Recent advances with cyclin-dependent kinase inhibitors: therapeutic agents for breast cancer and their role in immuno-oncology

Introduction: Collaborative interactions between several diverse biological processes govern the onset and progression of breast cancer. These processes include alterations in cellular metabolism, anti-tumor immune responses, DNA damage repair, proliferation, anti-apoptotic signals, autophagy, epithelial-mesenchymal transition, components of the non-coding genome or onco-mIRs, cancer stem cells and cellular invasiveness. The last two decades have revealed that each of these processes are also directly regulated by a component of the cell cycle apparatus, cyclin D1.

Area covered: The current review is provided to update recent developments in the clinical application of cyclin/CDK inhibitors to breast cancer with a focus on the anti-tumor immune response.

Expert opinion: The cyclin D1 gene encodes the regulatory subunit of a proline-directed serine-threonine kinase that phosphorylates several substrates. CDKs possess phosphorylation site selectivity, with the phosphate-acceptor residue preceding a proline. Several important proteins are substrates including all three retinoblastoma proteins, NRF1, GCN5, and FOXM1. Over 280 cyclin D3/CDK6 substrates have b\een identified. Given the diversity of substrates for cyclin/CDKs, and the altered thresholds for substrate phosphorylation that occurs during the cell cycle, it is exciting that small molecular inhibitors targeting cyclin D/CDK activity have encouraging results in specific tumors.     

Plasma miRNA-based signatures in CRC screening programs

Colorectal cancer (CRC) screening programs help diagnose cancer precursors and early cancers and help reduce CRC mortality. However, currently recommended tests, the fecal immunochemical test (FIT) and colonoscopy, have low uptake. There is therefore a pressing need for screening strategies that are minimally invasive and consequently more acceptable to patients, most likely blood based, to increase early CRC identification. MicroRNAs (miRNAs) released from cancer cells are detectable in plasma in a remarkably stable form, making them ideal cancer biomarkers. Using plasma samples from FIT-positive (FIT+) subjects in an Italian CRC screening program, we aimed to identify plasma circulating miRNAs that detect early CRC. miRNAs were initially investigated by quantitative real-time PCR in plasma from 60 FIT+ subjects undergoing colonoscopy at Fondazione IRCCS Istituto Nazionale dei Tumori, then tested on an internal validation cohort (IVC, 201 cases) and finally in a large multicenter prospective series (external validation cohort [EVC], 1121 cases). For each endoscopic lesion (low-grade adenoma [LgA], high-grade adenoma [HgA], cancer lesion [CL]), specific signatures were identified in the IVC and confirmed on the EVC. A two-miRNA-based signature for CL and six-miRNA signatures for LgA and HgA were selected. In a multivariate analysis including sex and age at blood collection, the areas under the receiver operating characteristic curve (95% confidence interval) of the signatures were 0.644 (0.607–0.682), 0.670 (0.626–0.714) and 0.682 (0.580–0.785) for LgA, HgA and CL, respectively. A miRNA-based test could be introduced into the FIT+ workflow of CRC screening programs so as to schedule colonoscopies only for subjects likely to benefit most.     

Prevalence,Risk Factors,and Transmission Dynamics of Extended-Spectrum-β-Lactamase-Producing Enterobacteriaceae: a National Survey of Cattle Farms in Israel in 2013

Our objectives were to study the prevalence, risk factors for carriage, and transmission dynamics of extended-spectrum-β-lactamase (ESBL)-producing Enterobacteriaceae (ESBLPE) in a national survey of cattle. This was a point prevalence study conducted from July to October 2013 in Israel. Stool samples were collected from 1,226 cows in 123 sections on 40 farms of all production types. ESBLPE were identified in 291 samples (23.7%): 287 contained Escherichia coli and 4 contained Klebsiella pneumoniae. The number of ESBLPE-positive cows was the highest in quarantine stations and on fattening farms and was the lowest on pasture farms (P = 0.03). The number of ESBLPE-positive cows was the lowest in sections containing adult cows (age, >25 months) and highest in sections containing calves (age, <4 months) (P < 0.001). Infrastructure variables that were significant risk factors for ESBLPE carriage included crowding, a lack of manure cleaning, and a lack of a cooling (P < 0.001 for each), all of which were more common in sections containing calves. Antimicrobial prophylaxis was given almost exclusively to calves and was associated with a high number of ESBLPE carriers (P < 0.001). The 287 E. coli isolates were typed into 106 repetitive extragenic palindromic (REP)-PCR types and mostly harbored bla_CTX-M-1 or bla_CTX-M-9 group genes. The isolates on the six farms with ≥15 isolates of ESBLPE were of 4 to 7 different REP-PCR types, with one dominant type being harbored by about half of the isolates. Fourteen types were identified on more than one farm, with only six of the farms being adjacent to each other. The prevalence of ESBLPE carriage is high in calves in cowsheds where the use of antimicrobial prophylaxis is common. ESBLPE disseminate within cowsheds mainly by clonal spread, with limited intercowshed transmission occurring.     

