Copper-Catalyzed Asymmetric Sulfonylative Desymmetrization of Glycerol.

Glycerol is the main side product in the biodiesel manufacturing process, and the development of glycerol valorization methods would indirectly contribute the sustainable biodiesel production and decarbonization. Transformation of glycerol to optically active C3 units would be one of the attractive routes for glycerol valorization. We herein present the asymmetric sulfonylative desymmetrization of glycerol by using a CuCN/(R,R)-PhBOX catalyst system to provide an optically active monosulfonylated glycerol in high efficiency. A high degree of enantioselectivity was achieved with a commercially available chiral ligand and an inexpensive carbonate base. The optically active monosulfonylated glycerol was successfully transformed into a C3 unit attached with differentially protected three hydroxy moieties. In addition, the synthetic utility of the present reaction was also demonstrated by the transformation of the monosulfonylated glycerol into an optically active synthetic ceramide, sphingolipid E.

Establishment of oxaliplatin-resistant gastric cancer organoids: importance of myoferlin in the acquisition of oxaliplatin resistance.

BACKGROUND: The attainment of drug resistance in gastric cancer (GC) is a problematic issue. Although many studies have shown that cancer stem cells (CSCs) play an important role in the acquisition of drug resistance, there is no clinically available biomarker for predicting oxaliplatin (L-OHP) resistance in relation to CSCs. Organoid technology, a novel 3D cell culture system, allows harboring of patient-derived cancer cells containing abundant CSCs using niche factors in a dish. METHODS: In this study, we established L-OHP-resistant gastric cancer organoids (GCOs) and evaluated their gene expression profile using microarray analysis. We validated the upregulated genes in the L-OHP-resistant GCOs compared to their parental GCOs to find a gene responsible for L-OHP resistance by qRT-PCR, immunohistochemistry, in vitro, and in vivo experiments. RESULTS: We found myoferlin (MYOF) to be a candidate gene through microarray analysis. The results from cell viability assays and qRT-PCR showed that high expression of MYOF correlated significantly with the IC50 of L-OHP in GCOs. Immunohistochemistry of MYOF in GC tissue samples revealed that high expression of MYOF was significantly associated with poor prognosis, T grade, N grade, and lymphatic invasion, and showed MYOF to be an independent prognostic indicator, especially in the GC patients treated with platinum-based chemotherapy. The knockdown of MYOF repressed L-OHP resistance, cell growth, stem cell features, migration, invasion, and in vivo tumor growth. CONCLUSIONS: Our results suggest that MYOF is highly involved in L-OHP resistance and tumor progression in GC. MYOF could be a promising biomarker and therapeutic target for L-OHP-resistant GC cases.

Eczema herpeticum subsequent to septic shock in early pregnancy: a first case report.

BACKGROUND: Eczema herpeticum (EH) is a severe skin complication caused by human simplex virus (HSV) infection concomitant with immune dysfunction and dermatological conditions, mainly atopic dermatitis. We present the first case of EH subsequent to sepsis-related immunological suppression in pregnancy. CASE PRESENTATION: Septic shock developed in a 30-year-old primiparous woman at 14 weeks of pregnancy during admission for hyperemesis gravidarum. Although her life-threatening status due to sepsis improved by prompt treatment, on day 3 of treatment in the intensive care unit, blisters suddenly erupted on her face and neck and spread over her body. EH was diagnosed according to HSV type-1 antigen positivity and a past medical history of EH and atopic dermatitis. Antiviral agents were administered immediately, with positive results. Her general condition improved quickly, without central nervous system defects. This is the first report of EH following septic shock in early pregnancy. At present, we speculate that EH develops as a complication due to immunological changes in the late phase of sepsis because sepsis is mainly characterized by both an inflammatory state in the acute phase and an immunosuppressive state in the late phase. Pregnancy can also contribute to its pathogenesis, as it causes an immunosuppressive state. Mortality due to EH is relatively high; in this case, a history of EH and atopic dermatitis contributed to the initiation of prompt medical interventions for the former, with improvement in the patient's severe condition. The combination of immunological changes in sepsis and pregnancy can cause HSV reactivation, resulting in EH recurrence. CONCLUSIONS: In conclusion, if dermatological symptoms develop in a pregnant woman with a history of EH and/or atopic dermatitis treated for sepsis, EH should be suspected based not only on clinical features but also on immunological changes along with sepsis, and prompt medical interventions should be initiated.

