tbuckley/cabot-search huggingface dataset:
Abstract 6325: CXCR4 intracellular protein regulates chemotherapy resistance by modulating the expression of death receptor 5
Authors: Mushtaq Ahmad Nengroo, Shrankhla Maheshwari, Akhilesh Singh, Anup Kumar Singh, Priyank Chaturvedi, Ayushi Verma, Rakesh Kumar Arya, Krishan Kumar Saini, Annapurna Gupta, Anjali Mishra, Dipak Datta
Journal: Cancer Research (2020)

Abstract Chemotherapy resistance is one of the pivotal reasons for cancer-associated huge mortality and morbidity. Cancer cells become therapy resistant by smartly evading the execution of apoptosis. Death Receptors (DR) are critical pro-apoptotic factors that regulate cell death, and paucity of death receptors in cancer cells promotes therapy resistance. High expression of CXCR4 is strongly correlated with poor prognosis and adverse clinical outcomes. Inhibitors of the CXCL12-CXCR4 axis, such as FDA approved drug plerixafor (AMD3100), and Nox-A12 have shown limited clinical success in cancer treatment. Alternately, CXCR7, another CXCL12 binding receptor, could be the reason for the limited success of the CXCR4 blockade in clinics. However, recent preclinical data for blocking both the chemokine receptors failed to explain the pro-tumorigenic functions of these axes. Therefore, CXCR4-CXCL12 signaling may not be the exclusive contributor to its pro-tumorigenic functions. In our continuous effort to understand the chemokine receptor signaling inhibition as cancer therapy, here we unexpectedly discovered that instead of CXCR4-CXCL12 signaling, CXCR4 intracellular protein augments therapy resistance and pro-tumorigenic functions. By utilizing stable gain and loss of function approaches, we observed that CXCR4 selectively resists and sensitizes cancer cells against paclitaxel therapy. Our unbiased apoptosis array followed by immunoblot, FACS, real-time PCR, and ChIP analysis clearly demonstrate that CXCR4 promotes downregulation of pro-apoptotic protein DR5 via modulating differential recruitment of transcription factors p53 and YY1 to the promoter of DR5 gene. Inhibiting CXCR4 mediated signals failed to block the above phenotype. Irrespective of CXCR4 surface expression, three different colon cancer xenograft models evidently exhibited loss of CXCR4 protein results in compromised colon tumor growth in vivo. Finally, performing TCGA data mining, real-time PCR, immunofluorescence microscopy of human cancer patient samples and cell lines, we observed that expression of CXCR4 and DR5 are inversely correlated in human cancer. Together, we showed for the first time that targeting intracellular CXCR4 protein may be critical to dampen the pro-tumorigenic functions of CXCR4. Citation Format: Mushtaq Ahmad Nengroo, Shrankhla Maheshwari, Akhilesh Singh, Anup Kumar Singh, Priyank Chaturvedi, Ayushi Verma, Rakesh Kumar Arya, Krishan Kumar Saini, Annapurna Gupta, Anjali Mishra, Dipak Datta. CXCR4 intracellular protein regulates chemotherapy resistance by modulating the expression of death receptor 5 [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 6325.
Abstract A42: Total laryngopharyngoesophagectomy with gastric transposition for hypopharyngeal cancer: A tertiary care center experience
Authors: Prerit Rao, K. Devaraja, Kailesh Pujary, Dipak Ranjan Nayak, R. Balakrishnan
Journal: Clinical Cancer Research (2020)

