Extrarenal expression of α-klotho, the kidney related longevity gene, in Heterocephalus glaber, the long living Naked Mole Rat.

The Naked Mole Rat (NMR), Heterocephalus glaber, provides an interesting model for studying biomarkers of longevity due to its long lifespan of more than 30 years, almost ten times longer than that of mice and rats. α-Klotho (klotho) is an aging-suppressor gene, and overexpression of klotho is associated with extended lifespan in mice. Klotho is predominantly expressed in the kidney. The expression profile of klotho in the NMR has not previously been reported. The present investigation studied the expression of klotho in the kidney of NMR with that of Rattus Norvegicus (RN) and demonstrated that klotho was expressed in the kidney of NMR at the same level as found in RN. Besides, a significant expression of Kl mRNA was found in the liver of NMR, in contrast to RN, where no hepatic expression was detected. The Klotho expression was further confirmed at the protein level. Thus, the results of the present comparative study indicate a differential tissue expression of klotho between different species. Besides its important function in the kidney, Klotho might also be of significance in the liver of NMR. It is suggested that the hepatic extrarenal expression of klotho may function as a further longevity-related factor in supplement to the Klotho in the kidney.

Association of Regulatory and Adaptive Status in Humans with Serotonergic Transmitter System Gene Polymorphism.

The regulatory and adaptive status was determined in 202 healthy subjects by the parameters of the cardiorespiratory synchronism probe. We performed molecular-genetic analysis of polymorphic variants of the main gene of serotonin biosynthesis, tryptophan hydroxylase TPH1 (A218C polymorphism) and TPH2 (G703T polymorphism), and serotonin receptors (HTR2C and HTR2A genes). The association of the regulatory and adaptive status of a subject with the polymorphism of serotonergic mediator system genes was revealed.

AKT overactivation can suppress DNA repair via p70S6 kinase-dependent downregulation of MRE11.

Deregulated AKT kinase activity due to PTEN deficiency in cancer cells contributes to oncogenesis by incompletely understood mechanisms. Here, we show that PTEN deletion in HCT116 and DLD1 colon carcinoma cells leads to suppression of CHK1 and CHK2 activation in response to irradiation, impaired G2 checkpoint proficiency and radiosensitization. These defects are associated with reduced expression of MRE11, RAD50 and NBS1, components of the apical MRE11/RAD50/NBS1 (MRN) DNA damage response complex. Consistent with reduced MRN complex function, PTEN-deficient cells fail to resect DNA double-strand breaks efficiently after irradiation and show greatly diminished proficiency for DNA repair via the error-free homologous recombination (HR) repair pathway. MRE11 is highly unstable in PTEN-deficient cells but stability can be significantly restored by inhibiting mTORC1 or p70S6 kinase (p70S6K), downstream kinases whose activities are stimulated by AKT, or by mutating a residue in MRE11 that we show is phosphorylated by p70S6K in vitro. In primary human fibroblasts, activated AKT suppresses MRN complex expression to escalate RAS-induced DNA damage and thereby reinforce oncogene-induced senescence. Taken together, our data demonstrate that deregulation of the PI3K-AKT/ mTORC1/ p70S6K pathways, an event frequently observed in cancer, exert profound effects on genome stability via MRE11 with potential implications for tumour initiation and therapy.

A phase III trial comparing oral S-1/cisplatin and intravenous 5-fluorouracil/cisplatin in patients with untreated diffuse gastric cancer.

