Exploiting induced vulnerability to overcome PARPi resistance and clonal heterogeneity in BRCA mutant triple-negative inflammatory breast cancer

xlomafota13 shared this article with you from Inoreader Exploiting induced vulnerability to overcome PARPi resistance and clonal heterogeneity in BRCA mutant triple-negative inflammatory breast cancer Via American Journal of Cancer Research Am J Cancer Res. 2022 Jan 15;12(1):337-354. eCollection 2022. ABSTRACT Acquired resistance and clonal heterogeneity are critical challenges in cancer treatment, and the lack of effective computational tools hampers the discovery of new treatments to overcome resistance. Using high-throughput transcriptomic databases of compound perturbation profiles, we have developed a bioinformatic strategy for identifying candidate drugs to overcome resistance with combinatorial therapy. We devised this strategy during an investigation into the acquired resistance against PARP inhibitors (PARPi) in a triple-negative inflammatory breast cancer cell line. In this study, we derived multiple PARPi-resistant clones and characterized their transcriptomic adaptations compared to the parental clone. The transcriptomes of the resistant clones showed substantial heterogeneity, highlighting the importance of characterizing multiple clones from the same tumour. Surprisingly, we found that these transcriptomic changes may not actually confer PARPi resistance, but they may nevertheless induce a shared secondary vulnerability. By modeling our data in relation to transcriptomic perturbation profiles of compounds, we uncovered deficiencies in Ras signaling that resulted from transcriptional adaptation to long-term PARPi treatment across multiple resistant clones. Due to these induced deficiencies, we predicted that the resistant clones would be sensitive to pharmacological reinforcement of PARPi-induced transcriptional adaptation. We then experimentally validated this predicted vulnerability that is shared by multiple resistant clones. Our results thus provide a promising paradigm for integrating transcriptomic data with compound perturbation profiles in order to identify drugs that can exploit an induced vulnerability and overcome therapeutic resistance, thus providing another strategy towards precision oncology. PMID:35141022 | PMC:PMC8822293 View on the web Inoreader. Take back control of your news feed. Follow us on Twitter and Facebook.

Concomitant use of oral anticoagulants in patients with advanced prostate cancer receiving apalutamide: A post-hoc analysis of TITAN and SPARTAN studies

xlomafota13 shared this article with you from Inoreader Concomitant use of oral anticoagulants in patients with advanced prostate cancer receiving apalutamide: A post-hoc analysis of TITAN and SPARTAN studies Via American Journal of Cancer Research Am J Cancer Res. 2022 Jan 15;12(1):445-450. eCollection 2022. ABSTRACT Apalutamide, an androgen receptor signaling inhibitor, in combination with androgen-deprivation therapy (ADT), is approved for treatment of patients with nonmetastatic castration-resistant prostate cancer and metastatic castration-sensitive prostate cancer, based on the data from the phase 3 SPARTAN and TITAN studies respectively. Apalutamide is an inducer of cytochrome P450 enzymes and P-glycoprotein, which are involved in the metabolism of oral anticoagulants (OACs) and may thus have potential drug-drug interactions when co-administered with OACs. Concomitant use of certain OACs such as apixaban, rivaroxaban, edoxaban, dabigatran, and warfarin was allowed in the SPARTAN and TITAN studies. A post-hoc analysis was conducted to evaluate the incidence of treatment-emergent thrombotic and embolic adverse events (AEs) in patients receiving concomitant OACs with apalutam ide + ADT or placebo + ADT in both the studies. Anticoagulants were identified by WHO Drug Anatomical Therapeutic Chemical level 4 classifications. Thrombotic and embolic AEs were coded using the Medical Dictionary for Regulatory Activities Version 22.1. Data were analyzed from patients receiving concurrent OACs among all treated patients in SPARTAN (apalutamide + ADT: 95/803 [11.8%]; placebo + ADT: 48/398 [12.1%]) and TITAN (apalutamide + ADT: 31/524 [5.9%]; placebo + ADT: 28/527 [5.3%]). No consequential differences were observed in the occurrence of thrombotic and embolic events between apalutamide + ADT and placebo + ADT groups receiving concomitant OACs in SPARTAN (11.6% vs 12.5%) or TITAN (19.4% vs 21.4%). Grade 3/4 thrombotic and embolic AEs observed in patients receiving concomitant OACs with apalutamide + ADT or placebo + ADT were 6 (6.3%) vs 5 (10.4%) in SPARTAN and 3 (9.7%) vs 1 (3.6%) in TITAN. This analysis suggests that when necessary, concomitant OACs can be used with apalutamide with appropriate monitoring. PMID:35141028 | PMC:PMC8822273 View on the web Inoreader. Take back control of your news feed. Follow us on Twitter and Facebook.

