Anticancer potential of grifolin in lung cancer treatment through PI3K/AKT pathway inhibition.

Objective: Grifolin is a natural secondary metabolite isolated from edible fruiting bodies of the mushroom Albatrellus confluens. Grifolin has antitumor activities in several types of cancer. We aimed to determine the effects of grifolin on lung cancer. Methods: We determined the proliferation, migration, invasion, and apoptosis of lung cancer cells using 3-(4,5-Dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide, Ethynyl deoxyuridine, colony formation, wound scratch, transwell, flow cytometry, and xenograft mouse assays. Molecular docking evaluated the binding relation between grifolin and phosphatidylinositol-4,5-bisphosphate 3-kinase catalytic subunit alpha (PIK3CA). The levels of PIK3CA, AKT, and p-AKT were measured by western blot. Results: Grifolin (10, 20, or 40 µM) inhibited the proliferation, migration, and invasion of lung cancer cells, and induced cell cycle arrest and apoptosis. Grifolin also decreased CDK4, CDK6, and CyclinD1 expression and significantly decreased PIK3CA and p-AKT expression in lung cancer cells. These anticancer effects were abolished by 740Y-P. Conclusions: Grifolin regulates the PI3K/AKT pathway, thus inhibiting lung cancer progression.

Effect of resveratrol on herpesvirus encephalitis: Evidences for its mechanisms of action.

BACKGROUND: Herpes simplex virus type 1 (HSV-1)-induced herpes simplex encephalitis (HSE) has a high mortality rate in clinically immunocompromised patients, while recovered patients often experience neurological sequelae due to neuroinflammation. Nucleoside drugs and nucleoside analogues such as acyclovir and ganciclovir are mainly used in clinical treatment, and the emergence of resistant viral strains makes the development of new anti-herpesvirus encephalitis drugs urgent. Resveratrol is a multifunctional, plant-derived bioactive compound and its antiviral potential is attracting much attention. PURPOSE: This study aimed to investigate the anti-HSV-1 mechanism of resveratrol in microglial cells and in the HSE mouse model. METHODS: The antiviral effect of resveratrol on HSV-1 infection was investigated by plaque assay, virus titer, immunofluorescence, Western blot and time-of-addition assay. The influence of resveratrol on stimulator of interferon gene (STING)/Nuclear Factor kappa B (NF-κB) signaling pathway-mediated neuroinflammation was examined by Western blot, RT-qPCR and ELISA. The interaction between resveratrol and STING/heat shock protein 90 beta (HSP90ß) was evaluated by molecular modeling, co-immunoprecipitation, and drug affinity responsive target stability assay. The therapeutic effect of resveratrol on HSE was evaluated in the HSE mouse model by analyzing weight loss, neurodegenerative symptoms and histopathological scores. RESULTS: Resveratrol inhibited the early process of HSV-1 infection, and interfered with the STING/NF-κB signaling pathway to attenuate HSV-1-induced neuroinflammation and microglial M1 polarization, independent of its classical target Sirtuin1. Mechanistically, resveratrol completely bound to Glu515 and Lys491 of HSP90ß, thus disrupting the HSP90ß-STING interaction and promoting STING degradation. Resveratrol also significantly alleviated viral encephalitis and neuroinflammation caused by HSV-1 in the HSE mouse model. CONCLUSION: Resveratrol acted as a non-classical HSP90ß inhibitor, binding to the STING-HSP90ß interaction site to promote STING degradation and attenuate HSV-1-induced encephalitis and neuroinflammation. These findings suggest the alternative strategy of targeting HSP90ß and resveratrol-mediated inhibition of HSP90ß as a potential antiviral approach.

Mimicking pneumonia with septic shock: A case report and literature review.