BACKGROUND: The effect of histology-based treatment regimen on diffuse gastric adenocarcinoma has not been evaluated in clinical trials. This international phase III trial evaluated the efficacy and safety of S-1 (a contemporary oral fluoropyrimidine)/cisplatin versus 5-fluorouracil (5-FU)/cisplatin in chemotherapy-naïve patients with diffuse-type adenocarcinoma involving the gastroesophageal junction or stomach. PATIENTS AND METHODS: Eligibility criteria included untreated, measurable, advanced diffuse adenocarcinoma confirmed by central pathology and performance status of 0-1. Patients were randomized (2 : 1) to receive S-1/cisplatin or 5-FU/cisplatin. Primary end point was overall survival (OS), and secondary end points were progression-free survival, time to treatment failure, overall response rate, and safety. A multivariable analysis was also carried out. RESULTS: Overall, 361 patients were randomized (S-1/cisplatin, n = 239; 5-FU/cisplatin, n = 122); half (51%) were men, and median age was 56.0 years. In each group, median number of treatment cycles per patient was 4 (range, S-1/cisplatin: 1-20; 5-FU/cisplatin: 1-30), and dose intensity was >95%. OS was not different in the two groups {median OS with S-1/cisplatin, 7.5 [95% confidence interval (CI): 6.7, 9.3]; 5-FU/cisplatin, 6.6 [95% CI: 5.7, 8.1] months; hazard ratio, 0.99 [95% CI: 0.76, 1.28]; P = 0.9312}. Overall response rate was significantly higher in the S-1/cisplatin than 5-FU/cisplatin group (34.7% versus 19.8%; P = 0.01), but progression-free survival and time to treatment failure were not different. Safety was similar between the 2 groups; however, fewer patients treated with S-1/cisplatin than 5-FU/cisplatin had ≥1 grade 3/4 treatment-emergent adverse event or ≥1 adverse event resulting in treatment discontinuation. One treatment-related death occurred in each group. Slow accrual led to early termination. CONCLUSIONS: These data suggest that S-1/cisplatin and 5-FU/cisplatin are similar in efficacy and safety in untreated patients with advanced diffuse adenocarcinoma of the gastroesophageal junction or stomach. The primary end point was not met. CLINICALTRIAL.GOV REGISTRATION NUMBER: NCT01285557.

[CDC73 mutations in young patients with primary hyperparathyroidism: A description of two clinical cases]. / Mutatsii v gene CDC73 u molodykh patsientok s pervichnym giperparatireozom (opisanie dvukh klinicheskikh sluchaev).

The article describes two clinical cases of severe primary hyperparathyroidism (PHPT) caused by parathyroid carcinoma in young female patients who underwent molecular genetic testing to rule out the hereditary forms of PHPT. In both patients, heterozygous germline nonsense mutations of tumor suppressor gene CDC73 encoding parafibromin (p.R91X and p.Q166X) were identified using next-generation sequencing with Ion Torrent Personal Genome Machine (Thermo Fisher Scientific - Life Technologies, USA). It is the first description of CDC73 mutations in Russia, one of the mutations is described for the first time in the world. Identification of germline mutations in the CDC73 gene in patients with PHPT necessitates regular lifelong screening for other manifestations of hyperparathyroidism-jaw tumor syndrome (HPT-JT), PHPT recurrence due to parathyroid carcinoma as well, and identification of mutation carriers among first-degree relatives.

[Chemoradiotherapy for locally advanced cervical cancer].

Cervical cancer takes second place in morbidity and third place in mortality from gynecological cancer. Advanced stages among newly diagnosed cases is still large. The "gold standard" of treatment for locally advanced cervical cancer is chemoradiotherapy with cisplatin that results in a lower risk of death. Improvement of radiotherapy methods allowed to bring optimal dose to the primary tumor with the inclusion of regional metastasis areas with less risk of damage to surrounding healthy tissue and organs. The search for alternative combinations of cytostatics, modes of drug administration, adjuvant chemotherapy after chemoradiotherapy showed an increase in survival of patients with locally advanced cervical cancer.

Maintenance bevacizumab-pemetrexed after first-line cisplatin-pemetrexed-bevacizumab for advanced nonsquamous nonsmall-cell lung cancer: updated survival analysis of the AVAPERL (MO22089) randomized phase III trial.