De-glycosylated membrane PD-L1 in tumor tissues as a biomarker for responsiveness to atezolizumab (Tecentriq) in advanced breast cancer patients

xlomafota13 shared this article with you from Inoreader De-glycosylated membrane PD-L1 in tumor tissues as a biomarker for responsiveness to atezolizumab (Tecentriq) in advanced breast cancer patients Via American Journal of Cancer Research Am J Cancer Res. 2022 Jan 15;12(1):123-137. eCollection 2022. ABSTRACT The atezolizumab (Tecentriq), a humanized antibody against human programmed death ligand 1 (PD-L1), combined with nab-paclitaxel was granted with accelerated approval to treat unresectable locally advanced or metastatic triple-negative breast cancer (TNBC) due to the encouraging positive results of the phase 3 IMpassion130 trial using PD-L1 biomarker from immune cells to stratify patients. However, the post-market study IMpassion131 did not support the original observation, resulting in the voluntary withdrawal of atezolizumab from the indication in breast cancer by Genentech in 2021. Emerging evidence has revealed a high frequency of false negative result using the standard immunohistochemical (IHC) staining due to heavy glycosylation of PD-L1. The removal of glycosylation prevents from the false negative staining, enabling more accurate assessment of PD-L1 levels and improving prediction for response to immune checkpoint therapy. In the present study, the natural and de-glycosylated PD-L1 expression in tumor and immune cells from nine TNBC patients were analyzed by using clone 28-8 monoclonal antibody to correlate with treatment outcome. Our results demonstrate that: (1) Removal of the glycosylation indeed enhances the detection of PD-L1 by IHC staining, (2) The PD-L1 levels on tumor cell surface after removal of the glycosylation correlates well with clinical responses for atezolizumab treatment; (3) The criteria used in the IMpassion130 and IMpassion131 trials which scored the natural PD-L1 in the immune cells failed to correlate with the clinical response. Taken together, tumor cell surface staining of PD-L1 with de-glycosylation has a significant correlation with the clinical response for atezolizumab treatment, suggesting that treatment of atezolizumab may be worthy of further consideration with de-glycosylation procedure as a patient s tratification strategy. A larger cohort to validate this important issue is warranted to ensure right patient population who could benefit from the existing FDA-approved drugs. PMID:35141008 | PMC:PMC8822291 View on the web Inoreader. Take back control of your news feed. Follow us on Twitter and Facebook.

Artificial intelligence for early diagnosis of lung cancer through incidental nodule detection in low- and middle-income countries-acceleration during the COVID-19 pandemic but here to stay

