tbuckley/cabot-search huggingface dataset:
Abstract 660: Combination of mTOR kinase inhibitors with Src inhibitors in PTEN-<i>mt</i> prostate cancer cells
Authors: Yao Dai, Dietmar Siemann
Journal: Cancer Research (2020)

Abstract Although Src inhibitors are able to suppress malignant functions, their clinical outcomes are modest for the treatment of advanced prostate cancer, many of which harbor mutated PTEN. mTOR pathway is commonly hyperactivated in prostate cancer due to frequent PTEN mutation, and it is known that two mTOR complexes are both critical in prostate cancer progression. However, the functional role of mTOR kinase in Src inhibitor-mediated response remains unknown. In the current study, we combined mTOR kinase inhibitor AZD8055 and Src inhibitor dasatinib to evaluate functional behaviors in PTEN-deleted prostate cancer cells. Gene silencing was achieved by siRNA or shRNA transfection. Cell proliferation and clonogenic survival were performed by MTT and colony formation assay, respectively. “Wound-healing” scratch assay was conducted to monitor cell migration, and Matrigel-based transwell assay was applied to assess cell invasion. Protein expression was detected by Western blotting. We found that in PTEN-mt cells, C4-2B showed greater expression of p-Akt, p-S6, p-4EBP1 and p-eIF4E, all of which are mTOR complexes downstream components. Such molecular profile is consistent with functional observation that C4-2B cells are more resistant to dasatinib. Interestingly, single knockdown of either 4EBP1, S6RP or AKT showed little effects of inhibiting cell survival, while double knockdown of both 4EBP1 and AKT, cell survival was significantly inhibited. Consistently, two agents together showed significantly greater inhibition on proliferation and clonogenic survival than either single agent. Such combination effects were either additive or synergistic depending on the cell types, as reflected by combination index calculation. In addition, cell migration and invasion were inhibited in a greater extent by AZD8055 plus dasatinib, compared to either treatment alone. At the molecular level, co-targeting mTOR and Src kinases leads to strong inhibition of mTOR and Src pathways, such as FAK, Akt, S6RP and 4E-BP1. These data indicate that adding AZD8055 to dasatinib may achieve better treatment outcomes in PTEN-mt prostate cancer models. Such combination modality hold potential for future development as a novel strategy for PTEN-mutated prostate cancer patients who are less responsive to Src inhibitors. Citation Format: Yao Dai, Dietmar Siemann. Combination of mTOR kinase inhibitors with Src inhibitors in PTEN-mt prostate cancer cells [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 660.
Demystifying the Role of Tumor Mutational Burden for Immunotherapy Selection—Reply
Authors: Saiama N. Waqar, Ramaswamy Govindan
Journal: JAMA Oncology (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 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
Abstract 3691A: Targeting MARK2-HDAC-YAP signaling to overcome paclitaxel resistance in PDAC
Authors: Yongji Zeng, Yuanhong Chen, Jixin Dong
Journal: Cancer Research (2020)

