x, Kaushal Aradhana
Journal: Blood (2012)