Extensive-Disease Small-Cell Lung Cancer With Severe Immune-Related Adverse Events Due to Atezolizumab Maintaining a Complete Response for Two Years: A Case Report.

A 75-year-old male with diabetes mellitus was referred to our hospital with an abnormal shadow on chest radiography, based on which he was diagnosed with extensive-disease small-cell lung cancer (ED-SCLC; cT2bN2M1a). The first-line therapy comprised atezolizumab, carboplatin, and etoposide. After four cycles, the patient achieved complete response (CR), and maintenance therapy was initiated with atezolizumab. However, even though CR was maintained, maintenance therapy was discontinued after 16 cycles due to persistent grade 2 anorexia and fatigue. Simultaneously, the HbA1c decreased to 5.5%, and antidiabetic therapy was discontinued. Six months after the last dose of atezolizumab, the patient visited the emergency room because of anorexia, dry mouth, and fatigue. Laboratory findings were as follows: blood glucose was 668 mg/dL, glycated hemoglobin (HbA1c) was 8.8%, urine ketone was 2+, sodium (Na) was 127 mmol/L, potassium (K) was 6.5 mmol/L, creatinine (Cre) was 1.43 mg/dL, and arterial pH was 7.29. Based on these findings, his presentation was consistent with fulminant type 1 diabetes mellitus (T1DM) complicated by diabetic ketoacidosis (DKA). Regular continuous insulin and saline administration was initiated in the intensive care unit, and acidosis and electrolyte abnormalities were corrected. His C-peptide was <0.03 ng/mL. His insulin secretory capacity was considered to be depleted, and he required continuous subcutaneous insulin injections. Glutamic acid decarboxylase and insulin autoantibodies were absent. The complete response persisted without further therapy until two years since the event.

GWAS for systemic sclerosis identifies six novel susceptibility loci including one in the Fcγ receptor region.

Here we report the largest Asian genome-wide association study (GWAS) for systemic sclerosis performed to date, based on data from Japanese subjects and comprising of 1428 cases and 112,599 controls. The lead SNP is in the FCGR/FCRL region, which shows a penetrating association in the Asian population, while a complete linkage disequilibrium SNP, rs10917688, is found in a cis-regulatory element for IRF8. IRF8 is also a significant locus in European GWAS for systemic sclerosis, but rs10917688 only shows an association in the presence of the risk allele of IRF8 in the Japanese population. Further analysis shows that rs10917688 is marked with H3K4me1 in primary B cells. A meta-analysis with a European GWAS detects 30 additional significant loci. Polygenic risk scores constructed with the effect sizes of the meta-analysis suggest the potential portability of genetic associations beyond populations. Prioritizing the top 5% of SNPs of IRF8 binding sites in B cells improves the fitting of the polygenic risk scores, underscoring the roles of B cells and IRF8 in the development of systemic sclerosis. The results also suggest that systemic sclerosis shares a common genetic architecture across populations.

Cooperative Carbene Photocatalysis for ß-Amino Ester Synthesis.

ß-Amino acids are useful building blocks of bioactive molecules, including peptidomimetics and pharmaceutical compounds. The current limited accessibility to ß2,2-type amino acids which bear an α-quaternary center has limited their use in chemical synthesis and biological investigations. Disclosed herein is the development of a new N-heterocyclic carbene/photocatalyzed aminocarboxylation of olefins, affording ß2,2-amino esters with high regioselectivity. The generation of nitrogen-centered radicals derived from simple imides via a sequence of deprotonation and single-electron oxidation allows for the subsequent addition to geminal-disubstituted olefins regioselectively. The intermediate tertiary radicals then cross-couple with a stabilized azolium-based radical generated in situ to efficiently construct the quaternary centers. Mechanistic studies, including Stern-Volmer fluorescence quenching experiments, support the proposed catalytic cycle.

Various Organ Damages in Rats with Fetal Growth Restriction and Their Slight Attenuation by Bifidobacterium breve Supplementation.

