Neoadjuvant chemotherapy and trastuzumab versus neoadjuvant chemotherapy followed by post-operative trastuzumab for patients with HER2-positive breast cancer

Neoadjuvant chemotherapy plus trastuzumab (NCT) increases the rate of pathological complete response (pCR) and event-free survival (EFS) compared to neoadjuvant chemotherapy (NC) alone in women with HER2 positive breast cancer (BC). pCR in this setting is associated with improved EFS. Whether NCT preferentially improves EFS in comparison to NC followed by adjuvant trastuzumab initiated postoperatively (NCAT) has not been addressed. Using clinical data from women with HER2 positive BC treated at 7 European institutions between 2007 and 2010 we sought to investigate the impact on breast cancer outcomes of concomitant (NCT) versus sequential (NCAT) treatment in HER2 positive early BC. The unadjusted hazard ratio (HR) for event free survival with NCT compared with NCAT was 0.63 (95% CI 0.37–1.08; p = 0.091). Multivariable analysis revealed that treatment group, tumour size and ER status were significantly associated with EFS from diagnosis. In the whole group NCT was associated with a reduced risk of an event relative to NCAT, an effect that was confined to ER negative (HR: 0.25; 95% CI, 0.10–0.62; p = 0.003) as opposed to ER positive tumours (HR: 1.07; 95% CI, 0.46–2.52; p = 0.869). HER2 positive/ER negative BC treated with NC gain greatest survival benefit when trastuzumab is administered in both the neoadjuvant and adjuvant period rather than in the adjuvant period alone. These data support the early introduction of targeted combination therapy in HER2 positive/ER negative BC

Neoadjuvant chemotherapy and trastuzumab versus neoadjuvant chemotherapy followed by post-operative trastuzumab for patients with HER2-positive breast cancer

Neoadjuvant chemotherapy plus trastuzumab (NCT) increases the rate of pathological complete response (pCR) and event-free survival (EFS) compared to neoadjuvant chemotherapy (NC) alone in women with HER2 positive breast cancer (BC). pCR in this setting is associated with improved EFS. Whether NCT preferentially improves EFS in comparison to NC followed by adjuvant trastuzumab initiated postoperatively (NCAT) has not been addressed. Using clinical data from women with HER2 positive BC treated at 7 European institutions between 2007 and 2010 we sought to investigate the impact on breast cancer outcomes of concomitant (NCT) versus sequential (NCAT) treatment in HER2 positive early BC. The unadjusted hazard ratio (HR) for event free survival with NCT compared with NCAT was 0.63 (95% CI 0.37–1.08; p = 0.091). Multivariable analysis revealed that treatment group, tumour size and ER status were significantly associated with EFS from diagnosis. In the whole group NCT was associated with a reduced risk of an event relative to NCAT, an effect that was confined to ER negative (HR: 0.25; 95% CI, 0.10–0.62; p = 0.003) as opposed to ER positive tumours (HR: 1.07; 95% CI, 0.46–2.52; p = 0.869). HER2 positive/ER negative BC treated with NC gain greatest survival benefit when trastuzumab is administered in both the neoadjuvant and adjuvant period rather than in the adjuvant period alone. These data support the early introduction of targeted combination therapy in HER2 positive/ER negative BC

Hereditary cataract of the Nakano mouse: Involvement of a hypomorphic mutation in the coproporphyrinogen oxidase gene

The Nakano cataract (NCT) is a recessive disorder in the mouse linked to the nct locus on chromosome 16. In this study, we positionally cloned the critical gene in the nct locus. Herein, we report that cataracts in the BALB/c-nct/nct mouse are caused by a hypomorphic mutation in the coproporphyrin oxidase gene (Cpox), encoding the enzyme responsible for catalyzing oxidative decarboxylation of the heme precursor, coproporphyrinogen III, in the heme biosynthetic pathway. BALB/c-nct/nct mice are homozygous for a G to T nucleotide substitution in the Cpox gene, which results in a p.R380L amino acid substitution in the CPDX protein. The CPDX isoform with the p.R380L substitution retained only 15% of the activity of the wild type isoform. BALB/c-nct/nct mice had excessive accumulation of coproporphyrin HI in the lens. The NCT phenotype was normalized by the introduction of a wild type Cpox transgene. The mechanisms by which impairment of CPDX leads to lens opacity in the NCT are elusive. However, our data illuminate a hitherto unanticipated involvement of the heme biosynthesis pathway in lens physiology.ArticleEXPERIMENTAL EYE RESEARCH. 112:45-50 (2013)journal articl

