Cap Group Research Articles

COOLHAIR: A prospective randomized trial to investigate the efficacy and tolerability of scalp cooling in patients undergoing neoadjuvant chemotherapy for early breast cancer.

525 Background: Chemotherapy induced alopecia (CIA) is a distressing side effect for women with breast cancer (BC) undergoing chemotherapy (CT). Scalp cooling is a method aiming to prevent CIA, but its efficacy is not well defined. Observational studies show a positive effect of scalp cooling to reduce hair loss, but randomized trials until recently have been lacking. Methods: In our monocentric prospective randomized trial patients with early BC undergoing (neo)adjuvant CT were 1:1 randomized to either scalp cooling (CAP) or not (noCAP). All patients received 18 to 24 weeks of anthracycline (A) and/or taxane (T)-based CT. The DigniCap System was used for scalp cooling. The primary endpoint was patient reported rate of alopecia according to the Dean Scale (Grade 0: no hair loss, grade 1: > 0 - 25%; grade 2: > 25 - 50%; grade 3: > 50 - 75%; grade 4: > 75%). Hair preservation was defined as hair loss £ grade 2. Secondary endpoints were rate of alopecia determined by nursing staff and an independent and blinded evaluator, rate of wig/scarf use as well as quality of life. Results: From August 2014 until January 2016 seventy-nine patients were included (41 CAP and 38 noCAP). The drop-out rate was 32% in the CAP arm and 34% in the noCAP arm. Main reasons for drop out were hair loss, adverse events (CAP) and randomization into control arm. At the time of this analysis all patients had completed CT. Hair preservation was observed in 39% of patients in the CAP arm versus 0% in the No CAP arm (p < 0.001). There was a strong concordance between patients and staff evaluation (weighted Cohen's Kappa = 0.92). Wig/scarf use was significantly less frequent in the CAP group (36% vs 92% at home, p < 0.001; 64% vs 91% outside, p < 0.001). We did not observe any differences in hair preservation between A-based and non A-based regimens. Conclusions: Our prospective randomized trial shows that scalp cooling is effective in preventing CIA in a relevant number of patients. This option should be made available for patients undergoing T+/-A-based (neo)adjuvant chemotherapy for EBC.

Addition of oxaliplatin to neoadjuvant radiochemotherapy in MRI-defined T3, T4 or N+ rectal cancer: a randomized clinical trial.

Clinical trials investigating the effects of addition of oxaliplatin to neoadjuvant radiochemotherapy in locally advanced rectal cancers (LARCs) have brought controversial results for pathologic complete response as an endpoint. This randomized clinical trial investigated downstaging as a short-term surrogate for progression-free survival (PFS). Patients with magnetic resonance imaging (MRI) defined T3, T4 or N+ histologically proven adenocarcinoma of rectum within 15 cm from anal verge were randomly assigned to receive 50-50.4 Gy external beam radiation in 25-28 fractions and concurrent capecitabine 825 mg/m2 twice daily 5 days a week with or without oxaliplatin 60 mg/m2 weekly as neoadjuvant radiochemotherapy (Capox and Cap group, respectively). T downstage was defined as at least one stage regression in pathologic report after surgery comparing to MRI image before the preoperative treatment. Adverse effects of treatment were recorded on a weekly basis according to National Cancer Institute Common Toxicity Criteria, version 4. Sixty-three patients were randomly assigned to Cap (n = 31) and Capox (n = 32) groups. There was no grade 4 toxicity. The only grade 3 toxicity that occurred more in Capox group was diarrhea (22% vs 0%; P = 0.006). Histopathologic stage of 52 patients (27 patients in Cap and 25 patients in Capox groups) was compared to their preoperative stage defined by MRI. There was a greater rate of T downstage in Capox group (59% vs 42%; P = 0.037). Eleven patients in Capox group (34%) achieved pathologic complete response, comparing to four in Cap group (13%); P = 0.072. The addition of oxalipatin to neoadjuvant radiochemotherapy in LARC led to higher rate of tumor downstaging. Longer follow-up is needed to evaluate PFS.

Design and Synthesis of Mercaptoacetamides as Potent, Selective, and Brain Permeable Histone Deacetylase 6 Inhibitors.