Abstract Nanoparticle albumin-bound (Nab)-paclitaxel (taxol) combined with gemcitabine has been approved as a first-line chemotherapy for advanced pancreatic ductal adenocarcinoma (PDAC) patients. However, the response rate is still very low due to the occurrence of drug resistance and attempts in reversing the resistance have not been successful in the clinic. MARK (microtubule affinity-regulating kinase) proteins (MARK1-4) are critical for microtubule dynamics by modulating MAPs (microtubule-associated proteins). They are members of the AMPK/Snf1 family and control cell polarity and asymmetric cell division. Dysregulation of MARKs has also been associated with pathological conditions such as cancer and Alzheimer disease. Several recent studies showed that MARK family members are important regulators of Hippo-YAP (Yes-associated protein) signaling, which is critical in cancer development, drug resistance, and stem cell biology. Through Phos-tag-based kinome-wide screens, we identified MARK2 as a critical determinant for mitotic progression and paclitaxel chemosensitivity. MARK2 is phosphorylated by cyclin-dependent kinase 1 (CDK1) during paclitaxel-induced mitotic arrest and normal mitosis. MARK2 inhibition did not affect growth under normal conditions, but greatly sensitized PDAC cells to paclitaxel-induced apoptosis. Mechanistically, our findings also suggest that MARK2 controls paclitaxel chemosensitivity by regulating class IIa HDACs (histone deacetylase). MARK2 directly phosphorylates HDAC4 on multiple sites upon paclitaxel treatment. Inhibition (with knockdown or inhibitors) of HDACs significantly enhanced paclitaxel-induced cell death in a MARK2-phosphorylation dependent manner in PDAC cells. MARK2-phosphorylated HDAC4 positively regulates YAP (the transcriptional coactivator of the Hippo pathway) activity and controls expression of YAP target genes induced by paclitaxel. MARK2, class IIa HDACs, and YAP expression levels are upregulated and positively correlated in PDAC patients. Importantly, combination of HDAC inhibition (Vorinostat/SAHA, FDA-approved) and paclitaxel overcomes paclitaxel-resistance in preclinical PDAC animal models. Together, our findings reveal the MARK2-HDAC-YAP axis as a druggable target for overcoming paclitaxel resistance in PDAC. Citation Format: Yongji Zeng, Yuanhong Chen, Jixin Dong. Targeting MARK2-HDAC-YAP signaling to overcome paclitaxel resistance in PDAC [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 3691A.
Custom insoles versus sham and GP-led usual care in patients with plantar heel pain: results of the STAP-study - a randomised controlled trial
Authors: Nadine Rasenberg, Sita M A Bierma-Zeinstra, Lars Fuit, Michael Skovdal Rathleff, Amy Dieker, Peter van Veldhoven, Patrick J E Bindels, Marienke van Middelkoop
Journal: British Journal of Sports Medicine (2020)

Objectives To compare custom-made insoles to sham insoles and general practice (GP)-led usual care in terms of pain at rest and during activity at 12 weeks follow-up in individuals with plantar heel pain. Methods In this randomised clinical trial 185 patients aged 18 to 65 years, with a clinical diagnosis of plantar heel pain for at least 2 weeks, but no longer than 2 years were recruited. Patients were randomly allocated into three groups: (1) GP-led treatment, plus an information booklet with exercises (usual care; n=46), (2) referral to a podiatrist for treatment with a custom-made insole plus an information booklet with exercises (custom-made insole; n=70) and (3) referral to a podiatrist and treatment with a sham insole plus an information booklet with exercises (sham insole; n=69). As well as the primary outcome of pain severity (11-point Numerical Rating Scale) we used the Foot Function Index (0 to 100) as a secondary outcome. Results Of 185 randomised participants, 176 completed the 12-week follow-up. There was no difference in pain or function between the insole and the sham groups at 12 weeks. Participants in the GP-led usual care group reported less pain during activity at 12 weeks, (mean difference (MD) 0.94, 95% CI 0.23 to 1.65), less first step pain (MD 1.48, 95% CI 0.65 to 2.31), better function (MD 7.37, 95% CI 1.27 to 13.46) and higher recovery rates (RR 0.48, 95% CI 0.24 to 0.96) compared with participants in the custom insole group. Conclusions Referral to a podiatrist for a custom-made insole does not lead to a better outcome compared to sham insoles or compared to GP-led usual care. Trial registration number NTR5346.
Abstract 3402: BCAT1 as a druggable target in immuno-oncology
Authors: Adonia E. Papathanassiu, Francesca Lodi, Hagar Elkafrawy, Michelangelo Certo, Hong Vu, Jeong Hun Ko, Jacques Behmoaras, Claudio Mauro, Diether Lambrechts
Journal: Cancer Research (2020)

