Malonate given at reperfusion prevents post-myocardial infarction heart failure by decreasing ischemia/reperfusion injury.

The mitochondrial metabolite succinate is a key driver of ischemia/reperfusion injury (IRI). Targeting succinate metabolism by inhibiting succinate dehydrogenase (SDH) upon reperfusion using malonate is an effective therapeutic strategy to achieve cardioprotection in the short term (< 24 h reperfusion) in mouse and pig in vivo myocardial infarction (MI) models. We aimed to assess whether inhibiting IRI with malonate given upon reperfusion could prevent post-MI heart failure (HF) assessed after 28 days. Male C57BL/6 J mice were subjected to 30 min left anterior coronary artery (LAD) occlusion, before reperfusion for 28 days. Malonate or without-malonate control was infused as a single dose upon reperfusion. Cardiac function was assessed by echocardiography and fibrosis by Masson's trichrome staining. Reperfusion without malonate significantly reduced ejection fraction (~ 47%), fractional shortening (~ 23%) and elevated collagen deposition 28 days post-MI. Malonate, administered as a single infusion (16 mg/kg/min for 10 min) upon reperfusion, gave a significant cardioprotective effect, with ejection fraction (~ 60%) and fractional shortening (~ 30%) preserved and less collagen deposition. Using an acidified malonate formulation, to enhance its uptake into cardiomyocytes via the monocarboxylate transporter 1, both 1.6 and 16 mg/kg/min 10 min infusion led to robust long-term cardioprotection with preserved ejection fraction (> 60%) and fractional shortening (~ 30%), as well as significantly less collagen deposition than control hearts. Malonate administration upon reperfusion prevents post-MI HF. Acidification of malonate enables lower doses of malonate to also achieve long-term cardioprotection post-MI. Therefore, the administration of acidified malonate upon reperfusion is a promising therapeutic strategy to prevent IRI and post-MI HF.

Drastically Accelerated Radical Recombination Kinetics of a Hexaarylbiimidazole Derivative.

More than 60 years have passed since the discovery of hexaarylbiimidazole (HABI), which exhibits a characteristic photochromism that produces colored lophyl radicals through a radical dissociation reaction induced by light irradiation and reverts to its original state through a radical recombination reaction in the dark. Lophyl radicals are relatively stable among organic radicals, have low reactivity with oxygen, and have a very slow radical recombination reaction rate. HABI has been used industrially as a photoinitiator to date. However, the guidelines for molecular design to accelerate the thermal reverse reaction of HABI are still unknown and remain a challenge. We found that suppressing the rotation of the phenyl groups attached to the 4- and 5-positions of the imidazole ring of HABI is effective in accelerating the radical recombination reaction. The simple molecular design strategy to accelerate the thermal reverse reaction of HABI is expected to improve the performance of photoinitiators and photoresponsive materials that utilize HABI as a photoresponsive unit.

A Nonlinear Photochromic Reaction Based on Sensitizer-Free Triplet-Triplet Annihilation in a Perylene-Substituted Rhodamine Spirolactam.

Nonlinear photochromic reactions that work with weak incoherent light are important for molecular operations with high spatial resolution and multiple photofunctions based on single molecules. However, nonlinear photochromic compounds generally require complex molecular design, restricting accessibility in various fields. Herein, we report nonlinear photochromic properties in a perylene-substituted rhodamine spirolactam derivative (Rh-Pe), which is synthesized from rhodamine B in facile procedures. Direct excitation of Rh-Pe produces the triplet excited state via the charge-transfer (CT) state. The triplet excited state causes triplet-triplet annihilation to bring the generation of the intensely colored ring-open form with nonlinear behavior. Furthermore, green- and red-light-induced photochromism was achieved in Rh-Pe using triplet sensitizers, although Rh-Pe can be directly excited only by ultraviolet and blue light. Our findings are expected to contribute to the development of photofunctional materials showing nonlinear behavior and low-energy light responsivity.

An unusual case of severe asphyxia with the fetal position unexpectedly inverted in a malformed uterus: a case report.