Hydrochlorothiazide (HCTZ) is a commonly used diuretic antihypertensive drug that can cause electrolyte disorders, hyperglycemia and hyperuricemia as well as rare life-threatening adverse drug reactions. These include non-cardiogenic pulmonary edema, interstitial pneumonia, angioedema and aplastic anemia. The present report describes a case of a 59-year-old man who developed a hypersensitivity reaction to HCTZ. Specifically, the patient presented with symptoms of cough, chest tightness and shortness of breath, with pneumonic consolidation on chest CT and elevated levels of white blood cell count, neutrophil percentage, C-reactive protein and procalcitonin. A presumptive diagnosis of severe pneumonia was made initially. However, during the gradual recovery of the patient through treatment, he mistakenly ingested HCTZ containing losartan potassium intended for another patient, which resulted in symptoms similar to those observed upon admission. Upon further inquiry into the medical history, it was revealed that the patient had also taken irbesartan/HCTZ 4 h prior to hospitalization. There was no evidence of a pathogenic infection. Therefore, HCTZ-induced anaphylactic reaction was considered to be the most likely etiology for his severe shock. Treatments including epinephrine, methylprednisolone and respiratory support were administered. After 7 days, the patient was transferred from the Respiratory Intensive Care Unit [The Affiliated Jiangning Hospital of Nanjing Medical University (Nanjing, China)] to a general ward. During the follow-up, 12 months after advising the patient to discontinue HCTZ, there had been no recurrence of the aforementioned symptoms. At the time of publication, the patient is currently alive.

An Intriguing Structural Modification in Neutrophil Migration Across Blood Vessels to Inflammatory Sites: Progress in the Core Mechanisms.

The role and function of neutrophils are well known, but we still have incomplete understanding of the mechanisms by which neutrophils migrate from blood vessels to inflammatory sites. Neutrophil migration is a complex process that involves several distinct steps. To resist the blood flow and maintain their rolling, neutrophils employ tether and sling formation. They also polarize and form pseudopods and uropods, guided by hierarchical chemotactic agents that enable precise directional movement. Meanwhile, chemotactic agents secreted by neutrophils, such as CXCL1, CXCL8, LTB4, and C5a, can recruit more neutrophils and amplify their response. In the context of diapedesis neutrophils traverse the endothelial cells via two pathways: the transmigratory cup and the lateral border recycling department. These structures aid in overcoming the narrow pore size of the endothelial barrier, resulting in more efficient transmembrane migration. Interestingly, neutrophils exhibit a preference for the paracellular pathway over the transcellular pathway, likely due to the former's lower resistance. In this review, we will delve into the intricate process of neutrophil migration by focusing on critical structures that underpins this process.

The obesity paradox in intracerebral hemorrhage: a systematic review and meta-analysis.

Background: Intracerebral hemorrhage (ICH) has a mortality rate which can reach 30-40%. Compared with other diseases, obesity is often associated with lower mortality; this is referred to as the 'obesity paradox'. Herein, we aimed to summarize the studies of the relations between obesity and mortality after ICH. Method: For this systematic review and meta-analysis (PROSPERO registry CRD42023426835), we conducted searches for relevant articles in both PubMed and Embase. Non-English language literature, irrelevant literature, and non-human trials were excluded. All included publications were then qualitatively described and summarized. Articles for which quantitative analyses were possible were evaluated using Cochrane's Review Manager. Results: Ten studies were included. Qualitative analysis revealed that each of the 10 studies showed varying degrees of a protective effect of obesity, which was statistically significant in 8 of them. Six studies were included in the quantitative meta-analysis, which showed that obesity was significantly associated with lower short-term (0.69 [0.67, 0.73], p<0.00001) and long-term (0.62 [0.53, 0.73], p<0.00001) mortality. (Data identified as (OR [95%CI], p)). Conclusion: Obesity is likely associated with lower post-ICH mortality, reflecting the obesity paradox in this disease. These findings support the need for large-scale trials using standardized obesity classification methods. Systematic review registration: https://www.crd.york.ac.uk/prospero/display_record.php?ID=CRD42023426835, identifier CRD42023426835.

Needle-tip electrocautery versus steel scalpel incision in neurosurgery: study protocol for a prospective single-centre randomised controlled double-blind trial.