A series of nonhydroxamate HDAC6 inhibitors were prepared in our effort to develop potent and selective compounds for possible use in central nervous system (CNS) disorders, thus obviating the genotoxicity often associated with the hydroxamates. Halogens are incorporated in the cap groups of the designed mercaptoacetamides in order to increase brain accessibility. The indole analogue 7e and quinoline analogue 13a displayed potent HDAC6 inhibitory activity (IC50, 11 and 2.8 nM) and excellent selectivity against HDAC1. Both 7e and 13a together with their ester prodrug 14 and disulfide prodrugs 15 and 16 were found to be effective in promoting tubulin acetylation in HEK cells. The disulfide prodrugs 15 and 16 also released a stable concentration of 7e and 13a upon microsomal incubation. Administration of 15 and 16in vivo was found to trigger an increase of tubulin acetylation in mouse cortex. These results suggest that further exploration of these compounds for the treatment of CNS disorders is warranted.

Exploring Derivatives of Quinazoline Alkaloid l-Vasicine as Cap Groups in the Design and Biological Mechanistic Evaluation of Novel Antitumor Histone Deacetylase Inhibitors.

l-Vasicine is a quinazoline alkaloid with an electron dense ring and additional functionalities in its structure. Employing target oriented synthesis (TOS) based on in silico studies, molecules with significant docking scores containing different derivatives of l-vasicine as caps were synthesized. Interestingly, one molecule, i.e., 4a, which contained 3-hyroxypyrrolidine as a cap group and a six carbon long aliphatic chain as a linker was found to inhibit HDACs. 4a showed more specificity toward class I HDAC isoforms. Also 4a was found to be less cytotoxic toward normal cell lines as compared to cancer cell lines. 4a inhibited cancer cell growth and induced cell death by various mechanisms. However, 4a was found to induce cell death independent of ROS generation, and unlike many natural product based HDAC inhibitors, 4a was found to be nontoxic under in vivo conditions. Importantly, we for the first time report the possibility of using a 3-hydroxypyrrolidine cap for the synthesis of HDAC inhibitors with good potency.

Exploration of some indole-based hydroxamic acids as histone deacetylase inhibitors and antitumor agents

In our search for novel small molecules targeting histone deacetylases, we have designed and synthesized a series of novel hydroxamic acids incorporating indole moiety as a cap group (3a–l). Biological evaluation showed that these hydroxamic acids potently inhibited HDAC2 with IC50 values in submicromolar range and up to tenfold (compound 3j) better than that of SAHA (also known as suberoylanilide hydroxamic acid). In four human cancer cell lines [SW620 (colon), PC-3 (prostate), AsPC-1 (pancreatic), NCI-H23 (lung)], the synthesized compounds that exhibited potent cytotoxicity with several compounds (3k, 3l) were found to be 12- to 77-fold more cytotoxic than SAHA. Docking experiments indicated that the compounds tightly bound to HDAC2 at the active binding site with binding affinities much higher than that of SAHA. Our present results demonstrate that these novel hydroxamic acids are potential for further development as anticancer agents.

Histone deacetylase inhibitors containing a benzamide functional group and a pyridyl cap are preferentially effective human immunodeficiency virus-1 latency-reversing agents in primary resting CD4+ T cells.

Antiretroviral therapy (ART) can control human immunodeficiency virus-1 (HIV-1) replication in infected individuals. Unfortunately, patients remain persistently infected owing to the establishment of latent infection requiring that ART be maintained indefinitely. One strategy being pursued involves the development of latency-reversing agents (LRAs) to eliminate the latent arm of the infection. One class of molecules that has been tested for LRA activity is the epigenetic modulating compounds histone deacetylases inhibitors (HDACis). Previously, initial screening of these molecules typically commenced using established cell models of viral latency, and although certain drugs such as the HDACi suberoylanilide hydroxamic acid demonstrated strong activity in these models, it did not translate to comparable activity with patient samples. Here we developed a primary cell model of viral latency using primary resting CD4+ T cells infected with Vpx-complemented HIV-1 and found that the activation profile using previously described LRAs mimicked that obtained with patient samples. This primary cell model was used to evaluate 94 epigenetic compounds. Not surprisingly, HDACis were found to be the strongest activators. However, within the HDACi class, the most active LRAs with the least pronounced toxicity contained a benzamide functional moiety with a pyridyl cap group, as exemplified by the HDACi chidamide. The results indicate that HDACis with a benzamide moiety and pyridyl cap group should be considered for further drug development in the pursuit of a successful viral clearance strategy.