BACKGROUND: We present a severe neonatal consequence due to the unexpected and crucial inversion of the fetal position after sudden termination of tocolysis during early labor of a woman with congenital uterine anomaly. It has been reported that congenital uterine anomalies latently affect the fetal position. The clinical pitfalls in childbirth with uterine anomalies are discussed here on the basis of clinical evidence. CASE PRESENTATION: At a perinatal medical center in Japan, a 29-year-old Japanese mother who had a history of bicornuate uterus, received tocolysis to prolong her pregnancy for 5 days during the late preterm period after preterm-premature rupture of the membrane. She gave birth to a 2304 g male neonate of the gestational age of 35 weeks and 5 days with severe asphyxia by means of crash cesarean section for fetal sustained bradycardia after sudden termination of tocolysis. We found the fetal position to reverse from cephalic to breech position during early labor. He ended up having severe cerebral palsy after brain cooling against hypoxic-ischemic encephalopathy for 3 days. The mechanism of inversion from cephalic to breech position without amnionic fluid remains unclear, although women with a known diagnosis of a uterine anomaly have higher risk of adverse outcomes such as malpresentation. CONCLUSIONS: When considering the clinical course of this case on the basis of the medical reports, we suspected that uterine anomalies and changes in intrauterine pressure could cause fetal malpresentation and adverse neonatal outcomes.

Clinical, Genomic, and Transcriptomic Featurses of Lung Adenocarcinoma With Uncommon EGFR Mutation.

PURPOSE: The purpose of this study is to identify the clinical, genomic, and transcriptomic features of patients with lung adenocarcinoma (LUAD) harboring uncommon epidermal growth factor receptor (EGFR) mutations (UCM) compared with common EGFR mutations (CM). MATERIALS AND METHODS: In this multicenter retrospective cohort study, clinicopathological data were collected from 1047 consecutive patients who underwent complete surgical resection for LUAD, as well as EGFR mutation analysis, between 2005 and 2012 at 4 institutions. Differences in postoperative overall survival (OS) and recurrence-free survival (RFS) according to EGFR mutation status were evaluated. For the genomic and transcriptomic analyses, 5 cohorts from public databases were evaluated. RESULTS: Of 466 eligible patients, 415 (89.1%) and 51 (10.9%) had CM and UCM, respectively. The 5-year OS and RFS rates in the CM/UCM groups were 86.8%/77.0% and 74.8%/59.0%, respectively. OS and RFS were significantly shorter in the UCM than CM group (both P < .01). Multivariable analysis of OS showed that UCM was an independent prognostic factor (hazard ratio 1.72, 95% confidential interval 1.01-2.93). According to the genomic analysis, tumors with UCM had a significantly higher tumor mutation burden and TP53 mutation frequency. Transcriptomic analysis showed that the T-cell-inflamed gene signature, a biomarker of the treatment for immunotherapy, was significantly associated with tumors with UCM. CONCLUSION: UCM were associated with a poor prognosis in patients with surgically resected EGFR-mutated LUAD. Tumors with UCM had unique genomic and transcriptomic features suggestive of a tumor microenvironment responsive to immunotherapy.

CD271 promotes proliferation and migration in bladder cancer.

Bladder cancer is a urothelial cancer and effective therapeutic strategies for its advanced stages are limited. Here, we report that CD271, a neurotrophin receptor, promotes the proliferation and migration of bladder cancer cells. CD271 knockdown decreased proliferation in both adherent and spheroid cultures, and vice versa when CD271 was overexpressed in bladder cancer cell lines. CD271 depletion impaired tumorigenicity in vivo. Migration activity was reduced by CD271 knockdown and TAT-Pep5, a known CD271-Rho GDI-binding inhibitor. Apoptosis was induced by CD271 knockdown. Comprehensive gene expression analysis revealed alterations in E2F- and Myc-related pathways upon CD271 expression. In clinical cases, patients with high CD271 expression showed significantly shortened overall survival. In surgically resected specimens, pERK, a known player in proliferation signaling, colocalizes with CD271. These data indicate that CD271 is involved in bladder cancer malignancy by promoting cell proliferation and migration, resulting in poor prognosis.

