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Cancer treatments often require combinations of molecularly targeted agents to be effective. mTORi (rapamycin) and HDACi (MS-275/entinostat) inhibitors have been shown to be effective in limiting tumor growth, and here we define part of the cooperative action of this drug combination. More than 60 human cancer cell lines responded synergistically (CIin vivo. Mol Cancer Ther; 16(9); 2008–21. ©2017 AACR.

supplementary statistical methods and primer sequences

PURPOSE We developed a deep neural network that queries the lung computed tomography–derived feature space to identify radiation sensitivity parameters that can predict treatment failures and hence guide the individualization of radiotherapy dose. In this article, we examine the transportability of this model across health systems. METHODS This multicenter cohort-based registry included 1,120 patients with cancer in the lung treated with stereotactic body radiotherapy. Pretherapy lung computed tomography images from the internal study cohort (n = 849) were input into a multitask deep neural network to generate an image fingerprint score that predicts time to local failure. Deep learning (DL) scores were input into a regression model to derive iGray, an individualized radiation dose estimate that projects a treatment failure probability of < 5% at 24 months. We validated our findings in an external, holdout cohort (n = 271). RESULTS There were substantive differences in the baseline patient characteristics of the two study populations, permitting an assessment of model transportability. In the external cohort, radiation treatments in patients with high DL scores failed at a significantly higher rate with 3-year cumulative incidences of local failure of 28.5% (95% CI, 19.8 to 37.8) versus 10.2% (95% CI, 5.9 to 16.2; hazard ratio, 3.3 [95% CI, 1.74 to 6.49]; P < .001). A model that included DL score alone predicted treatment failures with a concordance index of 0.68 (95% CI, 0.59 to 0.77), which had a similar performance to a nested model derived from within the internal cohort (0.70 [0.64 to 0.75]). External cohort patients with iGray values that exceeded the delivered doses had proportionately higher rates of local failure ( P < .001). CONCLUSION Our results support the development and implementation of new DL-guided treatment guidance tools in the image-replete and highly standardized discipline of radiation oncology.

Our focus is on the need for novel devices and the careful investigation of an electrically doped III–V ternary alloy-based gate-all-around tunnel field effect transistor (GAA-TFET) and its circuit applicability. We explored the role of band gap engineering in analyzing GAA-TFET using lattice-matched GaPSb and InP in the source region and channel/drain regions, respectively. This enhances DC and analog characteristics. The device features were then extracted using Silvaco and imported into a Cadence Virtuoso environment using the Verilog-A method to design a sigma delta ADC. The ADC output was then filtered and decimation using MATLAB, resulting into an 11-bit data converter with a 71.24-dB signal to-noise ratio.

PURPOSE Immune checkpoint blockade (ICB) in conjunction with chemotherapy is approved for the treatment of extensive-stage small-cell lung cancer (SCLC). Although specific genomic abnormalities such as KEAP1 and STK11 gene mutations are associated with resistance to ICB in non-SCLC, no genomic abnormality has been found in association with resistance to ICB in SCLC. MATERIALS AND METHODS We first analyzed a retrospective cohort of 42 patients with SCLC treated with single-agent ICB or ICB combination (data set A). We then validated our results in a large prospective clinical trial of 460 patients (CheckMate 032, data set B). DNA and RNA sequencing were performed. RESULTS In data set A, patients treated with ICB with RB1 wild-type (WT) had a median overall survival (OS) of 23.1 months (95% CI, 9 to 37.5), whereas the RB1 mutant OS was 5 months (95% CI, 2.5 to 26; P = .04). Differentially expressed gene analysis between RB1 mutant and RB1 WT samples indicated the enrichment of downregulated immune-related genes and an immune exclusion phenotype among RB1 mutant but not in the RB1 WT tumor samples. We then assessed results from 460 patients enrolled in CheckMate 032, a trial of nivolumab (NIVO) or NIVO + ipilimumab only in SCLC. In this large cohort, RB1 WT patients had significantly improved outcome with NIVO therapy compared with mutant patients (hazard ratio, 1.41; 95% CI, 1.02 to 2.01; P = .041). High RB1 loss-of-function (LOF) signature scores significantly associated with neuroendocrine subtypes (ASCL1 and NeuroD1). However, neuroendocrine subtypes did not associate with OS. Remarkably, patients with lower RB1 LOF scores had longer OS following treatment with NIVO. CONCLUSION SCLC patients with RB1 WT status or lower RB1 LOF signature scores by transcriptomics have better outcomes with ICB monotherapy.

