Dual-inhibitory domain iCARs improve the efficiency of the AND-NOT gate CAR T strategy.

CAR (chimeric antigen receptor) T cell therapy has shown clinical success in treating hematological malignancies, but its treatment of solid tumors has been limited. One major challenge is on-target, off-tumor toxicity, where CAR T cells also damage normal tissues that express the targeted antigen. To reduce this detrimental side-effect, Boolean-logic gates like AND-NOT gates have utilized an inhibitory CAR (iCAR) to specifically curb CAR T cell activity at selected nonmalignant tissue sites. However, the strategy seems inefficient, requiring high levels of iCAR and its target antigen for inhibition. Using a TROP2-targeting iCAR with a single PD1 inhibitory domain to inhibit a CEACAM5-targeting CAR (CEACAR), we observed that the inefficiency was due to a kinetic delay in iCAR inhibition of cytotoxicity. To improve iCAR efficiency, we modified three features of the iCAR-the avidity, the affinity, and the intracellular signaling domains. Increasing the avidity but not the affinity of the iCAR led to significant reductions in the delay. iCARs containing twelve different inhibitory signaling domains were screened for improved inhibition, and three domains (BTLA, LAIR-1, and SIGLEC-9) each suppressed CAR T function but did not enhance inhibitory kinetics. When inhibitory domains of LAIR-1 or SIGLEC-9 were combined with PD-1 into a single dual-inhibitory domain iCAR (DiCARs) and tested with the CEACAR, inhibition efficiency improved as evidenced by a significant reduction in the inhibitory delay. These data indicate that a delicate balance between CAR and iCAR signaling strength and kinetics must be achieved to regulate AND-NOT gate CAR T cell selectivity.

Molecular mechanisms underlying the development of neuroendocrine prostate cancer.

Prostate cancer is the most common non-cutaneous cancer and the second leading cause of cancer-associated deaths among men in the United States. Androgen deprivation therapy (ADT) is the standard of care for advanced prostate cancer. While patients with advanced prostate cancer initially respond to ADT, the disease frequently progresses to a lethal metastatic form, defined as castration-resistant prostate cancer (CRPC). After multiple rounds of anti-androgen therapies, 20-25% of metastatic CRPCs develop a neuroendocrine (NE) phenotype. These tumors are classified as neuroendocrine prostate cancer (NEPC). De novo NEPC is rare and accounts for less than 2% of all prostate cancers at diagnosis. NEPC is commonly characterized by the expression of NE markers and the absence of androgen receptor (AR) expression. NEPC is usually associated with tumor aggressiveness, hormone therapy resistance, and poor clinical outcome. Here, we review the molecular mechanisms underlying the emergence of NEPC and provide insights into the future perspectives on potential therapeutic strategies for NEPC.

ACAA2 is a novel molecular indicator for cancers with neuroendocrine phenotype.

BACKGROUND: Neuroendocrine phenotype is commonly associated with therapy resistance and poor prognoses in small-cell neuroendocrine cancers (SCNCs), such as neuroendocrine prostate cancer (NEPC) and small-cell lung cancer (SCLC). Expression levels of current neuroendocrine markers exhibit high case-by-case variability, so multiple markers are used in combination to identify SCNCs. Here, we report that ACAA2 is elevated in SCNCs and is a potential molecular indicator for SCNCs. METHODS: ACAA2 expressions in tumour xenografts, tissue microarrays (TMAs), and patient tissues from prostate and lung cancers were analysed via immunohistochemistry. ACAA2 mRNA levels in lung and prostate cancer (PC) patients were assessed in published datasets. RESULTS: ACAA2 protein and mRNA levels were elevated in SCNCs relative to non-SCNCs. Medium/high ACAA2 intensity was observed in 78% of NEPC PDXs samples (N = 27) relative to 33% of adeno-CRPC (N = 86), 2% of localised PC (N = 50), and 0% of benign prostate specimens (N = 101). ACAA2 was also elevated in lung cancer patient tissues with neuroendocrine phenotype. 83% of lung carcinoid tissues (N = 12) and 90% of SCLC tissues (N = 10) exhibited medium/high intensity relative to 40% of lung adenocarcinoma (N = 15). CONCLUSION: ACAA2 expression is elevated in aggressive SCNCs such as NEPC and SCLC, suggesting it is a potential molecular indicator for SCNCs.

