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The detection of lies told about one's identity challenges traditional methods considering characteristics of the lie. This study explored the neural activities underlying identity deception by using electroencephalogram recordings to promote the development of a detection tool. The participants (N = 18) were required to tell a lie or the truth about true and false identity information with the differentiation of deception paradigm. The results showed deceptive (vs. honest) responses to true identity information were associated with a prolonged reaction time and enhanced upper alpha oscillations as well as the attenuated P300 and theta activities, which indicates identity concealment engaged portent honest response control and reduced processing of self-relevant information. By contrast, deceptive (vs. honest) responses to false identity information were associated with absent reaction time cost and decreased alpha activities, which suggests identity faking involved low cognitive conflict but required some degree of behavioral regulation.

The worldwide steady increase in the number of cancer patients motivates the development of innovative drug delivery systems for combination therapy as an effective clinical modality for cancer treatment. Here, we explored a design concept based on poly(ethylene glycol)

Biophysical & Biochemical Characterization of NP-ALT.

Supplementary Figure Legends 1-6

NP-ALT induces RIPK1 and necroptosis in uterine lines.

Phase 1, 2, and 3 studies

Resistance to cyclin D-CDK4/6 inhibitors (CDK4/6i) represents an unmet clinical need and is frequently caused by compensatory CDK2 activity. Here we describe a novel strategy to prevent CDK4i resistance by using a therapeutic liposomal:peptide formulation, NP-ALT, to inhibit the tyrosine phosphorylation of p27Kip1(CDKN1B), which in turn inhibits both CDK4/6 and CDK2. We find that NP-ALT blocks proliferation in HR+ breast cancer cells, as well as CDK4i-resistant cell types, including triple negative breast cancer (TNBC). The peptide ALT is not as stable in primary mammary epithelium, suggesting that NP-ALT has little effect in nontumor tissues. In HR+ breast cancer cells specifically, NP-ALT treatment induces ROS and RIPK1-dependent necroptosis. Estrogen signaling and ERα appear required. Significantly, NP-ALT induces necroptosis in MCF7 ESRY537S cells, which contain an ER gain of function mutation frequently detected in metastatic patients, which renders them resistant to endocrine therapy. Here we show that NP-ALT causes necroptosis and tumor regression in treatment naïve, palbociclib-resistant, and endocrine-resistant BC cells and xenograft models, demonstrating that p27 is a viable therapeutic target to combat drug resistance.Implications:This study reveals that blocking p27 tyrosine phosphorylation inhibits CDK4 and CDK2 activity and induces ROS-dependent necroptosis, suggesting a novel therapeutic option for endocrine and CDK4 inhibitor-resistant HR+ tumors.

NP-ALT inhibits palbociclib-resistant cells, but still requires estrogen to induce ROS and necroptosis.

Biophysical & Biochemical Characterization of NP-ALT.

ALT treatment does not cause apoptosis or autophagy

ERalpha status of cell lines and ALT is delivered to normal cells.