PURPOSE Circulating tumor DNA (ctDNA) has emerged as a promising noninvasive biomarker for baseline characterization and longitudinal monitoring of a tumor throughout disease management. The aim of this study was to evaluate the utility of ctDNA across a wide spectrum of tumor types. METHODS We retrospectively identified 1,763 patients with advanced cancers who had next-generation sequencing of ctDNA or tumor tissue completed by a designated commercial assay at Northwestern University. RESULTS ctDNA identified at least one gene alteration in 90% of patients. The number of detected alterations (NDA) and mutant allele frequency (MAF) of the most frequently mutated genes varied significantly across tumor types, with the highest MAF observed in gastric, colorectal, and breast cancers and the highest NDA observed in colorectal, lung squamous, and ovarian/endometrial cancers. TP53 was the most mutated gene in all tumor types. PIK3CA, ERBB2, BRCA1, and FGFR1 alterations were associated with breast cancer, and ESR1 mutations were exclusively detected in this tumor type. Colorectal cancer was characterized by alterations in KRAS and APC mutations, whereas KRAS, EGFR, PIK3CA, and BRAF mutations were common in lung adenocarcinoma. Concordance between blood and tissue sequencing was notably observed for truncal gene alterations (eg, APC and KRAS), whereas low concordance was often observed in genes associated with treatment resistance mechanisms (eg, RB1 and NF1). Tumor mutational burden (TMB) varied significantly across tumor types, and patients with high MAF or NDA had a significantly higher TMB score with one of the investigated platforms. CONCLUSION The study provided new insights into the ctDNA mutational landscape across solid tumors, suggesting new hypotheses-generating data and caveats for future histotype-agnostic workflows integrated with tissue-based biomarkers such as TMB.

ImportanceThere are few studies assessing the association of tumor mutational burden (TMB) and clinical outcomes in a large cohort of patients with diverse advanced cancers.ObjectiveTo clinically validate a TMB biomarker from a next-generation sequencing targeted gene panel assay.Design, Setting, and ParticipantsA prespecified cohort study using the deidentified clinicogenomic Tempus database of patients sequenced between 2018 and 2022, which contained retrospective, observational data originating from 300 cancer sites including 199 community sites and 101 academic sites. Patients with advanced solid tumors across 8 cancer types and more than 20 histologies, sequenced with Tempus xT who were treated with immune checkpoint inhibitors (ICIs) in the first-line or second-line setting were included. Data were analyzed from September 2018 to August 2022.ExposureTreatment with US Food and Drug Administration (FDA)–approved antiprogrammed cell death-1/programmed cell death-ligand 1 (PD-1/PD-L1) ICI and/or in combination with a cytotoxic T-lymphocyte-associated protein-4 ICI.Main Outcomes and MeasuresThe primary outcome was the association of tumor mutational burden (TMB) binary category (high [≥10 mut/mb] vs low) with overall survival (OS) in patients treated with ICIs. Secondary outcomes were progression-free survival (PFS), and time to progression (TTP).ResultsIn the evaluable cohort of 674 patients, the median (IQR) age was 69.4 (28.6-89.8) years, 271 patients (40.2%) were female, and 435 patients (64.5%) were White. The most common advanced cancers were non–small cell lung cancer (330 patients [49.0%]), followed by bladder cancer (148 patients [22.0%]), and head and neck squamous cell carcinoma (96 patients [14.8%]). Median (IQR) follow-up was 7.2 (3.2-14.1) months. High TMB (TMB-H) cancers (206 patients [30.6%]) were significantly associated with longer OS than low TMB (TMB-L) cancers (hazard ratio [HR], 0.72; upper confidence bound [UCB], 0.91; P = .01). In a prospective subset of 403 patients treated with ICIs after TMB testing, TMB-H cancers (135 patients [33.5%]) were significantly associated with longer OS (HR, 0.61; UCB, 0.84; P = .005), PFS (HR, 0.62; UCB, 0.82; P = .003), and TTP (HR, 0.67; UCB, 0.92; P = .02) than TMB-L cancers. An overall survival benefit was seen regardless of the type of ICI used (pembrolizumab, 339 patients; HR, 0.67; UCB, 0.94; P = .03), other ICIs (64 patients; HR, 0.37; UCB, 0.85; P = .03), and after adjusting for PD-L1 and microsatellite stability status (403 patients; HR = 0.67; UCB, 0.92; P = .02).Conclusions and RelevanceIn this cohort study of patients with advanced solid tumors treated with ICIs in diverse clinics, TMB-H cancers were significantly associated with improved clinical outcomes compared with TMB-L cancers.

