Expanding the Repertoire of Natural Product-Inspired Ring Pairs for Molecular Recognition of DNA

A furan amino acid, inspired by the recently discovered proximicin natural products, was incorporated into the scaffold of a DNA-binding hairpin polyamide. While unpaired oligomers of 2,4-disubstituted furan amino acids show poor DNA-binding activity, furan (Fn) carboxamides paired with N-methylpyrrole (Py) and N-methylimidazole (Im) rings demonstrate excellent stabilization of duplex DNA as well as discrimination of noncognate sequences, consistent with function as a Py mimic according to the Py/Im polyamide pairing rules

Synaptic metaplasticity with multi-level memristive devices

Deep learning has made remarkable progress in various tasks, surpassing human performance in some cases. However, one drawback of neural networks is catastrophic forgetting, where a network trained on one task forgets the solution when learning a new one. To address this issue, recent works have proposed solutions based on Binarized Neural Networks (BNNs) incorporating metaplasticity. In this work, we extend this solution to quantized neural networks (QNNs) and present a memristor-based hardware solution for implementing metaplasticity during both inference and training. We propose a hardware architecture that integrates quantized weights in memristor devices programmed in an analog multi-level fashion with a digital processing unit for high-precision metaplastic storage. We validated our approach using a combined software framework and memristor based crossbar array for in-memory computing fabricated in 130 nm CMOS technology. Our experimental results show that a two-layer perceptron achieves 97% and 86% accuracy on consecutive training of MNIST and Fashion-MNIST, equal to software baseline. This result demonstrates immunity to catastrophic forgetting and the resilience to analog device imperfections of the proposed solution. Moreover, our architecture is compatible with the memristor limited endurance and has a 15× reduction in memory footprint compared to the binarized neural network case

Long-term efficacy and safety of dose-dense and dose-intense ABVD without consolidation radiotherapy in patients with advanced Hodgkin lymphoma: A 15-year follow-up of the ABVDDD-DI phase II study

: We demonstrated that dose-densified and dose-intensified ABVD (doxorubicin, bleomycin, vinblastine, dacarbazine; ABVDDD-DI) was safe and effective. Here, we present a post hoc long-term analysis of the 82 patients enrolled in the original study. The median observation time was 175 months (IQR 159-197). At 15 years, progression-free and overall survival rates were 81.2% (95% CI, 69.9%-88.7%) and 92.7% (95% CI, 82.6%-97.0%), respectively. Four patients with multiple cardiovascular risk factors experienced delayed G3 cardiac events. The cumulative incidence of second malignancies at 20 years was 6.1%. Fertility and childbearing potential were unaffected. Data support an ongoing benefit for ABVDDD-DI without uneven late toxicities

Full wafer integration of NEMS on CMOS by nanostencil lithography

Wafer scale nanostencil lithography is used to define 200 nm scale mechanically resonating silicon cantilevers monolithically integrated into CMOS circuits. We demonstrate the simultaneous patterning of ~2000 nanodevices by post-processing standard CMOS wafers using one single metal evaporation, pattern transfer to silicon and subsequent etch of the sacrificial layer. Resonance frequencies around 1.5 MHz were measured in air and vacuum and tuned by applying dc voltages of 10V and 1V respectively.LMIS

Biological activity and DNA sequence specificity of synthetic carbamoyl analogues of distamycin

A new penta(N-methylpyrrole carboxamide) analogue of the antibiotic distamycin has been synthesized in which the N-terminal formylamino group was replaced by a carbamoyl moiety. It was substantially more stable than distamycin in aqueous solution and bound to DNA with about the same affinity constant. It had an exemplary margin of selectivity against herpes simplex virus type 1-infected HEp-2 cells in culture compared to uninfected control cells, and was equipotent with distamycin. For comparison, data for analogues containing fewer N-methylpyrrole carboxamide units and/or lacking the carbamoyl replacement are presented. Extensive DNase I footprinting experiments were conducted and revealed that all the distamycin analogues bound to AT-rich nucleotide sequences in three different restriction fragments, irrespective of how many pyrrole rings or which terminal moiety they contained. However, the relative strength of footprints differed significantly among the various compounds, though the apparent size of the binding site did not. With semi-synthetic DNA containing inosine and 2,6-diaminopurine residues in place of guanosine and adenine, respectively, the compounds recognized new binding sites composed of IC-rich clusters and were excluded from binding to their canonical sites. This showed that the process of specific sequence recognition was critically dominated by the placement of the purine 2-amino group in the minor groove of the double helix. </jats:p

Clinical Efficacy of Isatuximab Plus Carfilzomib and Dexamethasone in Relapsed/Refractory Multiple Myeloma Patients

