scholarly journals Molecular Profiling and Research of Therapeutic Targets

2015 ◽  
Vol 33 (4) ◽  
pp. 586-589 ◽  
Author(s):  
Sumera Rizvi ◽  
Gregory J. Gores
Keyword(s):  
Hepatocellular Carcinoma ◽  
Clinical Practice ◽  
Patient Care ◽  
Targeted Therapies ◽  
Genetic Information ◽  
Therapeutic Targets ◽  
Molecular Profiling ◽  
Heterogeneous Nature ◽  
Promoter Mutations ◽  
Made In

The heterogeneous nature of hepatocellular carcinoma (HCC) poses a challenge to effective therapy. Significant strides have been made in molecular profiling. Telomerase promoter mutations are now known to represent early events in linear carcinogenesis. However, the translation of these advances into clinical practice has been limited. Although further work is needed to extrapolate genetic information to patient care, progress has been made in using genetics and stratification for HCC therapy. Targeted therapies for patients with c-MET overexpression, VEGF-A amplification and Wnt β-catenin-driven tumors offer promise.

scholarly journals Molecular profiling-based decision for targeted therapies in IDH wild-type glioblastoma

2020 ◽  
Vol 2 (1) ◽  
Author(s):  
Tobias Kessler ◽  
Anne Berberich ◽  
Belen Casalini ◽  
Katharina Drüschler ◽  
Hannah Ostermann ◽  
...  
Keyword(s):  
Decision Making ◽  
Clinical Practice ◽  
Targeted Therapies ◽  
Clinical Decision Making ◽  
Molecular Profiling ◽  
Copy Number Variations ◽  
Wild Type ◽  
Number Of Patients ◽  
Mgmt Promoter ◽  
Molecular Assessment

Abstract Background Molecular profiling allows tumor classification as well as assessment of diagnostic, prognostic, and treatment-related molecular changes. Translation into clinical practice and relevance for patients has not been demonstrated yet. Methods We analyzed clinical and molecular data of isocitrate dehydrogenase wild-type glioblastoma patients with sufficient clinical follow-up from the Heidelberg Neuro-Oncology Center and with molecular analysis of tumor tissue that consisted of DNA methylation array data, genome-scale copy number variations, gene panel sequencing, and partly mTOR immunohistochemistry between October 2014 and April 2018. Results Of 536 patients screened, molecular assessment was performed in 253 patients (47%) in a prospective routine clinical setting with further clinical appointments. Therapy decision was directly based on the molecular assessment in 97 (38%) patients. Of these, genetic information from MGMT (n = 68), EGFR (n = 7), CDKN2A/B (n = 8), alterations of the PI3K–AKT–mTOR pathway (n = 5), and BRAF (n = 3) have been the most frequently used for decision making with a positive overall survival signal for patients with glioblastoma harboring an unmethylated MGMT promoter treated according to the molecular assignment. Based on detected molecular alterations and possible targeted therapies, we generated an automated web-based prioritization algorithm. Conclusion Molecular decision making in clinical practice was mainly driven by MGMT promoter status in elderly patients and study inclusion criteria. A reasonable number of patients have been treated based on other molecular aberrations. This study prepares for complex molecular decisions in a routine clinical decision making.

Diagnosis and Management of Cardiomyopathies – A Focus on Genetics, Cardiac Magnetic Resonance and Clinical Features

2011 ◽  
Vol 7 (3) ◽  
pp. 225
Author(s):  
Gianfranco Sinagra ◽  
Michele Moretti ◽  
Giancarlo Vitrella ◽  
Marco Merlo ◽  
Rossana Bussani ◽  
...  
Keyword(s):  
Clinical Practice ◽  
Cardiac Magnetic Resonance ◽  
Magnetic Resonance ◽  
Imaging Techniques ◽  
Molecular Genetic ◽  
Molecular Genetic Analysis ◽  
Routine Clinical Practice ◽  
Clinical Approach ◽  
Diagnosis And Management ◽  
Made In

In recent years, outstanding progress has been made in the diagnosis and treatment of cardiomyopathies. Genetics is emerging as a primary point in the diagnosis and management of these diseases. However, molecular genetic analyses are not yet included in routine clinical practice, mainly because of their elevated costs and execution time. A patient-based and patient-oriented clinical approach, coupled with new imaging techniques such as cardiac magnetic resonance, can be of great help in selecting patients for molecular genetic analysis and is crucial for a better characterisation of these diseases. This article will specifically address clinical, magnetic resonance and genetic aspects of the diagnosis and management of cardiomyopathies.

Targeted Therapies in Hepatocellular Carcinoma

2014 ◽  
Vol 21 (8) ◽  
pp. 966-974 ◽  
Author(s):  
F. Bronte ◽  
G. Bronte ◽  
S. Cusenza ◽  
E. Fiorentino ◽  
C. Rolfo ◽  
...  
Keyword(s):  
Hepatocellular Carcinoma ◽  
Targeted Therapies

Imaging of Bacteria: Is there Any Hope for the Future Based on Past Experience?