BACKGROUND: The randomized, phase III AVAPERL trial evaluated the safety and efficacy of bevacizumab maintenance with or without pemetrexed in nonsquamous nonsmall-cell lung cancer (nsNSCLC). Progression-free survival (PFS) was significantly prolonged with bevacizumab-pemetrexed, but overall survival (OS) data were immature. In this article, we report an independent, updated analysis of survival outcomes in AVAPERL. PATIENTS AND METHODS: Patients with advanced nsNSCLC received first-line bevacizumab (7.5 mg/kg), cisplatin (75 mg/m(2)), and pemetrexed (500 mg/m(2)) every 3 weeks (q3w) for four cycles. Nonprogressing patients were randomized to maintenance bevacizumab (7.5 mg/kg) or bevacizumab-pemetrexed (500 mg/m(2)) q3w until progression or consent withdrawal. The primary end point of the trial was PFS; in this independent OS analysis, participating study centers were contacted to collect survival data on patients still alive at the time of the first analysis. RESULTS: A total of 376 patients received induction treatment. Disease control was confirmed in 71.9% of patients; 253 patients were randomized to maintenance treatment with bevacizumab (n = 125) or bevacizumab-pemetrexed (n = 128). At a median follow-up of 14.8 months, patients allocated to bevacizumab-pemetrexed had significantly improved PFS versus those on bevacizumab when measured from randomization [7.4 versus 3.7 months, hazard ratio (HR), 0.57, 95% confidence interval (CI) 0.44-0.75); P < 0.0001]. OS events occurred in 58% of all patients. OS was numerically longer with bevacizumab-pemetrexed versus bevacizumab when measured from randomization [17.1 versus 13.2 months, HR 0.87 (0.63-1.21); P = 0.29]. Second-line therapy was administered in 77% and 70% of patients in the bevacizumab and bevacizumab-pemetrexed arms, respectively. No new adverse events were reported during this updated analysis. CONCLUSION: In an unselected population of nsNSCLC patients achieving disease control on platinum-based induction therapy, maintenance with bevacizumab-pemetrexed was associated with a nonsignificant increase in OS over bevacizumab alone.

Combination of cisplatin/S-1 in the treatment of patients with advanced gastric or gastroesophageal adenocarcinoma: Results of noninferiority and safety analyses compared with cisplatin/5-fluorouracil in the First-Line Advanced Gastric Cancer Study.

BACKGROUND: The aim of developing oral fluorouracil (5-FU) is to provide a more convenient administration route with similar efficacy and the best achievable tolerance. S-1, a novel oral fluoropyrimidine, was specifically designed to overcome the limitations of intravenous fluoropyrimidine therapies. PATIENTS AND METHODS: A multicentre, randomised phase 3 trial was undertaken to compare S-1/cisplatin (CS) with infusional 5-FU/cisplatin (CF) in 1053 patients with untreated, advanced gastric/gastroesophageal adenocarcinoma. This report discusses a post-hoc noninferiority overall survival (OS) and safety analyses. RESULTS: Results (1029 treated; CS = 521/CF = 508) revealed OS in CS (8.6 months) was statistically noninferior to CF (7.9 months) [hazard ratio (HR) = 0.92 (two-sided 95% confidence interval (CI), 0.80-1.05)] for any margin equal to or greater than 1.05. Statistically significant safety advantages for the CS arm were observed [G3/4 neutropenia (CS, 18.6%; CF, 40.0%), febrile neutropenia (CS, 1.7%; CF, 6.9%), G3/4 stomatitis (CS, 1.3%; CF, 13.6%), diarrhoea (all grades: CS, 29.2%; CF, 38.4%) and renal adverse events (all grades: CS, 18.8%; CF, 33.5%)]. Hand-foot syndrome, infrequently reported, was mainly grade 1/2 in both arms. Treatment-related deaths were significantly lower in the CS arm than the CF arm (2.5% and 4.9%, respectively; P<0.047). CONCLUSION: CS is noninferior to CF with a better safety profile and provides a new treatment option for patients with advanced gastric carcinoma.