Abstract Introduction: With the emergence of organ preservation protocol in head and neck cancer, management of hypopharyngeal carcinoma is generally by nonsurgical approach; however, a significant number of hypopharyngeal cancer patients present in advanced stage and exhibit poor prognosis. For such cases, thorough aggressive surgical excision of laryngopharyngoesophageal complex with appropriate reconstruction might be a viable option. Objective: To evaluate quality-of-life measures and survival outcomes in hypopharyngeal carcinoma cases undergoing above-mentioned procedure at a tertiary health care center. Methodology: A retrospective study on patients with hypopharyngeal carcinoma undergoing above-mentioned procedure was done in our tertiary care institute between September 2016 to October 2018. Results: A total of 12 patients were operated during the study period; however, 3 patients were excluded due to inadequate data. In our study, mean age of presentation was 51.3 years and majority were men (n=8). Most of the patients at the time of presentation were stage IVA or more. Postcricoid was most common subsite, followed by pyriform fossa. 4 out of 12 were operated after failed chemoradiation. Perioperative morbidity primarily in terms of complications and duration of hospital stay and quality-of-life measures consisting mainly of swallowing score were analyzed, which suggested that this procedure is tolerable and produces a reliable outcome. Conclusion: Total laryngopharyngoesophagectomy with gastric transposition is a feasible and efficacious treatment option with reasonable quality of life in carcinoma hypopharynx patients, especially after failed chemoradiation. Citation Format: Prerit Rao, K. Devaraja, Kailesh Pujary, Dipak Ranjan Nayak, R. Balakrishnan. Total laryngopharyngoesophagectomy with gastric transposition for hypopharyngeal cancer: A tertiary care center experience [abstract]. In: Proceedings of the AACR-AHNS Head and Neck Cancer Conference: Optimizing Survival and Quality of Life through Basic, Clinical, and Translational Research; 2019 Apr 29-30; Austin, TX. Philadelphia (PA): AACR; Clin Cancer Res 2020;26(12_Suppl_2):Abstract nr A42.
The persistent breach between evidence and practice in the prevention of surgical site infection. Qualitative study
Authors: Josep M. Badia, Inés Rubio-Pérez, José López-Menéndez, Cecilia Diez, Bader Al-Raies Bolaños, Julia Ocaña-Guaita, Xose M. Meijome, Manuel Chamorro-Pons, Ramón Calderón-Nájera, Gloria Ortega-Pérez, Rosa Paredes-Esteban, Cristina Sánchez-Viguera, Ramon Vilallonga, Antonio L. Picardo, Elena Bravo-Brañas, Eloy Espin, José M. Balibrea
Journal: International Journal of Surgery (2020)

Despite the dissemination of guidelines for surgical site infection (SSI) prevention, a gap between the theoretical measures and their compliance persists. Accurate estimates of the implementation of preventative measures is crucial before planning dissemination strategies. A web-based survey was distributed to members of 11 Associations of operative nurses and surgeons. Questions aimed to determine their awareness of evidence, personal beliefs and actual use of the main preventative measures. Of 1105 responders, 50.5% receive no feed-back of their SSI rate. Responders show a moderate rate of awareness of the recommendations about not removing hair, hair clipping, skin antisepsis with alcoholic solutions, and normothermia. Antibiotic prophylaxis is given for more than 24 h by 18.8% of respondents. Screening for S. aureus is performed by 27.6%. Hair removal by shaving is used by 16.6% of responders. The most common antiseptic solutions are alcoholic chlorhexidine (57.2%) and aqueous povidone (23.3%). 62.8% of surgeons allow the solution to air dry before applying surgical drapes. Adhesive drapes in the surgical field are used routinely in 33.4% of cases. Perioperative normothermia, glucose control and hyperoxia are used in 84.3%, 65.9% and 23.3% of cases. Antimicrobial sutures and negative pressure therapy are used by 20.2% and 43.5% of teams, respectively. Prior to closing the incision, 83.9% replace surgical instruments always or selectively. Wound irrigation before closing is used in 78.1% of cases, mostly with saline. Check-lists, standardized orders, surveillance, feed-back and educational programs were rated most highly by respondents as a means to improve compliance with preventative guidelines, but few of these strategies were in place at their institutions. Gaps in the translation of evidence into practice remain in the prevention of SSI among different surgical specialities. Several areas for improvement have been identified, as some core prevention measures are not in common use.
Abstract 5446: Genetic bases of testicular seminoma and non-seminoma tumors
Authors: Paloma Martin-Gimeno, Beatriz Paumard-Hernandez, Oriol Calvete, Javier Benitez
Journal: Cancer Research (2020)

