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Abstract Introduction Large cell neuroendocrine carcinoma (LCNEC) is a rare type of high-grade pulmonary neuroendocrine tumor. The study objective is to investigate its survival outcomes, incidence of brain metastases, and patterns of recurrence. Methods This is a single center study of patients with pathologic diagnosis of pulmonary LCNEC. Patient data were collected retrospectively and analyzed, including survival, incidence of brain metastases, and patterns of recurrence. Results Of 87 patients (stages I: 24, II: 14, III: 23, IV: 26), 52 were managed curatively and 35 palliatively. The median follow-up time was 17.3 months (range 0.6-89.5) for those treated with curative intent and 7.0 months (range 0.1-28.6) for those treated palliatively. The 2- and 5-year overall survival (OS) rates are 48.4% and 25.5% for the curative group, with a median OS of 13.5 months. In the palliative group, the OS are 30.8% at 1 year and 6.8% at 2 years, with a median OS of 7.0 months. Thirty-eight of 52 (73%) patients treated with curative intent had disease relapse, with the common sites being regional lymph nodes (20), brain (18), bones (11), and liver (9). The incidence of brain recurrence among those managed curatively are 21.4% and 41.3%, respectively at 1 and 2 years. Of 18 patients experiencing brain metastases, 14 developed them as part of a first relapse. Conclusions LCNEC's survival outcomes are poor. The incidence of brain metastases is higher than what is observed for other types of nonsmall cell lung cancers. Prophylactic cranial irradiation should be investigated as a means of improving outcomes. [ABSTRACT FROM AUTHOR]

A direct and selective method for the α,β-dehydrogenation of esters using palladium catalysis in the presence of free O H and N H functionalities is reported herein. Allyl-palladium catalysis allows for preservation of readily oxidizable functionalities such as amines and alcohols. Furthermore, an economical protocol using LDA was developed for the dehydrogenation of β-amino esters. [ABSTRACT FROM AUTHOR]

Three-dimensional (3D) printing is suitable for the fabrication of complex radiotherapy bolus. Although investigated from dosimetric and feasibility standpoints, there are few reports to date of its use for actual patient treatment. This study illustrates the versatile applications of 3D printing in clinical radiation oncology through a selection of patient cases, namely, to create bolus for photon and modulated electron radiotherapy (MERT), as well as applicators for surface high-dose rate (HDR) brachytherapy. Photon boluses were 3D-printed to treat a recurrent squamous cell carcinoma (SCC) of the nasal septum and a basal cell carcinoma (BCC) of the posterior pinna. For a patient with a mycosis fungoides involving the upper face, a 3D-printed MERT bolus was used. To treat an SCC of the nose, a 3D-printed applicator for surface brachytherapy was made. The structures' fit to the anatomy and the radiotherapy treatment plans were assessed. Based on the treatment planning computed tomography (CT), the size of the largest air gap at the interface of the 3D-printed structure was 3 mm for the SCC of the nasal septum, 3 mm for the BCC of the pinna, 2 mm for the mycosis fungoides of the face, and 2 mm for the SCC of the nose. Acceptable treatment plans were obtained for the SCC of the nasal septum (95% isodose to 99.8% of planning target volume [PTV]), the BCC of the pinna (95% isodose to 97.7% of PTV), and the mycosis fungoides of the face (90% isodose to 92.5% of PTV). For the latter, compared with a plan with a uniform thickness bolus, the one featuring the MERT bolus achieved relative sparing of all the organs at risk (OARs) distal to the target volume, while maintaining similar target volume coverage. The surface brachytherapy plan for the SCC of the nose had adequate coverage (95% isodose to 95.6% of clinical target volume [CTV]), but a relatively high dose to the left eye, owing to its proximity to the tumor. 3D printing can be implemented effectively in the clinical setting to create highly conformal bolus for photon and MERT, as well as applicators for surface brachytherapy. [ABSTRACT FROM AUTHOR]