Design and Synthesis of Novel Anti-Plasmodial Histone Deacetylase Inhibitors Containing an Alkoxyamide Connecting Unit.

Despite recent declines in mortality, malaria remains an important global health problem. New therapies are needed, including new drugs with novel modes of action compared to existing agents. Among new potential therapeutic targets for malaria, inhibition of parasitic histone deacetylases (HDACs) is a promising approach. Homology modeling of PfHDAC1, a known target of some anti-plasmodial HDAC inhibitors, revealed a unique threonine residue at the rim of the active site in close proximity to the location of the cap group of vorinostat-type HDAC inhibitors. Aiming to obtain HDAC inhibitors with potent and preferential anti-plasmodial activity, we synthesized a mini-library of alkoxyamide-based HDAC inhibitors containing hydrogen bond acceptors in the cap group. Using a 5-step synthetic route, 12 new inhibitors were synthesized and assayed against Plasmodium falciparum asexual blood stage parasites (clones 3D7 and Dd2) and human cells (HepG2). The most active compound 6h (Pf3D7 IC50 : 0.07 µM; PfDd2 IC50 : 0.07 µM) was 25-fold more toxic against the parasite versus human HepG2 cells. Selected compounds were shown to cause hyperacetylation of P. falciparum histone H4, indicating inhibition of one or more PfHDACs.

Echocardiographic diagnosis of total or left congenital pericardial absence with positional change

ObjectivesCongenital absence of the pericardium (CAP) is often confused with other conditions presenting with right ventricular dilatation and usually warrants CT or cardiac MR (CMR) to confirm. It would be...

Capsaicin reduces Alzheimer-associated tau changes in the hippocampus of type 2 diabetes rats.

Type 2 diabetes (T2D) is a high-risk factor for Alzheimer’s disease (AD) due to impaired insulin signaling pathway in brain. Capsaicin is a specific transient receptor potential vanilloid 1 (TRPV1) agonist which was proved to ameliorate insulin resistance. In this study, we investigated whether dietary capsaicin could reduce the risk of AD in T2D. T2D rats were fed with capsaicin-containing high fat (HF) diet for 10 consecutive days (T2D+CAP). Pair-fed T2D rats (T2D+PF) fed with the HF-diet of average dose of T2D+CAP group were included to control for the effects of reduced food intake and body weight. Capsaicin-containing standard chow was also introduced to non-diabetic rats (NC+CAP). Blood glucose and insulin were monitored. The phosphorylation level of tau at individual sites, the activities of phosphatidylinositol 3 kinase/protein kinase B (PI3K/AKT) and glycogen synthase kinase-3β (GSK-3β) were analyzed by Western blots. The results revealed that the levels of phosphorylated tau protein at sites Ser199, Ser202 and Ser396 in hippocampus of T2D+CAP group were decreased significantly, but these phospho-sites in T2D+PF group didn’t show such improvements compared with T2D group. There were almost no changes in non-diabetic rats on capsaicin diet (NC+CAP) compared with the non-diabetic rats with normal chow (NC). Increased activity of PI3K/AKT and decreased activity of GSK-3β were detected in hippocampus of T2D+CAP group compared with T2D group, and these changes did not show in T2D+PF group either. These results demonstrated that dietary capsaicin appears to prevent the hyperphosphorylation of AD-associated tau protein by increasing the activity of PI3K/AKT and inhibiting GSK-3β in hippocampus of T2D rats, which supported that dietary capsaicin might have a potential use for the prevention of AD in T2D.

Combined universal and selective prevention for adolescent alcohol use: a cluster randomized controlled trial.

