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.

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.

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.

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.

Trends in Diagnosis of NIFTP and Total Thyroidectomies for Papillary Thyroid Neoplasms

xlomafota13 shared this article with you from Inoreader Trends in Diagnosis of NIFTP and Total Thyroidectomies for Papillary Thyroid Neoplasms Via JAMA Otolaryngology–Head & Neck Surgery Current Issue This cohort study determines adoption rates of 2 recent strategies developed to limit overtreatment of low-risk thyroid cancers: a new classification, noninvasive follicular thyroid neoplasm with papillarylike nuclear features, and hemithyroidectomy for selected papillary thyroid carcinomas up to 4 cm in size. View on the web Inoreader. Take back control of your news feed. Follow us on Twitter and Facebook.

Overcoming Vaccine Hesitancy Around Bell Palsy in Otolaryngology–Head and Neck Surgery—Reply

xlomafota13 shared this article with you from Inoreader Overcoming Vaccine Hesitancy Around Bell Palsy in Otolaryngology–Head and Neck Surgery—Reply Via JAMA Otolaryngology–Head & Neck Surgery Current Issue In Reply We thank the authors of the Letter to the Editor for stimulating further discussion. Tamaki et al explored the relationship between COVID-19 and the COVID-19 vaccine on Bell palsy (BP). Patients were counted as having Bell palsy if they received a diagnosis of International Statistical Classification of Diseases and Related Health Problems, Tenth Revision (ICD-10) code G51.0. Granular patient-level data may be lacking in an analysis of this magnitude, and it was not possible to differentiate persistent or recurrent BP. Likewise, it is difficult to accurately quality check the accuracy of coding without the benefit of reviewing clinical data. We plan to expand on our work with further analysis. We agree that research using large databases may be at risk for misclassification. However, such databases can be an effective resource i n studying rare pathologies, especially in specific populations such as those who have had COVID-19 or received the COVID-19 vaccination. Our propensity score matched analysis suggests that rates of BP are higher in patients who are positive for COVID-19 and this incidence exceeds the reported incidence of BP with the COVID-19 vaccine. View on the web Inoreader. Take back control of your news feed. Follow us on Twitter and Facebook.

Human Papillomavirus Vaccine and Head and Neck Cancer

xlomafota13 shared this article with you from Inoreader Human Papillomavirus Vaccine and Head and Neck Cancer Via JAMA Otolaryngology–Head & Neck Surgery Current Issue This Patient Page describes the association between human papillomavirus and cancer and outlines how early vaccination against the infection is the best preventative measure. View on the web Inoreader. Take back control of your news feed. Follow us on Twitter and Facebook.

Dermatomyositis With Carcinoma of Unknown Primary Disease

xlomafota13 shared this article with you from Inoreader Dermatomyositis With Carcinoma of Unknown Primary Disease Via JAMA Otolaryngology–Head & Neck Surgery Current Issue This case report describes a unique case of dermatomyositis in a patient with carcinoma of unknown primary cancer in the head and neck in which neck dissection was a preceding treatment. View on the web Inoreader. Take back control of your news feed. Follow us on Twitter and Facebook.

The clinicopathological and prognostic significances of LATS1 expression in breast cancer

xlomafota13 shared this article with you from Inoreader The clinicopathological and prognostic significances of LATS1 expression in breast cancer Via Cellular and Molecular Biology Histol Histopathol. 2022 Feb 10:18433. doi: 10.14670/HH-18-433. Online ahead of print. ABSTRACT AIM: Large tumor suppressor gene 1 (LATS1) belongs to the PKA/PKG/PKC serine/threonine kinase subfamily of the Hippo signaling pathway and inactivates nuclear co-activators YAP1 and WWTR1 by phosphorylation. This study aimed to discern the clinicopathological and prognostic significances of LATS1 expression in breast cancer. METHODS: We examined LATS1 expression in breast carcinogenesis and compared it with clinicopathological parameters and survival information of breast cancer patients using immunohistochemistry, western blotting, RT-PCR, and bioinformatics analysis. RESULTS: LATS1 expression was downregulated in breast cancer at both mRNA and protein levels (P<0.05). LATS1 mRNA expression was negatively correlated with young age, nodal metastasis status, TNM staging, ER and PR expression, TP53 mutation, aggressive subtypes (TNBC and HER2+ vs. luminal), and poor survival (P<0.05). Its protein expression was negatively linked to patient age, T stage, N stage, histological grade, PR status, and unfavorable prognosis (P<0.05). There was a positive correlationship between nuclar and cytoplasmic LATS1 expression in breast cancer (P<0.05). CONCLUSIONS: The downregulation of LATS1 expression plays a vital role in the carcinogenesis and progression of breast cancer. Thus, LATS1 loss was employed to indicate the aggressive behaviors and poor prognosis of breast cancer. PMID:35142365 | DOI:10.14670/HH-18-433 View on the web Inoreader. Take back control of your news feed. Follow us on Twitter and Facebook.

Irradiated fibroblasts increase interleukin-6 expression and induce migration of head and neck squamous cell carcinoma

xlomafota13 shared this article with you from Inoreader Irradiated fibroblasts increase interleukin-6 expression and induce migration of head and neck squamous cell carcinoma Via Head and neck squamous cell carcinoma by Shinsuke Suzuki, Satoshi Toyoma, Yohei Kawasaki, Takechiyo Yamada Background Cytotoxic effects of radiation play an important role in the treatment of head and neck cancer. However, irradiation is known to lead to the migration of various cancer cells, including those of head and neck cancer. Recently, fibroblasts in the cancer microenvironment have been reported to be involved in this mechanism. Nevertheless, the mechanism underlying migration of head and neck cancer cells remains unclear. Herein, we aimed to elucidate this migration mechanism induced by irradiation in terms of the interaction of head and neck cancer cells with fibroblasts. Methods We used the head and neck squamous cell carcinoma (HNSCC) cell lines SAS and FaDu as well as fibroblast cell lines. These cells were irradiated and their viability was compared. In fibroblasts, changes in interleukin-6 (IL-6) secretion caused by irradiation were measured by enzyme-linked immunosorbent assay (ELISA). The cell migration ability of cancer cells was evaluated via a migration assay using a semipermeable membrane. HNSCC cells were cocultured with irradiated and nonirradiated fibroblasts, and their migration ability under each condition was compared. We also examined the effect of IL-6 on the migration of HNSCC cells. Furthermore, to investigate the effect of fibroblast-derived IL-6 on the migration ability of HNSCC cells, we conducted a coculture study using IL-6 neutralizing antibody. Results Irradiation reduced the survival of HNSCC cells, whereas fibroblasts were resistant to irradiation. Irradiation also increased IL-6 secretion by fibroblasts. Migration of HNSCC cells was enhanced by coculture with fibroblasts and further enhanced by coculture with irradiated fibroblasts. We also confirmed that the migration of HNSCC cells was induced by IL-6. The enhanced migration of cancer cells caused by coculturing with fibroblasts was canceled by the IL-6 neutralizing antibody. Conclusion These results show that fibroblasts survive irradiation and indu ce the migration ability of HNSCC cells through increased secretion of IL-6. View on the web Inoreader. Take back control of your news feed. Follow us on Twitter and Facebook.