LIBRETTO-431: Confirming the Superiority of Selpercatinib to Chemotherapy and the Lack of Efficacy of Immune Checkpoint Inhibitors in Advanced RET Fusion-Positive (RET+) NSCLC, Another Unique Never-Smoker Predominant Molecular Subtype of NSCLC

Alexandria TM Lee,1 Sai-Hong Ignatius Ou2 1Department of Medicine, University of California Irvine School of Medicine, Orange, CA, 92868, USA; 2Chao Family Comprehensive Cancer Center, Orange, CA, 92868, USACorrespondence: Sai-Hong Ignatius Ou, Department of Medicine, Division of Hematology-Oncology, Chao Family Comprehensive Cancer Center, University of California Irvine School of Medicine, 200 South Manchester, Suite 400, Orange, CA, 92868-3298, USA, Email [email protected]; [email protected]: Selpercatinib, a potent and highly selective RET kinase inhibitor with significant CNS activity, has recently gained US approval for the treatment of NSCLC harboring RET fusions (RET+) based on a large-scale single-arm study. The LIBRETTO-431 trial was the global pivotal registration phase 3 trial comparing selpercatinib to platinum-based chemotherapy with or without pembrolizumab as the first-line treatment of patients with advanced RET+ NSCLC. Never-smokers constituted 67.4% of the RET+ NSCLC patients enrolled. KIF5B-RET made up the vast majority (77%) of the RET+ fusion variant with known fusion partner. The results of this study demonstrated significant improvement in progression-free survival (PFS) benefit as well as impressive intracranial disease response in participants treated with selpercatinib as compared to those treated with chemotherapy, with a HR [hazard ratio] of 0.46 (95% CI 0.33– 0.70; P < 0.001) for the intention-to-treat (ITT)-pembrolizumab group and HR of 0.46 (95% CI 0.31– 0.70, P < 0.001) for the overall ITT-group of patients. The addition of pembrolizumab to platinum/pemetrexed chemotherapy resulted in numerically identical PFS (11.2 months). These results point to selpercatinib’s superiority to traditional chemotherapy regimens in the treatment of NSCLC harboring RET fusions and add to literature on the salience of targeted precision oncology and lack of efficacy of immune checkpoint inhibitor in NSCLC patients with never-smoker predominant actionable driver mutations. RET+ NSCLC should be added to the list of molecular subtypes (EGFR+, ALK+, ROS1+) of NSCLC to be excluded in chemoimmunotherapy trial.Keywords: LIBRETTO-431, selpercatinib, RET fusion positive NSCLC, pralsetinib, immunotherapy in never-smokers, relative dose intensit

Zelena sinteza i primjena zeolita ZSM-5

A ZSM-5 molecular sieve composite with a wide pore prepared by the solid phase in-situ synthesis method and fluid catalytic cracking, and an FCC catalyst additive prepared by the same ZSM-5 molecular sieve for increasing the amount of light olefin yield were investigated. The samples were characterized by XRD, N2 adsorption/desorption, SEM, and NH3-TPD, respectively. The results showed that the structure of the ZSM-5 molecular sieve composite prepared by solid phase in-situ synthesis method was pure MFI-type zeolite material. The crystallinity of ZSM-5 molecular sieve was 59.8 wt%. The synthesized ZSM-5 molecular sieve had more acid content and a wide-pore structure. The average pore size was 5.9 nm, and BET specific surface area and micropore specific surface area of sample were 213 m2 g–1 and 124 m2 g–1, respectively. The evaluated results indicated that the FCC catalyst additive had good selectivity for LPG, propylene, and butene, increasing propylene and butene yields by 2.28 wt% and 2.15 wt%, respectively, as well as had better heavy oil cracking capability and coke selectivity. This work is licensed under a Creative Commons Attribution 4.0 International License.Istražen je kompozit molekularnog sita ZSM-5 sa širokim porama pripremljen sintezom na krutoj fazi in-situ i katalitičkim krekiranjem u vrtložnom sloju (FCC) te aditiv katalizatora FCC pripremljen istim molekularnim sitom ZSM-5 u svrhu povećanja količine prinosa lakog olefina. Uzorci su karakterizirani rendgenskom difrakcijom na prahu (XRD), adsorpcijom/desorpcijom N2, skenirajućim elektronskim mikroskopom (SEM) te temperaturno programiranom desorpcijom amonijaka (NH3-TPD). Rezultati su pokazali da je struktura smjese molekularnog sita ZSM-5 pripremljena metodom sinteze in-situ u čvrstoj fazi čisti zeolitni materijal skupine MFI. Kristaliničnost molekularnog sita ZSM-5 iznosila je 59,8 %. Sintetizirano molekularno sito ZSM-5 imalo je više kiseline i strukturu sa širokim porama. Prosječna veličina pora bila je 5,9 nm, a specifična površina (BET) i specifična površina mikropora uzoraka iznosile su 213 m2 g–1, odnosno 124 m2 g–1. Evaluirani rezultati ukazali su na to da aditiv katalizatora FCC pokazuje dobru selektivnost za ukapljeni naftni plin (UNP), propilen i buten, povećavajući prinos propilena i butena za 2,28 %, odnosno 2,15 %, kao i da ima bolju sposobnost krekiranja teškog ulja i selektivnost koksa. Ovo djelo je dano na korištenje pod licencom Creative Commons Imenovanje 4.0 međunarodna

