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This work proposes a new measurement technique to extend the dose range of MOS dosimeters. The technique consists on alternating stages of positive oxide charge buildup with stages of radiation induced charge neutralization, maintaining a uniform sensitivity along the whole measurement. The technique was applied with 70 nm MOS dosimeters, extending the dose measurement range from less than a kilogray to more than 675 kGy without showing wear effects. An initial saturation of interface traps creation ensures repeatability in the responses. Index Terms--Dosimetry, gamma rays, MOS devices, radiation effects.

The response of floating gate (FG) devices to 60Co $\gamma $ -rays under switched bias conditions is studied by real-time monitoring of the threshold voltage evolution with accumulated dose. Samples were fabricated in a 1.5- $\mu \text{m}$ CMOS process, suitable for dosimetry applications. A physics-based numerical model of total ionizing dose (TID) effects in FG MOS devices is developed, taking into consideration the dominant microscopic processes leading to charge accumulation/neutralization across the structure. The main parameters of the model are the capture and neutralization rates in both oxides (tunnel and interpoly), and the initial FG charge. A dataset of experimental measurements is used to extract those parameters. Then, the model is applied to predict the response of later experiments. In one case, the device is irradiated under different switching bias voltages, yielding a mean absolute error of 1.8%. With the same set of parameters, but using another device, the model is able to predict with an error of 2.1%, an exposition performed with a $V_{t}$ -shift range twice the one in the first experiment. The predictive power of the model in a wide range of experimental conditions relies on the physics principles behind it. Combined experiments plus simulations allow to distinguish how charges in each layer of the structure evolve and contribute to the overall response. As an application of the model, cycled measurement technique for dosimetry is investigated. [ABSTRACT FROM AUTHOR]

Charge trapping dynamics induced by exposition to γ-ray (60Co) radiation and bias switching in MOS capacitors with atomic layer deposited Al2O3 as insulating layer was studied. Electrical characterization prior to irradiation showed voltage instabilities due to electron tunneling between the substrate and preexisting defects inside the dielectric layer. Real-time capacitance-voltage (C-V) measurements during irradiation showed two distinct regimes: For short times, the response is strongly bias dependent and linear with log(t), consistent with electron trapping/detrapping; for long times, the voltage shift is dominated by the radiation-induced hole capture being always negative and linear with dose. A simple model that takes into account these two phenomena can successfully reproduce the observed results. [ABSTRACT FROM AUTHOR]

Techniques based on bias switching during the irradiation allow to extend the measurement range of MOS dosimeters. To well predict the response of these sensors under operation conditions it is mandatory to understand the physical phenomena involved. A physics-based numerical model is presented here to reproduce the response of MOS dosimeters under switched bias irradiations. Reported non-monotonic responses after a bias switch were previously explained by the presence of two types of hole traps with different characteristic times. The model presented in this work shows that this behavior can be explained by the spatial charge redistribution using a single trap. The electric field dependences of hole capture and neutralization rates are analyzed and compared with previous experimental results and models in the literature. The spatial distribution of hole traps within the oxide is also analyzed. [ABSTRACT FROM AUTHOR]

We propose the use of a CMOS differential circuit with inherent amplification to enhance the performance of n-channel field oxide MOSFETs as ionizing radiation dosimeters. These new dosimeters are aimed to be used in low dose applications such as X-ray diagnosis. The circuit is presented and described, and a discrete-level prototype was tested as regards sensitivity, temperature variations compensation and signal-to-noise ratio at different operation conditions. Results show that, comparing to a single MOSFET dosimeter, on chip amplification is possible along with temperature induced error attenuation. The highest sensitivity measured with respect to \gamma radiation was 0.4 V/rad. The circuit successfully measured the dose delivered in an X-ray image diagnosis environment with a sensitivity of approximately 0.5 V/rad. [ABSTRACT FROM PUBLISHER]