INTRODUCTION: Electrocautery is used widely in surgical procedures, but making skin incision has routinely been performed with scalpel rather than electrocautery, for fear that electrocautery may cause poor incision healing, excessive scarring and increased wound complication rates. More and more studies on general surgery support the use of electrocautery for skin incision, but research comparing the two modalities for scalp incision in neurosurgery remains inadequate. This trial aims to evaluate the safety and efficacy of needle-tip monopolar for scalp incision in supratentorial neurosurgery compared with steel scalpel. METHODS AND ANALYSIS: In this prospective, randomised, double-blind trial, 120 eligible patients who are planned to undergo supratentorial neurosurgery will be enrolled. Patients will be randomly assigned to two groups. In controlled group scalp incision will be made with a scalpel from the epidermis to the galea aponeurotica, while in intervention group scalp will be first incised with a steel scalpel from the epidermis to the dermis, and then the subcutaneous tissue and galea aponeurotica will be incised with needle-tip monopolar on cutting mode. The primary outcomes are scar score (at 90 days). The secondary outcomes include incision pain (at 1 day, on discharge, at 90 days) and alopecia around the incision (at 90 days), incision blood loss and incision-related operation time (during operation), incision infection and incision healing (on discharge, at 2 weeks, 90 days). ETHICS AND DISSEMINATION: This trial will be performed according to the principles of Declaration of Helsinki and good clinical practice guidelines. This study has been validated by the ethics committee of West China Hospital. Informed consent will be obtained from each included patient and/or their designated representative. Final results from this trial will be promulgated through publications. TRIAL REGISTRATION NUMBER: ChiCTR2200063243.

CircUBR1 knockdown relieves ventilator-induced lung injury through regulating miR-20a-5p/GGPPS1 pathway.

OBJECTIVE: To assess the influences and underlying mechanism of circular RNA UBR1 (circUBR1) in ventilator-induced lung injury (VILI). METHODS: In mice and mouse alveolar epithelial cells, VILI model was established. CircUBR1 and miR-20a-5p expression was assessed via quantitative real time polymerase chain reaction. Western blot and immunohistochemistry were applied to assess geranylgeranyl diphosphate synthase 1 (GGPPS1) protein expression. In lung tissues, the histopathological changes were utilized using hematoxylin and eosin staining. Cell counting kit-8 assay and flow cytometer were applied to detect cell proliferation and apoptosis. The levels of inflammatory cytokines [interleukin (IL)-1ß, IL-18, IL-6, and tumor necrosis factor (TNF)-α] were measured by western blot and enzyme-linked immunosorbent assay. RESULTS: In lung tissues of VILI mice, circUBR1 and GGPPS1 expression were upregulated, while miR-20a-5p expression was downregulated. In vivo, circUBR1 knockdown alleviated lung injury, inhibited cell apoptosis, and decreased the levels of inflammatory cytokines. In cells treated with cyclic stretch (CS), circUBR1 knockdown promoted cell viability, inhibited cell apoptosis, and reduced inflammatory cytokines. CircUBR1 could sponge miR-20a-5p, and GGPPS1 was the target gene of miR-20a-5p. In addition, in cells treated with CS, downregulation of miR-20a-5p or the overexpression of GGPPS1 reversed the promotive effect of circUBR1 knockdown on cell viability and the inhibitive effect of circUBR1 knockdown on cell apoptosis and inflammation production. CONCLUSIONS: In VILI, knockdown of circUBR1 attenuated lung injury and inflammation via regulating the miR-20a-5p/GGPPS1 pathway. Our study may provide a potential therapeutic target for treatment of VILI.

Laser frequency noise correction in LFM-based interferometric fiber-optic hydrophone array.