: Isatuximab, a novel anti-CD38 monoclonal antibody, is approved in combination with carfilzomib and dexamethasone (Isa-Kd) in relapsed/refractory multiple myeloma (RRMM) patients. Because of its recent introduction, real-world efficacy and safety are poorly reported. In this Italian multicenter real-life observational retrospective study, efficacy and safety of the Isa-Kd regimen were evaluated in a cohort of 103 RRMM patients. Overall response rate (ORR) was 85%, with stringent (sCR) or complete response (CR) in 18% of cases and very good partial response (VGPR) in 39%. Median PFS and OS were not reached within the study period, while 1-year PFS and OS were 72% and 77%, respectively. Hematological toxicities were observed in 42% of subjects, and cardiac toxicities occurred in 24% of cases. Moreover, we conducted a subanalysis on patients (N = 69) treated with Isa-Kd after one prior line of therapy, showing an ORR of 88%, with sCR + CR in 20% of subjects, VGPR in 46%, and PR in 22% of patients. In this group, median PFS and OS were not reached, while 1-year PFS and OS were 92% and 95%, respectively. In conclusions, our study confirmed Isa-Kd as an effective treatment option for RRMM with a manageable safety profile even in real-life settings

Inkjet Metrology: High-Accuracy Mass Measurements of Microdroplets Produced by a Drop-on-Demand Dispenser

We describe gravimetric methods for measuring the mass of droplets generated by a drop-on-demand (DOD) microdispenser. Droplets are deposited, either continuously at a known frequency or as a burst of known number, into a cylinder positioned on a submicrogram balance. Mass measurements are acquired precisely by computer, and results are corrected for evaporation. Capabilities are demonstrated using isobutyl alcohol droplets. For ejection rates greater than 100 Hz, the repeatability of droplet mass measurements was 0.2%, while the combined relative standard uncertainty (uc) was 0.9%. When bursts of droplets were dispensed, the limit of quantitation was 72 μg (1490 droplets) with uc = 1.0%. Individual droplet size in a burst was evaluated by high-speed videography. Diameters were consistent from the tenth droplet onward, and the mass of an individual droplet was best estimated by the average droplet mass with a combined uncertainty of about 1%. Diameters of the first several droplets were anomalous, but their contribution was accounted for when dispensing bursts. Above the limits of quantitation, the gravimetric methods provided statistically equivalent results and permit detailed study of operational factors that influence droplet mass during dispensing, including the development of reliable microassays and standard materials using DOD technologies

A Unique Carrier for Delivery of Therapeutic Compounds beyond the Blood-Brain Barrier

BACKGROUND: Therapeutic intervention in many neurological diseases is thwarted by the physical obstacle formed by the blood-brain barrier (BBB) that excludes most drugs from entering the brain from the blood. Thus, identifying efficacious modes of drug delivery to the brain remains a "holy grail" in molecular medicine and nanobiotechnology. Brain capillaries, that comprise the BBB, possess an endogenous receptor that ferries an iron-transport protein, termed p97 (melanotransferrin), across the BBB. Here, we explored the hypothesis that therapeutic drugs "piggybacked" as conjugates of p97 can be shuttled across the BBB for treatment of otherwise inoperable brain tumors. APPROACH: Human p97 was covalently linked with the chemotherapeutic agents paclitaxel (PTAX) or adriamycin (ADR) and following intravenous injection, measured their penetration into brain tissue and other organs using radiolabeled and fluorescent derivatives of the drugs. In order to establish efficacy of the conjugates, we used nude mouse models to assess p97-drug conjugate activity towards glioma and mammary tumors growing subcutaneously compared to those growing intracranially. PRINCIPAL FINDINGS: Bolus-injected p97-drug conjugates and unconjugated p97 traversed brain capillary endothelium within a few minutes and accumulated to 1-2% of the injected by 24 hours. Brain delivery with p97-drug conjugates was quantitatively 10 fold higher than with free drug controls. Furthermore, both free-ADR and p97-ADR conjugates equally inhibited the subcutaneous growth of gliomas growing outside the brain. Evocatively, only p97-ADR conjugates significantly prolonged the survival of animals bearing intracranial gliomas or mammary tumors when compared to similar cumulated doses of free-ADR. SIGNIFICANCE: This study provides the initial proof of concept for p97 as a carrier capable of shuttling therapeutic levels of drugs from the blood to the brain for the treatment of neurological disorders, including classes of resident and metastatic brain tumors. It may be prudent, therefore, to consider implementation of this novel delivery platform in various clinical settings for therapeutic intervention in acute and chronic neurological diseases