Abstract Testicular Germ Cell Tumor (TGCT) is the most common cancer type in men between 15-45 years old (1 per 250 men). Around 1-2% of all cases are familial (with at least two affected individuals within the same family), between 3-5% are bilateral (they develop two tumors, one in each testicle), and the rest are sporadic patients. There are two main types of histologies, seminomas and non-seminomas, and there are also tumors that contain both seminoma and non-seminoma cells, and are called mixed tumors. No great genetic differences have been found so far between them. In order to identify susceptibility genes that could explain these histological differences, we performed Whole Exome Sequencing (WES) in peripheral blood of 61 members from 17 families with at least two affected members with TGCT. Twenty one members had seminoma, seven members had non-seminomas, and nine had mixed tumor. We did not find significant genetic differences between the two histological types at the germline level. Therefore, an evaluation at a somatic level was carried out to determine if the differences between the tumor types are in the tumor. To this end, WES of blood and tumor tissue was performed in three bilateral cases with different histologies (a seminoma in one testicle and a non-seminoma in the other). The comparison between pairs of tumors from each of the patients showed that they shared in average a 30% of the somatic mutations between both the histologies. Even more, 27 genes were shared among the two tumors in the three patients. We next performed independency tests, comparing the somatic similarities and differences between the two tumors from each patient (intrapatient) and the two histologies (interpatients), which suggest a common genetic background that could predispose to testicular cancer development. We are currently performing gene ontology analysis with the genes that were shared among the pairs of tumors from each patient. Partially supported by CIBERER and FIS 16/00440 Citation Format: Paloma Martin-Gimeno, Beatriz Paumard-Hernandez, Oriol Calvete, Javier Benitez. Genetic bases of testicular seminoma and non-seminoma tumors [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 5446.
<scp>NK</scp> cell alloreactivity in acute myeloid leukemia in the post‐transplant cyclophosphamide era
Authors: Catharina H. M. J. Van Elssen, Stefan O. Ciurea
Journal: American Journal of Hematology (2020)

Allogeneic hematopoietic stem cell transplantation (alloSCT) for myeloid leukemia remains one of the most effective anti-tumor treatments available, capable of curing an increasingly higher proportion of patients. Alloreactivity generated by T cells has limited efficacy in the early post-transplant period while most patients will relapse within 6 months after transplantation. Prior studies in T cell depleted grafts showed that, with the elimination of T cells, natural killer (NK) cells provide most of the anti-tumor effect in the early post-transplant period. Administration of unmodified T cells to mitigate infections and relapse will expose the patient to a high risk of graft-vs-host disease (GvHD). Post-transplant cyclophosphamide (PTCy), initially used for haploidentical (haplo) donor transplants, is now also increasingly utilized in HLA matched donor transplants to prevent GvHD. In most patients, PTCy eliminates, at least in part, alloreactive T and NK cells early post-transplant. Administration of modified NK cells in the early post-transplant period makes intuitive sense to enhance the anti-tumor effect of the graft and thereby prevent relapse. Effective application of cellular therapy early after transplant has opened a new direction and could revolutionize the field of hematopoietic stem cell transplantation.
Automated closed-loop <i>versus</i> standard manual oxygen administration after major abdominal or thoracic surgery: an international multicentre randomised controlled study
Authors: Erwan L'Her, Samir Jaber, Daniel Verzilli, Christophe Jacob, Brigitte Huiban, Emmanuel Futier, Thomas Kerforne, Victoire Pateau, Pierre-Alexandre Bouchard, Maëlys Consigny, François Lellouche
Journal: European Respiratory Journal (2020)