ALT treatment does not cause apoptosis or autophagy

Almost 270,000 US women will be diagnosed with breast cancer (BC) this year, anddespite advances in treatment, ~40,000 women will die. ER/PR+ (endocrineresponsive), Her2- tumors occur in approximately 40% of breast cancer patients andare candidates for drugs targeting estrogen responsiveness, such as letrozole orfulvestrant. CDK4 targeting drugs (CDK4i) like palbociclib, abemaciclib, or ribociclib arenow approved in combination with letrozole or fulvestrant as a front- and second-linetherapy for metastatic ER/PR+, Her2- patients. However, while combined ER andCDK4i treatment significantly extends Progression Free Survival (PFS), those treatedinvariably develop resistance. Thus, drug resistance remains an urgent unmet need, as current treatments only marginally improve Overall Survival (OS) for these patients.Resistance to palbociclib develops because of compensation by another kinase, CDK2, suggesting that to be effective, therapies must be developed to inhibit both CDK4 andCDK2. Concarlo has taken a different approach to inhibit CDK4 and CDK2 by targetingp27Kip1 (p27). p27 interacts specifically with CDK4/6 and CDK2, and is responsible forturning these kinases ON and OFF. This transition from ON to OFF is mediated by aspecific modification to p27 itself, by the tyrosine kinase BRK (breast tumor relatedkinase). Published work has shown that a naturally occurring ALTernatively splicedform of BRK, ALT, can bind to p27, blocking BRK's association, and preventing BRK'sphosphorylation of p27. This locks CDK4 and CDK2 into the OFF conformation andsimultaneously inhibits activities of both kinases. As the naked 144 aa ALT peptidedoes not enter cells, it was formulated within a lipid nano-particle (NP), and called IpY.1.IpY.1 inhibits proliferation of HR+ and triple negative (TN) BC cells, but not non-cancerous breast cells MCF10A. IpY.1 arrests CDK4i-resistant and endocrine-resistantBC cells and it is both cytostatic and cytotoxic, demonstrating that p27 is a viabletherapeutic target to combat drug resistance. In vivo, IpY reduces tumor volumes and increase OS in cell line-derived xenografts (CDX). In order to convert manufacturing of the therapeutic peptide portion of IpY from recombinant to synthetic production, Concarlo truncated the large ALT peptide and bioengineered it to a more stable form. IpY.20 has a comparable IC50 as IpY.1 in HR+and TNBC cells and does not cause growth arrest in non-cancerous MCF10A cells. Using the fluorescent-labeled variant of IpY.20 (fluo-IpY.20) injected into tumor-bearingsyngeneic CDX model, followed by IVIS imaging, we could detect fluo-IpY.20 in tumorsas early as 15 min and up to 24h post injection. 6-10% of the total fluorescent signal isallocated to tumor at all timepoints. In addition, fluo-IpY.20 inhibits the activation of itstarget in tumors within 24h, suggesting fluo-IpY.20 not only reaches tumors but alsoengages with its target. IpY.20 induces tumor regression in CDX models and animmunocompetent genetically engineered model that overexpresses the potent Erbb2oncogene. Overall, repeated dosing of IpY.20 does not exhibit significant adverseeffects and is well tolerated in immunocompetent mice. However, in these treated mice, there was an increase in platelets and production of some cytokines compared to vehicle-treated mice, suggesting that an immune response may have been initiated. By targeting p27 instead of the conserved CDK4 or CDK2 active sites, IpY.20 will bemore selective and have fewer off-target effects than the ATP-competitive smallmolecule CDK4is currently in use. As the majority of the drug resistance seen withCDK4 inhibitory drugs is a result of compensatory CDK2 activity, IpY.20 preventsacquired drug resistance by hitting both CDK4 and CDK2 simultaneously, resulting in amore durable response to the drug. Concarlo is currently in manufacturing with IpY.20. Citation Format: Grace Chen, Stacy W Blain, Irina Jilishitz, Allison Vanlnwegen, Lingyue Yan, Yun Wu. Developing IpY: A novel inhibitor for the treatment of ER+ CDK4i-resistant breast cancer [abstract]. In: Proceedings of the 2021 San Antonio Breast Cancer Symposium; 2021 Dec 7-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2022;82(4 Suppl):Abstract nr P5-16-18.

A zwitterionic polymer-drug conjugate (ZPDC) strategy is developed for the co-delivery of paclitaxel (PTX) and gemcitabine (GEM) chemotherapeutics, as well as a near-infrared fluorescence imaging agent cyanine5.5 (Cy5.5). The well-defined ZPDC is synthesized by tandem azide-alkyne and thiol-ene click functionalization of a biodegradable acetylenyl/allyl-functionalized polylactide and zwitterionic character is conferred by sulfobetaine. It has a number-average molecular weight of 53.6 kDa, comprising 6.5% PTX and 17.7% GEM by weight. Cy5.5 moieties are readily introduced to the ZPDC via conjugation. In aqueous solutions, the ZPDC exhibits a hydrodynamic diameter of 46 nm. In vitro MIA PaCa-2 human pancreatic cancer cells show strong ZPDC cellular uptake and cytotoxicity. In mice, the ZPDC exhibits long blood circulation, effective tumor accumulation, biocompatibility, therapeutic effect, and integrated imaging capacity. Overall, this work illustrates that ZPDCs are promising systems for chemotherapy delivery and bioimaging applications.

A multifunctional biodegradable brush polymer-drug conjugate (BPDC) is developed for the co-delivery of hydrophobic paclitaxel (PTX) and hydrophilic gemcitabine (GEM) chemotherapeutics, as well as a tumor imaging agent. A novel ternary copolymer of conventional, acetylenyl-functionalized and allyl-functionalized lactides is prepared to serve as the backbone precursor of BPDC. Acetylenyl groups of the copolymer are then reacted with poly(ethylene glycol) (PEG) side chains and cyanine5.5, a fluorescent probe, via azide-alkyne click reactions. Subsequently, the allyl groups of the yielded PEG-grafted brush polymer are used to covalently link PTX and GEM onto the backbone via thiol-ene click reactions. The resulting BPDC exhibits an average hydrodynamic diameter of 111 nm. Sustained and simultaneous release of PTX and GEM from the BPDC is observed in phosphate buffered saline, with the release of PTX showing sensitivity in mild acidic conditions. In vitro studies using MIA PaCa-2 human pancreatic cancer cells illustrate the cellular uptake and cytotoxicity of the BPDC. In vivo, the BPDC possesses long blood circulation, tumor accumulation, and enables optical tumor imaging. Further development and testing is warranted for multifunctional conjugated brush polymer systems that integrate combination chemotherapies and imaging.

