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Histone modifications play crucial roles in transcriptional activation, and aberrant epigenetic changes are associated with oncogenesis. Lysine (K) acetyltransferases 5 (TIP60, also known as KAT5) is reportedly implicated in cancer development and maintenance, although its function in lung cancer remains controversial. Here we demonstrate that TIP60 knockdown in non-small cell lung cancer cell lines decreased tumor cell growth, migration, and invasion. Furthermore, analysis of a mouse lung cancer model with lung-specific conditional Tip60 knockout revealed suppressed tumor formation relative to controls, but no apparent effects on normal lung homeostasis. RNA-seq and ChIP-seq analyses of inducible TIP60 knockdown H1975 cells relative to controls revealed transglutaminase enzyme (TGM5) as downstream of TIP60. Investigation of a connectivity map database identified several candidate compounds that decrease TIP60 mRNA, one that suppressed tumor growth in cell culture and in vivo. In addition, TH1834, a TIP60 acetyltransferase inhibitor, showed comparable antitumor effects in cell culture and in vivo. Taken together, suppression of TIP60 activity shows tumor-specific efficacy against lung cancer, with no overt effect on normal tissues. Our work suggests that targeting TIP60 could be a promising approach to treating lung cancer.

Aiming at overcoming practical issues of successive interference cancellation (SIC), this paper proposes a dual-polarized rate-splitting multiple access (RSMA) technique for a downlink massive multiple-input multiple-output (MIMO) network. By modeling the effects of polarization interference, an in-depth theoretical analysis is carried out, in which we derive tight closed-form approximations for the outage probabilities and ergodic sum-rates. Simulation results validate the accuracy of the theoretical analysis and confirm the effectiveness of the proposed approach. For instance, under low to moderate cross-polar interference, our results show that the proposed dual-polarized MIMO-RSMA strategy outperforms the single-polarized MIMO-RSMA counterpart for all considered levels of residual SIC error., Comment: arXiv admin note: substantial text overlap with arXiv:2211.00851

Mobocertinib, an oral epidermal growth factor receptor (EGFR) inhibitor targeting EGFR gene mutations, including exon 20 insertions (EGFRex20ins), in non-small cell lung cancer, was evaluated in a phase I/II dose-escalation/expansion trial (ClinicalTrials.gov NCT02716116). Dose escalation identified 160 mg/d as the recommended phase 2 dose and maximum tolerated dose. Among 136 patients treated with 160 mg/d, the most common any-grade treatment-related adverse events (TRAE; >25%) were diarrhea (83%), nausea (43%), rash (33%), and vomiting (26%), with diarrhea (21%) the only grade ≥3 TRAE >5%. Among 28 EGFRex20ins patients treated at 160 mg/d, the investigator-assessed confirmed response rate was 43% (12/28; 95% confidence interval, 24%-63%) with median duration of response of 14 months (5.0-not reached) and median progression-free survival of 7.3 months (4.4-15.6). Mobocertinib demonstrated antitumor activity in patients with diverse EGFRex20ins variants with a safety profile consistent with other EGFR inhibitors. SIGNIFICANCE: No oral EGFR-targeted therapies are currently approved for patients with EGFRex20ins NSCLC. Mobocertinib demonstrated antitumor activity with manageable toxicity in patients with advanced EGFRex20ins NSCLC in this study, supporting additional development of mobocertinib in this patient population.See related commentary by Pacheco, p. 1617.This article is highlighted in the In This Issue feature, p. 1601.

Wireless communications empowered by Reconfigurable Intelligent Surfaces (RISs) are recently gaining remarkable research attention due to the increased system design flexibility offered by RISs for diverse functionalities. In this paper, we consider a Multiple Input Multiple Output (MIMO) physical layer security system with multiple data streams including one legitimate and one eavesdropping passive RISs, with the former being transparent to the eavesdropper and the latter's presence being unknown at the legitimate link. We first focus on the eavesdropping subsystem and present a joint design framework for the eavesdropper's combining matrix and the reflection coefficients of the eavesdropping RIS. Then, focusing on the secrecy rate maximization, we propose a physical layer security scheme that jointly designs the legitimate precoding matrix and the Artificial Noise (AN) covariance matrix, as well as the legitimate combining matrix and the reflection coefficients of the legitimate RIS. Our simulation results reveal that, in the absence of a legitimate RIS, transceiver spatial filtering and AN are incapable of offering nonzero secrecy rates, even for eavesdropping RISs with small numbers of elements. However, when an L-element legitimate RIS is deployed, confidential communication can be safeguarded against cases with even more than a 5L-element eavesdropping RIS.