Introduction Hypoxaemia and hyperoxaemia may occur after surgery, with related complications. This multicentre randomised trial evaluated the impact of automated closed-loop oxygen administration after high-risk abdominal or thoracic surgeries in terms of optimising the oxygen saturation measured by pulse oximetry time within target range. Methods After extubation, patients with an intermediate to high risk of post-operative pulmonary complications were randomised to “standard” or “automated” closed-loop oxygen administration. The primary outcome was the percentage of time within the oxygenation range, during a 3-day frame. The secondary outcomes were the time with hypoxaemia and hyperoxaemia under oxygen. Results Among the 200 patients, time within range was higher in the automated group, both initially (≤3 h; 91.4±13.7% versus 40.2±35.1% of time, difference +51.0% (95% CI −42.8–59.2%); p&lt;0.0001) and during the 3-day period (94.0±11.3% versus 62.1±23.3% of time, difference +31.9% (95% CI 26.3–37.4%); p&lt;0.0001). Periods of hypoxaemia were reduced in the automated group (≤3 days; 32.6±57.8 min (1.2±1.9%) versus 370.5±594.3 min (5.0±11.2%), difference −10.2% (95% CI −13.9–−6.6%); p&lt;0.0001), as well as hyperoxaemia under oxygen (≤3 days; 5.1±10.9 min (4.8±11.2%) versus 177.9±277.2 min (27.0±23.8%), difference −22.0% (95% CI −27.6–−16.4%); p&lt;0.0001). Kaplan–Meier analysis depicted a significant difference in terms of hypoxaemia (p=0.01) and severe hypoxaemia (p=0.0003) occurrence between groups in favour of the automated group. 25 patients experienced hypoxaemia for &gt;10% of the entire monitoring time during the 3 days within the standard group, as compared to the automated group (p&lt;0.0001). Conclusion Automated closed-loop oxygen administration promotes greater time within the oxygenation target, as compared to standard manual administration, thus reducing the occurrence of hypoxaemia and hyperoxaemia.
Abstract 13111: Cardiac Determinants of Right Ventricular Pressure-Flow Response to Exercise in Heart Failure: A Non-Invasive Approach Combining Cardiopulmonary Exercise Testing and Exercise-Echocardiography
Authors: Greta Generati, Francesco Bandera, Marta Pellegrino, Francesco Carbone, Valentina Labate, Eleonora Alfonzetti, Marco Guazzi
Journal: Circulation (2015)

Background: The pulmonary pressure (PAP) over cardiac output (CO) exercise response has been proposed as expression of right ventricular (RV) to pulmonary circulation (PC) coupling. The functional implications and cardiac phenotype of PAP/CO slope in heart failure (HF) have never been investigated. Aim: To define the functional and cardiac characteristics related to an unfavorable RV-PC coupling in HFrEF. Methods: 87 HFrEF patients (mean age 65±11 y, male 70%, mean LVEF 33±9%) underwent a maximal CPET (incremental ramp protocol) combined with exercise-echo. MeanPAP/CO slope is calculated as the slope between the exercise increase in mean PAP and CO. Results: Population was divided into 2 groups according to mPAP/CO slope: Group A (n=27) slope &lt;3.5 mmHg/L*min and B (n= 60) slope≥3.5 mmHg/L*min. Patients with abnormal response (Group B) exhibited a worse functional capacity (lower maximal workload and peak oxygen consumption) and ventilatory efficiency (steeper VE/VCO2). Group B had also worse LV remodeling and higher prevalence of dynamic severe mitral regurgitation (MR), associated with elevated pulmonary arterial pressure (systolic PAP) and an impaired rest and peak CO. The best linear regression model identified age, gender, LV EDVi and rest and peak severe MR as main cardiac determinants of mPAP/CO slope. Conclusions: In HFrEF population, an unfavorable pulmonary pressure to cardiac output exercise response, or steeper mPAP/CO slope, is associated with advanced eccentric LV remodeling and dynamic severe MR, overall resembling the most unfavorable functional phenotype.
Abstract B34: LINC00886, a risk locus-associated long noncoding RNA, promotes ovarian cancer progression
Authors: Koji Nakamura, Brett M. Reid, Thomas A. Sellers, Florian A. Karreth
Journal: Clinical Cancer Research (2020)

