scholarly journals USP28 enables oncogenic transformation of respiratory cells and its inhibition potentiates molecular therapy targeting mutant EGFR, BRAF and PI3K.

2021 ◽  
Author(s):  
Cristian Prieto-Garcia ◽  
Oliver Hartmann ◽  
Michaela Reissland ◽  
Fabian Braun ◽  
Sueleyman Bozkurt ◽  
...  
Keyword(s):  
Transcription Factors ◽  
Early Stage ◽  
Standard Of Care ◽  
Lung Epithelial Cells ◽  
Molecular Therapy ◽  
Protein Abundance ◽  
Oncogenic Transformation ◽  
Current Standard ◽  
Growth And Survival ◽  
Activating Mutations

Oncogenic transformation of lung epithelial cells is a multi-step process, frequently starting with the inactivation of tumor suppressors and subsequent activating mutations in proto-oncogenes, such as members of the PI3K or MAPK family. Cells undergoing transformation have to adjust to changes, such as metabolic requirements. This is achieved, in part, by modulating the protein abundance of transcription factors, which manifest these adjustments. Here, we report that the deubiquitylase USP28 enables oncogenic reprogramming by regulating the protein abundance of proto-oncogenes, such as c-JUN, c-MYC, NOTCH and DNP63, at early stages of malignant transformation. USP28 is increased in cancer compared to normal cells due to a feed-forward loop, driven by increased amounts of oncogenic transcription factors, such as c-MYC and c-JUN. Irrespective of oncogenic driver, interference with USP28 abundance or activity suppresses growth and survival of transformed lung cells. Furthermore, inhibition of USP28 via a small molecule inhibitor reset the proteome of transformed cells towards a pre-malignant state, and its inhibition cooperated with clinically established compounds used to target EGFRL858R, BRAFV600E or PI3KH1047R driven tumor cells. Targeting USP28 protein abundance already at an early stage via inhibition of its activity therefore is a feasible strategy for the treatment of early stage lung tumours and the observed synergism with current standard of care inhibitors holds the potential for improved targeting of established tumors.

scholarly journals De-Escalation of Therapy for Patients with Early-Stage Squamous Cell Carcinoma of the Anus

Cancers ◽  
2021 ◽  
Vol 13 (9) ◽  
pp. 2099
Author(s):  
Eric Miller ◽  
Jose Bazan
Keyword(s):  
Squamous Cell Carcinoma ◽  
Radiation Therapy ◽  
Cell Carcinoma ◽  
Squamous Cell ◽  
Early Stage ◽  
Intensity Modulated Radiation Therapy ◽  
Late Toxicity ◽  
Standard Of Care ◽  
The Elderly ◽  
Current Standard

The incidence of squamous cell carcinoma of the anus (SCCA) is increasing, particularly in the elderly, with increased mortality in this age group. While the current standard of care for localized SCCA remains chemoradiation (CRT), completion of this treatment can be challenging with risks for severe acute and late toxicity. It remains unclear if full course CRT is required for the management of early-stage SCCA or if de-escalation of treatment is possible without compromising patient outcomes. Alternative therapies include radiation therapy alone or local excision for appropriate patients. Modifying standard CRT may also reduce toxicity including the routine use of intensity-modulated radiation therapy for treatment delivery, modification of treatment volumes, and selection and dosing of concurrent systemic therapy agents. Finally, we provide an overview of currently accruing prospective trials focused on defining the role of de-escalation of therapy in patients with early-stage SCCA.

scholarly journals Recent advances in managing gastrointestinal stromal tumor

F1000Research ◽  
2017 ◽  
Vol 6 ◽  
pp. 1689 ◽  
Author(s):  
Florence Duffaud ◽  
Axel Le Cesne
Keyword(s):  
Gastrointestinal Stromal Tumors ◽  
Growth Factor Receptor ◽  
Standard Of Care ◽  
Platelet Derived Growth Factor ◽  
Proof Of Concept ◽  
Current Standard ◽  
Stromal Tumors ◽  
Concept Model ◽  
Activating Mutations ◽  
Effective Proof

Constitutive activating mutations inKITand platelet-derived growth factor receptor α (PDGFRα) are heavily involved in the pathobiology of gastrointestinal stromal tumors (GISTs). This disease has served as an effective “proof-of-concept” model for targeting gain-of-function kinase mutations in cancer. This review discusses the current standard of care in terms of pharmacotherapy in the management of localized and metastatic GISTs.

scholarly journals Cis-acting Super-Enhancer lncRNAs as Biomarkers of Early-Stage Breast Cancer

2021 ◽  
Author(s):  
Ali Salman Ropri ◽  
Rebecca DeVaux ◽  
Jonah Eng ◽  
Sridar V. Chittur ◽  
Jason Herschkowitz
Keyword(s):  
Breast Cancer ◽  
Ductal Carcinoma ◽  
Early Stage ◽  
Global Analysis ◽  
Standard Of Care ◽  
Differentially Expressed ◽  
Current Standard ◽  
Cis Acting ◽  
Super Enhancer ◽  
Estrogen Production