Characterization of ω3 fatty acid desaturases from oomycetes and their application toward eicosapentaenoic acid production in Mortierella alpina.

ω3 Polyunsaturated fatty acids are currently obtained mainly from fisheries; thus, sustainable alternative sources such as oleaginous microorganisms are required. Here, we describe the isolation, characterization, and application of 3 novel ω3 desaturases with ω3 polyunsaturated fatty acid-producing activity at ordinary temperatures (28 °C). First, we selected Pythium sulcatum and Plectospira myriandra after screening for oomycetes with high eicosapentaenoic acid/arachidonic acid ratios and isolated the genes psulω3 and pmd17, respectively, which encode ω3 desaturases. Subsequent characterization showed that PSULω3 exhibited ω3 desaturase activity on both C18 and C20 ω6 polyunsaturated fatty acids while PMD17 exhibited ω3 desaturase activity exclusively on C20 ω6 polyunsaturated fatty acids. Expression of psulω3 and pmd17 in the arachidonic acid-producer Mortierella alpina resulted in transformants that produced eicosapentaenoic acid/total fatty acid values of 38% and 40%, respectively, at ordinary temperatures. These ω3 desaturases should facilitate the construction of sustainable ω3 polyunsaturated fatty acid sources.

[A Case of Long-Term Survival in a Patient with Small Intestinal Adenocarcinoma with Peritoneal Dissemination].

Primary small intestinal adenocarcinoma is rare and its outcome is poor. A 46-year-old man admitted for vomiting was found in enhanced abdominal CT to have local jejunum stenosis and dilation at its oral site. A partial jejunectomy was performed and a jejunal tumor with multiple disseminated nodules in the peritoneum was revealed. Histologically, the adenocarcinoma of the jejunum appeared to be a papillary adenocarcinoma, and also, in part, a moderately differentiated tubular adenocarcinoma. After the jejunectomy, the patient was treated with S-1 chemotherapy, but 22 months after the initial diagnosis, a recurrence was detected. The patient underwent a second partial jejunectomy, and a weekly dose of paclitaxel (PTX) plus doxifluridine (5'-DFUR) was selected as the second-line treatment. The patient is still responding to the treatment 55 months after the last operation. Combination chemotherapy with weekly PTX/5'-DFUR may improve the prognosis for S-1-resistant small intestinal adenocarcinoma.

ATP generation in a host cell in early-phase infection is increased by upregulation of cytochrome c oxidase activity via the p2 peptide from human immunodeficiency virus type 1 Gag.

BACKGROUND: Human immunodeficiency virus type 1 (HIV-1) must take advantage of its own proteins with two or more functions to successfully replicate. Although many attempts have been made to determine the function of viral proteins encoded in the HIV-1 genome, the role of the p2 peptide, a spacer between the capsid and the nucleocapsid in HIV-1 Gag in early-phase HIV infection still remains unclarified. RESULTS: In this study, we show that the p2 peptide enhances HIV-1 acute infection by increasing intracellular ATP production via the activation of mitochondrial cytochrome c oxidase (MT-CO) involved in the respiratory chain. We found that cell-permeable p2-peptide-treated cells were more effectively infected by HIV-1 than control cells. To characterize the effect of the p2 peptide on HIV-1 replication in MAGIC-5 cells, various HIV-1 cDNA products were measured by quantitative real-time PCR. The levels of the late (R/gag), 2-LTR circular (2-LTR), and integrated (Alu) forms of viral cDNAs increased in the presence of the p2 peptide. Interestingly, yeast two-hybrid analysis revealed a novel interaction between the p2 peptide and the mitochondrial intermembrane space domain (N(214)-F(235)) of MT-CO subunit I (MT-CO1). Mutational analysis indicated that Gln(6) in the p2 peptide is important for the interaction with MT-CO1. The p2 peptide activated MT-CO1 in vitro in a concentration-dependent manner, and fluorescence-microscopy analysis demonstrated that the p2 peptide had a significant effect on mitochondrial targeting. Furthermore, the analysis of HIV-1 lacking a functional p2 peptide demonstrated the inhibition of intracellular ATP production in MT-4 cells and monocyte-derived macrophages (MDMs) and a decrease in reverse transcription efficiency following infection of MT-4 cells and MDMs. CONCLUSIONS: These findings provide evidence that the p2 peptide is a viral positive allosteric modulator of MT-CO and the increased intracellular ATP production after HIV infection in a p2-peptide-dependent manner is essential for efficient reverse transcription in early-phase HIV-1 infection.