[Current possibilities of targeted therapy in the treatment of breast cancer with overexpression of HER-2/neu and metastatic lesions in the brain].

Targeted therapy (lapatinib and/or trastuzumab) in combination with chemotherapy (capecitabine) is highly effective in metastatic lesions of the brain in breast cancer patients with overexpress HER-2/neu. An objective response in the brain was achieved in 19 patients (55.9%). Complete regression was observed in 5 cases (14.7%), partial regression--14 (41.2%). Stabilization of tumor process in the brain was revealed in 12 patients (35.3%). There was marked improvement in the quality of life of the majority of patients due to the regression of symptoms and good tolerability of treatment.

[Results of combined treatment of patients with metastatic gastric cancer. Case study].

We present the clinical observation of combined treatment of a patient with metastatic gastric cancer. The patient underwent combined chemotherapy for initially inoperable gastric cancer with metastases to the liver, paragastric lymph nodes, and peritoneal carcinomatosis with complete regression of distant metastases, which allowed radical surgery. The patient is currently under regular team observation without signs of disease. His present survival is 44 months.

A human iPSC model of Ligase IV deficiency reveals an important role for NHEJ-mediated-DSB repair in the survival and genomic stability of induced pluripotent stem cells and emerging haematopoietic progenitors.

DNA double strand breaks (DSBs) are the most common form of DNA damage and are repaired by non-homologous-end-joining (NHEJ) or homologous recombination (HR). Several protein components function in NHEJ, and of these, DNA Ligase IV is essential for performing the final 'end-joining' step. Mutations in DNA Ligase IV result in LIG4 syndrome, which is characterised by growth defects, microcephaly, reduced number of blood cells, increased predisposition to leukaemia and variable degrees of immunodeficiency. In this manuscript, we report the creation of a human induced pluripotent stem cell (iPSC) model of LIG4 deficiency, which accurately replicates the DSB repair phenotype of LIG4 patients. Our findings demonstrate that impairment of NHEJ-mediated-DSB repair in human iPSC results in accumulation of DSBs and enhanced apoptosis, thus providing new insights into likely mechanisms used by pluripotent stem cells to maintain their genomic integrity. Defects in NHEJ-mediated-DSB repair also led to a significant decrease in reprogramming efficiency of human cells and accumulation of chromosomal abnormalities, suggesting a key role for NHEJ in somatic cell reprogramming and providing insights for future cell based therapies for applications of LIG4-iPSCs. Although haematopoietic specification of LIG4-iPSC is not affected per se, the emerging haematopoietic progenitors show a high accumulation of DSBs and enhanced apoptosis, resulting in reduced numbers of mature haematopoietic cells. Together our findings provide new insights into the role of NHEJ-mediated-DSB repair in the survival and differentiation of progenitor cells, which likely underlies the developmental abnormalities observed in many DNA damage disorders. In addition, our findings are important for understanding how genomic instability arises in pluripotent stem cells and for defining appropriate culture conditions that restrict DNA damage and result in ex vivo expansion of stem cells with intact genomes.

A randomized phase II study evaluating the combination of carboplatin-based chemotherapy with pertuzumab versus carboplatin-based therapy alone in patients with relapsed, platinum-sensitive ovarian cancer.

BACKGROUND: Pertuzumab, a humanized monoclonal antibody targeting human epidermal growth factor receptor (HER)-mediated signalling, has shown activity in ovarian cancer in preclinical models and in the clinic. This randomized phase II study evaluated efficacy and safety of pertuzumab in combination with carboplatin-based chemotherapy in patients with platinum-sensitive, recurrent advanced ovarian cancer. PATIENTS AND METHODS: Patients were randomized to receive six cycles of chemotherapy (carboplatin and either paclitaxel (Taxol) or gemcitabine) with or without pertuzumab. The primary end point was progression-free survival (PFS) as determined by Response Evaluation Criteria in Solid Tumors and/or by CA 125 measurements. Secondary end points evaluated the response rate, safety profile, duration of response, time to progression and overall survival for both treatment arms. RESULTS: A total of 149 patients received either chemotherapy with pertuzumab (arm A, n=74) or chemotherapy alone (arm B, n=75). There was no significant difference either in median PFS or in the secondary end points between the two arms. No differences were seen in an exploratory biomarker analysis of HER3 mRNA expression between the two arms. Pertuzumab was well tolerated, with no increase in cardiac adverse events compared with chemotherapy alone. CONCLUSIONS: The addition of pertuzumab to carboplatin-based chemotherapy did not substantially prolong PFS in unselected patients with platinum-sensitive ovarian cancer.