xlomafota13 shared this article with you from Inoreader Artificial intelligence for early diagnosis of lung cancer through incidental nodule detection in low- and middle-income countries-acceleration during the COVID-19 pandemic but here to stay Via American Journal of Cancer Research Am J Cancer Res. 2022 Jan 15;12(1):1-16. eCollection 2022. ABSTRACT Although the coronavirus disease of 2019 (COVID-19) pandemic had profound pernicious effects, it revealed deficiencies in health systems, particularly among low- and middle-income countries (LMICs). With increasing uncertainty in healthcare, existing unmet needs such as poor outcomes of lung cancer (LC) patients in LMICs, mainly due to late stages at diagnosis, have been challenging-necessitating a shift in focus for judicious health resource utilization. Leveraging artificial intelligence (AI) for screening large volumes of pulmonary images performed for noncancerous reasons, such as health checks, immigration, tuberculosis screening, or other lung conditions, including but not limited to COVID-19, can facilitate easy and early identification of incidental pulmonary nodules (IPNs), which otherwise could have been missed. AI can review every chest X-ray or computed tom ography scan through a trained pair of eyes, thus strengthening the infrastructure and enhancing capabilities of manpower for interpreting images in LMICs for streamlining accurate and early identification of IPNs. AI can be a catalyst for driving LC screening with enhanced efficiency, particularly in primary care settings, for timely referral and adequate management of coincidental IPN. AI can facilitate shift in the stage of LC diagnosis for improving survival, thus fostering optimal health-resource utilization and sustainable healthcare systems resilient to crisis. This article highlights the challenges for organized LC screening in LMICs and describes unique opportunities for leveraging AI. We present pilot initiatives from Asia, Latin America, and Russia illustrating AI-supported IPN identification from routine imaging to facilitate early diagnosis of LC at a potentially curable stage. PMID:35141002 | PMC:PMC8822269 View on the web Inoreader. Take back control of your news feed. Follow us on Twitter and Facebook.

The ADAM9/UBN2/AKR1C3 axis promotes resistance to androgen-deprivation in prostate cancer

xlomafota13 shared this article with you from Inoreader The ADAM9/UBN2/AKR1C3 axis promotes resistance to androgen-deprivation in prostate cancer Via American Journal of Cancer Research Am J Cancer Res. 2022 Jan 15;12(1):176-197. eCollection 2022. ABSTRACT Metastatic and castration-resistant disease is a fatal manifestation of prostate cancer (PCa). The mechanism through which resistance to androgen deprivation in PCa is developed remains largely unknown. Our understanding of the tumor microenvironment (TME) and key signaling pathways between tumors and their TME is currently changing in light of the generation of new knowledge with regard to cancer progression. A disintegrin and metalloproteinase domain-containing protein 9 (ADAM9) is a membranous bridge forming cell-cell and cell-matrix connections that regulate tumor aggressiveness and metastasis. However, it is not known whether ADAM9 expressed in the TME contributes to the CRPC phenotype. In this study, we aimed to investigate the expression patterns of ADAM9 in prostate cancer-associated fibroblasts (CAFs). We also intended to elucidate the effects of both strom al cell- and cancer cell-derived ADAM9 on the progression of CRPC and the implicated molecular pathways. By using both clinical specimens and cell lines, we herein showed that unlike the membrane anchored ADAM9 overexpressed by both PCa cells and prostate CAFs, the secreted isoform of ADAM9 (sADAM9) was strongly detected in CAFs, but rarely in tumor cells, and that could be a serum marker for PCa patients. We demonstrated that functionally sADAM9 are characterized as chemoattractant for the directed movement of androgen-independent PCa cells through integrin downstream FAK/AKT pathway, supporting that elevated sADAM9 by prostate CAFs could be responsible for the promotion of CRPC metastasis. Moreover, by stimulating PCa cells with sADAM9, we found that ubinuclein-2 (UBN2) expression was increased. A positive correlation of ADAM9 and UBN2 expression was observed in androgen receptor-expressing PCa cell lines and further confirmed in clinical PCa specimens. Using a genetic modificatio n approach, we identified UBN2 as a downstream target gene of ADAM9 that is critical for the survival of androgen-dependent PCa cells in response to androgen deprivation, through the induction and effect of the aldo-keto reductase family 1 member C3 (AKR1C3). Collectively, our results reveal a novel action of ADAM9 on the transition of androgen-dependent PCa cells into an androgen-independent manner through the UBN2/AKR1C3 axis; the aforementioned action could contribute to the clinically-observed acquired androgen-deprivation therapy resistance. PMID:35141012 | PMC:PMC8822277 View on the web Inoreader. Take back control of your news feed. Follow us on Twitter and Facebook.

