Diaphragmatic clear cell carcinoma with Lynch syndrome after surgery for atypical endometrial hyperplasia and ovarian endometriosis: A case report.

Clear cell carcinoma (CCC) of the diaphragm is rare, with an origin that is reported to be associated with malignant transformation of extraperitoneal endometriosis. Lynch syndrome (LS) is an autosomal dominant hereditary cancer syndrome caused by germline pathogenic variants in one of the DNA mismatch repair (MMR) genes, MLH1, MSH2, MSH6 and PMS2. Women with LS have a significantly increased lifetime risk of endometrial and ovarian cancer. CCC is a common histology of endometriosis- and LS-associated malignancy. The present study describes the case of a 51-year-old woman with an intra-abdominal mass found during a routine physical examination. The patient had undergone total hysterectomy and bilateral adnexectomy for atypical endometrial hyperplasia (AEH) and ovarian endometriosis, respectively, 3 years previously. Enhanced computed tomography showed a mass on the surface of the liver. Laparoscopic examination of the abdominal cavity revealed a tumor on the underside of the right diaphragm, which was then surgically excised. Pathological examination of the excised tumor, along with immunohistochemistry, led to a diagnosis of CCC. Since LS was suspected due to the genetic family history of the patient, microsatellite instability analysis was performed on the diaphragmatic tumor, and the results were positive. Immunohistochemistry was performed for MMR proteins in AEH and CCC cells, both of which revealed loss of MSH2 and MSH6 expression. Following detailed genetic counseling, genetic testing of MMR genes was performed, revealing a germline pathogenic variant in MSH2 (c.1000C>T, p.Gln344*), thus confirming the diagnosis of LS. To the best of our knowledge, this is the first case report of concurrent diaphragmatic CCC and LS. Patients with LS and endometriosis are at risk of developing ovarian cancer or intra-abdominal malignant tumors. In addition, immunohistochemistry screening for MMR proteins should be considered in patients with AEH and a family history of LS-related cancer, to enable early clinical intervention in cases of endometrial cancer.

Spin dynamics phenomena of a cerium(III) double-decker complex induced by intramolecular electron transfer.

Switchable spin dynamic properties in single-molecule magnets (SMMs) via an applied stimulus have applications in single-molecule devices. Many SMMs containing heavy lanthanoid ions with strong uniaxial magnetic anisotropy have been reported to exhibit SMM characteristics in the absence of an external magnetic field. On the other hand, SMMs containing light lanthanoid cerium(III) (Ce3+) ions exhibit field-induced slow magnetic relaxation. We investigated the chemical conversion of a diamagnetic Ce4+ ion (4f0) to a paramagnetic Ce3+ ion (4f1) in Ce-phthalocyaninato double-decker complexes (TBA+[Ce(obPc)2]- (1) and TBA+[Ce(Pc)2]- (2)) which exhibit field-induced SMM behaviour due to a 4f1 system. The phthalocyaninato ligands with electron-donating substituents (obPc2- = 2,3,9,10,16,17,23,24-octabutoxyphthalocyaninato) in 1 have a significant effect on the valence state of the Ce ion, which is reflected in its magnetic properties due to the mixed valence state of the Ce ion. Given that Ce double-decker complexes with π-conjugated ligands undergo intramolecular electron transfer (IET) to the Ce ion mixed valence state, characterised by a mixture of 4f0 and 4f1 configurations, we examined the dynamic disorder inherent in IET influencing magnetic relaxation.

Successful Management of Ovarian Cancer Progressing on Olaparib by Niraparib Following Cytoreduction: A Case Report.

BACKGROUND: Polyadenosine 5'-diphosphoribose polymerase inhibitors (PARP-Is) are novel, effective agents for treating newly diagnosed epithelial ovarian cancer (EOC). However, the effect of PARP-I on the progression of recurrent EOC has not yet been determined. In particular, there is limited evidence regarding retreatment with PARP-I for recurrent EOC that has progressed on PARP-I in the short term. CASE REPORT: A 69-year-old woman with a BRCA1 mutated EOC relapsed five months after starting olaparib maintenance following neoadjuvant chemotherapy and interval debulking surgery. Although the platinum-free interval was within six months, secondary cytoreductive surgery was performed because the tumor was locoregional. Following two cycles of weekly nedaplatin, niraparib induced a complete response, and the patient maintained a progression-free status for 15 months. CONCLUSION: Even with short-term progression on PARP-I, local control combined with different platinum agents and PARP-I can be used to achieve good responses.