In this paper, we propose a novel time-division multiplexed (TDM) array for a large-scale interferometric fiber-optic hydrophone system, in which we introduce a power-optimized reference probe and effectively reduce the additional white noise while correcting for light source frequency noise. Laser frequency noise usually introduces appreciable phase noise during demodulation of interferometric fiber-optic hydrophones. In the previous means, one would introduce an additional probe isolated from the environment in sensor array, and use it as a reference to calibrate the demodulation results of the other actual sensors. However, while correcting, the reference probe also introduces a large white noise. In our array, the echo of the reference probe is higher than the other sensors, thus solving this problem. The novel array design is applied to our previously proposed fiber-optic hydrophone based on a linear frequency modulated (LFM) light source. Experiments show that the deterioration of phase noise floor caused by additional white noise is improved from at least 3 dB originally to within 1 dB. This paper analyzes the factors that need to be concerned for the successful implementation of correction algorithms in hydrophone systems based on LFM sources. Particular focus is given to the impact of the power optimization of reference probe on the white noise and the corrected phase noise. Our proposal allows a significant relaxation of the demanding linewidth requirement for interferometric hydrophone. It is shown that laser with linewidth of 338.06 MHz can replace that with 1.417 kHz in our new system, while achieves the same demodulation noise floor.

Advances of nanotechnology for intracerebral hemorrhage therapy.

Intracerebral hemorrhage (ICH), the most devastating subtype of stoke, is of high mortality at 5 years and even those survivors usually would suffer permanent disabilities. Fortunately, various preclinical active drugs have been approached in ICH, meanwhile, the therapeutic effects of these pharmaceutical ingredients could be fully boosted with the assistance of nanotechnology. In this review, besides the pathology of ICH, some ICH therapeutically available active drugs and their employed nanotechnologies, material functions, and therapeutic principles were comprehensively discussed hoping to provide novel and efficient strategies for ICH therapy in the future.

Topology Optimization of Turbulent Flow Cooling Structures Based on the k-ε Model.

Topology optimization (TO) is an effective approach to designing novel and efficient heat transfer devices. However, the TO of conjugate heat transfer has been essentially limited to laminar flow conditions only. The present study proposes a framework for TO involving turbulent conjugate heat transfer based on the variable density method. Different from the commonly used and oversimplified Darcy model, this approach is based on the more accurate and widely accepted k-ε model to optimize turbulent flow channels. We add penalty terms to the Navier-Stokes equation, turbulent kinetic energy equation, and turbulent energy dissipation equation, and use interpolation models for the thermal properties of materials. A multi-objective optimization function, aiming to minimize the pressure drop and the average temperature, is set up to balance the thermal and hydraulic performance. A case study is conducted to compare various optimization methods in the turbulent regime, and the results show that the present method has substantially higher optimization effectiveness while remaining computationally inexpensive.

Luteolin inhibits herpes simplex virus 1 infection by activating cyclic guanosine monophosphate-adenosine monophosphate synthase-mediated antiviral innate immunity.

BACKGROUND: The successive outbreaks of large-scale infectious diseases due to virus infection have been a major threat to human health in recent decades. Herpes simplex virus I (HSV-1) is a widely-disseminated DNA virus that infects the central nervous system to cause herpes labialis, keratitis and herpes simplex virus encephalitis (HSE), resulting in recurrent lifelong clinical or subclinical episodes. Luteolin is a plant flavone that has been extensively used in the treatment of various human diseases, including carcinogenesis, inflammation and chronic degenerative diseases. PURPOSE: The aim of this study was to investigate the antiviral molecular mechanism of luteolin against HSV-1 infection in vitro and in vivo. METHODS: The antiviral effect of luteolin in cell lines was examined by viral plaque assay, RT-qPCR, Western blot and time-of-addition assay. The interaction between luteolin and cyclic guanosine monophosphate-adenosine monophosphate synthase (cGAS) was evaluated by molecular modeling and semi-denaturing detergent agarose gel electrophoresis. The efficacy of luteolin on HSE was evaluated in the HSE mouse model by analyzing weight loss, neurodegenerative symptoms and histopathological scores. Cytokine expression and protein levels were examined by RT-qPCR, Western blot and ELISA. RESULTS: Luteolin inhibited the early process of HSV-1 infection, without affecting the infection of acyclovir-resistant HSV-1 strains. In addition, luteolin enhanced antiviral type I interferon production and activated the cytoplasmic DNA-sensing cGAS-stimulator of interferon gene (STING) pathway. Luteolin directly bound the active substrate binding site and promoted the oligomerization of cGAS. Luteolin also inhibited HSE-related weight loss, neurodegeneration and neuroinflammation in mice caused by HSV-1 infection. Furthermore, luteolin enhanced type I interferon expression and stimulated the cGAS-STING signaling pathway in vivo. CONCLUSION: Luteolin inhibited the post-entry process of HSV-1 by activating the cGAS-STING pathway to promote antiviral interferon production. These results provided the rationale for luteolin as a potent cGAS activator and antiviral agent.