[Mesothelioma of Unknown Primary Site with Resection of Mediastinal Lymph Node Metastasis].

A 63-year-old male underwent biopsy of a mediastinal lymph node. Intra-operative frozen section diagnosis was metastatic mesothelioma. The primary site of mesothelioma was not detected in the thoracic cavity. One year later, he was again removed a mediastinal lymph node metastasis, but the primary site was not detected. Eight months later, he was performed right neck and mediastinal lymph node dissection due to additionally appeared lymph node metastases, but the primary site was not detected. He is well 6 months after last surgery with postoperative adjuvant chemotherapy.

[Localized Malignant Mesothelioma of the Pleura].

A 65-year-old man presented with the chief complaint of cough. Chest computed tomography showed the mediastinal tumor. The tumor was resected under the 4th intercostal thoracotomy and the mediastinal approach. The biphasic type of localized malignant mesothelioma was diagnosed by the pathological findings. The postoperative course was uneventful. After postoperative adjuvant radiotherapy and chemotherapy (cisplatin and pemetrexed sodium hydrate), he is well without relapse 7 months after surgery.

[Pulmonary dirofilariasis].

A 70-year-old man was admitted to our department for pulmonary nodule of 15 mm in diameter in the left lower lobe detected by chest computed tomography (CT). A possibility of malignant tumor could not be ruled out, and lung partial resection was performed. Pathological examination during operation revealed a coagulation necrosis and the lesion was finally diagnosed as pulmonary dirofilariasis.

Establishment of a novel overlay culture method that enables immune response assessment using gastric cancer organoids.

Organoid technology, a novel 3D cell culture system, can reproduce a patient's cancer and may be a novel immunotherapy experimental model. However, currently no gastric cancer organoid (GCO) models in which the organoid and immune cells are in free contact and sufficiently react with each other exist. In this study, we aimed to create a coculture model in which immune cells can move freely and stay in contact with GCOs. We coated the bottom surface of the plate with Matrigel and adhered stem cells to the Matrigel surface, instead of completely embedding them in Matrigel to culture organoids. This method allowed GCOs to grow on the Matrigel surface while maintaining a three-dimensional structure and reproducing the characteristics of the patient's cancer. We cocultured GCOs and immune cells. Using this model, immune cells could freely move and were in sufficient contact with the cultured GCOs. Our model allowed real-time observation of the immune response and tumor destruction with time. In addition, the GCO killing assay was assessed with natural killer cells from the same patient. This organoid culture model enabled repeated evaluation of the GCO killing assay with various immune cells in vitro. We established a new experimental model that allowed free movement of immune cells and sufficient contact with GCOs. Using this model, it may be possible to predict the effects of immune checkpoint inhibitors in vitro (using GCOs) before administering them to patients.

Preoperative High C-Reactive Protein to Albumin Ratio Predicts Short- and Long-Term Postoperative Outcomes in Elderly Gastric Cancer Patients.

