Cyclic Azahelicene Dimers Showing Bright Circularly Polarized Luminescence and Selective Fluoride Recognition.

Although helicenes are promising molecules, the synthetic difficulty and tediousness have often been problems, and only small amounts of optically pure helicenes have been obtained by using chiral HPLC in most cases. Herein, aza[7]helicenes or closed-aza[7]helicenes with (1R)-menthyl substituents were selectively synthesized via the intramolecular Scholl reaction, and the diastereomeric pairs were separated by silica gel column chromatography. The optically pure helicenes were further transformed into the corresponding cyclic dimers, and the chiroptical properties were investigated. The rigid π-frameworks of the dimers led to the high molar extinction coefficients and fluorescence quantum yields, while the twisted helicene moieties induced clear Cotton effects and CPL in the visible region, and the high CPL brightness (BCPL) was achieved. Furthermore, the cyclic dimers were found to have the macrocyclic cavity with the two NH groups suitable for the selective binding of a fluoride anion, which induced significantly redshifted fluorescence and CPL in the red region.

Definitive internal fracture fixation followed by staged free flap coverage ("fix followed by flap" protocol) for open Gustilo type IIIB fractures.

BACKGROUND: Although the concept of the "fix and flap" approach, in which definitive fracture fixation and flap coverage are completed in a single procedure at the earliest opportunity may seem ideal for the treatment of Gustilo type IIIB open fractures, the individual circumstances of patients, such as polytrauma or multiple fracture cases may not allow for the immediate fracture fixation and flap coverage ("fix and flap" approach). In our hospital, patients with Gustilo type IIIB open fractures are treated with definitive internal fixation of the fracture followed by staged flap coverage ("fix followed by flap" protocol) when the "fix and flap" approach was not feasible due to the patient's condition or difficulty in coordinating surgery schedules. The "fix followed by flap" protocol provides benefits in terms of flexibility in adjusting the surgical timetable, simplifying the planning of flap coverage following fracture fixation, and minimizing individual surgical invasion. METHODS: We reviewed 10 cases of severe open fractures treated with the "fix followed by flap" protocol and evaluated their outcomes. All surgical procedures, including wound debridement, fracture fixation, and flap coverage, were performed by orthoplastic surgeons specializing in both fracture surgery and microsurgery including soft tissue reconstruction. RESULTS: All free flaps survived, and no partial necrosis was observed. None of the patients developed postoperative deep infection up to the last follow-up. Fracture union was achieved in all patients with or without autologous bone grafts. The median time for union was 9.4 months (range, 4-12 months). CONCLUSIONS: This study presents favorable outcomes of treatment for Gustilo type IIIB open fractures with fracture fixation followed by staged flap coverage ("fix followed by flap" protocol). Despite a delay in flap coverage, the consistency of treatment provided by orthoplastic surgeons may have contributed to the favorable outcomes in this study.

Molecular Basis of Neuronal and Microglial States in the Aging Brain and Impact on Cerebral Blood Vessels.

Brain aging causes a wide variety of changes at the molecular and cellular levels, leading to the decline of cognitive functions and increased vulnerability to neurodegenerative disorders. The research aimed at understanding the aging of the brain has made much progress in recent decades. Technological innovations such as single-cell RNA-sequencing (scRNA-seq), proteomic analyses, and spatial transcriptomic analyses have facilitated the research on the dynamic changes occurring within neurons, glia, and other cells along with their impacts on intercellular communication during aging. In this review, we introduce recent trends of how neurons and glia change during aging and discuss the impact on the brain microenvironment such as the blood-brain barrier (BBB).

Synthesis of Closed-Heterohelicenes Interconvertible between Their Monomeric and Dimeric Forms.

Oxidative fusion reaction of cyclic heteroaromatic pentads consisting of pyrrole and thiophene gave closed-heterohelicene monomers and dimers depending on the oxidation conditions. Specifically, oxidation with [bis(trifluoroacetoxy)iodo]benzene (PIFA) gave closed-[7]helicene dimers connected at the ß-position of one of the pyrrole units with remarkably elongated C-C bonds of about 1.60 Å. Although this bond was intact against thermal and physical activations, homolytic bond dissociation took place in DMSO upon irradiation with UV light to give the corresponding monomers. Thus, interconversion between the closed-helicene monomer and dimer was achieved. The optically pure dimer was photo-dissociated into the monomers associated with a turn-on of circularly polarized luminescence (CPL).

