New hominin dental remains from the ∼2.04-1.95 Ma Drimolen Main Quarry, South Africa.

BACKGROUND: The Drimolen Palaeocave site is situated within the UNESCO Fossil Hominid Sites of South Africa World Heritage Area and has yielded numerous hominin fossils since its discovery in 1992. Most of these fossils are represented by isolated dental elements, which have been attributed to either of two distinct hominin genera, Paranthropus and Homo. AIM: This paper provides morphological descriptions for a further 19 specimens that have been recovered from the ∼2.04-1.95 Ma Drimolen Main Quarry (DMQ) deposits since 2008. This paper also discusses the two primary hypotheses used to explain Paranthropus robustus variation: sexual dimorphism, and micro-evolution within a lineage. SUBJECTS AND METHODS: These 19 fossils are represented by 47 dental elements and expand the sample of DMQ early Homo from 13 to 15, and the sample of Paranthropus robustus from 69 to 84. RESULTS: The evidence presented in this paper was found to be inconsistent with the sexual dimorphism hypothesis. CONCLUSION: Some support was found for the micro-evolution hypothesis.

Tuning molecular dynamics by hydration and confinement: antiplasticizing effect of water in hydrated prilocaine nanoclusters.

In glass-forming substances, the addition of water tends to produce the effect of lowering the glass transition temperature, Tg. In a previous work by some of us (Ruiz et al., Sci. Rep., 2017, 7, 7470) we reported on a rare anti-plasticizing effect of water on the molecular dynamics of a simple molecular system, the pharmaceutically active prilocaine molecule, for which the addition of water leads to an increase of Tg. In the present work, we study pure and hydrated prilocaine confined in 0.5 nm and 1 nm pore size molecular sieves, and carry out a comparison with the bulk compounds in order to gain a better understanding of the microscopic mechanisms that result in this rare effect. We find that the Tg of the drug under nanometric confinement can be lower than the bulk value by as much as 17 K. Through the concurrent use of differential scanning calorimetry and broadband dielectric spectroscopy we are able to observe the antiplasticizing effect of water in prilocaine also under nanometric confinement, finding an increase of Tg of up to almost 6 K upon hydration. The extension of our analysis to nanoconfined systems provides a plausible explanation for the very uncommon antiplasticizing effect, based on the formation of water-prilocaine molecular complexes. Moreover, this study deepens the understanding of the behavior of drugs under confinement, which is of relevance not only from a fundamental point of view, but also for practical applications such as drug delivery.

Estimating glomerular filtration rate in youth with obesity and type 2 diabetes: the iCARE study equation.

BACKGROUND: The validity of pediatric estimated glomerular filtration rate equations (eGFRs) in early stages of CKD including hyperfiltration is unknown. The purpose of this study was to develop an eGFR equation for adolescents with obesity and type 2 diabetes (T2D). METHODS: eGFRs were developed from iohexol-derived GFRs (iGFRs) in 26 overweight/obese (BMI > 85th percentile) youth and 100 with T2D from the iCARE (Improving renal Complications in Adolescents with T2D through REsearch) cohort. Twenty percent of the cohort was withheld as a validation dataset. Linear regression analyses were used to develop the best formula based on body size, sex, creatinine, urea, ± cystatin C. Comparable validity of commonly used eGFR equations was assessed. RESULTS: Mean age 15.4 + 2.4 years, BMI Z-score 2.5 + 1.2, 61% female, and mean iGFR 129.0 + 27.7 ml/min/ 1.73 m2. The best adjusted eGFR formula (ml/min/1.73 m2) was 50.7 × BSA0.816 × (height (cm)/creatinine)0.405 × 0.8994 if sex = female | 1 otherwise. It resulted in 53.8% of eGFRs within 10% of measured iGFR and 96.2% within 30%. Bland-Altman 95% limits of agreement in the external dataset were - 37.6 to 45.5 ml/min/1.73m2 (bias = 3.96), and the correlation was 0.62. This equation performed better than all previously published creatinine-based eGFRs. cystatin C did not significantly improve results; however, some other cystatin C formulas also performed well. CONCLUSIONS: The iCARE equation provides a more accurate creatinine-based eGFR in obese youth with and without T2D. Further studies are warranted to evaluate within-subject variability and applicability to lower GFRs and other populations.

