tbuckley/cabot-search huggingface dataset:
KDELR2 promotes breast cancer proliferation via HDAC3‐mediated cell cycle progression
Authors: Haoran Wei, Wenhao Ma, Xiaofei Lu, Haiying Liu, Kashuai Lin, Yinghui Wang, Zijian Ye, Linchong Sun, Zhitong Huang, Tingting Pan, Zilong Zhou, Eric Y. Cheng, Huafeng Zhang, Ping Gao, Xiuying Zhong
Journal: Cancer Communications (2021)

Histone deacetylases (HDACs) engage in the regulation of various cellular processes by controlling global gene expression. The dysregulation of HDACs leads to carcinogenesis, making HDACs ideal targets for cancer therapy. However, the use of HDAC inhibitors (HDACi) as single agents has been shown to have limited success in treating solid tumors in clinical studies. This study aimed to identify a novel downstream effector of HDACs to provide a potential target for combination therapy.Transcriptome sequencing and bioinformatics analysis were performed to screen for genes responsive to HDACi in breast cancer cells. The effects of HDACi on cell viability were detected using the MTT assay. The mRNA and protein levels of genes were determined by quantitative reverse transcription-PCR (qRT-PCR) and Western blotting. Cell cycle distribution and apoptosis were analyzed by flow cytometry. The binding of CREB1 (cAMP-response element binding protein 1) to the promoter of the KDELR (The KDEL (Lys-Asp-Glu-Leu) receptor) gene was validated by the ChIP (chromatin immunoprecipitation assay). The association between KDELR2 and protein of centriole 5 (POC5) was detected by immunoprecipitation. A breast cancer-bearing mouse model was employed to analyze the effect of the HDAC3-KDELR2 axis on tumor growth.KDELR2 was identified as a novel target of HDAC3, and its aberrant expression indicated the poor prognosis of breast cancer patients. We found a strong correlation between the protein expression patterns of HADC3 and KDELR2 in tumor tissues from breast cancer patients. The results of the ChIP assay and qRT-PCR analysis validated that HDAC3 transactivated KDELR2 via CREB1. The HDAC3-KDELR2 axis accelerated the cell cycle progression of cancer cells by protecting the centrosomal protein POC5 from proteasomal degradation. Moreover, the HDAC3-KDELR2 axis promoted breast cancer cell proliferation and tumorigenesis in vitro and in vivo.Our results uncovered a previously unappreciated function of KDELR2 in tumorigenesis, linking a critical Golgi-the endoplasmic reticulum traffic transport protein to HDAC-controlled cell cycle progression on the path of cancer development and thus revealing a potential therapeutical target for breast cancer.
Recurrent Mutations in Cyclin D3 Confer Clinical Resistance to FLT3 Inhibitors in Acute Myeloid Leukemia
Authors: Catherine C. Smith, Aaron D. Viny, Evan Massi, Cyriac Kandoth, Nicholas D. Socci, Franck Rapaport, Matthieu Najm, Juan S. Medina-Martinez, Elli Papaemmanuil, Theodore C. Tarver, Henry H. Hsu, Mai H. Le, Brian West, Gideon Bollag, Barry S. Taylor, Ross L. Levine, Neil P. Shah
Journal: Clinical Cancer Research (2021)

Abstract Purpose: Biomarkers of response and resistance to FLT3 tyrosine kinase inhibitors (TKI) are still emerging, and optimal clinical combinations remain unclear. The purpose of this study is to identify co-occurring mutations that influence clinical response to the novel FLT3 inhibitor pexidartinib (PLX3397). Experimental Design: We performed targeted sequencing of pretreatment blasts from 29 patients with FLT3 internal tandem duplication (ITD) mutations treated on the phase I/II trial of pexidartinib in relapsed/refractory FLT3-ITD+ acute myeloid leukemia (AML). We sequenced 37 samples from 29 patients with available material, including 8 responders and 21 non-responders treated at or above the recommended phase II dose of 3,000 mg. Results: Consistent with other studies, we identified mutations in NRAS, TP53, IDH2, and a variety of epigenetic and transcriptional regulators only in non-responders. Among the most frequently mutated genes in non-responders was Cyclin D3 (CCND3). A total of 3 individual mutations in CCND3 (Q276*, S264R, and T283A) were identified in 2 of 21 non-responders (one patient had both Q276* and S264R). No CCND3 mutations were found in pexidartinib responders. Expression of the Q276* and T283A mutations in FLT3-ITD MV4;11 cells conferred resistance to apoptosis, decreased cell-cycle arrest, and increased proliferation in the presence of pexidartinib and other FLT3 inhibitors. Inhibition of CDK4/6 activity in CCND3 mutant MV4;11 cells restored pexidartinib-induced cell-cycle arrest but not apoptosis. Conclusions: Mutations in CCND3, a gene not commonly mutated in AML, are a novel cause of clinical primary resistance to FLT3 inhibitors in AML and may have sensitivity to CDK4/6 inhibition.
Immune checkpoint inhibitor induced hepatitis: Risk factors, outcomes, and impact on survival.
Authors: Abdul Miah, Songzhu Zhao, Sandip H. Patel, Andrew Johns, Madison Grogan, Mingjia Li, Gabrielle Lopez, Tyler Haddad, Marium Husain, Kari Lynn Kendra, Gregory Alan Otterson, Lai Wei, Carolyn J Presley, Dwight Hall Owen
Journal: Journal of Clinical Oncology (2021)