Children with fetal growth restriction (FGR) and its resultant low birthweight (LBW) are at a higher risk of developing various health problems later in life, including renal diseases, metabolic syndrome, and sarcopenia. The mechanism through which LBW caused by intrauterine hypoperfusion leads to these health problems has not been properly investigated. Oral supplementation with probiotics is expected to reduce these risks in children. In the present study, rat pups born with FGR-LBW after mild intrauterine hypoperfusion were supplemented with either Bifidobacterium breve (B. breve) or a vehicle from postnatal day 1 (P1) to P21. Splanchnic organs and skeletal muscles were evaluated at six weeks of age. Compared with the sham group, the LBW-vehicle group presented significant changes as follows: overgrowth from infancy to childhood; lighter weight of the liver, kidneys, and gastrocnemius and plantaris muscles; reduced height of villi in the ileum; and increased depth of crypts in the jejunum. Some of these changes were milder in the LBW-B.breve group. In conclusion, this rat model could be useful for investigating the mechanisms of how FGR-LBW leads to future health problems and for developing interventions for these problems. Supplementation with B. breve in early life may modestly attenuate these problems.

European and multi-ancestry genome-wide association meta-analysis of atopic dermatitis highlights importance of systemic immune regulation.

Atopic dermatitis (AD) is a common inflammatory skin condition and prior genome-wide association studies (GWAS) have identified 71 associated loci. In the current study we conducted the largest AD GWAS to date (discovery N = 1,086,394, replication N = 3,604,027), combining previously reported cohorts with additional available data. We identified 81 loci (29 novel) in the European-only analysis (which all replicated in a separate European analysis) and 10 additional loci in the multi-ancestry analysis (3 novel). Eight variants from the multi-ancestry analysis replicated in at least one of the populations tested (European, Latino or African), while two may be specific to individuals of Japanese ancestry. AD loci showed enrichment for DNAse I hypersensitivity and eQTL associations in blood. At each locus we prioritised candidate genes by integrating multi-omic data. The implicated genes are predominantly in immune pathways of relevance to atopic inflammation and some offer drug repurposing opportunities.

Interlaboratory comparison of electron paramagnetic resonance tooth enamel dosimetry with investigations of the dose responses of the standard samples.

A total of seven Japanese laboratories participated in an intercomparison study to estimate the dose given to tooth enamel samples, using the electron spin resonance method. Each of four of the participating laboratories prepared a set of tooth enamel samples, using the electron spin resonance method. Four of the participating laboratories each prepared a set of tooth enamel samples, consisting of seven standard aliquots irradiated from 100 to 2000 mGy and three samples with an 'unknown' dose between 140 and 960 mGy, were intended to eliminate bias from sample preparation. Although not all seven laboratories measured all four sets of samples, the major finding was that systematic biases in estimating doses may be caused by differences in laboratory measurements rather than by the enamel extracting procedures. When doses were averaged by measurements made by multiple laboratories, the averaged values were close to the actual values. Scattering in the intercepts in the standard dose response would be a serious problem in actual dosimetry where no background sample is available.

A comprehensive microbial analysis of pediatric patients with acute appendicitis.

BACKGROUND: Pathogenesis of pediatric acute appendicitis (AA) is yet to be elucidated. Therefore, we performed a comprehensive microbial analysis of saliva, feces, and appendiceal lumen of AA patients using 16S ribosomal RNA (rRNA) gene amplicon sequencing to elucidate the pathogenesis of pediatric AA. METHODS: This study included 33 AA patients and 17 healthy controls (HCs) aged <15 y. Among the AA patients, 18 had simple appendicitis, and 15 had complicated appendicitis. Salivary and fecal samples were obtained from both groups. The contents of the appendiceal lumen were collected from the AA group. All samples were analyzed using 16S rRNA gene amplicon sequencing. RESULTS: The relative abundance of Fusobacterium was significantly higher in the saliva of AA patients as compared to that in HCs (P = 0.011). Bacteroides, Escherichia, Fusobacterium, Coprobacillus, and Flavonifractor were significantly increased in the feces of AA patients, as compared to that in HCs (P = 0.020, 0.010, 0.029, 0.031, and 0.002, respectively). In the appendiceal lumen, Bacteroides, Parvimonas, Fusobacterium, and Alloprevotella were the top bacterial genera with an average relative abundance >5% (16.0%, 9.1%, 7.9%, and 6.0%, respectively). CONCLUSIONS: The relative abundance of Fusobacterium was high in the appendiceal lumen of pediatric AA patients. Moreover, the relative abundance of Fusobacterium was significantly higher in the saliva and feces of pediatric AA patients than in those of healthy children. These results suggest that ectopic colonization of oral Fusobacterium in the appendix might play an important role in the pathogenesis of pediatric AA.