Phase II study of MLN8237 (Alisertib) in advanced/metastatic sarcoma.

BACKGROUND: Aurora kinase A (AURKA) is commonly overexpressed in sarcoma. The inhibition of AURKA by shRNA or by a specific AURKA inhibitor blocks in vitro proliferation of multiple sarcoma subtypes. MLN8237 (alisertib) is a novel oral adenosine triphosphate-competitive AURKA inhibitor. PATIENTS AND METHODS: This Cancer Therapy Evaluation Program-sponsored phase II study of alisertib was conducted through the Alliance for Clinical Trials in Oncology (A091102). Patients were enrolled into histology-defined cohorts: (i) liposarcoma, (ii) leiomyosarcoma, (iii) undifferentiated sarcoma, (iv) malignant peripheral nerve sheath tumor, or (v) other. Treatment was alisertib 50 mg PO b.i.d. d1-d7 every 21 days. The primary end point was response rate; progression-free survival (PFS) was secondary. One response in the first 9 patients expanded enrollment in a cohort to 24 using a Simon two-stage design. RESULTS: Seventy-two patients were enrolled at 24 sites [12 LPS, 10 LMS, 11 US, 10 malignant peripheral nerve sheath tumor (MPNST), 29 Other]. The median age was 55 years; 54% were male; 58%/38%/4% were ECOG PS 0/1/2. One PR expanded enrollment to the second stage in the other sarcoma cohort. The histology-specific cohorts ceased at the first stage. There were two confirmed PRs in the other cohort (both angiosarcoma) and one unconfirmed PR in dedifferentiated chondrosarcoma. Twelve-week PFS was 73% (LPS), 44% (LMS), 36% (US), 60% (MPNST), and 38% (Other). Grade 3-4 adverse events: oral mucositis (12%), anemia (14%), platelet count decreased (14%), leukopenia (22%), and neutropenia (42%). CONCLUSIONS: Alisertib was well tolerated. Occasional responses, yet prolonged stable disease, were observed. Although failing to meet the primary RR end point, PFS was promising. TRIAL REGISTRATION ID: NCT01653028.

EEG Topographic Mapping of Visual and Kinesthetic Imagery in Swimmers.

This study investigated differences in QEEG measures between kinesthetic and visual imagery of a 100-m swim in 36 elite competitive swimmers. Background information and post-trial checks controlled for the modality of imagery, swimming skill level, preferred imagery style, intensity of image and task equality. Measures of EEG relative magnitude in theta, low (7-9 Hz) and high alpha (8-10 Hz), and low and high beta were taken from 19 scalp sites during baseline, visual, and kinesthetic imagery. QEEG magnitudes in the low alpha band during the visual and kinesthetic conditions were attenuated from baseline in low band alpha but no changes were seen in any other bands. Swimmers produced more low alpha EEG magnitude during visual versus kinesthetic imagery. This was interpreted as the swimmers having a greater efficiency at producing visual imagery. Participants who reported a strong intensity versus a weaker feeling of the image (kinesthetic) had less low alpha magnitude, i.e., there was use of more cortical resources, but not for the visual condition. These data suggest that low band (7-9 Hz) alpha distinguishes imagery modalities from baseline, visual imagery requires less cortical resources than kinesthetic imagery, and that intense feelings of swimming requires more brain activity than less intense feelings.

Personalized therapy for breast cancer.

Breast cancer is a complex disease characterized by many morphological, clinical and molecular features. For many years, this disease has been classified according to histopathologic criteria, known as the tumor, node and metastasis (TNM) staging system. Clinical criteria that include immunohistochemical markers, such as the estrogen receptor (ER), the progesterone receptor (PR), and the human epidermal growth factor receptor 2 (HER2), provide a classification of breast cancer and dictates the optimal therapeutic approach for treatment. With genomic techniques, such as real-time reverse transcriptase PCR (RT-PCR), microarrays, next-generation sequencing, and whole-exome sequencing, breast cancer diagnostics is going through a significant evolution. Genomic and transcriptomic technologies make the analysis of gene expression signatures and mutation status possible so that tumors may now be classified more accurately with respect to diagnosis and prognosis. The -omic era has also made the possible identification of new biomarkers involved in breast cancer development, survival and invasion that can be gradually incorporated either into clinical testing or clinical trials. Together, clinical and molecular criteria can contribute to a more personalized management of the breast cancer patient. This article will present the progress made in the diagnosis and management of breast cancer using molecular information provided by genomic and transcriptomic technologies.