• Push-out tests were carried out on 13 steel-plate HSC shear wall specimens with group studs. • High-strength concrete/recycled aggregate concrete is used. • Replacement of some studs with tie bar connectors is considered. • The bond-slip constitutive relationship of specimens is given. Steel-plate-reinforced concrete composite shear walls have been widely used in high-rise and super-high-rise buildings. To improve the bond behaviour between the steel plate and high-strength concrete (HSC) in shear walls, 13 steel-plate HSC shear wall (SPHSCSW) specimens with group studs were designed for push-out tests. Specimens were constructed using HSC or high-strength recycled aggregate concrete (HSRAC). Concrete strength, concrete type, stud length-to-diameter ratio, and replacement of studs with tie bar connectors are considered. The influence of different parameters on the interfacial bond behaviour of specimens is discussed by analysing the load-slip curves, bond strength, and interface damage energy dissipation. The equations for the shearing capacity of studs and the interfacial bond-slip constitutive relationship under different connectors were obtained. Results show that the influence of concrete strength on the bond strength of SPHSCSWs is positively correlated, and the bond behaviour with HSRAC is similar to that of normal HSC. When the stud length-to-diameter ratio exceeds four, increasing the ratio has little effect on improving the shearing capacity, and a further increase reduces the residual bond strength. Replacing some studs with tie bars can significantly improve the residual bond strength and interfacial bond energy dissipation capacity. The proposed equations for the shearing capacity of studs in SPHSCSWs and the bond-slip constitutive relationship agree well with the test results, which can be used for engineering applications and further research. [ABSTRACT FROM AUTHOR]

Graphical abstract Abstract Proteasome-mediated degradation of proteins is a vital cellular process and is performed by the ubiquitin-dependent proteasome system (UPS) and the ubiquitin-independent proteasome system (UIPS). While both systems are necessary to maintain healthy cell function, many disease states are characterized by reduced activity of the UPS, and the UIPS cannot by itself maintain proper protein levels. It has been suggested that the 20S core particle (20S CP), the isoform of the proteasome in the UIPS that can degrade proteins without a ubiquitin tag, can be stimulated with a small molecule to assist the 20S CP to accept and hydrolyze substrates more rapidly. Several small molecule stimulators of the 20S CP have since been discovered, including AM-404, an arachidonic acid derivative. AM-404 has previously been shown to inhibit fatty acid amide hydrolase activity. We wished to evaluate what structural components of AM-404 are required to stimulate the 20S CP with the long-term goal of using this information to design a stimulator with better drug-like qualities. We synthesized numerous derivatives of AM-404, varying the chain length, substitutions, and degree of unsaturation. Through this endeavor, we obtained several molecules capable of stimulating the 20S CP to various degrees. We discovered that though chain length is important, the presence of a cis -alkene in a specific location in the aliphatic chain has the greatest impact on the ability to stimulate the 20S CP. Two of the derivatives maintain modest stimulatory activity, and have improved toxicity over AM-404. [ABSTRACT FROM AUTHOR]

We overview global clinical trials of targeted protein degradation (TPD) drugs for oncology across the past decade. The most common classes of TPD drugs in oncology clinical trials are selective estrogen receptor degraders (SERDs), immunomodulatory drugs (ImiDs), and proteolysis-targeting chimeras (PROTACs), all of which target protein degradation via the ubiquitin–proteasome system. Second-generation IMiDs with improved degradation potency could overcome resistance to lenalidomide and can treat more types of hematologic malignancies. The clinical development of oral SERDs still has many challenges, but several drugs have recently shown promising results in breast cancer patients with ESR1 mutations. Oral bioavailability and pharmacokinetics are two main issues that need to be addressed when developing clinically applicable PROTACs. Anticancer-targeted therapies inhibit various kinases implicated in cancer and have been used in clinical settings for decades. However, many cancer-related targets are proteins without catalytic activity and are difficult to target using traditional occupancy-driven inhibitors. Targeted protein degradation (TPD) is an emerging therapeutic modality that has expanded the druggable proteome for cancer treatment. With the entry of new-generation immunomodulatory drugs (IMiDs), selective estrogen receptor degraders (SERDs), and proteolysis-targeting chimera (PROTAC) drugs into clinical trials, the field of TPD has seen explosive growth in the past 10 years. Several challenges remain that need to be tackled to increase successful clinical translation of TPD drugs. We present an overview of the global landscape of clinical trials of TPD drugs over the past decade and summarize the clinical profiles of new-generation TPD drugs. In addition, we highlight the challenges and opportunities for the development of effective TPD drugs for future successful clinical translation. [ABSTRACT FROM AUTHOR]