[Which patients with ovarian cancer shows the combination of trabectedin with pegylated liposomal doxorubicin].

Given the high rate of recurrence of ovarian cancer, the search for new therapeutic strategies are topical issue. According to various studies the effectiveness of drug treatment relapse depends on the platinum-free interval, increasing in proportion to its duration. If therapy is platinum-resistant recurrent ovarian cancer is a standard approach, the treatment of platinum-sensitive recurrent algorithm is not fully defined. Comparison of platinum and non-platinum combinations revealed the advantage of combined platinum- treatment for patients with platinum-free interval of more than 6 months without an increase in life expectancy. Non-platinum combination of trabected in with pegylated liposomal doxorubicin has shown comparable efficacy with an advantage in overall survival in patients with platinum-free interval of 6-12 months. A platinum-free interval prolongation by the use of non-platinum mode increases the efficiency of subsequent platinum-based therapy, increasing the life expectancy of patients. Currently under study molecular markers and prognostic factors allowing to define a group of patients who have the greatest benefit from the use trabectedin with pegylated liposomal doxorubicin as second-line chemotherapy.

[Pharmacogenomics of cisplatin-based chemotherapy in ovarian cancer patients from Yakutia].

DNA polymorphism is an important component of the interindividual variation in reactions of patients to the same drugs. In this work, evaluation of the association between polymorphisms in 106 genes involved in key processes of cellular activity (xenobiotic metabolism, DNA repair, the cell cycle, and apoptosis), and outcomes in a cohort of Yakut ovarian cancer patients receiving cisplatin-based chemotherapy was carried out. The polymorphism in the CDKN1B gene (rs34330) was found to be associated with complete tumor response and progression-free survival. SNPs in EPXH1 gene (rs2234922 and rs2260863) were correlated with hearing impairment. A SNP in NBN gene (rs1063045) was associated with severe emesis.

[CYP2E1 gene polymorphism and ovarian cancer risk in the Yakut population].

The CYP2E1 gene polymorphism has been studied in Yakut women with ovarian cancer and without cancer. The two groups have been found to substantially differ in the frequency of the CYP2E1* 1D allele (with a 96-bp insertion in the promoter region of the gene): it is more frequent in healthy women (16.3 versus 7.4%, P = 0.007).

A multicenter international randomized phase III study comparing cisplatin in combination with irinotecan or etoposide in previously untreated small-cell lung cancer patients with extensive disease.

BACKGROUND: This study compared irinotecan plus cisplatin (IP) with etoposide plus cisplatin (EP) in small-cell lung cancer patients with extensive disease. PATIENTS AND METHODS: Patients were randomly assigned to receive cisplatin 80 mg/m(2) and either irinotecan 65 mg/m(2), days 1 and 8 or etoposide 100 mg/m(2), days 1-3, every 3 weeks. RESULTS: Baseline characteristics were balanced between patients receiving IP (N = 202) or EP (N = 203). Median overall survival was nonsignificantly superior for patients receiving IP versus EP, 10.2 versus 9.7 months [hazard ratio (HR) 0.81, 95% confidence interval (CI) 0.65-1.01, P = 0.06] and 1- and 2-year survival rates were 41.9% versus 38.9% and 16.3% versus 8.2%, respectively. Noninferiority of IP versus EP was established, upper bound of the 95% CI of HR 1.01 (prespecified margin IP/EP <1.25). Overall response (39.1% versus 46.6%) and time to tumor progression (5.4 versus 6.2 months) were not superior for IP. Grade 3/4 vomiting (10.9% versus 4.4%) and diarrhea (15.4% versus 0.5%) were more common in the IP versus EP arm; grade 3/4 neutropenia was more frequent in the EP (59.6%) versus IP arm (38.1%). CONCLUSIONS: Our data demonstrate the noninferiority of IP versus EP for survival in primarily Western patients with SCLC-ED. A meta-analysis is required to finally assess the role of irinotecan in this setting.