Insulin crosses the blood–brain barrier to enter the brain from the periphery. In the brain, insulin has well-established actions in the hypothalamus, as well as at the level of mesolimbic dopamine neurons in the midbrain. Notably, insulin also acts in the striatum, which shows abundant expression of insulin receptors (InsRs) throughout. These receptors are found on interneurons and striatal projections neurons, as well as on glial cells and dopamine axons. A striking functional consequence of insulin elevation in the striatum is promoting an increase in stimulated dopamine release. This boosting of dopamine release involves InsRs on cholinergic interneurons, and requires activation of nicotinic acetylcholine receptors on dopamine axons. Opposing this dopamine-enhancing effect, insulin also increases dopamine uptake through the action of insulin at InsRs on dopamine axons. Insulin acts on other striatal cells as well, including striatal projection neurons and astrocytes that also influence dopaminergic transmission and striatal function. Linking these cellular findings to behavior, striatal insulin signaling is required for the development of flavor–nutrient learning, implicating insulin as a reward signal in the brain. In this review, we discuss these and other actions of insulin in the striatum, including how they are influenced by diet and other physiological states.

Background: To better primary health care and better-trained nurses, knowing the causes of cancer provides a basis for understanding the potential for prevention or early detection of the disease. Our study aimed to assess knowledge and awareness about breast, cervical and oral cancer screening amongst oncology nurses at a tertiary cancer centre. Methodology: An anonymised questionnaire based study was conducted amongst nurses at a tertiary cancer centre. We used NCG e-leaning questionnaire to assess knowledge (which includes breast, oral and cervical knowledge and awareness related questionnaire). Results: A total of 313 participants fulfilled the inclusion criteria and were enrolled in this study. Age range of participants was from 21 to 54 years (mean = 29.8; SD = 8.14). Knowledge and awareness about breast cancer were significantly associated gender (p=0.014) and marital status (p=0.00). Although, Knowledge and awareness about cervical cancer were significantly associated with gender (p=0.002) and years of experience (p=0.03). The age (p=0.001), marital status (p=0.002) and years of experience (p=

In the Indian Capital market various platforms for the investor to take a position their money for getting more return. Among equity share, bond, Treasury bill, bond, open-end fund then many, but within the Indian capital market, an open-end fund is one among the foremost favorable platforms for an investor to increase their wealth. That is why here we are conducting a study on selected mutual funds in India, the sample of the study is 7 mutual funds The Financial ratio analysis is employed for performance evaluation of fund, therein taking NAV (Net assets value) and return of the three years from 17th July 2017 to 2019. Finding Sharpe ratio, Variance, BETA, and Jenson's alpha on the bases of three-year data. In this study found market sentiment affect more in aggressive hybrid open-end fund compare to conservative.

The Coronavirus Pandemic has been one of the most devastating events mankind has been through. It remain incurable for months before a vaccine was found and a sense of relief generated in the minds of human beings around the world. The Covid-19 virus as named by W.H.O. led to lockdowns observed around the world countrywide. Countries later on came out of the lockdowns but still frequent number of coronavirus cases led to imposition of lockdowns and curfews again and again of shorter intervals. The paper aimed at discussing the root cause of greatest ever downfalls observed in the stock markets around the globe ends with a conclusion that factors like increased technology, greater awareness, connectivity, sense of fear, perception, economic expectations, etc. have been the major drivers to such sudden events.