No existing models of alcohol prevention concurrently adopt universal and selective approaches. This study aims to evaluate the first combined universal and selective approach to alcohol prevention. A total of 26 Australian schools with 2190 students (mean age: 13.3 years) were randomized to receive: universal prevention (Climate Schools); selective prevention (Preventure); combined prevention (Climate Schools and Preventure; CAP); or health education as usual (control). Primary outcomes were alcohol use, binge drinking and alcohol-related harms at 6, 12 and 24 months. Climate, Preventure and CAP students demonstrated significantly lower growth in their likelihood to drink and binge drink, relative to controls over 24 months. Preventure students displayed significantly lower growth in their likelihood to experience alcohol harms, relative to controls. While adolescents in both the CAP and Climate groups demonstrated slower growth in drinking compared with adolescents in the control group over the 2-year study period, CAP adolescents demonstrated faster growth in drinking compared with Climate adolescents. Findings support universal, selective and combined approaches to alcohol prevention. Particularly novel are the findings of no advantage of the combined approach over universal or selective prevention alone.

Perfluorinated hydroxamic acids are potent and selective inhibitors of HDAC-like enzymes from Pseudomonas aeruginosa

A series of perfluorinated SAHA (PFSAHA) was prepared and profiled against a panel of human and bacterial members of the Histone deacetylase (HDAC) family. Some of the active substances show nanomolar inhibitory activity and several hundred fold selectivity for the HDAC like enzyme PA3774 from P. aeruginosa. The extraordinary selectivity against human HDACs results from the distinct oligomeric state of PA3774 which consists of two head-to-head dimers. The binding pocket is defined by the surface of both opposite monomers confining the access of ligands to the active site. In addition, the aromatic cap group of PFSAHA undergoes an edge-to-face aromatic interaction with phenylalanine from the opposite monomer.

Synthesis and Biochemical Evaluation of Biotinylated Conjugates of Largazole Analogues: Selective Class I Histone Deacetylase Inhibitors.

The synthesis of biotinylated conjugates of synthetic analogues of the potent and selective histone deacetylase (HDAC) inhibitor largazole is reported. The thiazole moiety of the parent compound's cap group was derivatized to allow the chemical conjugation to biotin. The derivatized largazole analogues were assayed across a panel of HDACs 1-9 and retained potent and selective inhibitory activity towards the class I HDAC isoforms. The biotinylated conjugate was further shown to pull down HDACs 1, 2, and 3.

Microbiological and Clinical Significance of Prior Hospitalization in Patients Admitted with Community-onset Pneumonia: A Propensity Score-matching Study

Background: Although prior hospitalization has been considered as a risk factor for infection with PDR pathogens in patients with CAP, the evidence is limited, We aimed to elucidate the clinical impact of PH on these patients. Methods: This retrospective observational cohort study with prospectively collected data was conducted at Jeju National University Hospital between January 2012 and December 2014. Propensity scores were constructed, and the clinical outcomes were compared. We also conducted subgroup analyses. Results: A total of 704 patients were identified. Patients with PHAP had more comorbidities than those with CAP. The median CURB-65 and PSI scores were higher in patients with PHAP than in those with CAP. After matching according to propensity scores, the baseline characteristics of the PHAP group were similar to those of the CAP group. The isolation rate of PDR pathogens as well as the 30-day and total in-hospital mortality did not differ between the PHAP and propensity score-matched CAP patients. PHAP patients with prior antibiotic use or duration of PH ＞ 10 days showed significantly higher isolation rates of PDR pathogens. Multivariate logistic regression analysis demonstrated that prior antibiotic use was associated with the isolation rate of PDR pathogens. Conclusion: PH itself might not be related with higher isolation rates of PDR pathogens or mortality in patients with CO-pneumonia. It seems reasonable that broad spectrum antibiotic therapy for PDR pathogens should be selectively applie to PHAP patients with prior antibiotic use.

Risk of Prostate Cancer and Cyclin D1 A870G polymorphism; a Study of Correlation

Cyclin D1 (CCND1) is a critical gene in regulating the progression of cell cycle from G1 to S phases. Like other cyclins, cyclin D1 is frequently dysregulated in multiple cancers. Various clinical and epidemiological studies have suggested the possible association of cyclin D1 A870G polymorphism with the development of various cancers. Hence, we investigated the role of cyclin D1 A870G polymorphism in modulating the risk of prostate cancer (CaP) in a Kashmiri population. We examined a case–control study in which 129 CaP cases were studied for cyclin D1 A870G polymorphism against 221 controls taken from the general population by employing the polymerase chain reaction–restriction length fragment polymorphism technique. We observed the cyclin D1 A allele was more frequently present in the CaP group than the control group. Furthermore, men with AA genotype have an increased risk for developing CaP as compared to the control groups. We found AA genotype statistically significantly associated with dwelling, lymph node metastases, histopathological grade, and PSA levels. Therefore, our findings suggest that A870G polymorphism is a risk factor for CaP development. Furthermore, men with AA genotype have an increased risk of developing CaP.