Unraveling Steric Effects on Ultrafast Bond-Dissociation Processes of Photochromic Radical Complexes.

Photochromic reactions of the phenoxyl-imidazolyl radical complex (PIC), which is one of the rate-tunable fast T-type photoswitches, dramatically change by the introduction of bulky substituents around the photochromic units. While these substituents are expected to affect the initial bond dissociation processes, they have not been elucidated yet. Here, we revealed the ultrafast bond dissociation processes of PIC derivatives with different bulky substituents by subpicosecond to nanosecond transient absorption spectroscopy. We revealed that the bulky substituents around the photochromic units decelerate the bond dissociation processes, whereas they largely accelerate the thermal back reactions of the photogenerated open-ring isomer. Moreover, we found clear correlations between the formation kinetics of the open-ring isomer and molecular structural changes. The initial bond-dissociation process dictates the products and the efficiency of photochromic reactions. Therefore, revealing these processes is important not only for fundamental photochemistry but also for optimizing photochromic properties for advanced functional materials.

Long-term follow-up of a consecutive cohort validating an epidermal growth factor receptor mutation as an independent risk factor for postoperative recurrence in lung adenocarcinoma.

OBJECTIVES: Third-generation epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors were recently reported to be effective as adjuvant therapy for resected lung adenocarcinoma (ADC) harbouring common EGFR mutations. However, whether the EGFR mutation is a direct risk factor for postoperative recurrence remains unknown. Therefore, we conducted a multi-institutional observational study to compare postoperative survival according to EGFR mutation status. METHODS: We collected the medical records of consecutive patients who underwent surgical resection for ADC between 2005 and 2012 at 4 participating institutions. Recurrence-free survival (RFS) and overall survival (OS) associated with EGFR mutation status were evaluated. We further analysed survival after pair-matching patients' clinicopathological characteristics. RESULTS: EGFR mutations were harboured by 401 of 840 (48%) enrolled patients. The number of patients with an EGFR mutation (M group) differed from that with the EGFR wild-type sequence (W group) in terms of sex, smoking history and pathological stage. The median follow-up period was 85 months. The five-year RFS/OS rates of the M and W groups were 70%/85% and 61%/75%, respectively (P < 0.001 for both groups). However, multivariable analysis revealed that EGFR mutation status was not independently related with both RFS and OS. In pair-matched analysis, the RFS and OS curves of the patients with an EGFR mutation and wild-type sequence were not statistically different, either. CONCLUSIONS: Long-term follow-up of consecutive patients did not show that a common EGFR mutation was an independent risk factor of recurrence or prognostic factor for completely resected lung ADC.

Photochromic dinuclear iridium(III) complexes having phenoxyl-imidazolyl radical complex derivatives.

We demonstrate that the phenoxyl-imidazolyl radical complex (PIC), which is a rate-tunable fast photoswitch, can be used as a ligand that directly coordinates with iridium (III) ions. The iridium complexes show the characteristic photochromic reactions originating from the PIC moiety, whereas the behaviour of transient species is substantially different from that of the PIC.

PRB inhibited cell proliferation through let-7b-E2F1 in breast cancer.