Aggregability of the SQSTM1/p62-based aggresome-like induced structures determines the sensitivity to parthanatos.

Overactivation of poly (ADP-ribose) polymerase-1 (PARP-1) triggers a noncanonical form of programmed cell death (PCD) called parthanatos, yet the mechanisms of its induction are not fully understood. We have recently demonstrated that the aggresome-like induced structures (ALIS) composed of the autophagy receptor SQSTM1/p62 and K48-linked polyubiquitinated proteins (p62-based ALIS) mediate parthanatos. In this study, we identified the D1 dopamine receptor agonist YM435 as a unique parthanatos inhibitor that acts as the disaggregating agent for the p62-based ALIS. We found that YM435 structurally reduces aggregability of the ALIS, and then increases its hydrophilicity and liquidity, which prevents parthanatos. Moreover, dopamine and L-DOPA, a dopamine precursor, also prevented parthanatos by reducing the aggregability of the ALIS. Together, these observations suggest that aggregability of the p62-based ALIS determines the sensitivity to parthanatos, and the pharmacological properties of YM435 that reduces the aggregability may be suitable for therapeutic drugs for parthanatos-related diseases such as neurodegenerative diseases.

Design and Synthesis of Orexin 1 Receptor-Selective Agonists.

Orexins are a family of neuropeptides that regulate various physiological events, such as sleep/wakefulness as well as emotional and feeding behavior, and that act on two G-protein-coupled receptors, i.e., orexin 1 (OX1R) and orexin 2 receptors (OX2R). Since the discovery that dysfunction of the orexin/OX2R system causes the sleep disorder narcolepsy, several OX2R-selective and OX1/2R dual agonists have been disclosed. However, an OX1R-selective agonist has not yet been reported, despite the importance of the biological function of OX1R. Herein, we report the discovery of a potent OX1R-selective agonist, (R,E)-3-(4-methoxy-3-(N-(8-(2-(3-methoxyphenyl)-N-methylacetamido)-5,6,7,8-tetrahydronaphthalen-2-yl)sulfamoyl)phenyl)-N-(pyridin-4-yl)acrylamide [(R)-YNT-3708; EC50 = 7.48 nM for OX1R; OX2R/OX1R EC50 ratio = 22.5]. The OX1R-selective agonist (R)-YNT-3708 exhibited antinociceptive and reinforcing effects through the activation of OX1R in mice.

Deprotonation-Induced Color Modulation in N,N'-Dihydroxynaphthalenediimide-Based Organic Crystals.

N,N'-dihydroxy-1,4,5,8-naphthalenetetracarboxdiimide (NDI-(OH)2 ) has attracted much attention in recent years, because its doubly deprotonated state, (O-NDI-O)2- , has metal-coordination ability and characteristic electronic transition useful for designing electronic and optical functions. In contrast, a molecular crystal with the mono-deprotonated (HO-NDI-O)- ion remains unknown. We herein report an organic crystal containing non-disproportionated (HO-NDI-O)- ions, which are connected by very strong O-H-O hydrogen bonds. Its lowest energy absorption band (450 to 650 nm) is observed in between that of NDI-(OH)2 (380 nm) and isolated (O-NDI-O)2- (500 to 850 nm) species, consistent with the molecular orbital calculations. This absorption originates from the electronic transition from deprotonated imide-based orbitals to NDI-core orbitals, which can be influenced by the hydrogen bonds around imide group. Consequently, the optical properties of NDI-(OH)2 can be modulated by the stepwise deprotonation and hydrogen-bonding interactions.

Intramolecular Ferromagnetism in Di-Nuclear 3 d-Transition-Metal Single-Molecule Magnets by Pseudo-Serial Arrangement.