Bifidobacterium breve during infancy attenuates mobility in low birthweight rats.

BACKGROUND: Children with low birthweight (LBW) have a higher risk for developing attention-deficit/hyperactivity disorder, for which no prophylactic measure exists. The gut microbiota in infants with LBW is different from that in infants with normal birthweight and is associated with attention-deficit/hyperactivity disorder. Oral supplementation with Bifidobacterium has several health benefits, such as suppressing inflammation. METHODS: We examined the effect of gavage supplementation with Bifidobacterium breve M-16V from postnatal days 1-21 in a rat model of intrauterine hypoperfusion. RESULTS: The open-field test at 5 weeks of age (equivalent to human pubertal age) showed that rats in the LBW-vehicle group were marginally hyperactive compared with rats in the sham group, while rats in the LBW-B.breve group were significantly hypoactive compared with rats in the LBW-vehicle group. The gut microbiota in the LBW-vehicle group exhibited a profile significantly different from that in the sham group, whereas the gut microbiota in the LBW-B.breve group did not exhibit a significant difference from that in the sham group. Anatomical/histological evaluation at 6 weeks of age demonstrated that the brain weight and the cerebral areas on coronal sections were reduced in the LBW groups compared with the sham group. Probiotic supplementation did not ameliorate these morphological brain anomalies in LBW animals. The percentage of Iba-1+ cells in the brain was not different among the LBW-B.breve, LBW-vehicle, and sham groups. CONCLUSION: Bifidobacterium breve supplementation during early life is suggested to have the potential to help children with LBW attenuate hypermobility in adolescence.

The effect of casirivimab with imdevimab on disease progression in nonsevere COVID-19 patients in a single hospital in Japan.

Background: Recent randomized trials have revealed that neutralizing monoclonal antibodies can reduce disease progression in mild-moderate COVID-19 patients. However, no studies have investigated the effect of neutralizing monoclonal antibodies on clinical outcomes in Japan. Methods: A single-center retrospective and prospective cohort study was conducted. All consecutive febrile nonsevere COVID-19 patients with at least one risk factor were included. The primary outcome was progression to severe COVID-19. Severe COVID-19 cases were defined as patients requiring oxygen therapy and dexamethasone. The differences in the primary outcomes between the patients who were treated with casirivimab with imdevimab (treatment group) and those who were not (control group) were compared using the chi-squared test. Results: A total of 128 patients were included. Of those, the mean age was 53.6 years old (SD 9.9), and 52 (40.6%) were women. Fifty-three patients were treated with casirivimab with imdevimab, and 75 patients were given the standard treatment only. The primary outcome occurred in eight (15.1%) of the 53 patients in the treatment group and 33 (44.0%) of the 75 patients in the control group (odd ratio [OR] 0.23, 95% CI 0.09 to 0.55). The multivariate analysis revealed that the use of casirivimab with imdevimab (OR 0.21, 95% CI 0.08 to 0.54) was the only independent risk factor associated with progression to severe COVID-19. No patients died during hospitalization in either group. Conclusion: Similar to other countries, casirivimab with imdevimab significantly reduced disease progression in early nonsevere COVID-19 patients with fever and risk factors in Japan.

Chondroprotective effects of CDK4/6 inhibition via enhanced ubiquitin-dependent degradation of JUN in synovial fibroblasts.

OBJECTIVE: Targeting synovial fibroblasts (SF) using a cyclin-dependent kinase (CDK) 4/6 inhibitor (CDKI) could be a potent therapy for RA via inhibition of proliferation and MMP-3 production. This study was designed to elucidate the mechanism of chondroprotective effects on SFs by CDK 4/6 inhibition. METHODS: CDK4/6 activity was inhibited using CDKI treatment or enhanced by adenoviral gene transduction. Chondroprotective effects were evaluated using a collagen-induced arthritis model (CIA). Gene and protein expression were evaluated with quantitative PCR, ELISA and Western blotting. The binding of nuclear extracts to DNA was assessed with an electrophoresis mobility shift assay. RNA-Seq was performed to identify gene sets affected by CDKI treatment. RESULTS: CDKI attenuated cartilage destruction and MMP-3 production in CIA. In RASFs, CDKI impaired the binding of AP-1 components to DNA and inhibited the production of MMP-1 and MMP-3, which contain the AP-1 binding sequence in their promoter. CDK4/6 protected JUN from proteasome-dependent degradation by inhibiting ubiquitination. The RNA-Seq analysis identified CDKI-sensitive inflammatory genes, which were associated with the pathway of RA-associated genes, cytokine-cytokine receptor interaction and IL-17 signalling. Notably, the AP-1 motif was enriched in these genes. CONCLUSION: The mechanism of chondroprotective effects by CDK4/6 inhibition was achieved by the attenuation of AP-1 transcriptional activity via the impaired stability of JUN. Because the pharmacologic inhibition of CDK4/6 has been established as tolerable in cancer treatment, it could also be beneficial in patients with RA due to its chondroprotective and anti-inflammatory effects.