Resistance to cyclin D-CDK4/6 inhibitors (CDK4/6i) represents an unmet clinical need and is frequently caused by compensatory CDK2 activity. Here we describe a novel strategy to prevent CDK4i resistance by using a therapeutic liposomal:peptide formulation, NP-ALT, to inhibit the tyrosine phosphorylation of p27Kip1(CDKN1B), which in turn inhibits both CDK4/6 and CDK2. We find that NP-ALT blocks proliferation in HR+ breast cancer cells, as well as CDK4i-resistant cell types, including triple negative breast cancer (TNBC). The peptide ALT is not as stable in primary mammary epithelium, suggesting that NP-ALT has little effect in nontumor tissues. In HR+ breast cancer cells specifically, NP-ALT treatment induces ROS and RIPK1-dependent necroptosis. Estrogen signaling and ERα appear required. Significantly, NP-ALT induces necroptosis in MCF7 ESRY537S cells, which contain an ER gain of function mutation frequently detected in metastatic patients, which renders them resistant to endocrine therapy. Here we show that NP-ALT causes necroptosis and tumor regression in treatment naïve, palbociclib-resistant, and endocrine-resistant BC cells and xenograft models, demonstrating that p27 is a viable therapeutic target to combat drug resistance. Implications: This study reveals that blocking p27 tyrosine phosphorylation inhibits CDK4 and CDK2 activity and induces ROS-dependent necroptosis, suggesting a novel therapeutic option for endocrine and CDK4 inhibitor-resistant HR+ tumors.

Nanophotonic resonators can confine light to deep-subwavelength volumes with highly enhanced near-field intensity and therefore are widely used for surface-enhanced infrared absorption spectroscopy in various molecular sensing applications. The enhanced signal is mainly contributed by molecules in photonic hot spots, which are regions of a nanophotonic structure with high-field intensity. Therefore, delivery of the majority of, if not all, analyte molecules to hot spots is crucial for fully utilizing the sensing capability of an optical sensor. However, for most optical sensors, simple and straightforward methods of introducing an aqueous analyte to the device, such as applying droplets or spin-coating, cannot achieve targeted delivery of analyte molecules to hot spots. Instead, analyte molecules are usually distributed across the entire device surface, so the majority of the molecules do not experience enhanced field intensity. Here, we present a nanophotonic sensor design with passive molecule trapping functionality. When an analyte solution droplet is introduced to the sensor surface and gradually evaporates, the device structure can effectively trap most precipitated analyte molecules in its hot spots, significantly enhancing the sensor spectral response and sensitivity performance. Specifically, our sensors produce a reflection change of a few percentage points in response to trace amounts of the amino-acid proline or glucose precipitate with a picogram-level mass, which is significantly less than the mass of a molecular monolayer covering the same measurement area. The demonstrated strategy for designing optical sensor structures may also be applied to sensing nano-particles such as exosomes, viruses, and quantum dots., Photonic sensors: trapping analytes by digging into nano-trenches An innovative sensor can make it easier to use infrared light for label-free, picogram-scale detection of amino acids and other molecules. Photonic sensors avoid the need for large quantities of analytes by using nanoscale gap structures to trap targets and subject them to ultrahigh optical fields. Peter Liu and colleagues at the State University of New York at Buffalo in the United States have developed a microchip that naturally drives molecules into nanoscale gap regions. The team fabricated arrays where aluminum ribbons overhang narrower strips of insulating crystals. When a drop of test solution is placed onto the chip and left to evaporate, surface tension creates concave profiles that concentrate molecules under the aluminum layers. The resonant frequencies within this device’s “nano-trenches” can be tuned to specific molecular targets by tweaking the array’s geometric parameters.