Di-nuclear citrate complexes, [CH6 N3 ]2 [M2 (citH)2 (H2 O)4 ] ⋅ 2H2 O (citH4 =citric acid; M=FeII (Fe-2), CoII (Co-2), and NiII (Ni-2)), are synthesized. The ligand, citH3- , is deprotonated only at the three carboxy groups, which is different from the previously reported tetra-nuclear structures with cit4- ligands. Magnetic measurements reveal that these complexes have intramolecular ferromagnetism with J=∼0 cm-1 (Ni-2), 0.02 cm-1 (Co-2), and 0.04 cm-1 (Fe-2). Co-2 and Fe-2 show slow magnetic relaxation, and are field-induced SMMs with activation energy of spin-reversal Ueff =27 cm-1 (Co-2) and 4.2 cm-1 (Fe-2). Density functional theory calculations indicate that the uniaxial anisotropy along the z-axis of each metal ion center forms the pseudo-serial arrangement, leading to intramolecular ferromagnetism via the magnetic dipole interaction. This work demonstrates the creation of ferromagnetic SMMs by the magnetic dipole engineering of 3d di-nuclear metal ion centers.

Porous Mn2+ Magnet with a Pt-Cl Framework: Correlation between Water Vapor Adsorption/Desorption and Slow Magnetic Relaxation.

We report the water adsorption/desorption behavior and dynamic magnetic properties of the Pt-Cl chain complex [{[Pt(en)2 ][PtCl2 (en)2 ]}3 ][{(MnCl5 )Cl3 }2 ] ⋅ 12H2 O (1). Upon heating 1 in a vacuum, we obtained the dehydrated form [{[Pt(en)2 ][PtCl2 (en)2 ]}3 ][{(MnCl5 )Cl3 }2 ] (1DH). The framework structures of 1 and 1DH are identical, and both complexes underwent slow magnetic relaxation. However, the magnetic relaxation times for 1DH were shorter than those for 1, meaning that the dynamic magnetic properties were controlled upon water vapor adsorption/desorption. From detailed analyses of the dynamic magnetic behavior, a phonon-bottleneck effect contributes to the magnetic relaxation processes. We discuss the mechanism for the changes in the magnetic relaxation processes upon dehydration in terms of the heat capacity and thermal conductivity.

Successful management of pelvic recurrence of MSI-High endometrial cancer by total pelvic exenteration followed by administration of pembrolizumab:A case report.

Surgery can be curative treatment for pelvic locoregional recurrence of endometrial cancer; however, a cure is contingent on complete resection. Here, we report the case of a patient in whom recurrent endometrial tumor remained in the pelvis after resection; long-term control was achieved with postoperative administration of pembrolizumab.The patient had recurrent endometrial cancer of stage IA and was treated with chemotherapy and radiation, but tumor persisted in the pelvic cavity. We therefore attempted total pelvic exenteration, but the tumor was adherent to the pelvic wall and complete resection could not be achieved. However, postoperative administration of pembrolizumab controlled the residual tumor for more than two years without regrowth. We believe that since the resected tumor was MSI-High, the residual tumor responded well to pembrolizumab. It is not known whether cytoreductive surgery contributes to a long-term response to pembrolizumab, but at least in our patient, pembrolizumab appeared to be a very effective drug therapy for MSI-High endometrial cancer that was refractory to chemotherapy and radiotherapy.

Discovery of novel orexin receptor antagonists using a 1,3,5-trioxazatriquinane bearing multiple effective residues (TriMER) library.

Structurally diverse small compounds are utilized to obtain hit compounds that have suitable pharmacophores in appropriate three-dimensional conformations for the target drug receptors. We have focused on the 1,3,5-trioxazatriquinane skeleton, which has a rigid bowl-like structure enabling the diverse orientation of side chain units, leading to a novel small-scale focused library based on the skeleton. In the library screening for the orexin receptor, some of the compounds showed orexin receptor antagonistic activity with a high hit rate of 7%. By optimizing the hit compounds, we discovered a potent dual orexin receptor antagonist, 38b, and a selective orexin 1 receptor antagonist, 41b carrying the same plane structure. Both compounds showed reasonable brain permeability and beneficial effects when administered intraperitoneally to wild-type mice. Docking simulations of their eutomers, (-)-38b and (+)-41b, with orexin receptors suggested that the interaction between the 1,3,5-trioxazatriquinane core structure and the hydrophobic subpocket in orexin receptors enables a U-shape structure, which causes tight van der Waals interactions with the receptors similar to SB-334867, a selective orexin 1 receptor antagonist. These results indicate that the library approach utilizing the 1,3,5-trioxazatriquinanes bearing multiple effective residues (TriMERs) might be useful for the hit discovery process targeting not only opioid and orexin receptors but other G-protein coupled receptors.

