[A Case of Non-Small Cell Lung Cancer Successfully Treated with Anti-PD-L1 Therapy after Exacerbation Caused by Anti-PD-1 Therapy].

A 52-year-old male was diagnosed with cT4N3M1b, cStage Ⅳ adenocarcinoma of the lung, and underwent 6 courses of pemetrexed(PEM), carboplatin(CBDCA), and bevacizumab(Bev)therapy, followed by 4 courses of PEM/Bev maintenance therapy. Due to the deterioration of his condition, 4 courses of pembrolizumab(Pembro)therapy were administered as second- line therapy, but the treatment was discontinued due to disease progression. Third-line therapy with docetaxel(DTX)/ ramucirumab(Rmab)was administered, resulting in a partial response, but discontinued due to adverse events. Finally, fourth-line therapy with atezolizumab(Atezo)was initiated. After 6 courses of Atezo therapy, partial response was achieved, and the tumor continued to shrink for 3 years. The aim of the treatment strategy for both PD-1 and PD-L1 antibody drugs is to suppress T-cell exhaustion, and if either drug fails, the other drug may theoretically fail. However, in this case, the PD-L1 antibody drug was effective against non-small cell lung cancer that had shown resistance to PD-1 antibody drugs, suggesting that even if a patient becomes resistant to PD-1 antibody drugs, PD-L1 antibody drugs may result in effective outcomes.

[Role of Palliative Care in the Introduction of Chemotherapy in Patients with Poor Performance Status].

Chemotherapy for patients with poor performance status(PS)is not recommended because it increases the risk of death and shortens their survival. We report on 3 cases in which palliative care improved PS and enabled chemotherapy, resulting in a prolonged prognosis. Case 1 involves a 57‒year‒old woman with multiple lung, liver, and bone metastases from breast cancer who was administered celecoxib and oxycodone. She received Mohs paste therapy. Her PS improved from 3 to 2, and paclitaxel and trastuzumab were started; however, the patient died on day 861. Case 2 involves a 53‒year‒old woman with multiple lymph node metastases from carcinoma of an unknown primary cause. She was administered oxycodone, loxoprofen, and dexamethasone. Her PS improved from 4 to 3. The biopsy of her bone marrow showed diffuse large B‒cell lymphoma. The patient is still alive, 6 years and 10 months after the introduction of R‒CHOP. In case 3, a 57‒year‒old man with multiple bone metastases from small cell lung cancer was administered loxoprofen and betamethasone. His PS improved from 4 to 3. Etoposide and carboplatin were administered to him, but the patient died on day 692. Palliative care may enable the introduction of chemotherapy and consequently improve prognosis.

Assessments of DNA Damage and Radiation Exposure Dose in Cattle Living in the Contaminated Area Caused by the Fukushima Nuclear Accident.

Since the Fukushima nuclear accident in 2011, various abnormalities have been reported in animals living in the contaminated area. In the present study, we examined DNA damage in cattle living in the "difficult-to-return zone" by 8-hydroxy-2'-deoxyguanosine, comet, and micronucleus assays using their peripheral blood. The radiation exposure dose rate at the sampling time was approximately 0.25 or 0.38 mGy/day and the cumulative dose was estimated at approximately 1000 mGy. Significant increase in DNA damage was not detected by any of the three methods. As DNA damage is a stochastic effect of radiation, it might be occurring in animals living in the contaminated area. However, the present results suggest that radiation-induced DNA damage in the cattle did not increase to the level detectable by the assays we used due to the low dose rate in this area.

[Advanced Gastric Cancer with Tumor Shrinkage Persisting after the Discontinuation of Nivolumab-A Case Report].

The patient was a 65-year-old man with advanced gastric cancer, cT4bN3aM1, cStage Ⅳ. The SOX therapy was administered as the primary treatment but discontinued after 9 courses because of disease progression. The PTX plus RAM therapy was then administered for 1 courses as the secondary treatment but discontinued because of the development of peritoneal dissemination, increased number of ascites, and increased number of lymph node metastases. The nivolumab(NIV)therapy was initiated as the tertiary treatment, but the patient complained of fatigue and diplopia after 2 courses. Ptosis was observed, and transaminase and creatine kinase levels were elevated. Electrocardiography showed complete right bundle branch block. The patient showed immune-related adverse events and was diagnosed with myocarditis and myasthenia gravis due to NIV. Consequently, systemic steroids were administered. Although 2 course of CPT-11 was administered as the fourth-line treatment, the treatment was discontinued upon the patient's request. Ten months after the discontinuation of chemotherapy, the disease showed no progression. The patient is being followed-up as an outpatient. Here, we reported a case of gastric cancer with tumor shrinkage after the discontinuation of NIV.