Comparison of the slow-pull and aspiration methods of endobronchial ultrasound-guided transbronchial needle aspiration for next-generation sequencing-compatible tissue collection in non-small cell lung cancer.

BACKGROUND: Personalized treatment for non-small cell lung cancer (NSCLC) has advanced rapidly, and elucidating the genetic changes that trigger this disease is crucial for appropriate treatment selection. Both slow-pull and aspiration methods of endobronchial ultrasound-guided transbronchial needle aspiration (EBUS-TBNA) are accepted methods for collecting samples suitable for next-generation sequencing (NGS) to examine driver gene mutations and translocations in NSCLC. Here, we aimed to determine which of these two methods is superior for obtaining higher-quality samples from patients with NSCLC. METHODS: Seventy-one patients diagnosed with NSCLC via EBUS-TBNA using the slow-pull or aspiration (20-mL negative pressure) methods between July 2019 and September 2022 were included. A total of 203 tissue samples from the 71 patients were fixed in formalin, embedded in paraffin, and mounted on slides. The presence of tissue cores, degree of blood contamination, and number of tumor cells were compared between the groups. The success rate of NGS, using Oncomine Dx Target Test Multi-CDx, was also compared between the groups. RESULTS: The slow-pull method was associated with a higher yield of tissue cores, lower degree of blood contamination, and higher number of tumor cells than the aspiration method. The success rate of the NGS was also significantly higher for the slow-pull group (95%) than for the aspiration group (68%). CONCLUSION: Overall, these findings suggest that the slow-pull method is a superior technique for EBUS-TBNA to obtain high-quality tissue samples for NGS. The slow-pull method may contribute to the identification of driver gene mutations and translocations and facilitate personalized treatment of NSCLC.

Cu-catalyzed carboxylation of organoboronic acid pinacol esters with CO2.

Chemical fixation of CO2 has received much attention. In particular, catalytic C-C bond formation with CO2 giving carboxylic acids is of great significance. Among the CO2 fixation methods, multiple carboxylation is one of the challenging subjects. Here we investigated the Cu-catalyzed carboxylation of a variety of boronic acid pinacol esters (C(sp2)-, C(sp3)-, and C(sp)-B compounds) with CO2, which efficiently provided the corresponding products, including aryl, alkenyl, alkyl, and alkynyl carboxylic acids. This carboxylation was also applicable to multiple CO2 fixation giving di- and tri-carboxylic acids under robust reaction conditions (totally 29 examples).

Predictors of lung injury during durvalumab maintenance therapy following concurrent chemoradiotherapy in unresectable locally advanced non-small cell lung carcinoma.

BACKGROUND: Based on the results of the PACIFIC trial, maintenance with durvalumab has emerged as the standard treatment following concurrent chemoradiotherapy in patients with unresectable locally advanced non-small cell lung carcinoma (NSCLC). However, adverse events attributed to durvalumab, especially lung injuries, including immune-related adverse events, and radiation pneumonitis, are concerning. This study retrospectively investigated the factors related to lung injury in patients receiving the PACIFIC regimen. METHODS: Patients with unresectable locally advanced NSCLC who received durvalumab maintenance therapy following concurrent chemoradiotherapy at Yokohama City University Medical Centre between July 2018 and March 2022 were included. Clinical data, volume of normal lung receiving 20 or 5 Gy or more (V20 or V5), planning target volume (PTV), and relative lung parenchyma volume in emphysematous lung receiving 20 or 5 Gy or more (RLPV20 or 5; V20 or V5/100-percentage of low-attenuation volume) were evaluated. RESULTS: Performance status (PS), V20, V5, PTV, RLPV20, and RLPV5 were significantly higher in the lung injury group in the univariate analysis. Furthermore, RLPV20 was the most significant factor in the lung injury group in the multivariate analysis comprising PS, PTV, V20, and RLPV20. CONCLUSION: RLPV20 and RLPV5 are useful in estimating lung inflammation. RLPV20 could be considered the most reliable risk factor for maintenance therapy with durvalumab following concurrent chemoradiotherapy in patients with unresectable locally advanced NSCLC.

Efficacy of osimertinib for lung squamous cell carcinoma with de novo EGFR T790M-positive: Case report and literature review.