Phosphorus recovery from incinerated sewage sludge ash using electrodialysis coupled with plant extractant enhancement technology.

Phosphorus (P) is an integral mineral nutrient for the growth of plants and animals. As the increasing population worldwide, the demand for P resources keeps increasing. Therefore, it is necessary to recover P from secondary resources. Unlike conventional P recovery processes, this work focused on the recovery of P from incinerated sewage sludge ash (ISSA) using electrodialysis as the main technology coupled with plant extractants. In this study, Amaranthus and hydrolyzed polymaleic anhydride (HPMA) were used as P extractants, investigating the effects of HPMA concentration and pH of the compound agent on the migration of P and heavy metals from ISSA. The results showed that the concentration of HPMA and pH of the compound agent had a significant influence on the mobility of P and heavy metals. Meanwhile, the impacts of eggshell additions and voltage on the recovery efficiency of P was also studied by using waste eggshells as calcium sources. We found that when eggshells were added at 10 g/L and the voltage was 10 V, the recovery efficiency of P reached 96.05%. Moreover, XRD patterns revealed that the mineral phase of recovered P-containing products was predominantly hydroxyapatite, which had good environmental benefits. Generally, the favorable results have been achieved in the recovery efficiency of P and has practical implications for P recovery from ISSA.

Impact of hypertensive disorders of pregnancy on short- and long-term outcomes of pregnancy-associated hemorrhagic stroke.

Background and purpose: Though hypertension disorders of pregnancy (HDP) are recognized as independent pregnancy-associated stroke risk factors, few studies have considered their impact on stroke prognosis. Therefore, we intended to evaluate the impact of HDP on short- and long-term outcomes of pregnancy-associated hemorrhagic stroke (HS). Methods: We conducted a retrospective analysis of patients admitted to our hospital from May 2009 to December 2021 with a diagnosis of pregnancy-associated HS. After dividing patients into two groups by the presence of a diagnosis of HDP or not, the short- (at the time of discharge) and long-term (after discharge follow-up) outcomes were compared by mRS (modified Rankin Scale) scores, and poor functional outcome defined as mRS > 2. Adjusted odds ratios (OR) and 95% confidence intervals (CI) were reported. Results: Twenty-two HDP and 72 non-HDP pregnancy-associated HS patients were enrolled and follow-up after 4.7 ± 3.6 years. There was no significant difference between the two groups regarding short-term outcomes, but patients with HDP were more likely to reach poor functional outcomes at long-term follow-up (aOR = 4.47, 95% CI = 1.28-15.67, p = 0.019). Conclusions: In this retrospective study, women with hypertension disorders of pregnancy did not show worse short-term outcomes of pregnancy-associated hemorrhagic stroke compared to those without but had poorer long-term functional outcomes. This underlines the importance of prevention, recognition, and treatment of hypertension disorders in these women.

Angiotensin Receptor Blocker Associated with a Decreased Risk of Lung Cancer: An Updated Meta-Analysis.