Simultaneous hyperthermia-chemotherapy effect by arterial injection of Fe(Salen) for femur tumor.

We previously identified a novel nanomagnetic particle, N,N'-bis(salicylidene)ethylenediamine iron [Fe(Salen)]. Fe(Salen) not only shows antitumor effects but also magnetic properties. We found that Fe(Salen) can be used for magnet-guided drug delivery and visualization of accumulated drug by magnetic resonance imaging (MRI) because of its magnetism. In addition, Fe(Salen) can generate heat by itself when exposed to an alternating current magnetic field (AMF), resulting in a hyperthermia effect. Herein, we partly elucidated the antitumor mechanism of Fe(Salen) and carried out an i.v. repeated dose toxicity study to decide the therapeutic amount. Furthermore, we evaluated the antitumor effect of selective intra-arterial injection or i.v. injection of Fe(Salen) by catheter and the hyperthermia effect of Fe(Salen) when exposed to AMF in vivo. We used a rabbit model grafted with VX2 cells (rabbit squamous cell carcinoma) on the right leg. Intra-arterial injection of Fe(Salen) showed a greater antitumor effect than did i.v. injection. The combination of Fe(Salen) intra-arterial injection and AMF exposure showed a greater antitumor effect than did either Fe(Salen) or methotrexate (MTX) without AMF exposure, suggesting that AMF exposure greatly enhanced the antitumor effect of Fe(Salen) by arterial injection by catheter. This is the first report that the effectiveness of Fe(Salen) was evaluated in the point of administration route; that is, selective intra-arterial injection by catheter. Taken together, these results indicate a new administration route; that is, selective arterial injection of Fe(Salen) by catheter, and the development of a new strategy of simultaneous hyperthermia-chemotherapy in the future.

Two-Pot Synthesis of Chiral 1,3-syn-Diols through Asymmetric Organocatalytic Aldol and Wittig Reactions Followed by Domino Hemiacetal/Oxy-Michael Reactions.

A two-pot synthetic method to construct the chiral syn-1,3-diol unit has been developed from three aldehydes and either Wittig or Horner-Wadsworth-Emmons reagents. In the first pot, chiral δ-hydroxy α,ß-unsaturated ketones are synthesized with excellent enantioselectivity by the organocatalyst-mediated asymmetric direct aldol reaction of two different aldehydes, followed by either Wittig or Horner-Wadsworth-Emmons reactions. In the second pot, domino acetalization with an aldehyde and subsequent oxy-Michael reaction proceeds in the presence of NaClO4 and a catalytic amount of Bi(OTf)3 (OTf=trifluoromethanesulfonate) to provide the chiral 1,3-syn-diol derivative with excellent diastereoselectivity. Diospongin C and yashabushidiol A have been synthesized efficiently by using the present method as a key step.

Point-to-Point Ultra-Remote Asymmetric Control with Flexible Linker.

An ultra-remote intramolecular (point-to-point) asymmetric control through 38 bonds (1,39-asymmetric induction) has been achieved by using the principle of direct supramolecular orientation of catalytic and reactive moieties in asymmetric autocatalysis. We found the highly stereoselective diisopropylzinc addition reaction using designed molecules possessing pyrimidine sites at each terminal of a conformationally flexible simple methylene chain.

The iron chelating agent, deferoxamine detoxifies Fe(Salen)-induced cytotoxicity.

Iron-salen, i.e., µ-oxo-N,N'-bis(salicylidene)ethylenediamine iron (Fe(Salen)) was a recently identified as a new anti-cancer compound with intrinsic magnetic properties. Chelation therapy has been widely used in management of metallic poisoning, because an administration of agents that bind metals can prevent potential lethal effects of particular metal. In this study, we confirmed the therapeutic effect of deferoxamine mesylate (DFO) chelation against Fe(Salen) as part of the chelator antidote efficacy. DFO administration resulted in reduced cytotoxicity and ROS generation by Fe(Salen) in cancer cells. DFO (25 mg/kg) reduced the onset of Fe(Salen) (25 mg/kg)-induced acute liver and renal dysfunction. DFO (300 mg/kg) improves survival rate after systematic injection of a fatal dose of Fe(Salen) (200 mg/kg) in mice. DFO enables the use of higher Fe(Salen) doses to treat progressive states of cancer, and it also appears to decrease the acute side effects of Fe(Salen). This makes DFO a potential antidote candidate for Fe(Salen)-based cancer treatments, and this novel strategy could be widely used in minimally-invasive clinical settings.