Association of machine learning ultrasound radiomics and disease outcome in triple negative breast cancer

xlomafota13 shared this article with you from Inoreader Association of machine learning ultrasound radiomics and disease outcome in triple negative breast cancer Via American Journal of Cancer Research Am J Cancer Res. 2022 Jan 15;12(1):152-164. eCollection 2022. ABSTRACT Triple negative breast cancer (TNBC) is a breast cancer subtype with unfavorable prognosis. We aimed to establish a machine learning-based ultrasound radiomics model to predict disease-free survival (DFS) in TNBC. Invasive TNBC>T1b between January 2009 and June 2018 with preoperative ultrasound were enrolled and assigned to training and independent test cohort. Radiomics and clinicopathological features related with DFS were selected by univariate and multivariate regression analysis. Training cohort of combined features was resampled with SMOTEENN to balance distribution and put into classifiers. Areas Under Curves (AUCs) of models were compared by DeLong's test. 562 women were included with 68 DFS events observed. Twenty prognostic radiomics features were extracted. Machine learning model by Naïve Bayes combining radiomics, clinicopathological features, and SM OTEENN had an AUC of 0.86 (95% CI 0.84-0.88), with sensitivity of 74.7% and specificity of 80.1% in training cohort. In independent test cohort, this three-combination model delivered an AUC of 0.90 (95% CI 0.83-0.95), higher than models based on radiomics (AUC=0.69, P=0.016) or radiomics + SMOTEENN (AUC=0.73, P=0.019). Integrating machine learning radiomics model based on ultrasound and clinicopathological features can predict DFS events for TNBC patients. PMID:35141010 | PMC:PMC8822271 View on the web Inoreader. Take back control of your news feed. Follow us on Twitter and Facebook.

Novel insights linking BRCA1-IRIS role in mammary gland development to formation of aggressive PABCs: the case for longer breastfeeding

xlomafota13 shared this article with you from Inoreader Novel insights linking BRCA1-IRIS role in mammary gland development to formation of aggressive PABCs: the case for longer breastfeeding Via American Journal of Cancer Research Am J Cancer Res. 2022 Jan 15;12(1):396-426. eCollection 2022. ABSTRACT Pregnancy-associated breast cancer (PABC) is diagnosed during or shortly after pregnancy. Although rare, PABC is a serious occurrence often of the triple negative (TNBC) subtype. Here we show progesterone, prolactin, and RANKL upregulate BRCA1-IRIS (IRIS) in separate and overlapping subpopulations of human mammary epithelial cell lines, which exacerbates the proliferation, survival, and the TNBC-like phenotype in them. Conversely, vitamin D3 reduces IRIS expression in TNBC cell lines, which attenuates growth, survival, and the TNBC-like phenotype in them. In the mouse, Brca1-Iris (Iris, mouse IRIS homolog) is expressed at low-level in nulliparous mice, increases ~10-fold in pregnant/lactating mice, to completely disappear in involuting mice, and reappears at low-level in regressed glands. Mice underwent 3 constitutive pregnancies followed by a forced invo lution (after 5 days of lactation) contained ~10-fold higher Iris in their mammary glands compared to those underwent physiological involution (after 21 days of lactation). While protein extracts from lactating glands promote proliferation in IRISlow and IRIS overexpressing (IRISOE) cells, extracts from involuting glands promote apoptosis in IRISlow, and aneuploidy in IRISOE cells. In a cohort of breast cancer patients, lack of breastfeeding was associated with formation of chemotherapy resistant, metastatic IRISOE breast cancers. We propose that terminal differentiation triggered by long-term breastfeeding reduces IRIS expression in mammary cells allowing their elimination by the inflammatory microenvironment during physiological involution. No/short-term breastfeeding retains in the mammary gland IRISOE cells that thrive in the inflammatory microenvironment during forced involution to become precursors for aggressive breast cancers shortly after pregnancy. PMID:35141026 | PMC:PMC8822284 View on the web Inoreader. Take back control of your news feed. Follow us on Twitter and Facebook.