Abstract BCAT1, the enzyme responsible for the reversible transamination of leucine in the cytosol, has recently been implicated in the development and growth of various types of cancer. The limited expression of BCAT1 in adult tissues under physiological conditions suggests that the enzyme is a sensible target for drug development. To better understand the role of BCAT1 in cancer, we examined its gene expression at the single cell level (scRNAseq) in specimens obtained from lung, colorectal, breast, and ovarian cancer patients (n=36; &amp;gt;200,000 single cells). In those samples, Bcat1 gene expression was primarily associated with myeloid cells and fibroblasts with the exception of ovarian cancer in which robust Bcat1 presence was also seen in cancer cells. In tumor infiltrating lymphocytes (TILs), enrichment in Bcat1 gene expression was observed in exhausted CD4+ and CD8+ T cells compared to other T cell subtypes; this was independent of the cancer type examined. We speculated that inhibition of BCAT1 in TILs reverses exhaustion and has a therapeutic impact in cancer. In the syngeneic CT26 colon cancer model, combination treatment of a BCAT1 inhibitor (ERG245; ip administration of 5 mg/kg, given at days 7, 8 and 9 after tumor cell inoculation) and an anti-PD1 antibody (ab) (clone RMP1-14; ip administration given at days 7, 11, 14, and 18) led to eradication of established tumors. In the same model, limited treatment of large tumors (average size of ~600 mm3) with ERG245+anti-PD1 ab suppressed tumor growth and increased the frequency of CD8+ T cells expressing Granzyme B and IFNγ by ~50% compared to anti-PD1 monotherapy. Mechanistically, in vitro treatment of newly activated hCD8+ T cells with ERG245 impaired translocation of the lactate transporter MCT1 to the cell surface and increased the levels of intracellular lactate within 30 min of activation leading to upregulation of transcription factor ATF3. ERG245-driven metabolic reprogramming of CD8+ T cells towards an oxidative phenotype (increased OXPHOS) was also observed at 24h of treatment. Withdrawal of ERG245 restored intracellular lactate levels without reversing the metabolic reprogramming of the cells. We propose that these are elements of a mechanism that links temporal inhibition of BCAT1 to the rise of highly energetic CD8+ T cells with increased cytotoxicity and proliferative capacity in vitro and in vivo. Citation Format: Adonia E. Papathanassiu, Francesca Lodi, Hagar Elkafrawy, Michelangelo Certo, Hong Vu, Jeong Hun Ko, Jacques Behmoaras, Claudio Mauro, Diether Lambrechts. BCAT1 as a druggable target in immuno-oncology [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 3402.
Abstract 6685: A retrospective observational study of telomerase peptide immunotherapy in heavily treated solid cancer patients
Authors: Jonggwon Choi
Journal: Cancer Research (2020)

Abstract Background: Telomerase is an active enzyme that produces and maintains telomere which is located at the end of chromosomes. In general, telomere become shorter as the number of cells divide increases, leading to apoptosis. However, telomerase prolongs and maintains the length of the telomere so that tumor cells continue proliferation without cell death. When the telomerase is reduced, the telomere DNA is not produced and maintained and the chromosomes become shorter and shorter. Telomerase is not well observed in normal cells and known to act as a specific antigen by over-expression in various cencer cell types. The riavex(GV1001) which is 16 amino acid sequences from the telomere combines with HLA classI to induce an immune response through activates the CD4 T cell. Methods: We analyzed 50 patients who were injected riavex. The riavex was provided through the application for emergency medication from the korea food and drug administration. Most patient who were given riavex failed several standard chemotherapy. The administration methods was injected riavex 0.2mili-liter in intradermal three times at first week and one time at 2weeks, 3weeks, 4 weeks, 6 weeks and then once per 28 days. A total of 12 doses were given to each patient. After the end of the administration, we evaluated anti-tumor response by RECIST 1.1 and quality of life by EORTC QLO-C30 and EQ-5D. Results: Partial response was founded in one patient with renal cell carcinoma. The rest of the patients showed a stable or progress response. However, quality of life was significantly improved in 19 patient and fifteen of them have applied for re-treatment. Only three patients had a fever of more than 38 celsius degree and no significant side effects were observed in other patients Conclusion:, Riavex as a anti-cancer vaccine is relatively safe to heavily treated solid cancer patient and is assessed to improve quality of life, although the treatment response is not promising. Keywords: Telomerase, Riavex, Quality of life, Safety Citation Format: Jonggwon Choi. A retrospective observational study of telomerase peptide immunotherapy in heavily treated solid cancer patients [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 6685.
Elizabeth Ward: pioneer of organ donor cards
Authors: John Illman
Journal: BMJ (2020)