Among epidermal growth factor receptor (EGFR) mutation-positive non-small cell lung cancers, squamous cell carcinoma is less common and shows lower responsiveness to first-generation EGFR tyrosine kinase inhibitors (TKIs) compared to adenocarcinoma. However, the efficacy of osimertinib for squamous cell carcinoma with EGFR mutations is not well known. This study reports the case of a 57-year-old male diagnosed as having stage IIIC squamous cell lung cancer. Oncomine Dx Target Test identified EGFR exon19 deletion and de novo EGFR T790M mutation with variant allele frequencies (VAF) of 21.6% and 25.2%, respectively. The patient was treated with osimertinib after progression on chemoradiotherapy followed by durvalumab, and a partial response was maintained for more than 20 months. To predict EGFR-TKI efficacy, confirmation of gene mutations and VAF using next-generation sequencing is helpful.

Synthesis and Photophysical Properties of Dihetero[8]circulenes.

Oxidation of dihydroxyhetero[7]helicenes gave dihetero[8]circulenes via the concomitant C-C coupling and dehydrative furan formation. The pristine dihetero[8]circulenes were synthesized in four steps and characterized for the first time. X-ray crystal structures and DFT-optimized structures revealed the distorted saddle-like structures, and the degree of the distortion was found to be correlated with the photophysical properties.

Thymic atypical carcinoid tumors with elevated mitotic counts in a patient with multiple endocrine neoplasia: A case report.

Thymic neuroendocrine tumors associated with multiple endocrine neoplasia are only defined as carcinoid and are not associated with large-cell neuroendocrine carcinoma (LCNEC). We report the case of a multiple endocrine neoplasia type 1 patient with atypical carcinoid tumors with elevated mitotic counts (AC-h), an intermediate condition between carcinoid and LCNEC. A 27-year-old man underwent surgery for an anterior mediastinal mass and was diagnosed with thymic LCNEC. Fifteen years later, a mass appeared at the same site, which was determined to be a postoperative recurrence based on the pathological results of a needle biopsy and the clinical course. The patient's disease remained stable for 10 months on anti-programmed death-ligand 1 antibody and platinum-containing chemotherapy. The needle biopsy specimen was submitted for next-generation sequencing, which revealed a MEN1 gene mutation, and after further examination, a diagnosis of multiple endocrine neoplasia type 1 was made. A re-examination of the surgical specimen from 15 years prior showed that it corresponded to AC-h. Although thymic AC-h is classified as thymic LCNEC according to the current definition, our data suggests that a search for multiple endocrine neoplasia is warranted in such patients.

Primary tracheal small-cell carcinoma detected 11 months after surgery for pulmonary large-cell neuroendocrine carcinoma: A case report.

Primary tracheal small-cell carcinoma is rare, and is often treated using small-cell lung cancer guidelines given that no standard treatment has been established for it. We report a patient in whom nodules appeared in the trachea and left main bronchus 11 months after surgery for pulmonary large-cell neuroendocrine carcinoma; a biopsy revealed small-cell carcinoma. Given the absence of malignant lesions elsewhere in the body, the lesions were diagnosed as primary tracheal small-cell carcinoma. Respiratory failure progressed rapidly owing to airway stenosis caused by the growing lesion, and the patient required nasal high-flow therapy. However, the lesions shrank a few days after commencing first-line chemotherapy, and his respiratory failure resolved. Accelerated hyperfractionated radiotherapy was administered in conjunction with the third course of chemotherapy, and the patient ultimately achieved a complete response. Although the lesions were initially suspected of being postoperative recurrence of pulmonary large-cell neuroendocrine carcinoma, the fact that the biopsy revealed them to be primary tracheal small-cell carcinoma indicates that intra-airway nodules that appear after lung cancer surgery may possibly be primary tracheal tumors.

Circularly polarized luminescence in molecular recognition systems: Recent achievements.

Circularly polarized luminescence (CPL) dyes are recognized to be new generation materials and have been actively developed. Molecular recognition systems provide nice approaches to novel CPL materials, such as stimuli-responsive switches and chemical sensing materials. CPL may be induced simply by mixing chiral or achiral, luminescent or nonluminescent host and guest; there are several combinations. Molecular recognition can potentially save time and effort to construct well-ordered chiral structures with noncovalent attractive interactions as compared with the multi-step synthesis of covalently bonded dyes. It is a challenging subject to engage molecular recognition events with CPL, and it is important and interesting to see how it is achieved. In fact, simple molecular recognition systems can even enable the fine adjustment of CPL performance and detailed conformational/configurational analysis of the excited state. Here we overview the recent achievements of simple host-guest complexes capable of exhibiting CPL, summarizing concisely the host/guest structures, CPL intensities, and characteristics.