This paper presents a differential MOSFET sensor reading technique based on the bias controlled cycled measurement. The circuit was implemented, and tested with gamma radiation from a 60-cobalt source. Temperature rejection performance was assessed during the exposure in real-time measurements. The results show that in comparison with a single MOSFET dosimeter the thermal drift is 20 times smaller and the radiation sensitivity is approximately 10% higher. The switched biasing allows to extend the measurement range beyond MOSFET’s threshold voltage saturation. [ABSTRACT FROM AUTHOR]

This paper presents a new technique to build MOS dosimeters using unmodified standard CMOS processes. The devices are n-channel MOS transistors built with the regular Field Oxide as a thick radiation-sensitive gate. The devices were fabricated in two different commercial 0.6~\mu m CMOS processes, gate oxide thicknesses of \sim 600 nm and \sim 400 nm. Responsivities up to 4.4 mV/rad with positive bias, and 1.7 mV/rad with zero gate bias were obtained in the thicker oxides. The effect of charge trapped in the oxide and interface states on the shift in the threshold voltage are analyzed. [ABSTRACT FROM PUBLISHER]

Through the injection of a Fowler-Nordheim tunnel current or the inversion of oxide fields during irradiation (Radiation-Induced Charge Neutralization), the oxide charge trapped in thick-oxide (300 nm) commercial RADFETs, often called QOT could be erased. Novel trapped-hole and interface characteristics were observed after treatments of this type at high doses. With both erasure techniques, it was possible only to neutralize a fraction of the oxide trapped charge. A non negligible amount of charge and border traps is deemed here to be “intractable”. That adjective an a symbol, QIN, are introduced for the first time in this paper. Later sections discuss the possible impact of these results. The conclusion for dosimetry is that a “reusable RADFET” dosimeter, working up to an unprecedented dose before wearing out, may be a practical possibility. [ABSTRACT FROM AUTHOR]

MIS capacitance structures, with Hafnium Oxide, Alumina and nanolaminate as dielectrics were studied under gamma photons ^60\Co, 25 MeV oxygen ions and 10 MeV protons radiation using capacitance-voltage (C-V) characterization. [ABSTRACT FROM AUTHOR]

Al2O3-based dielectrics are currently considered as promising materials to use in nonvolatile memories. The electron trap density in this material is much higher than in conventional SiO2, being their characteristics critical for the application. Conventional capacitance-voltage (C-V) techniques were used to study the main effects of the electron traps on the electrical characteristics of MOS capacitors with atomic layer deposited Al2O3 as insulating layer. More detailed information about the trapping kinetics was obtained through the study of the constant capacitance voltage transient. Two different types of traps were found. One is responsible for the instabilities observed in C-V measurements, the other has characteristic trapping times three orders longer. A physical model is presented to explain the observed trapping kinetics exhibiting good agreement between experiments and simulations. The energy levels of the studied traps were determined at 2.2 and 2.6 eV below the Al2O3 conduction band, with densities of 2.9 × 1018 cm-3 and 1.6 × 1018 cm-3, respectively. [ABSTRACT FROM AUTHOR]

The treatment of non-small cell lung cancer (NSCLC) patients has significantly improved with recent therapeutic strategies; however, many patients still do not benefit from them. As a result, new treatment approaches are urgently needed. In this study, we evaluated the antitumor efficacy of co-targeting G9a and DNMT1 enzymes and its potential as a cancer drug sensitizer. We observed co-expression and overexpression of G9a and DNMT1 in NSCLC, which were associated with poor prognosis. Co-targeting G9a/DNMT1 with the drug CM-272 reduced proliferation and induced cell death in a panel of human and murine NSCLC cell lines. Additionally, the transcriptomes of these cells were reprogrammed to become highly responsive to chemotherapy (cisplatin), targeted therapy (trametinib), and epigenetic therapy (vorinostat). In vivo, CM-272 reduced tumor volume in human and murine cell-derived cancer models, and this effect was synergistically enhanced by cisplatin. The expression of SCARA5 and AOX1 was induced by CM-272, and both proteins were found to be essential for the antiproliferative response, as gene silencing decreased cytotoxicity. Furthermore, the expression of SCARA5 and AOX1 was positively correlated with each other and inversely correlated with G9a and DNMT1 expression in NSCLC patients. SCARA5 and AOX1 DNA promoters were hypermethylated in NSCLC, and SCARA5 methylation was identified as an epigenetic biomarker in tumors and liquid biopsies from NSCLC patients. Thus, we demonstrate that co-targeting G9a/DNMT1 is a promising strategy to enhance the efficacy of cancer drugs, and SCARA5 methylation could serve as a non-invasive biomarker to monitor tumor progression., (© 2024. The Author(s).)