Credit: Kidney Care

Elizabeth Ward, the pioneer of organ donor cards, was a great fighter and a great charmer. This unlikely combination and her uncompromising resolve to save her son made her one of the most prominent healthcare crusaders in the last part of the 20th century.

Her son Timbo’s kidneys failed in 1970 when he was 12. Ward refused to accept his probable death and he went on to have three kidney transplantations, the last donated by his father, Nigel. His mother’s campaigning helped to buy him an unlikely 22 years of life. He died in 1987 aged 34.

Kidney transplantation was still in its infancy when he first became ill. The first UK operation was carried out in Edinburgh in 1960. In the 1970s and 1980s the procedure—to a far greater degree than today—was restricted to the lucky few.

The odds were further stacked against Elizabeth Ward’s campaign because of her sex and because doctors recoiled from lay people interfering in their world. But Ward’s entrance on to the public stage could not have been better timed.

Until the revolt of the “swinging sixties,” the …
Addressing Disparities in the Management of Obesity in Primary Care Settings
Authors: Thomas A. Wadden, Adam G. Tsai
Journal: New England Journal of Medicine (2020)

Approximately 90 million U.S. adults (42.4%) now live with obesity,1 which is disproportionately present in socioeconomically disadvantaged persons and affects 57% of Black women.1 Obesity increases the risk of many adverse health conditions, including cardiovascular disease, type 2 diabetes, multiple types of cancers, impaired quality of life, and (as recently discovered) complications from Covid-19.2,3 Despite this disease burden, the management of obesity in primary care settings has greatly lagged behind that of other chronic conditions. Only in the past decade has obesity been formally recognized as a disease rather than a perceived lifestyle choice, and reimbursement of behavioral and pharmacologic . . .
Abstract B26: The natural history of ovarian high-grade serous carcinoma from time effects of ovulation inhibition and progesterone clearance of p53-defective lesions
Authors: Tang-Yuan Chu, Na-Yi Yuan Wu, Jing Wang
Journal: Clinical Cancer Research (2020)

