tbuckley/cabot-search huggingface dataset:
Abstract 14679: LncRNA SNHG12 Regulates Vascular Senescence and Atherosclerosis by Targeting A DNA-PK-Mediated DNA Damage Response
Authors: Stefan Haemmig, Dafeng Yang, Debapria Das, Siavash Ghaffari, Yihuan Deng, Lei Chen, Xinghui Sun, Norman Moullan, Yevgenia Tesmenitsky, A.K.M. Khyrul Wara, Eugenia Shvartz, Galina Sukova, Jarrod A Marto, Peter H Stone, Warren L Lee, Johan Auwerx, Peter Libby, Mark W Feinberg
Journal: Circulation (2018)

Introduction: Non-coding RNAs have garnered widespread attention as emerging regulators of diverse biological processes. Herein, we identify and validate a unique role for the lncRNA Small Nucleola...
Congenital biliary atresia is correlated with disrupted cell junctions and polarity caused by Cdc42 insufficiency in the liver
Authors: Yongjie Zhou, Hongjie Ji, Qing Xu, Xiaoyun Zhang, Xiaoyue Cao, Yuwei Chen, Mingyang Shao, Zhenru Wu, Jie Zhang, Changli Lu, Jiayin Yang, Yujun Shi, Hong Bu
Journal: Theranostics (2021)

Rationale: Congenital biliary atresia (BA) is a destructive obliterative cholangiopathy of neonates that affects both intrahepatic and extrahepatic bile ducts. However, the cause of BA is largely unknown. Methods: We explored the cell junctions and polarity complexes in early biopsy BA livers by immunofluorescence staining and western blot. Cdc42, as a key cell junction and polarity regulator, was found dramatically decreased in BA livers. Therefore, in order to investigate the role of Cdc42 in BA development, we constructed liver-specific and tamoxifen induced cholangiocyte-specific Cdc42 deleted transgenic mice. We further evaluated the role of bile acid in aggravating biliary damage in Cdc42 insufficient mouse liver. Results: We found a dramatic defect in the assembly of cell junctions and polarity complexes in both cholangiocytes and hepatocytes in BA livers. This defect was characterized by the disordered location of cell junction proteins, including ZO1, β-catenin, E-cadherin and claudin-3. Cdc42 and its active form, Cdc42-GTP, which serves as a small Rho GTPase to orchestrate the assembly of polarity complexes with Par6/Par3/αPKC, were substantially reduced in BA livers. Selective Cdc42 deficiency in fetal mouse cholangiocytes resulted in histological changes similar to those found in human BA livers, including obstruction in both the intra- and extrahepatic bile ducts, epithelial atrophy, and the disruption of cell junction and polarity complexes. A reduction in bile acids notably improved the histology and serological indices in Cdc42-mutant mice. Conclusion: Our results illustrate that BA is closely correlated with the impaired assembly of cell junction and polarity complexes in liver cells, which is likely caused by Cdc42 insufficiency and aggravated by bile acid corrosion.
Metronomic cyclophosphamide and bevacizumab for the treatment of recurrent gynecologic carcinosarcoma: A multi-institution, retrospective study.
Authors: Sara Bouberhan, Jill S. Hyde, McKenzie Foxall, Richard T. Penson, Rebecca Christian Arend
Journal: Journal of Clinical Oncology (2021)