Patients with heart failure (HF) are more susceptible to cognitive impairment, but the mechanism is still unclear. This study aimed to observe the dynamic changes in brain glucose metabolism and neuronal structure in different stages of HF. An HF rat model was established by ligating the anterior descending branch of the left coronary artery. To simulate acute heart failure (AHF) and chronic heart failure (CHF) in the clinic, relevant laboratory indexes were detected 10 and 60 days after ligation. The results showed that the model rats had systolic HF. Cognitive function was not obviously impaired in 10-day rats with HF, while the memory and learning functions were significantly impaired in 60-day rats with HF. The brain glucose metabolism in 10-day rats compensatorily increased in the prefrontal cortex (PFC), medial PFC (mPFC), cingulate gyrus, and basal ganglia (BG). In contrast, the metabolism of 60-day rats reduced in the PFC and BG. Meanwhile, the neuronal structure slightly changed in 10-day rats with HF, but neuronal karyopyknosis, reduced Nissl bodies, and swollen organelles were found in 60-day rats with HF. In conclusion, brain glucose metabolism and neuronal structure showed a dynamic evolution. Rats with AHF were in a compensatory state for increased glucose metabolism and slight neuronal damage. As a result, no significant cognitive impairment was observed. However, rats with CHF had significantly decreased cerebral glucose metabolism and neuronal degeneration, contributing to the cognitive function after HF. [ABSTRACT FROM AUTHOR]

Currently, numerous thermal comfort models have been proposed; however, research on the combination of different models is lacking. This study aims to predict the overall thermal sensation (OTS*) and thermal comfort (OTC*) with different model combinations under hot and cold step changes. Three cold- and hot-shock processes are designed in the climate chamber. Accordingly, the skin temperature, thermal sensation, and thermal comfort votes of 16 participants are collected. The impacts of winter hot and cold step changes on subjective votes and skin temperatures are evaluated. Further, the OTS* and OTC* values are calculated, and their accuracy under different model combinations is analyzed. The results reveal that thermal sensation changes in human body exhibit distinct asymmetry under the cold and hot step-changes, except for the cycle of "15–30–15 °C" (I15). The parts farther from the core area become more asymmetrical after the step changes. The single models exhibit the highest accuracy in different model combinations. The combined form of a single model is recommended for thermal sensation or comfort prediction. • Discuss the thermal perception of the cold and hot impulse in winter. • Five model combinations in thermal sensation and comfort are obtained. • The parts farther from the core area become more asymmetrical after the step-changes. • The combination form of a single model is recommended for thermal sensation or comfort prediction. [ABSTRACT FROM AUTHOR]