Abstract Background: Recent genome-wide association studies (GWAS) have identified a plethora of SNPs that cluster at loci associated with increased epithelial ovarian cancer (EOC) risk. The functional validation of genes in such risk loci focused primarily on the protein-coding space while long noncoding RNAs (lncRNAs) were disregarded. Given the emerging evidence that lncRNAs can act as oncogenes and tumor suppressors, we seek to evaluate the functional role of EOC risk locus-associated lncRNAs in EOC development. Methods: We interrogated GWAS for EOC and the FANTOM-CAT database for lncRNAs to identify EOC risk-associated SNPs that lie within lncRNA regulatory regions. We first prioritized the lncRNAs that are associated with EOC risk loci using public databases including GTEx and TCGA. To assess the oncogenic potential of these lncRNAs, we performed in vitro functional assays such as proliferation, colony formation, anchorage-independent growth and migration by overexpressing and silencing candidate lncRNAs in fallopian tube secretory epithelial and ovarian cancer cells. To validate our findings in vivo, we intraperitoneally injected OVCAR-8 cells into immunocompromised mice and evaluated tumor growth. LncRNA subcellular localization was evaluated based on qPCR from cytoplasmic and nuclear RNA. Further, we investigated expression changes upon lncRNAs overexpression in OVCAR-8 and FT282 cells by RNA sequencing (RNA-seq) and predicted shared microRNAs (miRNA) binding sites using LncBase Predicted v.2 and TargetScanHuman 7.2. Results: We identified 5 candidate risk locus-associated lncRNAs (CATG00000115318.1, HAGLR, LINC00886, CATG00000117550.1, and CTD-2521M24.8). Functional assays showed that LINC00886 promoted cancer cell proliferation and colony formation in vitro. Overexpression of LINC00886 in OVCAR-8 cells significantly promoted peritoneal dissemination in a xenograft model. LINC00886 was mainly localized to the cytoplasm, suggesting it could function by decoying miRNAs. Interestingly, we observed that LINC00886 overexpression increased the levels of several oncogenes, of which several (ROR2, TNFSF14, GPNMB, LTB, and ZBTB20) share miRNA binding sites with LINC00886. Conclusion: LINC00886, a risk loci-associated lncRNA, promotes an aggressive phenotype in ovarian cancer, suggesting an oncogenic function. We are currently investigating the molecular mechanism of LINC00886 as a ceRNA in ovarian cancer progression. Citation Format: Koji Nakamura, Brett M. Reid, Thomas A. Sellers, Florian A. Karreth. LINC00886, a risk locus-associated long noncoding RNA, promotes ovarian cancer progression [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 B34.
Abstract 6224: Novel antitumor semi-synthetic heliomycin derivatives direct targeting tNOX-NAD+-SIRT1 axis to activate apoptosis/autophagy, as determined by the cellular thermal shift assay (CETSA)
Authors: Pin Ju Chueh, Atikul Islam, Xiao Qi Chen, Shi Han Chiu, Alexander S. Tikhomirov, Andrey E. Shchekotikhin
Journal: Cancer Research (2020)

Abstract The antibiotic heliomycin (resistomycin) has been studied since the 1950s, however, its low solubility in aqueous media has restricted its systemic bioavailability and therapeutic potential. We recently synthesized a series of novel aminomethyl derivatives that are readily soluble in aqueous solution. In this study, we examined their antiproliferative properties and underlying molecular mechanisms in p53 wild-type and p53-mutated cancer cells. We continuously monitored the cellular impact of these compounds using the xCELLigence System, a label-free, real-time cell monitoring platform that measures electrical impedance, displaying results as cell index values. The results from the system showed that heliomycin and its derivatives exhibited different biological effects on tumor cells. To further our understanding of the interactions between the novel derivatives and cellular targets, we utilized the cellular thermal shift assay (CETSA). Our CETSA results revealed that some of the derivatives that were directly engaged with tNOX enhanced its thermal stability, which in turn resulted in a marked attenuation of the intracellular NAD+/NADH ratio. This attenuated ratio signifies a decrease in the NAD+-dependent activity of Sirtuin 1 (SIRT1) deacetylase and triggers apoptosis/autophagy, with varying amounts of decrease depending on the cellular environment. We have successfully transformed heliomycin into derivatives that are much more soluble, allowing the more efficient modulating of biological activities - a significant step closer towards finding a novel anti-cancer candidate. Citation Format: Pin Ju Chueh, Atikul Islam, Xiao Qi Chen, Shi Han Chiu, Alexander S. Tikhomirov, Andrey E. Shchekotikhin. Novel antitumor semi-synthetic heliomycin derivatives direct targeting tNOX-NAD+-SIRT1 axis to activate apoptosis/autophagy, as determined by the cellular thermal shift assay (CETSA) [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 6224.