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.

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.

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.

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.

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.

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.

Falls Among People With Bilateral Vestibulopathy

xlomafota13 shared this article with you from Inoreader Falls Among People With Bilateral Vestibulopathy Via JAMA Otolaryngology–Head & Neck Surgery Current Issue This review examines the current knowledge and applied methods on fall incidence, causes, and injuries in bilateral vestibulopathy. View on the web Inoreader. Take back control of your news feed. Follow us on Twitter and Facebook.

Controversy over the temporal cortical terminations of the left arcuate fasciculus: a reappraisal

xlomafota13 shared this article with you from Inoreader Controversy over the temporal cortical terminations of the left arcuate fasciculus: a reappraisal Via cortical auditory Brain. 2022 Feb 10:awac057. doi: 10.1093/brain/awac057. Online ahead of print. ABSTRACT The arcuate fasciculus has been considered a major dorsal fronto-temporal white matter pathway linking frontal language production regions with auditory perception in the superior temporal gyrus, the so-called Wernicke's area. In line with this tradition, both historical and contemporary models of language function have assigned primacy to superior temporal projections of the arcuate fasciculus. However, classical anatomical descriptions and emerging behavioural data are at odds with this assumption. On one hand, fronto-temporal projections to Wernicke's area may not be unique to the arcuate fasciculus. On the other hand, dorsal stream language deficits have been reported also for damage to middle, inferior and basal temporal gyri which may be linked to arcuate disconnection. These findings point to a reappraisal of arcuate projections in the temporal lobe . Here, we review anatomical and functional evidence regarding the temporal cortical terminations of the left arcuate fasciculus by incorporating dissection and tractography findings with stimulation data using cortico-cortical evoked potentials and direct electrical stimulation mapping in awake patients. Firstly, we discuss the fibers of the arcuate fasciculus projecting to the superior temporal gyrus and the functional rostro-caudal gradient in this region where both phonological encoding and auditory-motor transformation may be performed. Caudal regions within the temporoparietal junction may be involved in articulation and associated with temporoparietal projections of the third branch of the superior longitudinal fasciculus, while more rostral regions may support encoding of acoustic phonetic features, supported by arcuate fibres. We then move to examine clinical data showing that multimodal phonological encoding is facilitated by projections of the arcuate fasciculus to superi or, but also middle, inferior and basal temporal regions. Hence, we discuss how projections of the arcuate fasciculus may contribute to acoustic (middle-posterior superior and middle temporal gyri), visual (posterior inferior temporal/fusiform gyri comprising the visual word form area) and lexical (anterior-middle inferior temporal/fusiform gyri in the basal temporal language area) information in the temporal lobe to be processed, encoded and translated into a dorsal phonological route to the frontal lobe. Finally, we point out surgical implications for this model in terms of the prediction and avoidance of neurological deficit. PMID:35142842 | DOI:10.1093/brain/awac057 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.