Ethnopharmacological relevance Panax notoginseng saponins (PNS) extracted from a traditional Chinese herbal medicine, Panax notoginseng (Burkill) F.H. Chen (Araliaceae), which has been extensively used in treating coronary heart disease, ischemic cerebrovascular disease and hemorrhagic disorders in China over hundreds of years. Aims of the study This study explored whether panax notoginseng saponins (PNS) provided neuroprotective effects by inhibiting the expressions of NgR1, RhoA, and ROCK2 following middle cerebral artery occlusion in rats and oxygen-glucose deprivation/reoxygenation (OGD/R) injury in SH-SY5Y cells. Materials and methods 2,3,5-Triphenyltetrazolium chloride staining was used to determine successful middle cerebral artery occlusion establishment in sham-operated and operated Sprague–Dawley rats 1 day after injury. The rats were randomly separated into sham, model, NEP1-40, PNS, and NEP1-40 plus PNS (N+P) groups. After 7 days of treatment, body mass and neurological deficit scores were analyzed. Tissues were harvested and analyzed by hematoxylin-eosin staining and immunohistochemical analysis, western blotting, and quantitative real-time PCR (qRT-PCR). The optimal drug concentration of NEP1-40 and PNS on SH-SY5Y cells exposed to OGD/R injury was determined by CCK8 analysis. qRT-PCR was used to measure mRNA expression profiles of NgR1, RhoA, and ROCK2 in SH-SY5Y cells subjected to OGD/R. Results The results showed that MCAO surgery successfully produced an infarct, and the PNS, NEP1-40, and N+P groups exhibited increased body mass and ameliorated neurological deficits compared with the model group. NEP1-40 treatment markedly reduced NgR1 and RhoA overexpression when compared to the model group, although there was no significant difference in ROCK2 expression. PNS and N+P treatment significantly decreased NgR1, RhoA, and ROCK2 overexpression compared with the model group. However, N+P treatment did not result in a synergistic effect, as assessed by immunohistochemistry, western blotting, and qRT-PCR. Following optimal administration of PNS (160 μg/ml) and NEP1-40 (10 ng/ml) on SH-SY5Y cells exposed to OGD/R injury, cell viability in the NEP1-40, PNS, and N+P groups significantly increased compared with the model group, as assessed by CCK8 analysis. Additionally, NgR1, RhoA, and ROCK2 mRNA expression profiles were significantly less in the NEP1-40, PNS, and N+P groups compared with the model group. Conclusion PNS provided neuroprotective effects in a rat model of cerebral ischemia and SH-SY5Y cells exposed to oxygen/glucose deprivation injury by inhibiting the overexpression of NgR1, RhoA, and ROCK2. [ABSTRACT FROM AUTHOR]

• Push-out tests were carried out on 16 concrete-filled square steel tube specimens with different constructions. • The size of square steel tubes is 400 mm. • The in-filled concrete adopted high-strength concrete or recycled concrete. • The constitutive relationship of specimens is given. To solve the problem of insufficient interface bond strength of concrete-filled square steel tubes (CFSSTs), 16 large CFSST specimens with eight different types of connectors (no additional connectors, built-in studs, built-in circular ribs, built-in vertical ribs, built-in reinforcement cage, and various combinations of the above) were designed for push-out testing. Specimens were constructed using high-strength concrete or high-strength recycled aggregate concrete (RAC). The bond behavior and slip failure mechanism were analyzed by comparing the force-slip curves, slip displacements, and steel tube strains. The bond strength calculation method and bond-slip constitutive relationship of the interface under multiple parameters were obtained. Experiments revealed the following: bond-slip curves for CFSST without additional connectors were composed of an ascending section and a residual section; for tubes with different connectors, the peak values of the curves were higher; the performance-price ratio of studs and circular ribs for improving bond strength was high, and the combined use of studs and circular ribs can work well; the combination of circular ribs and vertical ribs can significantly improve bond strength and energy dissipation capacity; RAC had better bond behavior than normal concrete in HSCFSST without additional connectors or built-in vertical ribs. The predicted force-slip curves agreed well with the test curves, providing a theoretical basis for CFSST applications. [ABSTRACT FROM AUTHOR]

To investigate the bond-slip behavior of the interface in large high-strength concrete-filled circular steel tubes (HSCFCSTs), 18 specimens with 6 different constructions (HSCFCSTs with no additional construction, with built-in studs, with built-in circular ribs, with built-in vertical ribs, and with various combinations of the above) were examined using push-out tests. Specimens were constructed from high-strength concrete or recycled aggregate concrete (RAC). The bond-slip behavior and slip-failure mechanisms were analyzed through comparison of load-slip curves, slip displacements, and steel tube strain to generate predicted load-slip curves based on multiple parameters. Experiments revealed that the bond-slip curves of HSCFCSTs with no additional constructions contained an ascending section, a rapidly descending section, and a residual section. For tubes with special constructions, the descending section was either postponed or not visible, the interfacial bonding properties were enhanced when using special constructions, the concrete strength and bond strength were positively correlated, and the RAC had better bonding behavior than normal concrete. The predicted load-slip curves agreed with the test curves and provided a theoretical basis for HSCFCST applications. • Push-out tests were carried out on 18 HSCFCST specimens with 6 different constructions. • The diameter of circular steel tubes is 400 mm. • The in-filled concrete adopted 3 types of high-strength concrete. • The constitutive relationship of HSCFCSTs with different constructions is given. [ABSTRACT FROM AUTHOR]