Advances in Early Detection of Melanoma and the Future of At-Home Testing.

The past decade has seen numerous advancements in approaches to melanoma detection, each with the common goal to stem the growing incidence of melanoma and its mortality rate. These advancements, while well documented to increase early melanoma detection, have also garnered considerable criticism of their efficacy for improving survival rates. In this review, we discuss the current state of such early detection approaches that do not require direct dermatologist intervention. Our findings suggest that a number of at-home and non-specialist methods exist with high accuracy for detecting melanoma, albeit with a few notable concerns worth further investigation. Additionally, research continues to find new approaches using artificial intelligence which have promise for the future.

STINGing the immune system: lessons learned through a model of G34-mutant pediatric high-grade glioma.

Pediatric high-grade gliomas (pHGGs) are aggressive diseases with poor outcomes. The diverse molecular heterogeneity in these rare tumors and inadequate tumor models have limited the development of effective therapies. In this issue of the JCI, Haase et al. produced a genetically engineered mouse model of H3.3-G34R-mutant pHGG to help identify vulnerabilities in DNA repair pathways. The authors designed a therapy that combined radiation with DNA damage response inhibitors to induce an adaptive immune response and extend survival. These findings suggest that combinations of small-molecule therapies with immunotherapies could drive a more durable response and improve mortality for patients with pHGG.

Metal-Metal Oxide Catalytic Interface Formation and Structural Evolution: A Discovery of Strong Metal-Support Bonding, Ordered Intermetallics, and Single Atoms.

In-depth investigation of metal-metal oxide interactions and their corresponding evolution is of paramount importance to heterogeneous catalysis as it allows the understanding and maneuvering of the structure of catalytic motifs. Herein, using a series of core/shell metal/iron oxide (M/FeOx, M = Pd, Pt, Au) nanoparticles and through a combination of in situ and ex situ electron and X-ray investigations, we revealed anomalous and dissimilar M-FeOx interactions among different systems under reducing conditions. Pd interacts strongly with FeOx after high-temperature reductive treatment, featured by the formation of Pd single atoms in the FeOx matrix and increased Pd-Fe bonding, while Pt transforms into ordered PtFe intermetallics and Pt single atoms immediately upon the coating of FeOx. In contrast, Au does not manifest strong bonding with FeOx. As a proof of concept of tailoring metal-metal oxide interactions for catalysis, optimized Pd/FeOx demonstrates 100% conversion and 86.5% selectivity at 60 °C for acetylene semihydrogenation.

Phenotypically distinguishing ESBL-producing pathogens using paper-based surface enhanced Raman sensors.

Antimicrobial stewardship practices are critical in preventing the further erosion of treatment options for bacterial infections. Yet, at the same time, determination of an infection's antimicrobial susceptibility requires multiple rounds of culture and expensive lab automation systems. In this work, we report the use of paper-based surface enhanced Raman spectroscopy (SERS) sensors and portable instrumentation to phenotypically discriminate multi-drug resistance with fewer culture steps than conventional clinical microbiology. Specifically, we demonstrate the identification of resistance to varying generations of ß-lactam antibiotics by detecting the activity of particular ß-lactamase enzymes in a multiplexed assay. The method utilizes molecular reporters that consist of ß-lactams with SERS barcodes. Hydrolysis of the ß-lactam by ß-lactamase enzymes in the sample expels the barcode; the released sulfur-containing barcode is then detected via SERS. Using this approach, we demonstrate the differentiation of E. coli strains with (1) extended spectrum ß-lactamase (ESBL), (2) narrow-spectrum ß-lactamase, and (3) no resistance, using only a single measurement on a single sample. In addition, we experimentally validate an approach to expand the library of reporters through the simple chemical synthesis of new barcoded ß-lactams. Importantly, the reported method determines the susceptibility based on phenotypic ß-lactamase activity, which is aligned with current microbiology lab standards. This new method will enable the precise selection of effective ß-lactam antibiotics (as opposed to defaulting to drugs of last resort) faster than current methods while using simple steps and low-cost portable instrumentation.