Individualized preoperative assessment of the general condition of elderly patients with gastric cancer is necessary for appropriate surgical treatment planning. This study investigated the efficacy of preoperative markers that could be easily calculated from preoperative peripheral blood to predict the short- and long-term postoperative outcomes of gastrectomy. In total, 571 patients who underwent R0 surgical resection for gastric cancer were enrolled. In the elderly patient group (≥65 years old), univariate analyses revealed that the incidence of postoperative complications was associated with poor performance status (p = 0.012), more comorbidities (p = 0.020), high C-reactive protein to albumin ratio (CAR, p = 0.003), total gastrectomy (p = 0.003), open approach (p = 0.034), blood transfusion (p = 0.002), and advanced cancer (p = 0.003). Multivariate analysis showed that a high CAR was associated with a high incidence of postoperative complications (p = 0.046). High CAR was also associated with poor OS (p = 0.015) and RFS (p = 0.035). However, these trends were not observed among younger patients (<65 years old). Preoperative CAR may play a significant role in predicting short- and long-term surgical outcomes, particularly in elderly patients with gastric cancer.

Intraoesophageal pressure in patients receiving proximal gastrectomy with hinged double flap method for gastric cancer: a retrospective cohort study.

Background: Objective functional assessment of esophagogastric anastomosis in patients who underwent proximal gastrectomy with the hinged double flap method for gastric cancer has not been well investigated. This study aimed to perform a functional analysis of reconstruction using high-resolution impedance manometry (HRIM). Materials and methods: The authors enroled 25 patients who underwent proximal gastrectomy for gastric cancer between May 2015 and April 2020 and subsequently underwent HRIM postoperatively. Eligible questionnaires [Postgastrectomy Syndrome Assessment Scale-37 (PGSAS-37)] were retrieved from 16 patients. The association between HRIM data and PGSAS-37 was analyzed. Results: The amplitudes of distal oesophageal peristaltic waves, contractile front velocity, and distal latency assessed by HRIM were almost normal after surgery. Most patient's lower oesophageal sphincter (LES) resting pressure created by the hinged double flap was within normal limits. Conversely, LES residual pressure values during swallowing-induced relaxation were abnormally high in most patients, and the lower the values, the more severe the reflux and diarrhoea symptoms (P=0.038, P=0.041, respectively). In addition, even when the integrated relaxation pressure (IRP) was normal, lower values corresponded to more severe reflux symptoms (P=0.020). The required LES pressure may be higher after proximal gastrectomy because of the relatively higher intragastric pressure due to the reduced volume of the remnant stomach. This also suggests that swallowing-induced relaxation of the LES was considered a trigger for oesophageal reflux in post-proximal gastrectomy patients. Conclusion: LES residual pressure and IRP values in HRIM correlated with reflux symptoms in patients after proximal gastrectomy.

PhaP phasins play a principal role in poly-ß-hydroxybutyrate accumulation in free-living Bradyrhizobium japonicum.

BACKGROUND: Bradyrhizobium japonicum USDA110, a soybean symbiont, is capable of accumulating a large amount of poly-ß-hydroxybutyrate (PHB) as an intracellular carbon storage polymer during free-living growth. Within the genome of USDA110, there are a number of genes annotated as paralogs of proteins involved in PHB metabolism, including its biosynthesis, degradation, and stabilization of its granules. They include two phbA paralogs encoding 3-ketoacyl-CoA thiolase, two phbB paralogs encoding acetoacetylCoA reductase, five phbC paralogs encoding PHB synthase, two phaZ paralogs encoding PHB depolymerase, at least four phaP phasin paralogs for stabilization of PHB granules, and one phaR encoding a putative transcriptional repressor to control phaP expression. RESULTS: Quantitative reverse-transcriptase PCR analyses of RNA samples prepared from cells grown using three different media revealed that PHB accumulation was related neither to redundancy nor expression levels of the phbA, phbB, phbC, and phaZ paralogs for PHB-synthesis and degradation. On the other hand, at least three of the phaP paralogs, involved in the growth and stabilization of PHB granules, were induced under PHB accumulating conditions. Moreover, the most prominently induced phasin exhibited the highest affinity to PHB in vitro; it was able to displace PhaR previously bound to PHB. CONCLUSIONS: These results suggest that PHB accumulation in free-living B. japonicum USDA110 may not be achieved by controlling production and degradation of PHB. In contrast, it is achieved by stabilizing granules autonomously produced in an environment of excess carbon sources together with restricted nitrogen sources.

