Plasma HIV-1 RNA decline within the first two weeks of treatment is comparable for nevirapine, efavirenz, or both drugs combined and is not predictive of long-term virologic efficacy: A 2NN substudy

BACKGROUND: The initial rate of plasma HIV-1 RNA (pVL) decline has been proposed as a marker of early efficacy of antiretroviral therapy (ART) and a possible predictor of late efficacy. We compared the rate of pVL decline in patients starting ART with nevirapine (NVP), efavirenz (EFV), or both drugs combined in addition to lamivudine (3TC) and stavudine (d4T). METHODS: Analysis of the viral decay constant (VDc) during the first 2 weeks of treatment in patients enrolled in the 2NN study who remained on allocated treatment. RESULTS: The median VDc (log10 copies per day, [interquartile range]) was similar for NVP (0.30 [0.25-0.36], EFV (0.31 [0.27-0.37]), and NVP + EFV (0.30 [0.27-0.36]). Patients with a baseline pVL >100,000 copies/mL were 8.7 (95% confidence interval [CI]: 6.2-12.3) times more likely to have a VDc >75th percentile. A high VDc was not associated with plasma drug concentration or with a decreased risk of virologic failure at week 48 after the start of therapy (hazard ratio = 0.8, 95% CI: 0.6-1.2). CONCLUSION: NVP, EFV, or NVP + EFV in combination with 3TC and d4T show similar rates of pVL decline during the first 2 weeks of treatment. The VDc with these regimens is not predictive of late virologic efficacy.     

Assessment of the genetic causes of recessive childhood non-syndromic deafness in the UK - implications for genetic testing

Approximately one in 2000 children is born with a genetic hearing impairment, mostly inherited as a non-syndromic, autosomal recessive trait, for which more than 30 different genes have been identified. Previous studies have shown that one of these genes, connexin 26 (GJB2), accounts for 30-60% of such deafness, but the relative contribution of the many other genes is not known, especially in the outbred UK population. This lack of knowledge hampers the development of diagnostic genetic services for deafness. In an effort to determine the molecular aetiology of deafness in the population, 142 sib pairs with early-onset, non-syndromic hearing impairment were recruited. Those in whom deafness could not be attributed to GJB2 mutations were investigated further for other mapped genes. The genetic basis of 55 cases (38.7%) was established, 33.1% being due to mutations in the GJB2 gene and 3.5% due to mutations in SLC26A4. None of the remaining 26 loci investigated made a significant contribution to deafness in a Caucasian population. We suggest that screening the GJB2 and SLC26A4 genes should form the basis of any genetic testing programme for childhood deafness and highlight a number of important issues for consideration and future work.     

Five-Year Breast Surgeon Experience in LYMPHA at Time of ALND for Treatment of Clinical T1–4N1–3M0 Breast Cancer

Annals of Surgical Oncology - Breast cancer-related lymphedema (BCRL) is a source of postoperative morbidity for breast cancer survivors. Lymphatic microsurgical preventive healing approach...     

Treatment of R-3327 prostate tumors with a somatostatin analogue (somatuline) as adjuvant therapy following surgical castration

This study addresses, in an animal tumor model, the clinical problem of "escape from castration inhibition." Somatuline (BIM-23014C), an octapeptide analogue of somatostatin with enhanced potency and longer duration of biological activity was administered as a therapeutic agent, over a period of 90 and 197 days, to male Copenhagen rats bearing syngeneic Dunning R-3327-H prostate tumors. Androgen sensitivity was confirmed by the response of tumors to castration and by the significant inhibition of tumor growth in intact animals by treatment with a luteinizing hormone-releasing hormone antagonist (BIM-21009). Inhibition of tumor growth resulting from castration persisted for 102 days, after which progressive regrowth occurred, indicating an escape from castration inhibition. When Somatuline treatment was initiated as an adjuvant therapy 5 days after castration, the rate of tumor regrowth during escape was significantly retarded. During the period of 197 days postcastration, tumors in the vehicle-treated, intact controls grew to an average diameter of 38.6 +/- 7.6 mm and tumors in vehicle-treated castrate controls grew to an average diameter of 23.3 +/- 4.1 mm (60% test/control). Treatment with the luteinizing hormone-releasing hormone antagonist induced no significant additional tumor inhibitory effects in castrated animals which developed tumors having an average diameter of 30.2 +/- 8.2 mm (78% test/control). Treatment of tumors in castrate animals with Somatuline, on the other hand, induced a significant (P less than 0.01) tumor-inhibitory effect that was greater than that produced by castration alone, developing an average tumor diameter of only 14.3 +/- 2.6 mm, (37% test/control). A growth inhibitory effect was also inducible in animals having tumors that had already escaped castration inhibition. The relative nontoxicity of a somatostatin analogue such as Somatuline suggests that chronic or maintenance therapy of slow-growing prostate cancers may be both feasible and acceptable in a clinical setting.     