Dynamic Electric Field Alignment of Metal-Organic Framework Microrods.

Alignment of metal-organic framework (MOF) crystals has previously been performed via careful control of oriented MOF growth on substrates, as well as by dynamic magnetic alignment. We show here that bromobenzene-suspended microrod crystals of the MOF NU-1000 can also be dynamically aligned via electric fields, giving rise to rapid electrooptical responses. This method of dynamic MOF alignment opens up new avenues of MOF control which are important for integration of MOFs into switchable electronic devices as well as in other applications such as reconfigurable sensors or optical systems.

Infective endocarditis caused by Klebsiella oxytoca in an intravenous drug user with cancer.

Infective endocarditis caused by Klebsiella species is rare, with most isolates being K. pneumoniae. We report the case of a 24-year-old intravenous drug user with newly diagnosed seminoma who developed K. oxytoca endocarditis. In addition to having K. oxytoca isolated from blood culture, cultures of that species were obtained from a retroperitoneal metastasis found on original presentation.

Modulation of Glucocorticoid Resistance in Pediatric T-cell Acute Lymphoblastic Leukemia by Increasing BIM Expression with the PI3K/mTOR Inhibitor BEZ235.

PURPOSE: The aim of our study is to evaluate the preclinical therapeutic activity and mechanism of action of BEZ235, a dual PI3K/mTOR inhibitor, in combination with dexamethasone in acute lymphoblastic leukemia (ALL). EXPERIMENTAL DESIGN: The cytotoxic effects of BEZ235 and dexamethasone as single agents and in combination were assessed in a panel of ALL cell lines and xenograft models. The underlying mechanism of BEZ235 and dexamethasone was evaluated using immunoblotting, TaqMan RT-PCR, siRNA, immunohistochemistry, and immunoprecipitation. RESULTS: Inhibition of the PI3K/AKT/mTOR pathway with the dual PI3K/mTOR inhibitor BEZ235 enhanced dexamethasone-induced anti-leukemic activity in in vitro (continuous cell lines and primary ALL cultures) and systemic in vivo models of T-ALL (including a patient-derived xenograft). Through inhibition of AKT1, BEZ235 was able to alleviate AKT1-mediated suppression of dexamethasone-induced apoptotic pathways leading to increased expression of the proapoptotic BCL-2 protein BIM. Downregulation of MCL-1 by BEZ235 further contributed to the modulation of dexamethasone resistance by increasing the amount of BIM available to induce apoptosis, especially in PTEN-null T-ALL where inhibition of AKT only partially overcame AKT-induced BIM suppression. CONCLUSIONS: Our data support the further investigation of agents targeting the PI3K/mTOR pathway to modulate glucocorticoid resistance in T-ALL.

A Sporadic Case of Advanced Metastatic Cholangiocarcinoma in a Child: A Case Report and Review of Literature.

Cholangiocarcinoma (CC) is a malignancy of the biliary tract that commonly presents in the seventh decade of life, but is extremely rare in children. We report on a sporadic case of malignant CC in an 11-year-old female. Originally presenting with dyspnea, chest x-ray identified multiple pulmonary metastases, and various imaging modalities revealed diffuse disease spread throughout the liver and lungs. Following pathologic diagnosis of CC, aggressive treatment was initiated with a dramatic initial response to chemotherapy, however, as often occurs with advanced disease in adults, this patient ultimately succumbed to the disease.

Activity of MM-398, nanoliposomal irinotecan (nal-IRI), in Ewing's family tumor xenografts is associated with high exposure of tumor to drug and high SLFN11 expression.