Retrospective analysis of independent predictors of progression-free survival in patients with EGFR mutation-positive advanced non-small cell lung cancer receiving first-line osimertinib.

BACKGROUND: Clinically measurable factors affecting the progression-free survival (PFS) of patients receiving osimertinib as first-line therapy for epidermal growth factor receptor (EGFR) mutation-positive advanced non-small cell lung cancer (NSCLC) have not yet been established. METHODS: We retrospectively reviewed the medical records of 61 patients treated with osimertinib as primary therapy for EGFR mutation-positive advanced NSCLC at Yokohama City University Medical Center between August 2018 and March 2022. Our objective was to identify the independent predictors of PFS. RESULTS: The median age of participants was 74 years. Overall, 73.8% had good (0-1) Eastern Cooperative Oncology Group performance status (PS), and 98.4% had histology of adenocarcinoma. The EGFR mutation was exon19 deletion in 52.5% and exon21 L858R in 44.3% of patients. Programmed death-ligand 1 tumor proportion score >50% was observed in 21.3% and liver metastasis in 9.9% of patients. Median PFS was 19.5 months (95% confidence interval [CI]: 10.6-31.6), and overall survival was not reached. The objective response rate was 68.9%, and disease control rate was 93.4%. Multivariate analysis showed that poor PS (2-4) negatively impacted PFS (hazard ratio, 3.79; 95% CI: 1.46-9.87; p = 0.006). Median PFS in the good PS and poor PS groups was 20.4 months (95% CI: 12.4-not evaluable) and 7.2 months (95% CI: 7.2-19.5), respectively. Interstitial lung disease of all grades and grade 3 was observed as an adverse event in 6.6 and 4.9% of patients, respectively. CONCLUSION: Poor PS was associated with poor prognosis in patients with EGFR mutation-positive advanced NSCLC treated with osimertinib as first-line therapy.

Combination of Pembrolizumab With Platinum-containing Chemotherapy for Pulmonary Enteric Adenocarcinoma.

Background/Aim: Pulmonary enteric adeno-carcinoma (PEAC) is a rare type of non-small cell lung cancer (NSCLC), for which no established standard treatment exists. Combination therapy with the anti-programmed cell death protein 1 antibody pembrolizumab and platinum-containing chemotherapy is the standard treatment for NSCLC patients, but its effectiveness in PEAC is uncertain. Case Report: We present a 68-year-old man with chemotherapy-naïve advanced PEAC who responded to a combination of pembrolizumab and platinum-containing chemotherapy. Conclusion: The number of PEAC cases is small, and no clinical trials have been conducted to determine an optimal chemotherapy regimen. In this case, we showed that pembrolizumab combined with platinum-containing chemotherapy might effectively treat PEAC.

Cystine supplementation sustains plasma mercaptalbumin levels in rats fed low-protein diets more effectively than methionine.

We recently reported that dietary cystine maintained plasma mercaptalbumin levels in rats fed low-protein diets. The present study aimed to compare the influence of low-protein diets supplemented with cystine and methionine, which is another sulfur amino acid, on plasma mercaptalbumin levels in rats. Male Sprague-Dawley rats were fed a 20% soy protein isolate diet (control group), 5% soy protein isolate diet (low-protein group) or 5% soy protein isolate diet supplemented with either methionine (low-protein + Met group) or cystine (low-protein + Cyss group) for 1 week. The percentage of mercaptalbumin within total plasma albumin of the low-protein + Met group was significantly lower than that of the control and low-protein + Cyss groups. No significant differences in the mRNA levels of tumor necrosis factor-α, interleukin-6, interleukin-1ß, and cyclooxygenase 2 in blood cells were observed between the low-protein + Met and low-protein + Cyss groups. Treatment with buthionine-(S,R)-sulfoximine, an inhibitor of glutathione synthesis, did not influence the percentage of mercaptalbumin within total plasma albumin in rats fed the low-protein diet supplemented with cystine. These results suggest that supplementation with cystine may be more effective than that with methionine to maintain plasma mercaptalbumin levels in rats with protein malnutrition. Cystine might regulate plasma mercaptalbumin levels via the glutathione-independent pathway.

Facile Synthesis of Azahelicenes and Diaza[8]circulenes through the Intramolecular Scholl Reaction.