Abstract Background Increased breast cancer screening over the past four decades has led to a substantial rise in the diagnosis of ductal carcinoma in situ (DCIS). Although DCIS lesions precede invasive ductal carcinoma (IDC), they do not always transform into cancer. The current standard-of-care for DCIS is an aggressive course of therapy to prevent invasive and metastatic disease resulting in over-diagnosis and over-treatment. Thus, there is a critical need to identify functional determinants of progression of DCIS to IDC to allow discrimination between indolent and aggressive disease. Recent studies show that super-enhancers, in addition to promoting other gene transcription, are themselves transcribed producing super-enhancer associated long noncoding RNAs (SE-lncRNAs). These SE-lncRNAs can interact with their associated enhancer regions in cis and influence activities and expression of neighboring genes. Furthermore, they represent a novel, untapped group of therapeutic targets.MethodsWith an integrative analysis of enhancer loci with global expression of SE-lncRNAs in the MCF10A progression series, we have identified differentially expressed SE-lncRNAs which can identify mechanisms for DCIS to IDC progression. Furthermore, cross-referencing these SE-lncRNAs with patient samples in the TCGA database, we have unveiled 31 clinically relevant SE-lncRNAs that potentially interact with their enhancer to regulate nearby gene expression. To complement SE-lncRNA expression studies, we conducted an unbiased global analysis of super-enhancers that are acquired or lost in progression. ResultsHere we designate SE-lncRNAs RP11-379F4.4 and RP11-465B22.8 as potential markers of progression of DCIS to IDC through regulation of the expression of their neighboring genes (RARRES1 and miR200b respectively). Moreover, we classified 403 super-enhancer regions in MCF10A normal cells, 627 in AT1, 1053 in DCIS, and 320 in CA1 cells. Comparison analysis of acquired/lost super-enhancer regions with super-enhancer regions classified in 47 ER positive patients, 10 Triple Negative Breast Cancer (TNBC) patients, and 11 TNBC cell lines reveal critically acquired pathways including STAT signaling and NF-kB signaling. In contrast, protein folding and local estrogen production are identified as major pathways lost in progression.ConclusionCollectively, these analyses identify differentially expressed SE-lncRNAs and acquired/lost super-enhancers in progression of breast cancer important for promoting DCIS lesions to IDC.

scholarly journals Current frontline approaches in the management of hepatocellular carcinoma: the evolving role of immunotherapy

2018 ◽  
Vol 11 ◽  
pp. 175628481880808 ◽  
Author(s):  
Gagandeep Brar ◽  
Tim F. Greten ◽  
Zachary J. Brown
Keyword(s):  
Hepatocellular Carcinoma ◽  
Survival Rate ◽  
Early Stage ◽  
Standard Of Care ◽  
Good Prognosis ◽  
Current Standard ◽  
Early Stage Disease ◽  
Advanced Hcc ◽  
Stage Disease

Hepatocellular carcinoma (HCC) is a major cause of cancer-associated mortality worldwide and is expected to rise. Patients with early-stage disease may have a good prognosis with a 5-year survival rate of greater than 70%. However, the majority of patients are diagnosed with late-stage disease with a dismal overall survival rate of less than 16%. Therefore, there is a great need for advances in the treatment of advanced HCC, which for approximately the past decade, has been sorafenib. Immunotherapy is an evolving cancer treatment and has shown promise in treating patients with advanced HCC. In this review, we discuss the current standard of care for advanced HCC and then discuss the evolving role of immunotherapies.

scholarly journals Cis-acting super-enhancer lncRNAs as biomarkers to early-stage breast cancer

2021 ◽  
Vol 23 (1) ◽  
Author(s):  
Ali S. Ropri ◽  
Rebecca S. DeVaux ◽  
Jonah Eng ◽  
Sridar V. Chittur ◽  
Jason I. Herschkowitz
Keyword(s):  
Breast Cancer ◽  
Ductal Carcinoma ◽  
Early Stage ◽  
Global Analysis ◽  
Standard Of Care ◽  
The Cancer Genome Atlas ◽  
Differentially Expressed ◽  
Current Standard ◽  
Super Enhancer ◽  
Estrogen Production