5532 Background: The recent findings from the GOG 261 trial established carboplatin and paclitaxel as the standard first-line therapy for advanced gynecologic carcinosarcoma (GCS). Response rates to alternative regimens are limited, and the optimal chemotherapy for later line treatment of gynecologic carcinosarcoma has not yet been determined. The objective of this retrospective study is to report clinical response to treatment regimens for patients with GCS treated at 2 large academic referral comprehensive cancer centers. Methods: This multi-institution, retrospective analysis identified patients with recurrent GCS treated between January 1, 2015 and August 1, 2020 at the Massachusetts General Hospital and the University of Alabama O’Neal Comprehensive Cancer Center. All eligible patients received platinum/taxane as their first-line treatment regimen and were subsequently treated for recurrent disease. Subsequent treatment strategies were investigated. Objective responses were determined based on the clinical radiologist’s interpretation. Time on treatment (TOT) and treatment toxicity were identified for each subject. Given the small number of patients in this series, descriptive statistics were employed. Results: 29 patients met inclusion criteria. 15 patients had recurrent uterine carcinosarcoma, and 14 patients had recurrent ovarian carcinosarcoma. The most commonly used treatment regimens were: liposomal doxorubicin (PLD)/bevacizumab (ORR: 13%; Range TOT: 2-7 months), metronomic oral cyclophosphamide (MOC)/bevacizumab (ORR: 17%; Range TOT: 1-18 months), weekly paclitaxel/bevacizumab (ORR 60%; Range TOT: 3-18.5 months), liposomal doxorubicin (PLD) (ORR: 0%; Range TOT: 1-3 months), and weekly paclitaxel (ORR: 33%; Range TOT: 4.5-5.5). All regimens were generally well tolerated, and only 3 patients discontinued treatment due to toxicity concerns. Conclusions: In summary, in our cohort of gynecologic carcinosarcoma patients, the most active regimen (defined by mean TOT) was paclitaxel/bevacizumab, but prolonged TOT was also observed in the patients treated with MOC/bevacizumab. Given the rarity and aggressive nature of this tumor, further studies into optimal second line chemo (and beyond) are warranted; although, the combination of MOC/bevacizumab should be considered given the tolerability and the duration of treatment in this patient population.
Rehabilitation after critical illness—don’t overlook technological and social factors
Authors: Charles Coughlan, Weronika Ranisz, Clare Leon-Villapolas, Victoria Newey, Claire Boynton, Eve Corner, Gordon Sturmey, Matt Wiltshire, Stephen Brett
Journal: BMJ (2021)

We support the call from White and colleagues for more expert, multidisciplinary, integrated and consistent follow-up for all patients admitted to Intensive Care Units (ICUs) in the UK
Inhibitory effect of lignans from <i>Ailanthus altissima</i> on proliferation of human lung cancer cells and its mechanism.
Authors: Yu Wang, Siming Wang, Yibing Wu, Mei Dong, Zhiyu Ni
Journal: Journal of Clinical Oncology (2021)

e15059 Background: Plants are thought to contain compounds that inhibit the proliferation of cancer cells in vitro, and many attempts have been made to isolate anti-cancer drugs from plants. Ailanthus altissima is a family of Simaroubaceae, the bark is gray to grayish-black, because of the smell of the gland patches at the base of the leaves. 3,5,3-trimethoxy-8,1-neoligna-4,2,7,9,9-pentol (TNP) isolated from Ailanthus altissima. Methods: (1) Apoptosis was detected by flow cytometry: the cells were incubated with 10 mmol/L TNP for 24 h, and the cells were collected. The cell concentration was adjusted to 5×10 5 ̃ 5×10 6 / L. While propionate iodide was added for DNA fluorescence staining (Propidium Iodide, PI: 50 mg/L，triton-x100 1.0%). (2) The changes of p53, Bax and caspase-3 were detected by Western blot. The cells were cultured in 10 μmol/L cisplatin and TNP medium for 24 hours. Image J image analysis software is used for semi quantitative analysis. The data were expressed by mean standard deviation, and the mean values of each group were compared by analysis of variance and the least significant difference. There was a significant difference in P&lt; 0.05. (3) A549 cells were treated with 10 μmol/L cisplatin and TNP. A549 cells were incubated with cisplatin and TNP, and then treated with solvent control (final concentration 0.1% dimethyl sulfoxide) with or without caspase inhibitor for 48 hours The OD value was determined by MTT method. Cell survival rate (%) = (OD value of control group /OD value of control group) 100%. Results: (1) The reverse effect of caspase inhibitor on the proliferation of A549 cells: the cell survival rates of A549 cells treated with 0.1, 1 and 10 μmol/L cisplatin and TNP were 96.11%, 72.36%, 27.57% and 71.42%, 28.97% and 4.34% respectively. The survival rate of A549 cells incubated with cisplatin and TNP 20 μmol/L increased to 100.00%, 81.92%, 57.54% and 85.69%, 48.57% and 16.95% respectively. Caspase inhibitor reversed the inhibitory effect of TNP on A549 cells. (2) The effect of TNP on apoptosis of A549 cells: after treatment with 10 μmol/L TNP for 24 h, the apoptosis rate of A549 cells was (24.01)%, which was significantly higher than that of the blank control group (6.79)% ( P&lt; 0.05). (3) The results showed that the up regulation of p53, Bax and caspase-3 protein by TNP was 10 μmol/L. Conclusions: TNP can induce apoptosis of human lung cancer cell line A549, and it can up regulate the expression of p53, Bax and Caspase-3, which may be one of the mechanisms of TNP inducing apoptosis of A549 cells. The experiment also proves that caspase inhibitor can reverse the effect of TNP. TNP inhibits the proliferation of A549 cells.
Investigating bacterial decolonization for the prevention of radiation dermatitis: A randomized controlled trial and quality of life assessment.
Authors: Karolina Mieczkowska, Alana Deutsch, Kosaku Shinoda, Johanna Daily, Nitin Ohri, Beth McLellan
Journal: Journal of Clinical Oncology (2021)