INTRODUCTION: There have been disputes in the association between angiotensin receptor blockers (ARB) and the incidence of lung cancer. Our meta-analysis reevaluated this problem from the perspectives of race, age, drug type, comparison objects and smoking. METHOD: We used the following databases to carry out our literature search: Pubmed, Medline, Cochrane Library, and Ovid (From 1 January 2020 to 28 November 2021). The correlation between ARBs and the incidence rate of lung cancer was calculated by risk ratios (RRs). Confidence intervals were selected with 95% confidence intervals. RESULTS: A total of 10 randomized controlled trials (RCTs), 18 retrospective studies and 3 case-control studies were found to satisfy the inclusion criteria. The use of ARB drugs reduced the incidence of lung cancer. The pooled results of 10 retrospective studies revealed a decreased lung cancer incidence in patients treated with ARBs, especially in patients using Valsartan. A significantly lower lung cancer incidence was found in the ARB drugs than in calcium channel blockers (CCBs) and angiotensin-converting enzyme inhibitors (ACEIs). Lung cancer occurrence was lower in Asian-based studies, especially in Mongolian-dominated and Caucasian-dominated patient populations. No significant decrease in lung cancer occurrence was found in RCTs or in patients receiving telmisartan, losartan, candesartan, irbesartan, or other placebo or in American and European-dominated patient populations. CONCLUSION: Compared with ACEIs and CCBs, ARBs significantly reduce the risk of lung cancer, especially in Asian and Mongolian populations. Valsartan has the best effect in reducing the risk of lung cancer in ARB drugs.

Nicotinamide n-Oxide Attenuates HSV-1-Induced Microglial Inflammation through Sirtuin-1/NF-κB Signaling.

HSV-1 is a typical neurotropic virus that infects the brain and causes keratitis, cold sores, and occasionally, acute herpes simplex encephalitis (HSE). The large amount of proinflammatory cytokines induced by HSV-1 infection is an important cause of neurotoxicity in the central nervous system (CNS). Microglia, as resident macrophages in CNS, are the first line of defense against neurotropic virus infection. Inhibiting the excessive production of inflammatory cytokines in overactivated microglia is a crucial strategy for the treatment of HSE. In the present study, we investigated the effect of nicotinamide n-oxide (NAMO), a metabolite mainly produced by gut microbe, on HSV-1-induced microglial inflammation and HSE. We found that NAMO significantly inhibits the production of cytokines induced by HSV-1 infection of microglia, such as IL-1ß, IL-6, and TNF-α. In addition, NAMO promotes the transition of microglia from the pro-inflammatory M1 type to the anti-inflammatory M2 type. More detailed studies revealed that NAMO enhances the expression of Sirtuin-1 and its deacetylase enzymatic activity, which in turn deacetylates the p65 subunit to inhibit NF-κB signaling, resulting in reduced inflammatory response and ameliorated HSE pathology. Therefore, Sirtuin-1/NF-κB axis may be promising therapeutic targets against HSV-1 infection-related diseases including HSE.

Knockout of GGPPS1 restrains rab37-mediated autophagy in response to ventilator-induced lung injury.

Mechanical ventilation may cause ventilator-induced lung injury (VILI) in patients requiring ventilator support. Inhibition of autophagy is an important approach to ameliorate VILI as it always enhances lung injury after exposure to various stress agents. This study aimed to further reveal the potential mechanisms underlying the effects of geranylgeranyl diphosphate synthase large subunit 1 (GGPPS1) knockout and autophagy in VILI using C57BL/6 mice with lung-specific GGPPS1 knockout that were subjected to mechanical ventilation. The results demonstrate that GGPPS1 knockout mice exhibit significantly attenuated VILI based on the histologic score, the lung wet-to-dry ratio, total protein levels, neutrophils in bronchoalveolar lavage fluid, and reduced levels of inflammatory cytokines. Importantly, the expression levels of autophagy markers were obviously decreased in GGPPS1 knockout mice compared with wild-type mice. The inhibitory effects of GGPPS1 knockout on autophagy were further confirmed by measuring the ultrastructural change of lung tissues under transmission electron microscopy. In addition, knockdown of GGPPS1 in RAW264.7 cells reduced cyclic stretch-induced inflammation and autophagy. The benefits of GGPPS1 knockout for VILI can be partially eliminated through treatment with rapamycin. Further analysis revealed that Rab37 was significantly downregulated in GGPPS1 knockout mice after mechanical ventilation, while it was highly expressed in the control group. Simultaneously, Rab37 overexpression significantly enhances autophagy in cells that are treated with cyclin stretch, including GGPPS1 knockout cells. Collectively, our results indicate that GGPPS1 knockout results in reduced expression of Rab37 proteins, further restraining autophagy and VILI.

The efficacy of postoperative radiotherapy for patients with non-small cell lung cancer: An updated systematic review and meta-analysis.