Abstract Background Increased breast cancer screening over the past four decades has led to a substantial rise in the diagnosis of ductal carcinoma in situ (DCIS). Although DCIS lesions precede invasive ductal carcinoma (IDC), they do not always transform into cancer. The current standard-of-care for DCIS is an aggressive course of therapy to prevent invasive and metastatic disease resulting in over-diagnosis and over-treatment. Thus, there is a critical need to identify functional determinants of progression of DCIS to IDC to allow discrimination between indolent and aggressive disease. Recent studies show that super-enhancers, in addition to promoting other gene transcription, are themselves transcribed producing super-enhancer associated long noncoding RNAs (SE-lncRNAs). These SE-lncRNAs can interact with their associated enhancer regions in cis and influence activities and expression of neighboring genes. Furthermore, they represent a novel, untapped group of therapeutic targets. Methods With an integrative analysis of enhancer loci with global expression of SE-lncRNAs in the MCF10A progression series, we have identified differentially expressed SE-lncRNAs which can identify mechanisms for DCIS to IDC progression. Furthermore, cross-referencing these SE-lncRNAs with patient samples in the The Cancer Genome Atlas (TCGA) database, we have unveiled 27 clinically relevant SE-lncRNAs that potentially interact with their enhancer to regulate nearby gene expression. To complement SE-lncRNA expression studies, we conducted an unbiased global analysis of super-enhancers that are acquired or lost in progression. Results Here we designate SE-lncRNAs RP11-379F4.4 and RP11-465B22.8 as potential markers of progression of DCIS to IDC through regulation of the expression of their neighboring genes (RARRES1 and miR-200b, respectively). Moreover, we classified 403 super-enhancer regions in MCF10A normal cells, 627 in AT1, 1053 in DCIS, and 320 in CA1 cells. Comparison analysis of acquired/lost super-enhancer regions with super-enhancer regions classified in 47 ER positive patients, 10 triple negative breast cancer (TNBC) patients, and 11 TNBC cell lines reveal critically acquired pathways including STAT signaling and NF-kB signaling. In contrast, protein folding, and local estrogen production are identified as major pathways lost in progression. Conclusion Collectively, these analyses identify differentially expressed SE-lncRNAs and acquired/lost super-enhancers in progression of breast cancer important for promoting DCIS lesions to IDC.

Correlation of next generation sequencing (NGS) of urine with tumor and plasma in patients with non-muscle invasive bladder cancer (NMIBC).

2017 ◽  
Vol 35 (15_suppl) ◽  
pp. e16002-e16002
Author(s):  
Chris Raymond ◽  
Alexandria Lahdya ◽  
Jenny Hernandez ◽  
Kavita Garg ◽  
Samantha Henderson ◽  
...  
Keyword(s):  
Tumor Resection ◽  
Standard Of Care ◽  
Gene Copy ◽  
Plasma Samples ◽  
Promoter Mutation ◽  
Current Standard ◽  
Activating Mutations ◽  
Plasma And Urine Samples ◽  
Number Variation ◽  
Muscle Invasive

e16002 Background: The current standard-of-care surveillance protocols for post-treatment NMIBC patients involve invasive procedures that result in poor patient compliance. Detection of recurrent NMIBC tumor DNA in plasma or urine would provide a less invasive alternative, and here we examine the feasibility of this approach by performing targeted NGS on tumor, plasma, and urine samples from NMIBC patients. Methods: 5 patients with untreated NMIBC (histology: Ta(n = 3), T1(n = 2)) have been analyzed to date. Urine and plasma samples were taken just prior to tumor resection. Samples were analyzed using a capture panel that includes common mutations found in > 80% of NMIBC patients. Coverage includes the promoter region of the TERT gene, the entire coding regions of KDM6A and FGFR3, and copy number variation in PD-L1 and JAK2. Results: Mutations were observed in all tumor samples, with the TERT -124C > T promoter mutation found in 4 patients (AF:16-84%) and the TERT -146C > T promoter mutation found in the other (AF:19%). Deleterious mutations were found in KDM6A for 4 patients, and FGFR3 activating mutations were found in 2 patients. Amplification of FGFR3 was seen in one sample. When the 4 matched pairs of urine and tumor samples were examined, all of the called mutations in tumor were also found in urine at similar allele frequencies. This includes the detection of gene copy alterations. No such mutations were observed in plasma samples despite extensive sequencing ( > 2000 unique read coverage). Conclusions: These data show that canonical NMIBC mutations are readily detectable in urine and correlate well with tumor, suggesting that NMIBC tumors shed prolifically into urine, and indicate that further investigation of NGS sequencing of urine as a means of detecting NMIBC recurrence is warranted.

scholarly journals The Double Life-Saving Approach of Abdominal Radical Trachelectomy during Pregnancy for Early-Stage Cervical Cancer—An Overview of the Literature and Our Institutional Experience

2021 ◽  
Vol 11 (1) ◽  
pp. 29
Author(s):  
Mihai Stanca ◽  
Victoria Ciobanu ◽  
Mihai Gheorghe ◽  
Szilard Leo Kiss ◽  
Alexandra Lavinia Cozlea ◽  
...  
Keyword(s):  
Cervical Cancer ◽  
Early Stage ◽  
Standard Of Care ◽  
Disease Recurrence ◽  
Current Evidence ◽  
Published Data ◽  
Radical Trachelectomy ◽  
Current Standard ◽  
Early Stage Cervical Cancer ◽  
Institutional Experience