Prostatic calculi detected in peripheral zone of the gland during a transrectal ultrasound biopsy can be significant predictors of prostate cancer.

Prostatic calculi (PC) are usually associated with benign prostatic hyperplasia or chronic inflammation. However, in several studies prostatic inflammation and calcification have been implicated in the pathogenesis of prostate cancer (CaP). We evaluated the prevalence of PC during transrectal ultrasound (TRUS) and correlate the ultrasonographic patterns with histological findings. A prospective study of 664 patients undergoing TRUS and prostate biopsy was planned. A standardized reproducible technique was used with using a GE Logiq 7 machine equipped with a 5-9MHz multi-frequency convex probe "end-fire". We defined marked presence of PC as multiple hyperechoic foci with significant area (≥ 3 mm in the largest diameter). PC were classified according to zone distribution into the gland: transitional zone (TZ), central zone (CZ), and peripheral zone (PZ). No significant difference was noted between the patients with PC and without PC, when comparing age, preoperative PSA level, prostate volume, and biopsy number, except for DRE findings. 168 patients (25.3%) had marked presence of PC on TRUS: 50.6% in TZ, 20.2% in CZ, and 29.2% in PZ. 31 patients (63.3%) with presence of PC in PZ had CaP on biopsy. The correlation observed between CaP and the presence of PC in PZ was statistically significant (p < 0.001). However, among patients in the CaP group there was no statistical association between PC and moderate or high Gleason grade. This study suggests that chronic prostatic inflammation and PC have a role in the biogenesis of cancer. CaP was more frequent in patients with PC in PZ of the gland, but was not associated with higher Gleason grade among these patients (p < 0.001).

The discovery of the Artemis polymetallic deposit

The Artemis Cu-Au-Zn-Ag deposit is located approximately 43 km southeast of Cloncurry and 19 km west of Eloise in northwest Queensland. The deposit, hosted within the Paleoproterozoic Mount Norna Quartzite unit which is part of the Lower Soldiers Cap Group, is a steeply-dipping massive sulphide body. The Artemis deposit was discovered by Minotaur in July 2014, only 9 months after taking possession of the project. The deposit is a new type of mineralisation that has previously not been identified in the Cloncurry district. The discovery was made by meticulously piecing together the historical geophysical and geological data, complimented by new geophysical data sets including airborne EM and ground EM to improve the understanding of prospective targets throughout the area. The dominant sulphide within the deposit is pyrrhotite, hence the deposit is highly conductive. Airborne and ground EM techniques were therefore the main tools in resolving the mineralisation. The pyrrhotite is non-magnetic and therefore the deposit has no discernible magnetic signature and magnetics played no part in the discovery process. The deposit had no associated surface geochemical anomalism and very little alteration, making this deposit geologically difficult to find and essentially reliant on EM techniques in making the discovery.

Combined effects of vacuum packaging and mint extract treatment on the biochemical, sensory and microbial changes of chill stored Indian mackerel.

The present study was aimed to investigate the combined effects of vacuum packaging and mint extract treatment on the quality changes of gutted Indian mackerel (Rastrelliger kanagurta) during storage at 0-2°C for 22days. Biochemical, total viable count and sensory quality of chill stored mackerel were analysed at periodic intervals. Mint extract treated [dipping in 0.5% (w/v) solution of mint extract for 30min] and vacuum packed fishes (MEVP) had significantly lower total volatile base nitrogen and trimethyl amine nitrogen compared to those packed under vacuum (CVP) and air (CAP) without mint extract treatment. Nucleotide degradation rate was lower in MEVP followed by CVP and CAP. Vacuum packaging in combination with ME treatment significantly inhibited lipid hydrolysis and lipid oxidation in mackerel as observed from its lower free fatty acid, peroxide value and thiobarbituric acid reactive substances values. Synergistic use of mint extract and vacuum packaging has markedly controlled microbial proliferation in the samples. Based on sensory evaluation, shelf life of Indian mackerel stored at 0-2°C was determined as 13days for CAP group, 16days for CVP group and 21days for MEVP group, respectively. The present study revealed that combination of vacuum packaging and mint extract treatment can be a promising technology to improve the storage quality of chill stored gutted mackerel.