Local variation of soil contamination with radioactive cesium at a farm in Fukushima.

Radioactive cesium concentration in soil was measured at 27 sections with 5 points per section, and surface dose of ground was measured at 10 sections with 13 points per section at a farm in Fukushima to assess local variation of soil contamination with radioactive cesium. As for the cesium in soil, averages of the coefficient of variance (CV) and the maximum/minimum ratio in each section were 49% and 4.9, respectively. As for the surface dose, average of its CV in each section was 20% and the maximum/minimum ratio reached a maximum of 3.0. These findings suggest that exact evaluation of soil contamination with cesium is difficult. Small changes or differences in soil contamination may not be detected in studies of the environmental radioactivity.

Long-Term Survey of Cadmium and Lead Contamination in Japanese Black Bears Captured in Iwate Prefecture, Japan.

Cadmium and lead were measured in liver and kidney samples of 242 Japanese black bears (Ursus thibetanus japonicus) captured from 1999 to 2014 from two local populations in Japan. The median concentration of cadmium was 0.54 (mean: 0.80) mg/kg-w.w. in liver and 7.7 (mean: 11.8) mg/kg-w.w. in kidney. The median concentration of lead was 0.24 (mean: 0.40) and 0.21 (mean: 0.32) mg/kg-w.w. in liver and kidney, respectively. Bears in the Kita-ou local population had higher concentrations of cadmium and lead than those in the Kitakami Highlands local population. No chronological change was observed in cadmium levels in tissues, but the percentage of bears whose lead levels exceeded 0.5 mg/kg-w.w. has been decreasing in recent years. Countermeasures against lead poisoning in wildlife, which were instituted in 2002, may have contributed to the decrease in lead contamination of the Japanese black bear.

Coupling of ß1-adrenergic receptor to type 5 adenylyl cyclase and its physiological relevance in cardiac myocytes.

Myocardial ß-adrenergic receptor (ß-AR) ß1- and ß2-subtypes are highly homologous, but play opposite roles in cardiac apoptosis and heart failure, as do cardiac adenylyl cyclase (AC) subtypes 5 (AC5) and 6 (AC6): ß1-AR and AC5 promote cardiac remodeling, while ß2-AR and AC6 activate cell survival pathways. However, the mechanisms involved remain poorly understood. We hypothesized that AC5 is coupled preferentially to ß1-AR rather than ß2-AR, and we examined this idea by means of pharmacological and genetic approaches. We found that selective inhibition of AC5 with 2'5'-dideoxyadenosine significantly suppressed cAMP accumulation and cardiac apoptosis induced by selective ß1-AR stimulation, but had no effect on cAMP accumulation and cardiac apoptosis in response to selective ß2-AR stimulation. The results of selective stimulation of ß1-AR and ß2-AR in neonatal cardiac myocytes prepared from wild-type and AC5-knockout mice were also consistent with the idea that ß1-AR selectively couples with AC5. We believe these results are helpful for understanding the mechanisms underlying the different roles of AR subtypes in healthy and diseased hearts.

Establishment of successively transplantable rabbit VX2 cancer cells that express enhanced green fluorescent protein.

Morphological detection of cancer cells in the rabbit VX2 allograft transplantation model is often difficult in a certain region such as serosal cavity where reactive mesothelial cells mimic cancer cells and both cells share common markers such as cytokeratins. Therefore, tagging VX2 cells with a specific and sensitive marker that easily distinguishes them from other cells would be advantageous. Thus, we tried to establish a successively transplantable, enhanced green fluorescent protein (EGFP)-expressing VX2 model. Cancer cells obtained from a conventional VX2-bearing rabbit were cultured in vitro and transfected with an EGFP-encoding vector, and then successively transplanted in Healthy Japanese White rabbits (HJWRs) (n = 8). Besides, conventional VX2 cells were transplanted in other HJWRs (n = 8). Clinicopathological comparison analyses were performed between the two groups. The success rate of transplantation was 100% for both groups. The sensitivity and specificity of EGFP for immunohistochemical detection of VX2 cells were 84.3 and 100%, respectively. No significant differences in cancer cell morphology, tumor size (P = 0.742), Ki-67 labeling index (P = 0.878), or survival rate (P = 0.592) were observed between the two. VX2 cells can be genetically altered, visualized by EGFP, and successively transplanted without significant alteration of morphological and biological properties compared to those of the conventional model.