e14525 Background: Immune checkpoint inhibitors (ICIs) have improved the survival of patients with multiple cancer types, however ICI treatment is associated with a unique set of immune-related adverse events (irAEs) that can affect any organ. Few studies have evaluated the risk factors and outcomes of ICI induced hepatitis (ICIH). Methods: We utilized an institutional database of patients with advanced cancers treated with ICI between 2011 and 2017 at The OSU Comprehensive Cancer Center to identify patients with ICIH. Any patient who received at least one dose of ICI alone or in combination with other systemic therapies either as part of clinical trial or standard of care were included. Clinical data were extracted through chart abstraction. irAEs were graded using the Common Terminology Criteria for Adverse Events v5. Overall survival (OS) was calculated from the date of ICI initiation to death from any cause or the date of the last follow-up. OS with 95% confidence intervals were estimated using the Kaplan–Meier method. OS was also evaluated by occurrence of ICIH using the log-rank test. Results: We identified 1,096 patients treated with at least one dose of ICI. Most common cancers included lung (n=224, 20%) and melanoma (n=342, 31%). The most common ICIs were PD1/L1 (n=774, 71%) and CTLA-4 inhibitors (n=195, 18%). ICIH of any grade occurred in 64 (6%) patients. Overall, 46 (71%) were male and median age was 60 years. Severity of hepatitis was grade 1-2 in 30 patients (47%) (Table 1). The incidence of ≥grade 3 ICIH in the entire cohort was 3.1%. Median time to ICIH diagnosis was 63 days. ICIH occurred alone in 24 patients, and co-occurred with other irAEs in 40 patients. The most common co-occurring irAEs were pneumonitis (n=7); colitis (n=15), thyroid abnormality (n=14); and dermatitis (n=15). ICIH was more common in women (p=0.038), in patients treated with combination ICIs (p&lt;0.001), and among patients receiving first line therapy (p=0.018). Patients who developed ICIH had significantly longer OS than patients who did not develop ICIH; there was no difference in OS between patients with ≥grade 3 ICIH vs grade 1-2 (Table). 33 out of 34 patients with ≥grade3 ICIH were treated with steroids; 3 received mycophenolate and one received infliximab. Of patients with ≥grade 3 ICIH, 11 resumed ICI therapy without recurrent ICIH. Conclusions: Female sex, combination immunotherapy, and line of therapy were associated with ICIH. Patients with ICIH had improved clinical outcomes compared to those that did not develop ICIH, even those with higher grade toxicity. Further study is needed to assist in developing risk stratification models and optimal treatment for ICIH. OS of patients with and without immune checkpoint inhibitor hepatitis.[Table: see text]
Impact of pre-treatment lymphocyte monocyte ratio and neutrophil lymphocyte ratio on pathologic response in breast cancer patients receiving neoadjuvant chemotherapy.
Authors: Osama Mosalem, Saud Alsubait, Shouq Kherallah, Venumadhavi Gogineni, Ling Wang, Jatin Rana, Daniel Isaac
Journal: Journal of Clinical Oncology (2021)