PURPOSE: To determine the pharmacokinetics and the antitumor activity in pediatric cancer models of MM-398, a nanoliposomal irinotecan (nal-IRI). EXPERIMENTAL DESIGN: Mouse plasma and tissue pharmacokinetics of nal-IRI and the current clinical formulation of irinotecan were characterized. In vivo activity of irinotecan and nal-IRI was compared in xenograft models (3 each in nu/nu mice) of Ewing's sarcoma family of tumors (EFT), neuroblastoma (NB), and rhabdomyosarcoma (RMS). SLFN11 expression was assessed by Affymetrix HuEx arrays, Taqman RT-PCR, and immunoblotting. RESULTS: Plasma and tumor concentrations of irinotecan and SN-38 (active metabolite) were approximately 10-fold higher for nal-IRI than for irinotecan. Two doses of NAL-IRI (10 mg/kg/dose) achieved complete responses maintained for >100 days in 24 of 27 EFT-xenografted mice. Event-free survival for mice with RMS and NB was significantly shorter than for EFT. High SLFN11 expression has been reported to correlate with sensitivity to DNA damaging agents; median SLFN11 mRNA expression was >100-fold greater in both EFT cell lines and primary tumors compared with NB or RMS cell lines or primary tumors. Cytotoxicity of SN-38 inversely correlated with SLFN11 mRNA expression in 20 EFT cell lines. CONCLUSIONS: In pediatric solid tumor xenografts, nal-IRI demonstrated higher systemic and tumor exposures to SN-38 and improved antitumor activity compared with the current clinical formulation of irinotecan. Clinical studies of nal-IRI in pediatric solid tumors (especially EFT) and correlative studies to determine if SLFN11 expression can serve as a biomarker to predict nal-IRI clinical activity are warranted.

Caspase-dependent Mcl-1 cleavage and effect of Mcl-1 phosphorylation in ABT-737-induced apoptosis in human acute lymphoblastic leukemia cell lines.

ABT-737 is a BH3-mimetic that has a wide spectrum of single-agent activity against acute lymphoblastic leukemia (ALL) cell lines and xenografts. Previously, we reported that in response to ABT-737, ABT-737-resistant ALL cell lines showed an apparent increase in Mcl-1 (an anti-apoptotic Bcl-2 family protein that is not effectively inhibited by ABT-737) while ABT-737-sensitive ALL cell lines showed decreased Mcl-1 levels. Here we explored the mechanism of Mcl-1 cleavage by ABT-737 and the effect of adjacent phosphorylation sites on Mcl-1 cleavage and apoptosis induced by ABT-737 in a human B-lineage ALL cell line. Caspase cleavage sites in Mcl-1 and the effect of mutation in Mcl-1 phosphorylation sites were determined by transducing Mcl-1 variants tagged with the V5 epitope into human ALL cells. Cytotoxicity was by fluorescence-based DIMSCAN, and changes in protein by immunoblotting. ABT-737 induced a caspase-dependent cleavage of Mcl-1. Of the two Mcl-1 caspase cleavage sites (D127 and D157), D157 was the site of ABT-737-induced cleavage in ALL cells. Cells with exogenously expressed Mcl-1 Δ157 fragment showed greater caspase-3 and caspase-9 activation when they were treated with ABT-737 compared with cells expressing wild-type or D157A mutant Mcl-1. Cells with mutated phosphorylation sites on Mcl-1 (S159A and T163A) were less susceptible to Mcl-1 cleavage and apoptosis induced by ABT-737. Our data showed that Mcl-1 is post-translationally regulated in response to ABT-737 treatment, primarily via a caspase-dependent cleavage that generates a pro-apoptotic Mcl-1 fragment.

Association of high-risk scores for obstructive sleep apnea with symptomatic bradyarrhythmias.

BACKGROUND: Obstructive sleep apnea (OSA) may have an association with bradyarrhythmias but often remains undiagnosed. Our aim was to determine if patients with a high risk of OSA attending our cardiology clinics had an association with symptomatic bradyarrhythmias, as this information might lead to changes in management strategy. METHODS: The Berlin questionnaire was used to assess risk of OSA in 190 patients, and they were divided into high-risk or low-risk groups. Demographic data and medical histories were recorded and patients groups were compared with t-tests and chi-square tests. A multivariate regression analysis was done to correct for confounding variables. RESULTS: The mean age of our sample population was 63.0 ± 14.7 years with a mean BMI of 29.5 ± 7.8 kg/m2. Using the Berlin questionnaire, 41.3% of the patients were classified as high risk; 15.7% of the patients had a known diagnosis of OSA. Between high-risk and low-risk groups, there was no significant difference in the prevalence of bradyarrhythmias (22.5 vs. 15.2% P = 0.21), symptomatic sinus node dysfunction (14.4 vs. 11.4% P = 0.66) or atrioventricular block (10.8 vs. 6.3% P = 0.33). A multivariable logistic regression analysis demonstrated that dyslipidemia had the strongest association with a high risk for OSA, but not bradyarrhythmias. CONCLUSIONS: Based on the Berlin questionnaire, patients at a high risk for OSA did not have an increased prevalence of bradyarrhythmias. More studies are needed to assess the utility of evaluating patients with bradyarrhythmias for OSA prior to implanting permanent pacing devices.