Romiplostim for management of chemotherapy-induced thrombocytopenia.

PURPOSE: Chemotherapy-induced thrombocytopenia (CIT) can cause delay or reduction in subsequent courses of chemotherapy. Here, we report on a series of 20 patients who had protracted CIT and were treated with romiplostim, a thrombopoietin receptor agonist. PATIENTS AND METHODS: We performed a retrospective review of the use of romiplostim for dose-limiting CIT at Memorial Sloan-Kettering Cancer Center from 2010-2012. Romiplostim was initiated at 1-2 mcg/kg weekly, with dose escalation by 1 mcg/kg per week until recovery of platelets (≥ 100 × 10(9)/L). If patients resumed chemotherapy, weekly romiplostim was continued. RESULTS: Romiplostim improved platelet counts in all 20 patients. In 19 of 20 patients, platelet counts of ≥ 100 × 10(9)/L were achieved. The mean dose of romiplostim to achieve adequate platelet recovery was 2.9 mcg/kg (range 1.0-5.1). Sixteen patients achieved platelet recovery by 2 weeks. Fifteen patients resumed cytotoxic chemotherapy with continued romiplostim support and 14 tolerated at least two subsequent cycles of chemotherapy, on schedule, without recurrence of dose-limiting CIT. Sepsis prevented continued chemotherapy in one patient. No resistance to romiplostim was observed. Three deep vein thromboses (DVT) were observed; one of which was a recurrent DVT in a patient who had previously experienced a DVT and was off anticoagulation. Three DVTs within 20 patients is within the anticipated thrombosis rates of patients with active cancer on chemotherapy. CONCLUSION: Romiplostim resulted in improvement in platelet counts, allowing resumption of chemotherapy without recurrence of dose-limiting CIT. No treatment-related toxicity was observed, but this would need to be confirmed in a larger, prospective trial. Our series differs from prior studies in that we selected only those patients who had already demonstrated persistent thrombocytopenia, and we continued weekly romiplostim during chemotherapy. Romiplostim may be a safe and effective treatment for CIT.

High-risk features in radiation-associated breast angiosarcomas.

BACKGROUND: Radiation-associated breast angiosarcoma (RT-AS) is an uncommon malignancy with an incidence of less than 1 % of all soft tissue sarcomas. The overall prognosis is quite dismal with high rates of recurrences and poor overall survival. There is an obvious paucity of data regarding clinical outcomes of patients with breast RT-AS. METHODS: We identified all patients with RT-AS treated at the Memorial Sloan-Kettering Cancer Center between 1982-2011 and collected their correlative clinical information. RESULTS: We identified 79 women with RT-AS with a median age of 68 (range 36-87). The median interval between radiation and development of RT-AS was 7 years (range 3-19). The median time to local and distant recurrence was 1.29 years (95 % CI 0.72-NA) and 2.48 years (95 % CI 1.29-NA), respectively. The median disease-specific survival was 2.97 years (95 % CI 2.21-NA). Independent predictors of worse disease-specific survival included age 68 years (HR 3.11, 95 % CI 1.20-8.08, P=0.020) and deep tumors (HR 3.23, 95 % CI 1.02-10.21, P=0.046.) CONCLUSION: RT-AS has high local/distant recurrence rates, limited duration on standard chemotherapy and poor disease-specific survival.

Phase II study of the HSP90-inhibitor BIIB021 in gastrointestinal stromal tumors.