2018 ◽  
Vol 24 (7) ◽  
pp. 772-786 ◽  
Author(s):  
Thomas Ebenhan ◽  
Elena Lazzeri ◽  
Olivier Gheysens
Keyword(s):  
Clinical Practice ◽  
Sterile Inflammation ◽  
Ageing Population ◽  
Major Health Problem ◽  
Major Health ◽  
Number Of Patients ◽  
Implanted Medical Devices ◽  
Neutropenic Patients ◽  
Socio Economic Impact ◽  
Made In

Infectious diseases remain a major health problem and cause of death worldwide. It is expected that the socio-economic impact will further intensify due to escalating resistance to antibiotics, an ageing population and an increase in the number of patients under immunosuppressive therapy and implanted medical devices. Even though radiolabeled probes and leukocytes are routinely used in clinical practice, it might still be difficult to distinguish sterile inflammation from inflammation caused by bacteria. Moreover, the majority of these probes are based on the attraction of leukocytes which may be hampered in neutropenic patients. Novel approaches that can be implemented in clinical practice and allow for swift diagnosis of infection by targeting the microorganism directly, are posing an attractive strategy. Here we review the current strategies to directly image bacteria using radionuclides and we provide an overview of the preclinical efforts to develop and validate new approaches. Indeed, significant progress has been made in the past years, but very few radiopharmaceuticals (that were promising in preclinical studies) have made it into clinical practice. We will discuss the challenges that remain to select good candidates for imaging agents targeting bacteria.

scholarly journals Transcriptional Regulation of Genes Encoding the Selenium-Free [NiFe]-Hydrogenases in the Archaeon Methanococcus voltae Involves Positive and Negative Control Elements

Genetics ◽  
1999 ◽  
Vol 152 (4) ◽  
pp. 1335-1341
Author(s):  
Izabela Noll ◽  
Steffen Müller ◽  
Albrecht Klein
Keyword(s):  
Intergenic Region ◽  
Genetic Information ◽  
Regulatory Element ◽  
Transcription Unit ◽  
Negative Control ◽  
Negative Regulation ◽  
Negative Regulatory Element ◽  
Methanococcus Voltae ◽  
Genes Encoding ◽  
Made In

Abstract Methanococcus voltae harbors genetic information for two pairs of homologous [NiFe]-hydrogenases. Two of the enzymes contain selenocysteine, while the other two gene groups encode apparent isoenzymes that carry cysteinyl residues in the homologous positions. The genes coding for the selenium-free enzymes, frc and vhc, are expressed only under selenium limitation. They are transcribed out of a common intergenic region. A series of deletions made in the intergenic region localized a common negative regulatory element for the vhc and frc promoters as well as two activator elements that are specific for each of the two transcription units. Repeated sequences, partially overlapping the frc promoter, were also detected. Mutations in these repeated heptanucleotide sequences led to a weak induction of a reporter gene under the control of the frc promoters in the presence of selenium. This result suggests that the heptamer repeats contribute to the negative regulation of the frc transcription unit.

scholarly journals Management of Hepatocellular Carcinoma in Japan: JSH Consensus Statements and Recommendations 2021 Update

Liver Cancer ◽  
2021 ◽  
pp. 1-43
Author(s):  
Masatoshi Kudo ◽  
Yusuke Kawamura ◽  
Kiyoshi Hasegawa ◽  
Ryosuke Tateishi ◽  
Kazuya Kariyama ◽  
...  
Keyword(s):  
Hepatocellular Carcinoma ◽  
Clinical Practice ◽  
Public Relations ◽  
Clinical Practice Guidelines ◽  
Practice Guidelines ◽  
Expert Panel ◽  
Clinical Practices ◽  
Fourth Edition ◽  
Level Of Evidence ◽  
Consensus Statements

The Clinical Practice Manual for Hepatocellular Carcinoma was published based on evidence confirmed by the Evidence-based Clinical Practice Guidelines for Hepatocellular Carcinoma along with consensus opinion among a Japan Society of Hepatology (JSH) expert panel on hepatocellular carcinoma (HCC). Since the JSH Clinical Practice Guidelines are based on original articles with extremely high levels of evidence, expert opinions on HCC management in clinical practice or consensus on newly developed treatments are not included. However, the practice manual incorporates the literature based on clinical data, expert opinion, and real-world clinical practice currently conducted in Japan to facilitate its use by clinicians. Alongside each revision of the JSH Guidelines, we issued an update to the manual, with the first edition of the manual published in 2007, the second edition in 2010, the third edition in 2015, and the fourth edition in 2020, which includes the 2017 edition of the JSH Guideline. This article is an excerpt from the fourth edition of the HCC Clinical Practice Manual focusing on pathology, diagnosis, and treatment of HCC. It is designed as a practical manual different from the latest version of the JSH Clinical Practice Guidelines. This practice manual was written by an expert panel from the JSH, with emphasis on the consensus statements and recommendations for the management of HCC proposed by the JSH expert panel. In this article, we included newly developed clinical practices that are relatively common among Japanese experts in this field, although all of their statements are not associated with a high level of evidence, but these practices are likely to be incorporated into guidelines in the future. To write this article, coauthors from different institutions drafted the content and then critically reviewed each other’s work. The revised content was then critically reviewed by the Board of Directors and the Planning and Public Relations Committee of JSH before publication to confirm the consensus statements and recommendations. The consensus statements and recommendations presented in this report represent measures actually being conducted at the highest-level HCC treatment centers in Japan. We hope this article provides insight into the actual situation of HCC practice in Japan, thereby affecting the global practice pattern in the management of HCC.