Administration of Nicotine Exacerbates the Quinine-induced Structural and Functional Alterations of Testicular Tissue in Adult Rats:An Experimental Study

Purpose: In this study the role of nicotine (NCT) administration on the intensity of rat testicular tissue alterations induced by quinine (QU) was evaluated. Materials and Methods: Forty adult Wistar rats were divided into four groups. Control (CON), NCT administrated (4 mg/kg) (NCT), QU treated (25 mg/kg for 7 days) (QU), and nicotine with quinine received (NCT+QU). After 28 days, serum testosterone and malondialdehyde (MDA) levels were measured. Testes and epididymides samples were prepared for determining tissue MDA levels, histomorphometry, microscopic indices of spermatogenesis, immunohistochemistry of p53 and sperm analysis. Results: Testosterone levels were decreased significantly (P =.0004) in treated groups compared to CON group. Serum MDA levels were increased significantly (P =.0004) in NCT and QU groups compared to CON group. Tissue MDA levels were increased significantly (P =.0012) in NCT+QU group in comparison to CON group. These parameters were changed significantly in NCT+QU group compared to QU group. Seminiferous tubules diameter decreased significantly (P Conclusion: The administration of nicotine could be involved in the exacerbation of testicular tissue alterations related to quinine therapy

ANALISIS SEMIOTIK MAKNA RASA PENYESALAN PADA LIRIK LAGU K-POP NCT DREAM “SORRY, HEART”

NCT Dream merupakan salah satu boygroup asal Korea Selatan yang telah berhasil mencapai kesuksesan di kancah internasional. Selain merangkul anak-anak remaja yang kehilangan semangat hidupnya, NCT Dream juga merangkul NCTzen (penggemar NCT) yang galau dan sedih akibat dari akhir sebuah hubungan. NCT Dream mengungkapkan perasaan tersebut kepada NCTzen melalui lagu-lagu mereka. Selanjutnya Penelitian ini berjudul Analisis Semiotik Makna Rasa Penyesalan Lirik Lagu “Sorry, Heart” karya NCT Dream. Penelitian ini dimaksudkan untuk mengetahui makna yang terkandung dalam lirik lagu tersebut dan mengkaji bagaimana penanda dan petandanya. Teori semiotika yang digunakan untuk mengupas lirik lagu NCT Dream dengan judul “Sorry, Heart” dan relevan adalah teori Ferdinand De Saussure. Metode dalam penelitian ini menggunakan metode kualitatif. Hasil dari penelitian ini yaitu ditemukan bahwa lirik lagu Sorry, Heart milik NCT Dream mengandung makna pesan rasa penyesalan. Selain itu, penelitian ini mampu memberikan makna lain dari perumpamaan yang digambarkan melalui teori analisis semiotik Ferdinand De Saussur

Phosphorylation of Nicastrin by SGK1 Leads to Its Degradation through Lysosomal and Proteasomal Pathways

The gamma-secretase complex is involved in the intramembranous proteolysis of a variety of substrates, including the amyloid precursor protein and the Notch receptor. Nicastrin (NCT) is an essential component of the gamma-secretase complex and functions as a receptor for gamma-secretase substrates. In this study, we determined that serum- and glucocorticoid-induced protein kinase 1 (SGK1) markedly reduced the protein stability of NCT. The SGK1 kinase activity was decisive for NCT degradation and endogenous SGK1 inhibited gamma-secretase activity. SGK1 downregulates NCT protein levels via proteasomal and lysosomal pathways. Furthermore, SGK1 directly bound to and phosphorylated NCT on Ser437, thereby promoting protein degradation. Collectively, our findings indicate that SGK1 is a gamma-secretase regulator presumably effective through phosphorylation and degradation of NCT

Gamma-secretase composed of PS1/Pen2/Aph1a can cleave notch and amyloid precursor protein in the absence of nicastrin