The presence of progesterone receptor (PR) and PR isoform B (PRB) in breast cancer is generally correlated with better clinical outcomes. Additionally, the significance of hormone-independent effects of PR/PRB correlated with better prognosis has been reported in non-small cell lung cancer (NSCLC). However, the detailed mechanism of that still remains unclear. In this study, we examined how microRNAs (miRNAs) could contribute to tumor inhibition via PR/PRB expression, in order to find miRNAs that have tumor-agnostic effects between breast cancer and NSCLC. We obtained miRNA data using human tissues of breast cancer and NSCLC from The Cancer Genome Atlas (TCGA) database and PCR array from NSCLC patients of our cohort. Subsequently, we examined the function of the miRNA through in vitro study using breast cancer cell lines. As a result, only let-7b expression was significantly correlated with PR expression in both cancers. Additionally, the expression of let-7b significantly inhibited cell proliferation by inducing PR and PRB expression in breast cancer cell lines. However, the positive correlation of let-7b and PRB required a mediated factor, E2 promoter binding factor 1 (E2F1), obtained from TCGA database analysis. In vitro experiments showed that let-7b significantly inhibited E2F1, and E2F1 significantly inhibited PRB. This study revealed that PRB inhibits the proliferation of breast cancer cells by the let-7b-E2F1 interaction. In addition, the immunohistochemical analysis in NSCLC was also consistent with these in vitro data. Our results could contribute to developing novel therapeutic strategies for patients with PR/PRB-positive cancer by targeting let-7b or PRB expression in breast cancer and possibly NSCLC.

Morphometric analysis of nuclear shape irregularity as a novel predictor of programmed death-ligand 1 expression in lung squamous cell carcinoma.

Immune checkpoint inhibitor (ICI) therapy has been established as one of the key treatment strategies for lung squamous cell carcinoma (LUSQ). The status of programmed death-ligand 1 (PD-L1) in tumor cells and/or immune cells using immunohistochemistry has been primarily used as a surrogate marker for determining ICI treatment; however, when the tissues to be examined are small, false-negative results could be unavoidable due to the heterogeneity of PD-L1 immunoreactivity. To overcome this practical limitation, we attempted to explore the status of nuclear atypia evaluated using morphometry as a potential predictor of PD-L1 status in LUSQ. We correlated the parameters related to nuclear atypia with PD-L1 status using two different cohorts of LUSQ patients (95 cases from The Cancer Genome Atlas database and 30 cases from the Miyagi Cancer Center). Furthermore, we studied the gene mutation status to elucidate the genetic profile of PD-L1 predictable cases. The results revealed that nuclear atypia, especially morphometric parameters related to nuclear shape irregularity, including aspect ratio, circularity, roundness, and solidity, were all significantly associated with PD-L1 status. Additionally, LUSQ cases with high PD-L1 expression and pronounced nuclear atypia were significantly associated with C10orf71 and COL14A1 mutations compared with those with low PD-L1 expression and mild nuclear atypia. We demonstrated for the first time that nuclear shape irregularity could represent a novel predictor of PD-L1 expression in LUSQ. Including the morphometric parameters related to nuclear atypia in conjunction with PD-L1 status could help determine an effective ICI therapeutic strategy; however, further investigation is required.

A case of infantile Barth syndrome with severe heart failure: Importance of splicing variants in the TAZ gene.

Barth syndrome (BTHS) is an X-linked disorder characterized by cardiomyopathy, skeletal myopathy, and 3-methylglutaconic aciduria. The causative pathogenic variants for BTHS are in TAZ, which encodes a putative acyltransferase named tafazzin and is involved in the remodeling of cardiolipin in the inner mitochondrial membranes. Pathogenic variants in TAZ result in mitochondrial structural and functional abnormalities. We report a case of infantile BTHS with severe heart failure, left ventricular noncompaction, and lactic acidosis, having a missense c.640C>T (p.His214Tyr) variant in TAZ, which is considered a pathogenic variant based on the previously reported amino acid substitution at the same site (c.641A>G, p.His214Arg). However, in this previously reported case, heart function was compensated and not entirely similar to the present case. Silico prediction analysis suggested that c.640C>T could alter the TAZ messenger RNA (mRNA) splicing process. TAZ mRNAs in isolated peripheral mononuclear cells from the patient and in vitro splicing analysis using minigenes of TAZ found an 8 bp deletion at the 3' end of exon 8, which resulted in the formation of a termination codon in the coding region of exon 9 (H214Nfs*3). These findings suggest that splicing abnormalities should always be considered in BTHS.

Clinical and genomic features of non-small cell lung cancer occurring in families.