(1) Background: Cervical cancer is the most common type of cancer encountered during pregnancy, with a frequency of 0.8–1.5 cases per 10,000 births. It is a dire condition endangering patients’ lives and pregnancy outcomes, and jeopardizing their fertility. However, there is a lack of current evidence and consensus regarding a standard surgical technique for pregnant patients who suffer from this condition during pregnancy. The study aims to comprehensively update all published data, evaluating the obstetrical and oncological results of pregnant patients who underwent abdominal radical trachelectomy during early stages of cervical cancer. (2) Methods: A literature search on the Medline, PubMed, and Google Scholar databases was performed, including all articles in question up to July 2020. This study presents an overview of the literature and our institutional experience. (3) Results: A total of 25 cases of abdominal radical trachelectomy were performed during pregnancy for early cervical cancer, including the five cases managed by the authors. Of these, 81% (19 patients) gave birth to live newborns through elective C-section, and 19% (6 patients) experienced miscarriage shortly after the procedure. None of the 25 patients (100%) reported disease recurrence. (4) Conclusions: The results of the current study were satisfactory. However, abdominal radical trachelectomy does not represent the current standard of care for cervical cancer during pregnancy, but it could play an important role if more evidence on its effectiveness will be provided.

Acute Rejection Following Kidney Transplantation: State-of-the-Art and Future Perspectives

2020 ◽  
Vol 26 (28) ◽  
pp. 3468-3496
Author(s):  
Emilio Rodrigo ◽  
Marcio F. Chedid ◽  
David San Segundo ◽  
Juan C.R. San Millán ◽  
Marcos López-Hoyos
Keyword(s):  
Kidney Transplantation ◽  
Acute Rejection ◽  
Rescue Therapy ◽  
Standard Of Care ◽  
Rejection Rate ◽  
New Drugs ◽  
High Dose ◽  
Current Standard ◽  
Antibody Mediated Rejection ◽  
Cellular Rejection

: Although acute renal graft rejection rate has declined in the last years, and because an adequate therapy can improve graft outcome, its therapy remains as one of the most significant challenges for pharmacists and physicians taking care of transplant patients. Due to the lack of evidence highlighted by the available metaanalyses, we performed a narrative review focused on the basic mechanisms and current and future therapies of acute rejection in kidney transplantation. : According to Kidney Disease/Improving Global Outcomes (KDIGO) guidelines, both clinical and subclinical acute rejection episodes should be treated. Usually, high dose steroids and basal immunosuppression optimization are the first line of therapy in treating acute cellular rejection. Rabbit antithymocytic polyclonal globulins are used as rescue therapy for recurrent or steroid-resistant cellular rejection episodes. Current standard-of-care (SOC) therapy for acute antibody-mediated rejection (AbMR) is the combination of plasma exchange with intravenous immunoglobulin (IVIG). Since a significant rate of AbMR does not respond to SOC, different studies have analyzed the role of new drugs such as Rituximab, Bortezomib, Eculizumab and C1 inhibitors. Lack of randomized controlled trials and heterogenicity among performed studies limit obtaining definite conclusions. Data about new direct and indirect B cell and plasma cell depleting agents, proximal and terminal complement blockers, IL-6/IL-6R pathway inhibitors and antibody removal agents, among other promising drugs, are reviewed.

scholarly journals Non-Albumin Proteinuria (NAP) as a Complementary Marker for Diabetic Kidney Disease (DKD)

Life ◽  
2021 ◽  
Vol 11 (3) ◽  
pp. 224
Author(s):  
Jaehyun Bae ◽  
Young Jun Won ◽  
Byung-Wan Lee
Keyword(s):  
Kidney Disease ◽  
Filtration Rate ◽  
Diabetic Kidney Disease ◽  
Estimated Glomerular Filtration Rate ◽  
Early Stage ◽  
Screening Tools ◽  
Tubular Injury ◽  
Current Standard ◽  
Diabetic Kidney ◽  
Wide Range

Diabetic kidney disease (DKD) is one of the most common forms of chronic kidney disease. Its pathogenic mechanism is complex, and it can affect entire structures of the kidney. However, conventional approaches to early stage DKD have focused on changes to the glomerulus. Current standard screening tools for DKD, albuminuria, and estimated glomerular filtration rate are insufficient to reflect early tubular injury. Therefore, many tubular biomarkers have been suggested. Non-albumin proteinuria (NAP) contains a wide range of tubular biomarkers and is convenient to measure. We reviewed the clinical meanings of NAP and its significance as a marker for early stage DKD.

Sign in / Sign up

Export Citation Format

Share Document