Oxidative Amidation of Nitroalkanes with Amine Nucleophiles using Molecular Oxygen and Iodine.

The formation of amides and peptides often necessitates powerful yet mild reagent systems. The reagents used, however, are often expensive and highly elaborate. New atom-economical and practical methods that achieve such goals are highly desirable. Ideally, the methods should start with substrates that are readily available in both chiral and non-chiral forms and utilize cheap reagents that are compatible with a wide variety of functional groups, steric encumberance, and epimerizable stereocenters. A direct oxidative method was developed to form amide and peptide bonds between amines and primary nitroalkanes simply by using I2 and K2 CO3 under O2 . Contrary to expectations, a 1:1 halogen-bonded complex forms between the iodonium source and the amine, which reacts with nitronates to form α-iodo nitroalkanes as precursors to the amides.

Asymmetric organocatalyzed Michael addition of nitromethane to a 2-oxoindoline-3-ylidene acetaldehyde and the three one-pot sequential synthesis of (-)-horsfiline and (-)-coerulescine.

(-)-Horsfiline and (-)-coerulescine were synthesized through three one-pot operations in 33 and 46% overall yield, respectively. Key to the success was the efficient use of a diarylprolinol silyl ether to catalyze the asymmetric Michael addition of nitromethane to a 2-oxoindoline-3-ylidene acetaldehyde. This allowed the all-carbon quaternary, spirocyclic carbon stereocenter to be constructed in good yield with excellent enantioselectivity.

Nef reaction with molecular oxygen in the absence of metal additives, and mechanistic insights.

A Nef reaction has been developed that is conducted under mildly basic conditions with molecular oxygen as an oxidant, without the need for metal additives. Whereas nitroalkanes are converted into ketones in good yield, nitroalkenes are transformed into α,ß-unsaturated ketones in one-pot by double-bond isomerization followed by the oxygen-mediated Nef reaction. The reaction protocol is both mild and general, and tolerates acid- and base-labile functionality or protecting groups. When oxygen-saturated solvents are employed, the reaction completes within 20 min. Mechanistically, the addition of nitronate ion and molecular oxygen is proposed to proceed initially through a single-electron transfer event, as indicated by radical clock experiments. This ultimately generates a putative 1,1-dioxirane, which reacts further with another nitronate ion to generate the ketone. Involvement of a 1,1-dioxirane is supported by intramolecular trapping experiments with sulfide at the γ-position of the nitro-moiety.

Diphenylprolinol silyl ether catalyzed asymmetric Michael reaction of nitroalkanes and ß,ß-disubstituted α,ß-unsaturated aldehydes for the construction of all-carbon quaternary stereogenic centers.

The asymmetric Michael reaction of nitroalkanes and ß,ß-disubstituted α,ß-unsaturated aldehydes was catalyzed by diphenylprolinol silyl ether to afford 1,4-addition products with an all-carbon quaternary stereogenic center with excellent enantioselectivity. The reaction is general for ß-substituents such as ß-aryl and ß-alkyl groups, and both nitromethane and nitroethane can be employed. The addition of nitroethane is considered a synthetic equivalent of the asymmetric Michael reaction of ethyl and acetyl substituents by means of radical denitration and Nef reaction, respectively. The short asymmetric synthesis of (S)-ethosuximide with a quaternary carbon center was accomplished by using the present asymmetric Michael reaction as the key step. The reaction mechanism that involves the E/Z isomerization of α,ß-unsaturated aldehydes, the retro-Michael reaction, and the different reactivity between nitromethane and nitroethane is discussed.

Self-replication and amplification of enantiomeric excess of chiral multifunctionalized large molecules by asymmetric autocatalysis.

Self-replication of large chiral molecular architectures is one of the great challenges and interests in synthetic, systems, and prebiotic chemistry. Described herein is a new chemical system in which large chiral multifunctionalized molecules possess asymmetric autocatalytic self-replicating and self-improving abilities, that is, improvement of their enantioenrichment in addition to the diastereomeric ratio. The large chiral multifunctionalized molecules catalyze the production of themselves with the same structure, including the chirality of newly formed asymmetric carbon atoms, in the reaction of the corresponding achiral aldehydes and reagent. The chirality of the large multifunctionalized molecules controlled the enantioselectivity of the reaction in a highly selective manner to construct multiple asymmetric stereogenic centers in a single reaction.

Development and validation of a new liquid chromatography-tandem mass spectrometry assay for the simultaneous quantification of afatinib, dacomitinib, osimertinib, and the active metabolites of osimertinib in human serum.