BACKGROUND: Exposure to environmental carcinogens, such as through smoking, is a major factor in the carcinogenesis of non-small cell lung cancer (NSCLC). However, genetic factors may also contribute. METHODS: To identify candidate tumor suppressor genes for NSCLC, we included 23 patients (10 related pairs and 3 individuals) with NSCLC who had other NSCLC-affected first-degree relatives in a local hospital. Exome analyses for both germline and somatic (NSCLC specimens) DNA were performed for 17 cases. Germline exome data of these 17 cases revealed that most of the short variants were identical to the variants in 14KJPN (a Japanese reference genome panel of more than 14 000 individuals) and only a nonsynonymous variant in the DHODH gene, p.A347T, was shared between a pair of NSCLC patients in the same family. This variant is a known pathogenic variant of the gene for Miller syndrome. RESULTS: Somatic genetic alterations in the exome data of our samples showed frequent mutations in the EGFR and TP53 genes. Principal component analysis of the patterns of 96 types of single nucleotide variants (SNVs) suggested the existence of unique mechanisms inducing somatic SNVs in each family. Delineation of mutational signatures of the somatic SNVs with deconstructSigs for the pair of germline pathogenic DHODH variant-positive cases showed that the mutational signatures of these cases included SBS3 (homologous recombination repair defect), SBS6, 15 (DNA mismatch repair), and SBS7 (ultraviolet exposure), suggesting that disordered pyrimidine production causes increased errors in DNA repair systems in these cases. CONCLUSION: Our results suggest the importance of the detailed collection of data on environmental exposure along with genetic information on NSCLC patients to identify the unique combinations that cause lung tumorigenesis in a particular family.

Bridged-Imidazole Dimer Exhibiting Three-State Negative Photochromism with a Single Photochromic Unit.

Photochromic molecules that can exhibit multiple states of photochromism in a single photochromic unit are considered more attractive than traditional bistable photochromic molecules because they can offer more versatility and control in photoresponsive systems. We have synthesized a negative photochromic 1-(1-naphthyl)pyrenyl-bridged imidazole dimer (NPy-ImD) that has three different isomers: a colorless isomer, 6MR, a blue-colored isomer, 5MR-B, and a red-colored isomer, 5MR-R. NPy-ImD can interconvert between these isomers via a short-lived transient biradical, BR, upon photoirradiation. 5MR-R is the most stable isomer, and the energy levels of 6MR, 5MR-B, and BR are relatively close to each other. The colored isomers 5MR-R and 5MR-B are photochemically isomerized to 6MR via the short-lived BR upon irradiation with blue light and red light, respectively. The absorption bands of 5MR-R and 5MR-B are well separated by more than 150 nm, with a small overlap, which means they can be selectively excited with different light sources, visible light for 5MR-R and NIR light for 5MR-B. The colorless isomer 6MR is formed from the short-lived BR through a kinetically controlled reaction. 6MR and 5MR-B can then be converted to the more stable isomer 5MR-R through a thermodynamically controlled reaction, which is facilitated by the thermally accessible intermediate, BR. Notably, 5MR-R photoisomerizes to 6MR when irradiated with CW-UV light, whereas it photoisomerizes to 5MR-B by a two-photon process when irradiated with nanosecond UV laser pulses.

Acceleration of the thermal back-reaction and the finding of a non-photochromic isomer for a negative photochromic binaphthyl-bridged imidazole dimer.

The development of visible or near-infrared (NIR) light-responsive fast photoswitchable molecules for the real-time, non-contact control of physical and chemical properties has received increased attention because of the non-invasive features to materials and biological tissues. We report a new molecular design to accelerate the thermal back-reaction of the negative photochromic binaphthyl-bridged imidazole dimer, BN-ImD. We also found that irradiation of the BN-ImD derivative with methyl groups on the bridging binaphthyl unit with visible light produced an unprecedented photoreaction product with a unique eight-membered ring structure. These observations provide fascinating clues for the future development of fast negative photochromic molecules.