Trop2 is a driver of metastatic prostate cancer with neuroendocrine phenotype via PARP1.

Resistance to androgen deprivation therapy, or castration-resistant prostate cancer (CRPC), is often accompanied by metastasis and is currently the ultimate cause of prostate cancer-associated deaths in men. Recently, secondary hormonal therapies have led to an increase of neuroendocrine prostate cancer (NEPC), a highly aggressive variant of CRPC. Here, we identify that high levels of cell surface receptor Trop2 are predictive of recurrence of localized prostate cancer. Moreover, Trop2 is significantly elevated in CRPC and NEPC, drives prostate cancer growth, and induces neuroendocrine phenotype. Overexpression of Trop2 induces tumor growth and metastasis while loss of Trop2 suppresses these abilities in vivo. Trop2-driven NEPC displays a significant up-regulation of PARP1, and PARP inhibitors significantly delay tumor growth and metastatic colonization and reverse neuroendocrine features in Trop2-driven NEPC. Our findings establish Trop2 as a driver and therapeutic target for metastatic prostate cancer with neuroendocrine phenotype and suggest that high Trop2 levels could identify cancers that are sensitive to Trop2-targeting therapies and PARP1 inhibition.

Protein signatures to distinguish aggressive from indolent prostate cancer.

BACKGROUND: Distinguishing men with aggressive from indolent prostate cancer is critical to decisions in the management of clinically localized prostate cancer. Molecular signatures of aggressive disease could help men overcome this major clinical challenge by reducing unnecessary treatment and allowing more appropriate treatment of aggressive disease. METHODS: We performed a mass spectrometry-based proteomic analysis of normal and malignant prostate tissues from 22 men who underwent surgery for prostate cancer. Prostate cancer samples included Grade Groups (3-5), with 8 patients experiencing recurrence and 14 without evidence of recurrence with a mean of 6.8 years of follow-up. To better understand the biological pathways underlying prostate cancer aggressiveness, we performed a systems biology analysis and gene enrichment analysis. Proteins that distinguished recurrent from nonrecurrent cancer were chosen for validation by immunohistochemical analysis on tissue microarrays containing samples from a larger cohort of patients with recurrent and nonrecurrent prostate cancer. RESULTS: In all, 24,037 unique peptides (false discovery rate < 1%) corresponding to 3,313 distinct proteins were identified with absolute abundance ranges spanning seven orders of magnitude. Of these proteins, 115 showed significantly (p < 0.01) different levels in tissues from recurrent versus nonrecurrent cancers. Analysis of all differentially expressed proteins in recurrent and nonrecurrent cases identified several protein networks, most prominently one in which approximately 24% of the proteins in the network were regulated by the YY1 transcription factor (adjusted p < 0.001). Strong immunohistochemical staining levels of three differentially expressed proteins, POSTN, CALR, and CTSD, on a tissue microarray validated their association with shorter patient survival. CONCLUSIONS: The protein signatures identified could improve understanding of the molecular drivers of aggressive prostate cancer and be used as candidate prognostic biomarkers.

Pulsed-chaos MIMO radar based on a single flat-spectrum and Delta-like autocorrelation optical chaos source.