BACKGROUND: HSP90 inhibition leads to proteosomal degradation of activated KIT and has in vitro activity against gastrointestinal stromal tumors (GIST). BIIB021 is an oral non-ansamycin HSP90 inhibitor. We carried out a phase II study of BIIB021 in patients with GIST refractory to imatinib and sunitinib. PATIENTS AND METHODS: The primary end-point was metabolic partial response (mPR) as assessed by fluorodeoxyglucose positron emission tomography (FDG-PET). The secondary end-points were pharmacokinetic assessments of BIIB021 and pharmacodynamic assessments of HSP70. Twenty-three patients were treated on two schedules: 12 pts received 600 mg twice a week (BIW) and 11 patients received 400 mg three times a week (TIW). All had prior imatinib and sunitinib but stopped>14 days before starting BIIB021. RESULTS: The median age was 59 years (33-88 years), 61% male, 44% Eastern Cooperative Oncology Group 1 (ECOG1). The best response was PR by FDG-PET for five patients (3/12 at 600 mg BIW and 2/9 at 400 TIW) for an overall response rate of 22%. The response duration was 25-138 days. Adverse events (AEs) were mild to moderate. The mean Cmax was 1.5 µmol and the mean AUC was 2.9 µmol h. Cmax>1.5 µmol was associated with a decrease in standardized uptake value (SUVmax). HSP70 increased substantially following treatment. CONCLUSIONS: This study met its primary end-point. BIIB021 leads to objective responses in refractory GIST patients. Pharmacodynamic studies confirmed HSP90 inhibition. Further evaluation of BIIB021 in GIST is warranted.

A call to action in thoracic transplant surgical training.

Thoracic organ recovery and implantation is increasing in complexity. Simultaneously the logistic burden and associated cost is rising. An electronic survey distributed to the surgical directors of thoracic transplant programs in the United States indicated dissatisfaction amongst 72% of respondents with current procurement training and 85% of respondents favored a process for certification in thoracic organ transplantation. These responses highlight concerns for the current paradigm of training in thoracic transplantation. We discuss the implications of advancements in organ retrieval and implant for surgical training and propose that the thoracic transplant community might address the need through formalized training in procurement and certification in thoracic transplantation.

Safety, tolerability, pharmacokinetics and pharmacodynamics of AZD8055 in advanced solid tumours and lymphoma.

BACKGROUND: This study assessed the safety, tolerability, pharmacokinetics and pharmacodynamics of the first-in-class dual mammalian target of rapamycin complex (mTORC)1/mTORC2 inhibitor, AZD8055. METHODS: Patients with advanced solid malignancies or lymphomas were recruited into this phase I, open-label, dose-escalation study of AZD8055 starting at 10 mg twice-daily oral dosing (BID). RESULTS: Forty-nine patients received AZD8055. Dose-limiting toxicities were reported at 40 mg (n=1), 90 mg (n=1) and 120 mg (n=3) BID; all were grade 3 rises in transaminases, reversible in all patients, apart from one who had liver metastases. The maximum tolerated dose was defined as 90 mg BID. The most frequent adverse events assessed to be related to AZD8055 were increased alanine aminotransferase (22%), increased aspartate aminotransferase (22%) and fatigue (16%). AZD8055 was rapidly absorbed (median t(max) ∼0.5 h) and exposure increased with increasing doses. Seven patients had stable disease for ≥ 4 months. Partial metabolic responses, assessed by fluorodeoxyglucose positron emission tomography, were observed at ≥ 40 mg BID (n=8 at day 35). CONCLUSION: The maximum tolerated dose for AZD8055 is 90 mg BID. Apart from elevated transaminases, which occurred at most dose levels, the drug had an acceptable toxicity profile; however, no RECIST responses were seen.

Advanced well-differentiated/dedifferentiated liposarcomas: role of chemotherapy and survival.

BACKGROUND: Data regarding the role of systemic therapy in patients with advanced well-differentiated/dedifferentiated liposarcomas (WDLPS/DDLPS) are limited. METHODS: From 2000 to 2010, 208 patients with advanced WDLPS/DDLPS received chemotherapy in 11 participating institutions. Clinical and pathological data were collected by reviewing medical records. RESULTS: Median age was 63 years (range 32-84). Combination chemotherapy was delivered in 85 cases (41%) and single agent in 123 cases (59%), respectively. One hundred and seventy-one patients (82%) received an anthracycline-containing regimen. Using RECIST, objective response was observed in 21 patients (12%), all treated with anthracyclines. Median progression-free survival (PFS) was 4.6 months [95% confidence interval (CI) 3.3-5.9]. On multivariate analysis, age and performance status (PS) were the sole factors significantly associated with poor PFS. Median overall survival (OS) was 15.2 months (95% CI 11.8 -18.7). On multivariate analysis, grade and PS were the sole factors significantly associated with OS. CONCLUSIONS: Chemotherapy was associated with clinical benefit in 46% of patients with advanced WDLPS/DDLPS. OS remains poor, even though visceral metastatic disease is less frequent than in other sarcomas.