Optimal First-Line Antibiotic Treatment for Pediatric Complicated Appendicitis Based on Peritoneal Fluid Culture.

PURPOSE: Consensus is lacking regarding the optimal antibiotic treatment for pediatric complicated appendicitis. This study determined the optimal first-line antibiotic treatment for pediatric patients with complicated appendicitis based on peritoneal fluid cultures. METHODS: This retrospective study examined the cases of pediatric patients who underwent appendectomy for complicated appendicitis at our institution between 2013 and 2019. Peritoneal fluid specimens obtained during appendectomy were cultured for the presence of bacteria. RESULTS: Eighty-six pediatric patients were diagnosed with complicated appendicitis. Of them, bacteria were identified in 54 peritoneal fluid samples. The major identified bacteria were Escherichia coli (n=36 [66.7%]), Bacteroides fragilis (n=28 [51.9%]), α-Streptococcus (n=25 [46.3%]), Pseudomonas aeruginosa (n=10 [18.5%]), Enterococcus avium (n=9 [16.7%]), γ-Streptococcus (n=9 [16.7%]), and Klebsiella oxytoca (n=6 [11.1%]). An antibiotic susceptibility analysis showed E. coli was inhibited by sulbactam/ampicillin in 43.8% of cases versus cefmetazole in 100% of cases. Tazobactam/piperacillin and meropenem inhibited the growth of 96.9-100% of the major identified bacteria. E. coli (100% vs. 84.6%) and P. aeruginosa (100% vs. 80.0%) were more susceptible to amikacin than gentamicin. CONCLUSION: Tazobactam/piperacillin or meropenem is a reasonable first-line antibiotic treatment for pediatric complicated appendicitis. In the case of aminoglycoside use, amikacin is recommended.

IsoChichibabin desmosine-13C3,15N1 synthesis and quantitative LC-MS/MS analysis of desmosine and isodesmosine in human skin.

Desmosine and isodesmosine are crosslinking amino acids of elastin, which is an essential component of the dermal extracellular matrix protein. Quantitative analysis of crosslinker desmosines in human skin dermis has not been fully achieved due to the insoluble nature of elastin protein. In the present study, chemical synthesis of isotopically labeled desmosine, desmosine-13C3,15N1, was carried out via isoChichibabin pyridinium synthesis starting from corresponding isotopically labeled amino acids. Isotope-dilution LC-MS/MS analysis of desmosine and isodesmosine utilizing synthetic desmosine-13C3,15N1 enabled the quantitative analysis of desmosines in human skin for the first time. Thus, ca. 1.43 µg of desmosines was detected from analysis of 1 mg of dry human skin.

Safety of vancomycin in patients with moderate and severe renal dysfunction.

AIM: The new guidelines in Japan do not recommend a vancomycin (VCM) loading dose for patients with an estimated glomerular filtration rate (eGFR) 30 < and ≤ 80 mL×min-1×1.73m-2 (moderate renal dysfunction) or administration to those with the eGFR < 30 mL×min-1×1.73m-2 (severe renal dysfunction). We investigated the safety and efficiency of VCM in patients with moderate and severe renal dysfunction based on the new guidelines. MATERIALS AND METHODS: The study involved patients admitted to our hospital between April 2014 and March 2018 with an eGFR < 80 mL×min-1×1.73m-2 and treated with VCM. VCM trough concentration and pre- and post-administration renal function were investigated retrospectively. The primary endpoints were the proportion of patients who achieved an effective trough concentration of 10 - 20 µg/mL and rate of acute kidney injury (AKI). RESULTS: We included 64 patients (32 moderate, 32 severe). The mean VCM trough concentration achieved for the first time was 9.3 and 11.6 µg/mL in the moderate and severe renal dysfunction groups, respectively (p = 0.91). The effective trough concentration endpoint was achieved by 50% and 43% of the patients in the severe and moderate renal dysfunction groups, respectively, and no significant difference was found in the AKI rate. The serum creatinine change was significantly different between the groups - the moderate group showed a slight deterioration and the severe renal dysfunction group an improvement. CONCLUSION: It may be necessary to increase the dose for these patients with severe renal dysfunction while implementing a VCM loading dose and monitoring trough concentrations and adverse effects.