INTRODUCTION: Osimertinib is approved for advanced epidermal growth factor receptor (EGFR)- mutated non-small-cell lung cancer (NSCLC), and identification of on-target mechanisms of resistance (i.e. EGFR-C797S) to this 3(rd) generation EGFR inhibitor are evolving. Whether durable control of subsequently osimertinib-resistant NSCLC with EGFR-sensitizing mutation (SM)/C797S is possible with 1(st) generation EGFR inhibitors (such as gefitinib or erlotinib) remains underreported, as does the resultant acquired resistance profile. METHODS: We used N-ethyl-N-nitrosurea (ENU) mutagenesis to determine the profile of EGFR-SM/C797S preclinical models exposed to reversible EGFR inhibitors. In addition, we retrospectively probed a case of EGFR-SM lung adenocarcinoma treated with first-line osimertinib, followed by second-line erlotinib in the setting of EGFR-SM/C797S. RESULTS: Use of ENU mutagenesis in the background of EGFR-L858R/C797S in conjunction with administration of gefitinib revealed preferential outgrowth of cells with EGFR-L858R/T790M/C797S. A patient with EGFR-delE746_T751insV NSCLC was treated with osimertinib with sustained response for 10 months before acquiring EGFR-C797S. The patient was subsequently treated with erlotinib with response for a period of 4 months, but disease progression ensued. Liquid biopsy disclosed EGFR-delE746_T751insV with T790M and C797S present in cis. CONCLUSIONS: EGFR-SM NSCLC can acquire resistance to osimertinib through development of the EGFR-C797S mutation. In this clinical scenario, the tumor may respond transiently to reversible 1(st) generation EGFR inhibitors (gefitinib/erlotinib) but evolving mechanisms of on-target resistance—in clinical specimens and preclinical systems—indicate that EGFR-C797S along with EGFR-T790M can evolve. This report adds to the growing understanding of tumor evolution/adaptability to sequential EGFR inhibition and augments support for exploring combination therapies to delay/prevent on-target resistance.

Capitalizing on the recently proposed Fisher-Snedecor F composite fading model, in this letter, we investigate the sum of independent but not identically distributed (i.n.i.d.) Fisher-Snedecor F variates. First, a novel closed-form expression is derived for the moment generating function of the instantaneous signal-to-noise ratio. Based on this, the corresponding probability density function and cumulative distribution function of the sum of i.n.i.d. Fisher- Snedecor F variates are derived, which are subsequently employed in the analysis of multiple branch maximal-ratio combining (MRC). Specifically, we investigate the impact of multipath and shadowed fading on the outage probability and outage capacity of MRC based receivers. In addition, we derive exact closed-form expressions for the average bit error rate of coherent binary modulation schemes followed by an asymptotic analysis which provides further insights into the effect of the system parameters on the overall performance. Importantly, it is shown that the effect of multipath fading on the system performance is more pronounced than that of shadowing., Comment: 5 pages, 3 figures

The paper presents a comprehensive closed-form performance analysis framework for multihop communications over Weibull fading channels. The analyzed scheme consists basically of multiple regenerative relays with generalized high-order quadrature amplitude modulation (M-QAM) transmissions. To take into consideration the channel fading in the mmWave range, we adopt the advocated Weibull model for its flexible ability to cover different channel conditions. The end-to-end performance is evaluated in terms of outage probability, bit error probability (BER), symbol error probability (SER), block error rate (BLER), ergodic capacity, and energy efficiency (EE). For all the metrics, we present exact closed-form expressions along with their asymptotic behavior, some in terms of generalized hypergeometric functions. Based on the obtained analytical results, we also present a practical application, we derive two BER- and EE-optimal transmit power allocation strategies, and we discuss the resulting performance gains. The exactness of our analysis is illustrated by numerical examples, and assessed via Monte-Carlo simulations for different system and channel parameters. Finally, as a secondary contribution, noting the increasing popularity of Fox's H and bivariate H functions, we provide new and generalized codes for computing these functions which are of practical utility in different contexts., Comment: Preprint V3, Submitted to IEEE Transactions on Wireless Communications