Ni(III) Mott-Hubbard-like State Containing High-Spin Ni(II) in a Semiconductive Bromide-Bridged Ni-Chain Compound.

Halogen-bridged linear chain metal complexes (MX-Chains) are fascinating compounds that have a quasi-one-dimensional (1D) electronic system. In this study, we synthesized the first Ni-based MX-Chain compound having hydroxy groups, i.e., [Ni(dabdOH)2Br]Br2·[Ni(dabdOHx)2Br]0.5·(2-PrOH)0.25·(MeOH)0.25 (1·solvent, x = ∼0.6, dabdOH = (2S,3S)-2,3-diaminobutane-1,4-diol). Single-crystal X-ray diffraction revealed that the MX-Chains in 1·solvent formed sheets and single-chain structures in the superlattice. It suggested an MH-like state, whereas the polarized reflection and Raman spectra suggested a CDW-like state. Magnetic and electron spin resonance measurements revealed that both high-spin Ni(II) (∼15%) and low-spin Ni(III) (∼85%) sites are present in the chain structures, i.e., the metal sites show mixed valency. Therefore, we concluded that 1·solvent adopts an intermediate state between the MH and CDW states. Moreover, a single crystal of 1·solvent exhibited semiconductive characteristics along the chain direction. This finding represents a new structural and electronic state of 1D electronic systems as well as MX-Chains.

Reversible Insulator-Metal Transition by Chemical Doping and Dedoping of a Mott Insulator.

The chemical carrier doping of molecular Mott insulators has been poorly investigated to date due to its difficulty. In this study, iodine doping of a molecular Mott insulator, lithium phthalocyanine crystallized in the x-form (x-LiPc), was performed to obtain metallic x-LiPcI. Crystal structure analysis revealed that iodine atoms penetrated channels of x-LiPc and formed one-dimensional chains. The Raman spectroscopy of x-LiPcI indicated the existence of linear I5 - , demonstrating a transition from a half-filled band of the Mott insulating state to a 2/5-filled band of the metallic state. Electrical resistivity measurements confirmed the metallic nature of x-LiPcI, whereas a thermally activated behavior was observed for pristine x-LiPc. Furthermore, the x-LiPc Mott insulator was reproduced by dedoping iodine from x-LiPcI, suggesting that the electronic state can be reversibly tuned between the Mott insulating and metallic states by chemical doping and dedoping.

An electrically conductive metallocycle: densely packed molecular hexagons with π-stacked radicals.

Electrical conduction among metallocycles has been unexplored because of the difficulty in creating electronic transport pathways. In this work, we present an electrocrystallization strategy for synthesizing an intrinsically electron-conductive metallocycle, [Ni6(NDI-Hpz)6(dma)12(NO3)6]·5DMA·nH2O (PMC-hexagon) (NDI-Hpz = N,N'-di(1H-pyrazol-4-yl)-1,4,5,8-naphthalenetetracarboxdiimide). The hexagonal metallocycle units are assembled into a densely packed ABCABC… sequence (like the fcc geometry) to construct one-dimensional (1D) helical π-stacked columns and 1D pore channels, which were maintained under the liberation of H2O molecules. The NDI cores were partially reduced to form radicals as charge carriers, resulting in a room-temperature conductivity of (1.2-2.1) × 10-4 S cm-1 (pressed pellet), which is superior to that of most NDI-based conductors including metal-organic frameworks and organic crystals. These findings open up the use of metallocycles as building blocks for fabricating conductive porous molecular materials.

Benzenetriimide-Based Molecular Conductor with Antiferro- to Ferromagnetic Switching Induced by Structural Change of π-stacked Array.

Benzenetriimide (BTI) is a promising building block for materials chemistry due to its characteristic 3-fold symmetry and redox properties, whereas little is known about its conductive and magnetic properties. In this study, we synthesized three charge-transfer complexes based on N,N',N''-trimethylbenzenetriimide (BTI-Me). One of the complexes contains isolated dimers of BTI-Me radical anion (BTI-Me⋅- ), while the other two have the infinite π-stacked array of BTI-Me with the formal charge of -0.5. The latter two complexes did not show metallic behavior but showed semiconducting behavior probably due to the characteristic insulation in one-dimensional electron system, so-called charge ordering and dimer-Mott insulation. The magnetic susceptibility of the complex in dimer-Mott state exhibits an unusual transition from antiferromagnetic to ferromagnetic spin states with the hysteresis loop of 15 K derived from the structural phase transition around 130 K. These properties were also supported by DFT calculations.