Selectivity switch in the catalytic functionalization of nonprotected carbohydrates: selective synthesis in the presence of anomeric and structurally similar carbohydrates under mild conditions.

A catalytic process for the chemo- and regioselective functionalization of nonprotected carbohydrates has been developed. This novel process allows selective thiocarbonylation, acylation, and sulfonylation of a particular hydroxy group in a particular carbohydrate in the simultaneous presence of structurally similar carbohydrates such as anomers. In addition, the chemoselectivity can be switched by regulating only the length of the alkyl chain in the organotin catalyst.

Multi-phasic gene profiling using candidate gene approach predict the capacity of specific antibody production and maintenance following COVID-19 vaccination in Japanese population.

Background: Vaccination against severe acute respiratory syndrome coronavirus type 2 is highly effective in preventing infection and reducing the severity of coronavirus disease (COVID-19). However, acquired humoral immunity wanes within six months. Focusing on the different tempo of acquisition and attenuation of specific antibody titers in individuals, we investigated the impact of genetic polymorphisms on antibody production after COVID-19 vaccination. Methods: In total 236 healthcare workers from a Japanese municipal hospital, who received two doses of the vaccine were recruited. We employed a candidate gene approach to identify the target genetic polymorphisms affecting antibody production after vaccination. DNA samples from the study populations were genotyped for 33 polymorphisms in 15 distinct candidate genes encoding proteins involved in antigen-presenting cell activation, T cell activation, T-B interaction, and B cell survival. We measured total anti-SARS-Cov2 spike IgG antibody titers and analyzed the association with genetic polymorphisms at several time points after vaccination using an unbiased statistical method, and stepwise logistic regression following multivariate regression. Results: Significant associations were observed between seven SNPs in NLRP3, OAS1, IL12B, CTLA4, and IL4, and antibody titers at 3 weeks after the first vaccination as an initial response. Six SNPs in NLRP3, TNF, OAS1, IL12B, and CTLA4 were associated with high responders with serum antibody titer > 4000 BAU/ml as boosting effect at 3 weeks after the second vaccination. Analysis of long-term maintenance showed the significance of the three SNPs in IL12B, IL7R, and MIF for the maintenance of antibody titers and that in BAFF for attenuation of neutralizing antibodies. Finally, we proposed a predictive model composed of gene profiles to identify the individuals with rapid antibody attenuation by receiver operating characteristic (ROC) analysis (area under the curve (AUC)= 0.76, sensitivity = 82.5%, specificity=67.8%). Conclusions: The candidate gene approach successfully showed shifting responsible gene profiles and initial and boosting effect mainly related to the priming phase into antibody maintenance including B cell survival, which traces the phase of immune reactions. These gene profiles provide valuable information for further investigation of humoral immunity against COVID-19 and for building a strategy for personalized vaccine schedules.

Current Evidence on Vasa Previa without Velamentous Cord Insertion or Placental Morphological Anomalies (Type III Vasa Previa): Systematic Review and Meta-Analysis.

Vasa previa carries a high risk of severe fetal morbidity and mortality due to fetal hemorrhage caused by damage to unprotected fetal cord vessels upon membrane rupture. Vasa previa is generally classified into types I and II. However, some cases are difficult to classify, and some studies have proposed a type III classification. This study aimed to review the current evidence on type III vasa previa. A systematic literature search was conducted, and 11 articles (2011-2022) were included. A systematic review showed that type III vasa previa accounts for 5.7% of vasa previa cases. Thirteen women with type III vasa previa were examined at a patient-level analysis. The median age was 35 (interquartile range [IQR] 31.5-38) years, and approximately 45% were assisted reproductive technology (ART) pregnancies. The median gestational week of delivery was 36 (IQR 34-37) weeks; the antenatal detection rate was 84.6%, and no cases reported neonatal death. The characteristics and obstetric outcomes (rate of ART, antenatal diagnosis, emergent cesarean delivery, gestational age at delivery, and neonatal mortality) were compared between types I and III vasa previa, and all outcomes of interest were similar. The current evidence on type III vasa previa is scanty, and further studies are warranted.

Improvement and characterization of oral absorption behavior of clofazimine by SNEDDS: Quantitative evaluation of extensive lymphatic transport.