Nanoparticles have emerged as versatile carriers for various therapeutics and can potentially treat a wide range of diseases in an accurate and disease-specific manner. Polymeric biomaterials have gained tremendous attention over the past decades, owing to their tunable structure and properties. Aliphatic polyesters have appealing attributes, including biodegradability, non-toxicity, and the ability to incorporate functional groups within the polymer backbone. Such distinctive properties have rendered them as a class of highly promising biomaterials for various biomedical applications. In this article, well-defined alkyne-functionalized poly(ethylene glycol)-b-poly(&epsilon, caprolactone) (PEG-b-PCL) diblock copolymer was synthesized and studied for pH-responsive delivery of doxorubicin (DOX). The alkyne-functionalized PEG-b-PCL diblock copolymer was prepared by the synthesis of an alkyne-functionalized &epsilon, caprolactone (CL), followed by ring-opening polymerization (ROP) using PEG as the macroinitiator. The alkyne functionalities of PEG-b-PCL were modified through copper(I)-catalyzed alkyne-azide cycloaddition (CuAAC) click reaction to graft aldehyde (ALD) groups and obtain PEG-b-PCL-g-ALD. Subsequently, DOX was conjugated on PEG-b-PCL-g-ALD through the Schiff base reaction. The resulting PEG-b-PCL-g-DOX polymer-drug conjugate (PDC) self-assembled into a nano-sized micellar structure with facilitated DOX release in acidic pH due to the pH-responsive linkage. The nanostructures of PDC micelles were characterized using transmission electron microscopy (TEM) and dynamic light scattering (DLS). In vitro studies of the PDC micelles, revealed their improved anticancer efficiency towards MCF-7 cells as compared to free DOX.

We demonstrate a high-sensitivity mid-infrared molecular absorption spectroscopy- based biomolecular sensor, which employs nanostructures for passively concentrating and trapping analyte molecules in a drying solution to photonic hotspots where optical fields are highly enhanced.

We experimentally demonstrate a nanophotonic biomolecular sensor which can passively concentrate and trap biomolecules in a drying analyte solution to regions of device structures where the field is highly enhanced, leading to improved sensing performance.

Glutathione is overexpressed in tumor cells and regulates cancer growth, metastasis, and drug resistance. Therefore, detecting glutathione levels may greatly facilitate cancer diagnosis and treatment response monitoring. Photoacoustic (PA) imaging is a noninvasive modality for high-sensitivity, high-resolution, deep-tissue optical imaging. Switchable PA probes that offer signal on/off responses to tumor targets would further improve the detection sensitivity and signal-to-noise ratio of PA imaging. Here, we explore the use of MnO2 nanotubes as a switchable and biodegradable PA probe for dynamic imaging of glutathione in cancer. Glutathione reduces black MnO2 nanotubes into colorless Mn2+ ions, leading to decreased and signal off PA amplitude. In phantoms, we observed a linear response of reduced PA signals of MnO2 nanotubes to increased glutathione concentrations. Using melanoma as the disease model, we demonstrated that MnO2 nanotube-based PA imaging of glutathione successfully distinguished B16F10 melan...

Biodegradable crosslinked zwitterionic nanocapsules were synthesized for cancer imaging. A polylactide (PLA)-based diblock copolymer with two blocks carrying acetylenyl and allyl groups respectively was synthesized by ring-opening polymerization (ROP). Azide-alkyne “click” reaction was conducted to conjugate sulfobetaine (SB) zwitterions and fluorescent dye Cy5.5 onto the acetylenyl-functionalized first block of the diblock copolymer. The resulting copolymer with a hydrophilic SB/Cy5.5-functionalized PLA block and a hydrophobic allyl-functionalized PLA block could stabilize miniemulsions because of its amphiphilic diblock structure. UV-induced thiol-ene “click” reaction between a dithiol crosslinker and the hydrophobic allyl-functionalized block of the copolymer at the peripheral region of nanoscopic oil droplets in miniemulsion generated crosslinked polymer nanocapsules (NCs) with zwitterionic outer shells. These NCs showed an average hydrodynamic diameter (D(h)) of 136 nm. They exhibited biodegradability, biocompatibility and high colloidal stability. In vitro study indicated that these NCs could be taken up by MIA PaCa-2 cancer cells. In vivo imaging study showed that, comparing to a small molecule dye, NCs had a longer circulation time, facilitating their accumulation at tumors for cancer imaging. Overall, this work demonstrates the applicability of biodegradable zwitterionic polymer-based materials in cancer diagnosis.