This paper attempts to study the outlook of citizens towards awareness with special reference to mutual funds. The population of the study is selected from the Gandhinagar city of Gujarat state of the country. The sample size is 60 and the researcher has used a convenient sampling method for the study. The findings of this study are that people are aware of mutual funds and people are also investing in mutual funds. Researcher also found that the majority of investors are considering mutual fund as a risk-free Instrument. It is expected that this study will help in Gujarat to plan successful strateg

Tunnel FET (TFET) has emerged as a small subthreshold swing (SS) and low OFF current device for power constraint applications. However, TFET faces low driving current and ambipolarity issues. Most research is focused on overcoming these issues, but there is a huge lack of quality checking of the devices. As the device dimensions are diminishing, it is difficult to maintain linearity and reliability of the devices with varying manufacture and environmental conditions. Considering the absence of physical junctions and random dopant fluctuations (RDF), we conducted a detailed linearity check-up of an electrically doped hetero material nanowire TFET (EDHM-NW-TFET). The main focus addressed here is on the sensitivity analysis of device linearity to mole fraction, drain underlapping and temperature variations. In terms of linearity, we found that mole fraction is a serious manufacturing issue as compared to drain underlapping change. Subsequently, as a reliability concern, it is shown that increasing temperature is unfavorable for ION/IOFF ratio, SS and ambipolarity with a major shift in second harmonics.

In this work, a fast and low-power sigma delta ∑ Δ analogue-to-digital converter (ADC) has been developed using a hetero-material electrically-doped nano-wire tunnel field effect transistor (HM-ED-NW-TFET) for the first time. The better gate controllability of nano-wire and immunity against process variations of electrically doped tunnel field effect transistor (TFET) enhances resolution. In this regard, the first step that has been performed is the material engineering using A l x G a 1 − x Sb / GaA s 1 − y P y , to achieve significant driving current at low subthreshold swing and high I ON / I OFF ratio. Secondly, the mole fraction is optimised to upgrade the critical analogue component – the op-amp. Also, drain under lapping is included in p-TFET to bring its characteristics as close to n-TFET. Latter, the look-up tables of the proposed device has been generated which is used to develop individual block of ∑ Δ ADC in Cadence. The blocks are well verified and integrated into final ∑ Δ ADC and its performance is evaluated. Hence, this work has explored the inherent merits of HM-ED-NW-TFET in the development of low power and fast ∑ Δ ADC by virtue of a high slew rate op-amp. Therefore, this work contributes a novel approach to explore the characteristics of emerging devices in mixed signal applications.

Introduction: Pregnancy is dynamic anabolic state in women’s life. During pregnancy women undergo profound hormonal, metabolic and physical changes. Aim of the present study was to compare the serum level of selenium and iron between pregnant and non-pregnant women. Materials and Methods: The present study was carried out in 50 first trimester pregnant women and 50 non pregnant women at tertiary care hospital in Surat, in age group of 30 years and in BMI groups of Blood was collected and serum was analyzed for selenium and iron concentration in atomic absorption spectrophotometry (AAS).We have also measured anthropological parameter like height, weight and based on this BMI calculated. SPSS software used for statistical analysis. Result: There was a significant lower level of serum selenium (p found in 1st trimester pregnant women compared to non-pregnant women. There was a significant decreased in selenium level in all BMI group in pregnant women except in 30 kg/m2 group and there was a decreased in serum iron level in all BMI group in pregnant women compared to non-pregnant women. Conclusion: There was a significant decrease in serum selenium and iron level in 1st trimester of pregnant women com pared to non- pregnant women, which indicate that during pregnancy requirement of trace elements increase to meet demand for fetus growth. A reduction in maternal selenium concentration during pregnancy can lead to various disorders such as miscarriage, premature birth, preeclampsia, pregnancy include hypertension, low birth weight, retinopathy of prematurity etc. Keywords: Selenium, Iron, Atomic absorption spectrophotometry.

Tunnel field effect transistors (TFETs) have been extensively explored for the possibility of replacing metal oxide semiconductor FET (MOSFET) due to its steeper slope and for being more energy efficient. In this regard, device level performance of AlGaSb/GaAsP gate all around (Nanowire) charge plasma TFET (CP-TFET) shows promising results. To further verify these results, an overview of circuit performance is provided in this work, where analysis of two-stage operational amplifier (op-amp) is shown. Further, based on this op-amp, working of the integrator is also demonstrated. Simulations are carried out with the aid of Verilog A model in the Cadence environment. The outcome of circuit performance exhibits that the proposed device is viable for analogue applications and can be seriously considered for future low-power analogue designs.