Negative Photochromic 3-Phenylperylenyl-Bridged Imidazole Dimer Offering Quantitative and Selective Bidirectional Photoisomerization with Visible and Near-Infrared Light.

Selective bidirectional photoisomerization reactions with high conversion ratios between stable and metastable isomers by irradiation of photochromic molecules with visible light of different wavelengths have been an important issue for many years. For negative photochromic molecules known so far, metastable isomers also absorb UV or visible light in the same region as stable isomers, making it difficult to selectively achieve the reverse reaction by visible-light irradiation. We have demonstrated that the absorption bands of the stable and metastable isomers of 3-phenylperylenyl-bridged imidazole dimer are largely separated by more than 140 nm and that almost quantitative and selective bidirectional photoconversion can be achieved by 660 and 460 nm light. Furthermore, the forward reaction can be achieved completely with near-infrared light of 785 nm.

Efficacy of platinum-based adjuvant chemotherapy for epidermal growth factor receptor-mutant lung adenocarcinoma.

Background: The ADAURA trial reported that osimertinib improved overall survival (OS) as an adjuvant chemotherapy for pathological stage IB-IIIA epidermal growth factor receptor (EGFR) mutant lung cancer compared with a placebo. Currently, platinum-based adjuvant chemotherapy is the standard treatment for patients with or without EGFR mutations. This study aimed to evaluate the efficacy of platinum-based adjuvant chemotherapy in patient with stage II-IIIA EGFR mutant lung adenocarcinoma. Methods: We collected the medical records of consecutive patients who underwent surgical resection for lung adenocarcinoma between 2005 and 2012 at the four participating institutions. The data of 173 patients with different EGFR mutation status were retrospectively evaluated to determine the efficacy of platinum-based adjuvant chemotherapy for OS and recurrence-free survival (RFS). We further analyzed OS using the inverse probability of treatment weighting method with propensity scores. Results: The median age was 69 years (range, 45-85 years); 95 (54.9%) were male and 74 (42.8%) had EGFR mutations. A total of 43 patients with EGFR mutants (58.1%) and 43 patients with wild-type EGFR tumors (43.4%) received platinum-based adjuvant chemotherapy. No differences in RFS and OS were observed between EGFR mutant and wild-type EGFR in lung adenocarcinoma without adjuvant therapy. However, wild-type EGFR showed an improvement in OS with platinum-based adjuvant chemotherapy in inverse probability of treatment weighting analysis, whereas those with EGFR mutations showed no significant difference in OS between the surgery-only group and the adjuvant group. The deletion of exon 19 and exon 21 L858R point mutation showed no significant differences in OS between the surgery-only group and the adjuvant group, respectively. The hazard ratio (HR) exceeded 1 for uncommon EGFR mutations. Conclusions: Platinum-based adjuvant chemotherapy may be less effective for EGFR-mutant lung adenocarcinoma, regardless of the mutation type.

Controlling Diradical Character of Photogenerated Colored Isomers of Phenoxyl-Imidazolyl Radical Complexes.

We propose a rational method for evaluating the diradical character of the photochromic phenoxyl-imidazolyl radical complex (PIC) derivatives based on their radical-radical coupling reaction rates. PIC consists of an imidazole ring, a phenoxyl ring, and a bridging unit that structurally connects them. The C-N bond formed between the imidazole and phenoxyl rings can be dissociated photochemically in a homolytic manner. The photochromism of PIC differs significantly from other photochromic molecules in that the transient colored open-ring isomer has a diradical character. The colored open-ring isomer returns promptly to the initial colorless closed-ring isomer by the intramolecular radical recombination reaction. By changing the aromaticity and substitution position of the bridging unit, it is possible to control the degree of contribution of the open-shell diradical and closed-shell quinoidal structures to the open-ring isomer. Systematic investigation of the photochromic reactions of several PIC derivatives revealed that the half-life of the open-ring isomers reflects the diradical character. Thus, the radical recombination reaction rate of the open-ring isomer of the PIC derivatives is an excellent parameter of the diradical character.