e12623 Background: Hematologic markers have been looked at as potential prognostic biomarkers in a variety of cancers. Ni and colleagues (2014) have shown that an elevated pre-treatment lymphocyte-to-monocyte ratio (LMR) was significantly associated with improved disease-free survival (DFS) in patients with locally advanced breast cancer receiving neoadjuvant chemotherapy (NACT). Given the prognostic implications of hematologic inflammatory parameters, we sought to understand if such biomarkers will predict response to neoadjuvant chemotherapy (NACT) in patients with breast cancer. Methods: We conducted a retrospective review of breast cancer patients treated with NACT at our institution (2008-2018). Data on patient characteristics, stage, pathologic characteristics, and blood counts were collected. Blood parameters prior to NACT were used to calculate LMR and neutrophil-to-lymphocyte ratio (NLR). To test the impact of LMR and NLR on pathologic response, a two sample mean test was used first as univariate analysis. Next, logistic regression was employed for multivariate analysis controlling for patient characteristics with interaction of LMR and NLR with ER, PR and HER2 status. Results: A total of 50 patients were included. 38% of patients achieved a pathologic complete response (pCR). The mean LMR was 3.69 (1.4-12.5), and the mean NLR was 2.55 (0.66 – 9.31). On univariate analysis, a high NLR was associated with a higher likelihood of achieving a pCR (OR = 1.64, 95% CI = 1.01-2.63). A high LMR was associated with a higher likelihood of pCR; however, this was not statistically significant (OR = 1.08, 95% CI = 0.78-1.47). On multivariate analysis, patients with HER-2 positive disease with a high LMR had a significantly higher chance of having a pCR (OR = 1.72, 95% CI = 1.06-2.78). Conclusions: Our study showed that NLR was a predictor of pCR in breast cancer patients receiving neoadjuvant chemotherapy. A high NLR was associated with achieving a pCR on univariate analysis. Multivariate analysis suggested that HER-2 positive disease with a high LMR had a significantly higher chance of achieving a pCR. The results of this cohort correlate with previous reports by others showing that pre-NACT LMR and NLR provide prognostic information in patients with breast cancer. Although limited by sample size, this adds to the growing body of literature supporting peripheral blood counts as a biomarker for outcomes in breast cancer.
Deep spatial profiling of human COVID-19 brains reveals neuroinflammation with distinct microanatomical microglia-T-cell interactions
Authors: Marius Schwabenland, Henrike Salié, Jovan Tanevski, Saskia Killmer, Marilyn Salvat Lago, Alexandra Emilia Schlaak, Lena Mayer, Jakob Matschke, Klaus Püschel, Antonia Fitzek, Benjamin Ondruschka, Henrik E. Mei, Tobias Boettler, Christoph Neumann-Haefelin, Maike Hofmann, Angele Breithaupt, Nafiye Genc, Christine Stadelmann, Julio Saez-Rodriguez, Peter Bronsert, Klaus-Peter Knobeloch, Thomas Blank, Robert Thimme, Markus Glatzel, Marco Prinz, Bertram Bengsch
Journal: Immunity (2021)
Prevalence of Left Atrial Thrombus in Anticoagulated Patients With Atrial Fibrillation
Authors: Antony Lurie, Jia Wang, Kyra J. Hinnegan, William F. McIntyre, Emilie P. Belley-Côté, Guy Amit, Jeff S. Healey, Stuart J. Connolly, Jorge A. Wong
Journal: Journal of the American College of Cardiology (2021)
A retrospective study of local hepatic artery infusion chemotherapy combined with regorafenib in the treatment of advanced colorectal cancer with predominant liver metastases.
Authors: Guang Cao, Xu Zhu, Renjie Yang, Hui Chen, Xiaodong Wang, Xu Liang
Journal: Journal of Clinical Oncology (2021)