We propose and demonstrate a pulsed-chaos multiple-input-multiple-output (MIMO) radar system in this paper. In the proposed MIMO radar system, multi-channel pulsed chaotic signals are extracted from an optical seed chaos source with Delta-like autocorrelation and flat spectrum. The seed chaos source is generated by passing the chaotic output of an external-cavity semiconductor laser through a dispersive self-feedback phase-modulation loop and used for MIMO radar signal generation. The cross-correlation characteristics of MIMO radar signals, the maximum channel number of separable mixed echoes, as well as the performances of multi-target ranging and anti-interference in the proposed pulsed-chaos MIMO radar system are systematically investigated. The results indicate that multi-channel pulsed-chaos signals with Delta-like autocorrelation can be simultaneously generated from the seed chaos source, and excellent quasi-orthogonality of transmission radar signals can be guaranteed. Moreover, it is demonstrated that the proposed pulsed-chaos MIMO radar supports multi-target ranging with a centimeter-level resolution and can maintain satisfactory performance under low SNR scenarios with various interferences.

Secure key distribution based on hybrid chaos synchronization between semiconductor lasers subject to dual injections.

We propose and numerically demonstrate a novel secure key distribution (SKD) scheme by using dynamically synchronized semiconductor lasers (SLs) subject to common dual injections from two mutually coupled SLs. The performance of hybrid chaos synchronization, complexity of chaotic signals, chaos-based key distribution, and the privacy of SKD scheme are systematically discussed. It is shown that high-quality hybrid chaos synchronization of zero lag and lead lag can be both achieved between two local lasers under different injection delay conditions, whereas low cross correlations are observed among the driving lasers and the local lasers. By randomly perturbing the injection delays with four independent random sequences, the outputs of local SLs can be dynamically synchronized. Extracting the outputs in the synchronization time slots of zero lag and lead lag, synchronous entropy sources are obtained and used to generate keys with high consistency at local ends of Alice and Bob, which are robust to the parameter mismatches of local lasers to some extent. Moreover, large BER is calculated in two types of typical illegal attacks, which demonstrates the security of the proposed scheme. This work proposed a high-level secure key distribution solution to one-time pad communication.

Adaptive time-delayed photonic reservoir computing based on Kalman-filter training.

We propose an adaptive time-delayed photonic reservoir computing (RC) structure by utilizing the Kalman filter (KF) algorithm as training approach. Two benchmark tasks, namely the Santa Fe time-series prediction and the nonlinear channel equalization, are adopted to evaluate the performance of the proposed RC structure. The simulation results indicate that with the contribution of adaptive KF training, the prediction and equalization performance for the benchmark tasks can be significantly enhanced, with respect to the conventional RC using a training approach based on the least-squares (LS). Moreover, by introducing a complex mask derived from a bandwidth and complexity enhanced chaotic signal into the proposed RC, the performance of prediction and equalization can be further improved. In addition, it is demonstrated that the proposed RC system can provide a better equalization performance for the parameter-variant wireless channel equalization task, compared with the conventional RC based on LS training. The work presents a potential way to realize adaptive photonic computing.

PDGFRß is an essential therapeutic target for BRCA1-deficient mammary tumors.

BACKGROUND: Basal-like breast cancers (BLBCs) are a leading cause of cancer death due to their capacity to metastasize and lack of effective therapies. More than half of BLBCs have a dysfunctional BRCA1. Although most BRCA1-deficient cancers respond to DNA-damaging agents, resistance and tumor recurrence remain a challenge to survival outcomes for BLBC patients. Additional therapies targeting the pathways aberrantly activated by BRCA1 deficiency are urgently needed. METHODS: Most BRCA1-deficient BLBCs carry a dysfunctional INK4-RB pathway. Thus, we created genetically engineered mice with Brca1 loss and deletion of p16INK4A, or separately p18INK4C, to model the deficient INK4-RB signaling in human BLBC. By using these mutant mice and human BRCA1-deficient and proficient breast cancer tissues and cells, we tested if there exists a druggable target in BRCA1-deficient breast cancers. RESULTS: Heterozygous germline or epithelium-specific deletion of Brca1 in p18INK4C- or p16INK4A-deficient mice activated Pdgfrß signaling, induced epithelial-to-mesenchymal transition, and led to BLBCs. Confirming this role, targeted deletion of Pdgfrß in Brca1-deficient tumor cells promoted cell death, induced mesenchymal-to-epithelial transition, and suppressed tumorigenesis. Importantly, we also found that pharmaceutical inhibition of Pdgfrß and its downstream target Pkcα suppressed Brca1-deficient tumor initiation and progression and effectively killed BRCA1-deficient cancer cells. CONCLUSIONS: Our work offers the first genetic and biochemical evidence that PDGFRß-PKCα signaling is repressed by BRCA1, which establishes PDGFRß-PKCα signaling as a therapeutic target for BRCA1-deficient breast cancers.