The theory of wireless information and power transfer in energy constrained wireless networks has caught the interest of researchers due to its potential in increasing the lifetime of sensor nodes and mitigate the environment hazards caused by conventional cell batteries. Similarly, the advancements in areas of cooperative spectrum sharing protocols has enabled efficient use of frequency spectrum between a licensed primary user and a secondary user. In this paper, we consider an energy constrained secondary user which harvests energy from the primary signal and relays the primary signal in exchange for the spectrum access. We consider Nakagami-m fading model and propose two key protocols, namely time-splitting cooperative spectrum sharing (TS-CSS) and power-sharing cooperative spectrum sharing (PS-CSS), and derive expressions for the outage probabilities of the primary and secondary user in decode-forward and amplify-forward relaying modes. From the obtained results, it has been shown that the secondary user can carry its own transmission without adversely affecting the performance of the primary user and that PS-CSS protocol outperforms the TS-PSS protocol in terms of outage probability over a wide range of Signal to noise ratio(SNRs). The effect of various system parameters on the outage performance of these protocols have also been studied.

Advanced squamous cell carcinoma (SqCC) of the lung carries a poor prognosis, and new therapeutic targets are needed. Several studies have examined dasatinib in non-small cell lung cancer; these report not only significant toxicities, but also responses in patients found to harbor mutations in discoidin domain receptor tyrosine kinase 2 or BRAF. An open-label phase II trial with dasatinib was carried out to determine the response rates in patients with SqCC who had previously failed standard chemotherapy and to correlate responses with patient genotype.Patients were treated with dasatinib 140 mg daily in 28-day cycles. Patients were included if they had stage IIIb/IV SqCC, Eastern Cooperative Oncology Group performance status of 0 or 1, and for whom treatment with standard chemotherapy had failed.The study was halted after enrolling five patients, all of whom were discontinued from the trial because of excess toxicity of dasatinib administered at 140 mg/day. The patients were treated for 9, 14, 24, 40, and 42 days. Three of five patients (60%) experienced grade 3 or more toxicities (dyspnea, fatigue, elevated level of aspartate transaminase, anorexia, nausea). Intolerable grade 2 pleural effusions were noted in two of five patients. Four of five patients died after 44, 52, 127, and 226 days; one patient remains alive at 279 days. No deaths were associated with the study drug.Similar to other studies, this study too found that dasatinib administered at 140 mg/day for the treatment of advanced SqCC of the lung is associated with excess adverse events, so is not recommended in unselected patients. Further work to identify patients likely to benefit from dasatinib and to manage dasatinib-related toxicities is needed.

We present a unified asymptotic framework for transmit antenna selection in multiple-input multiple-output (MIMO) multi-relay networks with Rician, Nakagami-m, Weibull, and Generalized-K fading channels. We apply this framework to derive new closed-form expressions for the outage probability and symbol error rate (SER) of amplify-andforward relaying in MIMO multi-relay networks with two distinct protocols: 1) transmit antenna selection with receiver maximalratio combining (TAS/MRC), and 2) transmit antenna selection with receiver selection combining (TAS/SC). Based on these expressions, the diversity order and the array gain with M-ary phase shift keying and M-ary quadrature amplitude modulation are derived.We corroborate that the diversity order only depends on the fading distribution and the number of diversity branches, whereas the array gain depends on the fading distribution, the modulation format, the number of diversity branches, and the average per-hop signal-to-noise ratios (SNRs). We highlight that the diversity order of TAS/MRC is the same as TAS/SC, regardless of the underlying fading distribution. As such, we explicitly characterize the SNR gap between TAS/MRC and TAS/SC as the ratio of their respective array gains. An interesting observation is reached that for equal per-hop SNRs, the SNR gap between the two protocols is independent of the number of relays.

An increasing number of nonagenarians are treated for non-small-cell lung cancer (NSCLC); however guidelines and case series describing the care of very elderly patients with advanced NSCLC are not available. Medical records of patients treated at Beth Israel Deaconess Medical Center between 2007 and 2009 who had NSCLC were reviewed, and those with stage IV NSCLC and age 90 or older were included in this case series. Three successive fit nonagenarians were identified out of the one hundred and one cases with stage IV NSCLC, and their clinical course was summarized. The first case depicts a conservative approach (best supportive care), while the later cases describe the use of platinum-based (carboplatin-pemetrexed) and anti-epidermal growth factor targeted therapies. This series illustrates the diversity of approaches now available and the evolving treatment paradigm as it applies to fit elderly with NSCLC, including nonagenarians. It also emphasizes the importance of considering performance status rather than biologic age when making treatment decisions.