USP47 stabilizes BACH1 to promote the Warburg effect and non-small cell lung cancer development via stimulating Hk2 and Gapdh transcription

xlomafota13 shared this article with you from Inoreader USP47 stabilizes BACH1 to promote the Warburg effect and non-small cell lung cancer development via stimulating Hk2 and Gapdh transcription Via American Journal of Cancer Research Am J Cancer Res. 2022 Jan 15;12(1):91-107. eCollection 2022. ABSTRACT Increasing studies demonstrated that ubiquitination plays a crucial part in the pathogenesis of non-small cell lung cancer (NSCLC), and targeted adjustment of the deubiquitination enzymes is a potential means for cancer treatment. However, the role of ubiquitin carboxyl-terminal hydrolase 47 (USP47) in NSCLC is still unclear. Here, we show that USP47 was upregulated in NSCLC clinical tissues and greatly related to advanced tumor stages and survival rate. Functional experimental results showed that USP47 promoted the cell proliferation in vitro and tumor growth in vivo. And the overexpression of USP47 promoted the glycolysis capacity of lung cancer cells. Mechanistic investigations showed that USP47 promoted NSCLC development, which depends a lot on directly binding to and deubiquitination of the basic leucine zipper transcription factor 1 (BACH1, BTB an d CNC homology 1). BACH1 was also significantly overexpressed in primary NSCLC tissues and positively correlated with the expression of USP47. The promotion of USP47 on the Warburg effect and NSCLC progression was mediated by the deubiquitination of BACH1 and the downstream transcriptional regulation of hexokinase 2 (Hk2) and glyceraldehyde-phosphate dehydrogenase (Gapdh). Therefore, targeting USP47/BACH1 axis might offer a new way to inhibit the progression of NSCLC. PMID:35141006 | PMC:PMC8822287 View on the web Inoreader. Take back control of your news feed. Follow us on Twitter and Facebook.

Ultrasonography vs Computed Tomography for Papillary Thyroid Cancer Cervical Lymph Node Metastasis

xlomafota13 shared this article with you from Inoreader Ultrasonography vs Computed Tomography for Papillary Thyroid Cancer Cervical Lymph Node Metastasis Via JAMA Otolaryngology–Head & Neck Surgery Current Issue This systematic review and meta-analysis compares ultrasonography and computed tomography in the preoperative evaluation of papillary thyroid cancer for cervical lymph node metastasis. View on the web Inoreader. Take back control of your news feed. Follow us on Twitter and Facebook.

Evaluation of Surgical Margin Status in Patients With Salivary Gland Cancer

xlomafota13 shared this article with you from Inoreader Evaluation of Surgical Margin Status in Patients With Salivary Gland Cancer Via JAMA Otolaryngology–Head & Neck Surgery Current Issue This cohort study evaluates the association of surgical margin status with use of postoperative radiotherapy and survival in patients with salivary gland cancer. View on the web Inoreader. Take back control of your news feed. Follow us on Twitter and Facebook.

Difficult Airway Management in a Patient With Hereditary Hemorrhagic Telangiectasia

xlomafota13 shared this article with you from Inoreader Difficult Airway Management in a Patient With Hereditary Hemorrhagic Telangiectasia Via JAMA Otolaryngology–Head & Neck Surgery Current Issue To the Editor In reference to the recent publication by Safi et al regarding rapid sequence induction and intubation in a patient with hereditary hemorrhagic telangiectasia (HHT), I would like to congratulate the authors on a successful outcome. Also, I would like to suggest that, rather than mask ventilation after induction of anesthesia, consideration be given to awake fiber-optic oral/nasal intubation, as directed by the preoperative assessment, to establish the airway in patients with HHT undergoing elective procedures. Rapid sequence induction and emergency tracheostomy, in that order, could then be further on in the difficult airway algorithm, if needed, as in this case. View on the web Inoreader. Take back control of your news feed. Follow us on Twitter and Facebook.