Small cell lung cancer (SCLC) is a devastating disease with high proliferative and metastatic capacity. SCLC has been classified into molecular subtypes based on differential expression of lineage-defining transcription factors. Recent studies have proposed new subtypes that are based on both tumor-intrinsic and -extrinsic factors. SCLC demonstrates substantial intratumoral subtype heterogeneity characterized by highly plastic transcriptional states, indicating that the initially dominant subtype can shift during disease progression and in association with resistance to therapy. Strategies to promote or constrain plasticity and cell fate transitions have nominated novel targets that could prompt the development of more durably effective therapies for patients with SCLC. In this review, we describe the latest advances in SCLC subtype classification and their biological and clinical implications., Competing Interests: Declaration of interests A.Q.V. has received honoraria from AstraZeneca. C.M.R. has consulted regarding oncology drug development with AbbVie, Amgen, D2G, Jazz, Mariana, Scorpion, and Treeline. He serves on the scientific advisory boards of Auron, Bridge Medicines, DISCO, Earli, and Harpoon Therapeutics., (Copyright © 2024. Published by Elsevier Inc.)

The POU2F3-POU2AF2/3 transcription factor complex is the master regulator of the tuft cell lineage and tuft cell-like small cell lung cancer (SCLC). Here, we identify a specific dependence of the POU2F3 molecular subtype of SCLC (SCLC-P) on the activity of the mammalian switch/sucrose non-fermentable (mSWI/SNF) chromatin remodeling complex. Treatment of SCLC-P cells with a proteolysis targeting chimera (PROTAC) degrader of mSWI/SNF ATPases evicts POU2F3 and its coactivators from chromatin and attenuates downstream signaling. B cell malignancies which are dependent on the POU2F1/2 cofactor, POU2AF1, are also sensitive to mSWI/SNF ATPase degraders, with treatment leading to chromatin eviction of POU2AF1 and IRF4 and decreased IRF4 signaling in multiple myeloma cells. An orally bioavailable mSWI/SNF ATPase degrader significantly inhibits tumor growth in preclinical models of SCLC-P and multiple myeloma without signs of toxicity. This study suggests that POU2F-POU2AF-driven malignancies have an intrinsic dependence on the mSWI/SNF complex, representing a therapeutic vulnerability., Competing Interests: Declaration of interests A.M.C. serves on the clinical advisory board of Aurigene Oncology Limited. C.A., S.S., and M.R. are employees of Aurigene Oncology Limited. C.R.V. has received consulting fees from Flare Therapeutics, Roivant Sciences, and C4 Therapeutics; he has served on the advisory boards of KSQ Therapeutics, Syros Pharmaceuticals, and Treeline Biosciences. C.R.V. has also received research funding from Boehringer-Ingelheim and Treeline Biosciences and owns stock in Treeline Biosciences. Aurigene Oncology Limited has filed patent applications on AU-15330 and AU-24118. C.M.R. has consulted regarding oncology drug development with AbbVie, Amgen, Astra Zeneca, D2G, Daiichi Sankyo, Epizyme, Genentech/Roche, Ipsen, Jazz, Kowa, Lilly, Merck, and Syros. C.M.R. serves on the scientific advisory boards of Auron, Bridge Medicines, DISCO, Earli, and Harpoon Therapeutics., (Copyright © 2024 The Author(s). Published by Elsevier Inc. All rights reserved.)