Eight novel susceptibility loci and putative causal variants in atopic dermatitis.

BACKGROUND: Atopic dermatitis (AD) is the most common allergic disease in the world. While genetic components play critical roles in its pathophysiology, a large proportion of its genetic background is still unexplored. OBJECTIVES: This study sought to illuminate the genetic associations with AD using genome-wide association study (GWAS) and its downstream analyses. METHODS: This study conducted a GWAS for AD comprising 2,639 cases and 115,648 controls in the Japanese population, followed by a trans-ethnic meta-analysis with UK Biobank data and downstream analyses including partitioning heritability analysis by linkage disequilibrium score regression. RESULTS: This study identified 17 significant susceptibility loci, among which 4 loci-AFF1, ITGB8, EHMT1, and EGR2-were novel in the Japanese GWAS. The trans-ethnic meta-analysis revealed 4 additional novel loci, namely-ZBTB38,LOC105755953/LOC101928272, TRAF3, andIQGAP1. This study found a missense variant (R243W) with a deleterious functional effect in NLRP10 and a variant altering expression of CCDC80 via enhancer expression as highly likely causal variants. These 2 regions were Asian-specific, and these population-specific associations could be explained by the frequency of causal variants. The gene-based test showed SMAD4 as an additional novel significant locus. Downstream analyses revealed substantial overlap of GWAS significant signals in enhancers of skin cells and immune cells, especially CD4 T cells. A highly shared polygenic architecture of AD between Europeans and Asians was also found. CONCLUSIONS: This study identified Japanese-specific loci and novel significant loci shared by different populations. Two putative causal variants were illuminated in Japanese-specific loci. Trans-ethnic analyses revealed strong heritability enrichment in immune-related pathways, and relevant cell types shared among populations.

Chichibabin/isoChichibabin pyridinium synthesis of ma'edamines C and D.

Ma'edamines C and D were isolated from an Okinawan marine sponge and exhibited a unique tetrasubstituted pyridinium skeleton. The proposed biosynthetic pathway is similar to that of desmosine and isodesmosine, which are elastin-crosslinking amino acids. In this study, first total synthesis of ma'edamines C and D was achieved via Pr(OTf)3-promoted Chichibabin/isoChichibabin pyridinium synthesis starting from the corresponding aldehydes and amine.

Dermatomyositis associated with prostate adenocarcinoma with neuroendocrine differentiation.

BACKGROUND: Although it is known that malignancies can be associated with dermatomyositis, there are few reports on dermatomyositis associated with prostate cancer with neuroendocrine differentiation. CASE PRESENTATION: A 63-year-old man visited our hospital due to pollakiuria. High levels of PSA and NSE were observed, and prostate biopsy revealed an adenocarcinoma with neuroendocrine differentiation. Multiple metastases to the lymph nodes, bones, and liver were identified, and androgen deprivation therapy (ADT) was started immediately. Following 2 weeks of treatment, erythema on the skin, and muscle weakness with severe dysphagia appeared. The patient was diagnosed with dermatomyositis, and high-dose glucocorticoid therapy was initiated. ADT and subsequent chemotherapy with etoposide and cisplatin (EP) were performed for prostate cancer, which resulted in decreased PSA and NSE and reduction of all metastases. After the initiation of EP therapy, dermatomyositis improved, and the patient regained oral intake function. Although EP therapy was replaced by docetaxel, abiraterone, and enzalutamide because of adverse events, no cancer progression was consistently observed. Dermatomyositis worsened temporarily during the administration of abiraterone, but it improved upon switching from abiraterone to enzalutamide and dose escalation of glucocorticoid. CONCLUSIONS: We successfully treated a rare case of dermatomyositis associated with prostate adenocarcinoma with neuroendocrine differentiation.