e15563 Background: The hepatic arterial infusion chemotherapy (HAIC) as a second/third-line therapy has resulted in promising clinical outcomes for unresectable liver metastatic colorectal cancer (CRC). HAIC combined with regorafenib has not been reported for advanced CRC patients with predominant liver metastases. This retrospective study explored the benefits and tolerability in advanced hepatic metastatic CRC patients who received HAIC combined with regorafenib after failure of standard systemic chemotherapy. Methods: This retrospective study collected and analyzed 47 patients treated with HAIC in combination with regorafenib after standard systemic oxaliplatin and/or irinotecan in combination with Bevacizumab or Cetuximab between Jan 2017 and Jun 2020 at the Beijing cancer hospitals in China. Regorafenib was taken for 3 weeks every 4-week cycles and mostly taken 5-7 days before or after the first HAIC. The overall survival (OS), progression-free survival (PFS), objective response rate (ORR), disease control rate (DCR), and adverse events (AEs) were observed. Results: Among these 47 patients, 32(68%) were males. The median age was 61 (range: 29-75) . The median follow-up was 22.2 months (range:3.7-50.7 months). Before receiving HAIC in combination with regorafenib, 34 (72.3%) patients had previously received ≥ 2 prior lines of systemic therapy and 37 (78.7%) patients had previously received targeted biological treatment (anti-VEGF or anti-EGFR, or both).These patients underwent HAIC for a median of 4 sessions (range2--8,). The starting doses of regorafenib were 40 mg/d (n = 1, 2.13%), 80 mg/d (n = 11, 23.43%), 120 mg/d (n = 2, 4.26%), and 160 mg/d (n = 23, 48.94%). The median OS was 22.2 months. The median PFS was 10.8 (95% CI: 9.0-13.7) months. The ORR was 51.3% and DCR was 100% among 39 patients whose tumor responses were evaluated in the liver. The ORR was 13.8% and DCR was 48.3% among 29 patients whose tumor responses were evaluated outside the liver. Toxicity profile of regorafenib was as expected, with common AE were hand-foot skin reaction (12.77%), fatigue (6.38%), vomiting (6.38%), and decreased appetite (6.38%). The most common grade 3 and 4 adverse events were hand-foot skin reaction (4.26%), hypertension (2.13%), diarrhea (2.13%), and stomachache (2.13%). Only 2 patients stopped regorafenib due to AEs. Conclusions: This real-world study demonstrated that regorafenib combined with HAIC was beneficial and tolerable in advanced CRC patients with liver metastases whose disease had progressed after standard systemic therapy. It also indicated a new promising treatment strategy for late stage CRC. Additional prospective and large-scale studies are required for further confirmation. Key words: hepatic artery infusion chemotherapy; regorafenib; colorectal cancer
Combination therapy with miR34a and doxorubicin synergistically inhibits Dox-resistant breast cancer progression via down-regulation of Snail through suppressing Notch/NF-κB and RAS/RAF/MEK/ERK signaling pathway
Authors: Xiaoxia Yang, Pengfei Shang, Bingfang Yu, Qiuyang Jin, Jing Liao, Lei Wang, Jianbo Ji, Xiuli Guo
Journal: Acta Pharmaceutica Sinica B (2021)

Resistance to breast cancer (BCa) chemotherapy severely hampers the patient's prognosis. MicroRNAs provide a potential therapeutic prospect for BCa. In this study, the reversal function of microRNA34a (miR34a) on doxorubicin (Dox) resistance of BCa and the possible mechanism was investigated. We found that the relative level of miR34a was significantly decreased in Dox-resistant breast cancer cell MCF-7 (MCF-7/A) compared with Dox-sensitive MCF-7 cells. Transfection with miR34a significantly suppressed the invasion, migration, adhesion of MCF-7/A cells without inhibiting their growth obviously. The combination of miR34a and Dox could significantly inhibit the proliferation, migration, invasion and induce the apoptosis of MCF-7/A cells. The synergistic effect of this combination on resistant MCF-7/A cells has no obvious relation with the expressions of classical drug-resistant proteins P-GP, MRP and GST-π, while closely related with the down-regulation on TOP2A and BCRP. Moreover, we found both protein and mRNA expression of Snail were significantly up-regulated in MCF-7/A cells in comparison with MCF-7 cells. Transfection with small interfering RNA (siRNA) of Snail could inhibit the invasion, migration and adhesion of drug-resistant MCF-7/A cells, while high-expression of Snail could remarkably promote the invasion, migration and adhesion of MCF-7 cells, which might be related with regulation of N-cadherin and E-cadherin. Transfection with miR34a in MCF-7/A cells induced a decrease of Snail expression. The potential binding sites of miR34a with 3′ UTR of Snail were predicted by miRDB target prediction software, which was confirmed by luciferase reporter gene method. Results showed that the relative activity of luciferase was reduced in MCF-7/A cells after co-transfection of miR34a and wild type (wt)-Snail, while did not change by co-transfection with miR34a and 3′ UTR mutant type (mut) Snail. Combination of miR34a and Dox induced a stronger decrease of Snail in MCF-7/A cells in comparison to miR34a or Dox treatment alone. What' more, for the first time, we also found miR34a combined with Dox could obviously inhibit the expression of Snail through suppressing Notch/NF-κB and RAS/RAF/MEK/ERK pathway in MCF-7/A cells. In vivo study indicated that combination of miR34a and Dox significantly slowed down tumor growth in MCF-7/A nude mouse xenograft model compared with Dox alone, which was manifested by the down-regulation of Snail and pro-apoptosis effect in tumor xenografts. These results together underline the relevance of miR34a-driven regulation of Snail in drug resistance and co-administration of miR34a and Dox may produce an effective therapy outcome in the future in clinic.
Peripheral blood levels of tumor-infiltrating lymphocytes (TILs) and circulating tumor cells (CTCs) in patients with colorectal cancer.
Authors: Inna A. Novikova, Oleg I. Kit, Elena Yu. Zlatnik, Anastasia O. Sitkovskaya, Oksana G. Shulgina, Elena P. Ulianova, Yuriy A. Gevorkyan, Natalya V. Soldatkina, Vladimir E. Kolesnikov, Maksim K. Aleksandrovich, Andrey V. Dashkov, Sergey I. Poluektov, Dmitry O. Kaymakchi, Ellada A. Mirzoyan, Vladislav K. Pavlov, Elena A. Dzhenkova, Aleksandr V. Shaposhnikov, Maksim A. Vereshchak, Oksana V. Katelnitskaya, Dmitriy A. Savchenko
Journal: Journal of Clinical Oncology (2021)