Introduction: Small Cell Lung Cancer (SCLC) can be classified into transcriptional subtypes with distinct degrees of neuroendocrine (NE) differentiation. Recent evidence supports plasticity among subtypes with a bias toward adoption of low-NE states during disease progression or upon acquired chemotherapy resistance. Here, we identify a role for SMARCA4, the catalytic subunit of the SWI/SNF complex, as a regulator of subtype shift in SCLC., Methods: ATACseq and RNAseq experiments were performed in SCLC cells after pharmacological inhibition of SMARCA4. DNA binding of SMARCA4 was characterized by ChIPseq in high-NE SCLC patient derived xenografts (PDXs). Enrichment analyses were applied to transcriptomic data. Combination of FHD-286 and afatinib was tested in vitro and in a set of chemo-resistant SCLC PDXs in vivo., Results: SMARCA4 expression positively correlates with that of NE genes in both SCLC cell lines and patient tumors. Pharmacological inhibition of SMARCA4 with FHD-286 induces the loss of NE features and downregulates neuroendocrine and neuronal signaling pathways while activating non-NE factors. SMARCA4 binds to gene loci encoding NE-lineage transcription factors ASCL1 and NEUROD1 and alters chromatin accessibility, enhancing NE programs. Enrichment analysis applied to high-confidence SMARCA4 targets confirmed neuron related pathways as the top GO Biological processes regulated by SMARCA4 in SCLC. In parallel, SMARCA4 also controls REST, a known suppressor of the NE phenotype, by regulating SRRM4-dependent REST transcript splicing. Furthermore, SMARCA4 inhibition drives ERBB pathway activation in SCLC, rendering SCLC tumors sensitive to afatinib., Conclusions: This study nominates SMARCA4 as a key regulator of the NE state plasticity and defines a novel therapeutic strategy for SCLC., (© 2024. The Author(s).)

Neuroendocrine (NE) transformation is a mechanism of resistance to targeted therapy in lung and prostate adenocarcinomas leading to poor prognosis. Up to date, even if patients at high risk of transformation can be identified by the occurrence of Tumor Protein P53 (TP53) and Retinoblastoma Transcriptional Corepressor 1 (RB1) mutations in their tumors, no therapeutic strategies are available to prevent or delay histological transformation. Upregulation of the cell cycle kinase Cell Division Cycle 7 (CDC7) occurred in tumors during the initial steps of NE transformation, already after TP53/RB1 co-inactivation, leading to induced sensitivity to the CDC7 inhibitor simurosertib. CDC7 inhibition suppressed NE transdifferentiation and extended response to targeted therapy in in vivo models of NE transformation by inducing the proteasome-mediated degradation of the MYC Proto-Oncogen (MYC), implicated in stemness and histological transformation. Ectopic overexpression of a degradation-resistant MYC isoform reestablished the NE transformation phenotype observed on targeted therapy, even in the presence of simurosertib. CDC7 inhibition also markedly extended response to standard cytotoxics (cisplatin, irinotecan) in lung and prostate small cell carcinoma models. These results nominate CDC7 inhibition as a therapeutic strategy to constrain lineage plasticity, as well as to effectively treat NE tumors de novo or after transformation. As simurosertib clinical efficacy trials are ongoing, this concept could be readily translated for patients at risk of transformation., (© 2024. The Author(s).)