UFH-001 cells: A novel triple negative,CAIX-positive,human breast cancer model system

Human cell lines are an important resource for research, and are often used as in vitro models of human diseases. In response to the mandate that all cells should be authenticated, we discovered that the MDA-MB-231 cells that were in use in our lab, did not validate based on the alleles of 9 different markers (STR Profile). We had been using this line as a model of triple negative breast cancer (TNBC) that has the ability to form tumors in immuno-compromised mice. Based on marker analysis, these cells most closely resembled the MCF10A line, which are a near diploid and normal mammary epithelial line. Yet, the original cells express carbonic anhydrase IX (CAIX) both constitutively and in response to hypoxia and are features that likely drive the aggressive nature of these cells. Thus, we sought to sub-purify CAIX-expressing cells using Fluorescence Activated Cell Sorting (FACS). These studies have revealed a new line of cells that we have name UFH-001, which have the TNBC phenotype, are positive for CAIX expression, both constitutively and in response to hypoxia, and behave aggressively in vivo. These cells may be useful for exploring mechanisms that underlie progression, migration, and metastasis of this phenotype. In addition, constitutive expression of CAIX allows its evaluation as a therapeutic target, both in vivo and in vitro.     

受体靶向多肽载体抗肿瘤药物

常规化疗药物对癌细胞没有选择性,常常会导致严重的副作用。提高这些药物的靶向特异性已成为药物开发的热点方向之一。一些小分子多肽能够靶向作用于特定的受体,因而被用作癌症化疗药物的载体。化疗药物与多肽载体偶联构成新的多肽载体抗肿瘤药物。这些药物具有高特异性、高亲和力和肿瘤渗透力等优点,能够通过细胞表面的特定受体将药物送到靶向癌细胞内,提高抗癌效果、减少副作用和癌细胞的耐药性。多肽载体靶向药物被誉为新一代的靶向特异性的抗肿瘤药物之一。     

Portal-systemic shunting and the disruption of circadian locomotor activity in the rat.

To determine if the extent of portal-systemic shunting (PSS) influences the disruption of circadian function in chronic liver disease, locomotor activity was examined in two rat models with varying degrees of PSS, i.e., portal vein ligation (PVL) and end-to-side portacaval anastomosis (PCA). Animals were housed in individual activity cages under conditions of 12 hour light/12 hour darkness (weeks 0-3), then under conditions of constant dim light (weeks 4-7). Cages were equipped with running wheels connected to a continuous recorder, and daily tracings of running activity were recorded for 7 weeks. Computer analysis of wheel revolutions per hour with a chi 2 periodogram was used to calculate Qp, a measure of the amplitude of a circadian rhythm. The degree of PSS was measured by means of radioactive microspheres injected into the ileocolic vein and spleen. PVL rats were found to have PSS from the splenic and mesenteric territories of 88% and 27%, respectively; circadian periodicity was maintained in all PVL rats. PCA rats had complete shunting (greater than 99%) and showed a range of disrupted circadian rhythms from blunting of the amplitude to complete absence of the locomotor activity rhythm. This spectrum of disorganization occurred in spite of similar degrees of liver atrophy and weight gain. Whereas PCA in rats markedly disturbs the circadian rhythm of locomotor activity, animals with considerably less PSS from PVL exhibit normal behavior. The extent of PSS could be a variable affecting the expression of circadian rhythms in liver disease.     

Prolonged inhibition of growth hormone secretion by peripheral injection of bombesin is mediated by somatostatin in the rat

Peripherally injected bombesin inhibits GH secretion in conscious, freely moving rats and in sodium pentobarbital-anesthetized rats. This inhibition of GH secretion is unusually prolonged, lasting up to 90 min after a single ip injection. The duration of inhibition of GH secretion by bombesin is greater than that observed for somatostatin (SRIF) in the same bioassay. The inhibition of GH release occurs concomitantly with stimulation of gastrin release and is independent of stimulatory effects of bombesin on plasma glucose. The structurally related mammalian gastrin-releasing peptide also inhibits GH secretion in the pentobarbital-anesthetized rat after peripheral injection. Peripherally administered bombesin blocks GH-releasing factor stimulation of GH secretion. Prior treatment of pentobarbital-anesthetized rats with SRIF-specific anti-serum blocks the inhibitory effect of bombesin on GH secretion. No effect of bombesin on GH secretion was observed in primary cultures of rat anterior pituitary cells. These data suggest that peripherally administered bombesin stimulates SRIF secretion, most probably of hypothalamic origin, which, in turn, inhibits pituitary secretion of GH. This sensitivity of the hypothalamus to a peripherally rather than centrally administered peptide has important mechanistic and therapeutic implications.     

Comparison of methionine-enkephalin and morphine in the stimulation of gastric acid secretion in the dog

In dogs with Heidenhain pouches and gastric fistulas, we studied acid secretion in response to systemic or portal infusion of methionine-enkephalin (met-enkephalin), enkephalin-analog, or morphine. All these opiate compounds caused a dose-dependent increase in acid secretion under basal conditions and resulted in a significant rise in pentagastrin- or histamine-induced acid secretion. The stimulation by opiates of gastric secretion was accompanied by an increase in the mucosal blood flow but without any significant change in serum gastrin concentration. Gastric acid stimulation by met-enkephalin and morphine was strongly inhibited not only by naloxone, an opiate antagonist, but also by blockers of H2-receptors (metiamide) or cholinergic receptors (atropine), suggesting a cooperative interaction between opiates and other stimuli of parietal cells. The gastric stimulation by met-enkephalin and its analog, but not by morphine, was markedly reduced by portal administration of these compounds, indicating a marked inactivation of opiate peptides by hepatic transit. This study shows that enkephalin and morphine stimulate gastric acid secretion by a gastrin-independent mechanism sensitive to atropine and H2-blocker and probably involving opiate receptors.