Discovery of PTN as a serum-based biomarker of pro-metastatic prostate cancer.

Distinguishing clinically significant from indolent prostate cancer (PC) is a major clinical challenge. We utilised targeted protein biomarker discovery approach to identify biomarkers specific for pro-metastatic PC. Serum samples from the cancer-free group; Cambridge Prognostic Group 1 (CPG1, low risk); CPG5 (high risk) and metastatic disease were analysed using Olink Proteomics panels. Tissue validation was performed by immunohistochemistry in a radical prostatectomy cohort (n = 234). We discovered that nine proteins (pleiotrophin (PTN), MK, PVRL4, EPHA2, TFPI-2, hK11, SYND1, ANGPT2, and hK14) were elevated in metastatic PC patients when compared to other groups. PTN levels were increased in serum from men with CPG5 compared to benign and CPG1. High tissue PTN level was an independent predictor of biochemical recurrence and metastatic progression in low- and intermediate-grade disease. These findings suggest that PTN may represent a novel biomarker for the presence of poor prognosis local disease with the potential to metastasise warranting further investigation.

Chaos synchronization based on cluster fusion in asymmetric coupling semiconductor lasers networks.

A novel cluster fusion method is proposed, based on which chaos synchronization in asymmetric coupling semiconductor lasers (ACSLs) networks is systematically demonstrated. Take the cluster fusion of a mutually-coupled network composed of 7 semiconductor lasers (SLs) for instance, the characteristics of chaos synchronization as well as the influences of coupling strength, bias current, and mismatches of intrinsic parameters and injection strength on the quality of chaos synchronization in hybrid clusters composed of ACSLs are thoroughly investigated. The results show that by using cluster fusion, the ACSLs which originally belong to different clusters can form three types of new hybrid clusters, namely, trivial-hybrid cluster, trivial-nontrivial-hybrid cluster, and nontrivial-hybrid cluster. Compared with the low-correlation inter-cluster ACSLs of original SLs network, high-quality chaos synchronization is achieved in three types of newly generated hybrid clusters over a wide parameter range. Moreover, the cluster fusion and synchronization of side-SLs clusters of star-type SLs networks are also verified, which indicate the universality of the proposed method. This work provides a new way to realize the chaos synchronization among ACSLs of different clusters.

Photonic decision-making for arbitrary-number-armed bandit problem utilizing parallel chaos generation.

In this paper, we propose and experimentally demonstrate a novel scheme that helps to solve an any-number-armed bandit problem by utilizing two parallel simultaneously-generated chaotic signals and the epsilon (ɛ)-greedy strategy. In the proposed scheme, two chaotic signals are experimentally generated, and then processed by an 8-bit analog-to-digital conversion (ADC) with 4 least significant bits (LSBs), to generate two amplitude-distribution-uniform sequences for decision-making. The correspondence between these two random sequences and different arms is established by a mapping rule designed in virtue of the ɛ-greedy-strategy. Based on this, decision-making for an exemplary 5-armed bandit problem is successfully performed, and moreover, the influences of the mapping rule and unknown reward probabilities on the correction decision rate (CDR) performance for the 4-armed to 7-armed bandit problems are investigated. This work provides a novel way for solving the arbitrary-number-armed bandit problem.

Quantitative secretome analysis of polymyxin B resistance in Escherichia coli.