Abstract High-grade serous carcinoma (HGSC) is the most common and devastating type of ovarian cancer; its etiology, mechanism of malignant transformation, and origin remain controversial. Recent studies have identified secretory cells at the fimbria of the fallopian tube as the cell of origin of HGSC, initiating TP53 mutation, evolving to tubal precursor lesions, including “p53 signature” and serous tubal intraepithelial carcinoma (STIC), and metastasizing to the ovary as clinically evident ovarian cancer. The etiologic mechanisms associated with the known epidemiologic risk factors, i.e., ovulation and retrograde menstruation, have also been unveiled. Mutagens and transforming growth factors, such as reactive oxygen species and IGF axis proteins, as well as the apoptosis-rescuing protein hemoglobin are abundantly present in the ovulatory follicular fluid and peritoneum fluid, which bathes the fimbrial epithelium, and induces malignant transformation after repeated exposure. Meanwhile, in accordance with the proposed therapeutic effect of progesterone from studies on oral contraceptive (OC) use or term pregnancy, our recent study indicated that the p53-null tubal epithelial cells are selectively cleared by progesterone depending on its progesterone receptor (PR). In this report, by analyzing different time-effects of OC use or pregnancy in the prevention of ovarian cancer and by aligning them with the carcinogenic and therapeutic clearance concepts of ovulation and P4, as well as the fact of progressive loss of PR during tubal transformation, we deduced the natural history of ovarian HGSC. The natural history begins at the first ovulation and spans more than 30 years, taking 10 years from the normal tubal epithelium to the “p53 signature” status, another 15 years to PR(-) STIC, and a final 5+ years to HGSC. The estimated natural history may help understand the pathogenesis of HGSC and defines the window for early detection and chemoprevention. Citation Format: Tang-Yuan Chu, Na-Yi Yuan Wu, Jing Wang. The natural history of ovarian high-grade serous carcinoma from time effects of ovulation inhibition and progesterone clearance of p53-defective lesions [abstract]. In: Proceedings of the AACR Special Conference on Advances in Ovarian Cancer Research; 2019 Sep 13-16, 2019; Atlanta, GA. Philadelphia (PA): AACR; Clin Cancer Res 2020;26(13_Suppl):Abstract nr B26.
Target-oriented delivery of self-assembled immunosuppressant cocktails prolongs allogeneic orthotopic liver transplant survival
Authors: Haiyang Xie, Hai Zhu, Ke Zhou, Jianqin Wan, Liang Zhang, Zhentao Yang, Liqian Zhou, Xiaona Chen, Xiao Xu, Shusen Zheng, Hangxiang Wang
Journal: Journal of Controlled Release (2020)
Reversing cold tumors to hot: An immunoadjuvant-functionalized metal-organic framework for multimodal imaging-guided synergistic photo-immunotherapy
Authors: Zhijin Fan, Hongxing Liu, Yaohua Xue, Jingyan Lin, Yu Fu, Zhaohua Xia, Dongming Pan, Jian Zhang, Kun Qiao, Zhenzhen Zhang, Yuhui Liao
Journal: Bioactive Materials (2020)

Immunotherapy assays using immunoadjuvants and tumor antigens could greatly increase the survival rates of patients with malignant tumors. As effective carriers, metal-organic frameworks (MOFs) have been widely utilized in cancer therapy due to their remarkable histocompatibility and low toxicity. Herein, we constructed a multimodal imaging-guided synergistic cancer photoimmunotherapy by employing a specific MOF (MIL101-NH2) as the core carrier; the MOF was dual-dressed with photoacoustic and fluorescent signal donors (indocyanine green, ICG) and immune adjuvants (cytosine-phosphate-guanine sequence, CpG) and named [email protected] This nanocarrier could passively target the tumor site through the EPR effect and achieve multimodal imaging (fluorescence, photoacoustic, photothermal and magnetic resonance imaging) of the tumor. Synergistic cancer photoimmunotherapy was achieved via simultaneous photodynamic and photothermal methods with 808 nm laser irradiation. [email protected] achieved the GSH-controlled release of immunoadjuvant into the tumor microenvironment. Furthermore, the released tumor-associated antigen along with CpG could induce the transformation of tumor cells from cold to hot by activating the immune system, which significantly enhanced tumor cytotoxicity and achieved high cure rates with minimal side-effects. This strategy utilizing multimodal imaging and synergistic cancer photoimmunotherapy provides a promising approach for the diagnosis and treatment of cancer.
Hydration for the Tokyo Olympics: to thirst or not to thirst?
Authors: Julien D Périard, Thijs Eijsvogels, Hein A M Daanen, Sebastien Racinais
Journal: British Journal of Sports Medicine (2020)

figure 1 Effects of exercise-induced dehydration and recommendations for optimising endurance performance in the heat.Exercise-induced water loss (>2% body mass) via sweating leads to hyperosmotic hypovolaemia, which triggers the sensation of thirst, but also reduces sweat rate for any given core temperature and increases the cardiovascular response to a given work rate.These adjustments impair endurance performance through exacerbated hyperthermia and reduced blood flow to exercising muscles and the skin.Both exercise-induced dehydration (process of losing body water) and hypohydration (state of body water deficit) induce these responses.The choice of drinking to thirst or adopting a planned hydration strategy should be considered based on exercise intensity, duration and climatic conditions, with the aim to minimise body mass loss within the constraints of the sport (rules and regulations), rather than fully replace the deficit.