Introduction Tafenoquine has been recently registered for the prevention of relapse in Plasmodium vivax malaria. Objective This study assessed the pharmacodynamic effects of 300-mg single-dose tafenoquine on the retina. Methods This phase I, prospective, multicenter, randomized, single-masked, placebo-controlled, parallel-group study was conducted between 2 February 2016 and 14 September 2017 at three US study centers. Adult healthy volunteers were randomized (2:1) to receive either a single 300-mg oral dose of tafenoquine or matched placebo on day 1. Ophthalmic assessments, including spectral domain optical coherence tomography (SD-OCT) and fundus autofluorescence (FAF), were conducted at baseline and day 90 and evaluated for pre-determined endpoints by an independent, masked reading center. Results One subject in each group met the composite primary endpoint for retinal changes identified with SD-OCT or FAF, i.e., one out of 306 (0.3%) with tafenoquine, one out of 161 (0.6%) with placebo. Both cases had unilateral focal ellipsoid zone disruption at day 90 with no effect on best-corrected visual acuity. The tafenoquine-treated subject had this abnormality at baseline, and was enrolled in error. There was no difference in ophthalmic safety between tafenoquine and placebo. Conclusion There was no evidence of any pharmacodynamic effect of 300-mg single-dose tafenoquine on the retina or any short-term clinically relevant effects on ophthalmic safety. This clinical trial is registered with ClinicalTrials.gov (identifier: NCT02658435). Electronic supplementary material The online version of this article (10.1007/s40264-019-00839-w) contains supplementary material, which is available to authorized users.

BACKGROUND Brain metastases (BMs) occur in 20–40% of patients with METex14 skipping NSCLC. Tepotinib, a highly selective MET inhibitor, demonstrated an objective response rate (ORR) of 49.1% and median duration of response (mDOR) of 13.8 months, in METex14 skipping NSCLC patients in the Phase II VISION study (Cohorts A+C; N=275). Here, we report the intracranial activity of tepotinib in VISION. METHODS Patients with METex14 skipping NSCLC received oral tepotinib 500 mg QD (450 mg active moiety). Patients with BM (asymptomatic and symptomatic/stable) were eligible. Primary endpoint was systemic ORR (RECIST v1.1); a subgroup analysis in patients with BM was predefined (data cut-off: February 1, 2021). An ad-hoc retrospective analysis of brain lesions was conducted by an IRC using RANO-BM criteria. Responses were determined in patients with ≥1 evaluable post-baseline tumor assessment. For those with only non-target lesions (NTLs) per RANO-BM (enhancing and non-enhancing NTLs), disease control was defined as non-complete response (CR)/nonprogressive disease (PD). Data cut-off: July 1, 2020. RESULTS Fifty-one patients had baseline BM (Cohorts A+C). Systemic efficacy was consistent with the overall population (ORR 52.9% [95% CI: 38.5, 67.1], mDOR 9.0 months [95% CI: 5.6, not estimable]). Fifteen patients were evaluable by RANO-BM (Cohort A); 12 received prior radiotherapy for BM (median 6.4 weeks before treatment). Systemic best objective responses (BORs) were partial response (PR, n=9), stable disease (SD, n=3), and PD (n=3). Seven patients had target CNS lesions per RANO-BM (all with prior radiotherapy); intracranial BORs were PR (n=5), SD (n=1), and PD (n=1). For patients with NTL only (n=8), one had PD, and seven achieved intracranial disease control with three patients achieving CR of the enhancing NTL. 13/15 patients achieved intracranial disease control. CONCLUSIONS Tepotinib demonstrated robust systemic activity in patients with METex14 skipping NSCLC with BM, complemented by intracranial activity in an ad-hoc analysis using RANO-BM.