Mapping and targeted viral activation of pancreatic nerves in mice reveal their roles in the regulation of glucose metabolism.

A lack of comprehensive mapping of ganglionic inputs into the pancreas and of technology for the modulation of the activity of specific pancreatic nerves has hindered the study of how they regulate metabolic processes. Here we show that the pancreas-innervating neurons in sympathetic, parasympathetic and sensory ganglia can be mapped in detail by using tissue clearing and retrograde tracing (the tracing of neural connections from the synapse to the cell body), and that genetic payloads can be delivered via intrapancreatic injection to target sites in efferent pancreatic nerves in live mice through optimized adeno-associated viruses and neural-tissue-specific promoters. We also show that, in male mice, the targeted activation of parasympathetic cholinergic intrapancreatic ganglia and neurons doubled plasma-insulin levels and improved glucose tolerance, and that tolerance was impaired by stimulating pancreas-projecting sympathetic neurons. The ability to map the peripheral ganglia innervating the pancreas and to deliver transgenes to specific pancreas-projecting neurons will facilitate the examination of ganglionic inputs and the study of the roles of pancreatic efferent innervation in glucose metabolism.

Phase I study of PD 0332991, a cyclin-dependent kinase inhibitor, administered in 3-week cycles (Schedule 2/1).

BACKGROUND: This phase I, open-label, first-in-human study determined dose-limiting toxicities (DLTs) and maximum tolerated dose (MTD) of PD 0332991, an oral cyclin-dependent kinase 4/6 inhibitor with potent anti-proliferative activity in vitro/vivo. METHODS: A total of 33 patients with retinoblastoma protein-positive advanced solid tumours or non-Hodgkin's lymphoma refractory to standard therapy or for which no therapy was available received PD 0332991 once daily (QD) for 14 days followed by 7 days off treatment (21-day cycles; Schedule 2/1). RESULTS: Six patients had DLTs (18%; four receiving 200 mg QD; two receiving 225 mg QD); the MTD was 200 mg QD. Treatment-related, non-haematological adverse events occurred in 29 patients (88%) during cycle 1 and 27 patients (82%) thereafter. Adverse events were generally mild-moderate. Of 31 evaluable patients, one with testicular cancer achieved a partial response; nine had stable disease (≥10 cycles in three cases). PD 0332991 was slowly absorbed (mean T(max) 4.2 h) and eliminated (mean half-life 26.7 h). Volume of distribution was large (mean 3241 l) with dose-proportional exposure. Using a maximum effective concentration model, neutropenia was proportional to exposure. CONCLUSION: PD 0332991 was generally well tolerated, with DLTs related mainly to myelosuppression. The MTD, 200 mg QD, is recommended for phase II study.

Erlotinib 'dosing-to-rash': a phase II intrapatient dose escalation and pharmacologic study of erlotinib in previously treated advanced non-small cell lung cancer.

BACKGROUND: To evaluate the anticancer activity of erlotinib in patients with previously treated, advanced non-small cell lung cancer (NSCLC) whose dose is increased to that associated with a maximal level of tolerable skin toxicity (i.e., target rash (TR)); to characterise the pharmacokinetics (PK) and pharmacodynamics (PD) of higher doses of erlotinib. METHODS: Patients initially received erlotinib 150 mg per day. The dose was successively increased in each patient to that associated with a TR. Anticancer activity was evaluated. Plasma, skin, and hair were sampled for PK and PD studies. RESULTS: Erlotinib dose escalation to 200-475 mg per day was feasible in 38 (90%) of 42 patients. Twenty-four (57%) patients developed a TR, but 19 (79%) did so at 150 mg per day. Five (12%) patients, all of whom developed a TR, had a partial response. Median progression-free survival (PFS) was 2.3 months (95% CI: 1.61, 4.14); median PFS was 3.5 months and 1.9 months, respectively, for patients who did and did not experience a TR (hazard ratio, 0.51; P=0.051). Neither rash severity nor response correlated with erlotinib exposure. CONCLUSION: Intrapatient dose escalation of erlotinib does not appreciably increase the propensity to experience a maximal level of tolerable skin toxicity, or appear to increase the anticancer activity of erlotinib in NSCLC.