e15510 Background: Tumor is a structure where malignant cells interact, among others, with cells of the adaptive and innate immune systems largely determining the tumor microenvironment. The role of TILs in the disease prognosis has been shown. The amount of CTCs is one of the factors that significantly affect the risk and rate of metastasis. The purpose of the study was to assess an association between TILs and CTCs in the peripheral blood of patients with various stages of colorectal cancer (CRC). Methods: The study included 299 patients (aged 42-86 years, mean age 64.2±1.7) with stage II-IV CRC T1-4N0-2M0-1. TILs were identified in tumor material after standard histological processing. Lymphocytes were counted per 100 epithelial cells in 5 fields of view at a magnification of x400; the result was expressed as a percentage ( &lt; 5% weak, 5-30% moderate, &gt;30% strong). The numbers of CTCs were measured in the peripheral blood using the Veridex CellSearch system (Janssen), taking into account the expression of epithelial cell adhesion markers EpCAM, cytokeratins 8,18,19 and absence of the CD45 expression. The blood sample was evaluated according to the following criteria: 0 CTCs, 1-3 CTCs, and more than 3 CTCs. Statistical analysis of results was performed in the Statistica 13.0 program (StatSoftInc., USA). Results: Weak lymphocytic infiltration was detected in 32.8%, moderate - in 48.1%, strong - in 19.1% of cases. CTCs were detected in 62.9% cases (in 188 of 299 patients). The percentages of patients with 1-3 CTCs and with &gt;3 CTCs were equal - 50% (94 of 188). CTCs were not registered in 37.1% cases (111 of 299). The absence of CTCs was noted equally often in moderate and strong lymphocytic infiltration – 43.7% and 43.8%. The presence of tumor cells in the peripheral blood was most often detected in weak lymphocytic infiltration, being 1.4 times more frequent than in moderate and strong infiltration (76.5% vs. 56.3% and 56.2%) (p = 0.019, c 2 = 11.890). Conclusions: The study demonstrated a significant relationship between the level of CTCs and the intensity of lymphocytic infiltration in the tumor (p≤0.05), which can be used as a new prognostic approach.
A Review of the Diagnosis and Treatment of Metastatic Colorectal Cancer—Reply
Authors: Leah H. Biller, Deborah Schrag
Journal: JAMA (2021)

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In vivo biocompatibility and degradability of a Zn–Mg–Fe alloy osteosynthesis system
Authors: Xiaoxi Shao, Xiang Wang, Fangfang Xu, Taiqiang Dai, Jack G. Zhou, Jiang Liu, Kun Song, Lei Tian, Bin Liu, Yanpu Liu
Journal: Bioactive Materials (2021)

Zinc is generally considered to be one of the most promising materials to be used in biodegradable implants, and many zinc alloys have been optimized to improve implant biocompatibility, degradation, and mechanical properties. However, long-term degradation leads to the prolonged presence of degradation products, which risks foreign body reactions. Herein, we investigated the in vivo biocompatibility and degradation of a biodegradable Zn–Mg–Fe alloy osteosynthesis system in the frontal bone, mandible, and femur in beagles for 1 year. Results of the routine blood, biochemical, trace element, and histological analyses of multiple organs, peripheral blood CD4/CD8a levels, and serum interleukin 2 and 4 levels showed good biocompatibility of the Zn–Mg–Fe alloy. Zinc content analysis revealed zinc accumulation in adjacent bone tissue, but not in the liver, kidney, and spleen, which was related to the degradation of the Zn–Mg–Fe alloy. The alloy demonstrated a uniform slowing degradation rate in vivo. No degradation differences in the frontal bone, mandible, and femur were observed. The degradation products included zinc oxide [ZnO], zinc hydroxide [Zn(OH)2], hydrozincite [Zn5(OH)6(CO3)2], and hopeite [Zn3(PO4)2·4H2O]. The good biocompatibility and degradation properties of the Zn–Mg–Fe alloy render it a very attractive osteosynthesis system for clinical applications.