Bacterial resistance has become a serious threat to human health. In particular, the gradual development of resistance to polymyxins, the last line of defense for human infections, is a major issue. Secreted proteins contribute to the interactions between bacteria and the environment. In this study, we compared the secretomes of polymyxin B-sensitive and -resistant Escherichia coli strains by data-independent acquisition mass spectrometry. In total, 87 differentially expressed secreted proteins were identified in polymyxin B-resistant E. coli compared to the sensitive strain. A GO enrichment analysis indicated that the differentially expressed proteins were involved in biological processes, including bacterial-type flagellum-dependent cell motility, ion transport, carbohydrate derivative biosynthetic process, cellular response to stimulus, organelle organization, and cell wall organization or biogenesis. The differentially expressed secreted proteins in polymyxin B-resistant bacteria were enriched for multiple pathways, suggesting that the resistance phenotype depends on complex regulatory mechanisms. A potential biomarker or drug target (YebV) was found in polymyxin B-resistant E. coli. This work clarifies the secretome changes associated with the acquisition of polymyxin resistance and may contribute to drug development.

Generation of synchronized wideband complex signals and its application in secure optical communication.

We propose and demonstrate a novel secure optical communication scheme, in which the message signal is encrypted and decrypted by two synchronized wideband complex signals. In our scheme, the wideband complex signals are generated by two private chaotic driving signals which are obtained from two local conventional external-cavity semiconductor lasers (ECSLs) subject to a common injection. Both the experimental and simulation results show that, the effective bandwidths of the chaotic driving signals are significantly improved and the time-delay signatures are completely suppressed, in virtue of the spectral broadening effect of chaotic phase-modulation and the phase-to-intensity conversion effect of dispersive components. Furthermore, the generated wideband complex signals are used as the optical carriers for achieving secure transmission. The message signal with a bit rate up to 10 Gb/s can be well hidden into the carrier, and cannot be recognized by the eavesdropper. The high-quality synchronization ensures that the message signal can be correctly recovered at the receiver.

Generation and synchronization of wideband chaos in semiconductor lasers subject to constant-amplitude self-phase-modulated optical injection.

We propose a novel wideband chaos generation scheme by using an external-cavity semiconductor laser (ECSL) subject to optical-electronic hybrid feedback. In this scheme, the output of ECSL is photo-detected and used to modulate the output of a continuous wave laser by an electro-optical phase modulator, the constant-amplitude self-phase-modulated light is then injected back into the ECSL. The experimental results indicate that, compared with the chaos generation with conventional optical feedback (COF), significant bandwidth enhancement is achieved in the proposed scheme. The effective bandwidth of generated chaos is increased from a few GHz to over 20 GHz, and moreover, the spectrum flatness and the complexity of generated chaos are also considerably improved. Furthermore, we propose a wideband chaos synchronization system based on the proposed chaos generation scheme. It is experimentally demonstrated that high-quality synchronization between two wideband chaos signals with an effective bandwidth greater than 20 GHz is achieved. This work simultaneously achieves the generation and the synchronization of wideband chaos, which shows valuable potential in chaos-based secure communication, such as enhancing the transmission capacity and improving the security.

Flexible multipoint-to-multipoint communication in semiconductor laser networks using one-way isolation.

We propose a type of semiconductor laser (SL) network that supports flexible chaos synchronization and multipoint-to-multipoint communications by using one-way isolation (OWI). The properties of chaos synchronization, influences of coupling strength and time delay mismatches on the quality of chaos synchronization, and the performance as well as the security of the SL network-based chaotic communications are systematically discussed. The numerical results demonstrate that, with the introduction of OWI, flexible chaos synchronization can be easily achieved in arbitrary-size SL clusters over wide parameter spaces of coupling strength and current factor. Based on the high-quality flexible chaos synchronization, satisfactory performance for Gb/s chaotic communications can be achieved in arbitrary-size clusters in the SL networks. Moreover, it is also indicated that in the SL networks, the security of intra-cluster communications can be guaranteed in three aspects. Firstly, the eavesdroppers cannot intercept any useful information by using a typical illegal attack. Secondly, due to the OWI, the chaotic carriers are only transmitted in the corresponding clusters, not transmitted among clusters, as such the security can be further improved. Thirdly, the high sensitivity of cross-correlation coefficient to the injection delay mismatches indicates that the injection delays of idle SLs to communicating SLs can be regarded as the keys of the communication clusters. The proposed scheme offers an alternative solution to flexible secure network-type communications.