Clofazimine, an anti-leprosy drug, has been anticipated for a candidate to treat tuberculosis, cryptosporidiosis, and coronavirus infection, but its low oral bioavailability is considered a reason for its limited activity. In the current study, we have tried to improve the oral bioavailability of clofazimine by several SNEDDS formulations and characterized the absorption behavior from various aspects. Among four SNEDDS formulations prepared, SNEDDS A, prepared with castor oil as an oil component, provided the highest bioavailability (around 61%) and SNEDDS D, prepared with Capryol 90, gave the second highest bioavailability. SNEDDS A formed the finest nanoparticles, which were maintained under gastric and intestinal luminal conditions. The comparison in oral bioavailability between the SNEDDS formulation and its corresponding preformed nanoemulsion suggested that SNEDDS A would efficiently form nanoemulsion in the gastrointestinal tract after oral administration. AUC of mesenteric lymph node concentration was the highest for SNEDDS A, which would be one of the reasons for SNEDDS A to reveal the highest oral bioavailability. A cycloheximide-treated oral absorption study and single-pass perfusion study by utilizing a vascular-luminal perfused small intestine-liver preparation clearly indicated that over 90% of clofazimine absorbed to systemic circulation should be derived from lymphatic transport for both SNEDDS A and D. Furthermore, the fraction of dose absorbed was around 65% for SNEDDS D, but SNEDDS A achieved around 94%, indicating the excellent performance of SNEDDS A.

Relationship between Abnormal Placenta and Obstetric Outcomes: A Meta-Analysis.

The placenta has several crucial physiological functions that help maintain a normal pregnancy. Although approximately 2-4% of pregnancies are complicated by abnormal placentas, obstetric outcomes remain understudied. This study aimed to determine the outcomes and prevalence of patients with abnormal placentas by conducting a systematic review of 48 studies published between 1974 and 2022. The cumulative prevalence of circumvallate placenta, succenturiate placenta, multilobed placenta, and placenta membranacea were 1.2%, 1.0%, 0.2%, and 0.004%, respectively. Pregnancies with a circumvallate placenta were associated with an increased rate of emergent cesarean delivery, preterm birth (PTB), and placental abruption compared to those without a circumvallate placenta. The succenturiate lobe of the placenta was associated with a higher rate of emergent cesarean delivery, whereas comparative results were observed in terms of PTB, placental abruption, and placenta previa in comparison to those without a succenturiate lobe of the placenta. A comparator study that examined the outcomes of multilobed placentas found that this data is usually unavailable. Patient-level analysis (n = 15) showed high-rates of abortion (40%), placenta accreta spectrum (40%), and a low term delivery rate (13.3%) in women with placenta membranacea. Although the current evidence is insufficient to draw a robust conclusion, abnormal placentas should be recognized as a high-risk factor for adverse outcomes during pregnancy.

Copper-catalyzed three-component borylstannylation of alkynes.

Regio- and stereoselective installation of boryl and stannyl moieties into a carbon-carbon triple bond of various alkynes has been achieved based on a three-component coupling reaction by using a diboron and a tin alkoxide with the aid of a copper(II) acetate-tricyclohexylphosphine complex, giving diverse vic-borylstannylalkenes in a straightforward manner. Carbon-tin and carbon-boron bonds of the resulting borylstannylation product are successively transformed into carbon-carbon bonds by a Migita-Kosugi-Stille and a Suzuki-Miyaura coupling, leading to the formation of (Z)-tamoxifen with anti-breast cancer activity.

Organotin-catalyzed highly regioselective thiocarbonylation of nonprotected carbohydrates and synthesis of deoxy carbohydrates in a minimum number of steps.

Nonprotected carbohydrates: The catalytic regioselective thiocarbonylation of carbohydrates by using organotin dichloride under mild conditions was demonstrated. The reaction afforded various deoxy saccharides in high yields and excellent regioselectivity in a minimum number of steps. The regioselectivity of the thiocarbonylation is attributed to the intrinsic character of the carbohydrates based on the stereorelationship of their hydroxy groups (see scheme).