The controversy over the efficacy of postoperative radiotherapy (PORT) has existed for a long time. The present study reassessed the overall survival (OS) and disease-free survival (DFS) data to investigate whether PORT can improve survival in resectable non-small cell lung cancer (NSCLC) patients. The following databases were used to perform literature search: PubMed, Web of Science, China National Knowledge Infrastructure (CNKI), and Embase (from January 1, 1986 to July 5, 2021). The results of overall survival (OS) and disease-free survival (DFS) were calculated as hazard ratio (HR). Confidence intervals are chosen with 95% confidence intervals. A total of 12 RCTs and 19 retrospective cohort studies were found to meet the inclusion criteria. A significant DFS improvement was detected in the PORT group (4111 patients from 15 studies), although statistical difference was not detected for OS between the non-PORT and PORT groups (31 studies, 49,342 total patients). PORT prolonged OS in patients undergoing PORT plus postoperative chemotherapy (POCT) and in pN2 patients. Patients with a median radiation dose of 50.4 Gy and a median radiation dose of 54 Gy had a better OS after PORT. However, if the total radiotherapy dose went up to 60 Gy, PORT increased the risk of death in NSCLC patients. Significant difference in OS was not found in the results of studies with regard to treatment methods, pathologic stages, study type, radiation beam quality, and radiation dose. Patients undergoing postoperative chemoradiotherapy and pN2 patients can benefit from PORT. Patients exposed to median radiation doses of 50.4 and 54 Gy demonstrated relatively good efficacy. For patients with non-small-cell lung cancer, PORT has not been proven to extend OS, but its effect on DFS remains strong.

Access to chiral α-substituted-ß-hydroxy arylphosphonates enabled by biocatalytic dynamic reductive kinetic resolution.

Ketoreductase (KRED)-catalyzed dynamic reductive kinetic resolution (DYRKR) of α-substituted-ß-keto arylphosphonates was developed as a generic and stereoselective approach to synthesize chiral α-substituted-ß-hydroxy arylphosphonates, with moderate-to-excellent isolated yield (up to 96%), good-to-excellent diastereoselectivity (up to >99 : <1 dr), and excellent enantioselectivity (up to >99% ee) being achieved.

Asymmetric Synthesis of a Key Dextromethorphan Intermediate and Its Analogues Enabled by a New Cyclohexylamine Oxidase: Enzyme Discovery, Reaction Development, and Mechanistic Insight.

(S)-1-(4-Methoxybenzyl)-1,2,3,4,5,6,7,8-octahydroisoquinoline [(S)-1-(4-methoxybenzyl)-OHIQ, (S)-1a] is a key synthetic intermediate in the industrial production of dextromethorphan, one of the most widely used over-the-counter antitussives. We report here that a new cyclohexylamine oxidase discovered by genome mining, named CHAOCCH12-C2, was able to completely deracemize 100 mM 1a under Turner's deracemization conditions to afford (S)-1a in 80% isolated yield and 99% ee at a semipreparative scale (0.4 mmol). When this biocatalytic reaction was scaled up to a gram scale (5.8 mmol), without reaction optimization (S)-1a was still isolated in 67% yield and 96% ee. The relatively higher kcat determined for CHAOCCH12-C2 was rationalized as one major factor rendering this enzyme capable of oxidizing 1a effectively at elevated substrate concentrations. Protein sequence alignment, analysis of our co-crystal structure of CHAOCCH12-C2 complexed with the product 1-(4-methoxybenzyl)-3,4,5,6,7,8-hexahydroisoquinoline [1-(4-methoxybenzyl)-HHIQ, 2a], and the structure-guided mutagenesis study together indicated L295 is one of the critical residues for this efficient enzymatic oxidation process and supported the presence of two cavities as well as a catalytically important "aromatic cage" formed by F342, Y433, and FAD. The synthetic applicability of CHAOCCH12-C2 was further underscored by the stereoselective synthesis of various enantioenriched 1-benzyl-OHIQ derivatives of potential pharmaceutical importance at a semipreparative scale.