TPS12137 Background: Radiation dermatitis (RD) can be therapy-limiting and detrimental to quality of life for cancer patients receiving radiation therapy (RT). Bacteria play an important role in many inflammatory dermatoses. In an observational clinical study, our group discovered that nasal colonization with bacteria, specifically with Staphylococcus aureus (SA), prior to RT was an independent predictor of higher-grade RD (grade ≥2). Higher-grade RD patients were also found to have more SA on the irradiated skin after treatment. If successful, bacterial decolonization could be a safe and cost-effective method to prevent RD. Methods: This is a randomized controlled trial assessing the efficacy of universal bacterial decolonization in preventing RD. Subject inclusion criteria include patients who are aged ≥ 18 years with a diagnosis of a solid tumor of the breast or head and neck with plans for fractionated RT (≥ 15 fractions) with curative intent. Based on previous studies and power analyses, we plan to recruit a total of 80 patients. Patients in the control arm will be treated according to standard of care, including daily application of emollients and gentle bathing. In addition to standard of care, patients in the intervention arm will receive a decolonization regimen consisting of intranasal mupirocin ointment used twice daily and chlorhexidine wash used daily for 5 days prior to the initiation of RT and repeated for 5 days every other week throughout RT. Study evaluations for both groups will include bacterial cultures obtained via superficial swab from the nares, irradiated skin, and contralateral non-radiated skin performed at the beginning, middle, and end of RT. Additionally, standardized photographs of the skin at the radiated site will be performed prior to and at the completion of RT, which will be graded by a dermatologist blinded to study arm. Lastly, at identical timepoints, each patient will complete the SKINDEX-16 questionnaire, a validated quality of life (QoL) assessment. The primary endpoint is development of grade ≥ 2 RD, as compared to low-grade RD (grade 0-1), during RT. The secondary endpoint includes the impact of bacterial decolonization on QoL. Pearson’s chi square or Fisher’s exact tests will be used to compare the incidence rates of higher-grade RD between the interventional arm and control arm to assess if the intervention is associated with a lower incidence rate of higher-grade RD. Paired t-tests will be used to compare the QoL score change from baseline to after RT between the two arms. Linear regression models will be used in both analyses to adjust for covariates. Clinical trial information: NCT03883828.
Sindilimab combined with nab-paclitaxel plus gemcitabine as first-line treatment for patients with advanced pancreatic cancer.
Authors: Huayun Zhu, Xiaofeng Sun, Xuan Pan, Pingping Wu, Jia Chen
Journal: Journal of Clinical Oncology (2021)