γ-secretase is a multiprotein intramembrane-cleaving protease with a growing list of protein substrates including the Notch receptors and the amyloid precursor protein. The four components of γ-secretase complex - presenilin (PS), nicastrin (NCT), Pen2, and Aph1 - are all thought to be essential for activity. The catalytic domain resides within PS proteins; NCT has been suggested to be critical for substrate recognition; the contributions of Pen2 and Aph1 remain unclear. The role of NCT has been challenged recently by the observation that a critical residue (E332) in NCT, thought to be essential for γ-secretase activity, is instead involved in complex maturation. Here we report that NCT is dispensable for γ-secretase activity. NCT-independent γ-secretase activity can be detected in two independent NCT-deficient MEF lines, and blocked by the γ-secretase inhibitors DAPT and L-685,458. This catalytic activity requires prior ectodomain shedding of the substrate, and can cleave ligand-activated endogenous Notch receptors, indicating presence at the plasma membrane. siRNA knockdown experiments demonstrated that NCT-independent γ-secretase activity requires the presence of PS1, Pen2 and Aph1a but can tolerate knockdown of PS2 or Aph1b. We conclude that a PS1/Pen2/Aph1a trimeric complex is an active enzyme, displaying similar biochemical properties to those of γ-secretase and roughly 50% of its activity when normalized to PS1 NTF levels. This PS1/Pen2/Aph1a complex, however, is highly unstable. Thus, NCT acts to stabilize γ-secretase, but is not required for substrate recognition

Tolerability of inhaled N-chlorotaurine in the pig model

<p>Abstract</p> <p>Background</p> <p>N-chlorotaurine, a long-lived oxidant produced by human leukocytes, can be applied in human medicine as an endogenous antiseptic. Its antimicrobial activity can be enhanced by ammonium chloride. This study was designed to evaluate the tolerability of inhaled N-chlorotaurine (NCT) in the pig model.</p> <p>Methods</p> <p>Anesthetized pigs inhaled test solutions of 1% (55 mM) NCT (n = 7), 5% NCT (n = 6), or 1% NCT plus 1% ammonium chloride (NH₄Cl) (n = 6), and 0.9% saline solution as a control (n = 7), respectively. Applications with 5 ml each were performed hourly within four hours. Lung function, haemodynamics, and pharmacokinetics were monitored. Bronchial lavage samples for captive bubble surfactometry and lung samples for histology and electron microscopy were removed.</p> <p>Results</p> <p>Arterial pressure of oxygen (PaO₂) decreased significantly over the observation period of 4 hours in all animals. Compared to saline, 1% NCT + 1% NH₄Cl led to significantly lower PaO₂values at the endpoint after 4 hours (62 ± 9.6 mmHg vs. 76 ± 9.2 mmHg, p = 0.014) with a corresponding increase in alveolo-arterial difference of oxygen partial pressure (AaDO₂) (p = 0.004). Interestingly, AaDO₂was lowest with 1% NCT, even lower than with saline (p = 0.016). The increase of pulmonary artery pressure (PAP) over the observation period was smallest with 1% NCT without difference to controls (p = 0.91), and higher with 5% NCT (p = 0.02), and NCT + NH₄Cl (p = 0.05).</p> <p>Histological and ultrastructural investigations revealed no differences between the test and control groups. The surfactant function remained intact. There was no systemic resorption of NCT detectable, and its local inactivation took place within 30 min. The concentration of NCT tolerated by A549 lung epithelial cells <it>in vitro </it>was similar to that known from other body cells (0.25–0.5 mM).</p> <p>Conclusion</p> <p>The endogenous antiseptic NCT was well tolerated at a concentration of 1% upon inhalation in the pig model. Addition of ammonium chloride in high concentration provokes a statistically significant impact on blood oxygenation.</p

DNA target sequence and FNR-dependent gene expression.

FNR proteins are global transcription regulators that respond to fluctuations in environmental oxygen. They recognise a DNA target consisting of an inverted repeat, TTGATN(1)N(2)N(3)N(4)ATCAA (where N(1-4) represents a non-conserved tetrad, NCT). Analysis of 68 known and predicted FNR sites from the Escherichia coli K12 genome revealed a bias toward A or T at positions N(2) and N(3) of the NCT. The effect of the NCT sequence on FNR-dependent transcription in vivo was assessed using a series of class II and class I model promoters with different NCT sequences. Changing the NCT sequence did not affect basal activity but altered anaerobic induction by as much as an order of magnitude. Thus, the NCT sequence is a fundamental component in setting the dynamic range of the FNR switch