Genetic polymorphisms and the efficacy and toxicity of cisplatin-based chemotherapy in ovarian cancer patients.

Platinum drugs are among the most active and widely used agents in the treatment of different cancers. However, the great individual variability in both outcome and toxicity of platinum chemotherapy requires the identification of genetic markers that can be used to screen patients before treatment. In this study, 21 polymorphisms in 10 genes, the protein activities of which may be addressed in different aspects of cisplatin metabolism, were tested for correlations with efficacy and toxicity of cisplatin-cyclophosphamide regimen in 104 ovarian cancer patients. The glutathione S-transferase P1 (GSTP1) Ile105Val polymorphism was strongly associated with progression-free survival (chi(2)=12.12, P=0.002). The allelic status of the GSTA1 -69 C>T polymorphism correlated with the overall survival: patients with T/T genotype survived longer than C/C carriers (P=0.044). Thrombocytopenia, anemia and neuropathy were less frequent among patients with the GSTM1-null or GSTM3 intron 6 AGG/AGG genotypes. Severe neutropenia was associated with the TP53 72 Pro/Pro, XPD 312 Asp/Asn and XRCC1 399 Arg/Arg genotypes. A higher risk of nephrotoxicity was noted for patients with the heterozygous ERCC1 19007 T/C and 8092 C/A genotypes. No correlations were found between genotypes and complete tumor responses.

Sequential therapy for the locally advanced larynx and hypopharynx cancer subgroup in TAX 324: survival, surgery, and organ preservation.

BACKGROUND: Locally advanced laryngeal and hypopharyngeal cancers (LHC) represent a group of cancers for which surgery, laryngectomy-free survival (LFS), overall survival (OS), and progression-free survival (PFS) are clinically meaningful end points. PATIENTS AND METHODS: These outcomes were analyzed in the subgroup of assessable LHC patients enrolled in TAX 324, a phase III trial of sequential therapy comparing docetaxel plus cisplatin and fluorouracil (TPF) against cisplatin and fluorouracil (PF), followed by chemoradiotherapy. RESULTS: Among 501 patients enrolled in TAX 324, 166 had LHC (TPF, n = 90; PF, n = 76). Patient characteristics were similar between subgroups. Median OS for TPF was 59 months [95% confidence interval (CI): 31-not reached] versus 24 months (95% CI: 13-42) for PF [hazard ratio (HR) for death: 0.62; 95% CI: 0.41-0.94; P = 0.024]. Median PFS for TPF was 21 months (95% CI: 12-59) versus 11 months (95% CI: 8-14) for PF (HR: 0.66; 95% CI: 0.45-0.97; P = 0.032). Among operable patients (TPF, n = 67; PF, n = 56), LFS was significantly greater with TPF (HR: 0.59; 95% CI: 0.37-0.95; P = 0.030). Three-year LFS with TPF was 52% versus 32% for PF. Fewer TPF patients had surgery (22% versus 42%; P = 0.030). CONCLUSIONS: In locally advanced LHC, sequential therapy with induction TPF significantly improved survival and PFS versus PF. Among operable patients, TPF also significantly improved LFS and PFS. These results support the use of sequential TPF followed by carboplatin chemoradiotherapy as a treatment option for organ preservation or to improve survival in locally advanced LHC.