e16257 Background: This study aimed to evaluate the efficacy and safety of Sindilimab combined with nab-paclitaxel plus gemcitabine as first-line treatment for advanced pancreatic cancer. Methods: This was a single-arm, simple-center, exploratory trial, which included advanced pancreatic cancer pts. Patients received Sindilimab combined with nab-paclitaxel plus gemcitabine. Combined chemotherapy lasted for no more than 12 cycles. Once chemotherapy intolerance occurred or at end of 12-cycle combined chemotherapy, pts with stable disease or objective response would continue to take Sindilimab as single agent until disease progression or intolerable toxicity. Response was assessed every 8 weeks. Results: 16 eligible patients were enrolled and 14 pts were evaluable for efficacy analysis. Baseline characteristics are shown in Table 2. Conclusions: This study has showed high anti-tumor efficacy and tolerant toxicity in first-line regimen for advanced pancreatic cancer. Furthermore, it is needed to be proved in update results and large scale studies. Efficacy As shown in Table 3, among 14 evaluable pts, unconfirmed ORR was 57.1% and DCR was 92.8%. 8 pts got partial response (PR), 5 pts stable disease (SD) and 1 pts progressive disease(PD) at best. PFS: The primary endpoint 6-month PFS rate was 2%(95% CI 50.4%-72.4%). Which indicated that the primary endpoint of the study was reached. And mPFS was 7.3 months(95% CI 5.9-8.1). OS: Median OS was not reached and 6m-OS rate was 85.7% (95%CI 5%-91.3%). Safety. All 16 pts were included in the safety analysis (Table 4). The overall AE incidence rate was 93.75% .≥Grade 3 irAE included GGT increased (37.5%) and peripheral neuropathy (6.25%). No TRAE led to death.[Table: see text][Table: see text][Table: see text][Table: see text]
Impact of radiotherapy for local control in T3 N0 rectal cancer managed with total mesorectal excision: A systematic review and meta-analysis.
Authors: Jesus C. Fabregas, Andrew Bang, Michael Tjong, Michael Kucharczyk
Journal: Journal of Clinical Oncology (2021)

3604 Background: Total mesorectal excision (TME) significantly improved rectal cancer outcomes. Radiotherapy (RT) is recommended for T3N0 rectal cancers, though benefit has not been demonstrated in combination with TME for this specific population. This meta-analysis could provide evidence to ameliorate toxicities from treatment. Methods: Randomized clinical trials and observational studies published until October 18, 2020 were identified via PubMed and Embase. Objective: To determine whether RT decreased the risk of local recurrence (LR) in T3N0 rectal cancer managed with TME. Study Selection and Extraction: Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines were observed for literature search, extraction, and screening. Studies with LR data specific to T3N0M0 rectal cancer, treated with and without RT, were included. Reviews, non-English articles, and non-TME studies were excluded. Newcastle Ottawa Scale (NOS) evaluated quality. Meta-analysis was done with a random-effects model. Main outcome: Meta-analysis of the relative risk of LR was conducted. Results: 7,246 studies were screened, 134 full-text studies assessed for eligibility, 5 studies were included in the final analysis. No randomized data reported results specific to our study population. Five retrospective cohort studies involving 932 participants reported LR outcomes. The median follow-up ranged from 38.4 months up to 71 months. Four studies took place in Asia (797 participants) and one in North America (135 participants) (Table). Quality according to NOS ranged from 7–9. The estimated average relative risk for LR at 5 years was 0.63 (95% CI 0.31–1.29; I 2 =41.8%) when RT was used. Conclusions: This meta-analysis’ supports that there is no clear benefit to LR with the addition of RT in T3N0 patients with rectal adenocarcinoma undergoing TME. As meta-analysis was limited to retrospective cohort studies, there is concern for bias. Registration Prospero number CRD42020216058 .[Table: see text]
Clinical Utility of Lipoprotein(a) for Screening Does Not Determine Clinical Utility of Lipoprotein(a) for the Patient—Reply
Authors: Mark Trinder, Pradeep Natarajan
Journal: JAMA Cardiology (2021)

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RBM8A promotes growth and invasion through the Notch/STAT3 pathway in glioblastoma.
Authors: Yan Lin, Jinyan Zhang, Beiquan Hu, Gang Qin, Rong Liang, Yingying Lin, Jiazhang Wei, Zhongrun Qian, Donghua Zou
Journal: Journal of Clinical Oncology (2021)