Classification and cyclic fatigue evaluation of new kinematics for endodontic instruments

This study evaluated the effect of new motions of the motor TriAuto ZX2 on the cyclic fatigue of endodontic instruments. Vortex Blue 35.06 instruments were divided into four groups (n = 10) and tested for fatigue in a curved artificial canal (90° and 2 mm radius) using the following motions: continuous rotation (CR), Optimum Torque Reverse (OTR) set at 180° and the Optimum Glide Path (OGP), which was tested at 90° and 240°. The time to fracture (TTF) and the lengths of the fractured fragments were recorded. The mean TTF was significantly different among the groups (anova , P < 0.05): OGP 90° (213.39 ± 27.45), OTR 180° (121.24 ± 17.03), OGP 240° (45.24 ± 5.61) and CR (8.43 ± 1.27). Weibull analysis confirmed the shortest life expectancy for CR and the longest survival for OGP at 90°. The resistance to fatigue was affected by motions and pre‐set angles. The proprietary movements that are currently available for endodontic instruments were classified according to their kinematics.     

Nucleolin protein expression in cutaneous melanocytic lesions

Background:  Nucleolin is a major nucleolar argyrophilic protein involved in carcinogenesis. There are only few studies on its tissue expression in human cancer and none in melanoma. We aimed at exploring this protein and its prognostic impact in cutaneous melanocytic lesions.
Methods:  We studied 193 cases including benign, dysplastic and malignant melanocytic lesions. Nuclear positivity was evaluated by immunohistochemistry and quantified by automated image analysis.
Results:  Most dysplastic and malignant lesions showed high percentages of cells with abnormal patterns of nuclear positivity (Abn+N) consisting in multiple, irregular, positive dots (ID+) and a coarse, irregularly positive nucleoplasm (CNpl+) or both (ID+CNpl+). The patterns CNpl+ and/or ID+CNpl+ were never observed in benign lesions, in which ID+ were also virtually absent. Abn+N% was significantly lower in dysplastic nevi than in primary melanomas and metastases and in primary melanomas than in metastases (p < 0.05). Furthermore, Abn+N was the second powerful prognostic discriminator, after melanoma thickness, and a significantly lower survival was observed in vertical growth phase melanoma patients showing Abn+N in more than 50% of melanoma cells.
Conclusion:  An altered nuclear nucleolin expression seems to accompany melanoma progression. Further investigation on nucleolin functionality and subcellular trafficking could add information on its altered role in melanoma.     

Die traumatische Pneumatocele — Ein Fallbericht

Zusammenfassung Die posttraumatische Pneumatocele ist eine seltene intrapulmonale Veränderung nach stumpfem Thoraxtrauma. Anhand eines gut dokumentierten Falles wird diese seltene Form der Lungenkontusion dargestellt und die klinisch bedeutsame Differentialdiagnose diskutiert.

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Traumatic pneumatocele — a case report

Summary The posttraumatic pneumatocele is a rare intrapulmonary lesion following blunt thoracic injury. By means of a well documented case report this rare form of lung contusion is demonstrated and the clinically important differential diagnosis is discussed.

     

Sonographic evaluation of gallbladder kinetics: in vitro and in vivo comparison of different methods to assess gallbladder emptying.

In an in vitro study, 10 gallbladders of adult pigs and 6 gallbladders of lambs, all removed immediately after slaughtering, were stimulated in a water bath by electric means to induce active contraction. Gallbladder emptying was followed by ultrasonography employing five measurement procedures: (1) gallbladder width, (2) longitudinal planimetry, (3) transverse planimetry, (4) ellipsoid method, and (5) sum of cylinders method. In an in vivo investigation, gallbladder emptying of 30 volunteers (12 healthy subjects, 18 diabetics) was evaluated in the same way after ingestion of a fatty meal. Gallbladder width was found to be unsuitable to estimate the decrease in gallbladder volume due to a nonlinear relation of the parameters. Longitudinal planimetry tended to be less valid than transverse planimetry in assessing gallbladder volume reduction. The most valid estimation of gallbladder volume decreases was obtained by the two three-dimensional procedures. However, in neither in vitro nor in vivo could a significant difference between the sum of cylinders method and the ellipsoid method in determining relative volume reduction be established. We conclude that a three-dimensional measurement procedure should be used for valid assessments of gallbladder motility. However, according to our data there is no advantage in using the time-consuming sum of cylinders method compared to the simple ellipsoid method.     

Novel pyrrolidines in the venom of the ant Monomorium indicum

New 2,5-dialkylpyrrolidines found in the venom of Monomorium indicum include trans-2-butyl-5-(4-pentenyl)pyrrolidine [1], trans-2-butyl-5-(6-heptenyl)pyrrolidine [4], trans-5-(5-hexenyl)-2-(4-pentenyl)pyrrolidine [6], trans-5-(6-heptenyl)-2-(5-hexenyl)pyrrolidine [8], and trans-5-heptyl-2-hexylpyrrolidine [16], whose structures were confirmed by synthesis. The concomitance of five previously reported trans-2,5-dialkyl-pyrrolidines along with small amounts of the cis isomers and N-methyl analogues makes the venom of M. indicum the most qualitatively diverse blend of alkaloids reported from an ant to date. The toxicities to termites of four of these alkaloids were determined.