Lung cancer holds second place in incidence and first place in mortality among all cancers, both in men and women, with metastasis contributing to the vast majority of deaths. Recently, expression of vascular endothelial growth factor receptor-2 (VEGFR2) on both endothelial and tumor cells was demonstrated as one of the key mechanisms contributing to growth of non-small cell lung cancer (NSCLC), the most common subtype of lung cancer. VEGFR2 dependent signaling is critical both for tumor autocrine functions related to NSCLC migration, and in paracrine control of tumor angiogenesis through action on tumor-proximal endothelial cells, suggesting a potential mechanism for growth control. Several drugs targeting VEGFR2 signaling pathway demonstrated their clinical efficacy in NSCLC setting, including VEGFR2 and VEGF-A inhibitors, VEGF-A/PIGF trap. Recently our group demonstrated that RNA-binding protein Musashi-2 (MSI2) is driving progression and metastasis of NSCLC. MSI2 regulates mRNA translation of multiple targets, its expression is upregulated in the metastasis-competent murine and human lung cancer cell lines and is progressively elevated in lung cancer samples. The goal of this study is to define the role of MSI2 in sustaining VEGFR2 signaling during NSCLC progression. Using reverse RNA immunoprecipitation (RIP) qPCR analysis, we demonstrate that MSI2 directly binds VEGFR2 mRNA. Reverse protein phase array (RPPA) of several NSCLC cell line models with expression or knockdown of MSI2 and subsequent direct validation showed that MSI2 strongly and positively regulates expression of VEGFR2. Subsequent mechanistical analysis revealed that MSI2 knockdown leads to decreased VEGFR2 protein and mRNA levels expression in several NSCLC cell lines in vitro, resulting in increased apoptosis via inhibition of VEGFR2 signaling pathway. To better characterize MSI2 biology, we’ve crossed the B6/129S4-Msi2tm1.1Cjl/J (M2) mice with B6/129S/Sv-Krastm3Tyj/J;Trp53tm1Brn/J (KP) mice and generated novel B6/129S/Sv-KP;Msi2-/- (KPM2) mouse model. Induction of tumorigenesis in KP mice using Cre adenovirus leads to development of lung adenocarcinoma. Induction of lung-specific Cre resulted in tumorigenesis in both KP and KPM2 mice. Interestingly, we observed significant decrease in both total lung tumor number and total lung tumor burden in KPM2 compared to KP mice. Next, we established three novel KP and KPM2 derived cell lines from mouse lung tumors and found that KPM2 cell lines demonstrate reduced proliferation capacity and VEGFR2 mRNA level relative to KP cell lines. Additional studies to understand an impact of MSI2 deletion in KP cell lines are ongoing. Taken together, MSI2 is a promising target for NSCLC treatment, as this protein regulates VEGFR2 signaling and apoptosis in cell models and contributes to KP tumorigenesis in vivo. Citation Format: Igor Bychkov, Alexander Deneka, Iuliia Topchu, Petr Makhov, Alexander Kudinov, Anna Nikonova, John Karanicolas, Erica Golemis, Christopher Lengner, Hossein Borghaei, Jyoti Patel, Yanis Boumber. MSI2 regulates VEGFR2 signaling and tumor progression in NSCLC [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 874.

Background and Aims: Thymosin β4 (Tβ4), is a small peptide implicated in mural VSMC differentiation in developing embryo. A proportion of Tβ4KO embryos die with vascular haemorrhage and surviving adults display aortic VSMC and elastin defects. We found an interaction between LRP1 and Tβ4. LRP1 an endocytic co regulator of PDGF-BB signalling was associated by GWAS with risk of abdominal aortic aneurysm (AAA) and shown, in animal studies, to protect against AAA and atherosclerosis. Hypothesis: Tβ4 controls vasculoprotective signalling by regulating endocytosis of LRP1. Methods: Predisposition to vascular disease was confirmed in global, endothelial- and VSMC- specific Tβ4KO mouse models of AAA and atherosclerosis. Inflammation, ECM composition and elastin were analysed, alongside VSMC phenotype and signalling. We used surface biotinylation assays to track LRP1 distribution in Tβ4 knockdown aortic VSMCs. Finally, we evaluated the potential of exogenous Tβ4 to protect against vascular disease. Results: Tβ4KO mice displayed increased susceptibility to AAA, ranging from aortic dilation to medial dissection in Conclusions: We identify Tβ4 as a key regulator of LRP1-PDGFRb endocytic signalling, for maintaining VSMC differentiation and vascular health. Tβ4 may emerge as a promising candidate for treatment of vascular disease.