e14038 Background: Glioblastoma (GBM) is a prevalent brain malignance with an extremely poor prognosis, which is attributable to its invasive biological behaviors. The RNA-binding motif protein 8A (RBM8A) has different effects on various human cancers. However, the implication of RBM8A in glioblastoma progression remains unclear. Methods: Glioblastoma (GBM) data set was downloaded from the Cancer Genome Atlas (TCGA). Differential expression analysis was used to screen the differentially expressed genes (DEGs) between GBM and control, RBM8A high and low expression samples, Gene Ontology (GO) analysis and Kyoto Encyclopedia of Gene Genomes (KEGG) analysis were performed on the co-upregulated DEGs. Additionally, We investigated the expression levels of RBM8A in 94 glioblastoma patients and explored the correlation between the RBM8A expressions with prognosis. Using in vitro and in vivo assays, we addressed the functional impacts of RBM8A on and the underlying mechanisms through which RBM8A contribute to glioblastoma progression. In addition, a comprehensive regulatory network of RBM8A regulation was constructed based on STRING database. Molecular docking model was used to predict the possibility of RBM8A binding to target genes. Combined with TCGA and Chinese glioma genome map (CGGA), gene set variance analysis (GSVA) was used to calculate the GSVA scores of the genes involved in the mechanism. Receiver operator characteristic curve (ROC) curve analysis and survival analysis were performed to explore the prognostic and diagnostic ability of GSVA score for GBM. Results: Our results indicate that higher RBM8A expression in glioblastoma tissues was associated with a poor prognosis. In addition, functional enrichment analysis based on genes related to RBM8A expression showed that RBM8A was related to cell cycle and Notch signaling pathway. RBM8A may promote glioblastoma cell proliferation and migration by activating Notch/STAT3 pathway in glioblastoma cells. In vitro and in vivo assays confirmed that knocking down RBM8A inhibited glioblastoma progression and invasion ability. We also observed that the pro-oncogenic effects of RBM8A in glioblastoma tissues were mediated by activation of the Notch/STAT3 pathway. Finally, it was concluded that the GSVA score has good diagnostic and prognostic value for GBM. Conclusions: RBM8A may promote glioblastoma cell proliferation and migration by activating Notch/STAT3 pathway in glioblastoma cells, suggesting that RBM8A may serve as a potential therapeutic target for the treatment of glioblastoma.
Daratumumab, pomalidomide, and dexamethasone in relapsed refractory multiple myeloma (RRMM): A comparison with contemporary clinical trials.
Authors: Barry Paul, Myra M. Robinson, Jordan Robinson, Ami Ndiaye, Manisha Bhutani, Peter Michael Voorhees, James Thomas Symanowski, Reed N. Friend, Mauricio Pineda-Roman, Saad Zafar Usmani, Shebli Atrash
Journal: Journal of Clinical Oncology (2021)

e20011 Background: Multiple Myeloma (MM) is an incurable malignancy of terminally differentiated plasma cells. The combination of pomalidomide/dexamethasone with either daratumumab or isatuximab is FDA approved for relapsed refractory multiple myeloma (RRMM) based on randomized phase III trial data. Herein, we compare our center’s experience with published data to help identify the most appropriate patient population for this regimen outside of the context of clinical trials. Methods: We interrogated our internal plasma cell disorder database to identify all patients with RRMM at our institution who were treated with the combination of daratumumab, pomalidomide, and dexamethasone (Dara-Pd). We evaluated the best response achieved, overall response rate (ORR), progression free survival (PFS), and overall survival (OS) measured from initiation on Dara-Pd. Kaplan Meier methods were used to estimate PFS and OS curves. Fisher’s exact tests and log rank tests were used to determine the association between outcomes and variables of interest. Results: Between Dec 2015 and Dec 2020, 98 patients were identified, of which 97 were evaluable for response. Median number of prior lines of therapy was 2 (range 1-12), with 23 patients (23%) previously treated with 3 prior lines and 24 patients (25%) previously treated with ≥4 lines of therapy. Most patients were refractory to an IMiD (79.6%), a PI (65.3%), or both (56.1%). The ORR was 69.1%, &gt; VGPR rate was 33%. ORR was significantly improved for patients who received Dara-Pd after 1 line (p = 0.03), but depth of response (≥VGPR), was similar (p = 0.62). At a median follow up of 10.8 months, 1-year PFS was 76.6% in patients after 1 line, 38.8% in patients after 2-3 lines, and 35% in patients after &gt; 4 lines. Overall response rates appear comparable to published phase III trials comparing the combination of Pd with or without an anti-CD38 monoclonal antibody (Table 1). While PFS was somewhat lower in our population, subset analysis showed that PFS was significantly lower in patients who were PI refractory (10.8 months vs 6 months; p = 0.014), and in patients who were both IMiD and PI refractory (20.4 months vs 6 months p = 0.01), but OS was similar in these populations. Conclusions: Our data suggests that the combination of Dara-Pd has activity in heavily pretreated patients, including patients who are both IMiD and PI refractory and remains a viable option for these patients outside the context of a clinical trial.[Table: see text]