Bcl-2 family of proteins as therapeutic targets in genitourinary neoplasms.

INTRODUCTION: Overexpression of antiapoptotic B-cell lymphoma (Bcl-2) proteins confers the dysregulation of apoptosis and results in drug resistance in a variety of cancers, including those of the genitourinary tract. Inhibitors that target prosurvival Bcl-2 proteins are in preclinical and clinical development. The objective of this review is to assess the involvement of Bcl-2 proteins as well as the preclinical and clinical activity of Bcl-2 inhibitors under evaluation for genitourinary neoplasms. MATERIALS AND METHODS: PubMed was used with both medical subject heading terms and free search to identify the relevant literature. Information on clinical trials was obtained using http://Clincaltrials.gov, EU Clinical Trials Register, and meeting abstracts of the American Society of Clinical Oncology. RESULTS: To date, 2 Bcl-2 inhibitors have been evaluated in clinical trials for genitourinary tumors (oblimersen and AT-101 (R-(-)-gossypol)). Both agents demonstrated some success in early stages of development, but their clinical activity did not meet expectations. Preclinical studies are under way for other Bcl-2 inhibitors including ABT-737, HA14-1, and Bcl-2 homology 3 inhibitors. CONCLUSION: Antiapoptotic Bcl-2 proteins are potential molecular targets in genitourinary cancers. Bcl-2 inhibitors might be effective as single agents or in combination with conventional therapies. However, the biology of the Bcl-2 family in genitourinary cancers remains poorly understood and robust preclinical studies are needed to inform clinical development. Such studies should aim to identify: (1) pharmacodynamic markers that could help guide patient selection for treatment with Bcl-2 inhibitors, and (2) optimal combinations of Bcl-2 inhibitors with other anticancer agents for future clinical investigation.

Synergistic activity of rapamycin and dexamethasone in vitro and in vivo in acute lymphoblastic leukemia via cell-cycle arrest and apoptosis.

Activation of the mTOR pathway subsequent to phosphatase and tensin homolog (PTEN) mutation may be associated with glucocorticoid (GC) resistance in acute lymphoblastic leukemia (ALL). The combination activity of rapamycin and dexamethasone in cell lines and xenograft models of ALL was determined. Compared with either drug alone, dexamethasone+rapamycin showed significantly greater apoptosis and cell cycle arrest in some cell lines, and was more frequently seen in T-lineage cell lines with PTEN mutation. The combination significantly extended the event-free survival of mice carrying PTEN mutated xenografts. Our data suggest that PI3K/mTOR pathway inhibitors could benefit patients with PTEN mutated T-ALL.

Methotrexate and aminopterin exhibit similar in vitro and in vivo preclinical activity against acute lymphoblastic leukaemia and lymphoma.

Due to the development of neurological toxicity and resistance to methotrexate (MTX), other antifolates have been evaluated for its potential replacement in the treatment of childhood acute lymphoblastic leukaemia (ALL). Aminopterin (AMT) has been suggested to provide clinical advantages over MTX and other antifolates. AMT activity, compared with MTX, was evaluated in ALL and lymphoma preclinical models. The minimum survival fraction at the range of concentrations tested was lower with AMT than with MTX in 3 out of 15 cell lines. Both AMT and MTX significantly extended the event-free survival of mice bearing 3 out of 4 xenografts with equivalent activity.