Comparison between DySc2N@C80 and Dy2ScN@C80 single-molecule magnetic metallofullerenes encapsulated in single-wall carbon nanotubes.

Encapsulation of a metallofullerene single-molecule magnet, Dy2ScN@C80, into single-wall carbon nanotubes (SWCNTs) accelerates magnetic relaxation processes. In contrast, encapsulation of DySc2N@C80 suppresses them. The effects of the encapsulation are discussed in terms of intermolecular magnetic interactions and charge transfer among metallofullerenes and SWCNTs.

Bromine Vapor Induced Continuous p- to n-Type Conversion of a Semiconductive Metal-Organic Framework Cu[Cu(pdt)2].

Guest-promoted modulation of the electronic states in metal-organic frameworks (MOFs) has brought about a new field of interdisciplinary research, including host-guest chemistry and solid-state physics. Although there are dozens of studies on guest-promoted enhancement of the electrical conductivity properties, including stoichiometry, conductive carriers and structure-property relationships have been scarcely studied in detail. Herein, we studied the effects of continuous and controlled bromine vapor doping on structural, optical, thermoelectric, and semiconducting properties of Cu[Cu(pdt)2] (pdt = 2,3-pyrazinedithiolate) as a function of bromine stoichiometry. We demonstrated that the same material could act as both p- and n-type semiconductors by tuning the stoichiometry of Br doped in Brx@Cu[Cu(pdt)2], and a change in the charge-carrier type from holes in pristine MOF to electrons upon bromine vapor doping was observed. Bromine molecules acted as an oxidant, causing the selective oxidation of [CuII(pdt)2] in the host framework. In addition, a redox hopping pathway between the partially oxidized CuII/CuIII center contributed to the enhancement of the electrical conductivity of the MOF.

Rare Hereditary Gynecological Cancer Syndromes.

Hereditary cancer syndromes, which are characterized by onset at an early age and an increased risk of developing certain tumors, are caused by germline pathogenic variants in tumor suppressor genes and are mostly inherited in an autosomal dominant manner. Therefore, hereditary cancer syndromes have been used as powerful models to identify and characterize susceptibility genes associated with cancer. Furthermore, clarification of the association between genotypes and phenotypes in one disease has provided insights into the etiology of other seemingly different diseases. Molecular genetic discoveries from the study of hereditary cancer syndrome have not only changed the methods of diagnosis and management, but have also shed light on the molecular regulatory pathways that are important in the development and treatment of sporadic tumors. The main cancer susceptibility syndromes that involve gynecologic cancers include hereditary breast and ovarian cancer syndrome as well as Lynch syndrome. However, in addition to these two hereditary cancer syndromes, there are several other hereditary syndromes associated with gynecologic cancers. In the present review, we provide an overview of the clinical features, and discuss the molecular genetics, of four rare hereditary gynecological cancer syndromes; Cowden syndrome, Peutz-Jeghers syndrome, DICER1 syndrome and rhabdoid tumor predisposition syndrome 2.

Incidence of Delirium With Different Oral Opioids in Previously Opioid-Naive Patients.

BACKGROUND: Opioids are known to induce delirium, but few studies have closely investigated differences in incidence of delirium among different opioids. OBJECTIVES: To determine whether there is a clinically significant difference in the incidence of delirium between oral opioids in previously opioid-naive patients. METHODS: Subjects were 259 opioid-naive in-patients with cancer who were started on morphine sulfate, oxycodone hydrochloride, or tapentadol hydrochloride extended-release tablets at our hospital between August 1, 2014, and September 30, 2018. The incidence of delirium during the first week of treatment was compared between the drugs. RESULTS: The incidence of delirium was 4.8% (n = 83) for morphine sulfate, 6.9% (n = 131) for oxycodone hydrochloride, and 6.7% (n = 45) for tapentadol hydrochloride. The incidence did not significantly differ between oxycodone hydrochloride (OR = .69, 95% CI = .20-2.30, P [Fisher's exact test] = .77) or tapentadol hydrochloride (OR = .71, 95% CI = .15-3.32, P [Fisher's exact test] = .70) and morphine sulfate (reference group). Moreover, the incidence did not significantly differ between tapentadol hydrochloride (OR = 1.03, 95% CI = .27-3.00, P [Fisher's exact test] = 1.00) and oxycodone hydrochloride (reference group). CONCLUSION: The incidence of delirium in previously opioid-naive patients did not differ significantly among morphine sulfate, oxycodone hydrochloride, and tapentadol hydrochloride extended-release tablets, suggesting similar risk of delirium in opioid-naive patients among these oral opioids.

