Our study aimed to analyze the evolution of molecular portraits of BRCA1-driven ovarian cancer (OC) during treatment. BRCA1 loss-of-heterozygosity status (LOH) and exome profiles were investigated in serial OC samples from 13 patients, which included primary tumors (n = 11) obtained before neoadjuvant therapy (NACT) or at primary debulking surgery, residual post-NACT cancer tissues (n = 13) and tumor relapses (16 samples from 13 patients). Loss of the wild-type BRCA1 allele was detected in 11/11 (100%) primary tumors, 6/13 (46%) residual post-NACT OC samples and 15/16 (94%) OC relapses. Full tumor triplets were available for four patients undergoing NACT; whereas primary carcinomas from these patients demonstrated BRCA1 LOH, the retention of the wild-type allele was detected in all four post-NACT residual tumors. These four women provided to the study 5 recurrent OC samples; 4 out of 5 tumor relapses had BRCA1 LOH thus resembling BRCA1 status observed in primary but not residual OC tissues. TP53 mutation was detected in 12 out of 13 patients and was retained across all serial samples. OC relapses tended to acquire additional intragenic mutations in genes involved in cell migration, adhesion and cell junction assembly. BRCA1-driven OCs demonstrate the plasticity of BRCA1 status during the treatment course. NACT results in rapid selection of pre-existing BRCA1-proficient cells. However, BRCA1 proficiency appears to be disadvantageous in the absence of platinum exposure, as tumor relapses usually re-acquire BRCA1 LOH during therapy holidays.Additional Supporting Information may be found in the online version of this article.
We studied the effect of 10-week treatment with intranasal insulin (0.5 IU/day) on glucose tolerance, glucose utilization, lipid metabolism, functions of pancreatic β cells, and insulin system in the liver of rats with cafeteria diet-induced metabolic syndrome. The therapy reduced body weight and blood levels of insulin, triglycerides, and atherogenic cholesterol that are typically increased in metabolic syndrome, normalized glucose tolerance and its utilization, and increased activity of insulin signaling system in the liver, thus reducing insulin resistance. The therapy did not affect the number of pancreatic islets and β cells. The study demonstrates prospects of using intranasal insulin for correction of metabolic parameters and reduction of insulin resistance in metabolic syndrome.
Aims:
The aim of the experiments was to find out the factors on which age-related sensitivity to the occurrence
of BPH depends.
Methods:
45 male Wistar rats aged 3 and 24 months were used. In each age group there were intact rats and animals with
induced BPH (by surgical castration + testosterone injections, 25 mg/kg x 7). On the 36th day of the experiment, blood
was taken from rats to determine serum testosterone, cholesterol, triglycerides and glucose; then the animals were
autopsied, their prostates were weighed, and their morphology was studied.
Results:
Young mature intact rats had much higher testosterone levels (6.2±0.93 nmol/l) than old intact (3.8±0.55 nmol/l),
while the ratio of prostate weight was inverse. The weight of the prostate and prostatic index in old rats with induced BPH
was significantly higher not only in comparison with the old intact rats but also with young animals after BPH induction.
Morphologically, the inflammatory foci were determined not only in the prostates of old rats, which induced BPH, but
also in intact animals. Besides in old intact rats, the foci of prostate hyperplasia were often noted.
Conclusions:
Our experimental model indicates the important role of non-bacterial prostatitis in the pathogenesis of BPH.
No metabolic disorders in BPH induction were revealed. The sensitivity of the prostate of old rats to BPH development is
increasing despite the low concentrations of testosterone in the body. Age sensitivity to BPH is probably determined by a
higher expression of androgen receptors in old animals.
Vemurafenib, a specific inhibitor of mutated BRAF kinase, may activate wild-type BRAF and therefore induce squamous cell skin carcinomas in patients treated for melanoma. All vemurafenib clinical trials excluded patients with multiple primary malignant tumors; therefore, the action of this drug on concurrent BRAF wild-type malignancies remains insufficiently studied. We observed a patient, who was administered vemurafenib for BRAF mutation-containing melanoma, but experienced immediate relapse of previously controlled breast cancer disease. Interestingly, breast cancer lesions underwent regression soon after vemurafenib discontinuation. Therefore, caution must be taken while considering vemurafenib treatment for patients with multiple tumors.
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