Resistance to cyclin D-cdk4/6 inhibitors (CDK4/6i) represents an unmet clinical need and is frequently caused by compensatory CDK2 activity. Here we describe a novel strategy to prevent CDK4i resistance by using a therapeutic liposomal:peptide formulation, NP-ALT, to inhibit the tyrosine phosphorylation of p27Kip1(CDKN1B), which in turn inhibits both CDK4/6 and CDK2. We find that NP-ALT blocks proliferation in HR+ breast cancer (BC) cells, as well as CDK4i-resistant cell types, including Triple Negative (TN) BC. The peptide ALT is not as stable in primary mammary epithelium, suggesting that NP-ALT has little effect in non-tumor tissues. In HR+ BC cells specifically, NP-ALT treatment induces ROS and RIPK1-dependent necroptosis. Estrogen signaling and ERα appear required. Significantly, NP-ALT induces necroptosis in MCR7 ESRY537S cells, which contain an ER gain of function mutation frequently detected in metastatic patients, which renders them resistant to endocrine therapy. Here we show that NP-ALT causes necroptosis and tumor regression in treatment naïve, palbociclib-resistant and endocrine-resistant BC cells and xenograft models, demonstrating that p27 is a viable therapeutic target to combat drug resistance. Because the RAS/MAPK axis is the target of many therapies, NP-ALT, with its ability to target p27, can deal with the backend drug resistance seen in the presence of other inhibitors, extending the addressable market of this line of therapy. Citation Format: Stacy Wister Blain, Irina Jilishitz, Jason L. Quinones, Priyank Patel, Grace Chen, Jared Pavetsky, Allison VanInwegen VanInwegen, Scott Schoninger, Manasi P. Jogalekar, Vladislav Tsiperson, Lingyue Yan, Yun Wu, Susan R. Gottesman, Jonathan Somma. Blocking p27Kip1phosphorylation with a liposomal:peptide drug induces Reactive Oxygen Species,necroptosis and tumor regression in breast cancer cells [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr LB115.

Glutathione is overexpressed in tumor cells and regulates cancer growth, metastasis, and drug resistance. Therefore, detecting glutathione levels may greatly facilitate cancer diagnosis and treatment response monitoring. Photoacoustic (PA) imaging is a noninvasive modality for high-sensitivity, high-resolution, deep-tissue optical imaging. Switchable PA probes that offer signal on/off responses to tumor targets would further improve the detection sensitivity and signal-to-noise ratio of PA imaging. Here, we explore the use of MnO

Numerous studies have shown there exist attention biases for self-related and negative stimuli. Few studies, however, have been carried out to compare the effects of such stimuli on the neural mechanisms of early attentional alertness and subsequent cognitive processing. The purpose of the present study was to examine the temporal primacy of both self-related stimuli and negative stimuli in the neurophysiologic level. In a modified oddball task, event-related potentials of the deviant stimuli (i.e., self-face, negative face and neutral face) were recorded. Results revealed that larger P2 amplitudes were elicited by self-related and negative stimuli than by neutral stimuli. Negative stimuli, however, elicited shorter P2 latencies than self-related and neutral stimuli. As for the N2 component, self-related and negative stimuli elicited smaller amplitudes and shorter latencies than neutral stimuli, but otherwise did not differ. Self-related stimuli also elicited larger P3 and late positive component (LPC) amplitudes than negative and neutral stimuli. The pattern of results suggests that the primacy of negative stimuli occurred at an early attention stage of processing, while the primacy of self-related stimuli occurred at the subsequent cognitive evaluation and memory stage.

Background/Study Context: The face is the most distinctive physical feature of a person. Previous work has shown that one's own face (self-face) is advantageous in perception. Here the authors investigate how aging influences the configural and featural processing of self-face.Older and young adults searched for their own faces and faces of strangers (Experiment 1) or acquaintances (Experiment 2) among distractor faces. The configural and featural processing of faces was assessed with face inversion in Experiment 1 and with changes in point of view in Experiment 2.Experiment 1 revealed a robust self-face advantage for upright faces in both young and older adults. A similar advantage was observed for inverted faces in young but not in older adults. Experiment 2 revealed a self-face advantage in older adults regardless of the point of view; in young adults, however, the self-face advantage only emerged for frontal view faces.The present study shows that older adults have a self-face advantage in configural but not in featural processing. The authors suggest that the impairment in featural processing in older adults is likely the result of age-related changes in perceptual experience.

Pseudomonas aeruginosa is a Gram-negative bacterium, which uses a variety of organic chemicals as carbon sources. Here, we report the genome sequence of the Cu1510 isolate from wastewater containing a high concentration of N , N -dimethyl formamide.