Spin Trapping Analysis of Radical Intermediates on the Thermo-Oxidative Degradation of Polypropylene.

The purpose of this study is to investigate the thermo-oxidative degradation behavior of polypropylene (PP) by comparing three types of pristine PP granules (consisting of homopolymer, random copolymer, and block copolymer) with their corresponding oxidized analogues. These analogues were intensely oxidized under oxygen at 90 °C for 1000 h by using the electron spin resonance (ESR) spin trapping method that can detect short-lived radical intermediates during the degradation. The degrees of oxidation could be evaluated by chemiluminescence (CL) intensity, which was related to the concentration of hydroperoxide groups generated in the PP chain. In the pristine PP samples, a small amount of hydroperoxides were found to be formed unintentionally, and their homolysis produces alkoxy radicals, RO•, which then undergo ß-scission to yield chain-end aldehydes or chain-end ketones. These oxidation products continue to take part in homolysis to produce their respective carbonyl and carbon radicals. On the other hand, in the oxidized PP granules, because of their much higher hydroperoxide concentration, the two-stage cage reaction and the bimolecular decomposition of hydroperoxides are energetically favorable. Carbonyl compounds are formed in both reactions, which are then homolyzed to form the carbonyl radical species, •C(O)-. PP homopolymer produced the largest amount of carbonyl radical spin adduct; thus, it was found that the homopolymer is most sensitive to oxygen attack, and the presence of ethylene units in copolymers enhances the oxidation resistance of PP copolymers.

Influence of genetic variants of opioid-related genes on opioid-induced adverse effects in patients with lung cancer: A STROBE-compliant observational study.

ABSTRACT: Despite the dramatic advancement of cancer chemotherapy and immunotherapy, the insufficient progress has been made in basic or translational research on personalization of opioid therapy. Predicting the effectiveness of opioid analgesic therapy and the risk of adverse effects prior to therapy are expected to enable safer and more appropriate opioid therapy for cancer patients. In this study, we compared the incidence of opioid-induced adverse effects between patients with different variants of the genes related to responsiveness to opioid analgesics.Participants were 88 patients with lung cancer who provided general consent for exome sequencing and were treated with morphine or oxycodone at Shizuoka Cancer Center Hospital between April 2014 and August 2018. Incidence rates for 6 adverse effects of opioid therapy (somnolence, nausea, constipation, delirium, urinary retention, and pruritus) were determined and the influence of single nucleotide polymorphisms in coding regions of the opioid µ receptor 1 (OPRM1) (rs1799971), opioid δ receptor 1 (rs2234918), opioid κ receptor 1 (rs1051660), catechol-O-methyltransferase (COMT) (rs4680), dopamine receptor D2 (rs6275), adenosine triphosphate binding cassette B1 (rs1045642), G-protein regulated inward rectifier potassium channel 2 (rs2070995), and fatty acid amide hydrolase (rs324420) genes on those adverse effects were analyzed.Analysis of OPRM1 gene variant status (Asn133Asp A > G) showed that G/G homozygotes were at significantly lower risk of somnolence compared with A allele carriers (0% vs 28.4%; Fisher exact test, P = .005; OR, 0; 95% CI, 0-0.6), and analysis of COMT gene variant status (Val158Met, G > A) showed that G/G homozygotes were at significantly higher risk of somnolence compared with A allele carriers (35.0% vs 10.4%; Fisher exact test, P = .008; OR, 4.5; 95% CI, 1.4-18.1). No relationship between variant status and adverse effects was found for the other genes.These findings demonstrate that OPRM1 and COMT gene variants influence the risk of somnolence as an adverse effect of opioid analgesic therapy.