PSAT1 prompted cell proliferation and inhibited cell apoptosis in multiple myeloma through regulating PI3K/AKT pathway

Purpose: To identify the biological function of phosphoserine aminotransferase 1 (PSAT1) in regulating cell proliferation and apoptosis in multiple myeloma (MM).Methods: The mRNA and protein levels of PSAT1 were determined using quantitative real-time polymerase chain reaction (PCR) and western blotting, respectively. Cell proliferation was measured using CCK-8 assay.Results: PSAT1 mRNA and protein expression levels were significantly increased in MM cell lines when compared to control cells. Moreover,&nbsp; downregulation of PSAT1 inhibited MM cell proliferation and induced cell apoptosis, whereas overexpression of PSAT1 promoted MM cell&nbsp; proliferation and suppressed cell apoptosis. Further analysis demonstrated that the underlying mechanism was via regulation of PI3K/AKT pathway.Conclusion: The results identified a novel role for PSAT1 in the progression of MM, which may provide a therapeutic and a new anticancer target for the therapy of MM. Keywords: Multiple myeloma, PSAT1, Cell proliferation, PI3K/AKT pathwa

UniPCM: Universal Pre-trained Conversation Model with Task-aware Automatic Prompt

Recent research has shown that multi-task pre-training greatly improves the model's robustness and transfer ability, which is crucial for building a high-quality dialog system. However, most previous works on multi-task pre-training rely heavily on human-defined input format or prompt, which is not optimal in quality and quantity. In this work, we propose to use Task-based Automatic Prompt generation (TAP) to automatically generate high-quality prompts. Using the high-quality prompts generated, we scale the corpus of the pre-trained conversation model to 122 datasets from 15 dialog-related tasks, resulting in Universal Pre-trained Conversation Model (UniPCM), a powerful foundation model for various conversational tasks and different dialog systems. Extensive experiments have shown that UniPCM is robust to input prompts and capable of various dialog-related tasks. Moreover, UniPCM has strong transfer ability and excels at low resource scenarios, achieving SOTA results on 9 different datasets ranging from task-oriented dialog to open-domain conversation. Furthermore, we are amazed to find that TAP can generate prompts on par with those collected with crowdsourcing. The code is released with the paper

Availability and functionality of sphygmomanometers at health care institutions in Enugu, Nigeria

Objective: Our aim was to investigate the availability of functional blood pressure monitors at health care institutions in Enugu, Nigeria.Methods: During repeated surveys of 15 (primary, secondary and tertiary) health care institutions in Enugu between 2007 and 2012, records were made of the availability and functional status of sphygmomanometers in the clinics and wards. We also assessed the degree of agreement between measurements by institutional staff and measurements by trained observers using the same or the standard sphygmomanometer.Results: Apart from three institutions, there was inadequate availability of fully functional sphygmomanometers: 61 staff attending to outpatients were sharing 35 sphygmomanometers, 6 of which were faulty i.e. needing repairs. Wards invariably had only one or two functional sphygmomanometers, regardless of bed occupancy. Institutional staff ignored recommended guidelines for blood pressure measurement. The overall mean difference in blood pressure measurements between institutional staff and a trained observer (1.6 mmHg; 95% confidence interval, CI: -0.3 to 3.4; P = 0.1) was greater and more significant than the mean difference between the two observers (0.1 mmHg; CI: -1.5 to 1.7; P = 0.9) and the mean difference between institutional and standard sphygmomanometers (-0.2 mmHg; CI: -1.7 to 1.3; P = 0.8).Conclusion: There has been a notable lack of reporting on the availability of blood pressure measuring devices in third world health care institutions. Our surveys have shown inadequate availability of functional sphygmomanometers in the institutions, but satisfactory agreement between measurements by institutional staff and trained observers. In view of recent guidelines and recommendations, there is need to supplement office readings with mercury devices with oscillometric home or automated office blood pressure recording.Keywords: Blood pressure measurement, healthcare quality, hospital care, mercury devices, Nigeria, sphygmomanometer

Behavior of wire arc additively manufactured 316L austenitic stainless steel single shear bolted connections

This paper aims to investigate the behavior of single shear bolted connections made of wire arc additively manufactured 316L austenitic stainless steel. A set of 44 wire arc additive manufacturing (WAAM) 316L austenitic stainless steel single shear bolted connections were included with consideration of various bolt positions, surface conditions and loading orientations respective to the printing layer direction. The geometric dimensions of the WAAM austenitic stainless steel plates were measured with the assistance of non-contact 3D laser scanning prior to tensile testing. Monotonic tensile tests were carried out to investigate the load-deformation responses, failure patterns and resistances determined by both the deformation and strength criteria of the single shear bolted connections. The effects of geometric and printing parameters on the single shear bolted connections were analyzed. Due to the absence of codified design provisions for WAAM austenitic stainless steel bolted connections, the suitability of the existing design rules originally developed for traditionally manufactured carbon steel and stainless steel bolted connections was examined. Design resistances calculated by the Eurocode 3 (prEN 1993-1-8 and prEN 1993-1-4), the American Specification (ANSI/AISC 370-21) as well as the prevalent design recommendations proposed in existing literature were compared with the obtained experimental results. It is shown that the abovementioned design methods offer conservative predictions for the resistances of WAAM 316L austenitic stainless steel single shear bolted connections. Further study is needed to improve the accuracy of design resistance predictions