Local scour prediction around piers with complex geometry

ABSTRACTA laboratory study of local scour at complex piers under steady clear-water conditions is presented. The term complex piers is used to define a bridge pier comprising of a column, pile cap, and pile group. Comprehensive data over the full range of possible pile cap elevations for complex piers with different geometries were obtained using five complex pier models, which were scaled down from existing bridges in Malaysia. The data are used to evaluate existing methodologies for characterizing the effective width of complex piers with varying pile cap location relative to the undisturbed streambed. The effect of pile cap location on scour depth is also addressed. To improve the predictions of local scour at complex piers, the new data and some previous data are used to propose a new method to predict local scour depth at complex piers.

Design, synthesis, and preliminary bioactivity evaluation of N1 -hydroxyterephthalamide derivatives with indole cap as novel histone deacetylase inhibitors.

Histone deacetylases inhibitors (HDACIs) have been widely recognized as significant therapeutic approach to cancers. In our efforts to develop novel histone deacetylases inhibitors (HDACIs) as potential anticancer agents, a series of N1 -hydroxyterephthalamide derivatives with an indole cap group were designed and synthesized. Compound 12m was identified to be the most potent one (IC50 =0.074μm against HeLa nuclear extract) and showed higher inhibitory activity than the positive control SAHA (IC50 =0.131μm), which was also verified by further molecular docking studies into active site of HDAC2. The results of selectivity on the inhibition of HDACs exhibited 12m being with similar isoform selective profile with PXD101. In addition, the representative compounds (8d, 12d, 12j, 12m) based on the outcomes of preliminary tumor cell screening demonstrated more potent or comparable to SAHA in the next antiproliferative activity assays. Collectively, the results encouraged further development of this chemical template to provide more potent analogs as HDACIs.

Synthesis of ST7612AA1, a Novel Oral HDAC Inhibitor, via Radical Thioacetic Acid Addition.

: BackgroundIn the expanding field of anticancer drugs, HDAC inhibitors are playing an increasingly important role. To date, four/five HDAC inhibitors have been approved by FDA. All these compounds fit the widely accepted HDAC inhibitors pharmacophore model characterized by a cap group, a linker chain and a zinc binding group (ZBG), able to bind the Zn2+ ion in a pocket of the HDAC active site. Romidepsin, a natural compound, is the only thiol derivative. We have selected a new class of synthetic HDAC inhibitors, the thio-ω(lactam-carboxamide) derivatives, with ST7612AA1 as drug candidate, pan-inhibitor active in the range of single- to two-digit nanomolar concentrations. Preliminary results of a synthetic optimization attempt towards a fast scale-up process are here proposed.MethodsIn the four steps of synthesis, from unsaturated amino acid intermediate to the final product, we explored different synthetic conditions in order to have a transferable process for a scale-up synthetic laboratory.ResultsIn the first step, isobutyl chloroformate was used and, after a simple work up with 1M HCl, 2 (96% yield) was obtained as a white solid, which was used directly in the next step. For thioacetic acid addition to the double bond of intermediate 2, two different routes were possible, with addition reaction in the first (D’) or last step (D). Reactions of 2 to give 5 or of 4 to give ST7612AA1 were both performed in dioxane. Reactions were fast and did not need the usually advised radical quenching with cyclohexene. The corresponding products were obtained in good yields (step D’, 89%; step D, 81%) after a flash chromatography.Conclusion: ST7612AA1, a thiol derivative prodrug of ST7464AA1, is the first of a new generation of HDAC inhibitors, very potent, orally administered, and well tolerated. Here, we have identified a synthetic route, competitive, versatile and easily transferable to industrial processes.