Numerical study of the lateral resolution in electrostatic force microscopy for dielectric samples.

We present a study of the lateral resolution in electrostatic force microscopy for dielectric samples in both force and gradient modes. Whereas previous studies have reported expressions for metallic surfaces having potential heterogeneities (Kelvin probe force microscopy), in this work we take into account the presence of a dielectric medium. We introduce a definition of the lateral resolution based on the force due to a test particle being either a point charge or a polarizable particle on the dielectric surface. The behaviour has been studied over a wide range of typical experimental parameters: tip-sample distance (1-20) nm, sample thickness (0-5) µm and dielectric constant (1-20), using the numerical simulation of the equivalent charge method. For potential heterogeneities on metallic surfaces expressions are in agreement with the bibliography. The lateral resolution of samples having a dielectric constant of more than 10 tends to metallic behaviour. We found a characteristic thickness of 100 nm, above which the lateral resolution measured on the dielectric surface is close to that of an infinite medium. As previously reported, the lateral resolution is better in the gradient mode than in the force mode. Finally, we showed that for the same experimental conditions, the lateral resolution is better for a polarizable particle than for a charge, i.e. dielectric heterogeneities should always look 'sharper' (better resolved) than inhomogeneous charge distributions. This fact should be taken into account when interpreting images of heterogeneous samples.

Positron annihilation and relaxation dynamics from dielectric spectroscopy and nuclear magnetic resonance: cis-trans-1,4-poly(butadiene).

We report a joint analysis of positron annihilation lifetime spectroscopy (PALS), dielectric spectroscopy (BDS), and nuclear magnetic resonance (NMR) on cis-trans-1,4-poly(butadiene) (c-t-1,4-PBD). Phenomenological analysis of the orthopositronium lifetime τ(3)-T dependence by linear fitting reveals four characteristic PALS temperatures: T(b1)(G)=0.63T(g)(PALS), T(g)(PALS), T(b1)(L)=1.22T(g)(PALS), and T(b2)(L)=1.52T(g)(PALS). Slight bend effects in the glassy and supercooled liquid states are related to the fast or slow secondary ß process, from neutron scattering, respectively, the latter being connected with the trans-isomers. In addition, the first bend effect in the supercooled liquid coincides with a deviation of the slow effective secondary ß(eff) relaxation related to the cis-isomers from low-T Arrhenius behavior to non-Arrhenius one and correlates with the onset of the primary α process from BDS. The second plateau effect in the liquid state occurs when τ(3) becomes commensurable with the structural relaxation time τ(α)(T(b2)). It is also approximately related to its crossover from non-Arrhenius to Arrhenius regime in the combined BDS and NMR data. Finally, the combined BDS and NMR structural relaxation data, when analyzed in terms of the two-order parameter (TOP) model, suggest the influence of solidlike domains on both the annihilation behavior and the local and segmental chain mobility in the supercooled liquid. All these findings indicate the influence of the dynamic heterogeneity in both the primary and secondary relaxations due to the cis-trans isomerism in c-t-1,4-PBD and their impact into the PALS response.

Differential effects of hypothalamic long-chain fatty acid infusions on suppression of hepatic glucose production.