Carbazole-based aza[7]helicenes and hetero[9]helicenes were successfully obtained via the intramolecular Scholl reaction of 3,6-bis(biphenyl-2-yl)carbazole congeners, while the reaction of 3,6-bis(naphthylphenyl)-appended carbazole gave a triple helicene via an unexpected simultaneous double aryl rearrangement. DFT calculations suggested that the rearrangement proceeded via an arenium cation intermediate. In addition, the reaction of methoxy-appended substrate gave an azahepta[8]circulene via the concurrent C-C bond formation. These helical dyes showed circularly polarized luminescence. The azahepta[8]circulene was further transformed into deeply saddle-distorted dibenzodiaza[8]circulenes as the first example of its solution-based synthesis and unambiguous structural determination.

Synthesis and electronic properties of carbazole-based core-modified diporphyrins showing near infrared absorption.

Directly linked carbazole-based core-modified diporphyrin D2 and fused diporphyrin F2 were synthesized. These diporphyrins showed significant electronic interactions and conjugation allowing for redshifted near infrared (NIR) absorption and small HOMO-LUMO gaps as confirmed by NIR absorption spectroscopy, cyclic voltammetry (CV) measurements, and DFT calculations.

Aluminum porphyrins with quaternary ammonium halides as catalysts for copolymerization of cyclohexene oxide and CO2: metal-ligand cooperative catalysis.

Bifunctional AlIII porphyrins with quaternary ammonium halides, 2-Cl and 2-Br, worked as excellent catalysts for the copolymerization of cyclohexene oxide (CHO) and CO2 at 120 °C. Turnover frequency (TOF) and turnover number (TON) reached 10 000 h-1 and 55 000, respectively, and poly(cyclohexene carbonate) (PCHC) with molecular weight of up to 281 000 was obtained with a catalyst loading of 0.001 mol%. In contrast, bifunctional MgII and ZnII counterparts, 3-Cl and 4-Cl, as well as a binary catalyst system, 1-Cl with bis(triphenylphosphine)iminium chloride (PPNCl), showed poor catalytic performances. Kinetic studies revealed that the reaction rate was first-order in [CHO] and [2-Br] and zero-order in [CO2], and the activation parameters were determined: ΔH ‡ = 12.4 kcal mol-1, ΔS ‡ = -26.1 cal mol-1 K-1, and ΔG ‡ = 21.6 kcal mol-1 at 80 °C. Comparative DFT calculations on two model catalysts, AlIII complex 2' and MgII complex 3', allowed us to extract key factors in the catalytic behavior of the bifunctional AlIII catalyst. The high polymerization activity and carbonate-linkage selectivity originate from the cooperative actions of the metal center and the quaternary ammonium cation, both of which facilitate the epoxide-ring opening by the carbonate anion to form the carbonate linkage in the key transition state such as TS3b (ΔH ‡ = 13.3 kcal mol-1, ΔS ‡ = -3.1 cal mol-1 K-1, and ΔG ‡ = 14.4 kcal mol-1 at 80 °C).

Tetrameric and Hexameric Porphyrin Nanorings: Template Synthesis and Photophysical Properties.

Hexameric and tetrameric porphyrin nanorings, Z6·T6 and Z4·T4, were synthesized in 53% and 14% yields, respectively, by the Sonogashira-type self-oligomerization of porphyrin monomer 1 using hexadentate template T6 and tetrapyridylporphyrin template T4. Template-free nanorings Z6 and Z4 were also prepared. The femtosecond transient absorption measurements revealed fast excitation energy hopping (EEH) along these nanorings with hopping rates of 2-5 ps. Treatment of Z6 with chiral template CT6 gave Z6·CT6 showing circular dichroism (CD) and circularly polarized luminescence (CPL) in the absorption and fluorescence regions of Z6, respectively, which indicates chirality transfer from CT6 to Z6.

Aggregation-Induced Circularly Polarized Luminescence from Boron Complexes with a Carbazolyl Schiff Base.

A variety of carbazolyl-appended Schiff bases were readily synthesized from 1-formylcarbazoles and aniline derivatives. Boron complexation of the resulting ligands allowed for facile preparation of new carbazole-based BODIPY analogues showing solid-state fluorescence. Furthermore, some dyes were converted into chiral compounds through the Et2 AlCl-mediated incorporation of a binaphthyl unit. The chiral dyes showed aggregation-induced fluorescence and circularly polarized luminescence (CPL) with the ΦF and glum of up to 0.22 and -3.5×10-3 , respectively, in the solid state. The solid-state fluorescence and CPL were well characterized by the crystal packing analyses and DFT calculations.