Bioactive peptides, which exhibited diverse biological activities such as anti-cancer, anti-inflammatory, bactericidal, antiviral, and quorum sensing properties, were considered promising alternative therapeutic agents. Sourced from various raw materials, particularly foods, these peptides garnered significant interest. In this context, the study focused on exploring bioactive peptides derived from bovine whole milk fermentation by Lacticaseibacillus casei LBC 237. Comprehensive peptidomic analysis and in silico predictions, with a specific emphasis on anti-cancer properties, were conducted. The study categorized peptides into BP-LBC, originating from the metabolism of L. casei LBC 237 and not matching any sequence in the Bos taurus database, and BP-MILK, matching a sequence in the Bos taurus database. Among the 143 identified peptides with potential biological activity, 33.56% were attributed to BP-LBC, while 66.43% originated from BP-MILK, demonstrating the important contribution of proteins in bovine milk in the generation of bioactive peptides. Hydrophobic peptides, enriched in Leucine, Lysine, and Proline, dominated both fractions, significantly influencing their functional properties. Pearson correlation analysis revealed inverse relationships between bioactive peptides, molecular weight, and anti-tumor activity in BP-MILK. The DGKVWEESLK peptide exhibited in silico activity against 10 different cancer cell lines. Studying the bioactive properties of peptides from familiar sources enhances the connection between food science and human health. In addition, in silico studies have been crucial in deepening our understanding of the bioactive potential of these peptides and their mode of action., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier Ltd. All rights reserved.)

In lung and prostate adenocarcinomas, neuroendocrine (NE) transformation to an aggressive derivative resembling small cell lung cancer (SCLC) is associated with poor prognosis. We previously described dependency of SCLC on the nuclear transporter exportin 1. Here, we explored the role of exportin 1 in NE transformation. We observed up-regulated exportin 1 in lung and prostate pretransformation adenocarcinomas. Exportin 1 was up-regulated after genetic inactivation of TP53 and RB1 in lung and prostate adenocarcinoma cell lines, accompanied by increased sensitivity to the exportin 1 inhibitor selinexor in vitro. Exportin 1 inhibition prevented NE transformation in different TP53/RB1-inactivated prostate adenocarcinoma xenograft models that acquire NE features upon treatment with the aromatase inhibitor enzalutamide and extended response to the EGFR inhibitor osimertinib in a lung cancer transformation patient-derived xenograft (PDX) model exhibiting combined adenocarcinoma/SCLC histology. Ectopic SOX2 expression restored the enzalutamide-promoted NE phenotype on adenocarcinoma-to-NE transformation xenograft models despite selinexor treatment. Selinexor sensitized NE-transformed lung and prostate small cell carcinoma PDXs to standard cytotoxics. Together, these data nominate exportin 1 inhibition as a potential therapeutic target to constrain lineage plasticity and prevent or treat NE transformation in lung and prostate adenocarcinoma.

Immunotherapy resistance in non-small cell lung cancer (NSCLC) may be mediated by an immunosuppressive microenvironment, which can be shaped by the mutational landscape of the tumor. Here, we observed genetic alterations in the PTEN/PI3K/AKT/mTOR pathway and/or loss of PTEN expression in >25% of patients with NSCLC, with higher frequency in lung squamous carcinomas (LUSC). Patients with PTEN-low tumors had higher levels of PD-L1 and PD-L2 and showed worse progression-free survival when treated with immunotherapy. Development of a Pten-null LUSC mouse model revealed that tumors with PTEN loss were refractory to antiprogrammed cell death protein 1 (anti-PD-1), highly metastatic and fibrotic, and secreted TGFβ/CXCL10 to promote conversion of CD4+ lymphocytes into regulatory T cells (Treg). Human and mouse PTEN-low tumors were enriched in Tregs and expressed higher levels of immunosuppressive genes. Importantly, treatment of mice bearing Pten-null tumors with TLR agonists and anti-TGFβ antibody aimed to alter this immunosuppressive microenvironment and led to tumor rejection and immunologic memory in 100% of mice. These results demonstrate that lack of PTEN causes immunotherapy resistance in LUSCs by establishing an immunosuppressive tumor microenvironment that can be reversed therapeutically., Significance: PTEN loss leads to the development of an immunosuppressive microenvironment in lung cancer that confers resistance to anti-PD-1 therapy, which can be overcome by targeting PTEN loss-mediated immunosuppression., (©2023 American Association for Cancer Research.)