scholarly journals Significance of TERT Genetic Alterations and Telomere Length in Hepatocellular Carcinoma

Cancers ◽  
2021 ◽  
Vol 13 (9) ◽  
pp. 2160
Author(s):  
Jeong-Won Jang ◽  
Jin-Seoub Kim ◽  
Hye-Seon Kim ◽  
Kwon-Yong Tak ◽  
Soon-Kyu Lee ◽  
...  
Keyword(s):  
Hepatocellular Carcinoma ◽  
Telomere Length ◽  
Differentially Expressed Gene ◽  
Genetic Alterations ◽  
Tissue Samples ◽  
Protein Protein Interaction ◽  
Tert Promoter ◽  
Tert Promoter Mutations ◽  
Promoter Mutations ◽  
Tert Expression

Telomerase reverse transcriptase (TERT) mutations are reportedly the most frequent somatic genetic alterations in hepatocellular carcinoma (HCC). An integrative analysis of TERT-telomere signaling during hepatocarcinogenesis is lacking. This study aimed to investigate the clinicopathological association and prognostic value of TERT gene alterations and telomere length in HCC patients undergoing hepatectomy as well as transarterial chemotherapy (TACE). TERT promoter mutation, expression, and telomere length were analyzed by Sanger sequencing and real-time PCR in 305 tissue samples. Protein–protein interaction (PPI) analysis was performed to identify a set of genes that physically interact with TERT. The PPI analysis identified eight key TERT-interacting genes, namely CCT5, TUBA1B, mTOR, RPS6KB1, AKT1, WHAZ, YWHAQ, and TERT. Among these, TERT was the most strongly differentially expressed gene. TERT promoter mutations were more frequent, TERT expression was significantly higher, and telomere length was longer in tumors versus non-tumors. TERT promoter mutations were most frequent in HCV-related HCCs and less frequent in HBV-related HCCs. TERT promoter mutations were associated with higher TERT levels and longer telomere length and were an independent predictor of worse overall survival after hepatectomy. TERT expression was positively correlated with tumor differentiation and stage progression, and independently predicted shorter time to progression after TACE. The TERT-telomere network may have a crucial role in the development and progression of HCC. TERT-telomere abnormalities might serve as useful biomarkers for HCC, but the prognostic values may differ with tumor characteristics and treatment.

scholarly journals Clinical Utility of Real-Time Targeted Molecular Profiling in the Clinical Management of Ovarian Cancer: The ALLOCATE Study

2019 ◽  
pp. 1-18
Author(s):  
Olga Kondrashova ◽  
Gwo-Yaw Ho ◽  
George Au-Yeung ◽  
Leakhena Leas ◽  
Tiffany Boughtwood ◽  
...  
Keyword(s):  
Ovarian Cancer ◽  
Real Time ◽  
Targeted Therapies ◽  
Clinical Management ◽  
Clinical Utility ◽  
Advanced Ovarian Cancer ◽  
Molecular Profiling ◽  
Molecular Testing ◽  
Low Grade ◽  
Ovarian Carcinomas

PURPOSE The ALLOCATE study was designed as a pilot to demonstrate the feasibility and clinical utility of real-time targeted molecular profiling of patients with recurrent or advanced ovarian cancer for identification of potential targeted therapies. PATIENTS AND METHODS A total of 113 patients with ovarian cancer of varying histologies were recruited from two tertiary hospitals, with 99 patient cases suitable for prospective analysis. Targeted molecular and methylation profiling of fresh biopsy and archived tumor samples were performed by screening for mutations or copy-number variations in 44 genes and for promoter methylation of BRCA1 and RAD51C. RESULTS Somatic genomic or methylation events were identified in 85% of all patient cases, with potentially actionable events with defined targeted therapies (including four resistance events) detected in 60% of all patient cases. On the basis of these findings, six patients received molecularly guided therapy, three patients had unsuspected germline cancer–associated BRCA1/ 2 mutations and were referred for genetic counseling, and two intermediate differentiated (grade 2) serous ovarian carcinomas were reclassified as low grade, leading to changes in clinical management. Additionally, secondary reversion mutations in BRCA1/ 2 were identified in fresh biopsy samples of two patients, consistent with clinical platinum/poly (ADP-ribose) polymerase inhibitor resistance. Timely reporting of results if molecular testing is done at disease recurrence, as well as early referral for patients with platinum-resistant cancers, were identified as factors that could improve the clinical utility of molecular profiling. CONCLUSION ALLOCATE molecular profiling identified known genomic and methylation alterations of the different ovarian cancer subtypes and was deemed feasible and useful in routine clinical practice. Better patient selection and access to a wider range of targeted therapies or clinical trials will further enhance the clinical utility of molecular profiling.

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