Our objective was to investigate whether the direct bilateral infusion of the monounsaturated fatty acid (MUFA) oleic acid (OA) within the mediobasal hypothalamus (MBH) is sufficient to reproduce the effect of administration of OA (30 nmol) in the third cerebral ventricle, which inhibits glucose production (GP) in rats. We used the pancreatic basal insulin clamp technique (plasma insulin ∼20 mU/ml) in combination with tracer dilution methodology to compare the effect of MBH OA on GP to that of a saturated fatty acid (SFA), palmitic acid (PA), and a polyunsaturated fatty acid (PUFA), linoleic acid (LA). The MBH infusion of 200 but not 40 pmol of OA was sufficient to markedly inhibit GP (by 61% from 12.6 ± 0.6 to 5.1 ± 1.6 mg·kg(-1)·min(-1)) such that exogenous glucose had to be infused at the rate of 6.0 ± 1.2 mg·kg(-1)·min(-1) to prevent hypoglycemia. MBH infusion of PA also caused a significant decrease in GP, but only at a total dose of 4 nmol (GP 5.8 ± 1.6 mg·kg(-1)·min(-1)). Finally, MBH LA at a total dose of 0.2 and 4 nmol failed to modify GP compared with rats receiving MBH vehicle. Increased availability of OA within the MBH is sufficient to markedly inhibit GP. LA does not share the effect of OA, whereas PA can reproduce the potent effect of OA on GP, but only at a higher dose. It remains to be determined whether SFAs need to be converted to MUFAs to exert this effect or whether they activate a separate signaling pathway to inhibit GP.

Safety, tolerability, pharmacokinetics and pharmacodynamics of the oral cyclin-dependent kinase inhibitor AZD5438 when administered at intermittent and continuous dosing schedules in patients with advanced solid tumours.

BACKGROUND: AZD5438 is an orally bioavailable inhibitor of cyclin E-cdk2, cyclin A-cdk2 and cyclin B-cdk1 complexes. Three phase I studies assessed the clinical safety, tolerability, pharmacokinetics and pharmacodynamics of AZD5438 when administered in different dosing schedules. PATIENTS AND METHODS: AZD5438 was administered four times daily, once every 7 days (study 1), for 14 consecutive days followed by 7 days of rest (study 2), or continuously (study 3), to patients with advanced solid tumours. Dose escalation proceeded until the emergence of dose-limiting toxic effects. RESULTS: Sixty-four patients were included across the three studies (19, 17 and 28, respectively). Nausea and vomiting were the most common adverse events. When dosed continuously, 40 mg four times daily was considered intolerable, and due to safety issues, all studies were terminated prematurely. Consequently, no intolerable dose was identified during the weekly schedule. Pharmacokinetics demonstrated dose-proportional exposure, high interpatient variability and accumulation after multiple doses. Skin biopsies indicated reduced retinoblastoma protein phosphorylation at cdk2 phospho-sites; other pharmacodynamic assessments did not reveal consistent trends. CONCLUSIONS: AZD5438 was generally well tolerated in a weekly dosing schedule, but not in continuous schedules. The clinical development programme for AZD5438 was discontinued owing to tolerability and exposure data from these studies.

Cellular remodeling of HCO3(-)-secreting cells in rabbit renal collecting duct in response to an acidic environment.

The renal cortical collecting duct (CCD) consists of principal and intercalated cells. Two forms of intercalated cells, those cells involved in H+/HCO3- transport, have recently been described. H+-secreting cells are capable of apical endocytosis and have H+ATPase on the apical membrane and a basolateral Cl-/HCO3- exchanger. HCO3(-)-secreting cells bind peanut agglutinin (PNA) to apical membrane receptors and have diffuse or basolateral distribution of H+ATPase; their Cl-/HCO3- exchanger is on the apical membrane. We found that 20 h after acid feeding of rabbits, there was a fourfold increase in number of cells showing apical endocytosis and a numerically similar reduction of cells binding PNA. Incubation of CCDs at pH 7.1 for 3-5 h in vitro led to similar, albeit less pronounced, changes. Evidence to suggest internalization and degradation of the PNA binding sites included a reduction in apical binding of PNA, decrease in pH in the environment of PNA binding, and incorporation of electron-dense PNA into cytoplasmic vesicles. Such remodeling was dependent on protein synthesis. There was also functional evidence for loss of apical Cl-/HCO3- exchange on PNA-labeled cells. Finally, net HCO3- flux converted from secretion to absorption after incubation at low pH. Thus, exposure of CCDs to low pH stimulates the removal/inactivation of apical Cl-/HCO3- exchangers and the internalization of other apical membrane components. Remodeling of PNA-labeled cells may mediate the change in polarity of HCO3- flux observed in response to acid treatment.