Injection-locking chaos synchronization and communication in closed-loop semiconductor lasers subject to phase-conjugate feedback.

The properties of injection-locking chaos synchronization and communication in closed-loop external-cavity semiconductor lasers (ECSL) subject to phase-conjugate feedback (PCF) are investigated systematically. We theoretically analyze the general conditions for the injection-locking, and numerically investigate the properties of injection-locking chaos synchronization in the phase and intensity domains, the influences of frequency detuning and intrinsic parameter mismatch on the injection-locking chaos synchronization, as well as the performance of injection-locking chaos synchronization-based communication in closed-loop PCF-ECSL systems. The numerical results demonstrate that with respect to the conventional optical feedback (COF) scenario, the injection-locking chaos synchronization in a PCF-ECSLs configuration shows a significantly wider high-quality synchronization region and excellent feasibility, and the performance of chaos communication can also be enhanced.

Simultaneous bandwidth-enhanced and time delay signature-suppressed chaos generation in semiconductor laser subject to feedback from parallel coupling ring resonators.

We propose and demonstrate an external-feedback semiconductor laser-based chaos generation scheme supporting simultaneous bandwidth enhancement and excellent time-delay-signature (TDS) suppression, by using parallel-coupling ring resonators (PCRR) as reflector. The characteristics of effective bandwidth and TDS of chaotic signals generated in three indicative PCRR configurations are thoroughly investigated. The numerical results demonstrate that with the nonlinear feedback of PCRR, the TDS of chaos can be efficiently suppressed toward an indistinguishable level, and the bandwidth of chaos in the proposed scheme can also be enhanced, with respect to the conventional optical feedback configuration. The proposed scheme shows a flexible way to generate wideband complex chaos.

Chaos synchronization and communication in global semiconductor laser network with coupling time delay signature concealment.

Chaos synchronization and pairwise bidirectional communication with coupling time delay signature (CTDS) concealment in a global heterogeneous coupled semiconductor laser (SL) network are achieved by introducing identical chaotic injections from an external SL with self-feedback. The properties of chaos synchronization and CTDSs in four indicative cases are comparatively discussed. Moreover, the influences of key parameters on the quality of chaos synchronization and the CTDS characteristics are thoroughly investigated. On the basis of the chaos synchronization, the chaotic communication performance is further analyzed. The numerical results demonstrate that with the joint contributions of heterogeneous couplings and external identical chaotic injections, isochronous chaos synchronization can be achieved between two arbitrary SLs, and simultaneously the CTDSs are suppressed to a distinguishable level close to zero, over a wide parameter range. Besides, bidirectional transmission with a bit rate beyond 6 Gbit/s can be achieved between the synchronized SLs. Comparing with the conventional two-user communication system, the proposed SL network with CTDS concealment supports flexible network-type message exchanges between pairwise SLs.

Wideband complex-enhanced chaos generation using a semiconductor laser subject to delay-interfered self-phase-modulated feedback.

A wideband complexity-enhanced chaos generation scheme is proposed by using a semiconductor laser subject to delay-interfered self-phase-modulated optical feedback. The influences of feedback strength, phase modulation index, and interference delay on the effective bandwidth and time-delay-signature (TDS) characteristics of the proposed scheme-generated chaos are extensively investigated both experimentally and numerically. The results demonstrate that with the joint effects of phase modulation-induced spectrum expansion and nonlinear filtering of delayed interference, wideband chaos with flat spectrum and excellent TDS suppression characteristics can be generated over a wide dynamic operation range. In comparisons with the relevant chaos generation schemes under conventional optical feedback, individual self-phase modulated optical feedback, and delay-interfered optical feedback, the proposed scheme cannot only significantly enhance the effective bandwidth of chaos but also considerably enhance the complexity of chaos by suppressing the TDS toward an indistinguishable level close to 0.