Gain of Function (GOF) Mutant p53 in Cancer-Current Therapeutic Approaches.

Continuous development of personalized treatments is undoubtedly beneficial for oncogenic patients' comfort and survival rate. Mutant TP53 is associated with a worse prognosis due to the occurrence of metastases, increased chemoresistance, and tumor growth. Currently, numerous compounds capable of p53 reactivation or the destabilization of mutant p53 are being investigated. Several of them, APR-246, COTI-2, SAHA, and PEITC, were approved for clinical trials. This review focuses on these novel therapeutic opportunities, their mechanisms of action, and their significance for potential medical application.

Gain-of-Function Mutations in p53 in Cancer Invasiveness and Metastasis.

Forty years of research has proven beyond any doubt that p53 is a key regulator of many aspects of cellular physiology. It is best known for its tumor suppressor function, but it is also a regulator of processes important for maintenance of homeostasis and stress response. Its activity is generally antiproliferative and when the cell is damaged beyond repair or intensely stressed the p53 protein contributes to apoptosis. Given its key role in preventing cancer it is no wonder that it is the most frequently mutated gene in human cancer. Surprisingly, a subset of missense mutations occurring in p53 (gain-of-function) cause it to lose its suppressor activity and acquire new functionalities that turn the tumor suppressor protein into an oncoprotein. A solid body of evidence exists demonstrating increased malignancy of cancers with mutated p53 in all aspects considered "hallmarks of cancer". In this review, we summarize current findings concerning the cellular processes altered by gain-of-function mutations in p53 and their influence on cancer invasiveness and metastasis. We also present the variety of molecular mechanisms regulating these processes, including microRNA, direct transcriptional regulation, protein-protein interactions, and more.

Glycolytic flux in Saccharomyces cerevisiae is dependent on RNA polymerase III and its negative regulator Maf1.

Protein biosynthesis is energetically costly, is tightly regulated and is coupled to stress conditions including glucose deprivation. RNA polymerase III (RNAP III)-driven transcription of tDNA genes for production of tRNAs is a key element in efficient protein biosynthesis. Here we present an analysis of the effects of altered RNAP III activity on the Saccharomyces cerevisiae proteome and metabolism under glucose-rich conditions. We show for the first time that RNAP III is tightly coupled to the glycolytic system at the molecular systems level. Decreased RNAP III activity or the absence of the RNAP III negative regulator, Maf1 elicit broad changes in the abundance profiles of enzymes engaged in fundamental metabolism in S. cerevisiae In a mutant compromised in RNAP III activity, there is a repartitioning towards amino acids synthesis de novo at the expense of glycolytic throughput. Conversely, cells lacking Maf1 protein have greater potential for glycolytic flux.

[Twenty years long experience in the breast conserving treatment of women with preinvasive breast cancer. Evaluation of long term results and analysis of prognostic factors.] / Dwadziescia lat doswiadczen w leczeniu oszczedzajacym u kobiet chorych na przedinwazyjnego raka gruczolu piersiowego. Ocena odleglych wyników i analiza czynników rokowniczych.

AIM: The aim of the study was to analyze long term results and prognostic factors in women with preinvasive breast cancer (DCIS - ductal carcinoma in situ) who underwent breast conserving surgery with subsequent radiotherapy. MATERIALS AND METHODS: A total number of 106 patients was analyzed aged 29-78 years; mean age was 54,3 years and median 55 years. In 78 (73,5%) patients the tumor was diagnosed incidentally on mammography or ultrasound scan, 28 (26,5%) had palpable lesion. 57 patients had the tumor in the left breast and 49 in the right one. Most often the tumor was localized in external quadrants, namely in 56 (52,8%) patients. All patients had breast conserving surgery and then adjuvant radiotherapy of the breast in typical doses. For evaluation of survival we used the Kaplan-Meier test and for evaluation of cumulated loco-regional recurrence we have applied the method of competing risks. RESULTS: At present 101 patients are still alive, 85 have no relapse. 15 patients had local recurrence and 8 had another cancer. Five patients died during follow-up period. Overall 15-years survival in analyzed group was 88% and disease free survival was 74%. Of all prognostic factors only the value of Van Nuys index was relevant. Patients who had the index value less than 7 had significantly worse prognosis than patients with value 7 or more (p=0,043). CONCLUSIONS: At present 101 patients are still alive, 85 have no relapse. 15 patients had local recurrence and 8 had another cancer. Five patients died during follow-up period. Overall 15-years survival in analyzed group was 88% and disease free survival was 74%. Of all prognostic factors only the value of Van Nuys index was relevant. Patients who had the index value less than 7 had significantly worse prognosis than patients with value 7 or more (p=0,043).

[Intracavitary 500KHZ hyperthermia treatment of patients with endometrial and cervical cancer--preliminary clinical and pathological results]. / Wstepne wyniki zastosowania sródjamowej hipertermii 500 kHz u chorych na raka szyjki i trzonu macicy--ocena kliniczna i patologiczna.

Therapeutic effectiveness of elevated temperature is a well known issue. However raising the temperature inside the tumor sparing concurrently surrounding healthy tissue is not an easy task. Intracavitary, radiofrequency hyperthermia in uterine tumor cases allows to obtain elevated temperature in a simple, effective and safe way. Hyperthermic procedure was performed in 30 patients with cervical and endometrial cancer. In 10 cases it was a part of standard radiotherapy, in 20 hyperthermia proceeded radical surgery. A computer--controlled 300W amplifier and generator was used. Energy was transmitted via a modified Fletcher--type applicator. One or two 45-60 minute lasting sessions, with temperature reaching 46-49 degrees C were performed in each case. No severe side effects were seen. In a group where surgery was performed a characteristic temperature-induced changes were observed on tissue and cellular level. Higher number of performed procedures will be a base for randomized trials and, in the future enables us to incorporate hyperthermia into standard radiotherapy.