Reports on the therapeutic drug monitoring (TDM) of second- and third-generation epidermal growth factor receptor-tyrosine kinase inhibitors (EGFR-TKIs) in non-small cell lung cancer patients are limited and are required to improve the safety of EGFR-TKI therapy. Some EGFR-TKIs have active metabolites with similar or higher potency compared with the parent compounds; thus, monitoring the parent compound as well as its active metabolites is essential for truly effective TDM. In this study, we developed and validated a method that simultaneously quantifies second- and third-generation EGFR-TKIs (afatinib, dacomitinib, and osimertinib) and the active metabolites of osimertinib, AZ5104 and AZ7550, in the human serum using liquid chromatography-tandem mass spectrometry (LC-MS/MS). The clinical application of the method was also evaluated. The analytes were extracted from a 100 µL serum sample using a simple protein precipitation method and analyzed using LC-MS/MS. Excellent linearity of calibration curves was observed at ranges of 2.5-125.0 ng/mL for afatinib, 2.5-125.0 ng/mL for dacomitinib, 4.0-800.0 ng/mL for osimertinib, 1.0-125.0 ng/mL for AZ5104, and 2.5-125.0 ng/mL for AZ7550. The precision and accuracy were below 14.9% and within ± 14.9% of the nominal concentrations, respectively. The mean recovery was higher than 94.7% and the coefficient of variation (CV) was lower than 8.3%. The mean internal-standard normalized matrix factors ranged from 94.6 to 111.9%, and the CVs were lower than 9.7%. This analytical method met the acceptance criteria of the U.S. Food and Drug Administration guidelines. The method was also successfully applied to the analysis of 45 clinical samples; it supports the efficient and valuable analysis for TDM investigations of EGFR-TKIs.

The effect of exposure on cattle thyroid after the Fukushima Daiichi nuclear power plant accident.

Nuclear plant accidents can be a risk for thyroid cancer due to iodine radioisotopes. Near the Fukushima Daiichi nuclear power plant, cattle were exposed to radiation after the accident occurred in May 2011. Here we estimated the total radiation exposure to cattle thyroid and its effects on thyroid function. Until October 2016, the estimated external exposure dose in Farm A was 1416 mGy, while internal exposure dose of 131I, 134Cs, and 137Cs were 85, 8.8, and 9.7 mGy in Farm A and 34, 0.2, and 0.3 mGy in Farm B, respectively. The exposed cattle had thyroid with relatively lower weight and lower level of stable iodine, which did not exhibit any pathological findings. Compared with the control, the plasma level of thyroid-stimulating hormone (TSH) was higher in Farm A cattle born before the accident, while the plasma thyroxine (T4) was higher in Farm A cattle born after the accident, suggesting that exposed cattle showed slight hyperactivation of the thyroid gland. In addition, Farm A cattle have higher level of cortisol, one of the anterior pituitary gland-derived hormones. However, we did not observe a causal relationship between the radiation exposure and cattle thyroid.

Human nails analysis as biomarker of exposure to perfluoroalkyl compounds.

Extensive human exposure to perfluoroalkyl compounds (PFAA) together with their persistence and various toxicities have arisen increasing concern. A noninvasive method would improve exposure assessment for large population, especially the children susceptible to contaminants. The aim of the study was to assess the use of PFAA measurements in human nails as a biomarker of exposure to PFAAs. Fingernail, toenail, and blood samples were collected from 28 volunteers. The PFAA concentrations were determined by high performance liquid chromatography-tandem mass spectrometry (HPLC-MS/MS). Six PFAA were detected in nails, with perfluorooctane sulfonate (PFOS) being the compound with the highest median concentration (33.5 and 26.1 ng/g in fingernail and toenail, respectively). Followed was perfluorononanoate (PFNA), with the median concentrations of 20.4 and 16.8 ng/g, respectively, in fingernail and toenail. Other PFAA detected were perfluorooctanoate (PFOA), perfluorodecanoate (PFDA), perfluorododecanoate (PFDoA), and perfluorotetradecanoate (PFTA), with median levels ranging between 0.19 and 8.94 ng/g. PFOS and PFNA concentrations in fingernail significantly correlated with those in serum. Fingernail PFOS and PFNA levels were 2.8 and 24.4 times, respectively, higher than the serum levels. The accumulation of PFAA in nails, together with its advantages in noninvasive sampling and ability of reflecting long-term exposure, made nails PFAA an attractive biomarker of exposure.